Alzheimer Disease: Ince PG

Lace GL, Wharton SB, Ince PG. · Neuropathology Group, Academic Unit of Pathology, University of Sheffield Medical School, Sheffield, UK. · Clin Neuropathol. · Pubmed #17416103 No free full text.

Abstract: The major historical milestones in tau-research are reviewed, with their implications for changing perspectives about the significance of tau-pathology in neurodegeneration. Abnormalities of tau-protein characterize the pathology of numerous neurodegenerative disorders, both sporadic and inherited. Over the years, opinions regarding the significance of tau in disease pathogenesis, particularly in Alzheimer's disease, have fluctuated. Early caution about the role of tau as a significant factor in neurodegenerative disease, especially Alzheimer's disease, has been superseded by acceptance of its key involvement in pathways which led to cell dysfunction and death. The discovery of familial "tauopathies", associated with tau-gene mutations, has confirmed that tau-dysmetabolism can independently lead to neurodegeneration. Debate about the centrality of its role remains, but current evidence makes it difficult to ignore the importance of tau in many neurodegenerative diseases. By examining the evolution of research on tau, related to advances in technology and the emergence of new diseases, the future developments needed to resolve remaining issues in the tau-story may be discerned.

Fernando MS, Ince PG, Anonymous00254. · Neuropathology, Academic Unit of Pathology, Division of Genomic Medicine, University of Sheffield, 'E' Floor, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK. · J Neurol Sci. · Pubmed #15537512 No free full text.

Abstract: The MRC Cognitive Function and Ageing Study (CFAS) is a prospective longitudinal study of a population-based cohort of elderly people in six UK sites, evaluated using psychometric instruments and questionnaires to elucidate physical and mental health. Data from the core study includes prevalence and incidence rates for dementia and longitudinal measures of cognitive decline together with data on genetic risk factors for dementia. A neuropathology study runs in collaboration with the core study based on premortem counselling of individual respondents or carers. Analysis of pathological data from the first 209 accumulated brain donations showed that both Alzheimer-type pathologies (ATP) and vascular pathologies (including congophilic amyloid angiopathy (CAA)) were common in both demented and non-demented respondents. Although many cases fulfil conventional diagnostic criteria for the pathological diagnosis of Alzheimer disease, the data differ from those published from conventional studies of hospital or memory clinic cohorts. In particular, there are individuals whose total burden of pathology is inappropriately high or low compared with their clinical dementia status, even when all pathologies are considered in a multivariable model of dementia risk factors (25% of respondents misdiagnosed from pathology findings). Vascular pathology is so common that few dementia cases lack a mixed component of both ATP and vascular lesions (pure AD cases, 21%). More recently, the study has examined white matter pathology in this cohort as a potential manifestation of small-vessel disease (SVD) in the ageing brain. Using an MRI strategy to image formalin-fixed brain slices, the study shows that white matter lesions (WMLs) are common (94% overall frequency) and are an independent risk factor for dementia using multivariable analysis.

Kalaria RN, Ballard CG, Ince PG, Kenny RA, McKeith IG, Morris CM, O'Brien JT, Perry EK, Perry RH, Edwardson JA. · MRC-Newcastle University Centre Development in Clinical Brian Ageing, Wolfson Research Centre, Institute for Health of the Elderly, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK. · Novartis Found Symp. · Pubmed #11280033 No free full text.

Abstract: Age is the single most important risk factor for progressive dementia in populations worldwide. In developed countries the prevalence of dementia is estimated to be 3-5% at age 65 years and expected to double every decade thereafter. Although there is ageing-related attrition of neural tissue accompanied by profound changes in brain glia, marked neuronal loss and severe cognitive impairment are associated with pathological changes. Accelerated somatic ageing of the vasculature comprising endothelial and smooth muscle cells and slowed glial replacement are also likely to pre-dispose to degenerative processes. Approximately 90% of patients with late-onset dementia have neuropathological features of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), or vascular dementia (VaD), alone or in combination. Both AD and DLB reveal extensive amyloid beta deposition within senile plaques. Neurofibrillary tangles evident as tau pathology are much reduced in DLB where symptoms may be more related to cholinergic transmitter abnormalities than structural pathology. Depletion of brain acetylcholine is also encountered in VaD, which like AD and DLB may respond to cholinergic therapy. Cerebrovascular pathology, ischaemic brain damage and neurovascular instability resulting in cerebral hypoperfusion appears fundamental in the pathogenesis of late-onset dementia. The apolipoprotein E epsilon 4 allele, a major genetic susceptibility factor for AD also associated with cardiovascular pathology, may contribute to neurodegenerative changes through vascular mechanisms. The interrelationships of these multiple substrates of late-onset dementia have major implications for neuroprotective and disease slowing therapies. Measures that improve cardiovascular function and increase brain perfusion would be useful to attenuate cognitive decline.

Ballard CG, Ayre G, O'Brien J, Sahgal A, McKeith IG, Ince PG, Perry RH. · MRC Neurochemical Pathology Unit, University of Newcastle upon Tyne, Newcastle upon Tyne, UK. · Dement Geriatr Cogn Disord. · Pubmed #10026383 No free full text.

Abstract: Consecutive patients from a dementia case register received a standardised evaluation which incorporated a neuropsychological assessment with the Cambridge Assessment for disorders in the elderly (CAMCOG). Operationalised clinical diagnoses were made (consensus criteria for dementia with Lewy bodies, DLB; NINCDS- ADRDA for Alzheimer's disease, AD, NINCDS AIRENS for vascular dementia, VaD). Two-hundred and twenty-eight patients were studied (DLB 54, AD102, VaD 72). DLB patients had significantly better performance on recent memory than AD patients, but more impaired visuospatial praxis. DLB patients also had significantly better recent memory than those with VaD. Optimal cut-off points for the recent memory:praxis ratio achieved good discrimination between DLB and both other dementias.

Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C, Anonymous00023. · Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, United Kingdom. · N Engl J Med. · Pubmed #19474427 No free full text.

Abstract: BACKGROUND: Research in Alzheimer's disease is focused mainly on younger old persons, whereas studies involving very old persons report attenuated relationships between the pathological features of Alzheimer's disease and dementia. METHODS: We assessed 456 brains donated to the population-based Medical Research Council Cognitive Function and Ageing Study from persons 69 to 103 years of age at death. We used a standard neuropathological protocol that included measures of the pathological features of Alzheimer's disease, cerebral atrophy, and cerebrovascular disease. Neuropathological variables were dichotomized to represent no burden or a mild burden of pathological lesions as compared with a moderate or severe burden. Logistic regression was used to estimate the effect of age on the relationship between neuropathological features and dementia. RESULTS: The difference in the prevalence of moderate and severe Alzheimer's-type pathological changes between persons with and those without dementia decreased with increasing age. The association between neocortical neuritic plaques and dementia was strong at 75 years of age (odds ratio, 8.63; 95% confidence interval [CI], 3.81 to 19.60) and reduced at 95 years of age (odds ratio, 2.48; 95% CI, 0.92 to 4.14), and similar attenuations with advancing age were observed in the association between other pathological changes related to Alzheimer's disease and dementia in all brain areas. In contrast, neocortical cerebral atrophy maintained a relationship with age in persons with dementia at both 75 years of age (odds ratio, 5.11; 95% CI, 1.94 to 13.46) and 95 years of age (odds ratio, 6.10; 95% CI, 2.80 to 13.28) and thus distinguished the cohort with dementia from the cohort without dementia. CONCLUSIONS: The association between the pathological features of Alzheimer's disease and dementia is stronger in younger old persons than in older old persons. Age must be taken into account when assessing the likely effect of interventions against dementia on the population.

Lace G, Savva GM, Forster G, de Silva R, Brayne C, Matthews FE, Barclay JJ, Dakin L, Ince PG, Wharton SB, Anonymous00038. · Academic Unit of Pathology, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK. · Brain. · Pubmed #19321462 No free full text.

Abstract: Deposits of abnormally phosphorylated tau protein are found in numerous neurodegenerative disorders; the 'tauopathies', which include Alzheimer's and Pick's diseases, but tau pathology is also found in the ageing brain. Variation in tau pathology in brain ageing and its relationship to development of tauopathies and cognitive impairment remains unclear. We aimed to determine the extent and pattern of spread of tau pathology in the hippocampus, a susceptible region important in dementia and milder states of memory impairment, using hippocampal samples from the elderly population-based Medical Research Council Cognitive Function and Ageing Study neuropathology cohort. Tau deposition was assessed in hippocampal anatomical sub-regions using the AT8 antibody to phosphorylated tau and isoform-specific antibodies to 3 and 4-repeat tau (RD3 and RD4). Abeta pathology was also assessed. In this population sample, which includes the full ageing spectrum from individuals with no cognitive impairment to those with dementia satisfying clinico-pathology criteria for Alzheimer's disease, we have demonstrated a high prevalence at death of tau pathology. AT8, Abeta, RD3 and RD4 showed similar regional distribution and increased RD3 was noted in late-stage ghost tangles. Abeta was shown to be a poor explanatory variable for tau pathology. Tau deposition progressed in a hierarchical manner. Hippocampal input regions and projection zones (such as lateral entorhinal cortex, CA1/subiculum border and outer molecular layer of dentate) were initially affected, with anterograde progression though the hippocampal circuitry. Six hippocampal tau anatomical stages were defined, each linking projectionally to their adjacent stages, suggesting spread of tau malfunction through neuroanatomical pathways in hippocampal ageing. These stages were significantly associated with dementia, and may provide a clinically useful tool in the clinico-pathological assessment of dementia and mild cognitive impairment.

Zaccai J, Brayne C, McKeith I, Matthews F, Ince PG, Anonymous00354. · Neuropathology, E Floor, Royal Hallamshire Hospital, Sheffield UK. · Neurology. · Pubmed #18362284 No free full text.

Abstract: BACKGROUND: It is proposed that alpha-synucleinopathy (AS) initially affects the medulla oblongata and progresses to more rostral brain areas in a hierarchical sequence ("Braak hypothesis"). Predominant involvement of the amygdala is also described. This study examines the applicability of these patterns, and their relationship to Alzheimer disease (AD) pathology, in brains of a population-based donor cohort. METHODS: Brains donated in two of six Cognitive Function and Ageing Study cohorts (Cambridgeshire and Nottingham) were examined. More than 80% were older than 80 years at death. The respondents were evaluated prospectively in life for cognitive decline and dementia. Immunocytochemistry for tau and alpha-synuclein was carried out in 208 brains to establish Braak stage and the pattern and severity of AS. RESULTS: Seventy-six brains showed Lewy bodies. Half (51%) conformed to the Braak hypothesis while 17% had pathology in a higher region which was absent in a lower region. A further 29% showed amygdala-predominant pathology. Six brains showed predominant neocortical pathology with minimal pathology in amygdala or substantia nigra. The stage of AD pathology was not associated with particular patterns of AS. CONCLUSION: alpha-Synucleinopathy (AS) is common in older people, and frequently associated with Alzheimer disease-type pathology. Although half of brains corresponded to the Braak hypothesis, and 29% to amygdala-predominant AS, there were a high proportion of cases which did not fit a staging system. An unexpectedly high proportion with a cortical form of Lewy body disease was identified.

Walker Z, Jaros E, Walker RW, Lee L, Costa DC, Livingston G, Ince PG, Perry R, McKeith I, Katona CL. · University College London and Royal Free Hospitals, London, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #17353255 links to  free full text

Abstract: BACKGROUND: Dementia with Lewy bodies (DLB) is a common form of dementia. The presence of Alzheimer's disease (AD) pathology modifies the clinical features of DLB, making it harder to distinguish DLB from AD clinically during life. Clinical diagnostic criteria for DLB applied at presentation can fail to identify up to 50% of cases. Our aim was to determine, in a series of patients with dementia in whom autopsy confirmation of diagnosis was available, whether functional imaging of the nigrostriatal pathway improves the accuracy of diagnosis compared with diagnosis by means of clinical criteria alone. METHODS: A single photon emission computed tomography (SPECT) scan was carried out with a dopaminergic presynaptic ligand [123I]-2beta-carbometoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (FP-CIT; ioflupane) on a group of patients with a clinical diagnosis of DLB or other dementia. An abnormal scan was defined as one in which right and left posterior putamen binding, measured semiquantitatively, was more than 2 SDs below the mean of the controls. RESULTS: Over a 10 year period it was possible to collect 20 patients who had been followed from the time of first assessment and time of scan through to death and subsequent detailed neuropathological autopsy. Eight patients fulfilled neuropathological diagnostic criteria for DLB. Nine patients had AD, mostly with coexisting cerebrovascular disease. Three patients had other diagnoses. The sensitivity of an initial clinical diagnosis of DLB was 75% and specificity was 42%. The sensitivity of the FP-CIT scan for the diagnosis of DLB was 88% and specificity was 100%. CONCLUSION: FP-CIT SPECT scans substantially enhanced the accuracy of diagnosis of DLB by comparison with clinical criteria alone.

Wharton SB, Williams GH, Stoeber K, Gelsthorpe CH, Baxter L, Johnson AL, Ince PG, Anonymous00313. · Academic Unit of Pathology, University of Sheffield, Medical School, UK. · Neurosci Lett. · Pubmed #15936508 No free full text.

Abstract: Cell-cycle mechanisms may be aberrantly reactivated in the ageing brain and associated with the development of pathology, including Alzheimer's disease. Activation of cell-cycle mechanisms in glia has, however, been little studied. Our aim was to determine whether expression of a marker for chromosomal replication licensing, Mcm2, occurs in glia of the ageing hippocampus, and to compare its expression to that of Ki67 and PCNA. Blocks of hippocampus were obtained from 19 elderly brains derived from the MRC-CFAS neuropathology cohort, which included a spectrum of Alzheimer-type pathology, semi-quantified using the Braak scoring system for neurofibrillary tangles. Mcm2, PCNA and Ki67 were detected immunohistochemically. Expression of Mcm2, Ki67 and PCNA was observed in glial cells and neurons, with a trend to increased expression in association with higher burdens of Alzheimer-type pathology. Mcm2 expression in glial cells showed a significant linear trend across Braak stages (P = 0.043). This study demonstrates that grey and white matter glial cells show expression of cell-cycle markers in the ageing brain and that re-licensing for chromosomal replication is a component of the mechanisms activated. A quantitative relationship to the burden of Alzheimer-type pathology suggests that cell-cycle re-entry in glial cells may be important in the pathogenesis of age-related neurodegeneration.

Singleton AB, Wharton A, O'Brien KK, Walker MP, McKeith IG, Ballard CG, O'Brien J, Perry RH, Ince PG, Edwardson JA, Morris CM. · Medical Research Council/University of Newcastle upon Tyne, Centre Development in Clinical Brain Ageing, MRC Building, Newcastle upon Tyne, UK. · Dement Geriatr Cogn Disord. · Pubmed #12411758 No free full text.

Abstract: Dementia with Lewy bodies (DLB) represents the second commonest cause of dementia in the elderly following Alzheimer's disease (AD). Whilst the presence of Lewy bodies is essential, DLB shares with AD the presence of senile plaques (SP), but neurofibrillary tangles (NFT) are not a necessary feature. The apolipoprotein E (APO E) epsilon4 allele is the most consistently associated genetic risk factor for AD and has also been shown to associate with DLB. We have therefore analysed the APO E epsilon4 allele in a large series of DLB cases coming to autopsy to: (1) determine if the epsilon4 allele describes a similar risk in DLB development as in AD and (2) determine how APO E epsilon4 allele status correlates with clinical and neuropathological findings in DLB, and in AD, as an indication of the role of APO E in underlying disease biology. Both DLB and AD share an increased epsilon4 allele frequency, though in DLB the epsilon2 allele frequency is not reduced and there is a relative lack of epsilon4 homozygotes. In contrast to previous studies, no association of the epsilon4 allele with age at onset or duration of disease was found in either disorders. In DLB cases, overall a significantly shorter duration of illness was observed when compared with AD cases, though no significant effect of the epsilon4 allele on disease onset or duration was seen. The survival rate was reduced by the presence of the epsilon4 allele in DLB, as with AD. No effect on SP or NFT counts was seen with the epsilon4 allele, though DLB cases showed a lower SP burden in addition to the expected lower NFT counts. This study demonstrates that DLB shares the APO epsilon4 allele with AD as a common risk factor, but that there are differences in the way the epsilon4 allele affects the phenotypic expression of disease.

Cottrell DA, Borthwick GM, Johnson MA, Ince PG, Turnbull DM. · Department of Neurology, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK. · Neuropathol Appl Neurobiol. · Pubmed #12366820 No free full text.

Abstract: Defects of mitochondrial function have been proposed as a potential mechanism in the development and pathogenesis of Alzheimer's disease (AD) and neuronal apoptosis. Mitochondrial enzyme-deficient pyramidal neurones are found in greater quantities in the hippocampus of AD patients than in age-matched controls. The presence of these neurones indicates that high levels of mutant mtDNA (mitochondrial DNA), sufficient to cause a biochemical deficiency within individual neurones, occur more frequently in AD than in normal ageing. This study analyses the relationship of cytochrome c oxidase (COX)-deficient neurones with the neuropathological markers of AD, neurofibrillary tangles (NFTs) and amyloid plaques, as well as markers of neuronal apoptosis known to occur in AD brains. Frozen sections of hippocampi from three AD patients were used to directly colocalize in situ the presence of histochemically COX-deficient neurones with immunohistology for the classical neuropathological markers of AD, tau and beta-amyloid. In addition, we also directly colocalized these mitochondrial-enzyme deficient neurones using terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling and cleaved caspase-3. The distribution of amyloid plaques is anatomically distinct from the COX-deficient hippocampal pyramidal neurones and the neurones that contained NFTs or apoptotic labelling were always COX-positive. COX-deficient, succinate dehydrogenase-positive hippocampal neurones indicative of high mtDNA mutation load do not appear to be prone to apoptosis or to directly participate in the over production of tau or beta-amyloid. Biochemically significant mitochondrial defects do occur in AD and are likely to contribute to the overall central nervous system dysfunction in impairing neuronal function and possibly causing neurodegeneration via mechanisms other than apoptosis.

Cottrell DA, Blakely EL, Johnson MA, Ince PG, Turnbull DM. · Department of Neurology, The Medical School, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #11468310 No free full text.

Abstract: OBJECTIVE: To determine whether hippocampal neurons and choroidal epithelial cells demonstrate a mitochondrial enzyme deficiency in AD more frequently than in normal aging. BACKGROUND: High levels of mutant mitochondrial DNA (mtDNA) cause a deficiency in cytochrome c oxidase (COX) (complex IV activity) because three of its 13 subunits are encoded for by mtDNA. In contrast, succinate dehydrogenase (SDH) (complex II activity) remains intact because all of its subunits are nuclear encoded. The histologic hallmark of cells containing high levels of mtDNA mutation in both primary mtDNA disorders and normal aging muscle is the presence of COX-deficient SDH-positive cells. METHODS: The authors applied a sequential histochemical method for COX and SDH to hippocampal sections in 17 AD and 17 age-matched control brains. This confers the advantages of both looking at individual cells in situ and measuring the actual mitochondrial complex activity rather than simply the complex quantity. RESULTS: COX-deficient SDH-positive hippocampal neurons and choroidal epithelial cells are more prevalent in patients with AD than in controls. In addition the COX-deficient SDH-positive choroidal cells are associated with an enlargement in size. CONCLUSION: This increase in number of COX-deficient SDH-positive hippocampal pyramidal neurons and choroid epithelial cells provides strong evidence that a substantial mitochondrial enzyme activity defect occurs in individual cells more frequently in AD than in normal aging and that mitochondria may play a significant role in the pathogenesis of AD.

Gibson AM, Singleton AB, Smith G, Woodward R, McKeith IG, Perry RH, Ince PG, Ballard CG, Edwardson JA, Morris CM. · Institute for the Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, UK. · Neurology. · Pubmed #10668708 No free full text.

Abstract: OBJECTIVE: Analysis of AD has revealed that the apolipoprotein E locus (APOE) cannot account for all of the genetic risk associated with AD. Whole genome scanning in AD families suggests that a chromosome 12 locus may contribute significantly to disease development. The alpha2-macroglobulin gene (A2M) has been suggested as a candidate locus for AD based on analysis of familial AD. METHOD: We determined, in 195 neuropathologically verified AD cases and 107 age-matched control subjects, the association of two common polymorphisms in A2M (a pentanucleotide deletion 5' to the bait domain exon, and a valine-1000-isoleucine polymorphism in the thiolester site of the protein). RESULTS: Evidence was observed for linkage disequilibrium between the deletion and Ile1000 polymorphisms. No evidence was observed for an association between the thiolester polymorphism and AD alone or when accounting for the APOE-epsilon4 allele. No alteration in the frequency of the bait domain deletion was observed, although a small excess (4%) of deletion homozygotes was found in the AD group, which were absent in the control population. CONCLUSIONS: The A2M deletion polymorphism at most accounts for a small fraction of the genetic contribution toward AD, and this is small compared with APOE. Furthermore, reverse transcriptase PCR of A2M RNA from the brains of patients homozygous for the deletion polymorphism showed that the bait domain exon still is present in the RNA. This suggests that the A2M deletion polymorphism may be nonfunctional and that the chromosome 12 AD locus is situated elsewhere.

Singleton AB, Gibson AM, McKeith IG, Ballard CA, Perry RH, Ince PG, Edwardson JA, Morris CM. · MRC Neurochemical Pathology Unit, Institute for the Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, UK. · Neuroreport. · Pubmed #10380971 No free full text.

Abstract: Dementia with Lewy bodies (DLB) is the second most common cause of dementia in the elderly after Alzheimer's disease (AD). The apolipoprotein E gene (APOE) is a major risk factor, but can only account for approximately 50% of AD cases. Whole genome scanning in late-onset AD families has suggested that a locus on chromosome 12 may contribute significantly to disease development. Recently the alpha2-macroglobulin gene (A2M) on chromosome 12 has been suggested as a candidate locus for AD. We therefore determined the influence of two polymorphisms in A2M, a pentanucleotide deletion 5' to the bait domain exon, and a valine to isoleucine polymorphism in the thiolester site of the protein, in AD and DLB cohorts. No evidence was observed for an association between the thiolester or deletion polymorphisms and AD or DLB alone or when accounting for the APOE epsilon4 allele. We did, however, identify a non-significant excess of deletion homozygotes in the AD and DLB groups. This genotype accounted for 4% of disease cases but was absent in the control population. Given that the A2M deletion polymorphism is non-functional, the chromosome 12 AD/DLB locus may be situated elsewhere and not with these A2M polymorphisms.

Atkinson A, Singleton AB, Steward A, Ince PG, Perry RH, McKeith IG, Fairbairn AF, Edwardson JA, Daly AK, Morris CM. · Medical Research Council Neurochemical Pathology Unit, Institute for the Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, UK. · Pharmacogenetics. · Pubmed #10208640 No free full text.

Abstract: The similarities between the clinical and pathological findings of dementia with Lewy Bodies (DLB) with Alzheimer's disease and Parkinson's disease are complex, and their significance for pathogenesis is unresolved. It is likely that DLB shares common disease determinants with both Alzheimer's disease and Parkinson's disease. Clinically DLB shows the presence of dementia similar, though not identical, to that found in Alzheimer's disease. A parkinsonian movement disorder is present in a proportion of DLB cases. Pathologically DLB shows senile plaques, as with Alzheimer's disease, and also substantia nigra neurone loss and Lewy bodies, as with Parkinson's disease. At a genetic level, DLB shows an elevated Apolipoprotein E epsilon4 frequency as described in Alzheimer's disease, but this is absent in Parkinson's disease. An elevated frequency of the CYP2D6*4 allele has been found in Parkinson's disease and we have therefore genotyped a large series of clinically and neuropathologically confirmed cases of DLB, Alzheimer's disease, Parkinson's disease and age-matched control individuals for the CYP2D6*4 allele. Whilst an elevated frequency of the CYP2D6*4 allele was found in Parkinson's disease, no such elevations were found in DLB or Alzheimer's disease. Stratification of the CYP2D6*4 allele with respect to the Apolipoprotein E epsilon4 also did not show any significant associations with the CYP2D6*4 allele. The CYP2D6*4 allele is not a major genetic determinant of DLB and the results place DLB with Alzheimer's disease rather than Parkinson's disease on a genetic level.

Middleton D, Mawhinney H, Curran MD, Edwardson JA, Perry R, McKeith I, Morris C, Ince PG, Neill D. · Northern Ireland Histocompatibility and Immunogenetics Laboratory, Belfast City Hospital, UK. · Neurosci Lett. · Pubmed #10203251 No free full text.

Abstract: The frequency of various allele types of the class I Major Histocompatibility Complex (MHC) genes HLA-A and HLA-B were compared between pathologically confirmed groups of late and early-onset Alzheimer's disease (AD) and a control group. DNA was extracted from frozen brain tissue and the highly polymorphic second and third exons of the HLA-A and HLA-B genes were independently PCR amplified using specific primers. Individual allele types were identified using sequence-specific oligonucleotide probes. The results showed that the main frequency differences occurred between the late-onset AD and the control group however none of these reached statistical significance.

Briel RC, McKeith IG, Barker WA, Hewitt Y, Perry RH, Ince PG, Fairbairn AF. · Institute for the Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #10084544 links to  free full text

Abstract: OBJECTIVES: To evaluate the role of the EEG in the diagnosis of dementia with Lewy bodies (DLB). METHODS: Standard EEG recordings from 14 patients with DLB confirmed at postmortem were examined and were compared with the records from 11 patients with Alzheimer's disease confirmed at postmortem RESULTS: Seventeen of the total of 19 records from the patients with DLB were abnormal. Thirteen showed loss of alpha activity as the dominant rhythm and half had slow wave transient activity in the temporal lobe areas. This slow wave transient activity correlated with a clinical history of loss of consciousness. The patients with Alzheimer's disease were less likely to show transient slow waves and tended to have less marked slowing of dominant rhythm. CONCLUSIONS: The greater slowing of the EEG in DLB than in Alzheimer's disease may be related to a greater loss of choline acetyltransferase found in DLB. Temporal slow wave transients may be a useful diagnostic feature in DLB and may help to explain the transient disturbance of consciousness which is characteristic of the disorder.