Wang, L., M. Zhu, et al. (2002). "[The application of Gallyas-Braak stainings in
pathologic diagnosis of neurodegenerative diseases]." Zhonghua Nei Ke Za Zhi41(2): 120-3.
OBJECTIVE: To evaluate the role of Gallyas silver staining in the diagnosis of
neurodegenerative diseases. METHOD: Modified Gallyas-Braak staining method was
used to investigate samples of the brain and spinal cord of 22 cases with
neurodegenerative disease including Alzheimer's disease (AD), Parkinson's diseas
(PD), Pick's disease, diffuse Lewy body disease (DLBD), progressive supranuclear
palsy (PSP), diagnosed by clinical and routine pathologic method. 10 cases
without clinical symptoms and pathologic abnormalities of the nervous system
served as control. RESULT: As compared with Bodian staining, Gallyas-Braak
staining demonstrated clearly neurofibrillary tangles in the hippocampus and the
cortex of frontal and temperal lobe in all the cases with Alzheimer's disease, 6
cases with dementia of other causes and 3 normal aged. However, global
neurofibrillary tangles in the midbrain and the basal ganglia were found only
with Gallyas-Braak staining in 4 cases with both dementia and extrapyramidal
features. In addition, tuft-shaped astrocytes were shown with this method in the
motor cortex, basal ganglia, midbrain of the above 4 cases and astrocytic
plaques in the same area in 2 cases of the 4 cases. In this connexion,
pathologic findings in 2 of the 4 cases corresponded to PSP and those of the
other two cases fufiled the diagnostic criteria of corticobasal degeneration (CBD)
Oligodendroglial cytoplasmic inclusions in the white matter of the brain and the
spinal cord were founded in 3 of the 4 cases with multiple system atrophy (MSA).
This silver staining demonstrated as well a lot of argyrophilic grains in the
neuropil of the temporal lobe and the hippocampus in one case with AD.
CONCLUSION: Gallyas silver staining could better reveal not only Alzheimer-like
neurofibrillary tangles but also different glial inclusions in other
neurodegenerative diseases such as PSP, CBD and MSA. Consequently, it is of
great value in the pathologic diagnosis and study of such degenerative diseases.
Power, J. H., J. M. Shannon, et al. (2002). "Nonselenium glutathione peroxidase
in human brain : elevated levels in Parkinson's disease and dementia with lewy
bodies." Am J Pathol161(3): 885-94.
Nonselenium glutathione peroxidase (NSGP) is a new member of the antioxidant
family. Using antibodies to recombinant NSGP we have examined the distribution
of this enzyme in normal, Parkinson's disease (PD), and dementia with Lewy body
disease (DLB) brains. We have also co-localized this enzyme with alpha-synuclein
as a marker for Lewy bodies. In normal brains there was a very low level of NSGP
staining in astrocytes. In PD and DLB there were increases in the number and
staining intensity of NSGP-positive astrocytes in both gray and white matter.
Cell counting of NSGP cells in PD and DLB frontal and cingulated cortices
indicated there was 10 to 15 times more positive cells in gray matter and three
times more positive cells in white matter than in control cortices. Some neurons
were positive for both alpha-synuclein and NSGP in PD and DLB, and double
staining indicated that NSGP neurons contained either diffuse cytoplasmic alpha-synuclein
deposits or Lewy bodies. In concentric Lewy bodies, alpha-synuclein staining was
peripheral whereas NSGP staining was confined to the central core.
Immunoprecipitation indicated there was direct interaction between alpha-synuclein
and NSGP. These results suggest oxidative stress conditions exist in PD and DLB
and that certain cells have responded by up-regulating this novel antioxidant
enzyme.
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.
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.
Kovacs, G., P. Zerbi, et al. (2002). "The prion protein in human
neurodegenerative disorders." Neurosci Lett329(3): 269.
We evaluate cellular prion protein (PrP(C)) immunoreactivity (IR) in
Alzheimer's, Parkinson's, diffuse Lewy body, and motor neuron diseases (MND),
progressive supranuclear palsy, and multiple system atrophy. We use
immunohistochemistry for PrP, including five monoclonal antibodies against
different epitopes and three different pretreatments, alpha-synuclein,
phosphorylated tau, beta-amyloid, and ubiquitin. Disease-specific inclusions are
devoid of PrP(C) IR. Using double immunofluorescence and confocal laser
microscopy we observe focal overlapping of PrP(C) with tau and with alpha-synuclein
in early, but not in fully developed inclusions. However, PrP(C) IR neurons may
contain abnormal tau or alpha-synuclein aggregates. Additionally, we observe a
loss of PrP(C) IR in anterior horn neurons in MND. Our results suggest that
expression of PrP(C) reflects a general response to cellular stress rather than
specific co-operation in aggregation of other proteins.
Kawamoto, Y., I. Akiguchi, et al. (2002). "14-3-3 proteins in Lewy bodies in
Parkinson disease and diffuse Lewy body disease brains." J Neuropathol Exp
Neurol61(3): 245-53.
Several components of Lewy bodies have been identified, but the precise
mechanism responsible for the formation of Lewy bodies remains undetermined. The
14-3-3 protein family is involved in numerous signal transduction pathways and
interacts with alpha-synuclein, which is a major constituent of Lewy bodies. To
elucidate the role of 14-3-3 proteins in neuro-degenerative disorders associated
with Lewy bodies, we performed immunohistochemical studies on 14-3-3 in brains
from 5 elderly control subjects and from 10 patients with Parkinson disease (PD)
or diffuse Lewy body disease (DLBD). In the normal controls, 14-3-3-like
immunoreactivity was mainly observed in the neuronal somata and processes in
various cortical and subcortical regions. In the PD and DLBD cases, a similar
immunostaining pattern was found and immunoreactivity was generally spared in
the surviving neurons from the severely affected regions. In addition, both
classical and cortical Lewy bodies were intensely immunolabeled and some
dystrophic neurites were also immunoreactive for 14-3-3. Our results suggest
that 14-3-3 proteins may be associated with Lewy body formation and may play an
important role in the pathogenesis of PD and DLBD.
Holdorff, B. (2002). "Friedrich Heinrich Lewy (1885-1950) and his work." J
Hist Neurosci11(1): 19-28.
In 1912, Friedrich Heinrich Lewy first described the inclusion bodies named
after him and seen in paralysis agitans (p.a.). Tretiakoff had found (1919) that
the nucleus niger is most likely to be affected but in a subsequent large-scale
series of post-mortem examinations (1923). Lewy was able to confirm this for a
minority of cases only, with the exception of those that displayed
postencephalitic Parkinsonism (and an unknown number of atypical Parkinson
syndrome cases not identified until the 1960s). In a speculative paper (1932),
he saw similarities between inclusion bodies in p.a. and viral diseases like
lyssa and postulated a viral genesis of p.a. In a historical review of basal
ganglia diseases (1942), he did not mention the putative significance of the
inclusion bodies for the post-mortem diagnosis. It seems that their importance
was seen only after Lewy's death, long after Tretiakoff's initial naming of the
'corps de Lewy'. Lewy, however, had already described their diffuse and cortical
distribution (1923). An identification of diffuse Lewy body disease or dementia
followed much later. Lewy's career in many diverse branches of neurology and
internal medicine was strongly affected by World War I and the difficult
situation faced by Jews in Germany. Shortly after the Neurological Institute was
founded in Berlin in 1932 (as a clinic and research institute), he was forced,
in 1933, to emigrate. His exile in England and the United States mirrors the
fate of many German Jews and academics in the first half of the 20th century.
Castellani, R. J., G. Perry, et al. (2002). "Hydroxynonenal adducts indicate a
role for lipid peroxidation in neocortical and brainstem Lewy bodies in humans."
Neurosci Lett319(1): 25-8.
Multiple lines of evidence indicate that oxidative stress is a critical
pathogenic factor in Parkinson disease (PD) and diffuse Lewy body disease (DLBD).
Previously, we demonstrated increased levels of redox-active iron in Lewy
bodies, and that Lewy bodies accumulate advanced glycation end-products. To
further characterize the role of oxidative stress in diseases with Lewy body
formation, we examined immunocytochemically eight cases of PD and five cases of
DLBD for adducts of the lipid peroxidation adduct 4-hydroxy-2-nonenal, and for
N(epsilon)-(carboxymethyl)lysine (CML). Our findings demonstrate
immunolocalization of 4-hydroxynonenal and CML to Lewy bodies in PD and DLBD.
These findings not only support prior studies indicating that lipid peroxidation
is increased in patients with PD and DLBD but that oxidative damage may play a
critical role in Lewy body formation.
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.
Zesiewicz, T. A., M. J. Baker, et al. (2001). "Diffuse Lewy Body Disease."
Curr Treat Options Neurol3(6): 507-518.
Diffuse Lewy body disease (DLB) is a neurodegenerative disorder characterized by
dementia, fluctuations in mental status, hallucinations, and parkinsonism.
Diffuse Lewy body disease is the second most common cause of dementia, following
Alzheimer's disease. The treatment of DLB includes cholinergic therapy for
cognitive impairment, atypical neuroleptics to alleviate hallucinations, and
levodopa/carbidopa to improve parkinsonism. The recognition and diagnosis of DLB
has critical treatment implications. Centrally acting cholinesterase inhibitors,
such as rivastigmine, donepezil, and galantamine partially reverse decreased
cortical cholinergic activity and may improve cognition and neuropsychiatric
symptoms in DLB. Rivastigmine has been demonstrated to improve cognition and
neuropsychiatric symptoms in patients with DLB without worsening parkinsonian
features. Due to the potential adverse events associated with neuroleptics in
this population, treatment with cholinesterase inhibitors is currently
considered first-line therapy in the treatment of hallucinations and mental
status fluctuations in DLB. Exquisite sensitivity to neuroleptic medications is
a hallmark of DLB and life-threatening complications have been reported. Caution
should be exercised when implementing antipsychotic therapy for the treatment of
behavioral disturbances of DLB. When required, atypical neuroleptics with the
least extrapyramdial side effects, such as quetiapine, should be used. The
parkinsonian features of DLB may respond to dopaminergic therapy with levodopa.
If parkinsonian symptoms result in clinical disability, a trial of levodopa is
warranted. Unfortunately, dopaminergic medications may worsen hallucinations.
Because dopamine agonists have a greater tendency to induce hallucinations and
somnolence, levodopa is the treatment of choice for parkinsonism in DLB. Rapid
eye movement (REM) sleep behavior disorder (RBD) is now recognized as a feature
of DLB. Awareness of the presence of this symptom in patients with DLB is
important and treatment with low dose clonazepam may help. Cholinergic
aumentation may also improve these symptoms in patients with DLB.
Suzuki, A., S. Ikebe, et al. (2001). "[A 64-year-old man with parkinsonism as an
initial symptom followed by dementia associated with marked abnormal behaviours]."
No To Shinkei53(11): 1075-87.
We report a 64-year-old man with parkinsonism as an initial symptom, which was
followed by dementia and abnormal behaviours. He was well until 1985, when he
was 49 years old, when he noted rest tremor in his right hand. Soon tremor
appeared in his left hand as well. He was seen in our clinic and levodopa was
prescribed. He was doing well with this medication, however, in 1993, he started
to suffer from on-off phenomenon. He also noted visual hallucination. In 1994,
he stole a watermelon and ate it in the shop. He repeated such abnormal
behaviours. In 1995, he was admitted to the neurology service of Hatsuishi
Hospital. On admission, he was alert and oriented. He did not seem to be
demented; however, he admitted stealing and hypersexual behaviours. No aphasia,
apraxia, or agnosia was noted. In the cranial nerves, downward gaze was markedly
restricted. He showed masked and seborrhoic face, and small voice. No motor
palsy was noted, but he walked in small steps with freezing and start
hesitation. Marked neck and axial rigidity was noted. Tremor was absent except
for in the tongue. No cerebellar ataxia was noted. Deep tendon reflexes were
diminished. Plantar response was extensor bilaterally. Forced grasp was noted
also bilaterally. He was treated with levodopa and pergolide, but he continued
to show on-off phenomenon. His balance problem and akinesia became progressively
worse; still he showed hypersexual behaviour problems. He also showed
progressive decline in cognitive functions. In 1997, he started to show
dysphagia. He developed aspiration pneumonia in July of 1998. In 1999, he
developed emotional incontinence and became unable to walk. He also developed
repeated aspiration pneumonia. He died on March 1, 2000. He was discussed in a
neurological CPC and the chief discussant arrived at a conclusion that the
patient had corticobasal degeneration. Other diagnoses entertained included
dementia with Lewy bodies, diffuse Lewy body disease, and frontotemporal
dementia. Majority of the participants thought that diffuse Lewy body disease
was most likely. Post-mortem examination revealed marked nigral neuronal loss,
gliosis and Lewy bodies in the remaining neurons. Abundant Lewy bodies of
cortical type were seen wide spread in the cortical areas, but particularly many
in the amygdaloid nucleus. Lewy bodies were also seen in the subcortical
structures such as the dorsal motor nucleus, oculomotor nucleus, Meynert
nucleus, putamen, and thalamus. What was interesting was marked neuronal loss of
the pontine nuclei, demyelination of the pontocerebellar fiber, and moderate
neuronal loss of the cerebellar Purkinje neurons, a reminiscent of
pontocerebellar atrophy. However, the inferior olivary nucleus was intact.
Rideout, H. J., K. E. Larsen, et al. (2001). "Proteasomal inhibition leads to
formation of ubiquitin/alpha-synuclein-immunoreactive inclusions in PC12 cells."
J Neurochem78(4): 899-908.
Proteasomal dysfunction has been recently implicated in the pathogenesis of
several neurodegenerative diseases, including Parkinson's disease and diffuse
Lewy body disease. We have developed an in vitro model of proteasomal
dysfunction by applying pharmacological inhibitors of the proteasome,
lactacystin or ZIE[O-tBu]-A-leucinal (PSI), to dopaminergic PC12 cells.
Proteasomal inhibition caused a dose-dependent increase in death of both naive
and neuronally differentiated PC12 cells, which could be prevented by caspase
inhibition or CPT-cAMP. A percentage of the surviving cells contained discrete
cytoplasmic ubiquitinated inclusions, some of which also contained synuclein-1,
the rat homologue of human alpha-synuclein. However the total level of
synuclein-1 was not altered by proteasomal inhibition. The ubiquitinated
inclusions were present only within surviving cells, and their number was
increased if cell death was prevented. We have thus replicated, in this model
system, the two cardinal pathological features of Lewy body diseases, neuronal
death and the formation of cytoplasmic ubiquitinated inclusions. Our findings
suggest that inclusion body formation and cell death may be dissociated from one
another.
Leech, R. W., R. A. Brumback, et al. (2001). "Dementia: the University of
Oklahoma autopsy experience." J Okla State Med Assoc94(11):
507-11.
The brain from 98 consecutive patients with the clinical diagnosis of dementia
were examined at autopsy in a standardized fashion. Alzheimer's Disease was
present in 79 of the cases, 76%, but represented the only diagnosis in 41%.
Thus, almost 60% had another associated pathologic disorder. Cerebral amyloid
angiopathy (CAA) represented the single largest subset, present in 25 cases. 40%
were accompanied by either 1) small, microscopic infarcts or cortical scars, or
2) small collections of macrophages containing hemosiderin or small hemorrhages.
CAA occurred with both atherosclerotic cortical infarcts and arteriolosclerotic
subcortical pallor or lacunar infarcts. Alzheimer's Disease occurred with
Diffuse Lewy Body (DLB) Disease in 13 cases. DLB Disease did not occur as a
distinct entity, and thus may represent the second largest subset of Alzheimer's
Disease. Both Alzheimer's Disease and DLB Disease accounted for dementia in
Parkinson's Disease. Almost 25% of all cases had a disorder other than
Alzheimer's Disease.
Kanazawa, A., S. Ikebe, et al. (2001). "[An 84-year-old woman with progressive
mental deterioration and abnormal behavior]." No To Shinkei53(2):
199-209.
We report an 84-year-old woman with progressive mental deterioration. She was
well until January 1994, when she was 80 years of the age. At that time she
developed a delusional ideation, in that she stated that she would be killed by
her fellow members of the society for elderly, in which she was belonging. At
times, she closed the shutter of her house saying that a stranger was wandering
outside of her house. In 1995, she could not identify the face of her son's
wife. When she went out for shopping, she lost her way to the home. She prowled
about in and out of her home. In 1996, she had to be admitted to a nursing home,
where quarrelled with other patients and behaved violently. She was admitted to
the neurology service of Hatsuishi Hospital on November 20th, 1997. Family
history revealed that her mother was said to be demented. On admission, she was
alert and behaved in a good manner. She was disoriented to the time and unable
to do serial 7. Her memory was very poor. She did not show aphasia or apraxia.
Cranial nerves appeared to be intact. She showed no weakness or muscle atrophy.
Gait was normal for her age. Plastic rigidity was noted in four limbs more on
the right side. No ataxia was noted. Deep tendon reflexes were exaggerated,
however, no Babinski sign was noted. Sensory examination was intact. Her
hospital course was characterized by the development of progressive gait
disturbance, violent behaviour, and prowling around. On November 30th, 1998, she
fell down and suffered from a fracture in the neck of her femur. Although
replacement of the femur head was performed, she became unable to walk after
this episode. Her mental functions deteriorated further. She developed pneumonia
and expired on February 2, 1999. She was discussed in a neurological CPC and the
chief discussant arrived at a conclusion that the patient probably had diffuse
Lewy body disease, because of the combination of dementia and parkinsonism.
Other possibilities discussed in the CPC included Pick's disease, frontotemporal
dementia and parkinsonism, and Alzheimer's disease. Post-mortem examination
revealed moderate atrophy in the frontal and temporal cortices. Microscopic
examination showed atrophy and gliosis in the hippocampus. Many diffuse plaque
and neuritic plaques were seen in the frontal cortex by methenamine silver
staining. Neurofibrillary tangles were also found. The Meynert nucleus was
preserved. The putamen and the substantia nigra were also intact. Pathologic
diagnosis was consistent with Alzheimer's disease.
Iwata, A., S. Miura, et al. (2001). "alpha-Synuclein forms a complex with
transcription factor Elk-1." J Neurochem77(1): 239-52.
alpha-Synuclein has been identified as a component of Lewy bodies in Parkinson's
disease and diffuse Lewy body disease, and glial cytoplasmic inclusions (GCIs)
in multiple system atrophy (MSA). To explore the role of alpha-synuclein in the
pathogenesis, we searched for molecules interacting with alpha-synuclein and
discovered that GCIs are stained by anti-Elk-1 antibody. To seek the role of
Elk-1 in synucleinopathies, we cotransfected alpha-synuclein and Elk-1 to
cultured cells, and found small granular structure complexes where the two
molecules colocalized. Moreover, alpha-synuclein and Elk-1 were co-immunoprecipitated
from the cell lysates. For formation of the complex, the presence of both ETS
and B-box domains of Elk-1 was required. Although there was no evidence of
direct binding between alpha-synuclein and Elk-1, we discovered that alpha-synuclein
and Elk-1 both bind to ERK-2, a MAP kinase. The effect of alpha-synuclein on the
MAP kinase pathway was assessed using the Pathdetect system, which showed
prominent attenuation of Elk-1 phosphorylation with alpha-synuclein, and
especially A53T mutant. Our results suggest that alpha-synuclein reacts with the
MAP kinase pathway, which might cause dysfunction of neurons and
oligodendrocytes and lead to neurodegeneration in Parkinson's disease and MSA.
Iwata, A., M. Maruyama, et al. (2001). "alpha-Synuclein affects the MAPK pathway
and accelerates cell death." J Biol Chem276(48): 45320-9.
Insoluble alpha-synuclein accumulates in Parkinson's disease, diffuse Lewy body
disease, and multiple system atrophy. However, the relationship between its
accumulation and pathogenesis is still unclear. Recently, we reported that
overexpression of alpha-synuclein affects Elk-1 phosphorylation in cultured
cells, which is mainly performed by mitogen-activated protein kinases (MAPKs).
We further examined the relationship between MAPK signaling and the effects of
alpha-synuclein expression on ecdysone-inducible neuro2a cell lines and found
that cells expressing alpha-synuclein had less phosphorylated MAPKs. Moreover,
they showed significant cell death when the concentration of serum in the
culture medium was reduced. Under normal serum conditions, the addition of the
MAPK inhibitor U0126 also caused cell death in alpha-synuclein-expressing cells.
Transfection of constitutively active MEK-1 resulted in MAPK phosphorylation in
alpha-synuclein-expressing cells and improved cell viability even under reduced
serum conditions. Thus, we conclude that alpha-synuclein regulates the MAPK
pathway by reducing the amount of available active MAPK. Our findings suggest a
mechanism for pathogenesis and thus offer therapeutic insight into
synucleinopathies.
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 Transm108(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.
Bogdanovic, N. (2001). "Intraneuronal Lewy body inclusions in Parkinson and
diffuse Lewy body disease." J Cell Mol Med5(3): 318-9.
Arahata, H., Y. Ohyagi, et al. (2001). "[A patient with probable dementia with
Lewy bodies, who showed improvement of dementia and parkinsonism by the
administratim of donepezil]." Rinsho Shinkeigaku41(7): 402-6.
We present a 73-year-old man with probable dementia with Lewy bodies(DLB). At 65
years of age, he gradually developed bradykinesia, gait disturbance and mild
amnesia. At 71 years of age, he noted resting tremor in bilateral hands, and
amnesia and disorientation were exacerbated. He was diagnosed as having
parkinsonism and took L-dopa/carbidopa at 100 mg/day. Since he developed
hallucination and abnormal behavior 2 days after the initiation of the drug, he
stopped taking L-dopa and was admitted to our hospital. A neurological
examination on admission revealed moderate amnesia, disorientation, finger
agnosia, constitutional apraxia, mask-like face, cogwheel rigidity, resting
tremor in bilateral hands, and bradykinesia. Brain MRI showed mild brain
atrophy, and single photon emission computerized tomography(SPECT) showed
diffuse moderate hypoperfusion in bilateral cerebral cortex. As he had
fluctuating cognitive dysfunction and parkinsonism, he was diagnosed to have
probable DLB. As his dementia was exacerbated by trihexyphenidyl, an
anti-cholinergic agent, at 2 mg/day, we treated him with donepezil, an anti-choline
esterase agent, at 3-5 mg/day. His parkinsonism, including rigidity and
bradykinesia, was markedly improved his dementia, consisting of amnesia and
disorientation. Electroencephalography (EEG) improved in the organization of the
dominant rhythm. The SPECT improved in the blood perfusion of the bilateral
frontal lobe as well as cognitive function and parkinsonism were maintained by
donepezil for 6 months after discharge. A therapeutic efficacy of donepezil for
DLB has recently been reported. It is notable that donepezil was beneficial not
only for cognitive dysfunction but also for parkinsonism in the present case
with probable DLB.
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.
Tatlidil, R., P. New, et al. (2000). "FDG positron emission tomography in
diffuse Lewy body disease: a case report." Clin Nucl Med25(12):
1004-6.
Lewy body disease is a clinicopathologic condition that includes Parkinson's
disease at one end and diffuse Lewy body disease at the other hand. The latter
is often associated with progressive cognitive deterioration, levodopa-responsive
parkinsonism, fluctuations of cognitive and motor functions, and visual and
auditory hallucinations. In addition, it can be a familial disease. Clinical and
positron emission tomographic findings are described in a patient with atypical
dementia and movement disorder and a pathologically proved diagnosis of diffuse
Lewy body disease.
Stocchi, F. and L. Brusa (2000). "Cognition and emotion in different stages and
subtypes of Parkinson's disease." J Neurol247 Suppl 2: II114-21.
This paper reviews the main neuropsychological features of movement disorders
such as Parkinson's disease (PD), progressive supranuclear palsy (PSP), multiple
system atrophy (MSA), Huntington's disease (HD), corticobasal degeneration (CBD),
and diffuse Lewy body disease (DLBD). These neurodegenerative disorders all
share a prominent frontal lobe-like syndrome which can be explained by damage to
connections between the basal ganglia and the cortical areas involved in
movement, and in behavioural and mood control. In this paper different types of
cognitive and mood alteration are described in an attempt to identify additional
reasons for the differential diagnosis of parkinsonism-like syndromes.
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.
Piao, Y. S., K. Wakabayashi, et al. (2000). "Aggregation of alpha-synuclein/NACP
in the neuronal and glial cells in diffuse Lewy body disease: a survey of six
patients." Clin Neuropathol19(4): 163-9.
BACKGROUND : alpha-Synuclein is now known to be a major component of Lewy bodies
(LBs) in Parkinson's disease (PD) and diffuse Lewy body disease (DLBD).
Recently, cytoplasmic aggregation of alpha-synuclein has also been reported to
occur in glial cells in these diseases. METHODS: We have conducted an
immunohistochemical survey to clarify in detail the distribution of alpha-synuclein
aggregates in the central nervous system of patients with DLBD. The cerebrum,
brainstem, cerebellum and spinal cord of six patients with DLBD were examined
immunohistochemically using anti-alpha-synuclein antibodies. RESULTS: In all
patients, alpha-synuclein-immunoreactive cytoplasmic inclusions, including those
with profiles of typical LBs, were visualized in neurons of the cerebral
neocortex, hippocampus, amygdaloid nucleus, hypothalamus, brainstem pigmented
nuclei and reticular formation. In some of these patients, similar spherical
cytoplasmic inclusions were also detected in neurons of the olfactory bulb,
basal ganglia, thalamus, the subthalamic, pontine, inferior olivary and
cerebellar dentate nuclei, and in the spinal gray matter. Moreover, alpha-synuclein-immunoreactive
cytoplasmic inclusions, which appeared circular or coil-like in shape, were
found in glial cells. In four patients with longstanding DLBD, these cytoplasmic
inclusions were distributed widely in brain areas, including brainstem, basal
ganglia, and cerebral and cerebellar white matter. CONCLUSION: The widespread
occurrence of alpha-synuclein aggregates in both neuronal and glial cells is a
pathological feature in patients suffering from DLBD.
Mizutani, T. (2000). "[Diagnostic criteria of diffuse Lewy body disease]."
Nippon Rinsho58(10): 2044-8.
DLBD is also called Dementia with Lewy bodies(DLB) which was proposed by the
consortium on DLB international workshop(CDLB) in 1995. CDLB criteria of
clinical diagnosis contain progressive cognitive decline as a mandatory feature,
and fluctuating cognition, recurrent visual hallucinations and parkinsonism as 3
core features. Supportive features include repeated falls, syncope, transient
loss of consciousness, neuroleptic sensitivity, and systematized delusions. CDLB
pathologic criteria include the presence of Lewy bodies as the only essential
feature, and associated features included Lewy-related neurites, senile plaques,
neurofibrillary tangles, and regional neuronal loss in the areas vulnerable to
Parkinson's disease. Lewy bodies are counted and scored from 0 to 2 in 5
designated cortical areas. Total Lewy body score of 7-10 indicates DLBD.
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.
Leopold, N. A. (2000). "Risperidone treatment of drug-related psychosis in
patients with parkinsonism." Mov Disord15(2): 301-4.
Risperidone, a novel neuroleptic with approximately equal D2 and 5HT2A receptor
blocking properties, has been used to treat drug-related hallucinations in
patients with Parkinson's disease. However, the results of only small numbers of
patients have been reported with the drug demonstrating limited usefulness. We
report our experience with this drug in 39 patients (25 women and 19 men) with
parkinsonism. Monitored clinical data included duration of disease, Hoehn and
Yahr score, Mini-Mental State Score, Unified Parkinson's Disease Rating Scale
(UPDRS) prior to drug administration and after 3 and 6 months of treatment, and
response to treatment. Twenty-three patients with Parkinson's disease had either
complete or near-complete resolution of hallucinations whereas an unsatisfactory
response (N = 6) or worsening of parkinsonism (N = 6) was noted in 12 patients,
only six of whom had Parkinson's disease. Excluding patients with diffuse Lewy
body disease, there was no significant worsening of the UPDRS scores after
either 3 or 6 months of treatment. The presence of dementia did not predict
response to treatment. Our results suggest that risperidone is a useful
treatment for hallucinations in patients with parkinsonism.
Jin, K., N. Sato, et al. (2000). "[Diffuse Lewy body disease searched out from
114 patients with parkinsonism]." Rinsho Shinkeigaku40(4):
329-33.
From 114 patients who had been previously diagnosed as Parkinson's disease, we
diagnosed six cases as clinically definite "diffuse Lewy body disease (DLBD)"
according to McKeith's criteria with more strict modifications. Besides a
central feature, dementia, and core features including parkinsonism, fluctuating
cognition, and recurrent visual hallucinations, the patients presented some of
supportive features, that is, repeated falls (4 cases), syncope (5 cases), and
transient loss of consciousness (all cases). Autopsy, which was performed in 2
of the cases, revealed Lewy bodies in various nervous tissues including
autonomic nervous systems in both cases. 7 cases of probable DLBD and 8 cases of
possible DLBD, which lacked fluctuating cognition and/or visual hallucinations,
demonstrated neither of repeated falls, syncope, nor transient loss of
consciousness. Episodes of these supportive features, which seem to be
associated with autonomic dysfunctions and/or fluctuating cognition, should be
important in the differential diagnosis of DLBD.
Ferrer, I. and R. Blanco (2000). "N-myc and c-myc expression in Alzheimer
disease, Huntington disease and Parkinson disease." Brain Res Mol Brain Res77(2): 270-6.
The present study examines N-myc and c-myc protein expression with Western
blotting and single and double-labeling immunohistochemistry in the hippocampus
in Alzheimer disease (AD), the striatum in Huntington disease (HD) and the
substantia nigra in Parkinson disease (PD). No modifications in the N-myc and
c-myc expression are found in hippocampal neurons in AD, striatal neurons in HD,
and pigmented neurons of the substantia nigra in PD. Yet punctate synaptic-like
N-myc immunoreactivity, matching enhanced synaptophysin expression, occurs in
diffuse plaques, but not in dystrophic neurites of neuritic plaques. In
contrast, c-myc immunoreactivity is found in dystrophic neurites, but not in
aberrant sproutings of neuritic plaques, as shown by double-labeling
immunohistochemistry to c-myc and phosphorylated tau or phosphorylated
neurofilament epitopes, and to c-myc and GAP-43, respectively. Strong N-myc and
c-myc are observed in reactive astrocytes in AD, HD and PD, as revealed by
double-labeling with N-myc or c-myc and GFAP. Finally, no relationship is found
between nuclear DNA fragmentation and increased N-myc or c-myc expression in
individual cells. These results demonstrate that neuron death in AD, HD and PD
is not associated with modifications in the steady-state expression of N-myc and
c-myc in individual neurons, and that neurofibrillary degeneration and Lewy body
formation are not accompanied by increased immunoreactivity to these
transcription factors. Increased N-myc and c-myc expression in reactive
astrocytes probably plays a role in reactive astrocytosis in human
neurodegenerative disorders.
Engelender, S., T. Wanner, et al. (2000). "Organization of the human synphilin-1
gene, a candidate for Parkinson's disease." Mamm Genome11(9):
763-6.
We have recently identified a protein we called synphilin-1, which interacts in
vivo with alpha-synuclein. Mutations in alpha-synuclein cause familial
Parkinson's disease (PD). Alpha-synuclein protein is present in the pathologic
lesions of familial and sporadic PD, and diffuse Lewy body disease, indicating
an important pathogenic role for alpha-synuclein. Here we describe the structure
of the human synphilin-1 gene (SNCAIP). The open reading frame of this gene is
contained within ten exons. We have designed primers to amplify each SNCAIP
exon, so these primers can now be used to screen for mutations or polymorphisms
in patients with Parkinson's disease or related diseases. We found a highly
polymorphic GT repeat within intron 5 of SNCAIP, suitable for linkage analysis
of families with PD. We have mapped SNCAIP locus to Chromosome (Chr) 5q23.1-23.3
near markers WI-4673 and AFMB352XH5. In addition, using immunohistochemistry in
human postmortem brain tissue, we found that synphilin-1 protein is present in
neuropil, similar to alpha-synuclein protein. Because of its association with
alpha-synuclein, synphilin-1 may be a candidate for involvement in Parkinson's
disease or other related disorders.
Stoessl, A. J. and J. Rivest (1999). "Differential diagnosis of parkinsonism."
Can J Neurol Sci26 Suppl 2: S1-4.
The diagnosis of Parkinson's disease is predominantly clinical, based on a
combination of the cardinal features of tremor, bradykinesia and rigidity. The
differential essentially lies between other conditions resulting in tremor, of
which essential tremor is the commonest, and other akinetic-rigid syndromes.
These include progressive supranuclear palsy, multiple system atrophy, toxins
and other degenerative disorders, including diffuse Lewy body disease and
corticobasal degeneration. The key clinical features of these disorders and a
practical diagnostic approach are briefly reviewed in this article.
Sohn, Y. K., N. Ganju, et al. (1999). "Neuritic sprouting with aberrant
expression of the nitric oxide synthase III gene in neurodegenerative diseases."
J Neurol Sci162(2): 133-51.
Neuronal loss, synaptic disconnection and neuritic sprouting correlate with
dementia in Alzheimer's disease (AD). Nitric oxide (NO) is an important synaptic
plasticity molecule generated by nitric oxide synthase (NOS) oxidation of a
guanidino nitrogen of L-arginine. Experimentally, the NOS III gene is modulated
with neuritic sprouting. In a previous study, NOS III expression was found to be
abnormal in cortical neurons, white matter glial cells, and dystrophic neurites
in AD and Down syndrome brains. The present study demonstrates the same
abnormalities in neuronal and glial NOS III expression with massive
proliferation of NOS III-immunoreactive neurites and glial cell processes in
other neurodegenerative diseases including: diffuse Lewy body disease, Pick's
disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, multiple
system atrophy, and Parkinson's disease. However, each disease, including AD,
was distinguished by the selective alterations in NOS III expression and
sprouting in structures marred by neurodegeneration. Double label
immunohistochemical staining studies demonstrated nitrotyrosine and NOS III
co-localized in only rare neurons and neuritic sprouts, suggesting that
peroxynitrite formation and nitration of growth cone proteins may not be
important consequences of NOS III enzyme accumulation. The results suggest that
aberrant NOS III expression and NOS III-associated neuritic sprouting in the CNS
are major abnormalities common to several important neurodegenerative diseases.
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.
Primavera, J., B. X. Lu, et al. (1999). "Brain Accumulation of Amyloid-beta in
Non-Alzheimer Neurodegeneration." J Alzheimers Dis1(3): 183-193.
We report an unusual case of amyotrophic lateral sclerosis (ALS) marked by
extensive cerebral amyloid-beta deposition in small and medium-size vessels,
capillaries, and perivascular plaques in the cerebral cortex, and in most
leptomeningeal vessels. Despite considerable cerebral amyloidosis, the patient
remained cognitively intact until death. For comparison with other
neuro-degenerative diseases and normal aging, we assessed the densities of
amyloid-beta-immunoreactive cortical vessels and plaques in matched frontal and
temporal lobe sections from archival uncomplicated cases of Alzheimer's disease
(N=10), Pick's disease (PkD; N=4), Parkinson's disease (PD; N=6), Diffuse Lewy
body disease (DLBD; N=7), progressive supranuclear palsy (PSP; N=5), multiple
systems atrophy (MSA; N=4), ALS (N=7), or normal aging (N=10) by
semi-quantitative grading (0 to 3+). Moderate (2+) or abundant (3+)
cerebrovascular amyloid-beta immunoreactivity was detected in 8/10 AD, 3/7 DLBD,
3/6 PD, 1 each with PSP or PkD, and 2/10 controls. Moderate or abundant
densities of amyloid-beta-immunoreactive diffuse plaques were detected in all
cases of AD or DLBD, 4/6 with PD, 3/5 with PSP, and 2/10 controls. Moderate or
abundant amyloid-beta-immunoreactive mature (dense core) plaques were present in
all cases of AD or DLBD, and 3 each with PD or PSP. Importantly,
amyloid-beta-immunoreactivity was not observed in the 4 MSA or 7 archival ALS
cases. This study demonstrates that prominent amyloid-beta accumulation in
cerebral vessels and plaques occurs frequently in AD, DLBD, PSP, and PD, but not
in ALS or MSA, indicating that the case described is unique. The lack of
cognitive impairment in the case presented argues against the idea that
extensive amyloid-beta deposition in the brain causes dementia.
Pakiam, A. S., C. Bergeron, et al. (1999). "Diffuse Lewy body disease presenting
as multiple system atrophy." Can J Neurol Sci26(2): 127-31.
OBJECTIVES: The majority of patients with diffuse Lewy body disease have
cognitive or psychiatric manifestations as part of their initial presentation. A
sizable minority present with parkinsonian features alone. Autonomic features
may also occur, typically after the development of cognitive changes. We aim to
demonstrate that diffuse Lewy body disease may rarely also present with
parkinsonism accompanied by marked autonomic dysfunction in the absence of
significant cognitive or psychiatric abnormalities. METHODS: Case report based
on a retrospective chart review and neuropathological examination. RESULTS: We
report on a patient in whom a clinical diagnosis of multiple system atrophy was
made based on a presentation of parkinsonism with prominent and early autonomic
involvement. The former included postural tremor, rigidity and bradykinesia,
while the latter consisted of repeated falls due to orthostasis and the
subsequent development of urinary incontinence midway through the course of her
illness. She was poorly tolerant of dopaminergic therapy due to accentuated
orthostasis. Benefit from levodopa was limited and only evident when attempted
withdrawal resulted in increased rigidity. There was no history of spontaneous
or drug-induced hallucinations, delusions or fluctuating cognition, and in
contrast to the prominence and progression of her parkinsonian and autonomic
features over the first several years, cognitive impairment did not occur until
the final stages of her illness, seven years after the onset of initial
symptoms. Neuropathological examination revealed numerous Lewy bodies in both
neocortical as well as subcortical structures consistent with a diagnosis of
diffuse Lewy body disease. There was marked neuronal loss in the substantia
nigra as well as the autonomic nuclei of the brainstem and spinal cord.
CONCLUSIONS: In addition to cognitive, psychiatric, and parkinsonian
presentations, diffuse Lewy body disease may present with parkinsonism and
prominent autonomic dysfunction, fulfilling proposed criteria for the
striatonigral form of MSA.
Mizutani, T. (1999). "[Familial parkinsonism and dementia with ballooned
neurons, argyrophilic neuronal inclusions, atypical neurofibrillary tangles,
tau-negative astrocytic fibrillary tangles, and Lewy bodies]." Rinsho
Shinkeigaku39(12): 1262-3.
We reported a new type of familial Parkinson's disease (familial PD) previously.
After that, we examined this family by both the immunohistochemical staining
using anti-alpha-synuclein antibody and the analysis of alpha-synuclein gene. We
reported these results, and briefly reviewed both familial PD and "familial
frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)".
Immunohistochemical staining with anti-alpha-synuclein antibody revealed that
the argyrophilic neuronal inclusions and atypical barely tau-positive
neurofibrillary tangles were strongly immunoreactive, whereas the ballooned
neurons and astrocytic fibrillary tangles were unreactive. DNA analysis of the
leukocytes obtained from one live patient of our family did not show any
mutations in the entire exons of alpha-synuclein gene. Our results indicated
that our family had familial diffuse Lewy body disease with atypical features
and without alpha-synuclein gene abnormalities. Features of familial PD included
1) autosomal dominant inheritance, 2) not uncommon atypical clinical features,
3) variable symptomatology and dopa-responsiveness, and 4) low incidence of
alpha-synuclein gene abnormalities. Our familial PD showed similar features, and
neuropathological findings of our patients also resembled FTPD-17 in the
presence of frequent ballooned neurons and neurofibrillary tangles in the
cerebral cortex, but were different in the presence of Lewy bodies and paucity
of tau pathology.
Mizukami, K., M. Sasaki, et al. (1999). "An autopsy case of myotonic dystrophy
with mental disorders and various neuropathologic features." Psychiatry Clin
Neurosci53(1): 51-5.
An autopsy case of myotonic dystrophy (MD) is reported. The patient was a
58-year-old male. He presented with muscular weakness and muscular atrophy at
the age of 33 and was diagnosed as having MD from myotonic symptoms (i.e.
percussion and grip myotonia) at 49 years old. Mental disorders including a
delusional hallucinatory state, mental slowness, indifference, and lack of
spontaneity as well as visual cognitive impairments were noted at the age of 55.
He showed Parkinsonism and died of septic shock. T2-weighted magnetic resonance
imaging demonstrated diffuse cortical atrophy with a marked frontal atrophy and
high-intensity signals in the white matter. Single photon emission computed
tomography demonstrated hypoperfusion in the frontal cortex. Neuropathologic
observation revealed neuronal loss in the superficial layer of the frontal and
parietal cortices and extensive neuronal loss in the occipital cortex,
intracytoplasmic inclusion body in the nerve cell of the medial thalamic nuclei,
neuronal loss and presence of Lewy bodies in the substantia nigra and locus
ceruleus corresponding to the pathologic features of Parkinson's disease, as
well as abnormalities of myelin in the white matter. The present case suggests
that in MD brain, various neuropathologic changes may occur and they contribute
to the mental disorders.
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.
Luis, C. A., W. Mittenberg, et al. (1999). "Diffuse Lewy body disease: clinical,
pathological, and neuropsychological review." Neuropsychol Rev9(3):
137-50.
The pathophysiological etiologies and clinical presentations of
neurodegenerative dementias have been found to be complex and heterogeneous.
Recently, Lewy body inclusions have been identified as an etiological factor in
20-34% of autopsied dementia cases. The term diffuse Lewy body disease (DLBD) is
generally accepted as the diagnostic term representative of this currently
under-reported and under-recognized disease. This article reviews the literature
on the clinical, pathological, and neuropsychological features of this disorder.
Differential diagnostic issues are discussed as well as current pharmacological
treatment. Nine confirmed cases of DLBD are presented to demonstrate the various
features of this disorder. The diagnostic implications of neuropsychological
examination results are discussed in relation to other common dementing
neurologic diseases.
Kosaka, K. (1999). "[Diffuse Lewy body disease]." Ryoikibetsu Shokogun
Shirizu(27 Pt 2): 82-5.
Iseki, E., W. Marui, et al. (1999). "Frequent coexistence of Lewy bodies and
neurofibrillary tangles in the same neurons of patients with diffuse Lewy body
disease." Neurosci Lett265(1): 9-12.
We examined the frequency of neurons with coexistent Lewy bodies (LB) and
neurofibrillary tangles (NFT) in diffuse Lewy body disease brains, by a
double-immunostaining method using MDV2 and Human tau. Double-positive neurons
were frequently observed in the limbic areas. These neurons mostly revealed the
feature of intermingled MDV2- and Human tau-positive substances. Immunoelectron
microscopically, the MDV2-positive components were not in continuity with the
MDV2-negative paired helical filaments (PHF). The MDV2-positive LB were
surrounded by the small PHF bundles, frequently accompanied by the randomly
oriented PHF within LB. In the intermingled neurons, MDV2-positive
non-filamentous components without LB were found among the large PHF bundles.
These non-filamentous components may represent the early stage of LB formation.
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.
Arai, T., K. Ueda, et al. (1999). "Argyrophilic glial inclusions in the midbrain
of patients with Parkinson's disease and diffuse Lewy body disease are
immunopositive for NACP/alpha-synuclein." Neurosci Lett259(2):
83-6.
Argyrophilic glial inclusions occur in the midbrain of patients with Parkinson's
disease (PD) and diffuse Lewy body disease (DLBD). These inclusions are
immunohistochemically positive for NACP/alpha-synuclein but negative for tau
protein. The results of the present study suggest that a primary degenerative
process involves NACP/alpha-synuclein in PD and DLBD and that the process takes
place not only in neurons but also in glial cells. Argyrophilic cytoplasmic
inclusions, both glial and neuronal, in a variety of degenerative diseases may
be grouped into two major categories; one related to aggregates of abnormally
phosphorylated tau protein and the other to unusual accumulations of
NACP/alpha-synuclein.
Arai, T., H. Akiyama, et al. (1999). "Immunohistochemical localization of
amyloid beta-protein with amino-terminal aspartate in the cerebral cortex of
patients with Alzheimer's disease." Brain Res823(1-2): 202-6.
We investigated immunohistochemically the localization of amyloid beta-protein
(Abeta) with amino-terminal aspartate (N1[D]) in brains of patients with
Alzheimer's disease, diffuse Lewy body disease and Down's syndrome. A monoclonal
antibody, 4G8, which recognizes the middle portion of Abeta, was used as a
reference antibody to label the total Abeta deposits. Double staining with
anti-Abeta(N1[D]) and 4G8 revealed that Abeta deposits in the subiculum and the
neocortical deep layers often lacked N1[D] immunoreactivity, indicating
N-terminal truncation of Abeta in these deposits. Abeta deposits in the
neocortical superficial layers and the presubicular parvopyramidal layer always
contained Abeta with N1[D]. Such regional as well as laminar differences in the
distribution of Abeta beginning at N1[D] suggest that some local factors
influence N-terminal processing of Abeta deposited in the brain.
Aksenova, M. V., M. Y. Aksenov, et al. (1999). "Oxidation of cytosolic proteins
and expression of creatine kinase BB in frontal lobe in different
neurodegenerative disorders." Dement Geriatr Cogn Disord10(2):
158-65.
The presence of the biomarkers of oxidative damage, protein carbonyl formation
and the inactivation of oxidatively sensitive brain creatine kinase (CK BB,
cytosolic isoform), were studied in frontal lobe autopsy specimens obtained from
patients with different age-related neurodegenerative diseases: Alzheimer's
disease (AD), Pick's disease (PkD), diffuse Lewy body disease (DLBD),
Parkinson's disease (PD), and age-matched control subjects. The CK activity was
significantly reduced in the frontal lobe of AD, PkD and DLBD subjects, and CK
BB-specific mRNA was significantly reduced in AD and DLBD. Protein carbonyl
content was significantly increased in AD, PkD and DLBD. The results of this
study confirm that the presence of biomarkers of oxidative damage is related to
the presence of histopathological markers of neurodegeneration. Our data suggest
that oxidative damage contributes to the development of the symptoms of frontal
dysfunction in AD, PkD and DLBD. The development of frontal dysfunction in
idiopathic PD might be secondary to oxidative damage and neuronal loss primarily
located in the nigrostriatal system. The results of CK BB expression analysis
demonstrate that the loss of the isoenzyme in different neurodegenerative
diseases is likely the consequence of its posttranslational modification,
possibly oxidative damage. Changes in CK BB expression may be an early indicator
of oxidative stress in neurons.
Wakabayashi, K., S. Hayashi, et al. (1998). "Autosomal dominant diffuse Lewy
body disease." Acta Neuropathol (Berl)96(2): 207-10.
We describe a Japanese family with parkinsonism and later-onset dementia. The
proband developed parkinsonism at the age of 61 years, followed by dementia
starting when she was 67. Her uncle, who was also her husband, died at the age
of 78 years after 7- and 5-year histories of parkinsonism and dementia,
respectively. Pathological examination of these two patients showed marked
neuronal loss with Lewy bodies (LBs) in the brain stem pigmented nuclei and
numerous cortical LBs and ubiquitin-positive hippocampal CA2/3 neurites were
observed. The proband also had many amyloid plaques. Their two sons developed
similar parkinsonism at the ages of 39 and 28 years and also suffered
later-on-set dementia. The apolipoprotein E genotype of the proband, her uncle
and one of their sons was epsilon3/4 and that of the other son was epsilon4/4.
These findings strongly suggest that this family has autosomal dominant diffuse
LB disease.
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.
Scarbrough, T. J. (1998). "Diffuse Lewy body disease: a common yet misdiagnosed
dementia in which neuroleptics may be contraindicated." Tenn Med91(2):
58-60.
Okuma, Y., N. Hattori, et al. (1998). "[A 74-year-old woman with parkinsonism
and dementia who died four years after the onset]." No To Shinkei50(7):
671-82.
We report a 74-year-old woman with parkinsonism and dementia, who died 4 years
after the onset of the disease. She was well until 70 years of the age (1993)
when she noted slowness in the movement in her left hand. She also developed
gait disturbance and the similar symptoms spread to the right upper and lower
extremities. Two years after the onset, she had difficulty in walk, and was
admitted to our hospital on March 9, 1995. Her daughter had the onset of hand
tremor at 50 years of the age and gait disturbance at 52. Her gait improved
after levodopa treatment, but her MRI revealed a liner T2-high signal lesion
along the outer surface of each putamen. On admission, the patient was alert but
slighted demented. Higher cerebral functions were normal. She had a masked face
and small voice. Her gait was of small step without arm swing. Retropulsion was
present. Rigidity was noted in the neck but not in the limbs. She was
bradykinetic but tremor was absent. She was treated with levodopa/carbidopa,
dops, and bromocriptine with considerable improvement and was discharged on
March 30, 1995. On January 19, 1996, she developed fever and hallucination; she
became more akinetic and admitted again. She showed marked dementia and stage IV
parkinsonism. She was treated by supportive measures with improvement in the
general condition, but she was found to have a gastric cancer for which a
subtotal gastrectomy was performed on March 11, 1996. Post-operative course was
uneventful, but her parkinsonism progressed to stage V. She was transferred to
another hospital on May 13, 1996. In July 21, 1996, she developed dyspnea and
fever and was admitted to our hospital again. She was somnolent. Rigidity was
moderate to marked and she was unable to stand or walk. By supportive cares, her
general condition improved and was discharged to home on November 4, 1996. She
developed fever on June 13, 1997 and admitted to our service again. Her BP was
150/90 mmHg. She was alert but markedly demented. Laboratory examination
revealed increases in liver enzymes (GOT 75 IU/l, GPT 101 IU/l) and renal
dysfunction (BUN 68 mg/dl, creatinine 3.27 mg/dl). Subsequent hospital course
was complicated by renal failure and thrombocytopenia (33,000/ml). She expired
on July 1, 1997. The patient was discussed in a neurologic CPC, and a chief
discussant arrived at the conclusion that the patient had diffuse Lewy body
disease and her daughter striatonigral degeneration. Some participants thought
both the patient and her daughter had diffuse Lewy body disease. Post-mortem
examination revealed marked degeneration of the substania nigra and the locus
coeruleus. The medial part of the nigra also showed marked cell loss. Lewy
bodies were found in the remaining nigral and coeruleus neurons. Cortical Lewy
bodies were very few and the striatum was intact. Pathologic diagnosis was
Parkinson's disease. Dementia was in part attributed to the marked degeneration
of the medial part of the substantia nigra.
Ohara, K. and N. Kondo (1998). "Changes of monoamines in post-mortem brains from
patients with diffuse Lewy body disease." Prog Neuropsychopharmacol Biol
Psychiatry22(2): 311-7.
1. In the present study, we measured the concentrations of 5-hydroxytryptamine
(5-HT), norepinephrine and dopamine in post-mortem brains from five patients
with diffuse Lewy body disease (DLBD), in comparison with five brains from
patients with Alzheimertype dementia (ATD), and five brains from normal
controls. 2. They were measured by means of high-performance liquid
chromatography fluorometric detection. 3. Compared with the ATD and normal
control brains, the DLBD ones showed decreased concentrations of 5-HT,
norepinephrine and dopamine in the putamen, and lower 5-HT and norepinephrine
concentrations, and almost equal dopamine ones in the neocortex.
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.
Iseki, E. and K. Kosaka (1998). "[Hippocampal pathology in diffuse Lewy body
disease]." No To Shinkei50(10): 907-12.
Iseki, E., W. Marui, et al. (1998). "Degenerative terminals of the perforant
pathway are human alpha-synuclein-immunoreactive in the hippocampus of patients
with diffuse Lewy body disease." Neurosci Lett258(2): 81-4.
We investigated the hippocampal pathology in diffuse Lewy body disease (DLBD)
using alpha-synuclein immunohistochemistry. Ubiquitin-positive intrahippocampal
structures caused by the degeneration of terminal axons of the perforant pathway
were observed to be alpha-synuclein immunoreactive. These
alpha-synuclein-positive degenerative terminals contained granulo-filamentous or
vesiculo-tubular components similar to those of Lewy bodies (LB) immunoelectron
microscopically, suggesting that alpha-synuclein may abnormally aggregate into
filamentous or membranous cytoskeletal components including neurofilaments and
synaptic vesicles in DLBD. A 'dying back' degenerating process due to a blockage
of axonal transport may explain why the degenerative terminals and LB share
similar alpha-synuclein-positive components, but the origin cells of the
perforant pathway contain only a few LB.
Goetz, C. G., C. Vogel, et al. (1998). "Early dopaminergic drug-induced
hallucinations in parkinsonian patients." Neurology51(3): 811-4.
OBJECTIVE: To characterize patients who develop hallucinations early in the
course of dopaminergic therapy for Parkinson's disease (PD) and contrast them
with patients developing hallucinations after chronic drug treatment. METHODS:
Parkinsonian patients who met diagnostic criteria for PD, experienced
hallucinations, had a detailed hallucination interview at the onset time of
their first hallucination, and had a 5-year clinical follow-up or an autopsy in
those 5 years were identified and divided into two groups for comparison: 12
patients who developed early hallucinations within 3 months of starting levodopa
therapy and 58 PD patients who developed hallucinations after 1 year of
dopaminergic therapy. We contrasted the quality, content, diurnal nature, and
emotional elements of the hallucinations, as well as the 5-year follow-up data
on diagnosis, disease course, community home or nursing home outcome, and
mortality. RESULTS: Both groups experienced a predominance of visual
hallucinations, visions of people and animals, and vivid colors and definition.
Features distinctive to the early onset hallucinating patients included visions
that persisted in daytime as well as nighttime, frightening content with
paranoia, and accompanying nonvisual hallucinations, either auditory, olfactory,
tactile, or combinations thereof. At the 5-year follow-up, none of the early
onset hallucinators had PD as their sole disorder. Four of the 12 had an
underlying psychiatric illness that included hallucinations or psychosis
preceding their parkinsonism by several years. In the other eight patients at
the 5-year follow-up, their parkinsonism evolved to include additional signs
that were no longer consistent with PD. The primary diagnoses were diffuse Lewy
body disease and Alzheimer's disease (AD) with extrapyramidal signs. Patients
with early drug-induced hallucinations had significantly greater placement to
nursing homes and greater mortality. CONCLUSIONS: Early onset drug-related
hallucinations are not typical of PD. Their presence should signal an
investigation of two alternative diagnoses, either a comorbid psychotic illness
(often unrevealed by the patient initially) or an evolving parkinsonism-plus
syndrome.
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.
de la Monte, S. M., Y. K. Sohn, et al. (1998). "P53- and CD95-associated
apoptosis in neurodegenerative diseases." Lab Invest78(4):
401-11.
Apoptosis is likely to be an important mechanism of cell loss in
neurodegenerative diseases, but the signaling cascades activated before DNA
fragmentation have not yet been determined. p53 or CD95 gene up-regulation
precedes apoptosis in many cell types, and a potential role for these molecules
in apoptosis of neurons and glial cells has already been demonstrated in
Alzheimer's disease (AD). To determine whether apoptosis in other
neurodegenerative diseases is mediated by similar mechanisms, p53 and CD95
expression were examined in postmortem central nervous system tissues from
patients with diffuse Lewy body disease (DLBD), Pick's disease (PkD),
progressive supranuclear palsy (PSP), multiple system atrophy (MSA), Parkinson's
disease (PD), amyotrophic lateral sclerosis (ALS), and Down's syndrome plus
Alzheimer's disease (DN+AD). Quantitative immunoblot analysis demonstrated
higher temporal lobe levels of p53 and CD95 proteins in DLBD, PkD, and DN+AD,
and higher temporal lobe levels of CD95 only in MSA and PSP relative to PD and
aged controls (for all, p < 0.01). In histologic sections, increased p53
immunoreactivity was localized in neuronal and glial cell nuclei, neuronal
perikarya, and dystrophic neuritic and glial cell processes in the frontal (Area
1 1) and temporal (Area 21) lobes in DLBD, PkD, and DN+AD, the motor cortex and
spinal ventral horns in ALS, and the striatum and midbrain in DLBD, MSA, PD, and
PSP. Increased CD95 expression and nuclear DNA fragmentation were present in the
same cell types and structures that manifested increased nuclear p53
immunoreactivity. The results suggest that p53- or CD95-associated apoptosis may
be a common mechanism of cell loss in several important neurodegenerative
diseases. In addition, the presence of abundant p53-immunoreactive neurites and
glial cell processes appears to be a novel feature of neurodegeneration shared
by these distinct diseases.
Cras, P. (1998). "Differential diagnosis in dementia." Acta Neurol Belg98(2): 186-9.
Dementia is characterised by progressive memory loss, associated with agnosia,
aphasia, dyscalculia, apraxia, and deficits in executive functioning. Alzheimer
disease is the most frequent cause of dementia, with vascular dementia, diffuse
Lewy body disease, and other etiologies being important differential diagnoses.
A strategy and diagnostic hierarchy for diagnosis in dementia is proposed.
Diagnostic criteria for Alzheimer disease, diffuse Lewy body disease, and
vascular dementia are discussed.
Browne, S. E., A. C. Bowling, et al. (1998). "Metabolic dysfunction in familial,
but not sporadic, amyotrophic lateral sclerosis." J Neurochem71(1):
281-7.
Autosomal dominant familial amyotrophic lateral sclerosis (FALS) is associated
with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Previous
studies have implicated the involvement of metabolic dysfunction in ALS
pathogenesis. To further investigate the biochemical features of FALS and
sporadic ALS (SALS), we examined SOD activity and mitochondrial oxidative
phosphorylation enzyme activities in motor cortex (Brodmann area 4), parietal
cortex (Brodmann area 40), and cerebellum from control subjects, FALS patients
with and without known SOD mutations, SALS patients, and disease controls
(Pick's disease, progressive supranuclear palsy, diffuse Lewy body disease).
Cytosolic SOD activity, predominantly Cu/Zn SOD, was decreased approximately 50%
in all regions in FALS patients with SOD mutations but was not significantly
altered in other patient groups. Marked increases in complex I and II-III
activities were seen in FALS patients with SOD mutations but not in SALS
patients. We also measured electron transport chain enzyme activities in a
transgenic mouse model of FALS. Complex I activity was significantly increased
in the forebrain of 60-day-old G93A transgenic mice overexpressing human mutant
SOD1, relative to levels in transgenic wild-type animals, supporting the
hypothesis that the motor neuron disorder associated with SOD1 mutations
involves a defect in mitochondrial energy metabolism.
Ballard, C. and I. G. McKeith (1998). "Psychiatric features in diffuse Lewy body
disease." Neurology50(2): 573.
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.
Turjanski, N. and D. J. Brooks (1997). "PET and the investigation of dementia in
the parkinsonian patient." J Neural Transm Suppl51: 37-48.
Parkinsonism and dementia are present in a number of neurodegenerative
conditions. They may be a manifestation of isolated brain stem (Parkinson's
disease) or diffuse Lewy body disease (DLBD), or be secondary to combined Lewy
body and Alzheimer's disease (AD) pathologies. Positron emission tomography
(PET) studies show a resting pattern of fronto-temporo-parietal hypometabolism
in both, AD and in parkinsonism-dementia (PD-dementia) patients, even when only
isolated brain stem Lewy body disease is found at pathology. We have studied
three patients fulfilling clinical criteria for diagnosis of DLBD. Their
18F-fluorodeoxyglucose (FDG) PET results showed an AD pattern of
fronto-temporo-parietal hypometabolism, though these patients had only mild
cognitive dysfunction. Parkinsonism associated with apraxia is observed in
corticobasal degeneration (CBD) while impairment of frontal functions, such as
planning and sorting, is seen in patients with progressive supranuclear palsy
(PSP). PET studies in CBD patients have shown an asymmetric hypometabolism of
cortex and thalamus contralateral to the affected limbs, while in PSP patients
there is a global metabolic reduction most pronounced in frontal areas and the
basal ganglia. These results suggest that metabolic PET studies can help to
distinguish PD-dementia, PSP and CBD, but are unable to distinguish PD-dementia
from AD. Further studies with post-mortem confirmation are required to establish
if DLBD is associated with a distinctive pattern of resting hypometabolism.
Tortosa, A., E. Lopez, et al. (1997). "Bcl-2 and Bax proteins in Lewy bodies
from patients with Parkinson's disease and Diffuse Lewy body disease."
Neurosci Lett238(1-2): 78-80.
Double-labelling immunohistochemistry of Bcl-2 and Bax, and ubiquitin (as a
marker of Lewy bodies) was examined in the brains of patients with Parkinson's
disease and Diffuse Lewy body disease to learn about possible modifications of
protein expression and the presence of Lewy bodies. Bcl-2 and Bax
immunoreactivities were observed in Lewy body-bearing and non-Lewy body-bearing
neurons in patients with parkinsonism. These results show that Bcl-2 and Bax are
probably not implicated in Lewy body formation and that the presence of Lewy
bodies does not have a direct impact on the expression of Bcl-2 and Bax proteins
in individual neurons.
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).
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.
Snow, R. E. and S. E. Arnold (1996). "Psychosis in Neurodegenerative Disease."
Semin Clin Neuropsychiatry1(4): 282-293.
Psychosis has been recognized as a common feature in neurodegenerative disease
for many years. Hallucinations, delusions, and other psychotic phenomena occur
in a wide range of degenerative disorders including Alzheimer disease,
Huntington disease, Parkinson's disease, diffuse Lewy body disease, "Parkinson
plus" syndromes, Pikc's disease, and other frontotemporal degenerations,
amyotrophic lateral sclerosis, and prion associated diseases. It is also
interesting that neurodegenerative disease-type dementia may be a feature in
some psychotic illnesses such as schizophrenia. Clinical evaluation of psychosis
in the setting of dementia presents a significant challenge for clinicians and
researchers. Amnesia, language or speech impairments, and behavioral problems
amy distort and obscure the presentation of symptoms. However, recognition and
understanding of the psychotic manifestations may lead to the institution of
more effective therapeutic or preventive options that can serve to delay long
term care placement and improve patient and caregiver quality of life. In
addition, a more comprehensive understanding of the pathophysiology,
neuroanatomical substrates, and distinctive pathological features underlying the
development of psychotic symptoms in neurodegenerative diseases may provide
important insights into psychotic processes in general.
