[ Index ]

Note: Search keywords = "British Dementia"

(141 References)

Wilson, J. M., I. Khabazian, et al. (2002). "Behavioral and neurological correlates of ALS-parkinsonism dementia complex in adult mice fed washed cycad flour." Neuromolecular Med 1(3): 207-21.

            Consumption of cycad seed products (Cycas circinalis) is one of the strongest epidemiological links to the Guamian neurological disorder amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), however, the putative toxin which causes neurodegeneration has never been identified definitively. To reexamine this issue, 6-7-mo-old, male CD-1 mice were assessed for motor and cognitive behaviours during and following feeding with pellets made from washed cycad flour. Cycad-fed animals showed early evidence of progressive motor and cognitive dysfunctions. Neurodegeneration measured using TUNEL and caspase-3 labeling was found in neocortex, various hippocampal fields, substantia nigra, olfactory bulb, and spinal cord. In vitro studies using rat neocortex have identified toxic compounds in washed cycad flour that induce depolarizing field potentials and lead to release of lactate dehydrogenase (LDH), both blocked by AP5. High-performance liquid chromatography (HPLC)/mass spectrometry of cycad flour samples failed to show appreciable amounts of other known cycad toxins, cycasin, MAM, or BMAA; only trace amounts of BOAA were present. Isolation procedures employing these techniques identified the most toxic component as beta-sitosterol beta-D-glucoside (BSSG). The present data suggest that a neurotoxin, or a toxic metabolite, not previously identified in cycad, is able to gain access to central nervous system (CNS) resulting in neurodegeneration of specific neural populations and in motor and cognitive dysfunctions. These data are consistent with a number of major features of ALS-PDC in humans.

Ujiie, M., D. L. Dickstein, et al. (2002). "p97 as a biomarker for Alzheimer disease." Front Biosci 7: e42-7.

            The search is ongoing for a reliable serum biomarker for AD. The level of iron is elevated in the brain of Alzheimer's disease (AD) patients. Our studies have demonstrated that the level of the iron transport protein, p97, is increased in the serum of AD patients but not in various control groups. These results have recently been confirmed by another laboratory who extended our findings by demonstrating that p97 is not elevated in other neurodegenerative diseases. This qualifies p97 as a potentially powerful biomarker specific for AD. Although the relationship between increased level of iron and p97 in the AD brain is not well understood, our research supports the hypothesis that p97 over-expressed by senile plaque associated reactive microglia is exocytosed and appears in blood. The relationship between elevated levels of serum p97 and AD, together with the possible future clinical application of p97 are considered in this report.

Sanchez-Pulido, L., D. Devos, et al. (2002). "BRICHOS: a conserved domain in proteins associated with dementia, respiratory distress and cancer." Trends Biochem Sci 27(7): 329-32.

            A novel domain (the BRICHOS domain) of approximately 100 amino acids has been identified in several previously unrelated proteins that are linked to major diseases. These include BRI(2), which is related to familial British and Danish dementia (FBD and FDD); Chondromodulin-I (ChM-I), related to chondrosarcoma; CA11, related to stomach cancer; and surfactant protein C (SP-C), related to respiratory distress syndrome (RDS). In several of these, the conserved BRICHOS domain is located in the propeptide region that is removed after proteolytic processing. Experimental data suggest that the role of this domain could be related to the complex post-translational processing of these proteins.

Revesz, T., J. L. Holton, et al. (2002). "Sporadic and familial cerebral amyloid angiopathies." Brain Pathol 12(3): 343-57.

            Cerebral amyloid angiopathy (CAA) is the term used to describe deposition of amyloid in the walls of arteries, arterioles and, less often, capillaries and veins of the central nervous system. CAAs are an important cause of cerebral hemorrhage and may also result in ischemic lesions and dementia. A number of amyloid proteins are known to cause CAA. The most common sporadic CAA, caused by A beta deposition, is associated with aging and is a common feature of Alzheimer disease (AD). CAA occurs in several familial conditions, including hereditary cerebral hemorrhage with amyloidosis of Icelandic type caused by deposition of mutant cystatin C, hereditary cerebral hemorrhage with amyloidosis Dutch type and familial AD with deposition of either A beta variants or wild-type A beta, the transthyretin-related meningo-vascular amyloidoses, gelsolin as well as familial prion disease-related CAAs and the recently described BRI2 gene-related CAAs in familial British dementia and familial Danish dementia. This review focuses on the morphological, biochemical, and genetic aspects as well as the clinical significance of CAAs with special emphasis on the BRI2 gene-related cerebrovascular amyloidoses. We also discuss data relevant to the pathomechanism of the different forms of CAA with an emphasis on the most common A beta-related types.

Pickering-Brown, S. M., A. M. Richardson, et al. (2002). "Inherited frontotemporal dementia in nine British families associated with intronic mutations in the tau gene." Brain 125(Pt 4): 732-51.

            Genetic screening of 171 patients with frontotemporal lobar degeneration disclosed 14 patients, across nine pedigrees, with mutations in the intron to exon 10 in the tau gene, a region regulating the splicing of exon 10 via a stem loop mechanism. Thirteen of these patients had the +16 splice site mutation and one had the +13 splice site mutation. Affected members of all nine families presented with changes in behaviour and social conduct that were prototypical of frontotemporal dementia (FTD). In all patients with the +16 splice site mutation, the behavioural profile was characterized by disinhibition, restless overactivity, a fatuous affect, puerile behaviour and verbal and motor stereotypies. The single patient with the +13 mutation presented a contrasting picture of apathy and inertia. In addition, all patients had evidence of semantic loss. Pathologically, five of the six patients so far autopsied shared frontotemporal atrophy with involvement of the substantia nigra. The underlying histology was that of microvacuolar-type cortical degeneration with a few swollen cells. Tau pathology was widespread throughout the brain and present in neurones and glial cells, mostly in the frontal and temporal cortical regions. This was in the form of neurofibrillary tangles and amorphous tau deposits (pre-tangles); Pick bodies were not observed. Ultrastructurally, the tau filaments had a twisted, ribbon-like morphology distinct from the paired helical filaments of Alzheimer's disease. One patient died from an unrelated illness whilst in the early clinical stages of FTD. In this patient, cortical microvacuolar and astrocytic changes were absent, though there were scattered neurones and glial cells, immunoreactive to tau, throughout the cortical and subcortical regions. The disease process underlying the neurodegeneration within these inherited forms of FTD may therefore stem directly from early, primary alterations in the function of tau. All eight families with the +16 mutation seem to be part of a common extended pedigree, possibly originating from a founder member residing within the North Wales region of Great Britain.

Perry, J. (2002). "Wives giving care to husbands with Alzheimer's disease: a process of interpretive caring." Res Nurs Health 25(4): 307-16.

            Wives giving care to spouses with dementia are a particularly vulnerable segment of the caregiving population. In this article a grounded theory study of 20 such wives is described, with their experiences explained as a process of interpretive caring. Wives began the process by either seeing changes in their husbands or recognizing changes in their work. Following this, the wives moved on to a phase of drawing inferences about what they observed and then took over their husbands' roles and responsibilities. These changes prompted the wives to rewrite identities for their husbands that incorporated the dementia and to rewrite identities for themselves to reflect their new roles, abilities, and strengths. Finally, the wives set about constructing a new daily life to sustain both partners. This process is neutral and allows for positive aspects of caring to be considered along with grief and frustration.

Lindesay, J., M. Marudkar, et al. (2002). "The second Leicester survey of memory clinics in the British Isles." Int J Geriatr Psychiatry 17(1): 41-7.

            BACKGROUND: The number of memory clinics in the British Isles has increased since our first survey in 1993. OBJECTIVES: The aim of this survey was to determine the memory clinics' characteristics and functions, and to compare these with the findings of our previous survey. METHODS: An expanded version of the 1993 questionnaire was sent to 102 possible memory clinics, identified by various means. There were 72 replies, 58 of which were from currently active clinics. RESULTS: There has been a substantial growth in the number of clinics since our previous survey in 1993, apparently stimulated by the licensing of cholinesterase inhibitor durgs for Alzheimer's disease (AD) and the development of services for early-onset dementia. Most of the new memory clinics have been set up within NHS old age psychiatry services, and they tend to be smaller and have less of an academic focus than the older clinics. However, they are similar in many aspects of their functioning, and have a similar range of practice with regard to patient assessment. CONCLUSIONS: As memory clinics move out from academic centres into mainstream clinical services, there is potential for greater co-ordination of their activities, and the development of an agreed core data set for assessment that would be valuable in the national monitoring of new anti-dementia treatments in clinical practice.

Kirkitadze, M. D., G. Bitan, et al. (2002). "Paradigm shifts in Alzheimer's disease and other neurodegenerative disorders: The emerging role of oligomeric assemblies." J Neurosci Res 69(5): 567-77.

            Alzheimer's disease (AD) is a progressive, neurodegenerative disorder characterized by amyloid deposition in the cerebral neuropil and vasculature. These amyloid deposits comprise predominantly fragments and full-length (40 or 42 residue) forms of the amyloid beta-protein (Abeta) organized into fibrillar assemblies. Compelling evidence indicates that factors that increase overall Abeta production or the ratio of longer to shorter forms, or which facilitate deposition or inhibit elimination of amyloid deposits, cause AD or are risk factors for the disease. In vitro studies have demonstrated that fibrillar Abeta has potent neurotoxic effects on cultured neurons. In vivo experiments in non-human primates have demonstrated that Abeta fibrils directly cause pathologic changes, including tau hyperphosphorylation. In concert with histologic studies revealing a lack of tissue injury in areas of the neuropil in which non-fibrillar deposits were found, these data suggested that fibril assembly was a prerequisite for Abeta-mediated neurotoxicity in vivo. Recently, however, both in vitro and in vivo studies have revealed that soluble, oligomeric forms of Abeta also have potent neurotoxic activities, and in fact, may be the proximate effectors of the neuronal injury and death occurring in AD. A paradigm shift is thus emerging that necessitates the reevaluation of the relative importance of polymeric (fibrillar) vs. oligomeric assemblies in the pathobiology of AD. In addition to AD, an increasing number of neurodegenerative disorders, including Parkinson's disease, familial British dementia, familial amyloid polyneuropathy, amyotrophic lateral sclerosis, and prion diseases, are associated with abnormal protein assembly processes. The archetypal features of the assembly-dependent neuropathogenetic effects of Abeta may thus be of relevance not only to AD but to these other disorders as well.

Kim, S. H., J. W. Creemers, et al. (2002). "Proteolytic processing of familial British dementia-associated BRI variants: evidence for enhanced intracellular accumulation of amyloidogenic peptides." J Biol Chem 277(3): 1872-7.

            Different mutations in the BRI(2) gene cause rare neurodegenerative conditions, termed familial British dementia (FBD) and familial Danish dementia (FDD). The mutant genes encode BRI-L and BRI-D, the precursors of fibrillogenic ABri and ADan peptides, respectively. We previously reported that furin processes both BRI-L and its wild type counterpart, BRI, resulting in the secretion of C-terminal peptides; elevated levels of peptides were generated from BRI-L. In the present study, we show that inducible expression of alpha1-antitrypsin Portland, a furin inhibitor, inhibits the endoproteolysis of BRI and BRI-L in a dose-dependent manner. Moreover, comparison of the activities of several proprotein convertases reveals that furin is most efficient in endoproteolysis of BRI and BRI-L; PACE4, PC6A, PC6B, and LPC show much lower activities. Interestingly, LPC also exhibits enhanced cleavage of BRI-L compared with BRI. Finally, we demonstrate that BRI-D is also processed by furin and, like BRI-L, the cleavage of BRI-D is more efficient than that of BRI. Interestingly, while the ABri peptide is detected both intracellularly and in the medium, the ADan peptide accumulates predominantly in intracellular compartments. We propose that intracellular accumulation of amyloidogenic ADan or ABri peptides results in the neuronal damage leading to FDD and FBD, respectively.

Khabazian, I., J. S. Bains, et al. (2002). "Isolation of various forms of sterol beta-D-glucoside from the seed of Cycas circinalis: neurotoxicity and implications for ALS-parkinsonism dementia complex." J Neurochem 82(3): 516-28.

            The factors responsible for ALS-parkinsonism dementia complex (ALS-PDC), the unique neurological disorder of Guam, remain unresolved, but identification of causal factors could lead to clues for related neurodegenerative disorders elsewhere. Earlier studies focused on the consumption and toxicity of the seed of Cycas circinalis, a traditional staple of the indigenous diet, but found no convincing evidence for toxin-linked neurodegeneration. We have reassessed the issue in a series of in vitro bioassays designed to isolate non-water soluble compounds from washed cycad flour and have identified three sterol beta-d-glucosides as potential neurotoxins. These compounds give depolarizing field potentials in cortical slices, induce alterations in the activity of specific protein kinases, and cause release of glutamate. They are also highly toxic, leading to release of lactate dehydrogenase (LDH). Theaglycone form, however, is non-toxic. NMDA receptor antagonists block the actions of the sterol glucosides, but do not compete for binding to the NMDA receptor. The most probable mechanism leading to cell death may involve glutamate neuro/excitotoxicity. Mice fed cycad seed flour containing the isolated sterol glucosides show behavioral and neuropathological outcomes, including increased TdT-mediated biotin-dUTP nick-end labelling (TUNEL) positivity in various CNS regions. Astrocytes in culture showed increased caspase-3 labeling after exposure to sterol glucosides. The present results support the hypothesis that cycad consumption may be an important factor in the etiology of ALS-PDC and further suggest that some sterol glucosides may be involved in other neurodegenerative disorders.

Johnson, M. D., R. A. Bebb, et al. (2002). "Uses of DHEA in aging and other disease states." Ageing Res Rev 1(1): 29-41.

            Dehydro-3-epiandrosterone is a steroid hormone synthesized in large quantities by the adrenal gland whose physiologic role remains unclear. The effects of DHEA could be estrogenic or androgenic, depending on the hormonal milieu. Low levels of DHEA are associated with aging, cardiovascular disease in men, and an increased risk of pre-menopausal breast and ovarian cancer. High levels of DHEA might increase the risk of postmenopausal breast cancer. Therapeutically DHEA might be useful for improving psychological well-being in the elderly, reducing disease activity in people with mild to moderate systemic lupus erythematosus and myotonic dystrophy, improving mood in those clinically depressed, and improving various parameters in women with adrenal insufficiency. Although many other claims have been made for DHEA in diverse conditions, such as aging, dementia, and AIDS, no well-designed clinical trials have clearly substantiated the utility and safety of long-term DHEA supplementation.

Janssen, J. C., E. K. Warrington, et al. (2002). "Clinical features of frontotemporal dementia due to the intronic tau 10(+16) mutation." Neurology 58(8): 1161-8.

            OBJECTIVE: To describe the clinical features of nine British families with neuropathologically verified frontotemporal dementia (FTD) due to the intronic tau exon 10(+16) mutation. METHODS: Retrospective chart reviews of family members with FTD belonging to nine tau 10(+16) mutation pedigrees in whom neuropathologic examination had been carried out. APOE genotype was determined for those patients for whom DNA was available. RESULTS: The median age at onset was 50 years (range 37 to 59 years; n = 30). The median age at death was 61 years (range 42 to 72 years; n = 33). The median duration of the disease was 11 years (range 3 to 22 years; n = 25) for those who have died and is 17 years (range 15 to 23 years; n = 3) for those living. The most common presenting symptom was disinhibition (n = 23). A minority presented with frontal dysexecutive symptoms, apathy, impairment of episodic memory, or depression. All of these patients subsequently developed personality and behavioral change. Memory impairment, language deficits, ritualistic behavior, hyperphagia, and hyperorality were frequent symptoms. Parkinsonism, neuroleptic sensitivity, or primitive reflexes were present in half of the patients, where these data were available. The clinical features of ALS were absent. Neuropathologic examination of 12 patients demonstrated the hallmark tau-positive neuronal and glial inclusions. APOE genotype did not account for the considerable variation in age at onset, age at death, duration of disease, or severity of estimated brain atrophy. CONCLUSIONS: All cases fulfilled the clinical criteria for a diagnosis of FTD. Despite similar clinical phenotypes, there was considerable variation in age at onset and duration of disease both between and within families, suggesting the presence of an effect due to other genetic or environmental factors.

Filla, A., G. De Michele, et al. (2002). "Early onset autosomal dominant dementia with ataxia, extrapyramidal features, and epilepsy." Neurology 58(6): 922-8.

            OBJECTIVE: To perform a clinical and molecular study of a large autosomal dominant family with a complex neurologic syndrome that comprises early-onset dementia, extrapyramidal and cerebellar features, and epilepsy. BACKGROUND: Early-onset forms of dementia often are caused by genetic factors. Mutations of three different genes-amyloid precursor protein (APP), presenilin 1 (PS-1), presenilin 2 (PS-2)-have been found in early-onset autosomal dominant forms of AD, of the human microtubule associated-protein tau gene (MAPT) in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), of the BRI gene in familial British dementia, of the PI12 gene in familial encephalopathy with neuroserpin inclusion bodies. Linkage to chromosome 3 has been found in familial nonspecific dementia (FND) and linkage to chromosome 20 has been found in Huntington disease (HD)-like neurodegenerative disease. Dementia may be a feature of other neurodegenerative diseases such as HD, dentatorubro-pallidoluysian atrophy (DRPLA), diseases caused by mutations of the prion protein gene (PRNP), spinocerebellar ataxias (SCA), and familial parkinsonism. METHODS: A southern Italian family with autosomal dominant dementia-plus was observed. The family includes 57 individuals in 5 generations (14 affected, 7 personally observed). The authors performed linkage analysis to APP, PS-1, PS-2, FTDP-17, BRI, PI12, FND, HD-like, SCA4, SCA5, SCA10, SCA11, SCA13, PARK1, PARK2, PARK3 loci; direct mutation analysis of HD, DRPLA, SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, and PRNP genes; and sequencing of the PRNP open reading frame. RESULTS: Linkage to the examined loci was excluded. All of the direct mutation analyses were negative excluding mutations in the examined genes. CONCLUSIONS: This family has a peculiar phenotype and molecular analyses excluded genes known to cause hereditary dementias.

Ferguson, N. M., A. C. Ghani, et al. (2002). "Estimating the human health risk from possible BSE infection of the British sheep flock." Nature 415(6870): 420-4.

            Following the controversial failure of a recent study and the small numbers of animals yet screened for infection, it remains uncertain whether bovine spongiform encephalopathy (BSE) was transmitted to sheep in the past via feed supplements and whether it is still present. Well grounded mathematical and statistical models are therefore essential to integrate the limited and disparate data, to explore uncertainty, and to define data-collection priorities. We analysed the implications of different scenarios of BSE spread in sheep for relative human exposure levels and variant Creutzfeldt-Jakob disease (vCJD) incidence. Here we show that, if BSE entered the sheep population and a degree of transmission occurred, then ongoing public health risks from ovine BSE are likely to be greater than those from cattle, but that any such risk could be reduced by up to 90% through additional restrictions on sheep products entering the food supply. Extending the analysis to consider absolute risk, we estimate the 95% confidence interval for future vCJD mortality to be 50 to 50,000 human deaths considering exposure to bovine BSE alone, with the upper bound increasing to 150,000 once we include exposure from the worst-case ovine BSE scenario examined.

Cooper, B. (2002). "Thinking preventively about dementia: a review." Int J Geriatr Psychiatry 17(10): 895-906.

            BACKGROUND: The dementias of late life now constitute a major public health challenge to our society. OBJECTIVE: To examine the contributions of neuroscience, clinical treatment and health-care policy to the building of a national programme for preventive approaches to dementia. METHOD: Critical review of the literature, making use of international databases (Medline, Embase, Psychlit) and British official publications. RESULTS: Recent developments in a number of research fields afford prospects for advances in primary and secondary prevention. These include findings from case-control and cohort studies of associations with earlier head injury and vascular disease, possibilities of pharmacological protection for persons at high risk for Alzheimer's disease, and the use of more effective anti-dementia drugs in the mild to moderate stages of severity. Research aimed at tertiary prevention is lagging behind, but there are some indications that the worst features of late-stage decline could already be mitigated by improvements in community support services and nursing-home care. CONCLUSIONS: Containment of the growing social and economic burdens of dementia calls for a national policy to ensure that new research findings can be translated into practice and applied to the benefit of all old people who stand in need. For this purpose the most appropriate conceptual framework is supplied by a preventive model, broadly similar to those already developed for some other forms of chronic degenerative disease.

Yasojima, K., H. Akiyama, et al. (2001). "Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship to deficient degradation of beta-amyloid peptide." Neurosci Lett 297(2): 97-100.

            Neprilysin is an enzyme capable of degrading beta-amyloid protein. We measured neprilysin mRNA and protein levels in brain and peripheral organs of Alzheimer disease (AD) and control cases. Neprilysin mRNA levels were lowest in the hippocampus and temporal gyrus, which are vulnerable to senile plaque development. They were highest in the caudate and peripheral organs which are resistant to senile plaque development. Levels in AD were significantly lower than controls in the hippocampus and midtemporal gyrus but not in other brain areas or peripheral organs. We also measured levels of the mRNA for the neuronal marker microtubule-associated protein-2. They were remarkably constant in all brain areas and were not lowered in AD, indicating that the neprilysin mRNA reduction in the hippocampus and temporal gyrus was not correlated with simple neuronal loss. Relative levels of neprilysin protein generally paralleled those of the mRNA. These results suggest that deficient degradation of beta-amyloid protein caused by low levels of neprilysin may contribute to AD pathogenesis.

Yasojima, K., E. G. McGeer, et al. (2001). "3-hydroxy-3-methylglutaryl-coenzyme A reductase mRNA in Alzheimer and control brain." Neuroreport 12(13): 2935-8.

            Statins are widely used pharmaceutical agents which lower plasma cholesterol by inhibiting the rate controlling enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. One epidemiological study suggests that statin therapy may provide protection against Alzheimer disease (AD). The aim of the present study was to determine the relative expression of HMG-CoA reductase mRNAs in various areas of brain as well as in peripheral organs and to compare values in AD and control cases. High levels of the mRNA were found in all areas of brain but no obvious differences were found between AD and controls. We conclude that brain has a robust capacity to synthesize cholesterol which appears to be unaffected by AD pathology.

Yasojima, K., E. G. McGeer, et al. (2001). "Relationship between beta amyloid peptide generating molecules and neprilysin in Alzheimer disease and normal brain." Brain Res 919(1): 115-21.

            beta-Amyloid peptide (Abeta) is generated by two cleavages of amyloid precursor protein (APP). The initial cleavage by BACE is followed by gamma-secretase cleavage of the C-terminal APP fragment. Presenilin-1 (PS-1) is intimately related to gamma-secretase. Once formed, Abeta is mainly broken down by neprilysin. To estimate vulnerability to Abeta senile plaque formation, we measured the relative mRNA levels of APP695, APP751, APP770, BACE, presenilin-1 (PS-1) and neprilysin in nine brain areas and in heart, liver, spleen and kidney in a series of Alzheimer disease (AD) and control cases. Each of the mRNAs was expressed in every tissue examined. APP695 was the dominant APP isoform in brain. Compared with controls, APP695 and PS-1 mRNA levels were significantly elevated in high plaque areas of AD brain, while neprilysin mRNA levels were significantly reduced. BACE levels were not significantly different in AD compared with control brain. In peripheral organs, there were no significant differences in any of the mRNAs between AD and control cases. APP isoforms were differently expressed in the periphery than in brain, with APP 751>770>695. Neprilysin mRNA levels were much higher, while APP695 and PS-1 mRNA levels were much lower in the periphery than in brain. The data suggest that, in the periphery, the capacity to degrade Abeta is srong, accounting for the failure of Abeta deposits to form. In plaque prone areas of AD brain, the capacity to degrade Abeta is weak, while the capacity to generate Ab is upregulated. In plaque resistant areas of brain, a closer balance exists, but there is some tendency towards lower degrading and higher synthesizing capacity in AD brain compared with control brain. Overall, the data indicate that effectiveness of degradation by neprilysin may be a key factor in determining whether Abeta deposits develop.

Yasojima, K., E. G. McGeer, et al. (2001). "High stability of mRNAs postmortem and protocols for their assessment by RT-PCR." Brain Res Brain Res Protoc 8(3): 212-8.

            Measurement of gene expression is a major area of brain research. We report on the remarkable postmortem stability of a selection of brain mRNAs in both fresh and frozen brain tissue. We describe techniques for extracting total RNA, synthesizing cDNAs from the mRNAs, amplifying specific cDNAs by the polymerase chain reaction technique, and quantitating the products. We chose five genes to study: the housekeeping gene cyclophilin; the complement components C3 and C4; the microtubule associated protein-2 (MAP-2); and the strongly inducible cyclooxygenase COX-2. We found little deterioration in total RNA or in any of the mRNAs in postmortem tissue up to 96 h. When tissue was frozen, stored at -70 degrees C for 15 years and then thawed, there was no evidence of deterioration from storage, but there was gradual deterioration post thawing. All the mRNAs were stable for 1-2 h at 4 degrees C following thawing. Cyclophilin, C3 and C4 mRNAs were still stable after 8 h, MAP-2 and COX-2 mRNAs showed significant deterioration between 2 and 4 h, and COX-2 mRNA showed drastic deterioration between 4 and 8 h. The data give no indication of rapid postmortem degeneration of RNA. Reliable mRNA values may be obtained from postmortem brain with long autolysis times provided the tissue has been kept in the cold, and from frozen tissues for 1-2 h after thawing.

Williams, R. (2001). "Optimal dosing with risperidone: updated recommendations." J Clin Psychiatry 62(4): 282-9.

            BACKGROUND: Drug dosages utilized during controlled clinical trials are not always optimal for patients encountered in day-to-day practice. The original trials of risperidone, a novel antipsychotic, suggested that an initial target dose of 6 mg/day was appropriate, but these trials were necessarily conducted among patients who were chronically impaired, hospitalized, and often partly drug resistant. DATA SOURCES: Relevant data relating to the dosage of risperidone identified through an online (MEDLINE) search using the keywords risperidone, schizophrenia, schizoaffective disorder dementia, bipolar disorder, and dose were supplemented by a review of international and U.S. Congress abstracts in which the dose of risperidone was specifically described. CONCLUSION: On the basis of naturalistic studies, clinical audit, phase 4 trials, positron emission tomography data, and 5 years of clinical experience, the currently recommended target dose of risperidone is 4 mg/day for most patients, with less-rapid titration than previously recommended. Moreover, a lower dose than this and slower titration may be appropriate for elderly patients, young patients, and first-episode patients.

Tuokko, H. A., R. J. Frerichs, et al. (2001). "Cognitive impairment, no dementia: concepts and issues." Int Psychogeriatr 13 Supp 1: 183-202.

            This article reviews the concept of mild cognitive impairment in groups of people whose cognitive impairment does not warrant a diagnosis of dementia (cognitive impairment, no dementia; CIND). Problems with the application of existing sets of criteria to the Canadian Study of Health and Aging (CSHA) data sets are addressed and a procedure for identifying a subgroup presumed "at risk" for developing dementia is presented. Application of an informant's report of changes in cognitive functioning and neuropsychologists' ratings of mild to severe deficits in any of eight cognitive domains results in approximately half of the CIND cases being identified as "at risk." The rationale for the collection of specific information related to CIND in CSHA-2 is provided. A minority of people identified with CIND at CSHA-2 showed only memory impairment, and most demonstrated cognitive loss over the preceding five-year interval. This article provides a conceptual basis for procedures to identify people with cognitive impairment most likely to decline to dementia.

Sadovnick, A. D. (2001). "Genetic counselling and genetic screening for Alzheimer's disease and other dementias." Can J Neurol Sci 28 Suppl 1: S52-5.

            Genetic and nongenetic factors have been identified to have roles in the etiology of dementia. Etiologic heterogeneity and genetic heterogeneity are recognized, especially for Alzheimer's disease which is the most common form of dementia. Asymptomatic individuals are increasingly requesting genetic services such as genetic counselling, predictive testing and screening for genetic risk factors. This paper provides an overview of the current knowledge about genetic counselling and genetic screening for dementia as well as guidelines for the physician.

Rasmusen, L., B. Yan, et al. (2001). "Effects of washout and dose-escalation periods on the efficacy, safety, and tolerability of galantamine in patients previously treated with donepezil: ongoing clinical trials." Clin Ther 23 Suppl A: A25-30.

            With the increasing number of acetylcholinesterase inhibitors (AChEIs) being marketed for the treatment of Alzheimer's disease (AD), physicians will need protocols for discontinuing one AChEI and initiating another ("switching"). Three clinical trials have been designed to provide data that will assist in the determination of the optimal conditions for switching patients from donepezil (the most widely prescribed AChEI) to galantamine (the most recently approved AChEI). The main objective of these studies is to investigate the effects of different washout periods (0 to 7 days) and dose-escalation schedules (fixed, fast vs slow) on the efficacy, safety, and tolerability of galantamine in patients with AD who were previously taking donepezil. The duration of the trials ranges from 12 to 52 weeks, and the last trial is expected to end in May 2002. No conclusions can yet be drawn from these ongoing trials, but the results should be helpful in establishing guidelines for physicians to use when switching patients with AD from donepezil to galantamine.

Perry, J. and K. Bontinen (2001). "Evaluation of a weekend respite program for persons with Alzheimer disease." Can J Nurs Res 33(1): 81-95.

            The documented under-use of respite programs in the face of unmet family caregiver needs is puzzling. The purpose of this study was to explore family caregivers' experience with a pilot respite program of weekend care for persons with Alzheimer disease (AD) or a related dementia. The goal-free evaluation approach captured the responses of 18 family caregivers to a pilot program developed by a community nursing organization. A content analysis of the caregiver interviews identified 3 categories: caregiver self-care, relief for the caregiver, and safety and comfort of the family member. The results suggest a link between the family caregiver achieving respite and the safety and comfort of the family member. The caregivers' perspective regarding the costs and benefits of respite influences the frequency with which they use the program. Research implications are discussed.

Olin, J. and L. Schneider (2001). "Galantamine for Alzheimer's disease." Cochrane Database Syst Rev(1): CD001747.

            BACKGROUND: Galantamine (also called galanthamine, marketed as Reminyl (Janssen)) can be isolated from several plants, including daffodil bulbs, and now synthesized. Galantamine is a specific, competitive, and reversible acetylcholinesterase inhibitor. It is also an allosteric modulator at nicotinic cholinergic receptor sites potentiating cholinergic nicotinic neurotransmission. A small number of early studies showed mild cognitive and global benefits for patients with Alzheimer's disease, and recently several multicentre clinical trials have been published with positive findings. Galantamine has received regulatory approval in Sweden, is available in Austria, and awaits marketing approval in the United States, Europe, and other countries. OBJECTIVES: The objective of this review is to assess the clinical effects of galantamine in patients with probable Alzheimer's disease, and to investigate potential moderators of an effect. SEARCH STRATEGY: The Cochrane Dementia Group specialized register of clinical trials was searched using the terms 'galantamine,' and 'galanthamine' (15 February 2000) as was the Cochrane Controlled Trials Register (2000, Issue 2). These terms were also used to search the following databases: EMBASE, MEDLINE, PsychLit; Combined Health Information Database, NRR (National Research Register), ADEAR (Alzheimer's Disease Education and Referral Centre clinical database, BIOMED (Biomedicine and Health), Glaxo-Wellcome Clinical Trials Register, National Institutes of Health Clinical Trials Databases, Current Controlled Trials, Dissertation Abstracts (mainly North American dissertations) 1961-1994, Index to UK Theses (British dissertations) 1970-1994. Published reviews were inspected for further sources. Additional information was collected from an unpublished investigational brochure for galantamine. SELECTION CRITERIA: Trials selected were randomized, double-blind, parallel-group, and unconfounded comparisons of galantamine with placebo for a treatment duration of greater than 4 weeks in people with Alzheimer's disease. DATA COLLECTION AND ANALYSIS: Data were extracted independently by the reviewers and pooled where appropriate and possible. The pooled odds ratios (95%CI) or the average differences (95%CI) were estimated. Intention-to-treat and observed cases data were both reported, if the data were available to be reported. -Outcomes of interest include the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), clinical global impression of change (CIBIC-plus or CGIC), Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL), Disability Assessment for Dementia scale (DAD) and Neuropsychiatric Inventory (NPI). - Potential moderating variables of a treatment effect included trial duration and dose. MAIN RESULTS: Seven trials were identified that met criteria for entry, with 6 being Phase II or III industry-sponsored multicentre trials. One was of 12 weeks duration; one of 5 months; one of 29 weeks; and the rest of 6 months duration. Trials of 5 months or more were aggregated in the analyses as '6 months'. Overall, galantamine showed significant treatment effects at daily doses of 16-32 mg/d for trials of 3- to 6-months duration. For global ratings, trials of 3 months duration with doses of 24-32mg/d (Odds Ratio (OR) 2.2; 95%CI 1.4 to 3.7) and 36mg/d (OR 3.3; 95%CI 1.2 to 9.3) were statistically significant in favour of treatment. For trials of 6 months duration (5-months to 29 weeks), only doses of 8mg/d failed to be statistically significant (24mg: OR 2.0; 95%CI 1.5 to2.5; 32mg: OR 1.9; 95%CI 1.4 to 2.5). For cognitive function over 6 months duration: at a 24mg/d, improvements measured -3.5 points (k=3; 95%CI -4.3 to -2.8) on weighted mean difference on the ADAS-Cog scale, and -4.0 points at 32mg/d (k=2; 95%CI -5.0 to -3.0). Both observed cases (WMD 3.8; 95%CI 0.3 to 7.3) and intention to treat analyses using the Disability Assessment of Dementia gave statistically significant results in favour of treatment for daily doses of 32mg for 6 months duration. The small number of trials available for analysis, however, limited the power of analyses to detect differences. Galantamine consistently failed to show statistically significant treatment effects at doses of 8mg/day. Galantamine's adverse effects appear similar to those of other cholinesterase inhibitors, in that it tends to produce gastrointestinal effects acutely and with dosage increases. Overall, people treated with galantamine at doses of 24-32 mg/d were more likely to discontinue participation in most trials than were people treated with lower doses or placebo, but in the one trial with a slower rate of titration the discontinuation rate was not significantly greater than placebo for the 16 mg/day dose. (ABSTRACT TRUNCATED)

Narani, N. and J. B. Epstein (2001). "Classifications of oral lesions in HIV infection." J Clin Periodontol 28(2): 137-45.

            BACKGROUND: Manifestations of immunosuppression may take the form of opportunistic infection, and neoplasia. While this paper has focused on gingival and periodontal manifestations. these tissues cannot be evaluated in isolation. The presence of involvement of other oral tissues such as the cheek or tongue with manifestations associated with HIV such as hairy leukoplakia, Kaposi's sarcoma at these sites, and candidiasis in addition to periodontal manifestations may further increase the clincal suspicion of underlying immunosuppression and/or progression of the immunosuppressive state. DISCUSSION: The periodontist plays an essential r le in identifying the periodontal status of an individual and has an important r le to play in early recognition of signs and symptoms of HIV disease or progression of the medical condition. CONCLUSION: Only through such recognition can appropriate definitive diagnostic testing be conducted, and appropriate therapeutic intervention for the oral condition and the systemic condition be considered.

McGeer, P. L. and E. G. McGeer (2001). "Polymorphisms in inflammatory genes and the risk of Alzheimer disease." Arch Neurol 58(11): 1790-2.

            The concept of inflammation as a major factor in Alzheimer disease (AD) has heretofore been based on postmortem findings of autodestructive changes associated with the lesions coupled with epidemiological evidence of a protective effect of anti-inflammatory agents. Now there is evidence that the risk of AD is substantially influenced by a total of 10 polymorphisms in the inflammatory agents interleukin 1alpha, interleukin 1beta, interleukin 6, tumor necrosis factor alpha, alpha(2)-macroglobulin, and alpha(1)-antichymotrypsin. The polymorphisms are all common ones in the general population, so there is a strong likelihood that any given individual will inherit 1 or more of the high-risk alleles. The overall chances of an individual developing AD might be profoundly affected by a "susceptibility profile" reflecting the combined influence of inheriting multiple high-risk alleles. Since some of the polymorphisms in question have already been linked to peripheral inflammatory disorders, such as juvenile rheumatoid arthritis, myasthenia gravis, and periodontitis, associations between AD and several chronic degenerative diseases may eventually be demonstrated. Such information could lead to strategies for therapeutic intervention in the early stages of such disorders.

McGeer, P. L. and E. G. McGeer (2001). "Inflammation, autotoxicity and Alzheimer disease." Neurobiol Aging 22(6): 799-809.

            Neuroinflammation is a central feature of Alzheimer disease (AD). It involves an innate immune reaction of sufficient intensity that self attack on neurons occurs. This phenomenon is best described as autotoxicity to distinguish it from classical autoimmunity which involves cloning of peripheral lymphocytes. Many compounds have been identified in AD brain which are known to promote and sustain inflammatory responses. They include beta-amyloid protein; the pentraxins C-reactive protein and amyloid P; complement proteins; the inflammatory cytokines interleukin-1, interleukin-6 and tumor necrosis factor-alpha; the protease inhibitors alpha-2-macroglobulin and alpha-1-antichymotrypsin; and the prostaglandin generating cyclooxygenases COX-1 and COX-2. Orally effective agents which can counteract the influence of these inflammatory stimulators should be effective in treating AD. Epidemiological evidence, coupled with results from pilot clinical trials, suggest there is great promise for traditional COX-1 inhibiting NSAIDs. Inhibitors of mediators closer to the core processes might offer even greater therapeutic promise. Some theoretical opportunities are suggested, based on intervention in the action of the above mentioned mediators.

McGeer, E. G., K. Yasojima, et al. (2001). "The pentraxins: possible role in Alzheimer's disease and other innate inflammatory diseases." Neurobiol Aging 22(6): 843-8.

            Two short pentraxins, C-reactive protein and amyloid P, are found in association with the senile plaques and neurofibrillary tangles of Alzheimer disease (AD). Formerly thought to be made primarily if not solely in liver, recent work has shown that they are made not only in the brain but in other tissues such as heart and arteries. Their synthesis is markedly upregulated in affected brain regions in AD. Since they are known to activate the complement cascade in an antibody-independent fashion and chronic activation can cause destruction of host tissue, these pentraxins may be important initiators of an autodestructive process. As such, they may be prime targets for therapeutic intervention.

Mackenzie, I. R. (2001). "Postmortem studies of the effect of anti-inflammatory drugs on Alzheimer-type pathology and associated inflammation." Neurobiol Aging 22(6): 819-22.

            Examining postmortem tissue is the most direct way of evaluating the effect of antemortem drug use on the pathological processes believed to be important in Alzheimer's disease (AD). A small number of studies have recently been published in which data from human autopsy tissue and animal models provides important insight into the mechanisms by which anti-inflammatory (AI) agents may protect against AD. These indicate that certain classes of AI drugs may be capable of reducing the chronic inflammation which is consistently seen in AD brain tissue. In addition, a recent study using a transgenic mouse model of AD, suggests that AI therapy may also influence the accumulation of senile plaques and dystrophic neurites. The results of these and future postmortem studies will be invaluable in the development of optimum treatment strategies.

Lam, F. C., R. Liu, et al. (2001). "beta-Amyloid efflux mediated by p-glycoprotein." J Neurochem 76(4): 1121-8.

            A large body of evidence suggests that an increase in the brain beta-amyloid (Abeta) burden contributes to the etiology of Alzheimer's disease (AD). Much is now known about the intracellular processes regulating the production of Abeta, however, less is known regarding its secretion from cells. We now report that p-glycoprotein (p-gp), an ATP-binding cassette (ABC) transporter, is an Abeta efflux pump. Pharmacological blockade of p-gp rapidly decrease extracellular levels of Abeta secretion. In vitro binding studies showed that addition of synthetic human Abeta1-40 and Abeta1-42 peptides to hamster mdr1-enriched vesicles labeled with the fluorophore MIANS resulted in saturable quenching, suggesting that both peptides interact directly with the transporter. Finally, we were able to directly measure transport of Abeta peptides across the plasma membranes of p-gp enriched vesicles, and showed that this phenomenon was both ATP- and p-gp-dependent. Taken together, our study suggests a novel mechanism of Abeta detachment from cellular membranes, and represents an obvious route towards identification of such a mechanism in the brain.

Klegeris, A., C. Schwab, et al. (2001). "Induction of complement C9 messenger RNAs in human neuronal cells by inflammatory stimuli: relevance to neurodegenerative disorders." Exp Gerontol 36(7): 1179-88.

            Neurons express proteins of the classical complement pathway, including C9. Both the mRNA and protein levels for C9 are sharply upregulated in brain areas affected by Alzheimer's disease (AD). Since little is known about the signals that are responsible for this upregulation, we evaluated in human SH-SY5Y neuroblastoma cells the factors which stimulate C9 production. Interferon-gamma, phorbol myristate acetate and interleukin-6 all stimulated C9 mRNA expression but the inflammatory cytokines tumor necrosis factor-alpha, interleukin-1 beta, as well as the anaphylatoxin C5a and the bacterial lipopolysaccharide, were ineffective. Immunohistochemical analysis of postmortem human brains for C9 protein demonstrated its presence in many cortical pyramidal neurons in AD, Down's syndrome, the parkinsonism dementia complex of Guam and pallido-ponto-nigral degeneration, as well as in thalamic neurons of progressive supranuclear palsy and ballooned neurons of Pick's disease. Since C9 is required for the membrane attack complex of complement to become functional, interfering with signaling pathways that stimulate its production could offer new therapeutic strategies for treating various neurodegenerative disorders.

Iverson, G. L. and T. S. Woodward (2001). "Measuring adaptive behavior in inpatient neuropsychiatry: the Behavioural Assessment Scale." Assessment 8(2): 119-26.

            The Behavioural Assessment Scale (BAS) was administered to a sample of 95 inpatients with neuropsychiatric conditions. The total scores in the sample ranged from 26 to 145 (maximum possible score is 163), without any evidence of the "floor effect" encountered with other tests used with this population. Investigation into the psychometric structure of the BAS revealed three factors interpreted as Daily Living Skills, Communication/Social Skills, and Problem Behavior. The high intercorrelation between the two dominant factors was interpreted as general sensitivity of the BAS to global decline in functioning associated with severity of illness. These results confirm a previous psychometric investigation carried out on an elderly psychiatric sample. A recommendation is made for interpreting subscales based on these factor domains when specific abilities are of interest and using a Global Functioning subscale as a measure of overall adaptive behavior for both adult and geriatric inpatient neuropsychiatry patients.

Iverson, G. L. and P. Green (2001). "Measuring improvement or decline on the WAIS-R in inpatient psychiatry." Psychol Rep 89(2): 457-62.

            Psychologists in inpatient psychiatric settings sometimes are asked to assess whether patients improve or decline in intellectual functioning. The impetus for this referral question may be a perceived change in psychiatric status, an acute neuropathological event, e.g., a head injury, or a suspicion of an early dementing process. For this study, data from 100 inpatients who completed the WAIS-R on two separate admissions were used to calculate confidence bands for measurement error surrounding test-retest difference scores. The analysis indicated that, if the retest interval is three months or less, significant practice effects must be factored into the interpretation of difference scores. A table for the interpretation of difference scores at different testing intervals is provided

Holton, J. L., J. Ghiso, et al. (2001). "Regional distribution of amyloid-Bri deposition and its association with neurofibrillary degeneration in familial British dementia." Am J Pathol 158(2): 515-26.

            Familial British dementia (FBD), pathologically characterized by cerebral amyloid angiopathy (CAA), amyloid plaques, and neurofibrillary degeneration, is associated with a stop codon mutation in the BRI gene resulting in the production of an amyloidogenic fragment, amyloid-Bri (ABri). The aim of this study was to assess the distribution of ABri fibrillar and nonfibrillar lesions and their relationship to neurofibrillary pathology, astroglial and microglial response using immunohistochemistry, confocal microscopy, and immunoelectron microscopy in five cases of FBD. Abnormal tau was studied with immunoblotting. We present evidence that ABri is deposited throughout the central nervous system in blood vessels and parenchyma where both amyloid (fibrillar) and pre-amyloid (nonfibrillar) lesions are formed. Ultrastructurally amyloid lesions appear as bundles of fibrils recognized by an antibody raised against ABri, whereas Thioflavin S-negative diffuse deposits consist of amorphous electron-dense material with sparse, dispersed fibrils. In contrast to nonfibrillar lesions, fibrillar ABri is associated with a marked astrocytic and microglial response. Neurofibrillary tangles and neuropil threads occurring mainly in limbic structures, are found in areas affected by all types of ABri lesions whereas abnormal neurites are present around amyloid lesions. Immunoblotting for tau revealed a triplet electrophoretic migration pattern. Our observations confirm a close link between ABri deposition and neurodegeneration in FBD.

Gray, A. J., V. Staples, et al. (2001). "Olfactory identification is impaired in clinic-based patients with vascular dementia and senile dementia of Alzheimer type." Int J Geriatr Psychiatry 16(5): 513-7.

            AIMS: It is now well established that there are abnormalities in the sense of smell in patients suffering from Alzheimer's disease (AD). They have both raised olfactory thresholds and impaired odour identification. The situation in vascular dementia is unclear. We used the University of Pennsylvania Smell Identification Test (UPSIT), a 40-item, forced choice, cued, 'scratch-and- sniff' test, to examine olfactory identification in vascular dementia and to determine whether it would differentiate the disorder from AD and normal elderly. METHODS: We investigated three matched subject groups: 13 people having a Cambridge Examination for Mental Disorders in the Elderly (CAMDEX) diagnosis of definite senile dementia of Alzheimer type, 13 having a CAMDEX diagnosis of definite vascular dementia and 13 non-cognitively impaired controls. The subjects were then tested with the UPSIT in their own home by an independent blind researcher to see if the test could distinguish the different diagnostic groups in this setting. RESULTS: The median UPSIT score was 30 (out of a maximum of 40) for controls, 12 for the vascular group and 15 for the AD group. The difference was significant (p = 0.05) between both demented groups and the normal controls. Similarly there was a significant difference in the UPSIT score between the AD group and controls (p = 0.001) and between the vascular dementia group and controls (p = 0.001), but there was no significant difference between the AD group and the vascular dementia group. The UPSIT score correlated strongly with the degree of cognitive impairment as measured by the CAMCOG (r(s) = 0.683, p = 0.01) CONCLUSIONS: Patients with vascular dementia had a similar degree of olfactory impairment to those with AD. The UPSIT successfully differentiated between dementia patients and normal elderly British subjects tested in their own homes. The UPSIT did not differentiate between those with AD and vascular dementia.

Graham, J. E. (2001). "Harbinger of hope or commodity fetishism: "re-cognizing" dementia in an age of therapeutic agents." Int Psychogeriatr 13(2): 131-4.

Ghiso, J. A., J. Holton, et al. (2001). "Systemic amyloid deposits in familial British dementia." J Biol Chem 276(47): 43909-14.

            Familial British dementia (FBD) is an early onset inherited disorder that, like familial Alzheimer's disease (FAD), is characterized by progressive dementia, amyloid deposition in the brain, and neurofibrillary degeneration of limbic neurons. The primary structure of the amyloid subunit (ABri) extracted from FBD brain tissues (Vidal, R., Frangione, B., Rostagno, A., Mead, S., Revesz, T., Plant, G., and Ghiso, J. (1999) Nature 399, 776-781) is entirely different and unrelated to any previously known amyloid protein. Patients with FBD have a single nucleotide substitution at codon 267 in the BRI2 gene, resulting in an arginine replacing the stop codon and a longer open reading frame of 277 amino acids instead of 266. The ABri peptide comprises the 34 C-terminal residues of the mutated precursor ABriPP-277 and is generated via furin-like proteolytic processing. Here we report that carriers of the Stop-to-Arg mutation have a soluble form of the amyloid peptide (sABri) in the circulation with an estimated concentration in the range of 20 ng/ml, several fold higher than that of soluble Abeta. In addition, ABri species identical to those identified in the brain were also found as fibrillar components of amyloid deposits predominantly in the blood vessels of several peripheral tissues, including pancreas and myocardium. We hypothesize that the high concentration of the soluble de novo created amyloidogenic peptide and/or the insufficient tissue clearance are the main causative factors for the formation of amyloid deposits outside the brain. Thus, FBD constitutes the first documented cerebral amyloidosis associated with neurodegeneration and dementia in which the amyloid deposition is also systemic.

Ghiso, J., T. Revesz, et al. (2001). "Chromosome 13 dementia syndromes as models of neurodegeneration." Amyloid 8(4): 277-84.

            Two hereditary conditions, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with amyloid deposition in the central nervous system and neurodegeneration. The two amyloid proteins, ABri and ADan, are degradation products of the same precursor molecule BriPP bearing different genetic defects, namely a Stop-to-Arg mutation in FBD and a ten-nucleotide duplication-insertion immediately before the stop codon in FDD. Both de novo created amyloid peptides have the same length (34 amino acids) and the same post-translational modification (pyroglutamate) at their N-terminus. Neurofibrillary tangles containing the classical paired helical filaments as well as neuritic components in many instances co-localize with the amyloid deposits. In both disorders, the pattern of hyperphosphorylated tau immunoreactivity is almost indistinguishable from that seen in Alzheimer's disease. These issues argue for the primary importance of the amyloid deposits in the mechanism(s) of neuronal cell loss. We propose FBD and FDD, the chromosome 13 dementia syndromes, as models to study the molecular basis of neurofibrillary degeneration, cell death and amyloid formation in the brain.

Ghiso, J. and B. Frangione (2001). "Cerebral amyloidosis, amyloid angiopathy, and their relationship to stroke and dementia." J Alzheimers Dis 3(1): 65-73.

            Cerebral amyloid angiopathy (CAA) is the common term used to define the deposition of amyloid in the walls of medium- and small-size leptomeningeal and cortical arteries, arterioles and, less frequently, capillaries and veins. CAA is an important cause of cerebral hemorrhages although it may also lead to ischemic infarction and dementia. It is a feature commonly associated with normal aging, Alzheimer disease (AD), Down syndrome (DS), and Sporadic Cerebral Amyloid Angiopathy. Familial conditions in which amyloid is chiefly deposited as CAA include hereditary cerebral hemorrhage with amyloidosis of Icelandic type (HCHWA-I), familial CAA related to Abeta variants, including hereditary cerebral hemorrhage with amyloidosis of Dutch origin (HCHWA-D), the transthyretin-related meningocerebrovascular amyloidosis of Hungarian and Ohio kindreds, the gelsolin-related spinal and cerebral amyloid angiopathy, familial PrP-CAA, and the recently described chromosome 13 familial dementia in British and Danish kindreds. This review focuses on the various molecules and genetic variants that target the cerebral vessel walls producing clinical features related to stroke and/or dementia, and discusses the potential role of amyloid in the mechanism of neurodegeneration.

Frangione, B., T. Revesz, et al. (2001). "Familial cerebral amyloid angiopathy related to stroke and dementia." Amyloid 8 Suppl 1: 36-42.

            The term cerebral amyloid angiopathy (CAA) refers to the specific deposition of amyloid fibrils in the walls of leptomeningeal and cortical arteries, arterioles and, although less frequently in capillaries and veins. It is commonly associated with Alzheimers disease, Down's syndrome and normal aging, as well as with a variety of familial conditions related to stroke and/or dementia: hereditary cerebral hemorrhage with amyloidosis of Icelandic type (HCHWA-I), various inherited disorders linked to Abeta mutants (including the Dutch variant of HCHWA), and the recently described chromosome 13 familial dementia in British and Danish kindreds. This review focuses on four different types of hereditary CAA, emphasizing the notion that CAA is not only related to stroke but also to neurodegeneration and dementia of the Alzheimer's type.

Feldman, H., A. Sauter, et al. (2001). "The disability assessment for dementia scale: a 12-month study of functional ability in mild to moderate severity Alzheimer disease." Alzheimer Dis Assoc Disord 15(2): 89-95.

            The Disability Assessment for Dementia (DAD) scale was developed and validated as a measure of functional ability in dementia. DAD results have been reported in Alzheimer disease (AD) randomized, controlled treatment trials of up to 6 months, but results beyond 6 months have yet to be described. SAB INT 12 was a randomized, double-blind, placebo-controlled, parallel-group study in mild to moderate AD that included DAD assessments at baseline, month 6, and month 12. One hundred forty-four patients with AD in the placebo arm of SAB INT 12 were followed up for 12 months. DAD scores were obtained at baseline (mean DAD = 70.1, SD = 22.2), 6 months (mean DAD = 63.7, SD = 25.2), and 12 months (mean DAD = 59.3, SD = 28.9). The rate of decline was consistent across the domains of basic activities of daily living (ADLs) and instrumental ADLs, as well as the scoring of initiation, planning, and organization. The decline in DAD total scores in mild to moderate AD averages about one point per month, which equates to the loss of one item on the DAD scale every 2 months.

Feldman, H., R. Gabathuler, et al. (2001). "Serum p97 levels as an aid to identifying Alzheimer's disease." J Alzheimers Dis 3(5): 507-516.

            Background: The application of formal clinical diagnostic criteria for the identification of Alzheimer's Disease (AD) has improved diagnostic sensitivity. However, there remains a need for non-invasive biological markers and laboratory tests, which can facilitate case identification, and the assessment of treatment response. The p97 protein is a secreted protein specifically expressed by amyloid plaque associated reactive microglia that may have AD diagnostic ability. Methods: A quantitative radioimmunoassay was developed to measure serum p97. This study, under a double blind protocol, evaluated the utility of serum p97 as diagnostic test for AD. All subjects were referred to the UBC Clinic for Alzheimer's Disease and Related Disorders (CADRD) for clinical assessment of dementia. A serum p97 sample was obtained at the time of assessment but diagnosis of disease was determined independently of p97 examination. Results: "Possible" and "probable" AD cases (n = 41) and cognitively normal controls (n = 64) showed a highly significant difference in mean p97 concentration (41 vs. 20 ng/ml, p<0.001). There was some overlap in p97 distributions between AD cases and control subjects. The area under the curve (AUC) for the receiver operator curve (ROC) was 0.812. Conclusions: These results further support the specificity of high serum p97 levels in AD and its potential utility as a biological marker in AD. The reproducible elevation of serum p97 in AD underlines the need to further determine its role as a biological marker and diagnostic adjunct for AD.

El-Agnaf, O. M., J. M. Sheridan, et al. (2001). "Effect of the disulfide bridge and the C-terminal extension on the oligomerization of the amyloid peptide ABri implicated in familial British dementia." Biochemistry 40(12): 3449-57.

            Familial British dementia (FBD) is a rare neurodegenerative disorder and shares features with Alzheimer's disease, including amyloid plaque deposits, neurofibrillary tangles, neuronal loss, and progressive dementia. Immunohistochemical and biochemical analysis of plaques and vascular amyloid of FBD brains revealed that a 4 kDa peptide named ABri is the main component of the highly insoluble amyloid deposits. In FBD patients, the ABri peptide is produced as a result of a point mutation in the usual stop codon of the BRI gene. This mutation produces a BRI precursor protein 11 amino acids longer than the wild-type protein. Mutant and wild-type precursor proteins both undergo furin cleavage between residues 243 and 244, producing a peptide of 34 amino acids in the case of ABri and 23 amino acids in the case of the wild-type (WT) peptide. Here we demonstrate that the intramolecular disulfide bond in ABri and the C-terminal extension are required to elongate initially formed dimers to oligomers and fibrils. In contrast, the shorter WT peptide did not aggregate under the same conditions. Conformational analyses indicate that the disulfide bond and the C-terminal extension of ABri are required for the formation of beta-sheet structure. Soluble nonfibrillar ABri oligomers were observed prior to the appearance of mature fibrils. A molecular model of ABri containing three beta-strands, and two beta-hairpins annealed by a disulfide bond, has been constructed, and predicts a hydrophobic surface which is instrumental in promoting oligomerization.

El-Agnaf, O. M., S. Nagala, et al. (2001). "Non-fibrillar oligomeric species of the amyloid ABri peptide, implicated in familial British dementia, are more potent at inducing apoptotic cell death than protofibrils or mature fibrils." J Mol Biol 310(1): 157-68.

            Familial British dementia (FBD) is an autosomal dominant neurodegenerative disorder, with biochemical and pathological similarities to Alzheimer's disease. FBD is associated with a point mutation in the stop codon of the BRI gene. The mutation extends the length of the wild-type protein by 11 amino acids, and following proteolytic cleavage, results in the production of a cyclic peptide (ABri) 11 amino acids longer than the wild-type (WT) peptide produced from the normal gene BRI. ABri was found to be the main component of amyloid deposits in FBD brains. However, pathological examination of FBD brains has shown the presence of ABri as non-fibrillar deposits as well as amyloid fibrils. Taken together, the genetic, pathological and biochemical data support the hypothesis that ABri deposits play a central role in the pathogenesis of FBD. Here we report that ABri, but not WT peptide, can oligomerise and form amyloid-like fibrils. We show for the first time that ABri induces apoptotic cell death, whereas WT is not toxic to cells. Moreover, we report the novel findings that non-fibrillar oligomeric species of ABri are more toxic than protofibrils and mature fibrils. These findings provide evidence that non-fibrillar oligomeric species are likely to play a critical role in the pathogenesis of FBD and suggest that a similar process may also operate in other neurodegenerative diseases.

Dunn, H. G. and P. M. MacLeod (2001). "Rett syndrome: review of biological abnormalities." Can J Neurol Sci 28(1): 16-29.

            The Rett syndrome (RS) is a peculiar, sporadic, atrophic disorder, almost entirely confined to females. After the first six months of life there is developmental slowing with reduced communication and head growth for about one year. This is followed by a rapid destructive stage with severe dementia and loss of hand skills (with frequent hand wringing), apraxia and ataxia, autistic features and irregular breathing with hyperventilation. Seizures often supervene. Subsequently there is some stabilization in a pseudo-stationary stage during the preschool to school years, associated with more emotional contact but also abnormalities of the autonomic and skeletal systems. After the age of 15-20 years, a late motor deterioration occurs with dystonia and frequent spasticity but seizures become milder. RS has generally been considered an X-linked disorder in which affected females represent a new mutation, with male lethality. Linkage studies suggested a critical region at Xq28. In 1999, mutations in the gene MECP2 encoding X-linked methyl cytosine-binding protein 2 (MeCP2) were found in a proportion of Rett girls. This protein can bind methylated DNA. Analyses are leading to much further investigation of mutants and their effects on genes. Neuropathological and electrophysiological studies of RS are described. Description of neurometabolic factors includes reduced levels of dopamine, serotonin, noradrenaline and choline acetyltransferase (ChAT) in brain, also estimation of nerve growth factors, endorphin, substance P, glutamate and other amino acids and their receptor levels. The results of neuroimaging are surveyed, including volumetric magnetic resonance imaging (MRI) and positron emission tomography (PET).

Dunn, H. G. (2001). "Importance of Rett syndrome in child neurology." Brain Dev 23 Suppl 1: S38-43.

            The syndrome of brain atrophy in girls described by Andreas Rett in 1966 [Rett, Wien Klin Wochenschr, 1966;116:723-726] was brought to the attention of the English-speaking world by Hagberg et al. in 1983 [Hagberg et al., Ann Neurol, 1983;14:471-479]. Four clinical stages after the age of 6 months were described in classical cases of Rett syndrome (RS), namely early onset stagnation at 6 months to 1(1/2) years, the rapid destructive stage at 1-3 years, the pseudo-stationary stage from pre-school to school years, and the late motor deterioration stage at 15-30 or more years. The rapid destructive stage causes profound dementia with loss of speech and hand skills, stereotypic movements, ataxia, apraxia, irregular breathing with hyperventilation while awake, and frequently seizures. Most cases are isolated in their families, apart from identical twins. However, linkage studies in rare familial cases suggested a critical region at Xq28. In 1999 American investigators found several mutations in the X-linked gene MECP2 encoding Methyl-CpG-binding protein 2 in a proportion of Rett patients. The protein MeCP2 can bind methylated DNA and when mutated may interfere with transcriptional silencing of other genes and result in abnormal chromatin assembly. Many different mutations of the protein are being studied in humans and in mice. Neuropathological studies have shown decreased brain growth and decreased size of individual neurons, with thinned dendrites in some cortical layers, and abnormalities in substantia nigra, suggestive of deficient synaptogenic development, probably starting before birth. Electrophysiology demonstrates progressively abnormal electroencephalograms (EEG) in the first three stages of the syndrome, with some subsequent improvement and occurrence of pseudoseizures. Neurometabolic factors are discussed in detail, particularly reduced levels of dopamine, serotonin, noradrenaline and choline acetyltransferase (ChAT) in brain, also estimation of nerve growth factors, endorphin, substance P, glutamate and other amino acids and their receptor levels. Autonomic dysfunction is described, particularly reduced vagal and overactive sympathetic activity. Neuro-imaging may be required for further investigation, as shown in the differential diagnosis.

Donald, A. and L. Van Til (2001). "Evaluating screening tests for dementia and cognitive impairment in a heterogeneous population in the presence of verification bias." Int Psychogeriatr 13 Supp 1: 203-14.

            This article reviews two potentially serious sources of error in the evaluation of screening tests, namely, verification bias and the influence of demographic covariates. It demonstrates how to deal with these problems statistically. Verification bias arises when not all subjects receive a definitive diagnosis following a screening test. If only a small proportion of those who screen negative are sent for diagnosis, the calculated test sensitivity is an overestimate and the calculated specificity an underestimate. The methodology outlined in this article may be extended to psychological and medical screening tests in general.

Cousens, S., P. G. Smith, et al. (2001). "Geographical distribution of variant Creutzfeldt-Jakob disease in Great Britain, 1994-2000." Lancet 357(9261): 1002-7.

            BACKGROUND: Geographical variation in the distribution of variant Creutzfeldt-Jakob disease (vCJD) might indicate the transmission route of the infectious agent to man. We investigated whether regional incidences of vCJD were correlated with regional dietary data. METHODS: The National CJD Surveillance Unit prospectively identified 84 people with vCJD up to Nov 10, 2000, in Great Britain. Their lifetime residential histories were obtained by interviews with a close relative. Cumulative incidences of vCJD by standard region were calculated. Grid references for places of residence in 1991 were identified and evidence of geographical clusters were sought. Data on diet in the 1980s were analysed for regional correlations with vCJD incidence. The socioeconomic status of the places of residence of people with vCJD was compared with that of the general population. FINDINGS: vCJD incidence was higher in the north of Great Britain than the south. The rate ratio (north vs south) was 1.94 (95% CI 1.27-2.98). The mean Carstairs' deprivation score for areas of residence of people with vCJD was -0.09 (-0.73 to 0.55), which is close to the national average of zero. Regional rates of vCJD were correlated with consumption of other meat or meat products as classified and recorded by the Household Food Consumption and Expenditure Survey (r=0.72), but not with data from the Dietary and Nutritional Survey of British Adults. Five people with vCJD in Leicestershire formed a cluster (p=0.004). INTERPRETATION: Regional differences in vCJD incidence are unlikely to be due to ascertainment bias. We had difficulty determining whether regional variations in diet might cause these differences, since the results of dietary analyses were inconsistent.

Brown, P., R. G. Will, et al. (2001). "Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: background, evolution, and current concerns." Emerg Infect Dis 7(1): 6-16.

            The epidemic of bovine spongiform encephalopathy (BSE) in the United Kingdom, which began in 1986 and has affected nearly 200,000 cattle, is waning to a conclusion, but leaves in its wake an outbreak of human Creutzfeldt-Jakob disease, most probably resulting from the consumption of beef products contaminated by central nervous system tissue. Although averaging only 10-15 cases a year since its first appearance in 1994, its future magnitude and geographic distribution (in countries that have imported infected British cattle or cattle products, or have endogenous BSE) cannot yet be predicted. The possibility that large numbers of apparently healthy persons might be incubating the disease raises concerns about iatrogenic transmissions through instrumentation (surgery and medical diagnostic procedures) and blood and organ donations. Government agencies in many countries continue to implement new measures to minimize this risk.

Zaaijer, H. L. (2000). "[Bovine spongiform encephalopathy and food safety]." Ned Tijdschr Geneeskd 144(22): 1052-7.

            The governments of Great Britain and France disagree on the safety of British beef with respect to bovine spongiform encephalopathy (BSE). Eventually the consumer might have the burden to decide whether beef from Britain is safe to eat with regard to the new variant of Creutzfeldt-Jakob disease (vCJD). Outside Britain the incidence of BSE increases. Probably in continental Europe, the use of high risk material, derived from non-British cattle in the subclinical stage of BSE, poses a greater threat than beef imported from Great Britain. The risk to contract vCJD depends on two unknown factors: the susceptibility of man to BSE and the amount of success in keeping infectious tissue of BSE-incubating cattle out of the human food chain. Until the susceptibility of humans to BSE and the extent to which our food is contaminated become known, no clear-cut advice can be given on the safety of certain food items. There appears to be a genetic predisposition to vCJD, i.e. methionine homozygosity at codon 129 of the normal human prion protein gene. The European Community should ban the use of any high risk material for production of food, except in production processes for which inactivation of the BSE agent has been proven. The facts that are known at this moment allow the conclusion that gelatin and beef products of unknown origin and composition pose a greater health threat than eating genuine beef (muscle tissue).

Zaaijer, H. L. (2000). "[Confusion surrounding bovine spongiform encephalopathy (BSE) and the risk of new variant Creutzfeldt Jakob disease]." Ned Tijdschr Geneeskd 144(48): 2288-90.

            There is a lot of confusing news regarding the risks of consuming beef for contracting variant Creutzfeldt Jakob disease. Bureaucratic inertia and political expediency are fueled by the lack of pathogenetic and epidemiologic understanding of the mode of transmission. Consumers discard beef from their diet, which may be the least contaminated tissue, but other meat products, of which the risks are probably much higher, continue to enjoy free international trade and may be used in the human diet. British beef may be less harmful than French sausage. In addition, criminal and fraudulent practices pose a considerable threat to which an appropriate political answer has yet to be formulated.

Yasojima, K., J. Kuret, et al. (2000). "Casein kinase 1 delta mRNA is upregulated in Alzheimer disease brain." Brain Res 865(1): 116-20.

            The casein kinase-1 (Ck1) family are serine/threonine specific protein kinases. They are highly associated with Alzheimer disease (AD) brain-derived tau filaments and granulovacuolar bodies. Recently we have demonstrated that one family member, Ckidelta, colocalizes with tau containing neurofibrillary tangles (NFTs) and other tau deposits in a number of neurodegenerative diseases. Here we show that the association in AD is accompanied by a sharp upregulation of Ckidelta mRNA in brain but not in peripheral organs. The degree of upregulation in AD brain is correlated with the degree of regional pathology. There was a 24.4-fold increase of Ckidelta mRNA in AD hippocampus compared with control, 8.04-fold in the amygdala, 7.45 in the entorhinal cortex and 7.30-fold in the midtemporal gyrus. These are areas with a high burden of NFTs, neuropil threads and dystrophic neurites. In areas almost devoid of this tau pathology, such as the caudate nucleus, occipital cortex and cerebellum, the increases in AD compared to control brain were only 2.21-, 1.89- and 1.87-fold, respectively. Western blot analysis showed that the upregulation of Ckidelta mRNA was paralleled by an upregulation of Ckidelta protein. These data establish that the association of Ckidelta with the tau pathology of AD is reflective of an increase in gene transcription. Since Alzheimer-like phosphoepitopes of tau can be generated by Ck1, the Ckidelta isoform may play an important role in this fundamental aspect of AD pathology.

Yasojima, K., C. Schwab, et al. (2000). "Human neurons generate C-reactive protein and amyloid P: upregulation in Alzheimer's disease." Brain Res 887(1): 80-9.

            C-reactive protein (CRP) and amyloid P (AP) are pentraxins which are associated with many pathological lesions, including the amyloid deposits and neurofibrillary tangles (NFTs) of Alzheimer disease (AD). It has always been assumed that they are generated by liver and delivered to their sites of action by serum. Here we report by in situ hydridization, reverse transcriptase-polymerase chain reaction analysis, Western blotting and immunohistochemistry that the mRNAs and proteins of both CRP and AP are concentrated in pyramidal neurons and are upregulated in affected areas of AD brain. Controlling pentraxin production at the tissue level may be important in reducing inflammatory damage in AD.

White, K. D., P. G. Ince, et al. (2000). "Clinical and pathologic findings in hereditary spastic paraparesis with spastin mutation." Neurology 55(1): 89-94.

            OBJECTIVE: To describe a family with chromosome 2p-linked hereditary spastic paraparesis (HSP) associated with dementia and illustrate the cerebral pathology associated with this disorder. BACKGROUND: HSP comprises a heterogeneous group of inherited disorders in which the main clinical feature is severe, progressive lower limb spasticity. Nongenetic classification relies on characteristics such as mode of inheritance, age at onset, and the presence or absence of additional neurologic features. Several loci have been identified for autosomal dominant pure HSP. The most common form, which links to chromosome 2p (SPG4), has recently been shown to be due to mutations in spastin, the gene encoding a novel AAA-containing protein. RESULTS: The authors report four generations of a British family with autosomal dominant HSP in whom haplotype analysis indicates linkage to chromosome 2p. In addition, a missense mutation has been identified in exon 10 of the spastin gene (A1395G). Dementia was documented clinically in one member of the family, two other affected family members were reported to have had late onset memory loss, and a younger affected individual showed evidence of memory disturbance and learning difficulties. Autopsy of the demented patient confirmed changes in the spinal cord typical of HSP and also demonstrated specific cortical pathology. There was neuronal depletion and tau-immunoreactive neurofibrillary tangles in the hippocampus and tau-immunoreactive balloon cells were seen in the limbic and neocortex. The substantia nigra showed Lewy body formation. The pathologic findings are not typical of known tauopathies. CONCLUSIONS: The authors confirm that chromosome 2p-linked HSP can be associated with dementia and that this phenotype may be associated with a specific and unusual cortical pathology.

Wellington, C. L. and M. R. Hayden (2000). "Caspases and neurodegeneration: on the cutting edge of new therapeutic approaches." Clin Genet 57(1): 1-10.

            Unregulated apoptosis underlies many pathological conditions, including neurodegenerative diseases. In this review, we focus on the role of cysteine aspartate-specific proteases (caspase) activity in Huntington disease (HD) and Alzheimer disease (AD) as two representative neurodegenerative disorders that normally manifest in mid- to late-life. Caspases appear to be involved in the molecular pathology of HD by directly cleaving huntingtin and generating toxic protein fragments containing the polyglutamine tract, and by being recruited and activated by polyglutamine-containing aggregates composed mainly of truncated huntingtin fragments. Several proteins involved in AD, including beta-amyloid precursor protein (APP) and presenilins (PSs), are also cleaved by caspases. For APP, caspase cleavage may contribute to toxicity by generating toxic fragments or by shifting APP processing toward an amyloidogenic pathway. For PSs, caspase cleavage disables antiapoptotic functions attributed to PS C-terminal fragments. These observations suggest that caspases actively contribute to the molecular pathogenesis of these diseases and support the development of caspase inhibitors as potential therapeutic approaches for chronic neurodegenerative disorders.

Vidal, R., T. Revesz, et al. (2000). "A decamer duplication in the 3' region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred." Proc Natl Acad Sci U S A 97(9): 4920-5.

            Familial Danish dementia (FDD), also known as heredopathia ophthalmo-oto-encephalica, is an autosomal dominant disorder characterized by cataracts, deafness, progressive ataxia, and dementia. Neuropathological findings include severe widespread cerebral amyloid angiopathy, hippocampal plaques, and neurofibrillary tangles, similar to Alzheimer's disease. N-terminal sequence analysis of isolated leptomeningeal amyloid fibrils revealed homology to ABri, the peptide originated by a point mutation at the stop codon of gene BRI in familial British dementia. Molecular genetic analysis of the BRI gene in the Danish kindred showed a different defect, namely the presence of a 10-nt duplication (795-796insTTTAATTTGT) between codons 265 and 266, one codon before the normal stop codon 267. The decamer duplication mutation produces a frame-shift in the BRI sequence generating a larger-than-normal precursor protein, of which the amyloid subunit (designated ADan) comprises the last 34 C-terminal amino acids. This de novo-created amyloidogenic peptide, associated with a genetic defect in the Danish kindred, stresses the importance of amyloid formation as a causative factor in neurodegeneration and dementia.

Verity, C. M., A. Nicoll, et al. (2000). "Variant Creutzfeldt-Jakob disease in UK children: a national surveillance study." Lancet 356(9237): 1224-7.

            BACKGROUND: Variant Creutzfeldt-Jakob Disease (vCJD) was first reported in 1996; the youngest patient developed symptoms at 16 years of age. We have done 3 years of prospective active surveillance for progressive intellectual and neurological deterioration (PIND) in UK children, and have searched for vCJD among the children who were reported. METHODS: Since May, 1997, there has been active surveillance for patients younger than 16 years old with PIND by means of a monthly card sent to all UK consultant paediatricians by the British Paediatric Surveillance Unit. Clinical'details of cases of PIND are obtained from reporting paediatricians by telephone interview or site visit, and an expert group of paediatric neurologists then classifies the cases. FINDINGS: After 3 years, 885 patients with suspected PIND have been reported. Among them were two fatal cases of definite vCJD and one case of probable vCJD; all were reported in 1999. One girl was age 12 years at onset--the youngest ever case of vCJD. No other children with the clinical features of vCJD were identified. The expert group has discussed 655 cases, of which 360 have a confirmed underlying cause, being categorised into 88 known neurodegenerative diseases. INTERPRETATION: That this prospective active surveillance in the UK has found few children with suspected vCJD is relatively reassuring. However, 3 years is a short time to survey a disease with an unknown incubation period. Since one probable and two definite cases of vCJD were reported to the study in 1999, there is concern that more childhood cases may appear.

Tyas, S. L., J. J. Koval, et al. (2000). "Does an interaction between smoking and drinking influence the risk of Alzheimer's disease? Results from three Canadian data sets." Stat Med 19(11-12): 1685-96.

            Investigation of the relationship of smoking and drinking to Alzheimer's disease (AD) may advance research on the cause of AD and provide a basis for treatment. Pharmacological mechanisms for an involvement of smoking and drinking are plausible but epidemiologic reports are inconsistent. Evidence of behavioural and physiological interactions suggests that tobacco and alcohol use may not only individually affect AD, but may also modify each other's effects. A modelling strategy was developed to examine the interaction between smoking and drinking on the risk of AD. Three Canadian data sets were analysed: the University of Western Ontario Dementia Study (UWODS) (n=363); the Canadian Study of Health and Aging (CSHA) (n=516), and the database from the Clinic for Alzheimer Disease and Related Disorders at the Vancouver Hospital and Health Sciences Centre, University of British Columbia site (UBC) (n=843). Multiple logistic regression models were adjusted for the potential confounders age, age squared, sex, education, family history of dementia, head injury and hypertension. Analysis of the CSHA provided evidence consistent with the hypothesis that smoking and drinking influence each other's effects on AD, with smoking reducing the risk of AD among drinkers. A similar interaction was marginally significant (p=0.052) in the UWODS data set, but not significant in the UBC data. Extension of these analyses, particularly in longitudinal studies and within genetic risk groups, is needed to determine whether this interaction can be replicated. If so, research on the biological interactions of nicotine and alcohol may provide a basis for the development of therapeutic interventions as well as providing clues to the cause of this disorder.

Tolnay, M., M. Grazia Spillantini, et al. (2000). "A new case of frontotemporal dementia and parkinsonism resulting from an intron 10 +3-splice site mutation in the tau gene: clinical and pathological features." Neuropathol Appl Neurobiol 26(4): 368-78.

            Hereditary frontotemporal dementia and parkinsonism (FTDP) linked to chromosome 17 (FTDP-17) constitutes a new form of tauopathy, and mutations in the tau gene have recently been reported in some affected families. This report presents clinical and neuropathological data from a member of a British family (SOT 254) with a history of dementia and movement disorder. The medical history of the affected patient, a woman aged 44 years, was reviewed, and a detailed post-mortem examination of the brain was undertaken. A panel of well characterized phosphorylation-dependent and independent anti-tau antibodies was used to assess tau pathology, and inclusions were examined by electron microscopy. Neuronal loss and gliosis were widely distributed, but most severe in neocortical regions, and were associated with abundant neuronal and glial tau inclusions which consisted of a mixture of paired helical filaments (PHFs), similar to those in Alzheimer's disease, and distinct twisted ribbon-like filaments. Genomic DNA was obtained from post-mortem tissue from the index patient, and blood from two unaffected members of the same family. For the index case only, sequencing of intronic sequences flanking exon 10 of the tau gene identified a G to A transition at position +3 of the splice-donor site downstream of exon 10, identical to that reported in multiple system tauopathy with presenile dementia (MSTD). The clinical, neuropathological and genetic findings strongly suggest that SOT 254 represents a new example of FTDP-17 resulting from a mutation in the tau gene. These results are compared with those reported for other FTDP-17 families, i.e. for MSTD.

Thomas, N. J., C. M. Morris, et al. (2000). "Hereditary vascular dementia linked to notch 3 mutations. CADASIL in British families." Ann N Y Acad Sci 903: 293-8.

            The most common form of familial vascular dementia is considered to be CADASIL or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, which is now also increasingly manifest in the United Kingdom. CADASIL has been previously dubbed as a familial form of Binswanger disease. However, unlike in Binswanger disease CADASIL does not involve hypertension or other risk factors associated with cardiovascular disease. CADASIL appears to be essentially a disorder of the arteries that is linked to single missense mutations in the NOTCH 3 gene locus on chromosome 19. The pathogenesis of the disorder or the genetic mechanism leading to brain infarcts and dementia is not known. The elucidation of the microvascular pathology evident in CADASIL may be an interesting way to delineate effects of defective genes on brain cells from systemic vascular influences.

Spector, A., M. Orrell, et al. (2000). "Reminiscence therapy for dementia." Cochrane Database Syst Rev(2): CD001120.

            BACKGROUND: Reminiscence Therapy (RT) has been defined as vocal or silent recall of events in a person's life, either alone, or with another person or group of people. It typically involves group meetings, at least once a week. in which participants are encouraged to talk about past events, often assisted by aids such as photos, music, objects and videos of the past. There is, often, little consistent application of psychological therapies in dementia services. A number of these 'therapies' were greeted with enthusiasm by health care practitioners in understimulating care environments. They were expected to work miracles and their 'failure' to do this has led to their widespread disuse. A systematic review of the available evidence is important in order to identify the effectiveness of the different therapies. Subsequently, guidelines for their use can be made on a sound evidence base. OBJECTIVES: RT involves groups of elderly people talking of past events, assisted by aids such as videos, pictures and archives, as a means of communicating and reflecting upon their life experiences. The objective of the review is to assess the effects of RT for dementia. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, MEDLINE, PSYCHLIT, EMBASE, OMNI, BIDS, Dissertation Abstracts International, SIGLE and reference lists of relevant articles up to 1998, and we contacted specialists in the field. We also searched relevant internet sites and we handsearched Aging and Mental Health, the Gerontologist, Journal of Gerontology, Current Opinion in Psychiatry, Current Research in Britain: Social Sciences, British Psychological Society conference proceedings and Reminiscence database. SELECTION CRITERIA: Randomised controlled trials and quasi-randomised trials of RT for dementia in elderly people. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. MAIN RESULTS: Two trials are included in the review, but only one trial with 15 participants had extractable data. The results were statistically non-significant for both cognition and behaviour. REVIEWER'S CONCLUSIONS: No firm conclusions could be reached regarding the effectiveness of RT for dementia. The review highlighted the urgent need for more systematic research in the area.

Spector, A., M. Orrell, et al. (2000). "Reminiscence therapy for dementia." Cochrane Database Syst Rev(4): CD001120.

            BACKGROUND: Reminiscence Therapy (RT) has been defined as vocal or silent recall of events in a person's life, either alone, or with another person or group of people. It typically involves group meetings, at least once a week, in which participants are encouraged to talk about past events, often assisted by aids such as photos, music, objects and videos of the past. There is, often, little consistent application of psychological therapies in dementia services. A number of these 'therapies' were greeted with enthusiasm by health care practitioners in under stimulating care environments. They were expected to work miracles and their 'failure' to do this has led to their widespread disuse. A systematic review of the available evidence is important in order to identify the effectiveness of the different therapies. Subsequently, guidelines for their use can be made on a sound evidence base. OBJECTIVES: RT involves groups of elderly people talking of past events, assisted by aids such as videos, pictures and archives, as a means of communicating and reflecting upon their life experiences. The objective of the review is to assess the effects of RT for dementia. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, MEDLINE, PSYCHLIT, EMBASE, OMNI, BIDS, Dissertation Abstracts International, SIGLE and reference lists of relevant articles up to 1998, and we contacted specialists in the field. We also searched relevant Internet sites and we hand searched Aging and Mental Health, the Gerontologist, Journal of Gerontology, Current Opinion in Psychiatry, Current Research in Britain: Social Sciences, British Psychological Society conference proceedings and Reminiscence database. SELECTION CRITERIA: Randomised controlled trials and quasi-randomised trials of RT for dementia in elderly people. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. MAIN RESULTS: Two trials are included in the review, but only one trial with 15 participants had extractable data. The results were statistically non-significant for both cognition and behaviour. REVIEWER'S CONCLUSIONS: No firm conclusions could be reached regarding the effectiveness of RT for dementia. The review highlighted the urgent need for more systematic research in the area.

Small, J. A., S. Kemper, et al. (2000). "Sentence repetition and processing resources in Alzheimer's disease." Brain Lang 75(2): 232-58.

            Sentence processing in Alzheimer's disease (AD) has been found to be influenced by several grammatical and extragrammatical factors, including phrase structure and verb-argument relations, number of propositions/verbs, and processing resource capacity. This study examines the effects of these variables on sentence production in AD. Normal control and AD subjects were asked to repeat six types of sentences varying along the above dimensions of complexity. Subjects' processing resource capacity was measured using several verbal working memory tests. AD subjects' sentence-repetition performance was impaired compared to the normal control group. Significant effects were observed for branching direction of phrase structure, canonicity of verb-argument relations, and serial position of errors. Sentence-repetition performance significantly correlated with working memory scores. The findings are interpreted within a resource capacity theory of sentence processing.

Sicard, D. (2000). "[The precaution principle and blood transfusion]." Transfus Clin Biol 7(3): 220-7.

            Because of the HIV and HCV virus transmission by transfusion during the eighties, there has been a retrospective reflection about the non-application of the precautionary principle, which has appeared only recently in the medical world. Since it was difficult to identify the real cause of the above-cited transmission in France, mainly because of the bad selection of blood donors, we feel we are justified in applying this precautionary principle more and more, in a monopolistic way, for biological security reasons. As a result, the biological research is not limited to looking for a 'degree zero' risk. Whether it concerns the 'PCR', the research of a new potential virus, the excessive fear regarding the transfusion of the new ESB agent, the worry caused by the blood donors who lived in the British Isles, the need for security based upon the precautionary principle is increasing endlessly. It is, however, more reasonable to consider that the precautionary principle should be essence incite a multi-disciplinary reflection involving biological sciences as well as social sciences. The precautionary principle would not make sense if it were not questioned for bad estimations, its harmful influences or its opportunistic use. Transfusion security, which is so important as a goal and as a principle, cannot appeal to the precautionary principle all the time, since the excessive use of this principle would lead to the paradox of not being able to identify the issues anymore.