Zatloukal, K., C. Stumptner, et al. (2002). "p62 Is a common component of
cytoplasmic inclusions in protein aggregation diseases." Am J Pathol
160(1): 255-63.
Exposure of cells to stress, particularly oxidative stress, leads to misfolding
of proteins and, if they are not refolded or degraded, to cytoplasmic protein
aggregates. Protein aggregates are characteristic features of a variety of
chronic toxic and degenerative diseases, such as Mallory bodies (MBs) in
hepatocytes in alcoholic and non-alcoholic steatohepatitis, neurofibrillary
tangles in neurons in Alzheimer's, and Lewy bodies in Parkinson's disease. Using
2D gel electrophoresis and mass spectrometry, we identified p62 as a novel MB
component. p62 and cytokeratins (CKs) are major MB constituents; HSP 70, HSP 25,
and ubiquitinated CKs are also present. These proteins characterize MBs as a
prototype of disease-associated cytoplasmic inclusions generated by
stress-induced protein misfolding. As revealed by transfection of tissue culture
cells overexpressed p62 did not induce aggregation of regular CK filaments but
selectively bound to misfolded and ubiquitinated CKs. The general role of p62 in
the cellular response to misfolded proteins was substantiated by detection of
p62 in other cytoplasmic inclusions, such as neurofibrillary tangles, Lewy
bodies, Rosenthal fibers, intracytoplasmic hyaline bodies in hepatocellular
carcinoma, and alpha1-antitrypsin aggregates. The presence of p62 along with
other stress proteins and ubiquitin in cytoplasmic inclusions indicates
deposition as aggregates as a third line of defense against misfolded proteins
in addition to refolding and degradation.
Yokoyama, K., S. Ikebe, et al. (2002). "[A 68-year-old woman with dementia and
parkinsonism]." No To Shinkei54(2): 175-84.
We report a 68-year-old woman who developed progressive dementia and
parkinsonism. She was well until 1990 when she was 58 years of age. She started
to show memory loss. Four years later, she developed difficulty in dressing and
behavioral problems such as eating rice with her hands, going out of her house
without purposes, and difficulty in finding the rest room in her house. She was
admitted to the neurology service of Hatsuishi Hospital on January 19, 1996,
when she was 64 years of the age. On admission, she was alert but markedly
demented. The score of Hansegawa Dementia Scale was 0/30. She was unable to make
any coherent conversation. She appeared to have dressing apraxia but did not
appear to have aphasia. Cranial nerves were intact. She walked in small steps
with stooped posture. She did not have motor weakness but she showed plastic
rigidity in all four limbs. No tremor or ataxia was noted. Deep tendon reflexes
were within normal limits but the plantar response was extensor bilaterally. She
continued to deteriorate after admission. In May of 1998, she started to fall.
In June of 1998, she had a generalized convulsion. In January of 1999, she
became unable to take foods orally and a gastrostomy was placed. She expired on
May 29, 1990. She was discussed in a neurological CPC and the chief discussant
arrived at the conclusion that the patient had Alzheimer's disease. The question
was whether her parkinsonism was a part of her Alzheimer's disease or she had an
additional disease to explain her parkinsonism. Post-mortem examination revealed
moderate to marked atrophy of the frontal and the temporal lobes as well as in
the limbic areas with dilatation of the lateral ventricles. Marked neuronal loss
was noted in the CA 1 to the subiculum region with gliosis. Neurofibrillary
tangles were seen in the remaining neurons. Neuropil threads were seen by
Gallyas-Braak staining. Similar changes were seen in the parahippocampal gyrus
and in the entorhinal cortex. Senile plaques were seen in the insular cortex and
in other cortical areas. Cortical type Lewy bodies were seen in the cingulate
cortex. The Meynert nucleus showed marked neuronal loss and gliosis. The
substantia nigra and the locus coeruleus showed moderate loss of pigmented
neurons. Lewy bodies were seen in these regions. The dorsal motor nucleus of the
vagal nerve was retained, however, one Lewy body was observed. Pathologic
diagnosis was Alzheimer's disease plus Parkinson's disease. It is an interesting
question whether or not her parkinsonism was due to nigral lesion or frontal
lesions. It is known that parkinsonism may complicate in advanced Alzheimer's
disease not necessarily due to nigral lesion. On the other hand, in incidental
Lewy body disease, the substantia nigra shows mild Parkinson's disease-like
change without clinical parkinsonism. This patient appeared to have been a true
complication of Alzheimer's disease and Parkinson's disease.
Yokota, O., S. Terada, et al. (2002). "NACP/alpha-synuclein immunoreactivity in
diffuse neurofibrillary tangles with calcification (DNTC)." Acta Neuropathol
(Berl)104(4): 333-41.
Diffuse neurofibrillary tangles with calcification (DNTC) is a rare
tangle-predominant dementia, as well as one of the tauopathies lacking Abeta
deposition. It is characterized by temporo-frontal lobar atrophy, Fahr-type
calcification and, histopathologically, numerous neurofibrillary tangles in the
limbic system and neocortex. Recently, accumulation of alpha-synuclein (alphaS),
the precursor of the non-beta amyloid component (NAC) of Alzheimer's disease,
has been shown in diverse neurodegenerative disorders, including Parkinson's
disease, dementia with Lewy bodies, Alzheimer's disease, multiple system atrophy
and parkinsonism-dementia complex of Guam. To clarify whether alphaS accumulates
in other neurodegenerative disorders, we investigated eight DNTC brains using
immunohistochemistry and demonstrated remarkable alphaS deposition in the
neurons and astrocytes in many anatomical regions. Abundant Lewy bodies were
observed in the amygdala (seven cases) and hippocampus (seven cases), and, to a
lesser degree, in the substantia nigra (six cases) and dorsal vagal nucleus
(five cases). In the hippocampus, many Lewy neurites were distributed in the
stratum oriens and stratum pyramidale in the CA2-3 and the subiculum.
Furthermore, numerous NAC-positive astrocytes were detected in the hippocampus
and temporal cortex. This investigation reveals that neurons and astrocytes are
extensively involved in remarkable alphaS pathology in the DNTC brain, and that
the alphaS pathology compounds the cardinal pathological features of tau
pathology. These findings suggest that (1) DNTC shares a common
pathophysiological background with Parkinson's disease, dementia with Lewy
bodies, and multiple system atrophy in which abnormal alphaS aggregation is
observed, and (2) there is an interaction between alphaS and tau pathology that
does not involve amyloid in DNTC.
Windisch, M., B. Hutter-Paier, et al. (2002). "Development of a new treatment
for Alzheimer's disease and Parkinson's disease using anti-aggregatory beta-synuclein-derived
peptides." J Mol Neurosci19(1-2): 63-9.
The synaptic protein alpha-synuclein is a major constituent of Lewy bodies (LB),
pathological neuronal inclusion bodies found in Parkinson's disease (PD),
Alzheimer's disease (AD), and other neurodegenerative disorders. Owing to data
from patient brains, it was speculated that an imbalance between alpha-synuclein
and beta-synuclein might be one of the reasons for formation of LBs and the
consequent functional deficits. This was supported by the fact that beta-synuclein
is able to prevent abnormal alpha-synuclein aggregation. Transgenic mice
overexpressing alpha-synuclein display LB-like inclusions in different brain
regions and motor deficits. To verify if re-establishing a normal relation
between alpha-synuclein and beta-synuclein is able to prevent the pathology,
bigenic mice have been created that overexpress both synucleins. Beta-synuclein
decreased formation of LBs by 40% and prevented functional deficits. This is
considered as preliminary in vivo proof of antiaggregatory function of beta-synuclein
and its potential as therapeutic substance for treatment of neurodegenerative
disorders linked with abnormal protein aggregation. Peptide libraries have been
synthesized to explore the active structures of beta-synuclein. The first 15
N-terminal amino-acids turned out to be important for the antiaggregatory
effect. Further smaller beta-synuclein-derived peptides have screened for
antiaggregatory and neuroprotective potency in different tissue-culture systems.
Preliminary data suggest some of them can be used as leads for further drug
development.
Walker, Z., D. C. Costa, et al. (2002). "Differentiation of dementia with Lewy
bodies from Alzheimer's disease using a dopaminergic presynaptic ligand." J
Neurol Neurosurg Psychiatry73(2): 134-40.
BACKGROUND: Dementia with Lewy bodies (DLB) is one of the main differential
diagnoses of Alzheimer's disease (AD). Key pathological features of patients
with DLB are not only the presence of cerebral cortical neuronal loss, with Lewy
bodies in surviving neurones, but also loss of nigrostriatal dopaminergic
neurones, similar to that of Parkinson's disease (PD). In DLB there is 40-70%
loss of striatal dopamine. OBJECTIVE: To determine if detection of this
dopaminergic degeneration can help to distinguish DLB from AD during life.
METHODS: The integrity of the nigrostriatal metabolism in 27 patients with DLB,
17 with AD, 19 drug naive patients with PD, and 16 controls was assessed using a
dopaminergic presynaptic ligand, (123)I-labelled
2beta-carbomethoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl)nortropane (FP-CIT),
and single photon emission tomography (SPET). A SPET scan was carried out with a
single slice, brain dedicated tomograph (SME 810) 3.5 hours after intravenous
injection of 185 MBq FP-CIT. With occipital cortex used as a radioactivity
uptake reference, ratios for the caudate nucleus and the anterior and posterior
putamen of both hemispheres were calculated. All scans were also rated by a
simple visual method. RESULTS: Both DLB and PD patients had significantly lower
uptake of radioactivity than patients with AD (p<0.001) and controls (p<0.001)
in the caudate nucleus and the anterior and posterior putamen. CONCLUSION:
FP-CIT SPET provides a means of distinguishing DLB from AD during life.
Uversky, V. N. and A. L. Fink (2002). "Amino acid determinants of alpha-synuclein
aggregation: putting together pieces of the puzzle." FEBS Lett522(1-3):
9-13.
Parkinson's disease is the second most common neurodegenerative disease, and
results from loss of dopaminergic neurons in the substantia nigra. The
aggregation and fibrillation of alpha-synuclein in the form of intracellular
proteinaceous aggregates (Lewy bodies and Lewy neurites) have been implicated as
a causative factor in this disease, as well as in several other
neurodegenerative disorders, including dementia with Lewy bodies, Lewy body
variant of Alzheimer's disease, multiple system atrophy and Hallervorden-Spatz
disease. Thus, the aggregated forms of alpha-synuclein play a crucial role in
the pathogenesis of the synucleinopathies. However, the molecular mechanisms
underlying alpha-synuclein aggregation into specific filamentous inclusions
remained unknown until recently. Data on the aggregation and fibrillation
properties of human alpha-, beta- and gamma-synucleins, mouse alpha-synuclein
and familial Parkinson's disease mutants of human alpha-synuclein (A30P and
A53T) are analyzed in order to shed light on the amino acid determinants of
synuclein aggregation.
Tsuchiya, K., K. Ikeda, et al. (2002). "Parkinson's disease mimicking senile
dementia of the Alzheimer type: a clinicopathological study of four autopsy
cases." Neuropathology22(2): 77-84.
This report concerns four Japanese autopsy cases of Parkinson's disease (PD)
mimicking senile dementia of the Alzheimer type. Three patients with a clinical
diagnosis of senile dementia of the Alzheimer type developed memory disturbance
as the initial sign, and a patient with a clinical diagnosis of atypical senile
dementia presented with hallucination and delusion as the initial sign. Dementia
was evident in all four patients, and slight parkinsonism appeared in the middle
to late stages of the disease in two patients. Macroscopical examination of the
brain disclosed slight depigmentation of the substantia nigra and prominent
depigmentation of the locus ceruleus in all four cases. Histological examination
of the four patients showed neuronal loss with astrocytosis and the appearance
of Lewy bodies in the substantia nigra, locus ceruleus, and dorsal vagal
nucleus. The nucleus basalis of Meynert was involved in three cases, in which
this structure was examined. The total Lewy body scores of the four cases were 1
in three cases and 0 in the other, compatible with PD. Massive appearance of
senile plaques, consistent with Braak stage C, was found in one case, and the
slight appearance of senile plaques, consistent with Braak stage A, was evident
in two cases. One case had no evidence of senile plaques. In all four cases,
slight neurofibrillary changes were present in the limbic areas, compatible with
Braak stages II to III. Based on these clinicopathological findings and a review
of the literature, we concluded that PD simulating Alzheimer's disease without
overt parkinsonism rarely exists. Furthermore, we postulate that the clinical
features of PD are more widespread than previously believed.
Tamo, W., T. Imaizumi, et al. (2002). "Expression of alpha-synuclein, the
precursor of non-amyloid beta component of Alzheimer's disease amyloid, in human
cerebral blood vessels." Neurosci Lett326(1): 5-8.
The non-amyloid beta component of Alzheimer's disease amyloid (NAC) is detected
in cerebral amyloid angiopathy; and the precursor of NAC is now known to be
identical to alpha-synuclein (alpha-S), a major component of Lewy bodies in
Parkinson's disease. We studied if cerebral vascular cells express alpha-S.
Immunohistochemical studies of human cerebral tissues from control and cerebral
amyloid angiopathy patients revealed the expression of alpha-S in vascular
endothelial and smooth muscle cells. Then we studied the expression of alpha-S
in vitro using cultures of vascular cells. Cultures of human umbilical vein
endothelial cells and umbilical artery smooth muscle cells were found to
constitutively express alpha-S messenger RNA and protein. alpha-S is normally
expressed in vascular cells and may play some physiological role in the vascular
wall.
Tabner, B. J., S. Turnbull, et al. (2002). "Formation of hydrogen peroxide and
hydroxyl radicals from Abeta and alpha-synuclein as a possible mechanism of cell
death in Alzheimer's disease and Parkinson's disease(1,2)." Free Radic Biol
Med32(11): 1076-83.
The formation of extracellular or intracellular deposits of amyloid-like protein
fibrils is a prominent pathological feature of many different neurodegenerative
diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). In
AD, the beta-amyloid peptide (Abeta) accumulates mainly extracellularly at the
center of senile plaques, whereas, in PD, the alpha-synuclein protein
accumulates within neurons inside the Lewy bodies and Lewy neurites. We have
shown recently that solutions of Abeta 1-40, Abeta 1-42, Abeta 25-35, alpha-synuclein
and non-Abeta component (NAC; residues 61-95 of alpha-synuclein) all liberate
hydroxyl radicals upon incubation in vitro followed by the addition of small
amounts of Fe(II). These hydroxyl radicals were readily detected by means of
electron spin resonance spectroscopy, employing 5,5-dimethyl-1-pyrroline N-oxide
(DMPO) as a spin trapping agent. Hydroxyl radical formation was inhibited by the
inclusion of catalase or metal-chelators during Abeta or alpha-synuclein
incubation. Our results suggest that hydrogen peroxide accumulates during the
incubation of Abeta or alpha-synuclein, by a metal-dependent mechanism, and that
this is subsequently converted to hydroxyl radicals, on addition of Fe (II), by
Fenton's reaction. Consequently, one of the fundamental molecular mechanisms
underlying the pathogenesis of cell death in AD and PD, and possibly other
neurodegenerative or amyloid diseases, could be the direct production of
hydrogen peroxide during formation of the abnormal protein aggregates.
Szirmai, I. and T. Kovacs (2002). "[In Process Citation]." Ideggyogy Sz55(7-8): 220-5.
The cognitive (executive) ability of patients with Parkinson's-disease (PD)
deteriorates gradually during the progression of the disease. Fluency of speech,
word finding, working memory, ability to plan the future and flexibility
decline. Cognitive disturbance was found to be proportional with the speech,
posture, gait and balance problems and can not be influenced by L-dopa
substitution. Apart the dorsal and ventral mesolimbic dopaminergic systems the
coerulo-cortical noradrenergic, serotoninergic and cholinergic systems are also
impaired in PD. Subcortical dementia in PD can also be explained by the
functional disability of dorsolateral and anterior cingular circuits. Attention
deficit can be explained by the dopamine depletion of cingular cortex. Cortical
Lewy bodies, neurofibrillary tangles, neurit plaques and additional vascular
pathology should also play a role in cognitive impairment of PD. In several
systemic degenerative diseases associating with Parkinson's syndrome (PS) i.e.
progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple
system atrophy (MSA) dementia can be detected with various severity, therefore
the question arises concerning the correlation between cognitive disability and
PS. Parkinson syndrome can also develop in frontotemporal dementias (FTD),
Alzheimer's disease and cortical Lewy body disease (CLBD) but no correlation
exists between motor disability and severity of dementia. In CLBD dementia can
be the initial symptom in 18% of cases but PS can also preceeds the dementia. In
PSP profound depletion of other monoaminergic neurotransmitter system was also
reported. In FTDs associated with PS degeneration of substantia nigra, locus
coeruleus and basal nucleus of Meynert has been reported with increased number
of neurofibrillary tangles. In patients with vascular PS (VP) there is generally
no tremor and rigidity, but pseudobulbar palsy, dementia, gate disturbance,
incontinency appears; L-dopa treatment is generally ineffective. In VP no
cellular loss can be found within the substantia nigra, but leukoaraiosis,
lacunae in the white matter and basal ganglia are commonly demonstrated.
Rub, U., K. Del Tredici, et al. (2002). "Parkinson's disease: the thalamic
components of the limbic loop are severely impaired by alpha-synuclein
immunopositive inclusion body pathology." Neurobiol Aging23(2):
245-54.
The Parkinson's disease (PD)-related inclusion body pathology comprises Lewy
bodies (LBs) as well as Lewy neurites (LNs). The distribution and severity of
this pathology were investigated in the thalamus of 12 autopsy cases with
clinically diagnosed and neuropathologically confirmed PD. The LBs and LNs were
visualized by immunoreactions against the protein alpha-synuclein. In the human
thalamus during PD, a specific and highly stereotypical distribution pattern of
LBs and LNs evolves. As in cortical and other subcortical regions, the
components of human thalamus assigned to the limbic loop bear the brunt of the
PD-related pathology. In contrast, the thalamic components integrated into the
striatal and cerebellar loops as well as the primary sensory nuclei of the
thalamus show at best a mildly developed pathology. Damage to the thalamic
components of the limbic loop nuclei may contribute not only to the cognitive,
emotional, and autonomic symptoms of PD but to the somatomotor and oculomotor
dysfunctions as well.
Rosler, M. (2002). "The efficacy of cholinesterase inhibitors in treating the
behavioural symptoms of dementia." Int J Clin Pract Suppl(127): 20-36.
Multiple behavioural and psychological symptoms of dementia (BPSD) are commonly
associated with all dementia subtypes, and worsen during disease progression.
BPSD arise due to impairment of cholinergic function in the cortex, hippocampus
and related limbic systems. Recent studies have investigated the effect of
cholinesterase inhibitors on BPSD. The dual acetylcholinesterase/butyrylcholinesterase
(AChE/BuChE) inhibitor rivastigmine was shown to have several potential
advantages over the AChE-selective inhibitors donepezil and galantamine for the
treatment of BPSD. Rivastigmine appears to be effective across the range of
dementia severity from mild to severe, and across the spectrum of dementia
(Alzheimer's disease [AD], the AD variant with Lewy bodies, Parkinson's disease
dementia and vascular dementia subtypes). It also appears to have a
disease-modifying potential. Rivastigmine improved a wider range of behavioural
symptoms (apathy, anxiety/depression, hallucinations and delusions) than
donepezil and galantamine (which improved apathy and depression/anxiety only).
Unlike donepezil, rivastigmine reduced the need for psychotropic medications to
treat BPSD. Dual inhibition of AChE and BuChE and brain-region selectivity
through preferential inhibition of the G1 isoform of AChE may provide the
underlying reasons for the apparently greater and broader efficacy of
rivastigmine over AChE-selective inhibitors for the treatment of BPSD. However,
randomised, controlled trials are required to compare dual inhibitors, such as
rivastigmine, and AChE-selective agents, to confirm and quantify any differences
in their effects on BPSD.
Ransmayr, G. (2002). "[Dementia with Lewy bodies]." Wien Med Wochenschr152(3-4): 81-4.
Dementia with Lewy bodies (DLB) is the second most frequent neuropathologically
diagnosed degenerative dementing illness. The clinical characteristics are
progressive dementia, Parkinson syndrome, fluctuations of cognitive functions,
vigilance and attention, visual hallucinations (usually detailed and well
described), depression, REM-sleep behavior disorder, adverse responses to
standard doses of neuroleptics, falls, syncopes, systematized delusions, and
non-visual hallucinations. Mean age at disease onset ranges between 60 and 68
years. Male persons are more frequently affected than female. Disease duration
is six to seven years. The differential diagnoses of DLB are dementia of the
Alzheimer-type, Parkinson's disease, subcortical arteriosclerotic
encephalopathy, progressive supranuclear palsy, multiple system atrophy, and, in
rare cases, Creutzfeldt-Jakob disease. The genetic background of the disease is
unclear. Magnetic resonance imaging and single photon emission tomography can
contribute to the diagnosis. The disease is treated with L-dopa, atypical
neuroleptics, acetylcholine esterase inhibitors, antihypotensive agents, and
peripheral anticholinergic and alpha-receptor-blocking medicaments to improve
neurogenic bladder dysfunction.
McLean, P. J. and B. T. Hyman (2002). "An alternatively spliced form of rodent
alpha-synuclein forms intracellular inclusions in vitro: role of the carboxy-terminus
in alpha-synuclein aggregation." Neurosci Lett323(3): 219-23.
In the rat, the -synuclein gene is alternatively spliced and exists in three
forms, rat synuclein 1 (rSYN1), synuclein 2 (rSYN2) and synuclein 3. rSYN2 cDNA
encodes a 149 amino acid protein that is homologous to rSYN1 and human -synuclein
for the first 100 amino acids, but is divergent for the 49 amino acid carboxy-terminal
region. We demonstrate here that rSYN2 forms small aggregates throughout the
cytoplasm when overexpressed in human H4 cells, whereas rSYN1 expression is
diffuse. Inhibition of the proteasome promotes the formation of larger,
cytoplasmic rSYN2 inclusions in transfected cells. Although a survey of the
available databases suggests that there is no human splice form equivalent of
rSYN2, thus arguing against a direct role in Lewy body formation and Parkinson's
disease, these data nonetheless suggest that modifications of the carboxy-terminal
region of -synuclein predispose it to inclusion formation.
McKeith, I. G. (2002). "Dementia with Lewy bodies." Br J Psychiatry
180: 144-7.
BACKGROUND: Dementia with Lewy bodies (DLB) is a common dementia subtype that
has only been recognised in the past decade and that remains widely
underdiagnosed. AIMS: To review the pathological and clinical features of DLB,
to consider methods of investigation and diagnosis, and to recommend safe and
effective management strategies. METHOD: A selective review was made of the key
literature. RESULTS: Using operationalised criteria, DLB can be clinically
diagnosed with an accuracy similar to that achieved for Alzheimer's disease or
Parkinson's disease. Underdetection is largely due to poor definition of the
criterion of cognitive fluctuation. Ancillary investigations, particularly
neuroimaging, can aid in differential diagnosis. Extreme caution in the use of
neuroleptic medication is advised. Cholinesterase inhibitors may be particularly
effective in DLB. CONCLUSIONS: Clinicians should be aware of DLB as part of a
spectrum of Lewy body disorders. Neuroleptic sensitivity reactions and good
response to cholinergic therapies are important aspects of management.
Madsen, A. M., R. K. Lomholt, et al. (2002). "[Diagnosis and treatment of Lewy
body dementia]." Ugeskr Laeger164(18): 2383-6.
Dementia with Lewy bodies (DLB) has recently gained recognition as a separate
disease. Lewy bodies are pathoanatomical inclusion bodies in the CNS. They are
well known as part of Parkinson's disease where they are present mainly in the
substantia nigra, and they are also found in large numbers in the neocortex. It
is still an unanswered question why Lewy bodies are formed, but their appearance
is connected with cellular degeneration of unknown aetiology. Neuropathological
investigations of dementia populations show that DLB accounts for 12-36%, which
places it as the second most frequent dementia disease after Alzheimer's disease
(AD) with a frequency close to that of vascular dementia. This article reviews
the development of the term DLB and describes the clinical characteristics,
including the neuropsychological symptom profile, which can contribute to the
diagnostic discrimination between DLB and AD. Furthermore, relevant treatment
possibilities are discussed.
Lopez, O. L., J. T. Becker, et al. (2002). "Research evaluation and prospective
diagnosis of dementia with Lewy bodies." Arch Neurol59(1): 43-6.
OBJECTIVE: To evaluate the relative merits of recently developed criteria for
dementia with Lewy bodies (DLBs) in a longitudinal study of dementia. DESIGN:
The diagnosis of DLBs was used in combination with other clinical diagnosis.
Patients were classified primarily based on the NINCDS-ADRDA (National Institute
of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and
Related Disorders Association) clinical criteria for probable or possible
Alzheimer disease, or with other disease process that can cause dementia (eg,
Parkinson disease), and secondarily according to the consensus guidelines for
DLBs. This "double" clinical diagnosis was implemented to capture different
pathological entities. The neuropathological diagnosis of Lewy bodies was made
with monoclonal antibodies against alpha-synuclein. SETTING: Multidisciplinary
research clinic. RESULTS: Prospective application of the consensus guidelines
for DLBs from January 1, 1997, to September 29, 2000, identified 11 patients
having the diagnosis of probable DLBs and 35 having possible DLBs. The diagnosis
of probable or possible DLBs was associated with probable Alzheimer disease in
34 patients, with possible Alzheimer disease in 5 patients, with Parkinson
disease in 2 patients, and with other disease processes in 2 patients. Three
patients were diagnosed as having probable DLBs alone. An autopsy was performed
in 26 of the cases who were clinically examined during the study period.
Cortical Lewy bodies were identified in 13 cases; 4 had had premortem diagnosis
of DLBs (sensitivity, 30.7%; specificity, 100%). CONCLUSIONS: The prospective
validation of the clinical criteria for DLBs showed poor accuracy in this
series. We believe that current criteria for DLBs are useful when DLBs occur in
isolation, but have low sensitivity when Lewy bodies coexist with the
pathological abnormalities of Alzheimer disease.
Li, J. Y., P. Henning Jensen, et al. (2002). "Differential localization of
alpha-, beta- and gamma-synucleins in the rat CNS." Neuroscience113(2):
463-78.
alpha-Synuclein is a presynaptic protein that normally participates in the
homeostasis of synaptic vesicles. Missense mutations in its gene cause the
protein to participate actively in the development of heritable forms of
Parkinson's disease. Moreover, its metabolism is perturbed in all cases of
Parkinson's disease where alpha-synuclein accumulates in a filamentous form in
the Lewy body nerve cell lesion. Lewy bodies also develop in other common
neurodegenerative disorders, like dementia with Lewy bodies and Lewy body
variant of Alzheimer's disease. In the present study, we have studied the
detailed distribution of alpha-, beta- and gamma-synuclein in the rat
CNS.alpha-Synuclein was not observed in perikarya, but was distributed with high
intensity in nerve terminals in the caudate and putamen and ventral pallidum,
where beta-synuclein was much weaker and less densely distributed in the caudate
and putamen. gamma-Synuclein was not found in the caudate and putamen. alpha-Synuclein
was robustly distributed in the substantia nigra pars reticulata, but was very
weak or virtually absent from the perikarya of the neurons in the pars compacta.
In contrast, beta-synuclein was very weak or absent from the substantia nigra.
gamma-Synuclein was absent from the terminals of substantia nigra pars
reticulata, but sparsely distributed gamma-synuclein-containing neurons were
detected in the substantia nigra pars compacta. In the brainstem, alpha-synuclein
as well as gamma-synuclein were present in the locus coeruleus with high
intensity, while beta-synuclein was very weak. In addition, alpha-synuclein was
intense in the vagus nucleus, but weak in the oculomotor, facial, hypoglossal,
accessory and ambiguous nuclei, where beta-synuclein was very intensely present.
Furthermore, gamma-synuclein was localized in the terminals and in cell bodies
of the Edinger-Westphal nucleus, the red nucleus, locus coeruleus, and most
cranial nerve-related nuclei. In the spinal cord, alpha- and gamma-synucleins
were intensely present in laminae I and II and in the preganglionic sympathetic
nuclei, whereas beta-synuclein was very weak.These results indicate that alpha-synuclein
is abundant in central catecholaminergic regions. beta-Synuclein is more
localized in the somatic cholinergic components, while it is particularly weak
or absent from catecholaminergic neurons. gamma-Synuclein appears to be present
in both cholinergic and catecholaminergic regions, but very weak in the
forebrain.
Lang, C. J. and M. Bergmann (2002). "[Dementias with lewy bodies]." Fortschr
Neurol Psychiatr70(9): 476-94.
Dementias with Lewy bodies are no rare cause of cognitive and motor impairments
in old age. Neuropathologically, they must be distinguished into diffuse Lewy
body disease resp. dementia with Lewy bodies, Parkinson's disease with
concomitant Alzheimer's pathology, and the Lewy body variant of Alzheimer's
disease according to extent and concomitant pathology. The most reliable
diagnostic features of dementia with Lewy bodies are fluctuating disturbances of
cognition and consciousness, visual disorders (hallucinations, visuoperceptive
and visuoconstructive impairments), and early extrapyramidal signs of the
hypokinetic-rigid type with a propensity to frequent falls. The pertinent
diagnostic criteria are the consensus criteria according to McKeith et al.
Additional contributions are to be expected by functional neuroimaging (SPECT,
PET) and CSF examination (homovanillic acid). However, even assuming the most
favorable conditions a diagnostic accuracy of 85 % is presently hard to achieve.
Particularly, as is demonstrated using a case example, reliable antemortem
diagnosis of Lewy body variant of Alzheimer's disease is hardly possible.
Clinically, this group of diseases is important, since increased neuroleptic
sensitivity must be taken into account and modern central cholinergic agents
seem to be a promising therapeutic option.
Kurosinski, P., M. Guggisberg, et al. (2002). "Alzheimer's and Parkinson's
disease--overlapping or synergistic pathologies?" Trends Mol Med8(1):
3-5.
Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common
neurodegenerative disorders in humans. They are characterized by insoluble
protein deposits; beta-amyloid plaques and tau-containing neurofibrillary
lesions in AD, and alpha-synuclein-containing Lewy bodies in PD. As a
significant percentage of patients have clinical and pathological features of
both diseases, the patho-cascades of the two diseases might overlap. For the
first time, new animal models that express multiple transgenes provide the tools
to dissect the pathogenic pathways and to differentiate between additive and
synergistic effects.
Kim, K. S., S. Y. Choi, et al. (2002). "Aggregation of alpha-synuclein induced
by the Cu,Zn-superoxide dismutase and hydrogen peroxide system." Free Radic
Biol Med32(6): 544-50.
Alpha-synuclein is a major component of the abnormal protein aggregation in Lewy
bodies of Parkinson's disease (PD) and senile plaques of Alzheimer's disease
(AD). Previous studies have shown that the aggregation of alpha-synuclein was
induced by copper (II) and H(2)O(2) system. Since copper ions could be released
from oxidatively damaged Cu,Zn-superoxide dismutase (SOD), we investigated the
role of Cu,Zn-SOD in the aggregation of alpha-synuclein. When alpha-synuclein
was incubated with both Cu,Zn-SOD and H(2)O(2), alpha-synuclein was induced to
be aggregated. This process was inhibited by radical scavengers and spin
trapping agents such as 5,5'-dimethyl 1-pyrolline N-oxide and
tert-butyl-alpha-phenylnitrone. Copper chelators, diethyldithiocarbamate and
penicillamine, also inhibited the Cu,Zn-SOD/H(2)O(2) system-induced alpha-synuclein
aggregation. These results suggest that the aggregation of alpha-synuclein is
mediated by the Cu,Zn-SOD/H(2)O(2) system via the generation of hydroxyl radical
by the free radical-generating function of the enzyme. The Cu,Zn-SOD/H(2)O(2)-induced
alpha-synuclein aggregates displayed strong thioflavin-S reactivity, reminiscent
of amyloid. These results suggest that the Cu,Zn-SOD/H(2)O(2) system might be
related to abnormal aggregation of alpha-synuclein, which may be involved in the
pathogenesis of PD and related disorders.
Khotianov, N., R. Singh, et al. (2002). "Lewy body dementia: case report and
discussion." J Am Board Fam Pract15(1): 50-4.
BACKGROUND: Lewy body dementia is a common but frequently underdiagnosed cause
of dementia often mistaken for the more familiar entity of Alzheimer disease.
Clinically the distinction is important, because it can have profound
implications for management. METHODS: The medical literature was searched using
the keywords "Lewy bodies," "Lewy body dementia," "Alzheimer dementia," and "parkinsonian
disorders." A case of Lewy body dementia is described. RESULTS: An elderly man
had long-standing diagnoses of Alzheimer disease and Parkinson disease. After he
was evaluated thoroughly, the diagnosis was revised to Lewy body dementia,
leading to changes in treatment that were associated with dramatic improvement
in the patient's mental status. Evidence from the literature suggests that Lewy
body dementia can be diagnosed in primary care settings based on clinical
criteria. The physician should be alert to this diagnosis, and special attention
should be paid to dementia patients who exhibit parkinsonism, hallucinations,
fluctuating cognition, or prominent visuosperceptual deficits. CONCLUSIONS: The
diagnosis of Lewy body dementia has important implications. It is associated
with a high incidence of neuroleptic sensitivity, necessitating great caution in
the use of these common antipsychotic agents. Early studies indicate
cholinesterase inhibitors can be beneficial for treating the hallucinations and
behavior disturbances that afflict these patients and might also improve
cognition.
Jellinger, K. A. (2002). "Disturbance of the nigro-amygdaloid connections in
dementia with Lewy bodies." J Neurol Sci193(2): 157-8.
Harding, A. J., B. Lakay, et al. (2002). "Selective hippocampal neuron loss in
dementia with Lewy bodies." Ann Neurol51(1): 125-8.
Hippocampal volume and neuron number were measured using stereological
techniques in pathologically confirmed dementia with Lewy bodies (n = 8),
Parkinson's disease only (n = 4), and controls (n = 9). We, and others, have
previously shown considerable cell loss in the CA1 and subiculum subregions in
Alzheimer's disease. In contrast, these regions were spared in dementia with
Lewy bodies where a selective loss of lower presubiculum pyramidal neurons was
found. These findings suggest a selective loss of frontally projecting
hippocampal neurons in dementia with Lewy bodies versus those projecting to
temporal lobe regions in Alzheimer's disease.
Gu, G., P. E. Reyes, et al. (2002). "Mitochondrial DNA deletions/rearrangements
in parkinson disease and related neurodegenerative disorders." J Neuropathol
Exp Neurol61(7): 634-9.
Inhibition of mitochondrial respiratory chain function may contribute to
dopaminergic neurodegeneration in the substantia nigra (SN) of patients with
Parkinson disease (PD). Since large-scale structural changes (e.g. deletions and
rearrangements in mitochondrial DNA [mtDNA]) have been associated with
mitochondrial dysfunction, we tested the hypothesis that increased total mtDNA
deletions/rearrangements are associated with neurodegeneration in PD. This study
employed a well-established technique, long-extension polymerase chain reaction
(LX-PCR), to detect the multiple mtDNA deletions/rearrangements in the SN of
patients with PD, multiple system atrophy (MSA), dementia with Lewy bodies (DLB),
Alzheimer disease (AD), and age-matched controls. We also compared the total
mtDNA deletions/rearrangements in different brain regions of PD patients. The
results demonstrated that both the number and variety of mtDNA
deletions/rearrangements were selectively increased in the SN of PD patients
compared to patients with other movement disorders as well as patients with AD
and age-matched controls. In addition, increased mtDNA deletions/rearrangements
were observed in other brain regions in PD patients, indicating that
mitochondrial dysfunction is not just limited to the SN of PD patients. These
data suggest that accumulation of total mtDNA deletions/rearrangements is a
relatively specific characteristic of PD and may be one of the contributing
factors leading to mitochondrial dysfunction and neurodegeneration in PD.
Freo, U., G. Pizzolato, et al. (2002). "A short review of cognitive and
functional neuroimaging studies of cholinergic drugs: implications for
therapeutic potentials." J Neural Transm109(5-6): 857-70.
In the last 20 years a cholinergic dysfunction has been the major working
hypothesis for the pharmacology of memory disorders. Cholinergic antagonists and
lesions impair and different classes of cholinomimetics (i.e. acetylcholine
precursors, cholinergic agonists and acetylcholinesterase inhibitors) enhance
attention and memory in experiment animals, healthy human subjects and Alzheimer
disease patients. In addition, acetylcholinesterase inhibitors improve different
cognitive (i.e. visuospatial and verbal) functions in a variety of unrelated
disorders such as dementia with Lewy bodies, Parkinson disease, multiple
sclerosis, schizoaffective disorders, iatrogenic memory loss, traumatic brain
injury, hyperactivity attention disorder and, as we recently reported, vascular
dementia and mild cognitive impairment. In animals, different cholinomimetics
dose-dependently increased regional cerebral metabolic rates for glucose (rCMRglc)
and regional blood flow (rCBF), two indices of neuronal function, more markedly
in subcortical regions (i.e. thalamus, hippocampus and visual system nuclei). In
both healthy human subjects and Alzheimer disease patients acetylcholinesterase
inhibitors increased rCMRglc and rCBF in subcortical and cortical brain regions
at rest but attenuated rCBF increases during cognitive performances. Hence,
acetylcholinesterase inhibitors may enhance cognition and rCMRglc by acting
primarily on subcortical regions that are involved in attentional (i.e.
thalamus) and memory (i.e. hippocampus) processes; such an effect probably is
not specific for Alzheimer disease and can be beneficial in patients suffering
from a wide array of neuropsychiatric disorders.
Bergman, J. and V. Lerner (2002). "Successful use of donepezil for the treatment
of psychotic symptoms in patients with Parkinson's disease." Clin
Neuropharmacol25(2): 107-10.
The risk of psychosis among patients with Parkinson's disease (PD) is high, and
the management of these patients remains a substantial problem for physicians.
Atypical antipsychotics, despite their advantages over conventional
antipsychotics, can cause different side effects and deterioration of PD.
Several reports have suggested that donepezil can be helpful in the treatment of
psychotic conditions in patients with dementia with Lewy bodies and Alzheimer's
disease. This report presents the results of preliminary study of six patients
(four women, two men; age range, 60-75 years) with PD (range of duration, 3-7
years) and dementia complicated by psychosis. All patients were treated with
antiparkinsonian therapy, and donepezil was added to their regular treatment.
The severity of the psychotic symptoms was assessed using the Scale for the
Assessment of Positive Symptoms, and extrapyramidal symptoms were assessed using
the Simpson-Angus Scale. With the addition of donepezil (as much as 10 mg/day)
to their constant antiparkinsonian treatment, five patients had clinically
significant (more than 53%) improvement on the assessment scale, and one patient
had minimal (24%) improvement after 6 weeks of the treatment. None of the
patients had side effects or deterioration of parkinsonian symptoms. The results
suggest that donepezil may ameliorate psychotic symptoms in patients with PD,
but this will need to be tested further in controlled, double-blind trials.
Barber, R., I. McKeith, et al. (2002). "Volumetric MRI study of the caudate
nucleus in patients with dementia with Lewy bodies, Alzheimer's disease, and
vascular dementia." J Neurol Neurosurg Psychiatry72(3): 406-7.
OBJECTIVES: To determine whether parkinsonian symptoms in dementia with Lewy
bodies (DLB) are associated with greater atrophy of the caudate nucleus in
comparison with patients with Alzheimer's disease (AD) and vascular dementia (VaD).
METHODS: T1weighted MR scans were acquired in elderly patients with DLB, AD, VaD,
and healthy controls. Normalised volumetric measurements of the caudate nucleus
were obtained and parkinsonian symptoms rated using Hoehn and Yahr staging.
RESULTS: There were no significant differences in the volume of the caudate
nucleus between patients with dementia. However, the left caudate volume was
significantly reduced in AD and DLB compared with controls. Parkinsonian
symptoms did not correlate with caudate nucleus volume. CONCLUSIONS:
Parkinsonian symptoms in DLB may be more closely coupled to neurochemical rather
than structural changes in the caudate nucleus, and volumetric MRI analysis of
caudate nucleus does not discriminate between patients with DLB, AD, and VaD.
Assal, F. and J. L. Cummings (2002). "Neuropsychiatric symptoms in the
dementias." Curr Opin Neurol15(4): 445-50.
PURPOSE OF REVIEW: Neuropsychiatric, or non-cognitive symptoms are increasingly
recognized as manifestations of dementias. RECENT FINDINGS: In Alzheimer's
disease, recent advances have included the identification of behavioral
profiles, differentiation of apathy and depression, characterization of risk
factors for psychosis and its links to agitation and aggression, and an analysis
of depressive symptoms in the absence of major depression. Functional
neuroimaging data mainly supported the role of the anterior cingulate in apathy.
The orbitofrontal and anterior cingulate tangle burden were associated with
agitation, and increased orbitofrontal and mid-temporal muscarinic M2 receptors
with psychosis and hallucinations. Selected genetic polymorphisms of dopamine
and serotonin receptors or transporters were linked with aggression,
hallucinations or psychosis. When compared with other dementias, individuals
with frontotemporal dementia disclosed, as expected, different behaviors and
particularly aberrant social behavior. The frequency of delusions and visual
hallucinations was increased in Parkinson's disease, Parkinson's disease with
dementia, and dementia with Lewy bodies, suggesting common mechanisms such as
Lewy body pathology and cholinergic deficiency. The latter was supported by an
improvement of these symptoms by cholinesterase inhibitors. SUMMARY: Future
research directions include both clinical and basic neuroscience investigations.
The detection of early neuropsychiatric symptoms might be a marker for dementia,
and the possible existence of a mild neuropsychiatric impairment syndrome should
be explored. More longitudinal studies with pathological confirmation will
facilitate correlations with neuropsychiatric symptoms. Functional neuroimaging
and behavioral neurogenetics will permit in-vivo correlations and consequently
help patient management and care.
Arsland, D. (2002). "[Dementia with Lewy bodies]." Tidsskr Nor Laegeforen122(5): 525-9.
BACKGROUND: Some 10%-15% of patients with dementia are diagnosed as dementia
with Lewy bodies (DLB), a disorder characterised by the presence of Lewy bodies
in the brainstem and cortex. MATERIAL AND METHODS: Review of pathology, clinical
symptoms, pharmacological and nonpharmacological treatment, based on the
literature and on personal experience. RESULTS: Neurochemical findings are
marked cortical reduction of acetylcholine and nigrostriatal dopamine
deficiency. Key features of the clinical syndrome are dementia, fluctuating
consciousness, visual hallucinations and parkinsonism. There are pathological
and clinical overlaps between DLB and Alzheimer's disease on the one hand, and
between DLB and Parkinson's disease on the other; the relationship between these
diseases awaits further elucidation. Clinical consensus criteria for DLB have
been published and shown to have high sensitivity and specificity. Fluctuating
consciousness may be difficult to detect, but diagnostic instruments exist that
may help in the evaluation. Drug treatment of DLB is difficult. Cholinesterase
inhibitors have been shown to improve cognition and psychiatric symptoms.
Atypical antipsychotics may improve psychosis, but some patients develop severe
sensitivity reactions. The effect of antiparkinson agents is unknown.
Apaydin, H., J. E. Ahlskog, et al. (2002). "Parkinson disease neuropathology:
later-developing dementia and loss of the levodopa response." Arch Neurol59(1): 102-12.
OBJECTIVE: To investigate the neuropathologic substrate for dementia occurring
late in Parkinson disease (PD). DESIGN: We identified 13 patients with a
clinical diagnosis of PD who experienced dementia at least 4 years after
parkinsonism onset (mean, 10.5 years) and subsequently underwent postmortem
examination. Despite levodopa therapy, 9 patients later became severely impaired
and nonambulatory, requiring total or near-total care; this included 4 patients
treated with 1200 mg/d or more of levodopa (with carbidopa), which was
consistent with loss of the levodopa response. These 13 patients were compared
with 9 patients clinically diagnosed as having PD, but without dementia, who had
undergone autopsies. RESULTS: Twelve of 13 PD patients with dementia had
findings of diffuse or transitional Lewy body disease as the primary pathologic
substrate for dementia; 1 had progressive supranuclear palsy. This pathology
also apparently accounted for the levodopa refractory state. Among the 12 PD
patients with dementia, mean and median Lewy body counts were increased nearly
10-fold in neocortex and limbic areas compared with PD patients without dementia
(P< or =.002). Alzheimer pathology was modest. Only one patient met the criteria
defined by the National Institute on Aging and the Reagan Institute Working
Group on the Diagnostic Criteria for the Neuropathologic Assessment of
Alzheimer's Disease for "intermediate probability of Alzheimer's disease." There
were, however, significant correlations between neocortical Lewy body counts and
senile plaques as well as neurofibrillary tangles. Senile plaque counts did not
significantly correlate with tangle counts in any of the analyzed nuclei.
Arteriolar disease may have contributed to the clinical picture in 2 patients.
CONCLUSIONS: Diffuse or transitional Lewy body disease is the primary pathologic
substrate for dementia developing later in PD. This same pathologic substrate
seemed to account for end-stage, levodopa refractory parkinsonism. The
occurrence of Alzheimer pathology was modest, but was highly correlated with
Lewy body pathology, suggesting common origins or one triggering the other.
Yoshita, M., J. Taki, et al. (2001). "A clinical role for [(123)I]MIBG
myocardial scintigraphy in the distinction between dementia of the
Alzheimer's-type and dementia with Lewy bodies." J Neurol Neurosurg
Psychiatry71(5): 583-8.
OBJECTIVE: Scintigraphy with [(123)I]metaiodobenzyl guanidine ([(123)I]MIBG)
enables the quantification of postganglionic sympathetic cardiac innervation.
Recently, myocardial [(123)I]MIBG scintigraphy has been found to be useful in
distinguishing Parkinson's disease, a Lewy body disease, from other akinetic
rigid syndromes. Some patients initially diagnosed with dementia of the
Alzheimer's type (DAT) are discovered to have an alternative disease such as
dementia with Lewy bodies (DLB), despite the application of stringent diagnostic
criteria. In the present study, examinations were performed to clarify the
usefulness of myocardial [(123)I]MIBG scintigraphy in improving the differential
diagnosis between patients with DLB and DAT. METHODS: Fourteen patients with DLB
and 14 patients with DAT underwent scintigraphy with [(123)I]MIBG, combined with
orthostatic tests and cardiac examinations. RESULTS: In all patients with DLB,
the heart to mediastinum (H/M) ratio of MIBG uptake was pathologically impaired
in both early and delayed images, independently of the duration of disease and
autonomic failure. All patients with DAT had successful MIBG uptake in the heart
regardless of duration of disease and autonomic failure. Orthostatic hypotension
was seen in four patients with DAT and 13 patients with DLB. CONCLUSIONS:
[(123)I]MIBG myocardial scintigraphy might detect early disturbances of the
sympathetic nervous system in DLB and might provide useful diagnostic
information to discriminate DLB from DAT. The distinction between DLB and DAT
may be improved by greater emphasis on cardiac sympathetic disturbances.
Tabner, B. J., S. Turnbull, et al. (2001). "Production of reactive oxygen
species from aggregating proteins implicated in Alzheimer's disease, Parkinson's
disease and other neurodegenerative diseases." Curr Top Med Chem1(6):
507-17.
The deposition of abnormal protein fibrils is a prominent pathological feature
of many different 'protein conformational' diseases, including some important
neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease
(PD), motor neurone disease and the 'prion' dementias. Some of the
fibril-forming proteins or peptides associated with these diseases have been
shown to be toxic to cells in culture. A clear understanding of the molecular
mechanisms responsible for this toxicity should shed light on the probable link
between protein deposition and cell loss in these diseases. In the case of the
beta-amyloid (Abeta), which accumulates in the brain in AD, there is good
evidence that the toxic mechanism involves the production of reactive oxygen
species (ROS). By means of an electron spin resonance (ESR) spin-trapping
method, we have shown recently that solutions of Abeta liberate readily
detectable amounts of hydroxyl radicals upon incubation in vitro followed by the
addition of small amounts of Fe(II). We have also obtained similar results with
alpha-synuclein, which accumulates in Lewy bodies in PD. Our data suggest that
hydrogen peroxide accumulates during Abeta or alpha-synuclein incubation and
that this is subsequently converted to hydroxyl radicals, on addition of Fe
(II), by Fenton's reaction. Consequently, we now support the idea that one of
the fundamental molecular mechanisms underlying the pathogenesis of cell death
in AD, PD, and possibly some other protein conformational diseases, could be the
direct production of ROS during formation of the abnormal protein aggregates.
This hypothesis suggests a novel approach to the therapy of this group of
diseases.
Sung, J. Y., J. Kim, et al. (2001). "Induction of neuronal cell death by
Rab5A-dependent endocytosis of alpha-synuclein." J Biol Chem276(29):
27441-8.
The presynaptic alpha-synuclein is a prime suspect for contributing to Lewy
pathology and clinical aspects of diseases, including Parkinson's disease,
dementia with Lewy bodies, and a Lewy body variant of Alzheimer's disease. Here
we examined the pathogenic mechanism of neuronal cell death induced by
alpha-synuclein. The exogenous addition of alpha-synuclein caused a marked
decrease of cell viability in primary and immortalized neuronal cells. The
neuronal cell death appeared to be correlated with the Rab5A-specific
endocytosis of alpha-synuclein that subsequently caused the formation of Lewy
body-like intracytoplasmic inclusions. This was further supported by the fact
that the expression of GTPase-deficient Rab5A resulted in a significant decrease
of its cytotoxicity as a result of incomplete endocytosis of alpha-synuclein.
Strubel, D., J. M. Jacquot, et al. (2001). "[Dementia and falls]." Ann
Readapt Med Phys44(1): 4-12.
INTRODUCTION: Dementia is now a frequent disease in elderly and may be a major
risk of falling. Usually these falls are multiple and serious, but their
consequences are not specific. All types of dementia (Alzheimer's disease,
dementia with Lewy bodies, dementia in Parkinson's disease, fronto-temporal
dementia, vascular dementiaellipsis) and all stages of evolution are
concerned.Discussion: These falls result from cognitive and behavioural
disorders, visual and motor problems, gait and balance disturbances,
malnutrition, adverse effects of medication and fear of falling. CONCLUSION:
Prevention is possible. Attention must be given on the patient himself (keeping
in good health, limitation in sedative treatment and mechanical
restraintsellipsis) and on his environment (lighting, obstacles on the ground,
stress levelellipsis). After a fall, especially after a complicated fall,
rehabilitation modalities and aims must be adapted but caring must not be
defeatist. Randomized studies need to be realized.
Shiozaki, K., E. Iseki, et al. (2001). "Distribution of m1 muscarinic
acetylcholine receptors in the hippocampus of patients with Alzheimer's disease
and dementia with Lewy bodies-an immunohistochemical study." J Neurol Sci193(1): 23-8.
Of the five subtypes (m1-m5) of muscarinic acetylcholine receptors (mAChR), the
m1 subtype is the most abundant in the human cerebral cortex and hippocampus.
Impairment of the muscarinic cholinergic system in the brain may cause cognitive
dysfunction in patients with Alzheimer's disease (AD), and choline esterase
inhibitors (ChE-I) are used to improve cognitive dysfunction. Severe impairment
of the cholinergic system has also been reported in the brains of subjects with
dementia with Lewy bodies (DLB). There have been a few reports about the
distribution of mAChR subtypes in the human brain. In the present study, we
investigated the distribution of m1 mAChR in the human hippocampus using an
antibody against the m1 subtype.In the control brains, m1 immunoreactivity was
observed in the apical dendrites and cell bodies of granular neurons of the
dentate gyrus and pyramidal neurons of CA1-3 and the subiculum. The dendrites
and the cell bodies of the pyramidal neurons in layers III and V of the
parahippocampal cortex and other temporal cortices were also positive for m1
immunoreactivity. This m1 immunoreactivity was markedly reduced in AD and DLB
brains.
Sharma, N., J. Hewett, et al. (2001). "A close association of torsinA and
alpha-synuclein in Lewy bodies: a fluorescence resonance energy transfer study."
Am J Pathol159(1): 339-44.
TorsinA, a novel protein in which a mutation causes dominant, early onset
torsion dystonia, may serve as a chaperone for misfolded proteins that require
refolding or degradation. It has been hypothesized that misfolded
alpha-synuclein, a protein in which two mutations cause autosomal dominantly
inherited Parkinson's disease, serves as a nidus for the development of a Lewy
body. We hypothesized that torsinA plays a role in the cellular processing of
alpha-synuclein. We demonstrate that anti-torsin antibodies stain Lewy bodies
and Lewy neurites in the substantia nigra and cortex. Using sensitive
fluorescent resonance energy transfer (FRET) techniques, we find evidence of a
close association between torsinA and alpha-synuclein in Lewy bodies.
Preobrazhenskaia, I. S., V. P. Chekhonin, et al. (2001). "[Permeability of
hemato-encephalic barrier in Alzheimer's disease and parkinsonism with cognitive
disorders]." Zh Nevrol Psikhiatr Im S S Korsakova101(5): 39-42.
The study was made of 17 patients with expected Alzheimer's disease (AD), 29
patients with Parkinson's disease (PD) and 7 with a expected dementia with Levy
bodies (DLB). The severity of cognitive disorders was determined according to
the following scales: Global Deterioration Rating Scale, Mini-mental State
Examination, Mattis Dementia Rating Scale. Besides, the patients state was
evaluated, in the whole, according to some scales. Permeability of
hemato-encephalic barrier was evaluated according to the blood serum levels of 3
neurospecific proteins--neuron specific enolase, glial fibrillary protein and
alpha-glycoprotein. Their determination was performed by ELISA method. The
significant elevation of the levels of the proteins studied was found already on
the early stages of the disease. Their levels were higher in the patients with
the dementia as compared with the individuals without it. There were no
differences in cortical, subcortical and combined types of dementia. The authors
believe, that some of the proteins studied (neuron specific enolase, for
example) may serve as non specific markers of cerebral degeneration.
Muma, N. A., J. M. Lee, et al. (2001). "6-hydroxydopamine-induced lesions of
dopaminergic neurons alter the function of postsynaptic cholinergic neurons
without changing cytoskeletal proteins." Exp Neurol168(1):
135-43.
The neuropathological hallmarks of many neurodegenerative diseases are
intraneuronal inclusions containing cytoskeletal proteins such as neurofilaments
in Lewy bodies in Parkinson's disease and tau in neurofibrillary tangles in
Alzheimer's disease. Dysfunction in dopaminergic and cholinergic systems also
exist in both Alzheimer's disease and Parkinson's disease. Because the primary
pathology in Parkinson's disease is localized to the dopaminergic system, we set
out to determine if perturbations in cholinergic systems are a consequence of
dopaminergic neuron loss. Therefore, following intracerebral microinjections of
6-hydroxydopamine in rats, the activity of cholinergic neurons was measured by
hemicholinium binding in cholinergic terminal fields and perturbations in
cytoskeletal proteins were examined in dopaminoceptive neurons using
immunocytochemistry. The 6-hydroxydopamine injections robustly reduced the
number of monoaminergic cell bodies in the lateral midbrain and dramatically
decreased dopamine and its major metabolites in dopaminergic projection sites.
This treatment increased hemicholinium binding in the prefrontal cortex (200%)
and amygdala (284%); however, despite previous reports to the contrary, there
were no increases in immunoreactivity for phosphorylated neurofilaments,
microtubule-associated protein (MAP) 2, tau or paired helical filament (PHF)
tau. This lack of an increase in cytoskeletal proteins was observed following
either injections of moderate doses of the toxin directly into the medial
forebrain bundle or after high doses were administered
intracerebroventricularly. These results suggest that removal of dopaminergic
inputs to the forebrain results in hyperactivity of the cholinergic systems but
is not sufficient to induce postsynaptic perturbations in cytoskeletal proteins
which occur in neurodegenerative diseases.
McShane, R. H., Z. Nagy, et al. (2001). "Anosmia in dementia is associated with
Lewy bodies rather than Alzheimer's pathology." J Neurol Neurosurg Psychiatry70(6): 739-43.
OBJECTIVES: To assess olfactory function of patients with dementia. Odour
detection ability is impaired in clinical Parkinson's disease. Evidence of
impaired detection in patients with clinically diagnosed Alzheimer's disease is
inconsistent. No studies of olfaction have been neuropathologically validated.
METHODS: The olfactory function of 92 patients with dementia and 94 controls was
assessed using a simple bedside test as part of the Oxford Project To
Investigate Memory and Ageing (OPTIMA). Neuropathological assessment was made of
cortical Lewy bodies and substantia nigra (SN) cell counts and of Alzheimer's
disease in all 92 patients, 22 of whom had SN Lewy bodies and 43 of whom had
only Alzheimer's disease. RESULTS: Patients with Lewy bodies were more likely to
be anosmic than those with Alzheimer's disease or controls. Patients with
Alzheimer's disease were not more likely to be anosmic than controls. Nor was
anosmia associated with degree of neurofibrillary tangles, as assessed by Braak
stage. Among subjects with Lewy bodies, overall cortical Lewy body scores and
Lewy body density in the cingulate were higher in those who were anosmic.
Consensus clinical criteria for dementia with Lewy bodies had a sensitivity of
64% and specificity of 89%. In the absence of definite Alzheimer's disease, the
criteria had sensitivity of 100%. In patients with definite Alzheimer's disease,
anosmia was slightly more sensitive (55%) than the consensus criteria (33%).
However, the addition of anosmia to the consensus criteria did not improve their
overall performance. CONCLUSION: Dementia with Lewy bodies is associated with
impaired odour detection. Misdiagnosis may have accounted for some previous
reports of impaired odour detection in Alzheimer's disease. Simple but more
sensitive tests of anosmia are required if they are to be clinically useful in
identifying patients with dementia with Lewy bodies.
McLean, P. J., H. Kawamata, et al. (2001). "Alpha-synuclein-enhanced green
fluorescent protein fusion proteins form proteasome sensitive inclusions in
primary neurons." Neuroscience104(3): 901-12.
Alpha-synuclein accumulates in the brains of sporadic Parkinson's disease
patients as a major component of Lewy bodies, and mutations in alpha-synuclein
are associated with familial forms of Parkinson's disease. The pathogenic
mechanisms that precede and promote the aggregation of alpha-synuclein into Lewy
bodies in neurons remain to be determined. Here, we constructed a series of
alpha-synuclein-enhanced green fluorescent protein (alpha-synucleinEGFP,
SynEGFP) fusion proteins to address whether the Parkinson's disease-associated
mutations alter the subcellular distribution of alpha-synuclein, and to use as a
tool for experimental manipulations to induce aggregate formation. When
transfected into mouse cultured primary neurons, the 49-kDa alpha-synucleinEGFP
fusion proteins are partially truncated to a approximately 27-kDa form. This
non-fluorescent carboxy-terminally modified fusion protein spontaneously forms
inclusions in the neuronal cytoplasm. A marked increase in the accumulation of
inclusions is detected following treatment with each of three proteasome
inhibitors, n-acetyl-leu-leu-norleucinal, lactacystin and MG132. Interestingly,
Ala30Pro alpha-synucleinEGFP does not form the cytoplasmic inclusions that are
characteristic of wild-type and Ala53Thr alpha-synucleinEGFP, supporting the
idea that the Ala30Pro alpha-synuclein protein conformation differs from
wild-type alpha-synuclein. Similar inclusions are formed if alpha-synuclein
carboxy-terminus is modified by the addition of a V5/6xHistidine epitope tag. By
contrast, overexpression of unmodified alpha-synuclein does not lead to
aggregate formation. Furthermore, synphilin-1, an alpha-synuclein interacting
protein also found in Lewy bodies, colocalizes with the carboxy-terminally
truncated alpha-synuclein fusion protein in discrete cytoplasmic inclusions.Our
finding that manipulations of the carboxy-terminus of alpha-synuclein lead to
inclusion formation may provide a model for studies of the pathogenic mechanisms
of alpha-synuclein aggregation in Lewy bodies.
Mattila, P. M., M. Roytta, et al. (2001). "Choline acetytransferase activity and
striatal dopamine receptors in Parkinson's disease in relation to cognitive
impairment." Acta Neuropathol (Berl)102(2): 160-6.
Brain tissue from 44 patients with Parkinson's disease (PD) and 36 age-matched
controls was examined for choline acetyltransferase (ChAT) activity, and for
densities of D1 and D2 dopamine receptors. Brain samples were examined for
Alzheimer' disease (AD) type changes and for Lewy bodies (LBs), and for
apolipoprotein E genotype. Patients were evaluated for the stage of cognitive
impairment using Reisberg's global deterioration scale. ChAT activity in PD was
reduced in all brain areas examined, being 51% of the control mean in the
hippocampus (P<0.001), 57% in the prefrontal cortex (P< 0.001) and 64% in the
temporal cortex (P<0.001). The number of LBs had a significant negative
correlation with ChAT activity in both prefrontal (r=-0.33, P<0.05) and temporal
cortex (r=-0.32, P<0.05). The reduction in ChAT activity in the prefrontal
cortex had a significant negative correlation (r=-0.38, P=0.012) with the extent
of cognitive impairment. When the CERAD class 'C' was excluded, cognitive
impairment correlated significantly with both prefrontal ChAT activity (r=-0.52,
P=0.0051) and the density of D1 dopamine receptors in the caudate nucleus
(r=-0.40, P=0.037). The number of D1 and D2 dopamine receptors was reduced in
both caudate nucleus and putamen in PD patients without neuroleptics as compared
to controls. An increased D2 receptor number was found in the caudate nucleus
and putamen in PD patients treated with neuroleptics. The present study showed
that cognitive decline in PD is associated with reduced ChAT activity in the
prefrontal cortex and the D1 dopamine receptor number in the caudate nucleus,
even in the absence of AD-type pathology.
Lippa, C. F., M. L. Schmidt, et al. (2001). "Alpha-synuclein in familial
Alzheimer disease: epitope mapping parallels dementia with Lewy bodies and
Parkinson disease." Arch Neurol58(11): 1817-20.
BACKGROUND: Alpha-synuclein is a major component of Lewy bodies (LBs) in
Parkinson disease and dementia with LBs and of glial cytoplasmic inclusions in
multiple system atrophy. However, epitope mapping for alpha-synuclein is
distinctive in different neurodegenerative diseases. The reasons for this are
poorly understood but may reflect fundamental differences in disease mechanisms.
OBJECTIVE: To investigate the alpha-synuclein epitope mapping properties of LBs
in familial Alzheimer disease. DESIGN AND SETTING: We compared LBs in familial
Alzheimer disease with those in synucleinopathies by probing 6 brains of persons
with familial Alzheimer disease using a panel of antibodies to epitopes spanning
the alpha-synuclein protein. Results were compared with data from brains of
persons with Parkinson disease, dementia with LBs, and multiple system atrophy.
RESULTS: The brains of persons with familial Alzheimer disease showed consistent
staining of LBs with all antibodies, similar to Parkinson disease and dementia
with LBs but different from alpha-synuclein aggregates that occurred in multiple
system atrophy. CONCLUSIONS: These data suggest that the epitope profiles of
alpha-synuclein in LBs are similar, regardless of whether the biological trigger
is related to synuclein or a different genetic pathway. These findings support
the hypothesis that the mechanism of alpha-synuclein aggregation is the same
within cell types but distinctive between cell types.
Kuusisto, E., A. Salminen, et al. (2001). "Ubiquitin-binding protein p62 is
present in neuronal and glial inclusions in human tauopathies and
synucleinopathies." Neuroreport12(10): 2085-90.
We examined the immunoreactivity of ubiquitin-binding protein p62 and its
association with ubiquitin (Ub), alpha-synuclein, and paired helical filament
(PHF)-tau in the affected brain areas of human tauopathies and
synucleinopathies. Ubiquitin-binding protein p62 is a widely expressed protein
that can bind to Ub noncovalently and is involved in several signalling
pathways, making p62 a candidate regulator of Ub-mediated proteolysis. We show
that p62 immunoreactivity co-localizes with neuronal and glial Ub-containing
inclusions in Alzheimer's disease, Pick's disease, dementia with Lewy bodies,
Parkinson's disease, and multiple system atrophy. This is the first
demonstration of a common protein component, apart from Ub, that is present in
both PHF-tau and alpha-synuclein inclusions. In both tauo- and
synucleinopathies, the staining patterns for p62 and Ub were markedly similar,
suggesting that a common mechanism which requires interaction of p62 and Ub
contributes to the formation of PHF-tau and alpha-synuclein inclusions.
Kotzbauer, P. T., J. Q. Trojanowsk, et al. (2001). "Lewy body pathology in
Alzheimer's disease." J Mol Neurosci17(2): 225-32.
Lewy bodies, the characteristic pathological lesion of substantia nigra neurons
in Parkinson's disease (PD), are frequently observed to accompany the amyloid
plaque and neurofibrillary tangle pathology of Alzheimer's disease (AD). However
the typical anatomic distribution of Lewy bodies in AD is distinct from PD. The
most common site of occurrence is the amygdala, where Lewy bodies are observed
in approximately 60% of both sporadic and familial AD. Other common sites of
occurrence include the periamygdaloid and entorhinal cortex, while neocortical
and brainstem areas develop Lewy bodies in a lower percentage of cases. In
contrast, dementia with Lewy bodies (DLB), defined by widespread neocortical and
brainstem Lewy bodies but frequently accompanied by variable levels of AD-type
pathology, represents the other end of a spectrum of pathology associated with
dementia. The observation of Lewy bodies in familial AD cases suggests that like
neurofibrillary tangles, the formation of Lewy bodies can be induced by the
pathological state caused by Abeta-amyloid overproduction. The role of Lewy body
formation in the dysfunction and degeneration of neurons remains unclear. The
protein alpha-synuclein appears to be an important structural component of Lewy
bodies, an observation spurred by the discovery of point mutations in the
alpha-synuclein gene linked to rare cases of autosomal dominant PD. Further
investigation of alpha-synuclein and its relationship to pathological conditions
promoting Lewy body formation in AD, PD, and DLB may yield further insight into
pathogenesis of these diseases.
Kawamata, H., P. J. McLean, et al. (2001). "Interaction of alpha-synuclein and
synphilin-1: effect of Parkinson's disease-associated mutations." J Neurochem77(3): 929-34.
alpha-Synuclein is a major component of Lewy bodies, a neuropathological feature
of Parkinson's disease. Two alpha-synuclein mutations, Ala53Thr and Ala30Pro,
are associated with early onset, familial forms of the disease. Recently,
synphilin-1, a protein found to interact with alpha-synuclein by yeast two
hybrid techniques, was detected in Lewy bodies. In this study we report the
interaction of alpha-synuclein and synphilin-1 in human neuroglioma cells using
a sensitive fluorescence resonance energy transfer technique. We demonstrate
that the C-terminus of alpha-synuclein is closely associated with the C-terminus
of synphilin-1. A weak interaction occurs between the N-terminus of
alpha-synuclein and synphilin-1. The familial Parkinson's disease associated
mutations of alpha-synuclein (Ala53Thr and Ala30Pro) also demonstrate a strong
interaction between their C-terminal regions and synphilin-1. However, compared
with wild-type alpha-synuclein, significantly less energy transfer occurs
between the C-terminus of Ala53Thr alpha-synuclein and synphilin-1, suggesting
that the Ala53Thr mutation alters the conformation of alpha-synuclein in
relation to synphilin-1.
Kanazawa, I. (2001). "How do neurons die in neurodegenerative diseases?"
Trends Mol Med7(8): 339-44.
Given that neurons are post-mitotic cells, their life span is generally long
enough to reach that of humans. However, sometimes neurons die without
recognizable causes, as a result of a process called neurodegeneration. Apart
from when gene mutations can be correlated with disease, it is difficult to
pinpoint molecules that are responsible for neuronal death. Therefore, neurons
living in a 'sick state' for many years might reveal important information about
neuronal death. Systematic and extensive single-neuron analysis of 'sick'
neurons is expected to provide clues to the mechanisms of neurodegeneration.
Moreover, the elimination of putative triggering and promoting factors involved
in neurodegenerative disease might prevent disease progression.
Kahle, P. J., M. Neumann, et al. (2001). "Selective insolubility of
alpha-synuclein in human Lewy body diseases is recapitulated in a transgenic
mouse model." Am J Pathol159(6): 2215-25.
alpha-Synuclein (alpha-SYN) is deposited in intraneuronal cytoplasmic inclusions
(Lewy bodies, LBs) characteristic for Parkinson's disease (PD) and LB dementias.
alpha-SYN forms LB-like fibrils in vitro, in contrast to its homologue beta-SYN.
Here we have investigated the solubility of SYNs in human LB diseases and in
transgenic mice expressing human wild-type and PD-associated mutant
[A30P]alpha-SYN driven by the brain neuron-specific promoter, Thy1. Distinct
alpha-SYN species were detected in the detergent-insoluble fractions from brains
of patients with PD, dementia with LBs, and neurodegeneration with brain iron
accumulation type 1 (formerly known as Hallervorden-Spatz disease). Using the
same extraction method, detergent-insolubility of human alpha-SYN was observed
in brains of transgenic mice. In contrast, neither endogenous mouse alpha-SYN
nor beta-SYN were detected in detergent-insoluble fractions from transgenic
mouse brains. The nonamyloidogenic beta-SYN was incapable of forming insoluble
fibrils because amino acids 73 to 83 in the central region of alpha-SYN are
absent in beta-SYN. In conclusion, the specific accumulation of
detergent-insoluble alpha-SYN in transgenic mice recapitulates a pivotal feature
of human LB diseases.
Jellinger, K. A. and C. Stadelmann (2001). "Problems of cell death in
neurodegeneration and Alzheimer's Disease." J Alzheimers Dis3(1):
31-40.
Progressive cell loss in specific neuronal populations is a pathological
hallmark of neurodegenerative diseases, but its mechanisms remain unresolved.
Apoptosis or alternative pathways of neuronal death have been discussed in
Alzheimer disease (AD) and other disorders. However, DNA fragmentation in human
brain as a sign of neuronal injury is too frequent to account for the continuous
loss in these slowly progressive diseases. In autopsy cases of AD, Parkinson's
disease (PD), related disorders, and age-matched controls, DNA fragmentation
using the TUNEL method and an array of apoptosis-related proteins (ARP),
proto-oncogenes, and activated caspase 3, the key enzyme of late-stage
apoptosis, were examined. In AD, a considerable number of hippocampal neurons
and glial cells showed DNA fragmentation with a 3- to 6-fold increase related to
amyloid deposits and neurofibrillary tangles, but only one in 2.600 to 5.650
neurons displayed apoptotic morphology and cytoplasmic immunoreactivity for
activated caspase~3, whereas no neurons were labeled in age-matched controls.
Caspase~3 immunoreactivity was seen in granules of cells with granulovacuolar
degeneration, in around 25% In progressive supranuclear palsy, only single
neurons but oligodendrocytes in brainstem, around 25% TUNEL-positive and
expressed both ARPs and activated caspase 3. In PD, dementia with Lewy bodies,
and multisystem atrophy (MSA), TUNEL-positivity and expression of ARPs or
activated caspase~3 were only seen in microglia and oligodendrocytes with
cytoplasmic inclusions in MSA, but not in neurons. These data provide evidence
for extremely rare apoptotic neuronal death in AD and PSP compatible with the
progression of neuronal degeneration in these chronic diseases. Apoptosis mainly
involves reactive microglia and oligodendroglia, the latter occasionally
involved by deposits of insoluble fibrillary proteins, while alternative
mechanisms of neuronal death may occur. Susceptible cell populations in a
proapoptotic environment, particularly in AD, show increased vulnerability
towards metabolic or other noxious factors, with autophagy as a possible
protective mechanism in early stages of programmed cell death. The intracellular
cascade leading to cell death still awaits elucidation.
Iseki, E., M. Kato, et al. (2001). "A neuropathological study of the disturbance
of the nigro-amygdaloid connections in brains from patients with dementia with
Lewy bodies." J Neurol Sci185(2): 129-34.
We neuropathologically and immunohistochemically investigated characteristics of
the central amygdaloid nucleus lesion and its relationship with the substantia
nigra lesion in dementia with Lewy bodies (DLB) brains. Nine DLB, four
Parkinson's disease (PD) and four Alzheimer-type dementia (ATD) cases were
examined. The degree of neuronal loss in the substantia nigra was (+)-(+++) in
DLB cases, (+++) in PD cases and (+) in ATD cases. All DLB cases showed spongy
change and ubiquitin-positive spheroids in the central nucleus. The degree of
spongy change was (+)-(+++) in DLB cases, (+) in PD cases and (-)-(+) in ATD
cases, which was correlated with the degree of neuronal loss in the substantia
nigra in DLB cases. The number of ubiquitin-positive spheroids was parallel to
the degree of spongy change. The central nucleus receives dense dopaminergic
fibers from the substantia nigra. Many ubiquitin-positive spheroids were also
positive to alpha-synuclein and tyrosine-hydroxylase, suggesting that they
derive from the degeneration of terminal or distal axons of Lewy body-bearing
dopaminergic neurons in the substantia nigra. The disturbance of the
dopaminergic connections from the substantia nigra to the central nucleus may be
responsible for psychotic symptoms in DLB patients.
Imamura, T., K. Ishii, et al. (2001). "Occipital glucose metabolism in dementia
with lewy bodies with and without Parkinsonism: a study using positron emission
tomography." Dement Geriatr Cogn Disord12(3): 194-7.
Reduction of glucose metabolism in the occipital lobe is reported in dementia
with Lewy bodies (DLB) and Parkinson's disease. If dysfunction of the
nigrostriatal system is responsible for occipital hypometabolism, (1) DLB
patients with parkinsonism would show a lower occipital metabolism than do
patients without parkinsonism, and (2) DLB patients without parkinsonism would
show an occipital metabolism comparable to those of normal subjects and patients
with Alzheimer's disease (AD). To examine these hypotheses, we studied the
regional cerebral metabolic rate of glucose (rCMRglc) in patients with a
clinical diagnosis of DLB or AD, using (18)F-fluorodeoxyglucose and positron
emission tomography. The subjects consisted of 15 DLB patients with
parkinsonism, 7 DLB patients without parkinsonism and 7 AD patients without
parkinsonism. The medial and lateral occipital rCMRglc was significantly lower
in the DLB patients without parkinsonism than in the AD patients. There were no
significant differences in occipital metabolic rates between the DLB groups with
and without parkinsonism. DLB patients without parkinsonism showed a significant
reduction of occipital glucose metabolism which is comparable with that of DLB
patients with parkinsonism. The neurobiological bases of occipital
hypometabolism in DLB may be pathological processes in the brainstem or basal
forebrain structures other than the nigrostriatal system.
Hsu, Y. Y., A. T. Du, et al. (2001). "Magnetic resonance imaging and magnetic
resonance spectroscopy in dementias." J Geriatr Psychiatry Neurol14(3):
145-66.
This article reviews recent studies of magnetic resonance imaging and magnetic
resonance spectroscopy in dementia, including Alzheimer's disease,
frontotemporal dementia, dementia with Lewy bodies, idiopathic Parkinson's
disease, Huntington's disease, and vascular dementia. Magnetic resonance imaging
and magnetic resonance spectroscopy can detect structural alteration and
biochemical abnormalities in the brain of demented subjects and may help in the
differential diagnosis and early detection of affected individuals, monitoring
disease progression, and evaluation of therapeutic effect.
Hossain, S., A. Alim, et al. (2001). "Limited proteolysis of
NACP/alpha-synuclein." J Alzheimers Dis3(6): 577-584.
The NAC region of NACP/alpha-synuclein is a secondary component of Alzheimer's
disease amyloid. alpha-Synuclein is a major component of Lewy bodies, a typical
neuropathological feature of Parkinson's disease. However, the physiological
role and deposition mechanisms of alpha-synuclein are unknown. Structural
analyses of alpha-synuclein should provide a better understanding of its
biochemical characteristics. We investigated the digestion of alpha-synuclein
withalpha-chymotrypsin and cathepsin D, which are reported to be involved in
amyloidogenesis, under various conditions in vitro. There are many putative
cleavage sites for these enzymes in alpha-synuclein, including in the NAC
region. However, most of the predicted sites remained undigested, and the NAC
region was found to be intact even after extensive digestion. This peculiar
characteristic of alpha-synuclein may be relevant to the abnormal deposition of
this molecule in alpha-synuclein-associated neurodegenerative diseases.
Galvin, J. E., T. M. Schuck, et al. (2001). "Differential expression and
distribution of alpha-, beta-, and gamma-synuclein in the developing human
substantia nigra." Exp Neurol168(2): 347-55.
Although the functions of alpha-, beta-, and gamma-synuclein (alphaS, betaS,
gammaS, respectively) are unknown, these synaptic proteins are implicated in the
pathogenesis of Parkinson's disease (PD) and related disorders. For example,
alphaS forms Lewy bodies (LBs) in substantia nigra (SN) neurons of PD. However,
since it is not known how these hallmark PD lesions contribute to the
degeneration of SN neurons or what the normal function of alphaS is in SN
neurons, we studied the developing human SN from 11 weeks gestational age (GA)
to 16 years of age using immunohistochemistry and antibodies to alphaS, betaS,
gammaS, other synaptic proteins, and tyrosine hydoxylase (TH). SN neurons
expressed TH at 11 weeks GA and alphaS, betaS, and gammaS appeared initially at
15, 17, and 18 weeks GA, respectively. These synucleins first appeared in
perikarya of SN neurons after synaptophysin, but about the same time as
synaptotagmin and synaptobrevin. Redistribution of alphaS from perikarya to
processes of SN neurons occurred by 18 weeks GA in parallel with synaptophysin,
while betaS and synaptotagmin were redistributed similarly between 20 and 28
weeks GA and this also occurred with gammaS and synaptobrevin between 33 weeks
GA and 9 months postnatal. These data suggest that alphaS, betaS, and gammaS may
play a functional role in the development and maturation of SN neurons, but it
remains to be determined how sequestration of alphaS as LBs in PD contributes to
the degeneration of SN neurons.
Ferrer, I. (2001). "[Alpha-synucleinopathies]." Neurologia16(4):
163-70.
The term alpha-synucleinopathy is used to name a group of disorders having in
common the abnormal deposition of alpha-synuclein in the cytoplasm of neurons or
glial cells, as well as in extracellular deposits of amyloid. In Parkinson's
disease and Lewy body dementia, alpha-synuclein is the main component of Lewy
bodies and dystrophic neurites; alpha-synuclein also accumulates in the
cytoplasm of glial cells. In multiple system atrophy, alpha-synuclein conforms
the cytoplasmic oligodendroglial inclusions and the neuronal inclusions which
are the hallmark of this disease. Finally, the amyloidogenic fragment 61-95
amino acids of alpha-synuclein is the non-Abeta component of senile plaque
amyloid in Alzheimer disease. Accumulations of alpha-synuclein in all these
disorders have in common a fibrilar configuration, but they differ in the
binding of alpha-synuclein to distinct proteins with the exception of ubiquitin
whose binding to alpha-synuclein is common to all alpha-synuclein inclusions.
The mechanisms leading to alpha-synuclein fragmentation and aggegation into
extracellular amyloid are not known, although alpha-synuclein fragment and
betaA4 aggregates are the result of abnormal cleavage of large precursors. On
the other hand, several studies have shown that alpha-synuclein may adopt a
fibrilar conformation and give rise to insoluble forms and high molecular weight
aggregates in vitro. Similar complexes have also been observed in
alpha-synucleinopathies. Although studies in vitro and in vivo have shown toxic
effects of alpha-synuclein, the consequence of alpha-synuclein deposition on
cell survival in alpha-synucleinopathies is not known.
Ferrer, I., R. Blanco, et al. (2001). "Active, phosphorylation-dependent
mitogen-activated protein kinase (MAPK/ERK), stress-activated protein
kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 kinase expression in
Parkinson's disease and Dementia with Lewy bodies." J Neural Transm
108(12): 1383-96.
The expression of mitogen-activated protein kinases, extracellular
signal-regulated kinases (MAPK/ERK), stress-activated protein kinases, c-Jun
N-terminal kinases (SAPK/JNK), and p38 kinases is examined in Parkinson disease
(PD), in Dementia with Lewy bodies (DLB), covering common and pure forms, and in
age-matched controls. The study is geared to gaining understanding about the
involvement of these kinases in the pathogenesis of Lewy bodies (LBs) and
associated tau deposits in Alzheimer changes in the common form of DLB. Active,
phosphorylation dependent MAPK (MAPK-P) is found as granular cytoplasmic
inclusions in a subset of cortical neurons bearing abnormal tau deposits in
common forms of DLB. Phosphorylated p-38 (p-38-P) decorates neurons with
neurofibrillary tangles and dystrophic neurites of senile plaques in common
forms of DLB. Phosphorylated SAPK/JNK (SAPK/JNK-P) expression occurs in cortical
neurons with neurofibrillary tangles in the common form of DLB. Lewy bodies
(LBs) in the brain stem of PD and DLB are stained with anti-ERK-2 antibodies,
but they are not recognized by MAPK-P, SAPK/JNK-P and p-38-P. Yet MAPK-P, p-38-P
and SAPK/JNK-P immunoreactivity is found in cytoplasmic granules in the vicinity
of LBs or in association with irregular-shaped or diffuse alpha-synuclein
deposits in a small percentage of neurons, not containing phosphorylated tau, of
the brain stem in PD and DLB. MAPK-P, p-38-P and SAPK-P are not expressed in
cortical LBs or in cortical neurons with alpha-synuclein-only inclusions in DLB.
MAPK-P, p-38-P and SAPK/JNK-P are not expressed in alpha-synuclein-positive
neurites (Lewy neurites) in PD and DLB as revealed by double-labeling
immunohistochemistry. These results show that MAPKs are differentially regulated
in neurons with alpha-synuclein-related inclusions and in neurons with abnormal
tau deposits in DLB. Moreover, different kinase expression in brain stem and
cortical LBs suggest a pathogenesis of brain stem and cortical LBs in LB
diseases. Finally, no relationship has been observed between MAPK-P, p-38-P and
SAPK/JNK-P expression and increased nuclear DNA vulnerability, as revealed with
the method of in situ end-labeling of nuclear DNA fragmentation, and active,
cleaved caspase-3 expression in neurons and glial cells in the substantia nigra
in PD and DLB.
Ebadi, M., P. Govitrapong, et al. (2001). "Ubiquinone (coenzyme q10) and
mitochondria in oxidative stress of parkinson's disease." Biol Signals Recept10(3-4): 224-53.
Parkinson's disease is the second most common neurodegenerative disorder after
Alzheimer's disease affecting approximately1% of the population older than 50
years. There is a worldwide increase in disease prevalence due to the increasing
age of human populations. A definitive neuropathological diagnosis of
Parkinson's disease requires loss of dopaminergic neurons in the substantia
nigra and related brain stem nuclei, and the presence of Lewy bodies in
remaining nerve cells. The contribution of genetic factors to the pathogenesis
of Parkinson's disease is increasingly being recognized. A point mutation which
is sufficient to cause a rare autosomal dominant form of the disorder has been
recently identified in the alpha-synuclein gene on chromosome 4 in the much more
common sporadic, or 'idiopathic' form of Parkinson's disease, and a defect of
complex I of the mitochondrial respiratory chain was confirmed at the
biochemical level. Disease specificity of this defect has been demonstrated for
the parkinsonian substantia nigra. These findings and the observation that the
neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), which causes a
Parkinson-like syndrome in humans, acts via inhibition of complex I have
triggered research interest in the mitochondrial genetics of Parkinson's
disease. Oxidative phosphorylation consists of five protein-lipid enzyme
complexes located in the mitochondrial inner membrane that contain flavins (FMN,
FAD), quinoid compounds (coenzyme Q10, CoQ10) and transition metal compounds
(iron-sulfur clusters, hemes, protein-bound copper). These enzymes are
designated complex I (NADH:ubiquinone oxidoreductase, EC 1.6. 5.3), complex II
(succinate:ubiquinone oxidoreductase, EC 1.3.5.1), complex III
(ubiquinol:ferrocytochrome c oxidoreductase, EC 1.10.2.2), complex IV
(ferrocytochrome c:oxygen oxidoreductase or cytochrome c oxidase, EC 1.9.3.1),
and complex V (ATP synthase, EC 3.6.1.34). A defect in mitochondrial oxidative
phosphorylation, in terms of a reduction in the activity of NADH CoQ reductase
(complex I) has been reported in the striatum of patients with Parkinson's
disease. The reduction in the activity of complex I is found in the substantia
nigra, but not in other areas of the brain, such as globus pallidus or cerebral
cortex. Therefore, the specificity of mitochondrial impairment may play a role
in the degeneration of nigrostriatal dopaminergic neurons. This view is
supported by the fact that MPTP generating 1-methyl-4-phenylpyridine (MPP(+))
destroys dopaminergic neurons in the substantia nigra. Although the serum levels
of CoQ10 is normal in patients with Parkinson's disease, CoQ10 is able to
attenuate the MPTP-induced loss of striatal dopaminergic neurons.
Boeve, B. F., M. H. Silber, et al. (2001). "Association of REM sleep behavior
disorder and neurodegenerative disease may reflect an underlying
synucleinopathy." Mov Disord16(4): 622-30.
Our objective was to examine whether rapid eye movement (REM) sleep behavior
disorder occurs in disproportionally greater frequency in multiple system
atrophy (MSA), Parkinson's disease (PD), and dementia with Lewy bodies (DLB),
collectively known as the synucleinopathies, compared to other
nonsynucleinopathy neurodegenerative disorders. In study 1, we reviewed the
clinical records of 398 consecutive patients evaluated at Mayo Clinic Rochester
for parkinsonism and/or cognitive impairment. The frequency of suspected and
polysomnogram (PSG)-confirmed REM sleep behavior disorder (RBD) among subjects
with the synucleinopathies MSA, PD, or DLB was compared to the frequency among
subjects with the nonsynucleinopathies Alzheimer's disease (AD), frontotemporal
dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy
(PSP), mild cognitive impairment (MCI), primary progressive aphasia (PPA), and
posterior cortical atrophy (PCA). In study 2, we reviewed the clinical records
of 360 consecutive patients evaluated at Mayo Clinic Jacksonville for
parkinsonism and/or cognitive impairment. The frequency of probable RBD among
patients with PD and DLB was compared to the frequency among patients with AD
and MCI. In study 3, we reviewed the brain biopsy or postmortem autopsy
diagnoses of 23 Mayo Clinic Rochester patients who had been clinically examined
for possible RBD and a neurodegenerative disorder. In study 1, patients with
MSA, PD, or DLB were more likely to have probable and PSG-confirmed RBD compared
to subjects with the nonsynucleinopathies (probable RBD 77/120=64% vs. 7/278=3%,
p < 0.01; PSG-confirmed RBD 47/120=39% vs. 1/278=0%, p < 0.01). In study 2,
patients with PD and DLB were more likely to have probable RBD compared to those
with AD and MCI (56% vs. 2%, p < 0.01). In study 3, of the 23 autopsied patients
who had been questioned about possible RBD, 10 were clinically diagnosed with
RBD. The neuropathologic diagnoses in these 10 included Lewy body disease in
nine, and MSA in one. Of the other 13 cases, 12 did not have a history
suggesting RBD, and the one case who did had normal electromyographic atonia
during REM sleep on PSG and autopsy findings of PSP. Only one of these 13 had a
synucleinopathy. The positive predictive values for RBD indicating a
synucleinopathy for studies 1-3 were 91.7%, 94.3%, and 100.0%, respectively.
Clinically suspected and PSG-proven RBD occurs with disproportionally greater
frequency in MSA, PD, and DLB compared to other neurodegenerative disorders. In
the setting of degenerative dementia and/or parkinsonism, we hypothesize that
RBD is a manifestation of an evolving synucleinopathy.
Barbieri, S., K. Hofele, et al. (2001). "Mouse models of alpha-synucleinopathy
and Lewy pathology. Alpha-synuclein expression in transgenic mice." Adv Exp
Med Biol487: 147-67.
Arai, Y., M. Yamazaki, et al. (2001). "Alpha-synuclein-positive structures in
cases with sporadic Alzheimer's disease: morphology and its relationship to tau
aggregation." Brain Res888(2): 287-296.
Alzheimer's disease (AD) and Parkinson's disease share common clinical and
pathological features. In this study, we examined the relationship between AD
pathology and alpha-synuclein aggregation. The frequency and distribution of
alpha-synuclein-positive structures were systematically investigated in 27 cases
with sporadic AD by alpha-synuclein immuno-histochemistry. Thirteen (48.2%) of
27 cases had various alpha-synuclein-positive structures as well as Lewy bodies.
The frequency and density of senile plaques and neurofibrillary tangles were not
significantly different between cases with alpha-synuclein structures and those
without. alpha-Synuclein-positive structures were found most frequently in the
amygdala. The alpha-synuclein-positive inclusions that are different from Lewy
bodies were observed at the highest rate in the hippocampus. The discovery of
alpha-synuclein as the constituent of Lewy bodies facilitated the detection of
Lewy-related structures even in AD cases with widespread and numerous
neurofibrillary tangles. alpha-Synuclein-positive inclusions except for Lewy
bodies are exposed, and the distribution of them indicates that Lewy body
formation may be influenced by the degree of tau aggregation. This study also
supports the suggestion that cases with AD pathology can be classified into two
groups according to the existence or absence of alpha-synuclein aggregation.
Wakabayashi, K., S. Hayashi, et al. (2000). "NACP/alpha-synuclein-positive
filamentous inclusions in astrocytes and oligodendrocytes of Parkinson's disease
brains." Acta Neuropathol (Berl)99(1): 14-20.
The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP),
also called alpha-synuclein, is a major component of Lewy bodies in Parkinson's
disease (PD) as well as of neuronal and oligodendroglial cytoplasmic inclusions
in multiple system atrophy. We previously reported argyrophilic, tau-negative
glial inclusions in the midbrains of patients with PD and have now conducted
immunocytochemical and ultrastructural examinations. The PD glial inclusions
also are immunoreactive for NACP/alpha-synuclein, but not for beta-synuclein,
and ultrastructurally are composed of filamentous structures about 25-40 nm in
diameter. Double immunolabeling showed that the inclusions were present in both
astrocytic and oligodendroglial cells. They were located within the substantia
nigra in 13 of 30 patients with PD and outside the nigra in 24. The number of
inclusions was correlated with the severity of nigral neuronal loss. These
findings indicate that abnormal accumulation of NACP/alpha-synuclein in glial
cells is a pathological feature of PD related to its progression.
Waite, L. M., G. A. Broe, et al. (2000). "Motor function and disability in the
dementias." Int J Geriatr Psychiatry15(10): 897-903.
Epidemiological and neuropathological series have identified three predominant
dementing processes; Alzheimer's disease (AD), vascular dementia (VaD) and
dementia associated with Lewy bodies (termed Parkinson's disease dementia (PDD)
in this paper). While each has its own distinguishing features and by definition
all impact upon day to day functioning, no random community derived sample has
examined clinical features as defined by gait and balance abnormalities and
compared disability ratings of the three dementias simultaneously. Six hundred
and forty-seven community dwelling subjects participated in the Sydney Older
Persons Study and of these 537 participated in a medical assessment. Of these
537,482 informants rated disability. Gait and balance abnormalities of the three
major dementias were identified and the association of the dementias with
disability examined. The three major dementias showed evidence of both slowing
and ataxia in gait and balance tests. This was maximal in those with PDD.
Similarly, all showed evidence of disability that was maximal in those with PDD.
In conclusion, this study has identified that gait abnormalities are present in
all three dementias to a varying degree. It is hypothesised that the varying
levels of disability observed are a consequence of the varying levels of motor
impairment, resulting in greater levels of disability in those with PDD.
van der Putten, H., K. H. Wiederhold, et al. (2000). "Neuropathology in mice
expressing human alpha-synuclein." J Neurosci20(16): 6021-9.
The presynaptic protein alpha-synuclein is a prime suspect for contributing to
Lewy pathology and clinical aspects of diseases, including Parkinson's disease,
dementia with Lewy bodies, and a Lewy body variant of Alzheimer's disease.
alpha-Synuclein accumulates in Lewy bodies and Lewy neurites, and two missense
mutations (A53T and A30P) in the alpha-synuclein gene are genetically linked to
rare familial forms of Parkinson's disease. Under control of mouse Thy1
regulatory sequences, expression of A53T mutant human alpha-synuclein in the
nervous system of transgenic mice generated animals with neuronal
alpha-synucleinopathy, features strikingly similar to those observed in human
brains with Lewy pathology, neuronal degeneration, and motor defects, despite a
lack of transgene expression in dopaminergic neurons of the substantia nigra
pars compacta. Neurons in brainstem and motor neurons appeared particularly
vulnerable. Motor neuron pathology included axonal damage and denervation of
neuromuscular junctions in several muscles examined, suggesting that
alpha-synuclein interfered with a universal mechanism of synapse maintenance.
Thy1 transgene expression of wild-type human alpha-synuclein resulted in similar
pathological changes, thus supporting a central role for mutant and wild-type
alpha-synuclein in familial and idiotypic forms of diseases with neuronal
alpha-synucleinopathy and Lewy pathology. These mouse models provide a means to
address fundamental aspects of alpha-synucleinopathy and test therapeutic
strategies.
Tiraboschi, P., L. A. Hansen, et al. (2000). "Cholinergic dysfunction in
diseases with Lewy bodies." Neurology54(2): 407-11.
OBJECTIVE: To evaluate cholinergic activity in diseases with Lewy bodies (LB; LB
variant of AD [LBV], diffuse LB disease [DLBD], and Parkinson's disease [PD]) to
determine if 1) AD changes are requisite to cholinergic dysfunction, 2)
cholinergic activity declines to the same extent in neocortical and
archicortical areas, and 3) cholinergic loss is influenced by APOE genotype.
BACKGROUND: Like AD, diseases with LB are associated with decreased choline
acetyltransferase (ChAT) activity. Increased APOE epsilon4 allele frequency has
been reported in LBV. Whether APOE genotype affects cholinergic function in LBV
remains unclear. METHODS: An autopsy series of 182 AD (National Institute on
Aging and Consortium to Establish a Registry for Alzheimer's Disease criteria),
49 LBV, 11 PD, 6 DLBD, and 16 normal control (NC) subjects. APOE genotype and
ChAT activity (nmol/h/100 mg) in the midfrontal and hippocampal cortices were
determined. RESULTS: Mean midfrontal ChAT activity was markedly reduced in
diseases with LB (LBV: 53.3 +/- 39.0; PD: 54.8 +/- 35.7; DLBD: 41.3 +/- 24.8)
compared to NC (255.4 +/- 134.6; p < 0.001) and AD (122.6 +/- 78.9; p < 0.05).
Among diseases with LB, midfrontal ChAT activity was decreased to a similar
extent in patients with (LBV) and without (DLBD and PD) AD pathology. Although
mean ChAT activity for LBV was less than half that for AD in the midfrontal
cortex, it was similar to that for AD in the hippocampus (LBV: 243.5 +/- 189.7;
AD: 322.8 +/- 265.6; p > 0.05). However, hippocampal ChAT activity for both AD
and LBV was lower than that for NC (666.5 +/- 360.3; p < 0.001). The epsilon4
allele dosage did not influence midfrontal ChAT activity in LBV. CONCLUSION:
Marked losses in midfrontal ChAT activity occur in diseases with LB, independent
of coexistent AD changes. A greater midfrontal, as opposed to hippocampal,
cholinergic deficit may differentiate LBV from AD. The lack of a relationship
between epsilon4 allele dosage and midfrontal ChAT activity suggests that other
factors may play a role in its decline in LBV.
Terry, R. D. (2000). "Do neuronal inclusions kill the cell?" J Neural Transm
Suppl59: 91-3.
Neurofibrillary tangles, Pick bodies and Lewy bodies are considered
quantitatively in relation to neuron loss. It would seem that the inclusions are
not themselves the cause of neuron death.
Spillantini, M. G. and M. Goedert (2000). "The alpha-synucleinopathies:
Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy."
Ann N Y Acad Sci920: 16-27.
Parkinson's disease is the second most common neurodegenerative disease, after
Alzheimer's disease. Neuropathologically, it is characterized by the
degeneration of populations of nerve cells that develop filamentous inclusions
in the form of Lewy bodies and Lewy neurites. Recent work has shown that the
filamentous inclusions of Parkinson's disease are made of the protein
alpha-synuclein and that rare, familial forms of Parkinson's disease are caused
by missense mutations in the alpha-synuclein gene. Besides Parkinson's disease,
the filamentous inclusions of two additional neurodegenerative diseases, namely,
dementia with Lewy bodies and multiple system atrophy, have also been found to
be made of alpha-synuclein. Recombinant alpha-synuclein has been shown to
assemble into filaments with similar morphologies to those found in the human
diseases and with a cross-beta fiber diffraction pattern. The new work has
established the alpha-synucleinopathies as a major class of neurodegenerative
disease.
Sommer, B., S. Barbieri, et al. (2000). "Mouse models of alpha-synucleinopathy
and Lewy pathology." Exp Gerontol35(9-10): 1389-403.
The discovery of two missense mutations (A53T and A30P) in the gene encoding the
presynaptic protein alpha-synuclein (alphaSN) that are genetically linked to
rare familial forms of Parkinson's disease and its accumulation in Lewy bodies
and Lewy neurites has triggered several attempts to generate transgenic mice
overexpressing human alphaSN. Analogous to a successful strategy for the
production of transgenic animal models for Alzheimer's disease we generated mice
expressing wildtype and the A53T mutant of human alphaSN in the nervous system
under control of mouse Thy1 regulatory sequences. These animals develop neuronal
alpha-synucleinopathy, striking features of Lewy pathology, neuronal
degeneration and motor defects. Neurons in brainstem and motor neurons appeared
particularly vulnerable. Motor neuron pathology included axonal damage and
denervation of neuromuscular junctions, suggesting that alphaSN may interfere
with a universal mechanism of synapse maintenance. Thy1-transgene expression of
wildtype human alphaSN resulted in comparable pathological changes thus
supporting a central role for mutant and wildtype alphaSN in familial and
idiopathic forms of diseases with neuronal alpha-synucleinopathy and Lewy
pathology. The mouse models provide means to address fundamental aspects of
alpha-synucleinopathy and to test therapeutic strategies.
Simard, M., R. van Reekum, et al. (2000). "A review of the cognitive and
behavioral symptoms in dementia with Lewy bodies." J Neuropsychiatry Clin
Neurosci12(4): 425-50.
Dementia with Lewy bodies is a relatively common cause of dementia. Much has
been learned about this disorder, yet much remains to be elucidated, especially
in regard to early clinical diagnosis. To clarify the future research agenda in
this area, the authors critically appraise the literature on cognitive and
behavioral changes in DLB and provide a brief overview of the history of DLB,
the main pathological changes, and the findings related to extrapyramidal
symptoms and treatment issues. Twenty-one studies on cognition and 47 on
behavioral changes in DLB are reviewed. Impairments of working memory and
visuospatial functions, visual hallucinations, and depression (or symptoms of
depression such as apathy and anxiety) have been identified as early indicators
of DLB. However, longitudinal and cross-sectional data are lacking, particularly
for different aspects of working memory, visual perception, and non-psychotic
behavioral symptoms.
Shoji, M., Y. Harigaya, et al. (2000). "Accumulation of NACP/alpha-synuclein in
lewy body disease and multiple system atrophy." J Neurol Neurosurg Psychiatry68(5): 605-8.
OBJECTIVES: NACP/alpha-synuclein is an aetiological gene product in familial
Parkinson's disease. To clarify the pathological role of NACP/alpha-synuclein in
sporadic Parkinson's disease and other related disorders including diffuse Lewy
body disease (DLBD) and multiple system atrophy (MSA), paraffin sections were
examined immunocytochemically using anti-NACP/alpha-synuclein antibodies.
METHODS: A total of 58 necropsied brains, from seven patients with Parkinson's
disease, five with DLBD, six with MSA, 12 with Alzheimer's disease, one with
Down's syndrome, one with amyotrophic lateral sclerosis (ALS), three with ALS
and dementia, one with Huntington's disease, two with progressive supranuclear
palsy (PSP), one with Pick's disease, one with myotonic dystrophy, and three
with late cerebellar cortical atrophy (LCCA), and 15 elderly normal controls
were examined. RESULTS: In addition to immunoreactive Lewy bodies, widespread
accumulation of NACP/alpha-synuclein was found in neurons and astrocytes from
the brainstem and basal ganglia to the cerebral cortices in Parkinson's
disease/DLBD. NACP/alpha-synuclein accumulates in oligodendrocytes from the
spinal cord, the brain stem to the cerebellar white matter, and inferior olivary
neurons in MSA. These widespread accumulations were not seen in other types of
dementia or spinocerebellar ataxia. CONCLUSION: Completely different types of
NACP/alpha-synuclein accumulation in Parkinson's disease/DLBD and MSA suggest
that accumulation is a major step in the pathological cascade of both diseases
and provides novel strategies for the development of therapies.
Shimura, H., N. Hattori, et al. (2000). "Familial Parkinson disease gene
product, parkin, is a ubiquitin-protein ligase." Nat Genet25(3):
302-5.
Autosomal recessive juvenile parkinsonism (AR-JP), one of the most common
familial forms of Parkinson disease, is characterized by selective dopaminergic
neural cell death and the absence of the Lewy body, a cytoplasmic inclusion body
consisting of aggregates of abnormally accumulated proteins. We previously
cloned PARK2, mutations of which cause AR-JP (ref. 2), but the function of the
gene product, parkin, remains unknown. We report here that parkin is involved in
protein degradation as a ubiquitin-protein ligase collaborating with the
ubiquitin-conjugating enzyme UbcH7, and that mutant parkins from AR-JP patients
show loss of the ubiquitin-protein ligase activity. Our findings indicate that
accumulation of proteins that have yet to be identified causes a selective
neural cell death without formation of Lewy bodies. Our findings should enhance
the exploration of the molecular mechanisms of neurodegeneration in Parkinson
disease as well as in other neurodegenerative diseases that are characterized by
involvement of abnormal protein ubiquitination, including Alzheimer disease,
other tauopathies, CAG triplet repeat disorders and amyotrophic lateral
sclerosis.
Schwab, C., A. J. DeMaggio, et al. (2000). "Casein kinase 1 delta is associated
with pathological accumulation of tau in several neurodegenerative diseases."
Neurobiol Aging21(4): 503-10.
The distribution of casein kinase 1 delta (Cki delta) was studied by
immunohistochemistry and correlated with other pathological hallmarks in
Alzheimer's disease (AD), Down syndrome (DS), progressive supranuclear palsy
(PSP), parkinsonism dementia complex of Guam (PDC), Pick's disease (PiD),
pallido-ponto-nigral degeneration (PPND), Parkinson's disease (PD), dementia
with Lewy bodies (DLB), amyotrophic lateral sclerosis (ALS), and elderly
controls. Cki delta was found to be associated generally with granulovacuolar
bodies and tau-containing neurofibrillary tangles in AD, DS, PSP, PDC, PPND, and
controls, and Pick bodies and ballooned neurons in PiD. It was not associated
with tau-containing inclusions in astroglia and oligodendroglia in PPND, PSP,
and PDC. It was also not associated with tau-negative Lewy bodies in PD and DLB,
Hirano bodies in PDC, Marinesco bodies in PD, AD, and controls and "skein"-like
inclusions in anterior motor neurons in ALS. The colocalization of the kinase
Cki delta and its apparent substrate tau suggests a function for Cki delta in
the abnormal processing of tau.
Schipper, H. M. (2000). "Heme oxygenase-1: role in brain aging and
neurodegeneration." Exp Gerontol35(6-7): 821-30.
The mechanisms responsible for excessive iron deposition and mitochondrial
insufficiency in the aging and degenerating nervous system remain poorly
understood. Heme oxygenase-1 (HO-1) is a 32kDa stress protein that degrades heme
to biliverdin, free iron and carbon monoxide. Our laboratory has shown that
cysteamine, dopamine, beta-amyloid, IL-1beta and TNF-alpha up-regulate HO-1
followed by mitochondrial sequestration of non-transferrin-derived 55Fe in
cultured rat astroglia. In these cells and in rat astroglia transfected with the
human HO-1 gene, mitochondrial iron trapping is abrogated by the HO-1
inhibitors, tin-mesoporphyrin and dexamethasone. We determined that HO-1
immunoreactivity is enhanced greatly in neurons and astrocytes of the
hippocampus and cerebral cortex of Alzheimer subjects and co-localizes to senile
plaques and neurofibrillary tangles (NFT). HO-1 staining is also augmented in
astrocytes and decorates neuronal Lewy bodies in the Parkinson nigra.
Collectively, our findings suggest that HO-1 over-expression contributes to the
pathological iron deposition and mitochondrial damage documented in these
aging-related neurodegenerative disorders. We recently observed that,
paradoxically, HO-1 mRNA levels are markedly suppressed in peripheral
lymphocytes of patients with early sporadic Alzheimer disease and may thus
provide a useful biological marker of this condition.
Rozemuller, A. J., P. Eikelenboom, et al. (2000). "Activated microglial cells
and complement factors are unrelated to cortical Lewy bodies." Acta
Neuropathol (Berl)100(6): 701-8.
Inflammatory mechanisms have been demonstrated in Alzheimer's disease (AD) but
their presence in other neurodegenerative disorders is not well documented.
Complement factors and activated microglia have been reported in the substantia
nigra of Parkinson's disease (PD). In the present study we investigated the
cingulate gyrus of 25 autopsied patients with clinically and neuropathologically
well-documented PD, with or without dementia, for the presence of (activated)
microglial cells and their relation with Lewy body (LB)-bearing neurons. In
addition, we studied the presence of complement factors in LBs. Of the 25
patient, 15 were clinically demented, fulfilling criteria for dementia with LBs
(DLB); 7 also fulfilled CERAD morphological criteria for probable or definite
Alzheimer type of dementia. Microglia clustering was seen around congophilic
plaques with or without tau pathology. Microglial cells were not associated with
LB-bearing neurons or noncongophilic plaques. The cortex of DLB patients without
AD plaques did not show more microglial cells than the cortex of non-demented
controls. The number of microglia was the lowest in young control patients who
died immediately after trauma. Complement factor C3d was occasionally seen in
diffusely ubiquinated neurons but late complement factors were not detected in
these neurons. Double staining for complement and alpha-synuclein was negative,
suggesting the absence of complement in LBs. In contrast, AD plaques in the same
sections showed complement factors C3c, C3d, C1q and C5-9. In conclusion, we
have found no evidence that inflammatory mechanism are involved in LB formation
in cerebral cortex.
Ransmayr, G., G. K. Wenning, et al. (2000). "[Dementia with Lewy bodies]."
Nervenarzt71(12): 929-35.
Dementia with Lewy bodies (DLB) is the second most frequent neuropathologically
diagnosed degenerative dementing illness. The clinical characteristics are
progressive dementia, parkinsonian syndrome, fluctuations of cognitive
functions, alertness, and attention, visual hallucinations (usually detailed and
well described), depression, REM sleep behavior disorder, adverse responses to
standard neuroleptics doses, falls, syncopes, systematized delusions, and other
modalities of hallucinations. Specificity of the clinical diagnostic criteria is
high (95%), and sensitivity is considerably lower. Mean age at disease onset
ranges between 60 and 68 years. The male gender prevails. Disease duration is 6
to 8 years. The differential diagnoses of DLB are dementia of the Alzheimer
type, Parkinson's disease, subcortical arteriosclerotic encephalopathy,
progressive supranuclear palsy, multiple system atrophy, and rarely
Creutzfeldt-Jakob disease. The genetic background of the disease is unclear.
Magnetic resonance imaging and single photon emission tomography can contribute
to the diagnosis. Controlled pharmacological studies have so far not been
published. The disease is treated with L-dopa, atypical neuroleptics,
acetylcholine esterase inhibitors, antihypotensive agents, and peripheral
anticholinergic and alpha receptor-blocking medications to improve neurogenic
bladder dysfunction.
Ransmayr, G. (2000). "Dementia with Lewy bodies: prevalence, clinical spectrum
and natural history." J Neural Transm Suppl(60): 303-14.
The article summarises history, terminology, the clinical and neuropathological
diagnostic criteria, neurochemical and genetic findings, sensitivity and
specificity of the clinical diagnostic criteria, prevalence, demographical data
and nosology, differential diagnosis, and therapy of dementia with Lewy bodies
(DLB). DLB shares clinical symptoms of Parkinson's disease and dementia of the
Alzheimer-type (DAT). However, DLB is also different to PD and DAT (less tremor
and asymmetry of the motor symptoms, more falls, and less favourable response to
L-Dopa than PD; in contrast to DAT marked cognitive fluctuations and phases of
reduced alertness, hallucinations and delirium). There are genetic similarities
to DAT and PD in terms of common genetic risk factors. A genetic cause of the
disease has so far not been detected. Whether or not DLB is a disease entity or
an association of diseases (Lewy body disease and DAT) has so far not been
elucidated. Clinical distinction from DAT and PD has clinical importance because
of different therapeutic and prognostic implications. Studies are needed to
standardize the treatment of motor, cognitive, psychiatric and vegetative
symptoms.
Paik, S. R., H. J. Shin, et al. (2000). "Metal-catalyzed oxidation of
alpha-synuclein in the presence of Copper(II) and hydrogen peroxide." Arch
Biochem Biophys378(2): 269-77.
alpha-Synuclein is a component of abnormal protein depositions of Lewy bodies
and senile plaques found in Parkinson's and Alzheimer's diseases, respectively.
By using chemical coupling reagents such as dicyclohexylcarbodiimide or
N-(ethoxycarbonyl)-2-ethoxy-1, 2-dihydroquinoline, the protein was shown to
experience self-oligomerization in the presence of either copper(II) or
Abeta25-35. The oligomers which appeared as a ladder on a 10-20%
Tricine/SDS-PAGE have been suggested to participate in the formation of protein
aggregations by possibly providing a nucleation center. Since oxidatively
modified protein could increase its own tendency toward protein aggregation,
metal-catalyzed oxidation of alpha-synuclein has been examined with copper(II)
and hydrogen peroxide in the absence of the coupling reagent. Intriguingly, the
protein was also self-oligomerized into an SDS-resistant ladder on the gel. This
biochemically specific copper-mediated oxidative oligomerization was shown to be
dependent upon the acidic C-terminus of alpha-synuclein because the C-terminally
truncated proteins such as alpha-syn114 and alpha-syn97 were not affected by the
metal and hydrogen peroxide. More importantly, the oxidative oligomerization was
synergistically enhanced by the presence of Abeta25-35, indicating that the
peptide interaction with alpha-synuclein facilitated the copper(II) binding to
the acidic C-terminus and subsequent oxidative crosslinking. It has been,
therefore, suggested that abnormalities in copper and H(2)O(2) homeostasis and
certain pathological factors functionally similar to the Abeta25-35 could play
critical roles in the metal-catalyzed oxidative oligomerization of
alpha-synuclein, which may lead to possible protein aggregation and
neurodegenerations.
Ogawa, K., T. Yamada, et al. (2000). "Localization of a novel type trypsin-like
serine protease, neurosin, in brain tissues of Alzheimer's disease and
Parkinson's disease." Psychiatry Clin Neurosci54(4): 419-26.
Neurosin, a novel type of trypsin-like serine protease, has been shown to be
preferentially expressed in human brain by northern blotting. We examined
neurosin immunolabeling in the brains of neurologically normal persons and
patients with Alzheimer's disease (AD) and with Parkinson's disease. We also
identified the expression of the mRNA for neurosin by in situ hybridization
histochemistry and reverse transcription-polymerase chain reaction (RT-PCR). The
neurosin antibody stained all of the nuclei of various cell types. In neurons,
there was also staining of neuronal cytoplasm, nucleoli and their processes. In
AD, staining of neurons with processes was rare in the damaged areas. Some
senile plaques, extracellular tangles and Lewy bodies were also positive for
neurosin. Expression of the mRNA for neurosin was seen in neurons in the gray
matter, and in microglial cells in the white matter. In AD, the intensity of the
signal for neurosin mRNA in the gray matter was decreased compared with normal
control brains. The relative levels of neurosin mRNA in AD brains, measured by
RT-PCR, were lower than those in controls. These results suggest that in human
brain neurosin plays various physiological roles, and that in AD this molecule,
like other serine proteases, may have a role in the degradation of such
substances as beta-amyloid protein.
Nores, J. M., B. Biacabe, et al. (2000). "[Olfactory disorders in Alzheimer's
disease and in Parkinson's disease. Review of the literature]." Ann Med
Interne (Paris)151(2): 97-106.
Olfactory disorders in Alzheimer's disease and Parkinson's disease have been the
topic of a large body of work over the last decades. Work devoted to olfactory
disorders in Alzheimer's disease includes over 300 papers providing clinical and
fundamental data. Anatomy studies in Alzheimer's disease have demonstrated a
specific concentration of lesions in peripheral and central olfactory structures
(senile plaques, neurofibrillary degeneration) as well as lesions in layers II
and III of the entorhinal cortex. These neuropathological findings led to the
development of the hypothesis that olfactory disorders in Alzheimer's disease
would result from a toxic process. Observed olfactory deficits involve both
identification and recognition of odors and detection thresholds. Nevertheless,
patients with Alzheimer's disease rarely consult for sensorial deficits as the
other signs of the disease predominate. Neuropathology data on the olfactory
system are much more sparse in Parkinson's disease. Lewy bodies suggestive of
Parkinson's disease have been observed in the olfactory bulb and pathways, but,
unlike Alzheimer's disease, the olfactory disorders appear to be stable,
changing little over time, as opposed to the evolution of neurological symptoms
and cognition impairment. Clinicians should be aware that olfactory disorders
are an integral part of Alzheimer's disease and Parkinson's disease. Screening
for sensorial impairment however is a secondary objective in the context of
these neurodegenerative diseases.
Mukaetova-Ladinska, E. B., J. Hurt, et al. (2000). "Alpha-synuclein inclusions
in Alzheimer and Lewy body diseases." J Neuropathol Exp Neurol59(5):
408-17.
Alpha-synuclein has assumed particular neuropathological interest in the light
both of its identification as a non-beta-amyloid plaque constituent in Alzheimer
disease (AD), and the recent association between dominant inheritance of
Parkinson disease (PD) and 2 missense mutations at positions 30 and 53 of the
synuclein protein. We report a systematic study of alpha-synuclein, tau, and
ubiquitin immunoreactivity in representative neurodegenerative disorders of late
life. The alpha-synuclein association with Lewy bodies is variable, peripheral,
and is not stable with respect to proteases or acid treatment, whereas there is
no association with Pick bodies. Stable patterns of immunoreactivity included
neurites and a novel inclusion body. Although there is an overlap between the
presence of Lewy bodies and stable alpha-synuclein immunoreactivity, this is
seen only in the presence of concomitant neuropathological features of AD. The
novel alpha-synuclein inclusion body identified in pyramidal cells of the medial
temporal lobe in particular was found in AD and in the Lewy body variant of AD,
and was associated neither with ubiquitin nor tau protein. The inclusion is
therefore neither a Lewy body nor a PHF-core body, but may be confused with the
Lewy body, particularly in the Lewy body variant of AD. Abnormal processing of
alpha-synuclein leading to its deposition in the form of proteolytically stable
deposits is a particular feature of the intermediate stages of AD.
Mori, E. (2000). "[Dementia with Lewy bodies]." Nippon Ronen Igakkai Zasshi37(10): 772-6.
Dementia with Lewy bodies (DLB), the second most frequent cause of primary
degenerative dementias following Alzheimer's disease, has been increasingly
recognized since the proposal of the consensus name and clinical diagnostic
criteria. Although DLB overlaps in clinical, pathological, and genetic features
with Alzheimer's disease and Parkinson's disease, DLB should be understood as an
entity with the essential feature of the presence of Lewy bodies in the brain
stem and cerebral cortex. From the clinical point of view, DLB is characterized
by the presence of progressive dementia without severe memory disorders at the
early stage, with significant cognitive fluctuations, well-formed recurrent
visual hallucinations, and spontaneous Parkinsonism. This article reviews recent
clinical and research findings, including our own, to facilitate clinical
recognition of DLB. In addition to the supportive features described in the
consortium clinical diagnostic criteria for DLB such as falls and great
sensitivity to neuroleptic drugs, our studies found other frequent disorders
including disproportionately severe visuoconstructive and visuoperceptual
disturbances, transitory alterations in consciousness with reduplication
phenomena, misidentification delusions, and non-aphasic misnamings. Neuroimaging
features include relatively preserved hippocampal volume on MRI and occipital
involvement on metabolic and blood flow imagings. The correct diagnosis of DLB
is important to administer adequate treatment, to avoid adverse effects with
neuroleptic drugs, and to establish precise prognosis. The present summary of
the clinical features is hopefully helpful for clinical diagnosis of DLB. From a
therapeutic point of view, cholinesterase inhibitors seemingly show some
efficacy in the treatment of cognitive alterations. Further research would
result in advances in diagnostic methods and therapeutic approaches in the near
future.
McLean, P. J., H. Kawamata, et al. (2000). "Membrane association and protein
conformation of alpha-synuclein in intact neurons. Effect of Parkinson's
disease-linked mutations." J Biol Chem275(12): 8812-6.
Two missense mutations (Ala-30 --> Pro and Ala-53 --> Thr) in the gene encoding
alpha-synuclein are associated with rare autosomal dominant forms of familial
Parkinson's disease. In addition, alpha-synuclein is an abundant component of
Lewy bodies in sporadic Parkinson's disease and diffuse Lewy body disease.
However, the normal conformation of alpha-synuclein, its cellular localization
in neurons, and the effects of the mutations remain to be determined. In the
present study, we examine these questions using sensitive fluorescence resonance
energy transfer techniques. Transient transfection of alpha-synuclein expression
constructs into primary cortical neurons and counterstaining with the lipophilic
fluorescent marker, DiI, demonstrates a close association between
alpha-synuclein and cellular membranes. Both the N- and C-terminal regions of
alpha-synuclein are tightly associated with membranes. A weak interaction also
occurs between the N and C termini themselves. The Parkinson's
disease-associated mutations have no effect on membrane interaction; however,
the Ala-30 --> Pro mutation alters the three-dimensional conformation of
alpha-synuclein, as measured by significantly increased fluorescence resonance
energy transfer between the N and C termini.
McLean, P. J., S. Ribich, et al. (2000). "Subcellular localization of
alpha-synuclein in primary neuronal cultures: effect of missense mutations."
J Neural Transm Suppl(58): 53-63.
Numerous recent observations have implicated alpha-synuclein in the pathogenesis
of several neurodegenerative diseases, including Parkinson's disease,
Alzheimer's disease, dementia with Lewy bodies and multiple-system atrophy. Two
missense mutations in the gene for alpha-synuclein have been identified in some
cases of familial Parkinson's disease and it is thought that these may disrupt
the normal structure of the protein and thus promote aggregation into Lewy body
filaments. Here, we examine the subcellular localization of alpha-synuclein in
primary cortical neurons maintained in a monolayer culture. The protein has
widespread expression throughout neurons, including the nucleus, and has a
discete localization in the neurites of more mature neurons, reminiscent of
synaptic specializations. Interestingly, in a subpopulation of cortical neurons
transfected at 13 days in vitro, we find that alpha-synuclein appears to
aggregate into distinct punctate inclusions in the cytoplasm and proximal
neurites. Unlike Lewy bodies, these structures are not ubiquitin positive. These
regions of alpha-synuclein accumulation are observed following transfections
with wild-type, Ala30Pro or Ala53Thr alpha-synuclein; neither mutation alters
their frequency.
McKeith, I. G., J. B. Grace, et al. (2000). "Rivastigmine in the treatment of
dementia with Lewy bodies: preliminary findings from an open trial." Int J
Geriatr Psychiatry15(5): 387-92.
The objective of this study was to assess the tolerability and efficacy of
rivastigmine in a group of patients with probable dementia with Lewy bodies
(DLB), using an open label study. Open label treatment was with rivastigmine up
to maximum tolerated dose (mean 9.6 mg daily, range 3-12 mg). Eleven patients
with DLB, mean age 78.5 years, were treated with this cholinesterase inhibitor.
After 12 weeks of treatment, mean Neuropsychiatric Inventory scores fell by 73%
for delusions, 63% for apathy, 45% for agitation and 27% for hallucinations.
Five of the patients (45%) experienced very significant clinical improvements
that had not been achieved with other treatments, including low dose
neuroleptics. Medication was well tolerated and parkinsonian symptoms tended to
improve. Cholinesterase inhibition may be a safe and effective alternative to
neuroleptic treatment in DLB. Such effects may also prove to be applicable to
the management of neuropsychiatric symptoms in Parkinson's disease and
Alzheimer's disease.
McKeith, I. G. (2000). "Spectrum of Parkinson's disease, Parkinson's dementia,
and Lewy body dementia." Neurol Clin18(4): 865-902.
Dementia occurs more commonly in individuals with Parkinson's disease (PD) than
in the age-matched general population. Dementia in PD may result from a mixture
of cortical and subcortical dementia syndromes caused by a variety of underlying
pathologic processes and neurochemical deficits. A primary dementia syndrome has
been described that shares several pathologic and clinical characteristics with
PD. Dementia with Lewy bodies (DLB) accounts for 15% to 20% of all dementia
syndromes in old age, which makes it second only to Alzheimer's disease in
prevalence. The relationship between dementia in PD and DLB has not been fully
resolved but may be considered useful in terms of neuropathologic substrate,
clinical features, and response to treatment.
Mattila, P. M., J. O. Rinne, et al. (2000). "Alpha-synuclein-immunoreactive
cortical Lewy bodies are associated with cognitive impairment in Parkinson's
disease." Acta Neuropathol (Berl)100(3): 285-90.
Amygdala, hippocampus and six cortical gyri were examined for the Lewy body (LB)
degeneration and Alzheimer's disease (AD) type changes in 45 patients with
Parkinson's disease (PD). For detection of LBs, the brain areas were stained
with an antibody against alpha-synuclein. The extent of neuropathological
lesions was investigated in relation to cognitive dysfunction and apolipoprotein
E (apoE) epsilon4 allele dosage. At least one cortical LB was found in 95% of
cases (43/45). Furthermore, 40% of cases (18/45) had histological findings of
definite AD (CERAD class C). Those PD cases with the apoE epsilon4 allele had a
significantly greater number of cortical LBs than those without the apoE
epsilon4 allele, but this was statistically significant only in precentral,
angular and temporal gyri. The LB density correlated better with the number of
plaques than with the density of tangles. The number of LBs in several cortical
areas correlated significantly with the cognitive impairment. In stepwise linear
regression analysis, the number of LBs in the cingulate gyrus and the amount of
tangles in the temporal cortex remained statistically significant. When the
CERAD class C was excluded, the correlation between cognitive decline and the
number of LBs in cortical areas became even more pronounced. A stepwise linear
regression analysis in these cases found the number of LBs in the frontal gyrus
to be the statistically most significant predictor of cognitive impairment. This
study shows, for the first time, that in PD, alpha-synuclein-positive cortical
LBs are associated with cognitive impairment independent of AD-type pathology.
Marti Masso, J. F. and J. Ruiz Martinez (2000). "[Dementia with Lewy bodies]."
Neurologia15(1): 15-21.
Dementia with Lewy bodies (DLB) is the second most frequent cause of primary
degenerative dementias, following Alzheimer's disease (AD). The nosologic
situation of this disease has fragile limits. There is controversy as to whether
Parkinson's disease (PD) and DLB are two different entities or whether they make
up part of the same spectrum. The terms diffuse Lewy bodies disease and the
variant of Lewy bodies in senile dementia or AD have been used to describe
pathologic changes with clinical manifestations of dementia and parkinsonism. At
present, DLB should be understood as an entity with the essential feature being
the presence of Lewy bodies in the brain stem and cerebral cortex. From the
point of view of clinical examination, DLB is characterized by the presence of
subcortical or progressive cortical dementia, at times without severe memory
disorders, with great fluctuations and well detailed recurrent visual
hallucinations. These cognitive alterations are associated with parkinsonism.
Other frequent disorders are falls, syncopes, transitory alterations in
consciousness, great sensitivity to neuroleptic drugs and visual illusions with
pseudoperception. The correct diagnosis of this entity is important to
administer adequate treatment, to avoid classical neuroleptic drugs and to
establish precise prognosis. From a therapeutic point of view, cholinesterase
inhibitors show some efficacy in the treatment of cognitive alterations.
Mah, A. L., G. Perry, et al. (2000). "Identification of ubiquilin, a novel
presenilin interactor that increases presenilin protein accumulation." J Cell
Biol151(4): 847-62.
Mutations in the highly homologous presenilin genes encoding presenilin-1 and
presenilin-2 (PS1 and PS2) are linked to early-onset Alzheimer's disease (AD).
However, apart from a role in early development, neither the normal function of
the presenilins nor the mechanisms by which mutant proteins cause AD are well
understood. We describe here the properties of a novel human interactor of the
presenilins named ubiquilin. Yeast two-hybrid (Y2H) interaction, glutathione
S-transferase pull-down experiments, and colocalization of the proteins
expressed in vivo, together with coimmunoprecipitation and cell fractionation
studies, provide compelling evidence that ubiquilin interacts with both PS1 and
PS2. Ubiquilin is noteworthy since it contains multiple ubiquitin-related
domains typically thought to be involved in targeting proteins for degradation.
However, we show that ubiquilin promotes presenilin protein accumulation.
Pulse-labeling experiments indicate that ubiquilin facilitates increased
presenilin synthesis without substantially changing presenilin protein
half-life. Immunohistochemistry of human brain tissue with ubiquilin-specific
antibodies revealed prominent staining of neurons. Moreover, the anti-ubiquilin
antibodies robustly stained neurofibrillary tangles and Lewy bodies in AD and
Parkinson's disease affected brains, respectively. Our results indicate that
ubiquilin may be an important modulator of presenilin protein accumulation and
that ubiquilin protein is associated with neuropathological neurofibrillary
tangles and Lewy body inclusions in diseased brain.
Lucking, C. B. and A. Brice (2000). "Alpha-synuclein and Parkinson's disease."
Cell Mol Life Sci57(13-14): 1894-908.
The involvement of alpha-synuclein in neurodegenerative diseases was first
suspected after the isolation of an alpha-synuclein fragment (NAC) from amyloid
plaques in Alzheimer's disease (AD). Later, two different alpha-synuclein
mutations were shown to be associated with autosomal-dominant Parkinson's
disease (PD), but only in a small number of families. However, the discovery
that alpha-synuclein is a major component of Lewy bodies and Lewy neurites, the
pathological hallmarks of PD, confirmed its role in PD pathogenesis.
Pathological aggregation of the protein might be responsible for
neurodegeneration. In addition, soluble oligomers of alpha-synuclein might be
even more toxic than the insoluble fibrils found in Lewy bodies. Multiple
factors have been shown to accelerate alpha-synuclein aggregation in vitro.
Therapeutic strategies aimed to prevent this aggregation are therefore
envisaged. Although little has been learned about its normal function,
alpha-synuclein appears to interact with a variety of proteins and membrane
phospholipids, and may therefore participate in a number of signaling pathways.
In particular, it may play a role in regulating cell differentiation, synaptic
plasticity, cell survival, and dopaminergic neurotransmission. Thus,
pathological mechanisms based on disrupted normal function are also possible.
Kruger, R., T. Muller, et al. (2000). "Involvement of alpha-synuclein in
Parkinson's disease and other neurodegenerative disorders." J Neural Transm107(1): 31-40.
A major step in the elucidation of the pathogenesis of neurodegenerative
disorders was the identification of a mutation in the alpha-synuclein gene in
autosomal dominant Parkinson's disease (PD). Alpha-synuclein is the main
component of Lewy bodies (LB), the neuropathological hallmark of PD. Moreover, a
fragment of alpha-synuclein (NAC) is the second major component of amyloid
plaques in Alzheimer's disease (AD). Recent studies of other neurodegenerative
disorders such as dementia with LB (DLB), multiple system atrophy (MSA) and
amyotrophic lateral sclerosis (ALS) also revealed intracellular accumulations of
alpha-synuclein in affected brain regions. This may indicate that these
disorders partially share common pathogenic mechanisms. Recent data provide
first insights into the physiological function of alpha-synuclein and support
the concept of an essential role of alpha-synuclein in neurodegeneration.
Increasing knowledge on the pathogenic molecular mechanisms of neurodegeneration
and of the pathophysiological function of alpha-synuclein in particular may
influence future development of therapeutic strategies in neurodegenerative
disorders.
Kondo, K., K. Miyashita, et al. (2000). "[An autopsy case of dementia with Lewy
bodies who showed the typical parkinsonism in the initial five years]."
Nippon Ronen Igakkai Zasshi37(12): 999-1003.
A 76-year-old man with parkinsonism and dementia was reported. He developed
resting tremor at age 69 followed by hypokinesia, rigidity and small step gait.
L-dopa ameliorated his symptoms with no hallucinations for the initial 5 years.
His mental level did not decrease during that period. He was admitted to our
hospital because of dehydration and fever at age 74. Subsequently, his cognitive
function deteriorated, with visual hallucination. Serial brain CT studies
displayed a progressive cerebral cortical atrophy without focal lesions. He died
of respiratory distress syndrome and disseminated coagulopathy resulting from
pneumonia, dehydration and syndrome malin. Postmortem examination revealed a
marked bilateral loss of melanin-containing neurons with Lewy bodies in the
substantia nigra and locus ceruleus. Lewy bodies were also in the basal nucleus
of Meynert, with moderate neuronal cell loss. The distribution of Lewy bodies
was widespread in the cerebral cortical areas, corresponding to the neocortical
subtype according to the consensus guideline for the pathologic diagnosis of
dementia with Lewy bodies. According to the criteria of the Consortium to
Establish a Registry for Alzheimer's Disease, the age-related plaque score in
the present case suggested Alzheimer's disease, although cortical
neurofibrillary changes corresponded to stage II by the criteria of Braak and
Braak. These pathological findings established the diagnosis of dementia with
Lewy bodies from the quantitative and distributional viewpoints. Based on recent
neuropathological evidence, a spectral theory, which presents idiopathic
Alzheimer's disease and Parkinson's disease as the two extremes of a spectrum of
neurodegeneration, has been proposed. Dementia with Lewy bodies is located in
the middle of this spectrum. Pathological evaluation based on quantitative
consensus guidelines is important to establish the diagnosis in patients with
parkinsonism and dementia, since neuropathological changes of Alzheimer's
disease, Parkinson's disease and dementia with Lewy bodies are often observed in
a mixed manner in these patients.
Kawashima, M., S. O. Suzuki, et al. (2000). "alpha-Synuclein is expressed in a
variety of brain tumors showing neuronal differentiation." Acta Neuropathol
(Berl)99(2): 154-60.
alpha-Synuclein is presynaptic nerve terminal protein and its immunoreactivity
has been observed in such neurodegenerative structures as senile plaques of
Alzheimer's disease or Lewy bodies of Parkinson's disease. The physiological
role of alpha-synuclein is still unknown. It is speculated that alpha-synuclein
may be expressed in brain tumors, especially in those showing neuronal
differentiation. We examined the immunohistochemical localization of
alpha-synuclein in 77 human brain tumors. alpha-Synuclein was widely distributed
in the brain tumors showing neuronal differentiation. As a result, positive
immunostaining for alpha-synuclein was observed in ganglioglioma,
medulloblastoma, neuroblastoma, primitive neuroectodermal tumor,
pineocytoma/pineoblastoma, and central neurocytoma. Compared with other neuronal
markers, the positive ratio of alpha-synuclein was not as high as synaptophysin,
microtubule-associated protein 2, neuron-specific enolase and tau, but it was
higher than neurofilament and chromogranin A. The expression of synaptophysin
was diffusely observed in the cytoplasm, cellular processes and nucleus in
tumors showing neuronal differentiation; however, the expression of
alpha-synuclein was predominantly observed in the cytoplasm of the tumors as
well as in the cellular processes. On the other hand, non-neuronal brain tumors
such as astrocytic tumors or meningiomas were totally negative for
alpha-synuclein. In conclusion, the appearance of an alpha-synuclein-positive
structure was not limited to neurodegenerative diseases, but could also be
detected in neoplastic cells showing neuronal differentiation.
Jellinger, K. A. (2000). "Cell death mechanisms in Parkinson's disease." J
Neural Transm107(1): 1-29.
OBJECTIVE: While the causes of neuronal death in Parkinson's disease (PD) and
other neurodegenerative disorders are still unknown, several mechanisms are
under discussion: programmed vs. passive cell death (apoptosis vs. necrosis),
mainly based on conflicting results on the rare presence or absence of DNA
fragmentation in substantia nigra neurons using the in situ DNA-labeling (TUNEL)
method. DESIGN/METHODS: In 4 cases of Parkinson's disease (PD), 2 cases of
Dementia with Lewy bodies (DLB) and 3 age-matched controls, the TUNEL/ISEL
method was used to detect DNA fragmentation in substantia nigra locus coeruleus
and cerebral cortex [method by Gold et al. (1994)]. In addition,
immunohistochemistry was performed for an array of apoptosis-related proteins,
i.e. the recently described apoptosis specific protein cJun/AP1 (ASP), the
proto-oncogenes c-Jun, c-Jun AP1, Bcl2, Bax, Bcl-x, p53, CD 95 (Fas/Apo-1),
activated caspase 3, several heat shock proteins (alpha-B crystallin,
ubiquitin), and alpha-synuclein. RESULTS: None of the cases of PD, DLB, and
controls showed convincing TUNEL-positivity nor morphologic signs of apoptosis
in nigral, locus coeruleus or cortical neurons with or without Lewy bodies but
variable numbers of TUNEL-positive astrocytes and microglial cells in substantia
nigra of PD and DLB. There were no significant differences in the expression of
c-Jun, ASP, Bcl-2, Bax, and Bcl-x in substantia nigra neurons between PD, DLB,
and controls nor between cortical and subcortical neurons with and without Lewy
bodies. No expression of p53, and activated caspase 3, or any of the examined
stress proteins was seen in neurons, while reactive astroglia and microglia were
decorated by antibodies to Bcl-2, Bax, alpha-B-crystallin and less, to Bcl-x and
caspase 3. Lewy bodies, dystrophic neurites and axonal spheroids, all being
negative for the applied apoptosis regulating proteins, showed strong expression
of the examined stress proteins and of alpha-synuclein. CONCLUSIONS: These
findings which are in line with previous results in Alzheimer's disease
(Stadelmann et al., 1998) and Parkinson's disease (Banati et al., 1999) suggest
that mechanisms distinct from classical apoptosis play a central role in the
pathogenesis of PD and related neurodegenerative diseases. Further studies are
warranted to elucidate the intracellular cascade of events leading to cell death
in these disorders showing slow progression over many years.
Jellinger, K. A. and C. Stadelmann (2000). "Mechanisms of cell death in
neurodegenerative disorders." J Neural Transm Suppl59: 95-114.
OBJECTIVE: Progressive cell loss in specific neuronal populations is the
prominent pathological hallmark of neurodegenerative diseases, but its molecular
basis remains unresolved. Apoptotic cell death has been implicated as a general
mechanism in Alzheimer disease (AD) and other neurodegenerative disorders.
However, DNA fragmention in neurons is too frequent to account for the
continuous loss in these slowly progressive diseases. MATERIAL AND METHODS: In 9
cases of morphologically confirmed AD (CERAD criteria, Braak stages 5 or 6), 5
cases of Parkinson disease (PD) and 3 cases each of Dementia with Lewy bodies
(DLB), Progressive Supranuclear Palsy (PSP), and Multiple System Atrophy (MSA),
and 7 age-matched controls, the TUNEL method was used to detect DNA
fragmentation, and immunohistochemistry for an array of apoptosis-related
proteins (ARP), protooncogenes, and activated caspase-3 were performed. RESULTS:
In AD, a considerable number of hippocampal neurons showed DNA fragmentation
with a 3 to 5.7 fold increase related to neurofibrillary tangles and amyloid
deposits, but only exceptional neurons displayed apoptotic morphology (1 in
1100-5000) and cytoplasmic immunoreactivity for ARPs and activated caspase-3 (1
in 2600 to 5650 hippocampal neurons), whereas no neurons were labeled in
age-matched controls. Caspase-3 immunoreactivity was seen in granules of
granulovacuolar degeneration, only rarely colocalized with tau-immunoreactivity.
In PD, DLB, and MSA, TUNEL positivity and expression of ARPs or activated
caspase-3 was only seen in microglia, rare astrocytes and in oligodendroglia
with cytoplasmic inclusions in MSA, but not in nigral or other neurons with or
without Lewy bodies. In PSP, only single neurons but oligodendrocytes, some with
tau deposits, in brainstem tegmentum and pontine nuclei were TUNEL-positive and
expressed both ARPs and activated caspase-3. CONCLUSIONS: These data provide
evidence for extremely rare apoptotic neuronal death in AD compatible with the
progression of neuronal degeneration in this chronic disease. In other
neurodegenerative disorders, apoptosis mainly involves microglia and
oligodendroglia, while alternative mechanisms of neuronal death may occur.
Susceptible cell populations in a proapoptotic environment show increased
vulnerability towards metabolic and other pathogenic factors, with autophagy as
a possible protective mechanism in early stages of programmed cell death. The
intracellular cascade leading to cell death still awaits elucidation.
Jellinger, K. A. (2000). "Morphological substrates of mental dysfunction in Lewy
body disease: an update." J Neural Transm Suppl59: 185-212.
Mental dysfunction including cognitive, behavioural changes, mood disorders, and
psychosis are increasingly recognized in patients with Parkinson's disease (PD)
and related disorders. Their morphological correlates are complex due to
multiple system degeneration. CNS changes contributing to cognitive changes in
PD include 1. Dysfunction of subcorticocortical networks with neuron losses in
a) the dopaminergic nigrostriatal loop, causing striato-(pre)frontal
deafferentation and mesocortico-limbic system (medial substantia nigra, ventral
tegmentum); b) noradrenergic (locus coeruleus), and serotonergic systems (dorsal
raphe nuclei), c) cholinergic forebrain system (nucleus basalis of Meynert,
etc), and d) specific nuclei of amygdala and limbic system (thalamic nuclei,
hippocampus); 2. Limbic and/or cortical Lewy body and Alzheimer type pathologies
with loss of neurons and synapses, 3. Combination of subcortical, cortical, and
other pathologies. In general, degeneration of subcortical and striato-frontal
networks causes cognitive, executive, behavioural, and mood disorders but less
severe dementia than cortical changes which, when present in sufficient numbers,
are important factors for overt dementia. In PD, cortical tau pathology with
similar or differential patterns than in Alzheimer disease (AD) shows
significant linear correlation with cognitive decline. In dementia with Lewy
bodies (DLB), the second most frequent cause of dementia in the elderly,
cortical Lewy bodies (LB) may or may not be associated with amyloid plaques and
neuritic AD lesions. They predominantly affect the limbic system with less
frequent isocortical Braak stages, whereas the cholinergic forebrain system is
more severely affected than in AD. Both neuritic degeneration in limbic system
in PD and DLB and the density of cortical synapse markers correlate with
neuritic AD pathology and less with cortical LB counts. Apolipoprotein E
epsilon4 allele frequency may represent a common genetic background for both AD
and LB pathologies but there are different proportions of plaques between DLB
(less Abeta1-40) and AD (more frequent Abeta1-40). Familial parkinsonism with
dementia, linked to chromosome 17 (frontotemporal dementia with Parkinsonism
(FTDP-17), and other tauopathies pathologically resembling PD plus AD, are often
related to mutations of the tau gene, whereas familial PD with alpha-synuclein
and Parkin mutations usually show no cognitive impairment. Mood disorders, in
particular depression, and psychotic complications in both PD and DLB are
related to complex involvement of noradrenergic and serotonergic systems, not
confirmed in AD with depression, and both the prefrontal and limbic dopaminergic
systems. The specific contributions of cortical and subcortical pathologies to
mental dysfunction in PD and related disorders, their relationship to AD, and
their genetic and aetiological backgrounds await further elucidation.
Jellinger, K. A. and C. H. Stadelmann (2000). "The enigma of cell death in
neurodegenerative disorders." J Neural Transm Suppl(60): 21-36.
Progressive cell loss in specific neuronal populations is the pathological
hallmark of neurodegenerative diseases, but its mechanisms remain unresolved.
Apoptotic cell death has been implicated as a major mechanism in Alzheimer
disease (AD), Parkinson disease (PD) and other neurodegenerative disorders.
However, DNA fragmentation in human brain as a sign of neuronal cell injury is
too frequent to account for the continuous loss in these slowly progressive
diseases. In a series of autopsy confirmed cases of AD, PD, related disorders,
and age-matched controls, DNA fragmentation using the TUNEL method, an array of
apoptosis-related proteins (ARP), proto-oncogenes, and activated caspase-3, the
key enzyme of late-stage apoptosis, were examined. In AD, a considerable number
of hippocampal neurons and glial cells showed DNA fragmentation with a 3- to
6-fold increase related to neurofibrillary tangles and amyloid deposits, but
only 1 in 2.600 to 5.600 neurons displayed apoptotic morphology and cytoplasmic
immunoreactivity for activated caspase-3, whereas no neurons were labeled in
age-matched controls. caspase-3 immunoreactivity was seen in granules of cells
with granulovacuolar degeneration, in around 25% co-localized with early
cytoplasmic deposition of tau-protein. In progressive supranuclear palsy, only
single neurons and several oligodendrocytes in brainstem, some with
tau-deposits, were TUNEL-positive and expressed both ARPs and activated
caspase-3. In PD, dementia with Lewy bodies, multisystem atrophy (MSA), and
corticobasal degeneration, TUNEL-positivity and expression of ARPs or activated
caspase-3 were only seen in microglia and oligodendrocytes with cytoplasmic
inclusions, but not in neurons. These data provide evidence for extremely rare
apoptotic neuronal death in AD and PSP compatible with the progression of
neuronal degeneration in these chronic diseases. Apoptosis mainly involves
reactive microglia and oligodendroglia, the latter often involved by deposits of
insoluble fibrillary proteins, while alternative mechanisms of neuronal death
may occur. Susceptible cell populations in a proapoptotic environment show
increased vulnerability towards metabolic or other noxious factors, with
autophagy as a possible protective mechanism in early stages of programmed cell
death. The intracellular cascade leading to cell death still awaits elucidation.
Iwai, A. (2000). "Properties of NACP/alpha-synuclein and its role in Alzheimer's
disease." Biochim Biophys Acta1502(1): 95-109.
The precursor of the non-amyloid beta/A4 protein (non-Abeta) component of
Alzheimer's disease amyloid (NACP)/alpha-synuclein is the human homologue of
alpha-synuclein, a member of a protein family which includes alpha-, beta- and
gamma-synuclein. This protein is thought to be involved in neuronal plasticity
because of its unique expression, mainly in the telencephalon during maturation.
Consequently, disarrangement of NACP/alpha-synuclein might disrupt synaptic
activity, resulting in memory disturbance. Previous studies have shown that
damage to synaptic terminals is closely associated with global cognitive
impairment and is an early event in the pathogenesis of Alzheimer's disease.
Although the relationship between synaptic damage and amyloidogenesis is not
clear, some proteins at the synaptic site have been implicated in both neuronal
alteration and amyloid formation. Indeed, abnormal accumulation of both
NACP/alpha-synuclein and Abeta precursor protein occurs at synapses of
Alzheimer's patients. Other evidence suggests that NACP/alpha-synuclein is a
component of the Lewy bodies found in patients with Parkinson's disease or
dementia with Lewy bodies, and that a point mutation in this protein may be the
cause of familial Parkinson's disease. Consequently, abnormal transport,
metabolism or function of NACP/alpha-synuclein appears to impair synaptic
function, which induces, at least in part, neuronal degeneration in several
neurodegenerative diseases.
Hurtig, H. I., J. Q. Trojanowski, et al. (2000). "Alpha-synuclein cortical Lewy
bodies correlate with dementia in Parkinson's disease." Neurology54(10):
1916-21.
BACKGROUND: Dementia is a frequent complication of idiopathic parkinsonism or
PD, usually occurring later in the protracted course of the illness. The primary
site of neuropathologic change in PD is the substantia nigra, but the
neuropathologic and molecular basis of dementia in PD is less clear. Although
Alzheimer's pathology has been a frequent finding, recent advances in
immunostaining of alpha-synuclein have suggested the possible importance of
cortical Lewy bodies (CLBs) in the brains of demented patients with PD. METHODS:
The brains of 22 demented and 20 nondemented patients with a clinical and
neuropathologic diagnosis of PD were evaluated with standard neuropathologic
techniques. In addition, CLBs and dystrophic neurites were identified
immunohistochemically with antibodies specific for alpha-synuclein and
ubiquitin; plaques and tangles were identified by staining with thioflavine S.
Associations between dementia status and pathologic markers were tested with
logistic regression. RESULTS: CLBs positive for alpha-synuclein are highly
sensitive (91%) and specific (90%) neuropathologic markers of dementia in PD and
slightly more sensitive than ubiquitin-positive CLBs. They are better indicators
of dementia than neurofibrillary tangles, amyloid plaques, or dystrophic
neurites. CONCLUSION: CLBs detected by alpha-synuclein antibodies in patients
with PD are a more sensitive and specific correlate of dementia than the
presence of Alzheimer's pathology, which was present in a minority of the cases
in this series.
Haroutunian, V., M. Serby, et al. (2000). "Contribution of Lewy body inclusions
to dementia in patients with and without Alzheimer disease neuropathological
conditions." Arch Neurol57(8): 1145-50.
CONTEXT: Lewy bodies (LBs) are intraneuronal inclusions in the brain that have
been increasingly recognized as neuropathological lesions with relevance not
only to Parkinson disease but also to Alzheimer disease. However, the degree to
which the density of LBs in the brain contributes to the severity of dementia
has not been clear. OBJECTIVE: To determine the degree to which LB "burden"
contributes to dementia. DESIGN: Brain specimens were examined from 273
consecutive autopsies of elderly subjects residing in a nursing home. The
numbers and densities of LBs were determined in multiple brain regions, and
their correlation with a measure of cognition and functional status (Clinical
Dementia Rating) during the 6 months preceding death was determined. SETTING AND
PATIENTS: Postmortem study of nursing home residents. RESULTS: The severity of
dementia correlated significantly and positively with the density of LBs. These
correlations were independent of other neuropathological disorders commonly
associated with dementia, including Alzheimer disease. The density of LBs
correlated significantly with dementia severity whether or not the diagnostic
criteria for Alzheimer disease were met and after the contribution of classical
Alzheimer disease lesions, neuritic plaques, and neurofibrillary tangles had
been accounted for by partial correlation analysis. CONCLUSION: Lewy body
inclusions appear to contribute significantly to cognitive deficits in the
elderly in a manner that is independent of other neuropathological disorders.
Arch Neurol. 2000;57:1145-1150
Hardy, J. (2000). "Pathways to primary neurodegenerative disease." Ann N Y
Acad Sci924: 29-34.
Genetic analysis has revealed the pathogenic lesions that cause autosomal
dominant Alzheimer's disease, prion disease, and some forms of Parkinson's
disease. Molecular biological experiments based on these genetic findings allow
a hypothesis to be configured linking these and the other diseases in which
tangles or Lewy bodies are a pathological feature. In this article, this
hypothesis is presented in the context of deriving curative treatments for these
disorders.
Harding, A. J., J. J. Kril, et al. (2000). "Practical measures to simplify the
Braak tangle staging method for routine pathological screening." Acta
Neuropathol (Berl)99(2): 199-208.
The examination of neurofibrillary tangles is now recommended for the diagnosis
of Alzheimer's disease as their location and density can distinguish early,
intermediate and late disease stages. While the Braak tangle staging protocol
can identify these stages, it uses an uncommon silver stain and hippocampal
sample. The present study evaluates the Braak protocol using commonly used
methods and cases fulfilling either CERAD criteria for Alzheimer's disease,
criteria for dementia with Lewy bodies or without neurological disease. Temporal
and occipital cortices from 72 cases were stained using tau immunohistochemistry
and the Gallyas and modified Bielschowsky silver stains. The modified
Bielschowsky silver stain was equivalent to the Gallyas silver stain for tangle
staging. Semiquantitative evaluation of neurofibrillary tangles in the
hippocampus and the inferior temporal cortex provided equivalent information to
that obtained using the original Braak tangle staging protocol (kappa statistic
of 0.97). Comparison of this modification with the CERAD criteria provided
moderate agreement (0.51) between diagnostic categories when cases with dementia
with Lewy bodies were included, but substantially increased agreement (0.74)
when they were excluded. This simplification of the Braak tangle staging
protocol is easy to apply, can be readily incorporated into existing CERAD
procedures, and helps to distinguish cases with neurofibrillary tangles from
those with Lewy bodies.
Giasson, B. I., R. Jakes, et al. (2000). "A panel of epitope-specific antibodies
detects protein domains distributed throughout human alpha-synuclein in Lewy
bodies of Parkinson's disease." J Neurosci Res59(4): 528-33.
To facilitate studies of the normal biology of alpha-synuclein, a member of a
family of neuronal proteins of unknown function, and to elucidate the role of
alpha-synuclein pathologies in neurodegenerative diseases, we generated and
characterized a panel of anti-synuclein antibodies. Here we demonstrate that
these antibodies recognize defined epitopes spanning the entire length of human
alpha-synuclein, and that some of these antibodies also cross-react with zebra
finch and rodent synucleins. Since alpha-synuclein has been reported to be a
major component of Lewy bodies (LBs) in Parkinson's disease (PD), dementia with
LBs and common variants of Alzheimer's disease, we performed immunohistochemical
studies showing that these antibodies label numerous LBs in the PD substantia
nigra, thereby localizing protein domains throughout human alpha-synuclein in
LBs. Taken together, our data indicate that this panel of antibodies can be
exploited to probe the normal biology of alpha-synuclein as well as the role of
pathological forms of this protein in PD and related neurodegenerative
synucleinopathies.
Giasson, B. I., J. E. Duda, et al. (2000). "Oxidative damage linked to
neurodegeneration by selective alpha-synuclein nitration in synucleinopathy
lesions." Science290(5493): 985-9.
Aggregated alpha-synuclein proteins form brain lesions that are hallmarks of
neurodegenerative synucleinopathies, and oxidative stress has been implicated in
the pathogenesis of some of these disorders. Using antibodies to specific
nitrated tyrosine residues in alpha-synuclein, we demonstrate extensive and
widespread accumulations of nitrated alpha-synuclein in the signature inclusions
of Parkinson's disease, dementia with Lewy bodies, the Lewy body variant of
Alzheimer's disease, and multiple system atrophy brains. We also show that
nitrated alpha-synuclein is present in the major filamentous building blocks of
these inclusions, as well as in the insoluble fractions of affected brain
regions of synucleinopathies. The selective and specific nitration of
alpha-synuclein in these disorders provides evidence to directly link oxidative
and nitrative damage to the onset and progression of neurodegenerative
synucleinopathies.
El-Agnaf, O. M. and G. B. Irvine (2000). "Review: formation and properties of
amyloid-like fibrils derived from alpha-synuclein and related proteins." J
Struct Biol130(2-3): 300-9.
Synucleinsare small proteins that are highly expressed in brain tissue and are
localised at presynaptic terminals in neurons. alpha-Synuclein has been
identified as a component of intracellular fibrillar protein deposits in several
neurodegenerative diseases, and two mutant forms of alpha-synuclein have been
associated with autosomal-dominant Parkinson's Disease. A fragment of
alpha-synuclein has also been identified as the non-Abeta component of
Alzheimer's Disease amyloid. In this review we describe some structural
properties of alpha-synuclein and the two mutant forms, as well as
alpha-synuclein fragments, with particular emphasis on their ability to form
beta-sheet on ageing and aggregate to form amyloid-like fibrils. Differences in
the rates of aggregation and morphologies of the fibrils formed by
alpha-synuclein and the two mutant proteins are highlighted. Interactions
between alpha-synuclein and other proteins, especially those that are components
of amyloid or Lewy bodies, are considered. The toxicity of alpha-synuclein and
related peptides towards neurons is also discussing in relation to the aetiology
of neurodegenerative diseases.
Duda, J. E., V. M. Lee, et al. (2000). "Neuropathology of synuclein aggregates."
J Neurosci Res61(2): 121-7.
Beginning with the isolation of the fragment of alpha-synuclein (alpha-syn)
known as the non-Abeta component of amyloid plaques (NAC peptide) from
Alzheimer's disease (AD) brains, alpha-syn has been increasingly implicated in
the pathogenesis of neurodegenerative diseases, which now are classified as
synucleinopathies. Indeed, unequivocal evidence linking abnormal alpha-syn to
mechanisms of brain degeneration came from discoveries of missense mutations in
the alpha-syn gene pathogenic for familial Parkinson's disease (PD) in rare
kindreds. Shortly thereafter, alpha-syn was shown to be a major component of
Lewy bodies (LBs) and Lewy neurites in sporadic PD, dementia with LBs (DLB) and
the LB variant of AD. Also, studies of brains from patients with AD caused by
genetic abnormalities demonstrated many alpha-syn positive LBs. Further,
alpha-syn was implicated in the formation of the glial (GCIs) and neuronal
cytoplasmic inclusions of multiple system atrophy, and the LBs, GCIs and
neuraxonal spheroids of neurodegeneration with brain iron accumulation type 1.
Recently, two other members of the synuclein family, beta- and gamma-synuclein,
have also been recognized to play a role in the pathogenesis of novel axonal
lesions in PD and DLB. Evidence for a role of alpha-syn in the formation of
filamentous aggregates was reinforced by in vitro studies showing aggregation
and fibrillogenesis of mutant and wild type alpha-syn. Indeed, since the
aggregation of brain proteins into presumptively toxic lesions is emerging as a
common but poorly understood mechanistic theme in sporadic and hereditary
neurodegenerative diseases, clarification of the mechanism of synuclein
aggregation could augment efforts to develop novel and more effective therapies
for many neurodegenerative disorders.
Court, J. A., M. A. Piggott, et al. (2000). "Nicotine binding in human striatum:
elevation in schizophrenia and reductions in dementia with Lewy bodies,
Parkinson's disease and Alzheimer's disease and in relation to neuroleptic
medication." Neuroscience98(1): 79-87.
Striatal nicotinic acetylcholine receptors with high affinity for nicotinic
agonists are involved with the release of a number of neurotransmitters,
including dopamine. Previous findings as to whether these receptors are changed
in Parkinson's disease and Alzheimer's disease are inconsistent and no previous
investigations have focused on these receptors in dementia with Lewy bodies and
schizophrenia, which are also associated with disorders of movement. The present
autoradiographic study of striatal [3H]nicotine binding in Alzheimer's and
Parkinson's diseases, dementia with Lewy bodies and schizophrenia was conducted
with particular reference to the potentially confounding variables of tobacco
use and neuroleptic medication. [3H]Nicotine binding in both dorsal and ventral
caudate and putamen was significantly reduced in Parkinson's disease (43-67%,
n=13), Alzheimer's disease (29-37%, n=13) and dementia with Lewy bodies (50-61%,
n=20) compared to age-matched controls (n=42). Although tobacco use in the
control group was associated with increased [3H]nicotine binding (21-38%), and
neuroleptic treatment in dementia with Lewy bodies and Alzheimer's disease was
associated with reduced [3H]nicotine binding (up to 29%), differences between
neurodegenerative disease groups and controls persisted in subgroups of
Alzheimer's disease cases (26-33%, n=6, in the ventral striatum) and dementia
with Lewy body cases (30-49%, n=7, in both dorsal and ventral striatum) who had
received no neuroleptic medication compared to controls who had not smoked
(n=10). In contrast, striatal [3H]nicotine binding in a group of elderly (56-85
years) chronically medicated individuals with schizophrenia (n=6) was elevated
compared with the entire control group (48-78%, n=42) and with a subgroup that
had smoked (24-49%, n=8).The changes observed in [3H]nicotine binding are likely
to reflect the presence of these receptors on multiple sites within the
striatum, which may be differentially modulated in the different diseases.
Further study is warranted to explore which nicotinic receptor subunits and
which neuronal compartments are involved in the changes in [3H]nicotine binding
reported, to aid development of potential nicotinic receptor therapy.
Cordato, N. J., G. M. Halliday, et al. (2000). "Regional brain atrophy in
progressive supranuclear palsy and Lewy body disease." Ann Neurol47(6):
718-28.
There have been no previous three-dimensional volumetric studies of regional
brain atrophy in patients with pathologically confirmed progressive supranuclear
palsy (PSP). Postmortem cortical and subcortical volumes were compared with
neuropathology in 9 patients with PSP, 15 patients with Parkinson's disease, 10
patients with dementia with Lewy bodies, and 23 controls. Cases with the
neuritic pathology of Alzheimer's disease were excluded. The topography of brain
atrophy differed according to clinicopathological phenotype. Patients with
Parkinson's disease had atrophy confined to the amygdala. Atrophy of the frontal
lobe was found in both PSP and dementia with Lewy bodies and correlated with
increasing neurofibrillary tangle or Lewy body densities, respectively. Patients
with PSP could be differentiated by their marked atrophy of the internal globus
pallidus. Further analysis of variance revealed that trends for greater frontal
lobe atrophy correlated with clinical dementia in PSP, whereas both greater
frontal and hippocampal atrophy and higher densities of Lewy bodies and Lewy
neurites correlated with clinical dementia in cases with Lewy bodies. The
present study provides evidence for selective regional atrophy that correlates
with the underlying pathology of PSP and Lewy body disease.
Conway, K. A., J. D. Harper, et al. (2000). "Fibrils formed in vitro from
alpha-synuclein and two mutant forms linked to Parkinson's disease are typical
amyloid." Biochemistry39(10): 2552-63.
Two missense mutations in the gene encoding alpha-synuclein have been linked to
rare, early-onset forms of Parkinson's disease (PD). These forms of PD, as well
as the common idiopathic form, are characterized by the presence of cytoplasmic
neuronal deposits, called Lewy bodies, in the affected region of the brain. Lewy
bodies contain alpha-synuclein in a form that resembles fibrillar Abeta derived
from Alzheimer's disease (AD) amyloid plaques. One of the mutant forms of
alpha-synuclein (A53T) fibrillizes more rapidly in vitro than does the wild-type
protein, suggesting that a correlation may exist between the rate of in vitro
fibrillization and/or oligomerization and the progression of PD, analogous to
the relationship between Abeta fibrillization in vitro and familial AD. In this
paper, fibrils generated in vitro from alpha-synuclein, wild-type and both
mutant forms, are shown to possess very similar features that are characteristic
of amyloid fibrils, including a wound and predominantly unbranched morphology
(demonstrated by atomic force and electron microscopies), distinctive
dye-binding properties (Congo red and thioflavin T), and antiparallel beta-sheet
structure (Fourier transform infrared spectroscopy and circular dichroism
spectroscopy). alpha-Synuclein fibrils are relatively resistant to proteolysis,
a property shared by fibrillar Abeta and the disease-associated fibrillar form
of the prion protein. These data suggest that PD, like AD, is a brain amyloid
disease that, unlike AD, is characterized by cytoplasmic amyloid (Lewy bodies).
In addition to amyloid fibrils, a small oligomeric form of alpha-synuclein,
which may be analogous to the Abeta protofibril, was observed prior to the
appearance of fibrils. This species or a related one, rather than the fibril
itself, may be responsible for neuronal death.
Chung, T. F., J. D. Sipe, et al. (2000). "Serum amyloid A in Alzheimer's disease
brain is predominantly localized to myelin sheaths and axonal membrane."
Amyloid7(2): 105-10.
Immunohistochemical localization of the injury specific apolipoprotein, acute
phase serum amyloid A (A-apoSAA), was compared in brains of patients with
neuropathologically confirmed Alzheimer's disease (AD), multiple sclerosis (MS),
Parkinson's disease (PD); Pick's disease (Pick's), dementia with Lewy bodies
(DLB), coronary artery disease (CAD), and schizophrenia. Affected regions of
both AD and MS brains showed intense staining for A-apoSAA in comparison to an
unaffected region and non-AD/MS brains. The major site of A-apoSAA staining in
both diseases was the myelin sheaths of axons in layers V and VI of affected
cortex. A-apoSAA contains a cholesterol binding site near its amino terminus and
is likely to have a high affinity for cholesterol-rich myelin. These findings,
along with our recent evidence that A-apoSAA can inhibit lipid synthesis in
vascular smooth muscle cells suggest that A-apoSAA plays a role in the neuronal
loss and white matter damage occurring in AD and MS.
Castellani, R. J., S. L. Siedlak, et al. (2000). "Sequestration of iron by Lewy
bodies in Parkinson's disease." Acta Neuropathol (Berl)100(2):
111-4.
Central to the oxidative stress hypothesis of Parkinson's disease (PD)
pathogenesis is the ability of iron to generate hydroxyl radicals via the Fenton
reaction, and the consistent demonstration of iron elevation in the pars
compacta region of the substantia nigra. However, uncertainty exists as to
whether the excess iron exists in a state suitable for redox chemistry. Here,
using a method we developed that detects redox-active iron in situ, we were able
to demonstrate strong labeling of Lewy bodies in substantia nigra pars compacta
neurons in PD. In contrast, cortical Lewy bodies in cases of Lewy body variant
of Alzheimer's disease were unstained. While the presence of elevated iron in PD
substantiates the oxidative stress hypothesis, one must remember that these are
viable neurons, indicating that Lewy bodies may act to sequester iron in PD
brains in a protective, rather than degenerative, mechanism. The absence of
redox-active iron in neocortical Lewy bodies highlights a fundamental difference
between cortical and brain stem Lewy bodies.
Campbell, B. C., Q. X. Li, et al. (2000). "Accumulation of insoluble
alpha-synuclein in dementia with Lewy bodies." Neurobiol Dis7(3):
192-200.
The alpha-synuclein (alpha SN) protein is thought to play a central role in the
pathogenesis of neurodegenerative diseases where it aggregates to form
intracellular inclusions. We have used Western blotting to examine the
expression levels and solubility of alpha SN in brain homogenates from dementia
with Lewy bodies (DLB), Parkinson's disease (PD), Alzheimer's disease (AD), and
normal controls using samples from the parahippocampus/transentorhinal cortex.
Compared to controls, DLB brains accumulate significantly greater amounts of
sodium dodecyl sulfate (SDS)-soluble and SDS-insoluble alpha SN but levels of
TBS-soluble alpha SN did not change. Levels of synaptophysin, a marker of
synaptic integrity, were significantly lower in DLB cases than in normal aged
controls regardless of whether concurrent changes of AD were present. This
limbic synaptic dysfunction may contribute to cognitive impairment in DLB.
Whether aggregated alpha SN is a cause or effect of the disease process in DLB
and PD remains to be determined, but the presence of aggregated alpha SN is
consistent with a pathogenesis similar to that associated with aggregates of
Abeta amyloid in AD.
Bodles, A. M., D. J. Guthrie, et al. (2000). "Toxicity of non-abeta component of
Alzheimer's disease amyloid, and N-terminal fragments thereof, correlates to
formation of beta-sheet structure and fibrils." Eur J Biochem267(8):
2186-94.
The non-Abeta component of Alzheimer's disease amyloid (NAC) and its precursor
alpha-synuclein have been linked to amyloidogenesis in Alzheimer's disease (AD),
Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Previously we have
shown that NAC forms beta-sheet structures and fibrils [El-Agnaf, O.M.A.,
Bodles, A.M., Guthrie, D.J.S., Harriott, P. & Irvine, G.B. (1998) Eur. J.
Biochem. 258, 157-163]. As a measure of their neurotoxic potential we have
examined the ability of fresh and aged NAC and fragments thereof to inhibit the
reduction of the redox dye 3-(4, 5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium
bromide by rat pheochromocytoma PC12 cells. Micromolar concentrations of NAC and
fragments thereof display varying degrees of toxicity. On immediate dissolution
and after an incubation period for 3 days at 37 degrees C the full-length
peptide and fragments NAC(3-18) and NAC(1-18) scrambled sequence [NAC(1-18 s)]
were toxic, whereas fragments NAC(1-13) and NAC(6-14) were not. CD indicates
that NAC(3-18) and NAC(1-18 s) exhibit beta-sheet secondary structure in aqueous
solution, whereas NAC(1-13) and NAC(6-14) do not. NAC(3-18) aggregates, as
indicated by concentration of peptide remaining in solution after 3 days
measured by an HPLC assay, and forms fibrils, as determined by electron
microscopy. However, although some fibrils were detected for NAC(1-18 s) it does
not come out of solution to a significant degree. Fragments NAC(1-13) and
NAC(6-14) form few fibrils and remain in solution. These findings indicate that
the ability of the central region of NAC to form beta-sheet secondary structures
is important for determining the toxicity of the peptide. This contrasts with
what has been reported previously for most Abeta peptides as their toxicity
appears to require the peptide to have formed fibrillary aggregates as well as
displaying beta-sheet. These results suggest that an intermediate, which
exhibits beta-sheet structure, may be responsible for the toxic properties of
NAC and provides further evidence for the role of NAC in the pathogenesis of AD,
PD and DLB.
Ballard, C., J. O'Brien, et al. (2000). "One year follow-up of parkinsonism in
dementia with Lewy bodies." Dement Geriatr Cogn Disord11(4):
219-22.
The progression of parkinsonism over 1 year was evaluated in a prospective
cohort of patients (n = 338), suffering from dementia with Lewy bodies (DLB),
Alzheimer's disease (AD) or vascular dementia (VaD). Parkinsonism was assessed
using the modified Unified Parkinson's Disease Rating Scale. Significant
parkinsonism was significantly commoner in DLB sufferers (71%) than amongst
patients with AD (7%) or VaD (10%). DLB patients with established parkinsonism
had an annual increase in severity of 9%, but progression was more rapid (49% in
1 year) in patients with early parkinsonism. Parkinsonism was frequent at all
severities in DLB patients, but usually only present in other dementias when
MMSE <10.
Walker, Z., J. Grace, et al. (1999). "Olanzapine in dementia with Lewy bodies: a
clinical study." Int J Geriatr Psychiatry14(6): 459-66.
OBJECTIVES: Dementia with Lewy bodies (DLB) is now a well-recognized form of
dementia in which psychosis and behavioural disturbance are common. Treatment
with conventional neuroleptics is often very poorly tolerated. Olanzapine, a
newly introduced atypical neuroleptic which binds to multiple receptor types
with relatively low affinity for D2 receptors, may be a useful treatment option
in DLB. MAIN OUTCOME MEASURES: The Behavioural Pathology in Alzheimer's Disease
Rating Scale, The Neuropsychiatric Inventory, Unified Parkinson's Disease Rating
Scale and The Webster Disability Scale. DESIGN: We present the results of eight
DLB patients with associated psychotic and behavioural difficulties. All
patients were given olanzapine 2.5-7.5 mg. Their psychotic phenomena and
behavioural and extrapyramidal symptoms were monitored at 2-weekly intervals.
RESULTS: Three out of the eight patients could not tolerate olanzapine even at
the lowest available dose. Two patients had clear improvement in psychotic and
behavioural symptoms. Three patients were able to tolerate olanzapine but gained
only minimal benefit. CONCLUSIONS: Olanzapine at the doses used conferred little
advantage over conventional neuroleptics and should only be given with great
caution to patients with DLB. The utility of smaller doses deserves further
evaluation.
Wakabayashi, K., M. Yoshimoto, et al. (1999). "Widespread occurrence of
alpha-synuclein/NACP-immunoreactive neuronal inclusions in juvenile and
adult-onset Hallervorden-Spatz disease with Lewy bodies." Neuropathol Appl
Neurobiol25(5): 363-8.
Alpha-Synuclein (originally called precursor of the non-Abeta component of
Alzheimer's disease amyloid-NACP) is a presynaptic nerve terminal protein and is
now known to be a major component of Lewy bodies (LBs) in Parkinson's disease.
Previous studies have shown that LBs are occasionally found in patients with
Hallervorden-Spatz disease (HSD), a hereditary or sporadic neuroaxonal
dystrophy. Therefore, an immunocytochemical examination of the brain tissues
from two patients with HSD for alpha-synuclein/NACP was performed. In both
cases, LBs were observed in the substantia nigra, locus ceruleus and other
subcortical nuclei. These LBs were strongly immunolabelled with
anti-alpha-synuclein/NACP. Moreover, abnormal
alpha-synuclein/NACP-immunoreactive structures in the neuronal somata and
processes were found in the cerebral neocortex, hippocampus, basal ganglia,
thalamus, pontine and inferior olivary nuclei, spinal grey matter, and
peripheral sympathetic ganglia. Although numerous dystrophic axons (spheroids)
were found throughout the brain, either none or only a few were positive for
alpha-synuclein/NACP. These findings suggest that widespread accumulation of
alpha-synuclein/NACP is a pathological feature in patients suffering from HSD
with LBs, and that this phenomenon is unrelated to axonal spheroid formation.
Singleton, A. B., A. M. Gibson, et al. (1999). "Alpha2-macroglobulin
polymorphisms in Alzheimer's disease and dementia with Lewy bodies."
Neuroreport10(7): 1507-10.
Dementia with Lewy bodies (DLB) is the second most common cause of dementia in
the elderly after Alzheimer's disease (AD). The apolipoprotein E gene (APOE) is
a major risk factor, but can only account for approximately 50% of AD cases.
Whole genome scanning in late-onset AD families has suggested that a locus on
chromosome 12 may contribute significantly to disease development. Recently the
alpha2-macroglobulin gene (A2M) on chromosome 12 has been suggested as a
candidate locus for AD. We therefore determined the influence of two
polymorphisms in A2M, a pentanucleotide deletion 5' to the bait domain exon, and
a valine to isoleucine polymorphism in the thiolester site of the protein, in AD
and DLB cohorts. No evidence was observed for an association between the
thiolester or deletion polymorphisms and AD or DLB alone or when accounting for
the APOE epsilon4 allele. We did, however, identify a non-significant excess of
deletion homozygotes in the AD and DLB groups. This genotype accounted for 4% of
disease cases but was absent in the control population. Given that the A2M
deletion polymorphism is non-functional, the chromosome 12 AD/DLB locus may be
situated elsewhere and not with these A2M polymorphisms.
Shiozaki, K., E. Iseki, et al. (1999). "Alterations of muscarinic acetylcholine
receptor subtypes in diffuse lewy body disease: relation to Alzheimer's
disease." J Neurol Neurosurg Psychiatry67(2): 209-13.
OBJECTIVES: Dementia associated with Lewy bodies in cortical and subcortical
areas is classified as dementia of the non-Alzheimer type and termed diffuse
Lewy body disease (DLBD). The generic term "dementia with Lewy bodies (DLB)" was
proposed in the international workshop on Lewy body dementia to include the
similar disorders presenting Lewy bodies. In DLB, a lower level of choline
acetyltransferase (ChAT) activity in the neocortex was found compared with that
in Alzheimer's disease. The purpose of the present study was to determine the
total amount of muscarinic acetylcholine receptors (mAChRs) and relative
proportion of each subtype (m1-m4) of mAChRs in the frontal and temporal cortex
of seven DLBD and 11 Alzheimer's disease necropsied brains. METHODS: A
[(3)H]quinuclidinyl benzilate (QNB) binding assay and an immunoprecipitation
assay using subtype-specific antibodies were performed. Each antibody was raised
against fusion proteins containing peptides corresponding to the third
intracellular (i3) loops of the respective mAChR subtype. RESULTS: The total
amounts of mAChRs were significantly lower in the preparations of temporal
cortices from DLBD and Alzheimer's disease than in those from dead controls
(seven cases). In both diseases, the proportion of the m3 receptor in the
frontal cortex was significantly increased and that of the m4 receptor in the
temporal cortex was significantly decreased compared with the control specimens.
The proportions of the m1 and m2 subtypes were significantly different in the
temporal cortex. The proportion of the m1 receptor was significantly greater in
the DLBD brains, whereas that of the m2 receptor was significantly greater in
the Alzheimer's disease brains than in the controls. CONCLUSIONS: The m1
receptor is the major subtype in the cerebral cortex, and m2 is known to be
present at presynaptic terminals. The higher proportions of m1 in DLBD and m2 in
Alzheimer's disease suggest that the manner of degeneration in the cholinergic
system is different between the diseases. It is hypothesised that a severe
depletion of presynaptic cholinergic projective neurons causes the upregulation
of m1 receptor in the temporal cortex in DLBD.
Scott, L. (1999). "Parkinson's disease and dementia with Lewy bodies." Elder
Care11(4): 37-9.
Schulz, J. B. and J. Dichgans (1999). "Molecular pathogenesis of movement
disorders: are protein aggregates a common link in neuronal degeneration?"
Curr Opin Neurol12(4): 433-9.
Abnormal protein aggregation has been postulated to explain the molecular basis
for many neurodegenerative diseases, including Alzheimer's disease, Parkinson's
disease and prion diseases, as well as trinucleotide repeat disorders. The
recent findings that mutations in alpha-synuclein lead to autosomal-dominant,
early-onset Parkinson's disease in some families and that alpha-synuclein is
found in Lewy bodies of all Parkinson's disease patients prompted the hypothesis
that the pathophysiology of all Parkinson's disease patients starts with an
abnormal folding of alpha-synuclein, producing excessive aggregation that
overwhelms the antiaggregation mechanisms of the cell. The genetics of
Parkinson's disease and polyglutamine repeat disorders and the evidence of
abnormal processing and aggregation of the respective target proteins for the
aetiology and pathogenesis in these diseases are reviewed.
Piggott, M. A., E. F. Marshall, et al. (1999). "Striatal dopaminergic markers in
dementia with Lewy bodies, Alzheimer's and Parkinson's diseases: rostrocaudal
distribution." Brain122 ( Pt 8): 1449-68.
Dementia with Lewy bodies (DLB) is a neuropsychiatric disease associated with
extrapyramidal features which differ from those of Parkinson's disease,
including reduced effectiveness of L-dopa and severe sensitivity reactions to
neuroleptic drugs. Distinguishing Alzheimer's disease from DLB is clinically
relevant in terms of prognosis and appropriate treatment. Dopaminergic
activities have been investigated at coronal levels along the rostrocaudal
striatal axis from a post-mortem series of 25 DLB, 14 Parkinson's disease and 17
Alzheimer's disease patients and 20 elderly controls. [(3)H]Mazindol binding to
the dopamine uptake site was significantly reduced in the caudal putamen in DLB
compared with controls (57%), but not as extensively as in Parkinson's disease
(75%), and was unchanged in Alzheimer's disease. Among three dopamine receptors
measured (D1, D2 and D3), the most striking changes were apparent in relation to
D2. In DLB, [(3)H]raclopride binding to D2 receptors was significantly reduced
in the caudal putamen (17%) compared with controls, and was significantly lower
than in Parkinson's disease at all levels. D2 binding was significantly elevated
at all coronal levels in Parkinson's disease compared with controls, most
extensively in the rostral putamen (71%). There was no change from the normal
pattern of D2 binding in Alzheimer's disease. The only significant alteration in
D1 binding ([(3)H]SCH23390) in the groups examined was an elevation (30%) in the
caudal striatum in Parkinson's disease. There were no differences in D3 binding,
measured using [(3)H]7-OH-DPAT, in DLB compared with controls. A slight,
significant decrease in D3 binding in the caudal striatum of Parkinson's disease
(13%) patients and an increase in Alzheimer's disease (20%) in the dorsal
striatum at the level of the nucleus accumbens were found. The concentration and
distribution of dopamine were disrupted in both DLB and Parkinson's disease,
although in the caudate nucleus the loss of dopamine in DLB was uniform whereas
in Parkinson's disease the loss was greater caudally. In the caudal putamen,
dopamine was reduced by 72% in DLB and by 90% in Parkinson's disease. The
homovanillic acid : dopamine ratio, a metabolic index, indicated compensatory
increased turnover in Parkinson's disease, which was absent in DLB despite the
loss of substantia nigra neurons (49%), dopamine and uptake sites. These
differences between DLB, Parkinson's disease and Alzheimer's disease may explain
some characteristics of the extrapyramidal features of DLB and its limited
response to L-dopa and severe neuroleptic sensitivity. The distinct changes in
the rostrocaudal pattern of expression of dopaminergic parameters are relevant
to the interpretation of the in vivo imaging and diagnosis of DLB.
Perry, E., M. Walker, et al. (1999). "Acetylcholine in mind: a neurotransmitter
correlate of consciousness?" Trends Neurosci22(6): 273-80.
The cholinergic system is one of the most important modulatory neurotransmitter
systems in the brain and controls activities that depend on selective attention,
which are an essential component of conscious awareness. Psychopharmacological
and pathological evidence supports the concept of a 'cholinergic component' of
conscious awareness. Drugs that antagonize muscarinic receptors induce
hallucinations and reduce the level of consciousness, while the nicotinic
receptor is implicated as being involved in the mechanism of action of general
(inhalational) anaesthetics. In degenerative diseases of the brain, alterations
in consciousness are associated with regional deficits in the cholinergic
system. In Alzheimer's disease (AD), there is a loss of explicit (more than
implicit) memory and hypoactivity of cholinergic projections to the hippocampus
and cortex, while the visual hallucinations experienced by subjects with
Dementia with Lewy bodies (DLB) are associated with reductions in neocortical
ACh-related activity. In Parkinson's disease, the additional loss of
pedunculopontine cholinergic neurones, which control REM (rapid eye movement)
sleep or dreaming, is likely to contribute to REM abnormalities, which also
occur in DLB. Widespread basal-forebrain and rostral brainstem cholinergic
pathways, which include converging projections to the thalamus, appear to be
located strategically for generating and integrating conscious awareness.
Alleviation of a range of cognitive and non-cognitive symptoms by drugs that
modulate the cholinergic system, which are being developed for the treatment of
AD and related disorders, could be caused by changes in consciousness.
Paik, S. R., H. J. Shin, et al. (1999). "Copper(II)-induced self-oligomerization
of alpha-synuclein." Biochem J340 ( Pt 3): 821-8.
alpha-Synuclein is a component of the abnormal protein depositions in senile
plaques and Lewy bodies of Alzheimer's disease (AD) and Parkinson's disease
respectively. The protein was suggested to provide a possible nucleation centre
for plaque formation in AD via selective interaction with amyloid beta/A4
protein (Abeta). We have shown previously that alpha-synuclein has experienced
self-oligomerization when Abeta25-35 was present in an orientation-specific
manner in the sequence. Here we examine this biochemically specific
self-oligomerization with the use of various metals. Strikingly, copper(II) was
the most effective metal ion affecting alpha-synuclein to form self-oligomers in
the presence of coupling reagents such as dicyclohexylcarbodi-imide or
N-(ethoxycarbonyl)-2-ethoxy-1,2-dihydroquinoline. The size distribution of the
oligomers indicated that monomeric alpha-synuclein was oligomerized
sequentially. The copper-induced oligomerization was shown to be suppressed as
the acidic C-terminus of alpha-synuclein was truncated by treatment with
endoproteinase Asp-N. In contrast, the Abeta25-35-induced oligomerizations of
the intact and truncated forms of alpha-synuclein were not affected. This
clearly indicated that the copper-induced oligomerization was dependent on the
acidic C-terminal region and that its underlying biochemical mechanism was
distinct from that of the Abeta25-35-induced oligomerization. Although the
physiological or pathological relevance of the oligomerization remains currently
elusive, the common outcome of alpha-synuclein on treatment with copper or
Abeta25-35 might be useful in understanding neurodegenerative disorders in
molecular terms. In addition, abnormal copper homoeostasis could be considered
as one of the risk factors for the development of disorders such as AD or
Parkinson's disease.
Ostrerova, N., L. Petrucelli, et al. (1999). "alpha-Synuclein shares physical
and functional homology with 14-3-3 proteins." J Neurosci19(14):
5782-91.
alpha-Synuclein has been implicated in the pathophysiology of many
neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's
disease. Mutations in alpha-synuclein cause some cases of familial PD
(Polymeropoulos et al., 1997; Kruger et al., 1998). In addition, many
neurodegenerative diseases show accumulation of alpha-synuclein in dystrophic
neurites and in Lewy bodies (Spillantini et al., 1998). Here, we show that
alpha-synuclein shares physical and functional homology with 14-3-3 proteins,
which are a family of ubiquitous cytoplasmic chaperones. Regions of
alpha-synuclein and 14-3-3 proteins share over 40% homology. In addition,
alpha-synuclein binds to 14-3-3 proteins, as well as some proteins known to
associate with 14-3-3, including protein kinase C, BAD, and extracellular
regulated kinase, but not Raf-1. We also show that overexpression of
alpha-synuclein inhibits protein kinase C activity. The association of
alpha-synuclein with BAD and inhibition of protein kinase C suggests that
increased expression of alpha-synuclein could be harmful. Consistent with this
hypothesis, we observed that overexpression of wild-type alpha-synuclein is
toxic, and overexpression of alpha-synuclein containing the A53T or A30P
mutations exhibits even greater toxicity. The activity and binding profile of
alpha-synuclein suggests that it might act as a protein chaperone and that
accumulation of alpha-synuclein could contribute to cell death in
neurodegenerative diseases.
Nukina, N. (1999). "[Neuronal cell death--what we can see and what we cannot]."
Rinsho Shinkeigaku39(1): 2-3.
Recently several responsible genes for hereditary neurodegenerative disorders
were identified. In some of them the gene products were found to be aggregated.
In the case of Alzheimer disease beta protein and apolipoprotein E accumulated
in senile plaques. In CAG repeat diseases the polyglutamine aggregates in
neuronal nuclei. More recently alpha synuclein accumulates in Lewy bodies in
Parkinson disease and tau protein accumulates in NFT of hereditary
frontotemporal dementia with tau mutation. Those results suggested that the
responsible gene products accumulates in the lesion which the products involve
in. However, presenilin which is one of the genes for familial Alzheimer disease
accumulates in NFT and on the other hand its mutation changes the production
ratio of beta 1-42/40, suggesting that the abnormal gene products not simply
accumulate the lesion that it involved. The gene products accumulate in
different lesions such as in nuclei of polyglutamine diseases, extracellular
plaque and cytoplasm of prion disease and extracellular plaques in Alzheimer
disease. Some of them are ubiquitinated and some of them are not. Thus the
accumulating process in these disorders seems apparently same but is essentially
different. We should study more precisely each pathological process of those
disorders.
Mitchell, S. L. (1999). "Extrapyramidal features in Alzheimer's disease." Age
Ageing28(4): 401-9.
Mattila, P. M., J. O. Rinne, et al. (1999). "Neuritic degeneration in the
hippocampus and amygdala in Parkinson's disease in relation to Alzheimer
pathology." Acta Neuropathol (Berl)98(2): 157-64.
It has been suggested that dystrophic neurites in the hippocampal CA2-3 sector
are characteristic of diffuse Lewy body disease (DLBD) but not of Parkinson's
disease (PD). We investigated the severity of neuritic change in the CA2-3
sector of the hippocampus and in the periamygdaloid cortex (PAC) in 45 patients
with clinically diagnosed and neuropathologically verified PD. Samples from
amygdala, hippocampus, entorhinal cortex (ERC) and cortical gyri were examined
for Alzheimer-type (AD) changes and Lewy bodies (LBs) using antibodies against
ubiquitin and tau. Ubiquitin-positive but polyclonal tau-negative neurites were
detected in the CA2-3 region of the hippocampus in 88% of patients and in the
PAC in 91% of patients. The CA2-3 sector neurites correlated significantly only
with LBs in all other brain areas, except in the amygdala. The neurites in the
PAC correlated significantly with neuropathological variables in all other brain
areas examined, except with tangles in the pre-central and frontal gyrus and
with LBs in the amygdala and in the ERC. Unlike in the CA2-3 sector, the
neuritic change in the PAC was more prominent in those PD patients with more
severe cognitive impairment (P = 0.03). There was no significant correlation
between the apoE4 allele load and the neuritic change in the PAC or in the CA2-3
sector. Our study revealed that cortical LBs and neuritic change in the amygdala
and hippocampal CA2-3 sector co-exist in PD. Unlike hippocampal neurites, the
PAC neurites are related to AD pathology. There seems to be a relationship
between the PAC neurites and cognitive impairment in PD, but its significance
needs further elucidation.
Luis, C. A., W. W. Barker, et al. (1999). "Sensitivity and specificity of three
clinical criteria for dementia with Lewy bodies in an autopsy-verified sample."
Int J Geriatr Psychiatry14(7): 526-33.
OBJECTIVE: To evaluate the sensitivity and specificity of the clinical features
of three published diagnostic criteria for diffuse Lewy body disease (DLBD)
using autopsy-confirmed Alzheimer's (AD), DLBD and AD+DLBD (mixed) dementia
cases. DESIGN: Retrospective chart review of an autopsy series of 56 patients
selected from the State of Florida Brain Bank on the basis of a pathological
diagnosis of either pure AD, DLBD (pure and common forms) or AD+DLBD (mixed)
dementia. Clinical features were assessed by three raters blind to the
pathological diagnosis. RESULTS: The existing criteria for a clinical diagnosis
of DLBD were highly specific (90-100%) but not very sensitive (49-63%) in the
differential diagnosis of DLBD versus AD; sensitivity did improve (61-74%) when
mixed AD+DLBD cases were eliminated. Clinical features that occur more
frequently in DLBD than in AD were unspecified hallucinations, unspecified EPS,
fluctuating course and rapid progression. Post-hoc analysis also indicated that
hallucinations and EPS were more common early in the disease course of DLBD than
in AD. Empirically derived criteria, formulated using the most prevalent
clinical features, demonstrated sensitivity values of 57-96% for pure forms and
43-91% for mixed forms. CONCLUSIONS: This study demonstrated that additional
improvements in the established criteria for DLBD are needed. Our empirically
derived criteria enhanced the distinction of DLBD from AD while allowing the
clinician the choice of maximizing sensitivity with acceptable specificity, and
vice versa.
Kruger, R., A. M. Vieira-Saecker, et al. (1999). "Increased susceptibility to
sporadic Parkinson's disease by a certain combined
alpha-synuclein/apolipoprotein E genotype." Ann Neurol45(5):
611-7.
Parkinson's disease (PD) is one of the most common neurodegenerative disorders
affecting about 1% of Western populations older than age 50. The pathological
hallmark of PD are Lewy bodies, that is, intracytoplasmic inclusion bodies in
affected neurons of the substantia nigra. Recently, alpha-synuclein (alpha-SYN)
has been identified as the main component of Lewy bodies in sporadic PD,
suggesting involvement in neurodegeneration via protein accumulation. The
partially overlapping pathology of PD and Alzheimer's disease, as well as
striking structural similarities of alpha-SYN and apolipoprotein E, which is a
major risk factor for late-onset Alzheimer's disease, prompted us to investigate
the influence of different alpha-SYN and apolipoprotein E alleles for developing
sporadic PD. We performed association studies in 193 German PD patients and 200
healthy control subjects matched for age, sex, and origin. A polymorphism in the
promoter region of the alpha-SYN gene (NACP-Rep1) as well as of the closely
linked DNA markers D4S1647 and D4S1628 revealed significant differences in the
allelic distributions between PD patients and the control group. Furthermore,
the Apo epsilon4 allele but not the Th1/E47 promoter polymorphism of the
apolipoprotein E gene was significantly more frequent among early-onset PD
patients (age at onset, <50 years) than in late-onset PD. Regarding the
combination of the Apo epsilon4 allele and allele 1 of the alpha-SYN promoter
polymorphism, a highly significant difference between the group of PD patients
and control individuals has been found, suggesting interactions or combined
actions of these proteins in the pathogenesis of sporadic PD. PD patients
harboring this genotype have a 12.8-fold increased relative risk for developing
PD during their lives.
Kienzl, E., K. Jellinger, et al. (1999). "Iron as catalyst for oxidative stress
in the pathogenesis of Parkinson's disease?" Life Sci65(18-19):
1973-6.
The mechanisms leading to degeneration of melanized dopaminergic neurons in the
brain stem, and particularly in the substantia nigra zona compacta (SNZC) in
patients with Parkinson's disease (PD) are still unknown. Demonstration of
increased iron Fe(III) in SNZC of PD brain has suggested that Fe-melanin
interaction may contribute to oxidative neuronal damage. Energy dispersive X-ray
electron microscopic analysis of the cellular distribution of trace elements
revealed significant Fe-peaks, similar to those of a synthetic melanin-Fe(III)
complex in intracytoplasmic electron-dense neuromelanin granules of SNZC
neurons, with highest levels in a case of PD and Alzheimer's disease (AD). No Fe
increase was found in Lewy bodies or in SN neurons of control specimens. The
relevance of chemical reactions of dopamine (DA), 5-hydroxydopamine (5-OHDA),
and 6-hydroxydopamine (6-OHDA) with Fe(III) and with dioxygen for the
pathogenesis of PD was investigated. An initiating mechanism related to
interaction between Fe and neuromelanin is suggested which results in
accumulation of Fe(III) and a continuous production of cytotoxic species
inducing a cascade of pathogenic reactions ultimately leading to neuronal death.
Iwatsubo, T. (1999). "[Parkinson's disease, dementia with Lewy bodies, multiple
system atrophy and alpha-synuclein]." Rinsho Shinkeigaku39(12):
1285-6.
Lewy bodies (LBs) are hallmark lesions of degenerating neurons in the brains of
patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). DLB
is the second most common neurodegenerative dementia after Alzheimer's disease,
which is characterized clinically by fluctuating cognitive impairments, visual
hallucinations and parkinsonism, and pathologically by the appearance of
cortical LBs. To characterize the components of LBs, we have developed a
purification procedure for LBs from cortices of patients with DLB using sucrose
density separation followed by fluorescence-activated particle sorting. We then
raised monoclonal antibodies (mAbs) to purified LBs, and obtained a mAb (LB509)
that intensely immunolabeled LBs and specifically reacted with a approximately
18kDa brain protein, which was identified as alpha-synuclein. LB509 as well as
other antibodies to alpha-synuclein, but not to beta-synuclein, immunostained
brainstem and cortical LBs in sporadic PD and DLB brains. Recently, a point
mutation in alpha-synuclein gene was identified in some autosomal-deminantly
inherited familial PD pedigrees. Moreover, glial cytoplasmic inclusions in the
brains of patients with multiple system atrophy (MSA) were shown to be
alpha-synuclein positive. Taken together, our data strongly implicate
alpha-synuclein in the formation of LBs and the selective neuronal degeneration
in PD, DLB and MSA.
Imamura, T., N. Hirono, et al. (1999). "Clinical diagnosis of dementia with Lewy
bodies in a Japanese dementia registry." Dement Geriatr Cogn Disord10(3):
210-6.
We found 15 patients with dementia with Lewy bodies (DLB) and 232 patients with
Alzheimer's disease (AD) among 327 consecutive patients with mild to moderate
dementia in a Japanese dementia registry, using the clinical criteria of the
Consortium on DLB International Workshop. The percentage of females was
significantly lower in DLB than in AD (p < 0.01), while age at examination,
Mini-Mental State Examination score and duration of cognitive symptoms were
comparable between the two diseases. Eight of the 15 DLB patients (53%) had
spontaneous parkinsonism, which was observed in 6 of the 232 AD patients (2.6%).
Visual hallucinations were reported by 11 of the 15 DLB patients (73%) and 8 of
the 232 AD patients (3.4%). Cognitive fluctuation was positive in 13 of the 15
DLB patients (87%). We found two types of episodic cognitive deterioration: one
was characterized by pronounced disturbances of attention and alertness
(inattention type), and the other was characterized by marked and bizarre
disturbances of orientation in time and places, and misidentification of persons
(disorientation type). Systematized delusion was observed in 8 DLB patients, and
5 patients showed neuroleptic sensitivity. Patients with DLB have a unique
dementia syndrome even in the stage of mild to moderate cognitive impairments.
Further studies are recommended to establish diagnosis, treatment and
management.
Hattori, N., S. Sumino, et al. (1999). "[An 80-year-old woman with parkinsonism
and progressive dementia]." No To Shinkei51(6): 541-50.
We report an 80-year-old Japanese woman who presented levodopa-responsible
parkinsonism followed by progressive dementia. She was well until her 61 years
of age (in 1978) when she noted onset of resting tremor in her right hand
followed by tremor in her right leg. She was treated with levodopa and
trihexyphenidyl with good response, however, later on, she suffered from gait
disturbance. In 1985, she had an episode of cardio-pulmonary arrest from which
she was resuscitated, however, she started to show hypermetamorphosis, memory
defect, and aggressive behaviors. She also developed motor fluctuations and
dyskinesias from levodopa. She was admitted to our service in 1986; she showed
rather typical parkinsonism and mild dementia. She received left Vim thalamotomy
in the same year. Her dyskinesias improved, however, her gait disturbance became
progressively worse. In 1995, she was admitted to our service again; she showed
marked dementia and advanced parkinsonism; she was unable to walk unsupported.
She became bedridden in 1996 and gastrostomy was placed. She was transferred to
Zushi Aoki Hospital. Her dementia became progressively worse, and she was in the
akinetic and mute state. She expired on April 22, 1998. She was discussed in a
neurological CPC. The chief discussant arrived at a conclusion that the patient
had Parkinson's disease with complication by Alzheimer's disease in her later
clinical course. The diagnoses of participants were divided among Parkinson's
disease with dementia, Parkinson's disease and Alzheimer's disease, and diffuse
Lewy body disease. Postmortem examination revealed marked neuronal loss in the
substantia nigra and the locus coeruleus. Lewy bodies were found in the
substantia nigra. In addition, rather many Lewy bodies of cortical type were
seen in the cingulate gylus, inferior temporal gylus, and in the amygdaloid
nucleus. These Lewy bodies were positive for alpha-synuclein. Also, tau-positive
intra-neuronal tangles were seen in the hippocampus and in the substantia nigra.
The Meynert nucleus showed marked neuronal loss. Pathologic findings were
consistent with the diagnosis of diffuse Lewy body disease.
Hashimoto, M., L. J. Hsu, et al. (1999). "Oxidative stress induces amyloid-like
aggregate formation of NACP/alpha-synuclein in vitro." Neuroreport10(4):
717-21.
The precursor of non-amyloid beta protein component of Alzheimer's disease
amyloid (NACP/alpha-synuclein), found in Lewy bodies of Parkinson's disease
(PD), is a presynaptic protein genetically linked to some familial types PD.
Mechanisms of abnormal NACP/alpha-synuclein aggregation in neurodegenerative
diseases are unclear. Since oxidative stress might play a role in PD
pathogenesis, we investigated the role of iron and peroxide in
NACP/alpha-synuclein aggregation. Immunoblot analysis showed that human
NACP/alpha-synuclein (but not beta-synuclein) aggregated in the presence of
ferric ion and was inhibited by the iron chelator deferoxamine. Ferrous ion was
not effective by itself, but it potentially aggregated NACP/alpha-synuclein in
the presence of hydrogen peroxide. NACP/ alpha-synuclein aggregates displayed
strong thioflavine-S and congo-red reactivity, reminiscent of amyloid. This
study suggests that NACP/alpha-synuclein aggregation might be closely related to
oxidative reactions which may play a critical role in neurodegeneration in
disorders with Lewy bodies.
Harvey, G. T., J. Hughes, et al. (1999). "Magnetic resonance imaging differences
between dementia with Lewy bodies and Alzheimer's disease: a pilot study."
Psychol Med29(1): 181-7.
BACKGROUND: Temporal lobe atrophy on magnetic resonance imaging (MRI) has been
suggested as a specific diagnostic marker for Alzheimer's disease (AD). No
previous comparison with dementia with Lewy bodies (DLB) has been reported.
METHOD: T1-weighted MRI scans were performed on 11 subjects with AD (nine with
NINCDS/ADRDA probable AD and two with neuropathologically proven AD) and nine
subjects with DLB (four with probable DLB diagnosed by clinical criteria and
five with neuropathologically proven DLB). Groups were matched for age, duration
of illness and cognitive test score. Two raters, blind to diagnosis and
neuropathological findings, measured the volumes of the frontal lobes, temporal
lobes, hippocampi, parahippocampal gyri, amygdalae, and caudate nuclei using a
computerized volumetric analysis system. Scans were also rated for medial
temporal atrophy on a four-point scale by an experienced rater. RESULTS: AD
subjects had significantly smaller left temporal lobes and parahippocampal gyri
than those with DLB. Medial temporal atrophy was present in 9/11 AD cases (82%)
and absent in 6/9 (67%) of DLB cases. Two neuropathologically confirmed cases of
DLB had severe medial temporal atrophy; both had concurrent AD-type pathology in
the temporal lobe (Braak stage 4). CONCLUSIONS: This pilot study supports the
hypothesis that a greater burden of pathology centres on the temporal lobes in
AD compared with DLB, except in DLB cases with concurrent Alzheimer pathology. A
larger study is needed to confirm these findings and to determine whether MRI
has a role in assisting with the clinical differentiation between DLB and AD.
Hardy, J. and K. Gwinn-Hardy (1999). "Neurodegenerative disease: a different
view of diagnosis." Mol Med Today5(12): 514-7.
Neurodegenerative diseases have traditionally been defined as
clinicopathological entities. Although this has been a productive paradigm in
terms of the development of treatment strategies, molecular genetic approaches
have revealed that there is overlap between different entities in pathogenic
mechanisms. In this article, it is argued that neurodegenerative disease should
also be thought of as the consequences of sequential biochemical processes, and
that some parts of these processes appear to operate in more than one disease
entity. Defining these pathways and, in particular, developing an appreciation
of the commonalities between different diseases, should aid in the development
of therapies that are effective in several diseases.
Hanyu, H., T. Asano, et al. (1999). "[Is hippocampal atrophy a specific change
for Alzheimer's disease?]." No To Shinkei51(11): 947-51.
Although detection of hippocampal atrophy has been proposed for the diagnosis of
Alzheimer's disease (AD), atrophic changes in MRI can be found in other dementia
diseases. This study was undertaken to determine whether hippocampal atrophy was
a specific change for AD. Coronal T 1-weighted images were performed in 36
patients with AD, 40 patients with non-AD including vascular dementia,
frontemporal dementia, Parkinson's disease with dementia, dementia with Lewy
bodies, progressive supranuclear palsy, and normal pressure hydrocephalus, 9
patients with age-associated memory impairment (AAMI), and 24 control subjects.
Hippocampal atrophy was graded subjectively on a 5-point scale. Scores of
hippocampal atrophy for AD (2.11 +/- 0.95) and non-AD (1.80 +/- 0.91) were
significantly higher than those for controls (0.79 +/- 0.72). Scores for AD were
also significantly higher than those for AAMI (1.11 +/- 0.160), but no
difference was found between AD and non-AD. These results suggest that
hippocampal atrophy is not a specific marker for AD and appears to be a common
phenomenon in dementia syndromes.
Goedert, M. (1999). "Filamentous nerve cell inclusions in neurodegenerative
diseases: tauopathies and alpha-synucleinopathies." Philos Trans R Soc Lond B
Biol Sci354(1386): 1101-18.
Alzheimer's disease and Parkinson's disease are the most common
neurodegenerative diseases. They are characterized by the degeneration of
selected populations of nerve cells that develop filamentous inclusions before
degeneration. The neuronal inclusions of Alzheimer's disease are made of the
microtubule-associated protein tau, in a hyperphosphorylated state. Recent work
has shown that the filamentous inclusions of Parkinson's disease are made of the
protein alpha-synuclein and that rare, familial forms of Parkinson's disease are
caused by missense mutations in the alpha-synuclein gene. Besides Parkinson's
disease, the filamentous inclusions of two additional neurodegenerative
diseases, namely dementia with Lewy bodies and multiple system atrophy, have
also been found to be made of alpha-synuclein. Abundant filamentous tau
inclusions are not limited to Alzheimer's disease. They are the defining
neuropathological characteristic of frontotemporal dementias such as Pick's
disease, and of progressive supranuclear palsy and corticobasal degeneration.
The recent discovery of mutations in the tau gene in familial forms of
frontotemporal dementia has provided a direct link between tau dysfunction and
dementing disease. The new work has established that tauopathies and
alpha-synucleinopathies account for most late-onset neurodegenerative diseases
in man. The formation of intracellular filamentous inclusions might be the gain
of toxic function that leads to the demise of affected brain cells.
Galvin, J. E., K. Uryu, et al. (1999). "Axon pathology in Parkinson's disease
and Lewy body dementia hippocampus contains alpha-, beta-, and gamma-synuclein."
Proc Natl Acad Sci U S A96(23): 13450-5.
Pathogenic alpha-synuclein (alphaS) gene mutations occur in rare familial
Parkinson's disease (PD) kindreds, and wild-type alphaS is a major component of
Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of
Alzheimer's disease, but beta-synuclein (betaS) and gamma-synuclein (gammaS)
have not yet been implicated in neurological disorders. Here we show that in PD
and DLB, but not normal brains, antibodies to alphaS and betaS reveal novel
presynaptic axon terminal pathology in the hippocampal dentate, hilar, and CA2/3
regions, whereas antibodies to gammaS detect previously unrecognized axonal
spheroid-like lesions in the hippocampal dentate molecular layer. The
aggregation of other synaptic proteins and synaptic vesicle-like structures in
the alphaS- and betaS-labeled hilar dystrophic neurites suggests that synaptic
dysfunction may result from these lesions. Our findings broaden the concept of
neurodegenerative "synucleinopathies" by implicating betaS and gammaS, in
addition to alphaS, in the onset/progression of PD and DLB.
Forstl, H. (1999). "The Lewy body variant of Alzheimer's disease: clinical,
pathophysiological and conceptual issues." Eur Arch Psychiatry Clin Neurosci249 Suppl 3: 64-7.
In 1923, Friedrich H. Lewy described dementia with Lewy bodies in a large
proportion of his patients with paralysis agitans which had co-incident plaques
and neurofibrillary tangles. The potential contribution of Lewy bodies to a
dementia syndrome with fluctuating course, visual hallucinations, Parkinsonian
features and neuroleptic hypersensitivity was rediscovered many decades later.
The comorbidity of Alzheimer's and Parkinson's disease is not uncommon as both
diseases show an exponential increase with advancing age and their coincidence
is of great clinical importance. The combination of a cholinergic deficit--which
is particularly severe due to the double pathology targeting the basal nucleus
of Meynert--and a dopaminergic deficit requires cholinergic and cautious
dopaminergic treatment. Excessive dopamine (L-dopa), antidopaminergic
(neuroleptic) or anticholinergic treatment (anti-Parkinson or neuroleptic
medication) may further complicate the condition, worsen extrapyramidal,
psychotic or cognitive disturbances and even lead to a neuroleptic malignant
syndrome.
Duyckaerts, C., M. A. Colle, et al. (1999). "[Alzheimer's disease: lesions and
their progression]." Rev Neurol (Paris)155 Suppl 4: S17-27.
Alzheimer disease appears to be a stereotyped mode of reaction of the central
nervous system to various types of aggression such as different mutations
involving various proteins, trisomy 21 or repeated head trauma as in dementia
pugilistica. Rather than a disease, it appears to be a clinicopathological
syndrome due to various causes. Lesions may be considered under 3 headings:
neurofibrillary pathology, A beta peptide deposits and loss (neuronal and
synaptic). Neurofibrillary pathology includes the neurofibrillary tangle, the
crown of the senile plaque and the neuropil threads. All those lesions are
characterized by the same ultrastructure--i.e. the accumulation of paired
helical filaments--and the same immunohistochemistry: they are labelled by
antibodies directed against the tau proteins. The amyloid deposits, present in
the core of the senile plaque and in the vascular walls, are made of a 40 to 42
amino-acids long peptide, named A beta, derived from the amyloid precursor
protein (APP). Antibodies directed against the A beta peptide also label diffuse
deposits that are devoid of the tinctorial affinities and of the biochemical
properties of amyloid substances. Those diffuse deposits are insufficient to
cause dementia since they may be observed in high density in aged people without
intellectual deterioration. Neuronal loss occurs after neurofibrillary
pathology. The role of the synaptic pathology remains discussed. Besides tau
proteins, A beta peptide and APP, several other proteins may play an important
role: apolipoprotein E which could act as a chaperone protein, inducing or
facilitating the formation of amyloid, presenilins 1 and 2, mutated in some
cases of familial Alzheimer disease, alpha-synuclein which is present in the
Lewy bodies found in Parkinson disease and in dementia with Lewy bodies. The A
beta deposits are diffusely distributed in the cerebral cortex; the
neurofibrillary changes have a hierarchical distribution. The progression of the
neurofibrillary pathology in the various cortical areas follow a stereotyped
sequence that may help to grade the severity of the disease. Progression may
take decades. The relations between aging and Alzheimer disease are still poorly
understood. Frequency of Alzheimer type lesions in old people could suggest that
they are the inevitable burden of age, but this has been discussed.
Defebvre, L. J., V. Leduc, et al. (1999). "Technetium HMPAO SPECT study in
dementia with Lewy bodies, Alzheimer's disease and idiopathic Parkinson's
disease." J Nucl Med40(6): 956-62.
The aim of this study was to compare the regional cerebral blood flow
measurements studied by SPECT in dementia with Lewy bodies (DLB) and Alzheimer's
disease (AD) to determine the contribution of SPECT to the differential
diagnosis of these two diseases. METHODS: SPECT analysis with 99mTc-hexamethyl
propyleneamine oxime (HMPAO) was performed in 20 patients with probable DLB, 20
patients with probable AD and 20 patients with idiopathic Parkinson's disease
(IPD). Ten pairs of regions of interest were analyzed. Tracer uptake was
expressed as a corticocerebellar activity ratio. RESULTS: Compared with IPD, in
the DLB group there was a global decrease of HMPAO uptake in cortical regions of
interest except in the posterior frontal and occipital regions; in the AD group
there was limited left temporal and parietal hypoperfusion. In the DLB group,
frontal HMPAO uptake was significantly lower than in the AD group. Two
predictive scores were established by a factorial discriminant analysis from six
left cortical indices (medial frontal, lateral frontal, posterior frontal,
temporoparietal, parietal and parietooccipital) and the Mini-Mental State
Examination, which correctly classified 53 of 60 patients (88%) (DLB, 18 of 20;
AD, 16 of 20; IPD, 19 of 20). CONCLUSION: These findings indicate the presence
of diffuse cortical abnormalities in DLB and suggest that SPECT may be useful in
discriminating in vivo DLB from AD, revealing mainly frontal hypoperfusion in
the former group. We estimate that SPECT study increases the possibility of
separating DLB and AD because both disorders share different patterns of
cerebral blood flow abnormality.
Culvenor, J. G., C. A. McLean, et al. (1999). "Non-Abeta component of
Alzheimer's disease amyloid (NAC) revisited. NAC and alpha-synuclein are not
associated with Abeta amyloid." Am J Pathol155(4): 1173-81.
alpha-Synuclein (alphaSN), also termed the precursor of the non-Abeta component
of Alzheimer's disease (AD) amyloid (NACP), is a major component of Lewy bodies
and Lewy neurites pathognomonic of Parkinson's disease (PD) and dementia with
Lewy bodies (DLB). A fragment of alphaSN termed the non-Abeta component of AD
amyloid (NAC) had previously been identified as a constituent of AD amyloid
plaques. To clarify the relationship of NAC and alphaSN with Abeta plaques,
antibodies were raised to three domains of alphaSN. All antibodies produced
punctate labeling of human cortex and strong labeling of Lewy bodies. Using
antibodies to alphaSN(75-91) to label cortical and hippocampal sections of
pathologically proven AD cases, we found no evidence for NAC in Abeta amyloid
plaques. Double labeling of tissue sections in mixed DLB/AD cases revealed
alphaSN in dystrophic neuritic processes, some of which were in close
association with Abeta plaques restricted to the CA1 hippocampal region. In
brain homogenates alphaSN was predominantly recovered in the cytosolic fraction
as a 16-kd protein on Western analysis; however, significant amounts of
aggregated and alphaSN fragments were also found in urea extracts of
SDS-insoluble material from DLB and PD cases. NAC antibodies identified an
endogenous fragment of 6 kd in the cytosolic and urea-soluble brain fractions.
This fragment may be produced as a consequence of alphaSN aggregation or
alternatively may accelerate aggregation of the full-length alphaSN.
Clayton, D. F. and J. M. George (1999). "Synucleins in synaptic plasticity and
neurodegenerative disorders." J Neurosci Res58(1): 120-9.
Synucleins are small highly conserved proteins in vertebrates, especially
abundant in neurons and typically enriched at presynaptic terminals. Three genes
in humans produce closely related synuclein proteins, all of which share a large
amphipathic domain capable of reversible binding to lipid vesicles. Alpha
synuclein has been specifically implicated in neurodegenerative disease. Two
point mutations are genetically linked to familial Parkinson's disease, and
alpha synuclein appears to form the major fibrillary component of Lewy bodies.
Alpha synuclein also contributes to the intracellular inclusions of multiple
system atrophy, and a fragment has been found in senile plaques in Alzheimer's
disease. Although their normal cellular functions are unknown, several
observations suggest the synucleins may serve to integrate presynaptic signaling
and membrane trafficking. Alpha synuclein has been identified as a potent and
selective inhibitor of phospholipase D2, which produces phosphatidic acid (to
which synuclein binds) and is believed to function in the partitioning of
membranes between the cell surface and intracellular stores. We outline a
hypothesis whereby synuclein supports localized, experience-dependent turnover
of synaptic membranes. Such a process may be important for lifelong learning and
memory functions and may be especially vulnerable to disruption in
aging-associated neurodegenerative diseases.
Chen, J. S. and K. Mehta (1999). "Tissue transglutaminase: an enzyme with a
split personality." Int J Biochem Cell Biol31(8): 817-36.
Tissue transglutaminase (tTG) belongs to the family of transglutaminase enzymes
that catalyze the posttranslational modification of proteins via
Ca(2+)-dependent cross-linking reactions. The catalytic action of tTG results in
the formation of an isopeptide bond that is of great physiological significance
since it is highly resistant to proteolysis and denaturants. Although
tTG-mediated cross-linking reactions have been implicated to play a role in
diverse biological processes, the precise physiological function of the enzyme
remains unclear. Recent data, however, suggest that the protein polymers
resulting from tTG-catalyzed reactions may play a role in commitment of cells to
undergo apoptosis. On the same token, tTG-mediated formation of insoluble
protein aggregates may underlie the markers of numerous pathological conditions,
such as the senile plaques in Alzheimer's disease and the Lewy bodies in
Parkinson's disease. In addition to catalyzing Ca(2+)-dependent cross-linking
reactions, tTG can also bind and hydrolyze guanosine triphosphate and adenosine
triphosphate. By virtue of this ability, tTG has been identified as a novel
G-protein that interacts and activates phospholipase C following stimulation of
the alpha-adrenergic receptor. The ability of tTG to mediate signal transduction
may contribute to its involvement in the regulation of cell cycle progression.
The following review summarizes the important features of this multifunctional
enzyme that have emerged as a result of recent work from different laboratories.
Camicioli, R., J. Kaye, et al. (1999). "Apolipoprotein E epsilon4 is associated
with neuronal loss in the substantia nigra in Alzheimer's disease." Dement
Geriatr Cogn Disord10(6): 437-41.
Apolipoprotein E epsilon4 (ApoE epsilon4) is associated with an earlier age at
onset of Alzheimer's (AD) and possibly Parkinson's disease, suggesting a general
role for ApoE epsilon4 in neuronal plasticity. Among 31 prospectively assessed
subjects with pathologically confirmed AD (without Lewy bodies), epsilon4+
subjects had a longer duration of disease (by 2.8 years, p = 0.04). Only cell
loss in the substantia nigra (p = 0.002) was associated with epsilon4. Neither
neurofibrillary tangles nor plaque counts were associated with epsilon4. Cell
counts of pigmented neurons in single midbrain sections in epsilon4+ specimens
were 72% of those in epsilon4- substantia nigra (p = 0.04). These findings
confirm that cell loss in the substantia nigra is associated with epsilon4 in
AD. Copyrightz1999S.KargerAG,Basel
Bayer, T. A., P. Jakala, et al. (1999). "Alpha-synuclein accumulates in Lewy
bodies in Parkinson's disease and dementia with Lewy bodies but not in
Alzheimer's disease beta-amyloid plaque cores." Neurosci Lett266(3):
213-6.
A growing body of evidence suggests that the non-Abeta component of Alzheimer's
disease amyloid precursor protein (NACP) or alpha-synuclein contributes to the
neurodegenerative processes in Alzheimer's disease (AD), Parkinson's disease
(PD) and dementia with Lewy bodies (DLB). In the present study antisera to the N
terminus and the NAC domain of the alpha-synuclein protein were employed to
elucidate the expression pattern in brains of patients with AD, PD, DLB and
control specimen. Alpha-synuclein exhibited an overall punctuate expression
profile compatible with a synaptic function. Interestingly, while Lewy bodies
were strongly immunoreactive, none of the alpha-synuclein antisera revealed
staining in mature beta-amyloid plaques in AD. These observations suggest that
alpha-synuclein does not contribute to late neurodegenerative processes in AD
brains.
Atkinson, A., A. B. Singleton, et al. (1999). "CYP2D6 is associated with
Parkinson's disease but not with dementia with Lewy Bodies or Alzheimer's
disease." Pharmacogenetics9(1): 31-5.
The similarities between the clinical and pathological findings of dementia with
Lewy Bodies (DLB) with Alzheimer's disease and Parkinson's disease are complex,
and their significance for pathogenesis is unresolved. It is likely that DLB
shares common disease determinants with both Alzheimer's disease and Parkinson's
disease. Clinically DLB shows the presence of dementia similar, though not
identical, to that found in Alzheimer's disease. A parkinsonian movement
disorder is present in a proportion of DLB cases. Pathologically DLB shows
senile plaques, as with Alzheimer's disease, and also substantia nigra neurone
loss and Lewy bodies, as with Parkinson's disease. At a genetic level, DLB shows
an elevated Apolipoprotein E epsilon4 frequency as described in Alzheimer's
disease, but this is absent in Parkinson's disease. An elevated frequency of the
CYP2D6*4 allele has been found in Parkinson's disease and we have therefore
genotyped a large series of clinically and neuropathologically confirmed cases
of DLB, Alzheimer's disease, Parkinson's disease and age-matched control
individuals for the CYP2D6*4 allele. Whilst an elevated frequency of the
CYP2D6*4 allele was found in Parkinson's disease, no such elevations were found
in DLB or Alzheimer's disease. Stratification of the CYP2D6*4 allele with
respect to the Apolipoprotein E epsilon4 also did not show any significant
associations with the CYP2D6*4 allele. The CYP2D6*4 allele is not a major
genetic determinant of DLB and the results place DLB with Alzheimer's disease
rather than Parkinson's disease on a genetic level.
Arima, K., S. Hirai, et al. (1999). "Cellular co-localization of phosphorylated
tau- and NACP/alpha-synuclein-epitopes in lewy bodies in sporadic Parkinson's
disease and in dementia with Lewy bodies." Brain Res843(1-2):
53-61.
The precursor of the non-Abeta-component of Alzheimer's disease (AD) amyloid
(NACP, alpha-synuclein) aggregates into insoluble filaments of Lewy bodies (LBs)
in Parkinson's disease (PD) and dementia with LBs (DLB). The
microtubule-associated protein tau is an integral component of filaments of
neurofibrillary tangles (NFTs). NFTs are occasionally found in brains of PD and
DLB; however, the presence of NFTs or tau-epitopes within LB-containing neurons
is rare. Double-immunofluorescence study and peroxidase-immunohistochemical
study in serial sections, performed to examine the co-localization of tau- and
NACP-epitopes in the brainstem of PD and DLB, demonstrated that four different
epitopes of tau including phosphorylation-dependent and independent ones were
present in a minority of LBs, but more often than previously considered. A tau
(tau2)-epitope was localized to filaments in the outer layers of brainstem-type
LBs by immunoelectron microscopy. Therefore, we conclude that tau is
incorporated into filaments in certain LBs. Extensive investigation has enabled
us to classify this co-localization into four types: type 1, LBs with
ring-shaped tau-immunoreactivity; type 2, LBs surrounded by NFTs; type 3, NACP-
and tau-immunoreactive filamentous and granular masses; and type 4, NACP- and
tau-immunoreactive dystrophic neurites. This study raises a new question whether
aggregation and hyperphosphorylation of tau in PD and DLB are triggered by the
collapse of intraneuronal organization of microtubules due to NACP-filament
aggregation in neuronal perikarya and axons.
Ala, T. A., K. H. Yang, et al. (1999). "Clinical parkinsonism in dementia
patients with substantia nigra Lewy bodies." J Neural Transm106(1):
47-57.
In a retrospective clinicopathological study, we examined the substantia nigra
(SN) of 48 dementia patients with SN Lewy bodies (LBs) to determine if the
severity of degeneration correlated with either the occurrence of signs of
parkinsonism at dementia presentation or with the frequency of treatment for
parkinsonism during the disease course. The SN specimens were graded for
microscopic degeneration using a semi-quantitative five-tiered scale. Whereas no
correlation was found between the grade of degeneration and occurrence of signs
at presentation (r = -0.16, p = 0.18), with 16 of 38 patients having had signs
reported, a more severe grade was statistically correlated with an increased
frequency of treatment during the course (r = 0.41, p = 0.004), with ten of 41
patients having been treated for parkinsonism. Contrary to our expectations, we
found that fewer than half of the patients with the two most severe grades of
degeneration presented with signs of parkinsonism or were ever treated for
parkinsonism.
Wakabayashi, K., A. Kakita, et al. (1998). "Apolipoprotein E epsilon4 allele and
progression of cortical Lewy body pathology in Parkinson's disease." Acta
Neuropathol (Berl)95(5): 450-4.
To elucidate whether the apolipoprotein E epsilon4 allele (APOE4) affects
cortical neuropathology in Parkinson's disease (PD), we determined APOE
genotypes and quantified the densities of cortical Lewy bodies (LBs), amyloid
plaques and neurofibrillary tangles in 22 autopsy-proven PD cases (12 with
dementia; 10 without dementia) that were not accompanied by Alzheimer's disease.
The APOE4 frequency in the demented patient group was 0.21, which was
significantly higher than that in Japanese controls (P < 0.04). LB densities in
demented PD patients were significantly higher than those in non-demented PD
patients, despite the shorter disease duration in the former. Moreover, plaque
density in the temporal cortex and LB density in the cingulate cortex were
significantly higher in the group with APOE4 than in that without the allele.
There was no difference in tangle density between these two groups. These
results suggest that APOE4 may influence the increase in the number of cortical
LBs and amyloid plaques in PD. It is possible that when PD occurs in individuals
with APOE4, concomitantly evolving cortical LB pathology in a proportion of
cases results in limbic (transitional) or neocortical-type LB disease.
Wakabayashi, K., S. Hayashi, et al. (1998). "Accumulation of
alpha-synuclein/NACP is a cytopathological feature common to Lewy body disease
and multiple system atrophy." Acta Neuropathol (Berl)96(5):
445-52.
Recently, we have shown that the precursor of the non-Abeta component of
Alzheimer's disease amyloid (NACP), also known as alpha-synuclein, is a major
component of Lewy bodies (LBs) as well as neuronal and glial cytoplasmic
inclusions in multiple system atrophy (MSA). To elucidate whether the
accumulation of NACP is specific to LB disease and MSA, we further studied 83
autopsied cases with various neurological disorders, using anti-NACP antibodies.
In LB disease, NACP immunoreactivity was present in all of the LBs and Lewy
neurites in both the central and peripheral nervous systems, the pale bodies in
the substantia nigra, and dystrophic neurites in the hippocampal CA2/3 region.
Immunoelectron microscopy revealed that the reaction product was localized
within filamentous structures and associated granular structures. In MSA, NACP
immunoreactivity was found in the intracytoplasmic inclusions of both neuronal
and oligodendroglial cells, neuronal intranuclear inclusions, and swollen
neuronal processes. No NACP immunoreactivity was found in a variety of other
neuronal or glial inclusions in other disorders, including Alzheimer's disease,
Pick's disease, progressive supranuclear palsy, corticobasal degeneration, motor
neuron disease and triplet-repeat diseases. These findings strongly suggest that
the accumulation of NACP is a cytopathological feature common to LB disease and
MSA.
Verny, M. and C. Duyckaerts (1998). "Dementia with Lewy bodies." Ann Med
Interne (Paris)149(4): 209-15.
The presence of a high number of Lewy bodies--the morphological marker of
Parkinson's disease--in the cerebral cortex of some cases of dementia has been
frequently observed in association to Alzheimer type lesions (mainly senile
plaques) and changes in the substantia nigra, that may be held responsible for
the frequently associated symptoms of parkinsonism. The term "dementia with Lewy
body" (DLB) has recently been suggested by a consensus conference and indicates
that the pathogenetic mechanism of the dementia remains poorly understood.
Marked fluctuations of alertness and of the cognitive performances, moderate
parkinsonism and episodes of visual hallucinations may lead to suspect this
diagnosis in cases of dementia. Unexplained falls, syncopes, delirium or
alterations of consciousness may also be observed, and the patients may then be
admitted in departments of internal medicine or geriatrics. The Lewy body is an
intraneuronal spherical inclusion, present in Parkinson's disease. It is
observed in the brainstem (substantia nigra, locus coeruleus, dorsal nucleus of
the Xth nerve) and in the nucleus basalis of Meynert. The cortical Lewy bodies
have a different aspect, but retain their antigenic characteristics: they are,
in particular, stained by the antiubiquitin antibodies. Recently, they were
found to be also labeled by antisynuclein antibodies. A mutation of the
synuclein gene was recently identified in cases of familial Parkinson's disease.
Clinically as well as pathologically, DLB may thus be difficult to distinguish
from Alzheimer's disease on the one hand, and from Parkinson's disease, on the
other. That diagnosis, however, is associated with a poor prognosis and should
lead to specific therapeutic measures.
Tu, P. H., J. E. Galvin, et al. (1998). "Glial cytoplasmic inclusions in white
matter oligodendrocytes of multiple system atrophy brains contain insoluble
alpha-synuclein." Ann Neurol44(3): 415-22.
Recently, alpha-synuclein was shown to be a structural component of the
filaments in Lewy bodies (LBs) of Parkinson's disease (PD), dementia with LBs
(DLB) as well as the LB variant of Alzheimer's disease, and this suggests that
alpha-synuclein could play a mechanistic role in the pathogenesis of these
disorders. To determine whether alpha-synuclein is a building block of
inclusions in other neurodegenerative movement disorders, we examined brains
from patients with multiple system atrophy (MSA) and detected alpha-synuclein,
but not beta- or gamma-synuclein, in glial cytoplasmic inclusions (GCIs)
throughout the MSA brain. In MSA white matter, alpha-synuclein-positive GCIs
were restricted to oligodendrocytes, and alpha-synuclein was localized to the
filaments in GCIs by immunoelectron microscopy. Finally, we demonstrated that
insoluble alpha-synuclein accumulated selectively in MSA white matter with
alpha-synuclein-positive GCIs. Taken together with evidence that LBs contain
insoluble alpha-synuclein, our data suggest that a reduction in the solubility
of alpha-synuclein may induce this protein to form filaments that aggregate into
cytoplasmic inclusions, which contribute to the dysfunction or death of glial
cells as well as neurons in neurodegenerative disorders with different
phenotypes.
Trojanowski, J. Q., M. Goedert, et al. (1998). "Fatal attractions: abnormal
protein aggregation and neuron death in Parkinson's disease and Lewy body
dementia." Cell Death Differ5(10): 832-7.
The abnormal aggregation of proteins into fibrillar lesions is a
neuropathological hallmark of several sporadic and hereditary neurodegenerative
diseases. For example, Lewy bodies (LBs) are intracytoplasmic filamentous
inclusions that accumulate primarily in subcortical neurons of patients with
Parkinson's disease (PD), or predominantly in neocortical neurons in a subtype
of Alzheimer's disease (AD) known as the LB variant of AD (LBVAD) and in
dementia with LBs (DLB). Aggregated neurofilament subunits and alpha-synuclein
are major protein components of LBs, and these inclusions may contribute
mechanistically to the degeneration of neurons in PD, DLB and LBVAD. Here we
review recent studies of the protein building blocks of LBs, as well as the role
LBs play in the onset and progression of PD, DLB and LBVAD. Increased
understanding of the protein composition and pathological significance of LBs
may provide insight into mechanisms of neuron dysfunction and death in other
neurodegenerative disorders characterized by brain lesions containing massive
deposits of proteinacious fibrils.
Takeda, A., M. Mallory, et al. (1998). "Abnormal accumulation of
NACP/alpha-synuclein in neurodegenerative disorders." Am J Pathol152(2):
367-72.
The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP)
(also known as a-synuclein) is a presynaptic terminal molecule that accumulates
in the plaques of Alzheimer's disease. Recent studies have shown that a mutation
in NACP is associated with familial Parkinson's disease, and that Lewy bodies
are immunoreactive with antibodies against this molecule. To clarify the
patterns of accumulation and differences in abnormal compartmentalization, we
studied NACP immunoreactivity using double immunolabeling and laser scanning
confocal microscopy in the cortex of patients with various neurodegenerative
disorders. In Lewy body variant of Alzheimer's disease, diffuse Lewy body
disease, and Parkinson's disease, NACP was found to immunolabel cortical Lewy
bodies, abnormal neurites, and dystrophic neurites in the plaques.
Double-labeling studies showed that all three of these neuropathological
structures also contained ubiquitin, synaptophysin, and neurofilament (but not
tau) immunoreactivity. In contrast, neurofibrillary tangles, neuropil threads,
Pick bodies, ballooned neurons, and glial tangles (most of which were tau
positive) were NACP negative. These results support the view that NACP
specifically accumulates in diseases related to Lewy bodies such as Lewy body
variant of Alzheimer's disease, diffuse Lewy body disease, and Parkinson's
disease and suggests a role for this synaptic protein in the pathogenesis of
neurodegeneration.
Takeda, A., M. Hashimoto, et al. (1998). "Abnormal distribution of the non-Abeta
component of Alzheimer's disease amyloid precursor/alpha-synuclein in Lewy body
disease as revealed by proteinase K and formic acid pretreatment." Lab Invest78(9): 1169-77.
The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP)
(also known as alpha-synuclein) is a presynaptic terminal molecule that
abnormally accumulates in the plaques of Alzheimer's disease (AD) and in the
Lewy bodies (LBs) of Lewy body variant of AD, diffuse Lewy body disease, and
Parkinson's disease. To better understand the distribution of
NACP/alpha-synuclein and its fragments in the LB-bearing neurons and neurites,
as well as to clarify the patterns of NACP/alpha-synuclein compartmentalization,
we studied NACP/alpha-synuclein immunoreactivity using antibodies against the
C-terminal, N-terminal, and NAC regions after Proteinase K and formic acid
treatment in the cortex of patients with LBs. Furthermore, studies of the
subcellular localization of NACP/alpha-synuclein within LB-bearing neurons were
performed by immunogold electron microscopy. These studies showed that the
N-terminal antibody immunolabeled the LBs and dystrophic neurites with great
intensity and, to a lesser extent, the synapses. In contrast, the C-terminal
antibody strongly labeled the synapses and, to a lesser extent, the LBs and
dystrophic neurites. Whereas Proteinase K treatment enhanced
NACP/alpha-synuclein immunoreactivity with the C-terminal antibody, it
diminished the N-terminal NACP/alpha-synuclein immunoreactivity. Furthermore,
formic acid enhanced LB and dystrophic neurite labeling with both the C- and
N-terminal antibodies. In addition, whereas without pretreatment only slight
anti-NAC immunoreactivity was found in the LBs, formic acid pretreatment
revealed an extensive anti-NAC immunostaining of LBs, plaques, and glial cells.
Ultrastructural analysis revealed that NACP/alpha-synuclein immunoreactivity was
diffusely distributed within the amorphous electrodense material in the LBs and
as small clusters in the filaments of LBs and neurites. These results support
the view that aggregated NACP/alpha-synuclein might play an important role in
the pathogenesis of disorders associated with LBs.
Spillantini, M. G., R. A. Crowther, et al. (1998). "alpha-Synuclein in
filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with
lewy bodies." Proc Natl Acad Sci U S A95(11): 6469-73.
Lewy bodies and Lewy neurites are the defining neuropathological characteristics
of Parkinson's disease and dementia with Lewy bodies. They are made of abnormal
filamentous assemblies of unknown composition. We show here that Lewy bodies and
Lewy neurites from Parkinson's disease and dementia with Lewy bodies are stained
strongly by antibodies directed against amino-terminal and carboxyl-terminal
sequences of alpha-synuclein, showing the presence of full-length or close to
full-length alpha-synuclein. The number of alpha-synuclein-stained structures
exceeded that immunoreactive for ubiquitin, which is currently the most
sensitive marker of Lewy bodies and Lewy neurites. Staining for alpha-synuclein
thus will replace staining for ubiquitin as the preferred method for detecting
Lewy bodies and Lewy neurites. We have isolated Lewy body filaments by a method
used for the extraction of paired helical filaments from Alzheimer's disease
brain. By immunoelectron microscopy, extracted filaments were labeled strongly
by anti-alpha-synuclein antibodies. The morphologies of the 5- to 10-nm
filaments and their staining characteristics suggest that extended
alpha-synuclein molecules run parallel to the filament axis and that the
filaments are polar structures. These findings indicate that alpha-synuclein
forms the major filamentous component of Lewy bodies and Lewy neurites.
Sparks, D. L., T. G. Beach, et al. (1998). "Immunohistochemical localization of
nicotinic beta2 and alpha4 receptor subunits in normal human brain and
individuals with Lewy body and Alzheimer's disease: preliminary observations."
Neurosci Lett256(3): 151-4.
Optimum immunohistochemical methods were established to immuno-localize
nicotinic acetylcholine receptor alpha4 and beta2 subunits in temporal cortex
and substantia nigra of normal aged and diseased human brain. In normal aged
brain, fibers were immunoreactive for both the alpha4 and beta2 subunits of the
nicotinic receptor in the temporal cortex and the substantia nigra. In the
cortex of normal aged brain, rare neurofibrillary tangles occurring could be
identified with either anti-alpha4 or anti-beta2 antibodies, but existing senile
plaques were demonstrable with neither. In Alzheimer's disease temporal cortex,
there were diminished numbers of nicotinic receptor subunit immunoreactive
fibers, and there were appreciable numbers of neuropil threads, neurofibrillary
tangles and senile plaques immunoreactive with both the alpha4 and beta2
antibodies.
Shimomura, T., E. Mori, et al. (1998). "Cognitive loss in dementia with Lewy
bodies and Alzheimer disease." Arch Neurol55(12): 1547-52.
BACKGROUND: Dementia with Lewy bodies (DLB) is emerging as a common cause of
degenerative dementia. Some preliminary evidence exists that the pattern of
cognitive impairment in DLB is different from that in Alzheimer disease (AD).
OBJECTIVE: To delineate features of cognitive impairment of DLB on standardized
neuropsychological tests. METHODS: We performed neuropsychological assessments
of 26 patients with probable DLB (based on criteria of the consortium on DLB
international workshop) and of 52 patients with probable AD (based on criteria
of the National Institute of Neurological and Communicative Disorders and Stroke
[now the National Institute of Neurological Disorders and Stroke])-Alzheimer's
Disease and Related Disorders Association) who were matched to the patients with
DLB 2:1 by age, sex, education, and Mini-Mental State Examination score.
RESULTS: Compared with the group with probable AD, the group with probable DLB
scored significantly lower on the picture arrangement, block design, object
assembly, and digit symbol substitution subtests of the Wechsler Adult
Intelligence Scale-Revised and on the Raven Colored Progressive Matrices test
and significantly higher on the Mini-Mental State Examination locational
orientation subtest and the Alzheimer's Disease Assessment Scale word recall
subtest. A discriminant analysis revealed that the word recall score on the
Alzheimer's Disease Assessment Scale and the block design score on the Wechsler
Adult Intelligence Scale-Revised were the best discriminant factors.
CONCLUSIONS: The disproportionately severe visuoperceptual, visuoconstructive,
and visuospatial dysfunction and the disproportionately mild memory impairment
in DLB compared with AD, which likely reflect the distribution of the pathologic
changes in DLB, can help to differentiate DLB from AD.
Scarbrough, T. J. (1998). "Diffuse Lewy body disease: a common yet misdiagnosed
dementia in which neuroleptics may be contraindicated." Tenn Med91(2):
58-60.
Pirim, I. (1998). "Production of anti-polyubiquitin and anti-ubiquitin carboxyl
terminal hydrolase antibodies and immunohistochemically assessment of them on
brain sections of Alzheimer's disease and Lewy body disease." Int J Neurosci95(1-2): 33-42.
Several ubiquitin (ub) moieties are lined up head to tail by function of class
III genes which code for polyubiquitin proteins. Ubiquitin carboxyl terminal
hydrolyses (UCTH) disassemble the polyubiquitin chains. In our study we
synthetically produced polyubiquitin (last six amino acids of ub is linked with
first five amino acids of ub, UBI(71-76 + 1-5)) and purified anti-UCTH from
human brain to produce antibodies against them. These antibodies were used on
Alzheimer's and Lewy body disease brains. Anti-UBI(71-76 + 1-5) antibody stained
plaque neurites of both disease brains. Anti-UCTH antibody showed reactivity
with cortical Lewy bodies within the neurons and bulbous neurites of Alzheimer's
disease and Lewy body disease brains.
Petit, H., F. Lebert, et al. (1998). "[Lewy body dementia]." Rev Neurol
(Paris)154 Suppl 2: S99-105.
Dementia with Lewy Bodies (DLB) is an entity which now fulfils clinical and
neuropathological criteria according to international consensus guidelines
(McKeith et al., 1996). It is now possible, in clinical practice, to consider
the diagnosis of DLB from the beginning of the management of a demented patient.
The clinical, diagnostic and therapeutic aspects of DLB are investigated in a
prospective manner. Visual hallucinations, fluctuations and extrapyramidal
symptoms seem to have, in association with the progressive cognitive decline,
some particularities. However their specificity should be correlated with
neuropathological data. Other symptoms, such as repeated falls or syncope,
neuroleptic sensitivity, systematized delusions or other modalities of
hallucinations, are probably additional arguments giving more predictive value
to the association of the major symptoms. The role of neuropsychological
patterns at the beginning of the cognitive decline is shown. There are some
recent concordant results of functional imaging in DLB. The neuropathological
aspects of DLB and the links with Parkinson pathology and especially Alzheimer
pathology are emphasized.
Perry, E., J. Court, et al. (1998). "Clinical neurochemistry: developments in
dementia research based on brain bank material." J Neural Transm105(8-9):
915-33.
Brain tissue obtained at autopsy continues to provide unique opportunities in
current dementia research. Not only is tissue analysis still essential for
diagnosis, but investigation of neurochemical pathology, at a level of
resolution beyond current in vivo imaging, continues to provide new insights
into the involvement of neurotransmitter signalling systems. These are relevant
to therapy which, with respect to symptoms such as cognitive impairment,
psychosis and depression, is currently targeted to specific transmitter
(cholinergic, dopaminergic and serotonergic) systems. This paper focuses on
dopaminergic, cholinergic and histaminergic parameters in Alzheimer's disease
(AD), Dementia with Lewy bodies (DLB) and Parkinson's disease (PD). In the
normal striatum the dopamine transporter and D2 receptor exhibit distinct
rostral-caudal distributions and D2 binding is affected by genetic polymorphism
at the Taq 1A locus. The transporter is reduced in both DLB and PD but not AD,
correlating with severity of extrapyramidal dysfunction, and receptor
abnormalities are apparent in DLB patients responding adversely to neuroleptics.
Striatal nicotine receptors are lost in all 3 disorders, further reduced as a
result of neuroleptic medication, and elevated as a result of tobacco use. In
the thalamus there are selective reductions in presynaptic cholinergic activity
in DLB in the reticular nucleus which relate to symptoms of hallucinations and
fluctuating consciousness prevalent in this disorder. In the hippocampus
coupling of muscarinic M1 receptors, relevant to response to cholinergic
therapy, is impaired in areas most affected by beta-amyloid plaques and intact
in less affected areas. Analysis of histamine H2 receptors indicates that,
despite presynaptic histamine abnormalities in AD, receptor numbers are normal.
Such clinically and therapeutically relevant observations on human brain
neurochemistry provide a basis for improving therapeutic strategies and
prospects of diagnostic in vivo chemical imaging.
Perl, D. P., C. W. Olanow, et al. (1998). "Alzheimer's disease and Parkinson's
disease: distinct entities or extremes of a spectrum of neurodegeneration?"
Ann Neurol44(3 Suppl 1): S19-31.
Alzheimer's disease (AD) and Parkinson's disease (PD) are generally considered
to be separate and distinct disease entities. However, a considerable amount of
evidence demonstrates that these disorders share common clinical and
neuropathologic features and that overlap between the two conditions is
extensive. For example, a significant percentage of AD patients exhibit
extrapyramidal features, and many PD patients develop dementia. Similarly, at
autopsy many AD patients not only exhibit the neuropathologic features of that
disorder but also exhibit nigral pathology, including Lewy bodies. The vast
majority of demented PD patients show widespread neurofibrillary tangles and
senile plaques as well as Lewy body formation and nigral degeneration. The
extent of such overlap is far greater than one would anticipate by chance alone.
We argue that such overlap reflects a common pathogenic mechanism for the
neurodegeneration encountered within specific vulnerable neuronal populations.
Furthermore, we suggest that the current nosologic approach, which attempts to
separate AD from PD, fails to properly deal with the issue of overlap and that a
new classification of the neurodegenerative disorders should be considered.
Papka, M., A. Rubio, et al. (1998). "A review of Lewy body disease, an emerging
concept of cortical dementia." J Neuropsychiatry Clin Neurosci10(3):
267-79.
Dementia associated with cortical Lewy bodies on neuropathologic examination may
comprise the second largest category of age-related cognitive impairment, after
Alzheimer's disease. Despite its prevalence, a consensus has not yet been
reached regarding the terminology, neuropathologic criteria, or clinical
symptomatology of this postulated nosologic entity. Lewy body disease (LBD) is
beginning to be diagnosed clinically in neuropsychiatric clinics, but
universally accepted diagnostic criteria for LBD remain to be validated. In this
article the authors review the literature on LBD, including both neuropathologic
and clinical findings.
Olichney, J. M., D. Galasko, et al. (1998). "Cognitive decline is faster in Lewy
body variant than in Alzheimer's disease." Neurology51(2): 351-7.
OBJECTIVES: To quantify the rate of cognitive decline on the Mini-Mental State
Examination (MMSE) in autopsy-diagnosed Lewy body variant (LBV) of Alzheimer's
disease (AD) cases. We hypothesized that LBV patients would have a faster
cognitive decline and shorter survival compared with patients with pure AD.
BACKGROUND: Prior reports have shown extrapyramidal signs to be associated with
a poorer prognosis in AD. It has been suggested that LBV is often characterized
by a rapidly progressive course. Few data are available regarding the rate of
cognitive decline in autopsy-confirmed LBV dementia cases. METHODS: We searched
the databases of the University of California-San Diego Alzheimer's Disease
Research Center and the Consortium to Establish a Registry in Alzheimer's
Disease (CERAD) for dementia cases with 1) an autopsy diagnosis of definite or
probable AD (CERAD criteria) with concomitant Lewy bodies and 2) longitudinal
MMSE assessments. This resulted in a series of 40 LBV cases and 148 AD cases
without Lewy bodies, with comparable baseline MMSE scores, age, and education.
The rate of cognitive decline was calculated as the baseline MMSE -- final MMSE.
Methods were devised to reduce floor effects on the MMSE. RESULTS: The average
rate of cognitive decline was -5.8 +/- 4.5 points/y in LBV and -4.1 +/- 3.0
points/y in AD (t-test, p < 0.01). The LBV group declined a similar amount on
the MMSE (means, -10.0 versus -9.6 points) over a significantly shorter time
interval (1.9 versus 2.7 years; p = 0.005) than did AD patients. At baseline,
the mean MMSE scores were nearly identical (18.2 in LBV; 17.8 in AD), but on
follow-up examinations approximately 1, 2, and 3 years later, there were
intergroup mean differences of 1.8 points (two-tailed p = 0.19), 4.2 points (p =
0.04), and 5.6 points (p = 0.03), respectively. The LBV cases had shorter
survival time from the onset of cognitive symptoms (7.7 +/- 3.0 years versus 9.3
+/- 3.5 years; p = 0.007) and a shorter mean survival after entry/baseline,
which was of marginal significance (3.6 versus 4.1 years; p = 0.11).
CONCLUSIONS: This study demonstrates that LBV is characterized by a faster
cognitive decline and accelerated mortality compared with AD.
Mezey, E., A. M. Dehejia, et al. (1998). "Alpha synuclein is present in Lewy
bodies in sporadic Parkinson's disease." Mol Psychiatry3(6):
493-9.
A missense mutation in the human alpha synuclein gene was recently identified in
some cases of familial Parkinson's disease (FPD). We have developed an antibody
that recognizes the C-terminal 12 amino acids of the human alpha synuclein
protein and have demonstrated that alpha synuclein is an abundant component of
the Lewy bodies found within the degenerating neurons of patients with
Parkinson's disease (PD). The presence of alpha synuclein in Lewy bodies of
sporadic PD patients suggests a central role for alpha synuclein in the
pathogenesis of PD.
McKeith, I. G., P. Ince, et al. (1998). "What are the relations between Lewy
body disease and AD?" J Neural Transm Suppl54: 107-16.
Several hospital based autopsy series indicate dementia with Lewy bodies (DLB)
to be the second most common pathological subtype of degenerative dementia in
elderly subjects. The majority of DLB cases have high densities of beta amyloid
senile plaques, whereas neocortical neurofibrillary tangle density is only
slightly increased above age-matched normal control values and over tenfold
lower than the average in Alzheimer's disease. The interpretation of this
Alzheimer type pathology is problematic, reflecting in part changing views about
the neuropathological diagnosis of AD itself. AD is characterised by
hyperphosphorylation of the microtubular associated protein tau, and DLB by
neurofilament abnormalities including phosphorylation, ubiquitination,
proteolysis, and cross-linking of constituent proteins. The two diseases appear
therefore to be distinct at an ultrastructural and molecular level, a conclusion
which is consistent with the fact that the clinical syndromes associated with
DLB and AD are sufficiently differentiated to allow for accurate antemortem
diagnosis.
McGeer, P. L. and E. G. McGeer (1998). "Glial cell reactions in
neurodegenerative diseases: pathophysiology and therapeutic interventions."
Alzheimer Dis Assoc Disord12 Suppl 2: S1-6.
A variety of proteins known to be involved in inflammatory processes are
associated with lesions in chronic neurodegenerative disorders such as Alzheimer
disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).
This is particularly true of AD, in which inflammatory reactions are believed to
be important contributors to the neuronal loss. Inflammatory proteins associated
with AD include complement proteins, complement inhibitors, acute-phase
reactants, inflammatory cytokines, proteases, and protease inhibitors. Studies
of cultured human astrocytes and microglia obtained from postmortem brain have
established that almost all of these proteins are produced by one or the other
of these two cell types. Human neurons also produce many inflammatory proteins
and their inhibitors, creating complex interactions. Accumulations of amyloid,
extracellular tangles, or Lewy bodies apparently act as irritants, causing the
activation of complement, the initiation of reactive changes in microglia, and
the release of potentially neurotoxic products such as the membrane attack
complex, oxygen free radicals, and excess glutamate. A number of epidemiologic
studies indicate that populations taking anti-inflammatory drugs have a sharply
reduced prevalence of AD. One small clinical trial with indomethacin showed
arrest of the disease over a 6-month period. Therapeutic intervention in key
inflammatory processes holds great promise for the amelioration of AD and
possibly other neurodegenerative disorders.
Mattila, P. M., M. Roytta, et al. (1998). "Cortical Lewy bodies and
Alzheimer-type changes in patients with Parkinson's disease." Acta
Neuropathol (Berl)95(6): 576-82.
We investigated the role of cortical Lewy bodies (LB) and Alzheimer-type changes
in cognitive impairment in patients with idiopathic Parkinson's disease (PD). We
evaluated 44 cases for the extent of neuropathological lesions with a CERAD
neuropathological assessment battery and the stage of dementia using Reisberg's
global deterioration scale (GDS). Substantia nigra, amygdala, hippocampus and
cerebral cortex were examined for LB and Alzheimer-type changes. For detection
of LB, the cortical areas were stained with polyclonal antibodies against
ubiquitin and tau. We found at least one cortical LB in 93% of cases.
Furthermore, 43% of the cases had histological findings of definite Alzheimer's
disease (AD). The association between cognitive impairment and the number of
cortical LB and Alzheimer-type changes in the amygdala, hippocampus and six
selected gyri from cerebral cortex were analyzed using stepwise linear
regression. In this analysis the total number of cortical LB, and the amount of
neurofibrillary tangles in the temporal cortex remained statistically
significant. When the cases with neuropathological changes consistent with a
diagnosis of AD were excluded, the correlation between the total number of
cortical LB and cognitive impairment was more obvious. A stepwise linear
regression analysis in these cases found the total number of cortical LB to be
the statistically significant predictor of cognitive impairment. This study
revealed that LB densities in the cortex, especially in the temporal neocortex,
correlated significantly with the cognitive impairment in PD independent of or
in addition to Alzheimer-type pathology.
Mattila, P. M., T. Koskela, et al. (1998). "Apolipoprotein E epsilon4 allele
frequency is increased in Parkinson's disease only with co-existing Alzheimer
pathology." Acta Neuropathol (Berl)96(4): 417-20.
We determined the apolipoprotein E (apoE) genotype in clinically diagnosed and
neuropathologically verified cases of Parkinson's disease (PD) (n = 45), with or
without Alzheimer (AD)-type changes, and compared the apoE genotype with that in
healthy age-matched controls (n = 59). The PD cases were divided into two groups
according to the CERAD criteria: "O + A", with no or only uncertain histological
findings of AD, and "B + C" with histological findings suggestive or indicative
of AD. DNA was isolated from frozen brain samples, and the apoE genotypes were
determined using polymerase chain reaction amplification and subsequent
restriction analysis by HhaI enzyme. The frequency of the apo epsilon4 allele
(29.4%) was significantly increased in the B + C group. The odds ratio for an
apo epsilon4 allele in the B + C group was 2.5 as compared to controls (95%
confidence interval, 1.2-5.2). In the O + A group, the frequency of apo epsilon4
allele (13.6%) was similar to that in controls (14.4%) and the risk of an apo
epsilon4 allele was not increased (odds ratio 0.94). The PD cases with an apo
epsilon4 allele had a greater number of cortical (P = 0.02) but not nigral Lewy
bodies than those without an apo epsilon4 allele (P = 0.57). The results show
that neuropathologically verified PD as such is not associated with increased
apo epsilon4 allele frequency.
Lippa, C. F., H. Fujiwara, et al. (1998). "Lewy bodies contain altered
alpha-synuclein in brains of many familial Alzheimer's disease patients with
mutations in presenilin and amyloid precursor protein genes." Am J Pathol153(5): 1365-70.
Missense mutations in the alpha-synuclein gene cause familial Parkinson's
disease (PD), and alpha-synuclein is a major component of Lewy bodies (LBs) in
sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer's disease
(AD). To determine whether alpha-synuclein is a component of LBs in familial AD
(FAD) patients with known mutations in presenilin (n = 65) or amyloid precursor
protein (n = 9) genes, studies were conducted with antibodies to alpha-, beta-,
and gamma-synuclein. LBs were detected with alpha- but not beta- or
gamma-synuclein antibodies in 22% of FAD brains, and alpha-synuclein-positive
LBs were most numerous in amygdala where some LBs co-localized with tau-positive
neurofibrillary tangles. As 12 (63%) of 19 FAD amygdala samples contained
alpha-synuclein-positive LBs, these inclusions may be more common in FAD brains
than previously reported. Furthermore, alpha-synuclein antibodies decorated LB
filaments by immunoelectron microscopy, and Western blots revealed that the
solubility of alpha-synuclein was reduced compared with control brains. The
presence of alpha-synuclein-positive LBs was not associated with any specific
FAD mutation. These studies suggest that insoluble alpha-synuclein aggregates
into filaments that form LBs in many FAD patients, and we speculate that these
inclusions may compromise the function and/or viability of affected neurons in
the FAD brain.
Lindboe, C. F. and H. B. Hansen (1998). "The frequency of Lewy bodies in a
consecutive autopsy series." Clin Neuropathol17(4): 204-9.
In a consecutive autopsy series comprising 284 subjects > or = 50 years, 22
cases (7.7%) revealed Lewy bodies (LBs) of whom 21 had LBs in substantia nigra
and/or locus ceruleus and 9 (3.2%) in the cerebral cortex. Only one case had
cortical LBs without concomitant inclusions in the brain stem. The mean age of
subjects with LBs was significantly higher than in those without (78.0 vs. 72.3
years). Cortical LBs had not been demonstrated in routine HE stains in any case
and their identification necessitated the use of staining for ubiquitin.
Although great care was taken not to interpret globose neurofibrillary tangles
(NFTs) as LBs, anti-tau staining revealed that many of the suspected LBs were in
fact NFTs. Thus, we recommend to apply both anti-ubiquitin and anti-tau staining
for the demonstration of cortical LBs. In this material 21 of the 22 cases with
LBs (95.5%) also revealed Alzheimer type of pathology as compared with 187 of
262 cases without LBs (71.4%). This difference may be explained by the higher
age of subjects with LBs. Altogether 96 of the 284 cases (33.8%) had
cerebrovascular lesions. None of the 9 cases with cortical LBs were clinically
demented, and our results do not support the assertion that Lewy body-associated
dementias should outnumber those of vascular origins.
Lapalio, L. R. and S. S. Sakla (1998). "Distinguishing Lewy body dementia."
Hosp Pract (Off Ed)33(2): 93-6, 99-102, 107-8.
The presence of the distinctive formations known as Lewy bodies within brain
cells has been linked to senile dementia. A pattern of clinical features helps
distinguish Lewy body dementia from Alzheimer's and Parkinson's diseases.
Differentiation can be important, because many patients with Lewy body dementia
have a hypersensitivity to neuroleptic medications.
Langston, J. W., S. Sastry, et al. (1998). "Novel alpha-synuclein-immunoreactive
proteins in brain samples from the Contursi kindred, Parkinson's, and
Alzheimer's disease." Exp Neurol154(2): 684-90.
A specific mutation (A53T) in the encoding region for alpha-synuclein has been
identified in a large multigenerational family with an autosomal dominant
parkinsonism known as the Contursi kindred. In this study, we used a monoclonal
antibody directed against alpha-synuclein in order to identify novel proteins in
the brain of an affected member of this kindred who had come to autopsy.
Homogenates from the frontal cortex and caudate nucleus were examined using
Western blot techniques and compared to matched autopsy specimens from control
subjects and patients with various forms of parkinsonism. Western blots, using a
15-min exposure time, revealed the expected 19-kDa band representing
alpha-synuclein in all brain samples examined. However, a novel band in the
36-kDa range was also present in the Contursi brain which was not seen in cortex
or caudate from control brains or in frontal cortex from 14 cases of typical
Parkinson's disease. With a 24-h exposure time, this band was faintly seen in
the caudate nucleus of three of the Parkinson's disease cases. Surprisingly, the
36-kDa band (as well as other high-molecular-weight bands) was also present in
frontal cortex and caudate nucleus in 3 additional cases that met diagnostic
criteria for both Parkinson's disease and Alzheimer's disease. A preliminary
analysis of samples from the frontal cortex of 10 Alzheimer's disease cases
revealed a 36-kDa band in only one instance. The identification of novel
alpha-synuclein-immunoreactive bands in these various forms of parkinsonism may
open new research avenues for exploring the relationship between abnormal
protein deposition in the brain and one or more neurodegenerative disorders,
including the Contursi form of familial parkinsonism.
Lamb, H., J. Christie, et al. (1998). "Apolipoprotein E and alpha-1
antichymotrypsin polymorphism genotyping in Alzheimer's disease and in dementia
with Lewy bodies. Distinctions between diseases." Neurology50(2):
388-91.
The possibility of gene interactions in Alzheimer's disease (AD) has been
suggested by the finding of an association of the AA genotype of the alpha-1
antichymotrypsin (AACT) gene and the apolipoprotein E (apoE) epsilon 4/4
genotype in AD. We tested this possibility by genotyping a large series of
clinically and neuropathologically confirmed cases of AD and a series of cases
with dementia with Lewy bodies (DLB) with a matched control group for the AACT
locus and apoE. ApoE genotyping showed the established finding of an increased
frequency of the apoE epsilon 4 allele in AD and in DLB. The AD and DLB groups
differed between each other with a higher epsilon 2 allele frequency and a
reduced incidence of the epsilon 4/4 genotype in DLB. Differences in the apoE
frequencies may account for some of the differences between the two diseases. No
association was found for the AACT A allele in AD or DLB in the groups as a
whole or when stratified with respect to apoE, with the exception of a trend
showing an increased incidence of the apoE epsilon 4/4 AACT AA genotype
combination in AD patients (chi 2 = 3.18, p = 0.07), although in DLB this was
not apparent (chi 2 = 0.0, p = 1.0). The AACT A allele is not a major risk
factor for late-onset AD or DLB.
Kosaka, K. (1998). "Diffuse Lewy body disease." Intern Med37(1):
6-10.
Diffuse Lewy body disease (DLBD) has been studied from various viewpoints, and
although clinical diagnostic criteria for DLBD have been proposed, the diagnosis
remains difficult. It has been reported that DLBD is the second most frequent
degenerative dementia among the elderly, following Alzheimer-type dementia. Many
DLBD cases, however, are clinically misdiagnosed. Therefore, the search for
diagnostic markers for DLBD must continue. Very recently, "dementia with Lewy
bodies" (DLB) was proposed as a generic term including DLBD and similar
disorders. Cortical Lewy bodies are the most important pathological marker for
diagnosis of DLB. At this time, however, the mechanism of cortical Lewy body
formation is yet to be disclosed.
Kosaka, K. and E. Iseki (1998). "Recent advances in dementia research in Japan:
non-Alzheimer-type degenerative dementias." Psychiatry Clin Neurosci
52(4): 367-73.
In this article, we review recent reports by Japanese researchers on
non-Alzheimer-type degenerative dementias. These dementias can be classified
into the following subtypes: dementias with Lewy bodies, including diffuse Lewy
body disease, dementias with neurofibrillary tangles, dementias with glial
tangles, including progressive supranuclear palsy and corticobasal degeneration,
argyrophilic grain dementia, frontotemporal dementias including Pick's disease;
dementias with degeneration of subcortical nuclei, including Huntington's
disease and, last, unclassified dementias. Recently, these various forms of
dementia have received much attention in Japan, as elsewhere.
Jellinger, K. A. (1998). "Neuropathology of movement disorders." Neurosurg
Clin N Am9(2): 237-62.
This article reviews the cytoskeletal abnormalities, morphologic lesion
patterns, and resulting pathophysiology of the most frequent neurodegenerative
movement disorders caused by dysfunction of the basal ganglia and related
neuronal loops. The following topics are discussed: Among the akinetic-rigid
Lewy body disorders is idiopathic Parkinson's disease, which reveals specific
lesion patterns of pathophysiologic and therapeutic relevance. Dementia with
Lewy bodies characterized by cortical Lewy bodies appears intermediate between
Parkinson's and Alzheimer's diseases. Tau pathologic disorders may show some
clinical and morphologic overlap. Multiple system atrophy has ubiquitous
oligodendroglial inclusions as a cytopathologic hallmark. Secondary parkinsonism
includes drug-related, toxic, and other symptomatic disorders. Hyperkinetic
disorders include CAG-related inherited diseases, showing specific genetic
defects and morphologic lesions. Dystonia syndromes show inconsistent pathologic
findings, and myoclonus may be related to a variety of disorders. Consensus data
on clinical and neuropathologic criteria already existing for some disorders,
together with molecular genetic and biochemical data will provide further
insight into the complex pathophysiology and pathogenesis of movement disorders.
Jellinger, K. A. (1998). "Commentary on "Neuropathologic evidence that the Lewy
body variant of Alzheimer disease represents coexistence of Alzheimer disease
and idiopathic Parkinson's disease (1998;57:39-46)"." J Neuropathol Exp
Neurol57(5): 467-8.
Irizarry, M. C., W. Growdon, et al. (1998). "Nigral and cortical Lewy bodies and
dystrophic nigral neurites in Parkinson's disease and cortical Lewy body disease
contain alpha-synuclein immunoreactivity." J Neuropathol Exp Neurol57(4):
334-7.
A mutation in the alpha-synuclein gene has recently been linked to some cases of
familial Parkinson's disease (PD). We characterized the expression of this
presynaptic protein in the midbrain, striatum, and temporal cortex of control,
PD, and dementia with Lewy bodies (DLB) brain. Control brain showed punctate
pericellular immunostaining. PD brain demonstrated alpha-synuclein
immunoreactivity in nigral Lewy bodies, pale bodies and abnormal neurites. Rare
neuronal soma in PD brain were immunoreactive for alpha-synuclein. DLB cases
demonstrated these findings as well as alpha-synuclein immunoreactivity in
cortical Lewy bodies and CA2-3 neurites. These results suggest that, even in
sporadic cases, there is an early and direct role for alpha-synuclein in the
pathogenesis of PD and the neuropathologically related disorder DLB.
Ince, P. G., E. K. Perry, et al. (1998). "Dementia with Lewy bodies. A distinct
non-Alzheimer dementia syndrome?" Brain Pathol8(2): 299-324.
Lewy body formation is central to the pathological phenotype of a spectrum of
disorders. The most familiar of these is the extrapyramidal syndrome of
idiopathic Lewy-body Parkinson's disease (PD). Studies of dementia in the
elderly suggest that another manifestation of Lewy body pathology is equally or
more common than Parkinson's disease. This syndrome of Dementia with Lewy bodies
(DLB) has been given a number of diagnostic labels and is characterised by
dementia, relatively mild parkinsonism, visual hallucinations, and fluctuations
in conscious level. Although many of these features can arise in Parkinson's
disease, the patients with DLB tend to have early neuropsychiatric features
which predominate the clinical picture, and the diagnosis of the syndrome in
practice is more concerned with the differential diagnosis of Alzheimer's
disease (AD). Distinction from AD has clinical importance because of potentially
differing therapeutic implications. Diagnostic guidelines for the clinical
diagnosis and pathological evaluation of DLB are reviewed. Research into the
disorder has centered around characterising the clinical, neuropsychological,
pathological, neurochemical and genetic relationships with Alzheimer's disease
on the one hand, and Parkinson's disease on the other. Many cases of DLB have
prominent pathological features of AD and there are some shared genetic risk
factors. Differences from the pathology of PD are predominantly quantitative
rather than qualitative and evidence is discussed which suggests that DLB
represents a clinicopathological syndrome within the spectrum of Lewy body
disorders. The possibility that the syndrome represents a chance association of
PD and AD is not supported by published studies.
Higuchi, S., H. Arai, et al. (1998). "Mutation in the alpha-synuclein gene and
sporadic Parkinson's disease, Alzheimer's disease, and dementia with lewy
bodies." Exp Neurol153(1): 164-6.
Recently, alpha-synuclein attracted attention when Polymeropoulos and colleagues
identified a missense mutation of this gene (Science 276:2045-2047, 1997), which
is responsible for a form of early-onset familial Parkinson's disease (PD).
Immunohistochemically, alpha-synuclein is localized in Lewy bodies,
characteristic brain pathology of PD, dementia with Lewy bodies (DLB), and
Alzheimer's disease (AD), suggesting that this protein may link these common
neurological diseases. Exploration of the possibility that the same mutation of
the alpha-synuclein gene as that in familial PD (Ala53Thr) may also confer
susceptibility to sporadic PD, DLB, and AD revealed the mutation in none of the
samples of 329 cases and 230 controls examined, suggesting that this mutation is
not involved in these neurological diseases.
Hashimoto, M., L. J. Hsu, et al. (1998). "Human recombinant NACP/alpha-synuclein
is aggregated and fibrillated in vitro: relevance for Lewy body disease."
Brain Res799(2): 301-6.
The precursor of non-amyloid beta protein component of Alzheimer's disease
amyloid (NACP/alpha-synuclein) is aggregated and fibrillated under certain
conditions, i.e., increasing time lag, high temperature and low pH. These in
vitro aggregates form Thioflavine-S-positive filamentous structures, reminiscent
of amyloid-like fibrils. Since some Lewy bodies in Parkinson's disease display
Thioflavine-S reactivity, our results may suggest that amyloidogenic properties
of NACP/alpha-synuclein may play a crucial role in pathogenesis of disorders
with Lewy bodies such as Parkinson's disease.
Hashimoto, M., H. Kitagaki, et al. (1998). "Medial temporal and whole-brain
atrophy in dementia with Lewy bodies: a volumetric MRI study." Neurology51(2): 357-62.
OBJECTIVE: Dementia with Lewy bodies (DLB) is emerging as a common cause of
degenerative dementia. A recent pathologic study has indicated that the medial
temporal lobe in patients with DLB was less atrophic than that in patients with
AD. The purpose of this study was to examine whether medial temporal MRI
volumetry was useful to differentiate DLB from AD clinically. METHODS: We
compared the volumes of the hippocampal formation, amygdaloid complex, and whole
brain in 27 patients with probable DLB (based on the criteria of the Consortium
on DLB International Workshop), 27 patients with probable AD (based on criteria
of the National Institute of Neurological Disease and Stroke/Alzheimer's Disease
and Related Disorders Association), and 27 normal elderly subjects using an
MRI-based volumetric technique. The three groups were matched for age and sex.
Severity of cognitive disturbances represented by their Mini-Mental State
Examination score was comparable between the DLB and AD groups. RESULTS:
Hippocampal volume (normalized to intracranial volume) in the DLB group was
significantly larger than that in the AD group, but significantly smaller than
that in the normal control group. There were no significant differences in the
amygdala and whole-brain volume between the DLB group and the AD group, but the
atrophies of the amygdala and whole brain were more severe in the DLB group than
those in the control group. CONCLUSIONS: These findings indicate the usefulness
of MRI hippocampal volumetry in clinically discriminating patients with DLB from
patients with AD.
Harding, A. J. and G. M. Halliday (1998). "Simplified neuropathological
diagnosis of dementia with Lewy bodies." Neuropathol Appl Neurobiol24(3):
195-201.
Pathological criteria have recently been developed to differentiate those cases
where Lewy bodies contribute to the dementing process. We applied consensus
criteria to 20 cases with a pathological diagnosis of Alzheimer's disease (all
demented) and/or Parkinson's disease (three without dementia) and eight
controls. In addition, we applied the criteria to the different cortical layers
to determine whether the site of the semiquantification affected the diagnosis.
In the parietal lobe, few Lewy bodies were observed, and this region could be
excluded. Rare Lewy bodies present in the frontal association cortex in a number
of Parkinson's disease cases resulted in their classification as limbic or
transitional cases with Lewy bodies. Exclusion of this non-limbic association
cortex resulted in many of these cases with rare cortical Lewy bodies being
re-classified as having brain stem predominant Lewy bodies, thus improving the
diagnostic accuracy of the criteria. Most of these cases were non-demented. No
other case was re-classified by excluding these cortical regions from the
analysis. Few Lewy bodies were present in cortical layers I and II, and these
layers could be excluded from the semiquantitative procedure without change to
the overall classification of cases. The occasional presence of possible Lewy
bodies in cases with Alzheimer's disease and controls incorrectly classified
these cases as having brain stem predominant Lewy body disease, although these
cases had no brain stem Lewy bodies. These modifications to the consensus
criteria for assessing Lewy body disease (i.e. exclude parietal and frontal
lobe, cortical layers I and II, and cases without brain stem Lewy bodies),
provide significant time and cost savings for neuropathologists and researchers
using this criteria to diagnose and study dementia with Lewy bodies.
Hansen, L. A., S. E. Daniel, et al. (1998). "Frontal cortical synaptophysin in
Lewy body diseases: relation to Alzheimer's disease and dementia." J Neurol
Neurosurg Psychiatry64(5): 653-6.
OBJECTIVES: Dementia in Alzheimer's disease correlates closely with loss of
neocortical synapses. Similar synaptic loss has been shown in patients whose
Alzheimer's disease is also associated with neocortical and brain stem Lewy
bodies. The aim was to determine if dementia in Lewy body disease was associated
with diminished concentrations of midfrontal cortex synaptophysin. METHODS: An
immunobinding assay was used to measure synaptophysin in postmortem samples of
midfrontal cortex from 89 patients with Alzheimer's disease (ages 59-100, mean
79), 22 with combined Lewy body disease and Alzheimer's disease (ages 69-103,
mean 79), 15 demented patients with "pure" Lewy body disease (ages 57-80, mean
74), nine with neocortical and brain stem Lewy bodies who had Parkinson's
disease but were not demented (ages 68-85, mean 79), and 20 neurologically
normal controls (ages 58-89, mean 75). The diagnosis was confirmed in all cases
by detailed neuropathological examination of the contralateral hemibrain. Seven
of the patients in the pure Lewy body disease with dementia group had initially
presented with parkinsonism and eight with dementia. RESULTS: Synaptophysin
concentrations (arbitrary units (AU)/microg) in patients with Alzheimer's
disease (mean 79 (SD 28)) or combined Lewy body disease and Alzheimer's disease
(mean 83 (SD 33)) were significantly lower than in controls (mean 115 (SD 29))
(p=0.002). Synaptophysin concentrations in demented patients with pure Lewy body
disease (mean 106 SD 39) and patients with Lewy body disease who were not
demented (mean 101 (SD 18)) did not differ significantly from control values or
from each other. CONCLUSION: Loss of midfrontal cortex synapses probably
contributes to dementia in Lewy body disease when Alzheimer's disease is also
present but not to the dementia of pure Lewy body disease.
Gu, M., A. D. Owen, et al. (1998). "Mitochondrial function, GSH and iron in
neurodegeneration and Lewy body diseases." J Neurol Sci158(1):
24-9.
The cause of neuronal loss in patients with idiopathic Parkinson's disease is
unknown. Oxidative stress and complex I deficiency have both been identified in
the substantia nigra in Parkinson's disease but their place in the sequence of
events resulting in dopaminergic cell death is uncertain. We have analysed
respiratory chain activity, iron and reduced glutathione concentrations in
Parkinson's disease substantia innominata and in the cingulate cortex of
patients with Parkinson's disease, Alzheimer's disease and dementia with Lewy
bodies to investigate their association with neuronal death and Lewy body
formation. No abnormalities of mitochondrial function, iron or reduced
glutathione levels were identified in Parkinson's disease substantia innominata
or cingulate cortex. Mitochondrial function also appeared to be unchanged in
cingulate cortex from patients with Alzheimer's disease and from patients with
dementia with Lewy bodies, however, iron concentrations were mildly increased in
both, and reduced glutathione decreased only in Alzheimer's disease. These
results confirm the anatomic specificity of the complex I deficiency and
decreased levels of reduced glutathione within the Parkinson's disease brain and
suggest that these parameters are not associated with cholinergic cell loss in
Parkinson's disease nor with Lewy body formation in this or other diseases. We
propose that our data support a 'two-hit' hypothesis for the cause of neuronal
death in Parkinson's disease.
Good, P. F., A. Hsu, et al. (1998). "Protein nitration in Parkinson's disease."
J Neuropathol Exp Neurol57(4): 338-42.
Oxidative stress has been proposed as a pathogenetic mechanism in Parkinson's
disease (PD). One mechanism of oxidative cellular injury is the nitration of
protein tyrosine residues, mediated by peroxynitrite, a reaction product of
nitric oxide and superoxide radicals. We demonstrate here the presence of
nitrotyrosine immunoreactivity in Lewy bodies within melanized neurons and in
amorphous deposits associated with intact and degenerating neurons. The core of
the Lewy body was frequently intensely immunolabeled, while the rim was lightly
labeled or unlabeled. This likely reflects the fact that tyrosine residues of
neurofilament proteins are primarily localized to Lewy body cores, and suggests
that nitrotyrosine is present in neurofilament protein itself. Although these
observations are as yet unable to provide a definitive link between oxidative
stress and neuronal dysfunction, they demonstrate that oxidative stress has
occurred within the vulnerable neurons of PD, leaving a permanent marker of
oxidative modification of neuronal proteins within the target cells of
neurodegeneration. In addition, these observations provide a potential link
between excitotoxicity and oxidative stress within the vulnerable neurons of PD
and represent a pathogenetic mechanism in common with the 2 other major
age-related neurodegenerative diseases, Alzheimer disease and amyotrophic
lateral sclerosis.
Gomez-Tortosa, E., A. O. Ingraham, et al. (1998). "Dementia with Lewy bodies."
J Am Geriatr Soc46(11): 1449-58.
In the last decade, a new degenerative dementia, probably the second most common
after Alzheimer's disease (AD), has been increasingly recognized under the
consensus name of dementia with Lewy bodies (DLB). This article reviews current
clinical, genetic, and pathological DLB data and indicates directions for future
research. DLB overlaps in clinical, pathological, and genetic features with AD
and Parkinson's disease (PD). Clinically, it is characterized by progressive
cognitive impairment with significant fluctuations in alertness, parkinsonism,
and psychosis with recurrent hallucinations. The neuropathological hallmarks are
the intracytoplasmic inclusions in substantia nigra typical of PD, known as Lewy
bodies (LB) but distributed widely throughout paralimbic and neocortical
regions. Most of the cases also coexist with a plaque predominant AD. It is
probably the unique and differential distribution of the lesions throughout
cortical and subcortical structures in each of these disorders that supports a
specific clinical syndrome and may ultimately prove most useful in understanding
their different etiologies. Several genes have recently been implicated in LB
formation. Special interest arises from mutations in the alpha-synuclein gene,
which appears to be responsible for autosomal dominant PD in several kindreds.
This gene encodes a presynaptic protein, a fragment of which is present in AD
plaques. Recent studies show intense and quite specific alpha-synuclein
immunoreactivity in LB and related neurites, suggesting a potential role of this
protein in the aggregation or precipitation of LB inclusions.
Goedert, M., M. G. Spillantini, et al. (1998). "Filamentous nerve cell
inclusions in neurodegenerative diseases." Curr Opin Neurobiol8(5):
619-32.
Recent work has shown that abnormal filamentous inclusions within some nerve
cells is a characteristic shared by Alzheimer's disease, some frontotemporal
dementias, Parkinson's disease, dementia with Lewy bodies, multiple system
atrophy, as well as Huntington's disease and other trinucleotide repeat
disorders. This suggests that in each of these disorders, the affected nerve
cells degenerate as a result of these abnormal inclusions. Except for
trinucleotide repeat disorders, the filaments involved have been shown to
consist of either the microtubule-associated protein tau or alpha-synuclein.
Over the past year, mutations in the genes for tau and alpha-synuclein have been
identified as the genetic causes of some familial forms of frontotemporal
dementia and Parkinson's disease, respectively. The discovery last year of
neuronal intranuclear inclusions in Huntington's disease and other disorders
with expanded glutamine repeats has suggested a unifying mechanism underlying
the pathogenesis of this class of neurodegenerative diseases.
Ginsberg, S. D., J. E. Galvin, et al. (1998). "RNA sequestration to pathological
lesions of neurodegenerative diseases." Acta Neuropathol (Berl)96(5):
487-94.
Cytoplasmic RNA species have been identified recently within neurofibrillary
tangles and senile plaques of Alzheimer's disease brain. To determine whether
RNA sequestration is a common feature of other lesions found in progressive
neurodegenerative disorders, acridine orange histofluorescence was employed,
alone or in combination with immunohistochemistry and thioflavine-S staining to
identify RNA species in paraffin-embedded brain tissue sections. Postmortem
samples came from 39 subjects with the following diagnoses: Alzheimer's disease,
amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam,
corticobasal degeneration, diffuse Lewy body disease, normal controls, multiple
system atrophy, Parkinson's disease, Pick's disease, progressive supranuclear
palsy, and Shy-Drager syndrome. RNAs were detected in neurofibrillary tangles
and neuritic senile plaques as well as in Pick bodies. However, Lewy bodies,
Hirano bodies, and cytoplasmic glial inclusions did not contain abundant
cytoplasmic RNA species. These observations demonstrate the selective
localization of RNA species to distinct pathological lesions of
neurodegenerative disease brains.
Gibson, C. J. and D. G. Munoz (1998). "Chromogranin A inhibits dopamine release
from rat striatal slices." J Neural Transm105(10-12): 1083-9.
Chromogranin A (CGA), a prohormone and a protein component of endocrine and
neural secretory granules, neuritic plaques in Alzheimer's disease and Lewy
bodies in Parkinson's disease, inhibited the release of dopamine (DA) from
perfused rat striatal slices. Dopamine release was stimulated by a pulse of high
potassium (40mM) medium introduced at 20 minutes (K1) and 55 minutes (K2)
following equilibration. The ratio of K2/K1 was 0.80+/-0.04 in control tissues,
but fell significantly to 0.26+/-0.08 when 100nM purified CGA was added prior to
the second potassium pulse. This reduction in DA release was equivalent to that
seen when calcium was excluded from the buffer (0.19+/-0.05). Pancreastatin, a
centrally active peptide product of CGA, had no effect on stimulated DA release
(0.77+/-0.06), although it, as well as the other treatments, did reduce basal DA
release. It is likely that the parent molecule itself, CGA, or an as yet
unidentified product is responsible for inhibition of K-stimulated striatal DA
release.
Downes, J. J., N. M. Priestley, et al. (1998). "Intellectual, mnemonic, and
frontal functions in dementia with Lewy bodies: A comparison with early and
advanced Parkinson's disease." Behav Neurol11(3): 173-183.
Both Parkinson's disease (PD) and dementia with Lewy bodies (DLB) share a common
neuropathological marker, the presence of Lewy bodies in brain stem and basal
forebrain nuclei. DLB, in addition, is associated with Lewy bodies in the
neocortex, and, in it's more common form, with Alzheimer-type pathological
markers, particularly amyloid plaques. Published neuropsychological studies have
focused on the differential profiles of DLB and Alzheimer's disease (AD).
However, it is presently unclear whether DLB should be classified as a variant
of AD or PD. In the present study we compare a healthy age-matched control group
with three groups of patients, one with DLB, and two with PD. One of the PD
groups was early in the course (PD-E) and the second, more advanced group
(PD-A), was matched on severity of cognitive impairment with the DLB group. The
results show that DLB was associated with a different pattern of
neuropsychological impairment than the PD-A group, particularly in tests
believed to be mediated by prefrontal cortical regions.
Davidson, W. S., A. Jonas, et al. (1998). "Stabilization of alpha-synuclein
secondary structure upon binding to synthetic membranes." J Biol Chem
273(16): 9443-9.
alpha-Synuclein is a highly conserved presynaptic protein of unknown function. A
mutation in the protein has been causally linked to Parkinson's disease in
humans, and the normal protein is an abundant component of the intraneuronal
inclusions (Lewy bodies) characteristic of the disease. alpha-Synuclein is also
the precursor to an intrinsic component of extracellular plaques in Alzheimer's
disease. The alpha-synuclein sequence is largely composed of degenerate
11-residue repeats reminiscent of the amphipathic alpha-helical domains of the
exchangeable apolipoproteins. We hypothesized that alpha-synuclein should
associate with phospholipid bilayers and that this lipid association should
stabilize an alpha-helical secondary structure in the protein. We report that
alpha-synuclein binds to small unilamellar phospholipid vesicles containing
acidic phospholipids, but not to vesicles with a net neutral charge. We further
show that the protein associates preferentially with vesicles of smaller
diameter (20-25 nm) as opposed to larger (approximately 125 nm) vesicles. Lipid
binding is accompanied by an increase in alpha-helicity from 3% to approximately
80%. These observations are consistent with a role in vesicle function at the
presynaptic terminal.
Connor, D. J., D. P. Salmon, et al. (1998). "Cognitive profiles of
autopsy-confirmed Lewy body variant vs pure Alzheimer disease." Arch Neurol55(7): 994-1000.
OBJECTIVE: To compare the cognitive profiles of patients with autopsy-confirmed
Alzheimer disease (AD), with or without concomitant Lewy bodies, on 2 dementia
screening measures. METHODS: Profiles on subtests of the Mattis Dementia Rating
Scale (range, 105-125) and of component items of the Mini-Mental State
Examination were compared between 23 patients with uncomplicated AD and 23
patients with concomitant AD and Lewy body pathology (Lewy body variant [LBV]).
RESULTS: Although the groups did not differ significantly regarding age, years
of education, total Mini-Mental State Examination score, or total Mattis
Dementia Rating Scale score, the AD group performed significantly worse than the
LBV group on the Mattis Dementia Rating Scale Memory subscale (P < .005). In
contrast, the LBV group demonstrated poorer performance than the pure AD group
on the Initiation/Perseveration subscale (P < .02). The groups did not differ
significantly on the Attention, Construction, or Conceptualization subscales.
The same overall pattern of results was obtained when subgroups with mild to
moderate and moderate to severe dementia were examined separately, with the
additional finding that in the mild-to-moderate range patients with dementia and
LBV performed worse than patients with pure AD on the Construction subscale.
CONCLUSIONS: The difference in pattern of cognitive deficits among patients with
pure AD vs those with AD and LBV is similar to that seen between AD and more
subcortical/frontal dementias (eg, Huntington disease) This suggests that the
concomitant Lewy body pathology significantly contributes to the presentation of
the cognitive dysfunction in individuals with LBV.
Clayton, D. F. and J. M. George (1998). "The synucleins: a family of proteins
involved in synaptic function, plasticity, neurodegeneration and disease."
Trends Neurosci21(6): 249-54.
Synuclein proteins are produced, in vertebrates, by three genes.They share
structural resemblance to apolipoproteins, but are abundant in the neuronal
cytosol and present in enriched amounts at presynaptic terminals. Synucleins
have been specifically implicated in three diseases:Alzheimer's (AD),
Parkinson's (PD) and breast cancer. In AD, a peptide derived from
alpha-synuclein forms an intrinsic component of plaque amyloid. In PD, an
alpha-synuclein allele is genetically linked to several independent familial
cases, and the protein appears to accumulate in Lewy bodies. In breast cancer,
increased expression of gamma-synuclein correlates with disease progression. In
songbirds, alpha-synuclein expression is correlated with plasticity in the
developing song control system. Although the normal function of synucleins is
unknown, a role in membrane plasticity seems likely.
Brown, D. F., M. A. Dababo, et al. (1998). "Neuropathologic evidence that the
Lewy body variant of Alzheimer disease represents coexistence of Alzheimer
disease and idiopathic Parkinson disease." J Neuropathol Exp Neurol57(1):
39-46.
We undertook this study to investigate the neuropathologic relationships among
Alzheimer disease (AD), idiopathic Parkinson disease (PD), and the Lewy body
variant of AD (AD/LBV). We retrieved 30 autopsy cases in which Lewy bodies (LB)
had been identified in the substantia nigra (SN) in routine
hematoxylin-eosin-stained sections. Twenty-two of the cases had a primary
clinical diagnosis of dementia and neuropathologic changes of AD; 12 of these
demented patients also had clinical parkinsonism. Eight cases had clinical and
neuropathologic evidence of PD with minimal or no AD neuropathology, though 6
had clinical dementia. Controls consisted of 6 cases of AD without SN LB by
hematoxylin-eosin, and 5 neurologically normal aged controls. Paraffin sections
of SN, superior temporal gyrus, and cingulate gyrus from each case were
immunostained with rabbit anti-ubiquitin antiserum, randomized, and analyzed
individually by light microscopy, and the density of LB-like profiles in each
section were graded. None of 5 nondemented aged controls showed any neocortical
LB, even though 2 had significant numbers of incidental SN LB by ubiquitin
immunostaining. Of 6 AD cases without SN LB by hematoxylin-eosin, 3 had rare SN
LB on ubiquitin stain, 1 of which showed rare neocortical Lewy-like profiles.
Seven of 8 PD cases showed neocortical LB, including the 6 with dementia.
Twenty-one of 22 AD cases with SN LB showed ubiquitin-immunoreactive Lewy-like
bodies in the neocortex that were statistically significantly greater in number
than in either pure PD or pure AD cases. The frequent occurrence of LB in the
neocortex in PD alone suggests that AD/LBV likely represents mixed AD/PD.
However, AD neuropathology may favor or promote the formation of neocortical LB
in patients who go on to develop mixed AD/PD pathology.
Berg, L., D. W. McKeel, Jr., et al. (1998). "Clinicopathologic studies in
cognitively healthy aging and Alzheimer's disease: relation of histologic
markers to dementia severity, age, sex, and apolipoprotein E genotype." Arch
Neurol55(3): 326-35.
OBJECTIVE: To study differences between subjects with Alzheimer disease (AD) and
cognitively intact control subjects, with respect to brain histologic markers of
AD, and the relationship of those markers in the AD group to severity of
dementia, age at death, sex, and apolipoprotein E genotype. SETTING: Washington
University Alzheimer's Disease Research Center, St Louis, Mo. DESIGN AND
SUBJECTS: Consecutive neuropathologic series of 224 prospectively studied
volunteer research subjects, 186 with dementia of the Alzheimer type (DAT) or
"incipient" DAT and confirmed to have AD by postmortem examination and 13
cognitively intact subjects, confirmed to lack postmortem findings of AD. MAIN
OUTCOME MEASURES: Brain densities (number per square millimeter) of senile
plaques and neurofibrillary tangles, extent of cerebral amyloid angiopathy,
cortical Lewy bodies, and apolipoprotein E genotype. RESULTS: Neocortical
neurofibrillary tangle densities were substantially correlated with dementia
severity, and to a greater degree than was true for senile plaque densities.
When infarcts, hemorrhages, and Parkinson disease changes coexisted with AD,
neurofibrillary tangle and senile plaque densities were lower.
Plaque-predominant AD was found in a greater proportion of subjects with milder
than more severe dementia. Entorhinal cortical Lewy bodies were no more frequent
in plaque-predominant AD than in the remaining AD cases. Increasing age at death
was negatively correlated with dementia severity and densities of senile plaques
and neurofibrillary tangles. The apolipoprotein E epsilon4 allele frequency was
greater in AD than in control subjects but decreased with increasing age. After
controlling for dementia severity, senile plaque densities were only weakly
related to epsilon4 allele frequency, and only in hippocampus. However, the
degree of cerebral amyloid angiopathy was clearly related to epsilon4 allele
frequency. Among subjects diagnosed during life as having DAT or incipient DAT,
only 7% were found to have a neuropathologic disorder other than AD causing
their dementia. CONCLUSIONS: (1) The order of the strength of relationships
between densities of histologic markers and dementia severity in AD is
neurofibrillary tangles greater than cored senile plaques greater than total
senile plaques. (2) Advanced age at death is associated with somewhat less
severe dementia and fewer senile plaques and neurofibrillary tangles. (3)
Plaque-predominant AD may represent a developmental stage in AD. (4) Despite a
substantial effect of apolipoprotein E epsilon4 as a risk factor for AD, on
decreasing the age at AD onset, and increasing the amount of cerebral amyloid
angiopathy, its effect on senile plaque densities is variable and complex, being
confounded with age, dementia severity, and methodologic differences. (5)
Stringent clinical diagnostic criteria for DAT, even in the very mild stage, and
senile plaque-based neuropathologic criteria for AD are highly accurate.
Ballard, C., J. Grace, et al. (1998). "Neuroleptic sensitivity in dementia with
Lewy bodies and Alzheimer's disease." Lancet351(9108): 1032-3.
Ballard, C., F. Shaw, et al. (1998). "High prevalence of neurovascular
instability in neurodegenerative dementias." Neurology51(6):
1760-2.
Orthostatic hypotension and carotid sinus hypersensitivity were assessed in
patients meeting clinical criteria for dementia with Lewy bodies (DLB; n=30) and
AD (n=35). Cardioinhibitory carotid sinus hypersensitivity (CI) was the most
common sign (AD patients, 28%; DLB patients, 41%). Preliminary data from a
secondary analysis excluding patients with hypertension or EKG evidence of
ischemia suggested that CI may be significantly more common in DLB. Larger
studies are needed to evaluate the implications for treatment and to explore the
underlying mechanisms.
Arawaka, S., Y. Saito, et al. (1998). "Lewy body in neurodegeneration with brain
iron accumulation type 1 is immunoreactive for alpha-synuclein." Neurology51(3): 887-9.
In familial PD, a mutation of the alpha-synuclein gene has been identified.
Alpha-synuclein also was revealed in Lewy bodies in idiopathic PD. Lewy bodies
in neurodegeneration with brain iron accumulation type 1 (NBIA 1;
Hallervorden-Spatz syndrome) were found to show immunostaining for
alpha-synuclein/precursor of non-A beta component of Alzheimer's disease
amyloid, indicating that alpha-synuclein is commonly associated with the
formation of Lewy bodies in other sporadic and familial neurodegenerative
diseases apart from PD.
Yoshimura, M. (1997). "[Diffuse Lewy body disease]." Rinsho Shinkeigaku37(12): 1134-6.
Lewy body disease (LBD) is a progressive neurological disorder with
parkinsonism, having many Lewy bodies (LBs) and degenerative changes. LBD is
classified into the three types according to the distribution of LBs:
"brain-stem type", "transitional type" and "diffuse type". The brain-stem type
is identical to classical Parkinson's disease (PD). The diffuse type is
nominated as "diffuse Lewy body disease" (DLBD). DLBD is a neuropathological
entity, characterized by abundant LBs not only in the basal ganglia and
brain-stem but in the cerebral cortex, combined with senile changes. Juvenile
onset DLBD is called "pure form" of DLBD because of no or few senile changes.
The LBs are present in the amygdala, nucleus basalis of Meynert, hypothalamic
nuclei, substantia nigra, nucleus paranigralis, locus caeruleus, dorsal vagal
nucleus and reticular nuclei. The cerebral LBs are numerous in the
parahippocampal gyrus, cingular gyrus, and insular, frontal and temporal
cortices. The LBs show immunoreactivity to ubiquitin and the
ubiquitin-immunoreactive neurites in the CA2-3 region appear to be specific for
DLBD. The clinical features of DLBD in the senium are progressive dementia,
psychotic state, parkinsonism and autonomic signs. In general, progressive
dementia is an initial symptom, followed by parkinsonism in the later stage.
Some show progressive autonomic failure. A few present respiratory failure or
vocal cord palsy resulting in sudden death in DLBD. DLBD is characterized
neurochemically by severe affection of multiple neurotransmitters networks. In
DLBD an impairment of the innominato-cortical cholinergic and mesocortical
dopaminergic system, differentiating from Alzheimer's disease and PD, may play
an important role in developing disease process.
Wakabayashi, K., K. Matsumoto, et al. (1997). "NACP, a presynaptic protein,
immunoreactivity in Lewy bodies in Parkinson's disease." Neurosci Lett
239(1): 45-8.
NACP, originally identified as a precursor of the non-Abeta component of
Alzheimer's disease amyloid (NAC), is now known to be identical to
alpha-synuclein, a presynaptic protein in the human brain. Recently, a mutation
in the alpha-synuclein gene in families with autosomal dominant Parkinson's
disease (PD) was identified. We carried out immunohistochemical examinations of
the brains of sporadic PD patients using anti-NACP and anti-ubiquitin
antibodies. Consistent with previous studies, the anti-NACP antibody
immunostained the neuropil in a punctate pattern throughout the brain. Moreover,
much stronger NACP immunoreactivity was found in Lewy bodies and degenerating
neurites in the brainstem. Serial sections immunolabeled with anti-ubiquitin or
anti-NACP showed that all ubiquitin-immunoreactive LBs were also
NACP-immunoreactive. These findings suggest that alteration of NACP metabolism
is involved in the pathogenesis of PD, particularly in Lewy body formation,
leading to neurodegeneration.
Tompkins, M. M. and W. D. Hill (1997). "Contribution of somal Lewy bodies to
neuronal death." Brain Res775(1-2): 24-9.
Neuronal degeneration occurs in the substantia nigra pars compacta (SNpc) of
patients with Parkinson's disease and other Lewy body-associated disorders. Lewy
bodies (LBs) are abnormal inclusions found in the SNpc and other neurons of
these patients. It is not known what role LBs play in the disease process; they
may be harmful to the neuron or simply an epiphenomenon of the disease process.
We have previously shown that some of the neuronal death occurring in the SNpc
of Lewy body-associated disorders resembles apoptosis. The present study was
undertaken to determine whether apoptotic-like changes were more common in SNpc
neurons with somal LBs compared to those without somal LBs. Substantia nigra
from cases of Lewy body-associated disorders were labeled to colocalize
apoptotic-like changes and LBs using in situ end-labeling and an anti-ubiquitin
antibody. Three cases demonstrated that SNpc neurons with LBs in the perikarya
had the same proportion of apoptotic-like changes as SNpc neurons without somal
LBs. One case had no LB-containing SNpc neurons undergoing apoptotic-like cell
death. The majority of SNpc neurons undergoing apoptotic-like cell death did not
appear to contain somal LBs and thus may be dying before LB formation can occur.
These results support the theory that the presence of a somal LB does not
predispose a neuron to undergo apoptotic-like cell death.
St Clair, D. (1997). "Apolipoprotein E gene in Parkinson's disease, Lewy body
dementia and Alzheimer's disease." J Neural Transm Suppl51:
161-5.
Apolipoprotein E (Apo E) epsilon 4 allele is a risk factor for early and late
onset Alzheimer's disease. This prompted us to examine other neurophyschiatric
phenotypes. Epsilon 4 allele was significantly enriched in Lewy body dementia (n
= 39) but not in Parkinson's disease (n = 50) or Schizophrenia (n = 175)
compared to aged non-demented controls (n = 47) and the Scottish population (n =
400). We conclude that Lewy body disease should be regarded as a variant of
Alzheimer's but not Parkinson's disease.
Singleton, A. B., H. Lamb, et al. (1997). "No association between a polymorphism
in the presenilin 1 gene and dementia with Lewy bodies." Neuroreport8(16):
3637-9.
The discovery of mis-sense mutations linking the presenilin-1 (PS-1) gene on
chromosome 14 to Alzheimer's disease (AD) has lead to a thorough investigation
of this locus. The PS-1 gene contains a polymorphism creating two alleles. The
most common allele, allele 1, has been linked with late-onset AD. Given the
clinical and pathological overlaps between AD and dementia with Lewy bodies we
genotyped 46 pathologically confirmed cases of dementia with Lewy bodies for the
PS-1 polymorphism and compared the allelic frequencies with 87 age-matched
control cases and 103 age-matched AD cases. No association between dementia with
Lewy bodies and PS-1 allele 1 was found either in the group as a whole, or in
the group stratified according to dosage of the epsilon4 allele of the
apolipoprotein E gene. We suggest that either the presenilin polymorphism has no
effect on dementia with Lewy bodies or that any linkage is precluded by another,
more influential, locus.
Perry, R., I. McKeith, et al. (1997). "Lewy body dementia--clinical,
pathological and neurochemical interconnections." J Neural Transm Suppl51: 95-109.
Senile dementia of Lewy body type or Lewy body dementia (SDLT or LBD) is defined
as a Lewy body associated disease presenting in the elderly primarily with
dementia with variable extrapyramidal disorder. Characteristic clinical symptoms
include fluctuating cognitive impairment, psychotic features such as
hallucinations and a particular sensitivity to neuroleptic medication. Although
apolipoprotein e4 allele is increased 2-3 fold in SDLT (as in Alzheimer's
disease) and beta-amyloidosis occurs in most cases, the most robust
neurobiological correlate of the dementia so far identified appears to be
extensive cholinergic deficits in the neocortex. This is consistent with
previously reported correlations between cortical cholinergic activity and
dementia in Parkinson's disease (PD) and Alzheimer's disease. There is also a
significant interaction between the density of limbic cortical Lewy bodies and
dementia in both SDLT and PD, although the cortical neuronal population affected
remains to be identified. Cortical Lewy body density is positively correlated
with the age of disease onset in PD and SDLT. This may account for the increased
incidence of psychiatric syndromes, as opposed to extrapyramidal disorder in
Lewy body disease with advancing age as may age-related loss of cholinergic
activity in cortical areas such as the hippocampus.
Perry, E. and D. W. Kay (1997). "Some developments in brain ageing and
dementia." Br J Biomed Sci54(3): 201-15.
The aetiology of the common dementias of old age remains incompletely
understood. Here we describe some of the biological, neurophysiological and
psychological changes associated with ageing of the human brain, in terms of
those that occur throughout life and those that are characteristic of
senescence. Age-dependent diseases, such as Alzheimer's disease (AD), idiopathic
Parkinson's disease (IPD) and dementia with Lewy bodies (DLB), are considered
from these viewpoints, and risk factors described. Vascular dementia (VaD) is
related to hypertension and atherosclerosis and detailed description of its
pathogenesis is outside the scope of this review. The importance of age as the
main risk factor raises basic questions about the relationship of these diseases
to the ageing process itself. Similarities and differences between ageing and
disease may be important for a rational approach to prevention and treatment of
cognitive decline and dementia in later life.
Owen, A. D., A. H. Schapira, et al. (1997). "Indices of oxidative stress in
Parkinson's disease, Alzheimer's disease and dementia with Lewy bodies." J
Neural Transm Suppl51: 167-73.
The cause of neuronal cell death in Parkinson's disease is unknown but there is
accumulating evidence suggesting that oxidative stress may be involved in this
process. Current evidence shows that in the substantia nigra there is altered
iron metabolism, decreased levels of reduced glutathione and an impairment of
mitochondrial complex I activity. However, these changes seem to be unique to
the substantia nigra and have not been found in other areas of the brain known
to be altered in Parkinson's disease, such as substantia innominata. In addition
they do not appear to be related to the presence of Lewy bodies, as other areas
of the brain containing Lewy bodies do not show evidence of either oxidative
stress or mitochondrial dysfunction. Oxidative stress has now been demonstrated
in Alzheimer's disease and its presence appears to be correlated with regions of
marked pathological changes.
Mirra, S. S. (1997). "Neuropathological assessment of Alzheimer's disease: the
experience of the Consortium to Establish a Registry for Alzheimer's Disease."
Int Psychogeriatr9 Suppl 1: 263-8; discussion 269-72.
The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), a
multicenter longitudinal study, has worked to establish standardized instruments
for the evaluation of individuals clinically diagnosed as having Alzheimer's
disease (AD). Since its formation in 1986, clinical neuropsychological,
neuroimaging, and neuropathology assessment batteries have been developed. The
neuropathology protocol not only establishes levels of certainty for the
diagnosis of AD, but also facilitates correlations with clinical, genetic, and
other data. We find a high rate of diagnostic accuracy: the clinical diagnosis
of AD was confirmed in 176 of 201 (87.6%) CERAD dementia subjects. Coexistent
vascular lesions, usually infarcts, were found in 32% of these confirmed AD
cases, and 23% had coexisting Parkinson's disease (PD) changes (nigral
degeneration and Lewy bodies at any site). In the remaining 25 cases (12.4%),
neuropathologists attributed the primary cause of dementia to other conditions.
In studies comparing neuropathology protocols for AD, several groups have found
that the CERAD diagnosis most closely correlates with measures of dementia
severity, such as the Mini-Mental State Examination (MMSE). Others have adopted
the CERAD neuropathology protocol for multicenter brain banking, citing its
relative simplicity and adaptability among laboratories, the experience of many
AD centers with the protocol, and its application to other dementing conditions.
The CERAD data set and batteries are increasingly used for a wide array of
clinical, neuropathological, and genetic studies.
Lennox, G. G. and J. S. Lowe (1997). "Dementia with Lewy bodies." Baillieres
Clin Neurol6(1): 147-66.
Dementia with Lewy bodies (DLB) is the recommended term for a common cause of
dementia characterized by the histological presence of distinctive inclusions
within neurons, Lewy bodies (McKeith et al, 1996). Following increasing
pathological recognition, core clinical diagnostic features have been identified
to allow diagnosis in life. Insights into the biology of this type of
neurodegeneration suggest that the regional patterns of involvement might allow
therapeutic intervention. Although Lewy bodies had long been recognized in the
substantia nigra and other subcortical nuclei in patients with Parkinson's
disease (PD), it was only in the 1970s that a significant number of reports
began to be published from Japan describing patients with dementia and
parkinsonism associated with the presence of Lewy bodies in cortical neurons
(reviewed by Kosaka, 1990). Since these reports, different workers have used a
variety of terms to describe this disease process, including diffuse Lewy body
disease (Yoshimura, 1983), Lewy body dementia (Gibb et al, 1987), senile
dementia of Lewy body type (Perry et al, 1990a) and the Lewy body variant of
Alzheimer's disease (Hansen et al, 1990).
Jendroska, K., M. Kashiwagi, et al. (1997). "Amyloid beta-peptide and its
relationship with dementia in Lewy body disease." J Neural Transm Suppl51: 137-44.
Cerebral cortical Lewy bodies occur in a spectrum of clinical syndromes
including Parkinson's disease (PD) with and without dementia, and dementing
conditions clinically resembling Alzheimer's disease with few or without
parkinsonian features. It is unclear whether these conditions are variants of
one disease process or represent pathogenetically distinct entities. Here we
compared the cortical pathology in post mortem brains of three groups
representing the predominant clinical phenotypes of Lewy body disease, including
27 non-demented cases of PD, 23 demented PD cases, and 11 cases of Lewy body
disease who initially presented with dementia and showed only limited features
of parkinsonism during the course of their illness. In addition to
neuropathology, computer-assisted histoblot analysis was used to assess cortical
amyloid beta-peptide deposition. There was wide overlap of the pathomorphometric
features between the two groups of demented cases. It appears that substantial
cortical Alzheimer-type pathology present in most demented cases contributes
significantly to the development of dementia in Lewy body disease.
Jellinger, K. A. (1997). "Morphological substrates of dementia in parkinsonism.
A critical update." J Neural Transm Suppl51: 57-82.
Dementia in parkinsonism is caused by a variety of central nervous system (CNS)
lesions, of which the molecular and pathogenic causes are poorly understood but
probably include: 1. Degeneration of subcortical ascending systems with neuronal
losses in dopaminergic, noradrenergic, serotonergic, cholinergic or multiple
systems including the amygdyloid nucleus; 2. limbic and/or cortical Alzheimer
and/or Lewy body pathologies, with loss of synapses and neurons, and 3. a
combination of these lesions or additional CNS pathologies. In general,
degeneration of subcortical neuronal networks appears insufficient to induce
severe mental decline although, occasionally, cognitive impairment occurs
without apparent cortical lesions. On the other hand, neuritic cortical
Alzheimer change showing similar or differential distribution compared to
Alzheimer's disease (AD) displays a significant linear correlation with dementia
in Parkinsonism. Plaques can be associated with cortical Lewy bodies and, the
contribution of each to dementing processes remains unresolved. In a consecutive
autopsy series of 610 patients with parkinsonism, the total prevalence of
retrospectively assessed dementia was 34.6%. In Parkinson's disease (PD) of the
Lewy body type, it was 30.2%, mostly associated with other brain lesions, mainly
AD, while only 3.5% of "pure" PD without additional brain pathologies were
demented. There was no significant difference in age and duration of illness
between demented and non-demented PD patients. Secondary parkinsonian syndromes
showed a higher incidence of dementia (56.3%), again with predominant Alzheimer
pathology which was present in 73% of the total of demented parkinsonian
patients and in almost 82% of the demented PD cases in this series. The specific
contribution of cortical and subcortical lesions to mental impairment in
parkinsonism, their relationship to AD, and an etiology await further
elucidation.
Hansen, L. A. (1997). "The Lewy body variant of Alzheimer disease." J Neural
Transm Suppl51: 83-93.
The Lewy body variant of Alzheimer disease (LBV) occupies a messy middle ground
between Alzheimer disease (AD) on the one hand, and pure Lewy body diseases
(Parkinson's disease or diffuse Lewy body disease), on the other. In addition to
brainstem and neocortical Lewy bodies, LBV brains have enough neocortical
neuritic plaques to meet diagnostic criteria for AD. However, neurofibrillary
pathology in LBV is modest, since tangle densities in LBV are typically
intermediate between AD and age-matched controls or pure Lewy body disease
brains. Apolipoprotein E-4 is overrepresented in LBV, as it is in AD but is not
in PD or diffuse Lewy body disease (DLBD). Neurologically, LBV patients often
display sufficient parkinsonian signs to separate them from AD, but these
findings are usually too subtle to warrant clinical diagnoses of Parkinson's
disease (PD). Neuropsychological deficits in LBV include a subcortical dementia
pattern similar to DLBD, and more severe global cognitive impairment reminiscent
of AD.
Braak, H., E. Braak, et al. (1997). "Neurofibrillary tangles and neuropil
threads as a cause of dementia in Parkinson's disease." J Neural Transm Suppl51: 49-55.
Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common
age-related degenerative disorders of the human brain. Both diseases involve
multiple neuronal systems and are the consequences of cytoskeletal
abnormalities. In AD susceptible neurons produce neurofibrillary changes, while
in Parkinson's disease, they develop Lewy bodies. In AD six developmental stages
can be distinguished on account of the predictable manner in which the
neurofibrillary changes spread across the cerebral cortex. During the course of
PD numerous limbic determined parts of the brain undergo specific lesions
regulating endocrine and autonomic functions. In general, the extranigral
destructions are in themselves not sufficient to produce overt intellectual
deterioration. Fully developed Parkinson's disease with concurring incipient
Alzheimer's disease is likely to cause impaired cognition.
Ballard, C., I. McKeith, et al. (1997). "The UPDRS scale as a means of
identifying extrapyramidal signs in patients suffering from dementia with Lewy
bodies." Acta Neurol Scand96(6): 366-71.
The study aimed to evaluate the merits of the Unified Parkinson's Disease Rating
Scale (UPDRS) in the assessment of parkinsonism in patients suffering from
Dementia with Lewy Bodies (DLB). Parkinsonian symptoms were assessed in 73
dementia patients using the UPDRS and staged using the Hoehn & Yahr system. A
staging of 1 or greater was taken to indicate significant parkinsonism. DLB
(n=42) was diagnosed using the McKeith et al. criteria, Alzheimer's disease
(n=30) was diagnosed using the NINCDS ADRDA criteria. The inability of some
patients to comply with some of the more complicated tasks meant that the full
UPDRS assessment could only be completed in 35 (83%) of the DLB patients, 23
(66%) of whom had significant parkinsonism. Patients with parkinsonism were
significantly younger than those without. A Principal Components Analysis
derived a sub-scale including the items tremor at rest, action tremor,
bradykinesia, facial expression and rigidity. These items had a specificity of
100% and a sensitivity of 85% for significant parkinsonism using a cut-off of
7/8. The brief scale had several advantages over the complete UPDRS. Unlike the
full scale it was independent of the severity of cognitive impairment and the 5
key items could be assessed in 41 (98%) of the DLB patients. Autopsies have been
completed on 31 patients, with a specificity of greater than 90% for the
operationalized clinical diagnosis of DLB. It is suggested that a 5 item
subscale of the UPDRS provides a reliable and generally applicable instrument
for the assessment of parkinsonism in DLB patients.
Braak, H., E. Braak, et al. (1996). "Pattern of brain destruction in Parkinson's
and Alzheimer's diseases." J Neural Transm103(4): 455-90.
Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common
age-related degenerative disorders of the human brain. Both diseases involve
multiple neuronal systems and are the consequences of cytoskeletal abnormalities
which gradually develop in only a small number of neuronal types. In AD,
susceptible neurons produce neurofibrillary tangles (NFTs) and neuropil threads
(NTs), while in PD, they develop Lewy bodies (LBs) and Lewy neurites (LNs). The
specific lesional pattern of both illnesses accrues slowly over time and remains
remarkably consistent across cases. In AD, six developmental stages can be
distinguished on account of the predictable manner in which the neurofibrillary
changes spread across the cerebral cortex. The pathologic process commences in
the transentorhinal region (clinically silent stages I and II), then proceeds
into adjoining cortical and subcortical components of the limbic system (stages
III and IV - incipient AD), and eventually extends into association areas of the
neocortex (stages V and VI - fully developed AD). During the course of PD,
important components of the limbic system undergo specific lesions as well. The
predilection sites include the entorhinal region, the CA2-sector of the
hippocampal formation, the limbic nuclei of the thalamus, anterior cingulate
areas, agranular insular cortex (layer VI), and - within the amygdala - the
accessory cortical nucleus, the ventromedial divisions both of the basal and
accessory basal nuclei, and the central nucleus. The amygdala not only generates
important projections to the prefrontal association areas but also exerts
influence upon all non-thalamic nuclei which in a non-specific manner project
upon the cerebral cortex and upon the nuclei regulating endocrine and autonomic
functions. All these amygdala-dependent structures themselves exhibit severe
PD-specific lesions. In general, the extranigral destructions are in themselves
not sufficient to produce overt intellectual deterioration. Similarly,
AD-related pathology up to stage III may be asymptomatic as well. Fully
developed PD with concurring incipient AD, however, is likely to cause impaired
cognition. Presently available data support the view that the occurrence of
additional lesions in the form of AD stage III (or more) destruction is the most
common cause of intellectual decline in PD.
