Psychological and neuropsychiatric implications of COVID-19.

COVID-19 infections have spread quickly, resulting in massive healthcare burden to societies worldwide. The most urgent interventions needed in the present climate include epidemiological measures to reduce the spread of infection, efficient treatment of patients with severe illness to reduce mortality rates, as well as development of diagnostic tests. Alongside this, the acute, medium, and long-term mental-health consequences of the COVID-19 outbreak for patients, their family members, medical professionals, and the public at large should not be underestimated. Here, we draw on evidence from previous coronavirus outbreaks (i.e., SARS, MERS) and emerging evidence from China, Europe, Asia and the US to synthesize the current knowledge regarding the psychological and neuropsychiatric implications of the COVID-19 pandemic.

Biochemical markers in vascular cognitive impairment associated with subcortical small vessel disease - A consensus report.

BACKGROUND: Vascular cognitive impairment (VCI) is a heterogeneous entity with multiple aetiologies, all linked to underlying vascular disease. Among these, VCI related to subcortical small vessel disease (SSVD) is emerging as a major homogeneous subtype. Its progressive course raises the need for biomarker identification and/or development for adequate therapeutic interventions to be tested. In order to shed light in the current status on biochemical markers for VCI-SSVD, experts in field reviewed the recent evidence and literature data. METHOD: The group conducted a comprehensive search on Medline, PubMed and Embase databases for studies published until 15.01.2017. The proposal on current status of biochemical markers in VCI-SSVD was reviewed by all co-authors and the draft was repeatedly circulated and discussed before it was finalized. RESULTS: This review identifies a large number of biochemical markers derived from CSF and blood. There is a considerable overlap of VCI-SSVD clinical symptoms with those of Alzheimer's disease (AD). Although most of the published studies are small and their findings remain to be replicated in larger cohorts, several biomarkers have shown promise in separating VCI-SSVD from AD. These promising biomarkers are closely linked to underlying SSVD pathophysiology, namely disruption of blood-CSF and blood-brain barriers (BCB-BBB) and breakdown of white matter myelinated fibres and extracellular matrix, as well as blood and brain inflammation. The leading biomarker candidates are: elevated CSF/blood albumin ratio, which reflects BCB/BBB disruption; altered CSF matrix metalloproteinases, reflecting extracellular matrix breakdown; CSF neurofilment as a marker of axonal damage, and possibly blood inflammatory cytokines and adhesion molecules. The suggested SSVD biomarker deviations contrasts the characteristic CSF profile in AD, i.e. depletion of amyloid beta peptide and increased phosphorylated and total tau. CONCLUSIONS: Combining SSVD and AD biomarkers may provide a powerful tool to identify with greater precision appropriate patients for clinical trials of more homogeneous dementia populations. Thereby, biomarkers might promote therapeutic progress not only in VCI-SSVD, but also in AD.

Dysphoria is a risk factor for depression in medically ill older people.

OBJECTIVES: Depression in older people is commonly under diagnosed and is associated with increased morbidity and mortality. Because older people currently occupy 65% of acute hospital beds, it is crucial for them to be properly assessed for depression to optimise their medical care. The aim of this study was to identify potential risk factors for depression in the medically ill in order to improve their inpatient care. METHODS: This was a 2-year observational study of consequent referrals to the Newcastle Liaison Team for Older Adults. Out of a total number of 1586 referred patients, 1197 were included in the final analysis of data. Information about their age, main medical history, cognitive impairment and use of antidepressants was collected. All subjects were screened for dementia, depression and delirium. Proportions were compared using the chi-squared test. Clinical depression as a binary variable was modelled using logistic regression. RESULTS: Higher risk for depression was associated with pain (odds ratio (OR) = 1.76; p = 0.033) and a previous history of depression (OR = 2.22; p < 0.001). Cognitive impairment (OR = 0.44, p < 0.001) and delirium (OR = 0.49; p < 0.001) decreased the likelihood for having depression. Subjective feelings of emptiness, being unhappy and depressed alone (R2 = 37.4%) and cognitive impairment (R2 = 39.5%) were the best multivariable model to explain depression in medically ill people. CONCLUSION: Dysphoric mood results in depression in older people with medical health problems. Copyright © 2016 John Wiley & Sons, Ltd.

Ageing in people with autistic spectrum disorder.

BACKGROUND: Although autism in children and in adults attracts attention with respect to clinical and research needs, autism in the older individuals has not been considered to any degree. We review the evidence for urgently addressing the question of ageing in people with autistic spectrum disorder (ASD), focusing on those with disability. METHODS: Perspectives are reviewed in relation to demographics, experiences of relatives or carers, anticipated residential care needs, requirement for specifically designed cognitive assessment tools and importance of initiating new brain ageing research initiatives in this area. RESULTS: With escalating numbers of ASD individuals with disability reaching old age, provision of care is the paramount issue that is only beginning to be addressed in a few European communities and in the USA. How ageing affects cognition in such individuals as they reach an age no longer consistent with parental care is unknown, lacking any published evidence, and there is a clear need to design cognitive and behavioural assessment tools appropriate to ageing in ASD individuals with disability, as was the case with respect to dementia as a whole. Although there is a growing body of evidence on pathological, imaging, neuropharmacological and other key brain abnormalities in ASD, these are, to date, confined to children and young (only rarely to middle aged) adults. CONCLUSIONS: The need for new initiatives in research into ageing in ASD is urgent. Apart from a growing care crisis, the prospect of understanding brain ageing in this population may bring potential rewards beyond immediate clinical need given the precedent of Down syndrome.

Quantitative neurodegenerative pathology does not explain the degree of hippocampal atrophy on MRI in degenerative dementia.

OBJECTIVE: The purpose of this study was to investigate the neuropathological substrates underlying in vivo hippocampal atrophy on magnetic resonance imaging (MRI) in autopsy confirmed neurodegenerative dementia cases. METHODS: Thirty-one neuropathologically verified cases (23 with Lewy body dementia (LBD) and eight with Alzheimer's disease (AD)) were included who had undergone an MRI scan close to death (mean 1.5 years). Manual volumetric measurements were undertaken for the hippocampus, entorhinal cortex and amygdala on MRI, along with quantitative neuropathological analysis of plaque, tangle and Lewy body pathology in the same regions. The relationship between neuropathology and MRI volumes was assessed using correlations and linear regression. RESULTS: Hippocampal and amygdala volumes were significantly smaller in cases with AD than with LBD, but there was no difference in entorhinal cortex volume. Analysing all cases together, a significant positive correlation was observed between normalised hippocampal volume and percent area of Lewy bodies in the hippocampus (r=0.449, p=0.017) but not with tangles (r=0.059, p=0.766) or plaques (r=-0.361, p=0.119). There were no other significant correlations between regional MRI volume and measures of neuropathology. Regression analysis showed that overall diagnosis of AD rather than burden of individual pathological changes was the most significant predictor of hippocampal volume loss in autopsy confirmed cases. CONCLUSION: Our results suggest that (i) hippocampal and amygdala but not entorhinal cortex, volumes differ between AD and LBD and (ii) factors other than current markers of neurodegenerative pathological change are responsible for atrophy of medial temporal lobe structures in AD and LBD.

Synaptic changes in frontotemporal lobar degeneration: correlation with MAPT haplotype and APOE genotype.

AIMS: This immunohistochemical study quantified synaptic changes (synaptophysin and SNAP-25) in the frontal lobe of subjects with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD), and related these to APOE genotype and MAPT haplotype. METHODS: Frontal neocortex (BA9) of post mortem brains from subjects with FTLD (n = 20), AD (n = 10) and age-matched controls (n = 9) were studied immunohistochemically for synaptophysin and SNAP-25. RESULTS: We report that patients with FTLD have a significant increase in synaptophysin and depletion in SNAP-25 proteins compared to both control subjects and individuals with AD (P < 0.001). The FTLD up-regulation of synaptophysin is disease specific (P < 0.0001), and is not influenced by age (P = 0.787) or cortical atrophy (P = 0.248). The SNAP-25 depletion is influenced by a number of factors, including family history and histological characteristics of FTLD, APOE genotype, MAPT haplotype and gender. Thus, more profound loss of SNAP-25 occurred in tau-negative FTLD, and was associated with female gender and lack of family history of FTLD. Presence of APOEε4 allele and MAPT H2 haplotype in FTLD had a significant influence on the expression of synaptic proteins, specifically invoking a decrease in SNAP-25. CONCLUSIONS: Our results suggest that synaptic expression in FTLD is influenced by a number of genetic factors which need to be taken into account in future neuropathological and biochemical studies dealing with altered neuronal mechanisms of the disease. The selective loss of SNAP-25 in FTLD may be closely related to the core clinical non-cognitive features of the disease.

Medial temporal lobe atrophy on MRI differentiates Alzheimer's disease from dementia with Lewy bodies and vascular cognitive impairment: a prospective study with pathological verification of diagnosis.

The purpose of this study was to determine the diagnostic accuracy of medial temporal lobe atrophy (MTA) on MRI for distinguishing Alzheimer's disease from other dementias in autopsy confirmed cases, and to determine pathological correlates of MTA in Alzheimer's disease, dementia with Lewy bodies (DLB) and vascular cognitive impairment (VCI). We studied 46 individuals who had both antemortem MRI and an autopsy. Subjects were clinicopathologically classified as having Alzheimer's disease (n = 11), DLB (n = 23) or VCI (n = 12). MTA was rated visually using a standardized (Scheltens) scale blind to clinical or autopsy diagnosis. Neuropathological analysis included Braak staging as well as quantitative analysis of plaques, tangles and alpha-synuclein Lewy body-associated pathology in the hippocampus. Correlations between MTA and pathological measures were carried out using Spearman's rho, linear regression to assess the contributions of local pathologic changes to MTA. Receiver operator curve analysis was used to assess the diagnostic specificity of MTA for Alzheimer's disease among individuals with Alzheimer's disease, DLB and VCI. MTA was a highly accurate diagnostic marker for autopsy confirmed Alzheimer's disease (sensitivity of 91% and specificity of 94%) compared with DLB and VCI. Across the entire sample, correlations were observed between MTA and Braak stage (rho = 0.50, P < 0.001), per cent area of plaques in the hippocampus (rho = 0.37, P = 0.014) and per cent area of tangles in the hippocampus (rho = 0.49, P = 0.001). Linear regression showed Braak stage (P = 0.022) to be a significant predictor of MTA but not percent area of plaques (P = 0.375), percent area of tangles (P = 0.330) or percent area of Lewy bodies (P = 0.086). MTA on MRI had robust discriminatory power for distinguishing Alzheimer's disease from DLB and VCI in pathologically confirmed cases. Pathologically, it is more strongly related to tangle rather than plaque or Lewy body pathology in the temporal lobe. It may have utility as a means for stratifying samples in vivo on the basis of putative differences in pathology.

Decrease in 130 kDa- amyloid protein precursor protein (APP) and APP protein ratio in schizophrenia platelets.

Cognitive dysfunction is common among people with schizophrenia. The molecular substrates underlying this remain poorly understood. To address this, we analyzed changes in amyloid precursor protein (APP) in platelets of people with acute schizophrenia (n=24) and control subjects (n=20) by ECL-immunoblotting. APP bands corresponding to molecular masses of ∼130, ∼110 and ∼100 kDa, and the APP ratio (APPr: highest APP molecular mass vs lowest APP molecular mass bands) were quantified. The intensity of 130 kDa-APP and the APPr were significantly reduced in schizophrenia patients compared to control subjects. The age-associated decreases in the 130 kDa, ∼110 kDa proteins and APPr were present in patients, but not controls. Our results confirm peripheral APP metabolism is altered in people with schizophrenia. Further work is now warranted on a larger sample of diseased subjects with detailed cognitive assessment to determine the APP role in cognitive processing in schizophrenia, how it is related to severity and disease progression, as well as outcomes.

Alpha- and gamma-synuclein proteins are present in cerebrospinal fluid and are increased in aged subjects with neurodegenerative and vascular changes.

BACKGROUND: Disease-specific biomarkers should reflect a fundamental feature of neuropathology and be validated in neuropathologically confirmed cases. Several synaptic proteins have been described in cerebrospinal fluid (CSF) of patients with dementia. In Lewy body disease alpha-synuclein is incorporated within Lewy bodies and alpha-, beta- and gamma-synucleins in dystrophic neuritis. These pathological changes are expected to be seen in CSF. METHODS: A total of 25 CSF post-mortem samples (8 control and 17 subjects with dementia) were used to quantify alpha- and gamma-synucleins and IgG. RESULTS: We describe for the first time the presence of gamma-synuclein in CSF. There is an elevation of both alpha- and gamma-synucleins in CSF from elderly individuals with Alzheimer's disease, Lewy body disease (LBD) and vascular dementia (CVD), compared to normal controls. gamma-Synuclein showed a greater elevation in LBD, IgG in CVD. The elevation of alpha- and gamma-synucleins was seen from Braak stage III onwards and remained stable until Braak stage VI. These results were not influenced by age at death or post-mortem delay. CONCLUSIONS: The reported increases in alpha- and gamma-synucleins and IgG in the ventricular CSF of individuals with dementia are novel findings. They now need to be explored further using a greater number of cases in each subgroup, using lumbar CSF samples to determine their applicability and relevance to a clinical diagnostic setting. It needs to be established whether using these markers may help to discriminate LBD from other types of neurodegenerative and vascular dementias.

[Autism spectrum disorders in children and adults: the experience of reserches from different countries]. / Rasstroistva autisticheskogo spektra u detei i vzroslykh: podkhody k probleme v raznykh stran.

Current studies on the development autism spectrum disorders (ASD) at different ages are reviewed. The review highlights the increasing interest to this problem and converging positions of researchers from different countries, encouraged by the development of international and other classifications of mental diseases, on the terminology, classification and prevalence of ASD in children. An important feature of the present stage is to draw attention to an understudied problem of ASD in adults, including elderly, and provision of medical and social care to these patients.

The prevalence and clinical manifestations of delirium in sub-Saharan Africa: a systematic review with inferences.

BACKGROUND: In high-income countries with ageing populations, delirium is most prevalent in older adults and in palliative and intensive care settings. The prevalence and aetiology of delirium are likely to differ in low income countries, including sub-Saharan Africa (SSA), due to different population demographics, disease burden and exposure to pathogens. We reviewed published literature relating to the prevalence, clinical features and underlying causes of delirium in SSA and compare this with that published in high-income countries in order to identify knowledge and clinical service gaps, and priorities for further research. METHODS: We performed a narrative review by comprehensively searching the following databases: Medline, PsychInfo, Embase and PubMed. Studies published between January 1 1975 and December 31 2013 in all languages, including the terms 'delirium', 'acute brain syndrome', 'organic brain syndrome', or 'acute confusion' originating from SSA were included. In addition, reference lists of included articles and online databases of African medical literature were hand-searched. We also included case series and case reports due to paucity of published studies. RESULTS: We identified a total of 46 relevant studies. Delirium was the main focus of only one cross-sectional study, whereas most included delirium in studies on neuropsychiatric conditions. Only two studies reported prevalence in older adults. Most studies reported very low (<2%) delirium prevalence, whereas delirium in psychiatric inpatient and outpatient settings was higher than expected (18.2%-29.9%). Descriptive studies of 'bouffee delirante' from psychiatry settings were often describing delirium. Infection and HIV seropositivity were common associations of delirium throughout these studies. There were no studies of intensive, critical or surgical care settings or of management strategies. CONCLUSIONS: We currently know very little about the prevalence, presentation and aetiology of delirium in developing countries. This knowledge gap should be tackled with some urgency, in order to address questions of screening, diagnosis, prevention and management in this setting.

Alpha-synuclein inclusions in Alzheimer and Lewy body diseases.

Alpha-synuclein has assumed particular neuropathological interest in the light both of its identification as a non-beta-amyloid plaque constituent in Alzheimer disease (AD), and the recent association between dominant inheritance of Parkinson disease (PD) and 2 missense mutations at positions 30 and 53 of the synuclein protein. We report a systematic study of alpha-synuclein, tau, and ubiquitin immunoreactivity in representative neurodegenerative disorders of late life. The alpha-synuclein association with Lewy bodies is variable, peripheral, and is not stable with respect to proteases or acid treatment, whereas there is no association with Pick bodies. Stable patterns of immunoreactivity included neurites and a novel inclusion body. Although there is an overlap between the presence of Lewy bodies and stable alpha-synuclein immunoreactivity, this is seen only in the presence of concomitant neuropathological features of AD. The novel alpha-synuclein inclusion body identified in pyramidal cells of the medial temporal lobe in particular was found in AD and in the Lewy body variant of AD, and was associated neither with ubiquitin nor tau protein. The inclusion is therefore neither a Lewy body nor a PHF-core body, but may be confused with the Lewy body, particularly in the Lewy body variant of AD. Abnormal processing of alpha-synuclein leading to its deposition in the form of proteolytically stable deposits is a particular feature of the intermediate stages of AD.

Quantitative analysis of tau protein in paired helical filament preparations: implications for the role of tau protein phosphorylation in PHF assembly in Alzheimer's disease.

In Alzheimer's disease, there is a major redistribution of the tau protein pool from soluble to PHF-bound forms. PHF-bound tau can be distinguished from normal tau by acid reversible occlusion of a generic tau epitope in the tandem repeat region and characteristic sedimentation in the if-II protocol developed in this laboratory. We show that 85% of tau bound in the PHF-like configuration can be recovered in the if-II PHF-fraction. Less than 1% of this material was phosphorylated at the mAb AT8 site in aged clinical controls or in cases with minimal or mild dementia. Of tau phosphorylated at the mAb AT8 site, only 12% was found to co-sediment with PHFs. These low levels could not be explained by postmortem dephosphorylation. As more than 95% of PHF-tau is not phosphorylated, even at early stages of pathology, it is misleading to use the terms "PHF-tau" and "phosphorylated tau" as though they were synonymous, particularly as this implies a pathogenetic role which phosphorylation need not have.

Examination of phosphorylated tau protein as a PHF-precursor at early stage Alzheimer's disease.

Hyperphosphorylated tau protein which can be isolated on the basis of insolubility in 1% sarkosyl (A68-tau fraction) is thought to represent a precursor pool for PHF assembly, associated histologically with neuritic pathology, which feeds into a more resistant tangle-associated PHF pool via cross-linking and proteolysis. We examined these predictions at the earliest detectable stages of neurofibrillary pathology. We report that there is no evidence that neuritic pathology represents an early pathologic stage, no evidence of an association between neuritic pathology and phosphorylated tau, no evidence of selective accumulation of phosphorylated tau at early stages of pathology, and no evidence for a precursor/product relationship between phosphorylated tau and PHFs during progression of pathology. We conclude that altered phosphorylation is a secondary process affecting 5% of PHFs and does not explain PHF assembly in Alzheimer's disease.

Behavioral and psychological symptoms of dementia.

Behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric symptoms, represent a heterogeneous group of non-cognitive symptoms and behaviors occurring in subjects with dementia. BPSD constitute a major component of the dementia syndrome irrespective of its subtype. They are as clinically relevant as cognitive symptoms as they strongly correlate with the degree of functional and cognitive impairment. BPSD include agitation, aberrant motor behavior, anxiety, elation, irritability, depression, apathy, disinhibition, delusions, hallucinations, and sleep or appetite changes. It is estimated that BPSD affect up to 90% of all dementia subjects over the course of their illness, and is independently associated with poor outcomes, including distress among patients and caregivers, long-term hospitalization, misuse of medication, and increased health care costs. Although these symptoms can be present individually it is more common that various psychopathological features co-occur simultaneously in the same patient. Thus, categorization of BPSD in clusters taking into account their natural course, prognosis, and treatment response may be useful in the clinical practice. The pathogenesis of BPSD has not been clearly delineated but it is probably the result of a complex interplay of psychological, social, and biological factors. Recent studies have emphasized the role of neurochemical, neuropathological, and genetic factors underlying the clinical manifestations of BPSD. A high degree of clinical expertise is crucial to appropriately recognize and manage the neuropsychiatric symptoms in a patient with dementia. Combination of non-pharmacological and careful use of pharmacological interventions is the recommended therapeutic for managing BPSD. Given the modest efficacy of current strategies, there is an urgent need to identify novel pharmacological targets and develop new non-pharmacological approaches to improve the adverse outcomes associated with BPSD.

Liaison old age psychiatry service in a medical setting: description of the newcastle clinical service.

Liaison Old Age Psychiatry services (LOAP) have begun to emerge in the UK and further development of the service is supported by the latest health policies. Since qualitative and quantitative studies in this area are lacking, we have undertaken a detailed quantitative prospective review of referrals to the Newcastle LOAP to evaluate the clinical activity of the service. We report high referral rates and turnover for the LOAP service. Reasons for referral are diverse, ranging from requests for level of care and capacity assessments and transfer to other clinical services to management of behaviour, diagnosis, and treatment. We outline the value of a multidisciplinary model of LOAP activity, including the important role of the liaison nursing team, in providing a rapid response, screening, and followup of high number of clinical referrals to the service.

Loss of synaptophysin and synaptosomal-associated protein 25-kDa (SNAP-25) in elderly Down syndrome individuals.

AIMS: This study quantified the density of the synaptic proteins synaptophysin and synaptosomal-associated protein 25-kDa (SNAP-25) in brains from elderly Down's syndrome individuals. METHODS: Six areas (frontal, occipital, parietal and temporal lobes, cerebellum and hippocampus) of post mortem brains from elderly Down's syndrome (DS) individuals (with reported functional memory problems and pathologically established Alzheimer's disease) and elderly controls were studied. RESULTS: Collectively in the six brain areas studied, there were significantly lower levels of both synaptophysin and SNAP-25 immunostaining in the DS group compared with controls. The elderly control group displayed a significant decrease in the densities of synaptophysin and SNAP-25 as a function of age at death (AAD; P < or = 0.001), whereas the DS group only showed a significant decrease as a function of AAD for synaptophysin. Assessing synaptic density as a function of Braak stage (BST) revealed a significant decrease in synaptophysin density for both groups. SNAP-25 was only significantly decreased as a function of BST in the DS group. Synaptic protein density was also shown to vary according to gender. Thus, both DS and control female subjects had a higher synaptic density of SNAP-25 than their male counterparts. In contrast, male DS and control individuals had a significantly greater density of synaptophysin than females. CONCLUSIONS: These results indicate that elderly DS individuals have lower synaptic densities of both analysed proteins than cognitively intact elderly individuals. Although AAD and BST show varying significance to decreases in protein density for both DS and control groups, results suggest that gender differences also play a role in the type of synaptic protein lost in elderly DS individuals.

Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.

The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Alterations in tau protein metabolism during normal aging.

It is unknown whether aging and Alzheimer's disease (AD) are on the same continuum, or whether they are qualitatively distinct. Tau protein has been identified as a major constituent of paired helical filaments (PHFs) and AD is characterised by a major redistribution of the normal tau protein pool into PHFs. Little is known about the changes in tau protein distribution that occur in the course of normal aging. We have examined PHF-bound and normal tau fractions in frontal, temporal, parietal and occipital neocortex, cerebellum, hippocampus and entorhinal cortex in 15 cognitively unimpaired individuals aged 19-88 years at death. Insoluble tau protein in the PHF fraction did not increase with aging in any brain region, despite the appearance of neurofibrillary pathology at low density in the more elderly cases. By contrast, normal tau protein decreased with aging (r = 0.32, p < 0.001), with an average loss of 14% of soluble tau per decade after the age of 20 years. This was unrelated either to neurofibrillary or beta-amyloid pathology. Frontal grey matter and hippocampus were most vulnerable to age-related tau loss, decreasing by as much as 90% in the older subgroup. These findings contrast with those we have previously reported in AD, where the redistribution of tau protein into the PHF-bound fraction was highly correlated with the extent of neurofibrillary pathology, and suggest that the mechanisms of tau loss in aging and AD are distinct. Age-related tau loss may underlie the neuropsychological impairments seen in the non-demented elderly.

Presence of the apolipoprotein E type epsilon 4 allele is not associated with neurofibrillary pathology or biochemical changes to tau protein.

Alzheimer's disease (AD) represents a heterogeneous disorder, and several factors have been associated with its development. The presence of the apolipoprotein E type (APOE) epsilon 4 allele has been proposed as a risk factor for AD, but how it influences the development of the characteristic hallmarks of the disease remains unknown. In the present study, the neuropathological changes and levels of both core PHF-tau and normal tau protein in 4 neocortical areas, cerebellum and medial temporal cortex were determined in 18 AD cases. The extent of these changes was compared between 10 cases possessing an epsilon 4 allele and 8 cases without. These two groups were indistinguishable in terms of neurofibrillary pathology, whereas cases with an epsilon 4 allele had more diffuse plaques, particularly in the temporal neocortex. Biochemically, there was no difference in the levels of PHF-tau protein between the two groups. These data indicate that APOE epsilon 4 allele may influence deposition of diffuse amyloid, but altered tau protein processing, which underlies the development of the neurofibrillary pathology in AD, is not influenced by this allele.