Dementia subtypes, cognitive decline and survival among older adults attending a memory clinic in Cape Town, South Africa: a retrospective study.

BACKGROUND: There are no published longitudinal studies from Africa of people with dementia seen in memory clinics. The aim of this study was to determine the proportions of the different dementia subtypes, rates of cognitive decline, and predictors of survival in patients diagnosed with dementia and seen in a memory clinic. METHODS: Data were collected retrospectively from clinic records of patients aged ≥ 60 seen in the memory clinic at Groote Schuur Hospital, Cape Town, South Africa over a 10-year period. Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria were used to identify patients with Major Neurocognitive Disorders (dementia). Additional diagnostic criteria were used to determine the specific subtypes of dementia. Linear regression analysis was used to determine crude rates of cognitive decline, expressed as mini-mental state examination (MMSE) points lost per year. Changes in MMSE scores were derived using mixed effects modelling to curvilinear models of cognitive change, with time as the dependent variable. Multivariable cox survival analysis was used to determine factors at baseline that predicted mortality. RESULTS: Of the 165 patients who met inclusion criteria, 117(70.9%) had Major Neurocognitive Disorder due to Alzheimer's disease (AD), 24(14.6%) Vascular Neurocognitive Disorder (VND), 6(3.6%) Dementia with Lewy Bodies (DLB), 5(3%) Parkinson disease-associated dementia (PDD), 3(1.8%) fronto-temporal dementia, 4(2.4%) mixed dementia and 6(3.6%) other types of dementia. The average annual decline in MMSE points was 2.2(DLB/PDD), 2.1(AD) and 1.3(VND). Cognitive scores at baseline were significantly lower in patients with 8 compared to 13 years of education and in those with VND compared with AD. Factors associated with shorter survival included age at onset greater than 65 (HR = 1.82, 95% C.I. 1.11, 2.99, p = 0.017), lower baseline MMSE (HR = 1.05, 95% C.I. 1.01, 1.10, p = 0.029), Charlson's comorbidity scores of 3 to 4 (HR = 1.88, 95% C.I. 1.14, 3.10, p = 0.014), scores of 5 or more (HR = 1.97, 95% C.I. 1.16, 3.34, p = 0.012) and DLB/PDD (HR = 3.07, 95% C.I. 1.50, 6.29, p = 0.002). Being female (HR = 0.59, 95% C.I.0.36, 0.95, p = 0.029) was associated with longer survival. CONCLUSIONS: Knowledge of dementia subtypes, the rate and factors affecting cognitive decline and survival outcomes will help inform decisions about patient selection for potential future therapies and for planning dementia services in resource-poor settings.

Understanding the relationships between physiological and psychosocial stress, cortisol and cognition.

Stress is viewed as a state of real or perceived threat to homeostasis, the management of which involves the endocrine, nervous, and immune systems. These systems work independently and interactively as part of the stress response. The scientific stress literature, which spans both animal and human studies, contains heterogeneous findings about the effects of stress on the brain and the body. This review seeks to summarise and integrate literature on the relationships between these systems, examining particularly the roles of physiological and psychosocial stress, the stress hormone cortisol, as controlled by the hypothalamic-pituitary-adrenal (HPA) axis, and the effects of stress on cognitive functioning. Health conditions related to impaired HPA axis functioning and their associated neuropsychiatric symptoms will also be considered. Lastly, this review will provide suggestions of clinical applicability for endocrinologists who are uniquely placed to measure outcomes related to endocrine, nervous and immune system functioning and identify areas of intervention.

Societal Need for Interdisciplinary Ageing Research: An International Alliance of Research Universities "Ageing, Longevity and Health" Stream (IARU-ALH) Position Statement.

Ageing is a global concern with major social, health, and economic implications. While individual countries seek to develop responses to immediate, pressing needs, international attention and collaboration is required to most effectively address the multifaceted challenges and opportunities an ageing global population presents in the longer term. The Ageing, Longevity and Health stream of the International Alliance of Research Universities (IARU-ALH) was built on a solid foundation of first-class interdisciplinary research and on innovative outreach and communication centres. This interdisciplinary network conducts projects that span biology, medicine, social sciences, epidemiology, public health, policy, and demography, and actively engages with the public and other societal stakeholders. Here we posit that such international interdisciplinary networks are needed and uniquely placed to address major challenges related to health and ageing and ultimately will produce new understanding and knowledge to promote the awareness of healthy ageing and encourage societal change via novel, science-informed interventions. Global interdisciplinary research presents great potential and opportunities to accelerate our understanding of human ageing and to produce new, more effective solutions to a pressing, complex problem. However, more focused, strategic efforts and investments are required in order to deliver on these potentials and reap maximum benefits for individuals and societies. IARU-ALH members are determined to contribute, in collaboration with others, to delivering on this vision.

Viral protein R polymorphisms in the pathogenesis of HIV-associated acute ischaemic stroke: a case-control study.

HIV-1 viral proteins have been implicated in endothelial dysfunction, which is a major determinant of ischaemic stroke risk in HIV-infected individuals. Polymorphisms in HIV-1 viral protein R (Vpr) may alter its potential to promote endothelial dysfunction, by modifying its effects on viral replication, reactivation of latent cells, upregulation of pro-inflammatory cytokines and infection of macrophages. We analysed Vpr polymorphisms and their association with acute ischaemic stroke by comparing Vpr signature amino acids between 54 HIV-infected individuals with acute ischaemic stroke, and 80 age-matched HIV-infected non-stroke controls. Isoleucine at position 22 and serine at position 41 were associated with ischaemic stroke in HIV. Individuals with stroke had lower CD4 counts and CD4 nadirs than controls. These polymorphisms are unique to individuals with stroke compared to South African subtype C and the control group consensus sequences. Signature Vpr polymorphisms are associated with acute ischaemic stroke in HIV. These may increase stroke risk by promoting endothelial dysfunction and susceptibility to opportunistic infections. Therapeutic targeting of HIV-1 viral proteins may present an additional mechanism of decreasing stroke risk in HIV-infected individuals.

Psychosocial stress associated with memory performance in older South African adults.

Older adults with past or current chronic stress exposure perform poorly on memory assessments and are at higher risk for Alzheimer's disease (AD). In low- or middle-income countries, many older adults are, or have been, exposed to stress-provoking events. Few published studies examine such populations, however, and few take multiple measures of stress. In a sample of South African older adults with mild-to-moderate AD (n = 65) and healthy controls (n = 69), we assessed relations between stress (psychosocial and physiological), memory performance, and patient status. Participants, all aged > 60, were administered the Perceived Stress Scale (a questionnaire assessing subjective psychosocial stress) and the Cambridge Cognitive Examination-Revised (CAMCOG-R; a test battery measuring performance across several cognitive domains). We measured their salivary cortisol concentrations as a proxy for physiological stress. Patients reported significantly higher levels of psychosocial stress than controls, p = .008. Logistic regression showed that psychosocial stress, but not cortisol, predicted AD patient status. CAMCOG-R Memory subscale scores were significantly associated with psychosocial stress, r = -.18, p = .040, but not with cortisol levels. These findings are the first on the topic to emerge from a low-or middle-income country. We replicated findings from previous studies conducted in high-income countries, with data supporting predictions derived from the glucocorticoid cascade/neurotoxicity hypothesis. The results suggest that clinical interventions focused on increasing resilience of older adults to effects of chronic stress may help protect against declining memory performance and reduce the risk for AD.

Prevalence of HIV-1 Infection in an elderly rural population and associations with neurocognitive impairment.

OBJECTIVE: We explored the prevalence of HIV infection in older rural South Africans and its associations, as well as the point prevalence of dementia and its associations with HIV and aging. DESIGN: We utilized a cross-sectional analytic design. METHODS: Using the brief Community Screening Instrument for Dementia together with a rapid HIV test, we conducted a home-based screening survey among 1150 older South Africans. We explored the prevalence of HIV and dementia, and their associations using descriptive statistics and logistic regression analysis. RESULTS: The HIV prevalence was 4.78%. Overall, participants were on average 71.3 years old, with nearly 70% having no primary school education. HIV+ participants were significantly younger, more likely to be single and had lower BMI. The overall dementia prevalence was 11.04%. HIV+ participants had higher rates of dementia compared with HIV- participants (18.18 vs. 10.68%) but the difference was NS. In adjusted analysis, screened dementia was associated with older age, the presence of self-reported depression and HIV+ status. Participants were also more likely to self-report cognitive impairment if they were older, depressed and had objective evidence of dementia. CONCLUSION: Infection with HIV in rural older South Africans is a prevalent problem, and together with older age, is a significant contributor to cognitive impairment. It is possible that HIV infection contributes to dementia on the basis of an acceleration of degeneration - because our HIV-infected participants were younger - AND an accentuation of aging - because of the higher rates of impairment for similar age groups.

Both Reaction Time and Accuracy Measures of Intraindividual Variability Predict Cognitive Performance in Alzheimer's Disease.

Dementia researchers around the world prioritize the urgent need for sensitive measurement tools that can detect cognitive and functional change at the earliest stages of Alzheimer's disease (AD). Sensitive indicators of underlying neural pathology assist in the early detection of cognitive change and are thus important for the evaluation of early-intervention clinical trials. One method that may be particularly well-suited to help achieve this goal involves the quantification of intraindividual variability (IIV) in cognitive performance. The current study aimed to directly compare two methods of estimating IIV (fluctuations in accuracy-based scores vs. those in latency-based scores) to predict cognitive performance in AD. Specifically, we directly compared the relative sensitivity of reaction time (RT)-and accuracy-based estimates of IIV to cognitive compromise. The novelty of the present study, however, centered on the patients we tested [a group of patients with Alzheimer's disease (AD)] and the outcome measures we used (a measure of general cognitive function and a measure of episodic memory function). Hence, we compared intraindividual standard deviations (iSDs) from two RT tasks and three accuracy-based memory tasks in patients with possible or probable Alzheimer's dementia (n = 23) and matched healthy controls (n = 25). The main analyses modeled the relative contributions of RT vs. accuracy-based measures of IIV toward the prediction of performance on measures of (a) overall cognitive functioning, and (b) episodic memory functioning. Results indicated that RT-based IIV measures are superior predictors of neurocognitive impairment (as indexed by overall cognitive and memory performance) than accuracy-based IIV measures, even after adjusting for the timescale of measurement. However, one accuracy-based IIV measure (derived from a recognition memory test) also differentiated patients with AD from controls, and significantly predicted episodic memory performance. The findings suggest that both RT- and accuracy-based IIV measures may be useful indicators of underlying neuropathology. The present study therefore contributes toward an understanding of the relative utility of RT- and accuracy-based IIV measures in detecting neurocognitive impairment in older adults, and also advances the empirical evaluation of sensitive markers of cognitive change in patients with AD.

Dementia Prevalence in a Rural Region of South Africa: A Cross-Sectional Community Study.

BACKGROUND: Dementia is a growing concern for low- and middle-income countries where longevity is increasing and service provision is poor. Global prevalence estimates vary from 2% to 8.5% for those aged 60 years and older. There have been few dementia studies in sub-Saharan Africa, and prevalence data are lacking for South Africa. OBJECTIVE: To conduct a large dementia prevalence study in a low income rural population in South Africa. METHODS: 1,394 Xhosa-speaking community dwellers, aged ≥60 y (mean age±sd 71.3±8.3 y), in three clinic catchment areas, were screened at home. Trained community health workers administered the brief Community Screening Instrument for Dementia (CSID) to participants and informants to assess cognitive and functional capacity. Depressive symptoms were assessed with three questions from the EURO-D. RESULTS: The prevalence estimate using published CSID sensitivity/specificity values was 0.8 (95% CI: 0.06-0.09). Using CSID cut-off scores the estimated prevalence was 0.12 (95% CI: 0.10-0.13), with 161 screen-positives. Both methods gave a rate of 0.11 (95% CI: 0.09-0.13) for those over 65 years (n = 1051). 68.6% of participants were female and 69.8% had less than 7 years of education. Dementia risk was associated with older age and symptoms of depression, but not with sex. The association with education was not significant when controlled for by age. CONCLUSIONS: Dementia prevalence estimates were higher than expected for this low-income rural community. There is a need for increased dementia awareness and feasible support interventions. We also need further studies of regional prevalences, dementia subtypes, and modifiable risk factors in South Africa.

The soluble transcobalamin receptor (sCD320) in relation to Alzheimer's disease and cognitive scores.

The soluble transcobalamin receptor (sCD320) is present in cerebrospinal fluid and correlates with the dementia-related biomarkers phospho-tau and total-tau. Here we present data on the relation of sCD320 to Alzheimer's disease and scores of cognitive tests. Lumbar cerebrospinal fluid samples from 42 pathologically-confirmed cases of Alzheimer's disease and 25 non-demented controls were analyzed for sCD320 employing an in-house ELISA. The participants' cognitive functions were tested using the Cambridge Cognition Examination (CAMCOG) and the Mini-Mental State Examination (MMSE). There was no significant difference in the median CSF sCD320 concentration between patients and controls. The median (2.5-97.5 percentiles) sCD320 for all participants (n = 67) was 15 (3-29) pmol/L. We observed a non-linear correlation between sCD320 and cognitive scores. Spearman's correlation between sCD320 and total CAMCOG scores was 0.627 (n = 16, p = .009) for CAMCOG scores ≤27, and -0.293 (n = 39, p = .071) for CAMCOG scores ≥68. Spearman's correlation between sCD320 and both the low (≤9) and high (≥16) total MMSE scores was 0.274, -0.363 (n = 18, 44), p = .272, .016, respectively. In conclusion, sCD320 cannot be employed as a biomarker for differentiating Alzheimer dementia patients from controls. Further studies are warranted to explore the non-linear correlations between sCD320 and scores of cognitive function.

High levels of von Willebrand factor and low levels of its cleaving protease, ADAMTS13, are associated with stroke in young HIV-infected patients.

BACKGROUND: Stroke associated with human immunodeficiency virus infection may occur through a variety of mechanisms. Von Willebrand factor is a marker of endothelial dysfunction, and is elevated in human immunodeficiency virus infection. High levels of von Willebrand factor, a protein involved in platelet adhesion and aggregation, and low levels of ADAMTS13, a metalloproteinase that cleaves von Willebrand factor, have been associated with an increased risk of thrombosis. AIM: To investigate the role of von Willebrand factor and ADAMTS13 in the pathogenesis of human immunodeficiency virus-related stroke in young patients. METHODS: A case-control study (n = 100) comprising three participant groups: human immunodeficiency virus-positive antiretroviral therapy-naïve young strokes (n = 20), human immunodeficiency virus-negative young strokes (n = 40), and human immunodeficiency virus-positive antiretroviral therapy-naïve nonstroke controls (n = 40). von Willebrand factor and ADAMTS13 levels were measured in plasma samples collected five- to seven-days poststroke. RESULTS: Human immunodeficiency virus-positive stroke participants had higher von Willebrand factor levels than human immunodeficiency virus-negative strokes (173·5% vs. 135%, P = 0·032). They tended to have higher levels of von Willebrand factor than human immunodeficiency virus-positive nonstroke controls (173·5% vs. 129%, P = 0·061). Human immunodeficiency virus-positive stroke participants had lower levels of ADAMTS13 than human immunodeficiency virus-positive nonstroke controls (0% vs. 23·5% P = 0·018) most likely due to the effect of the acute stroke. However, in the nonstroke group, these levels were significantly reduced compared with population norms. von Willebrand factor levels in all human immunodeficiency virus-positive participants were negatively correlated with CD4 counts. CONCLUSIONS: Stroke in human immunodeficiency virus infection is associated with a prothrombotic state, characterized by elevated von Willebrand factor and low ADAMTS13 levels.

Cerebrospinal fluid biomarkers distinguish postmortem-confirmed Alzheimer's disease from other dementias and healthy controls in the OPTIMA cohort.

Cerebrospinal fluid (CSF) amyloid-ß (Aß) and tau have been studied as markers of Alzheimer's disease (AD). Combined Aß42 and t-tau distinguishes AD from healthy controls with a sensitivity and specificity (sens/spec) near 89% across studies. This study examined these markers in the homogeneous OPTIMA cohort, using extensive longitudinal follow up and postmortem evaluation to confirm clinicopathological status. Baseline CSF was analyzed from 227 participants with AD (97% autopsy-confirmed), mild cognitive impairment (MCI; 73% confirmed), other dementia syndrome (ODS; 100% confirmed), and controls (CTL; 27% confirmed, follow up approximately 9-13 years). Biomarker concentrations were analyzed using validated ELISAs. AD patients had lower CSF Aß42 and higher t-tau, p-tau, t-tau/Aß42, and t-tau/Aß40 compared to CTLs, with MCI intermediate. CTL and MCI participants who progressed to AD demonstrated more AD-like profiles. Aß40, sAßPPα, and sAßPPß were lower in AD compared to CTL. High-level discriminators of AD from CTL were t-tau/Aß40 (AUROC 0.986, sens/spec of 92%/94%), p-tau/Aß42 (AUROC 0.972, sens/spec of 94%/90%), and Aß42 (AUROC 0.941, sens/spec of 88%). For discriminating AD from ODS, p-tau/Aß42 demonstrated sens/spec of 88%/100% (95%/86% at the AD versus CTL cutoff) and Aß42 demonstrated sens/spec of 84%/100% (88%/100% at the AD versus CTL cutoff). In a well-characterized, homogeneous population, a single cutoff for baseline CSF Aß and tau markers can distinguish AD with a high level of sens/spec compared to other studies. It may be important to characterize sources of demographic and biological variability to support the effective use of CSF diagnostic assays in the broader AD population.

Associations between CAMCOG-R subscale performance and formal education attainment in South African older adults.

ABSTRACT Background: The Cambridge Cognitive Examination-Revised (CAMCOG-R) is a sensitive screening tool for the early diagnosis of dementia in older adults. Overall performance on the CAMCOG-R is influenced by educational attainment. Few studies have, however, examined the association between educational attainment and performance on the individual CAMCOG subscales. We aimed to address this question in a sample from a low-and middle-income country (LAMIC), where resource constraints may have compromised access to, and quality of, education for many older adults. Methods: Participants, all over 60 years of age, were 51 cognitively healthy community-dwelling volunteers and 47 individuals diagnosed with mild-moderate stage Alzheimer's disease (AD). Most participants had some high school education. They were administered the CAMCOG-R under standardized conditions. Results: Within both the control and AD patient groups, there were significant associations between years of completed education and CAMCOG-R total score, MMSE score, and CAMCOG-R Language subscale score. In both groups, level of education was not associated with scores on these subscales: in controls, recent memory, R 2 = .21, p = .055, learning memory, R 2 = .16, p = .398, attention/calculation, R 2 = .19, p = .467, and perception, R 2 = .18, p = .984; in AD patients, recent memory, R 2 = .14, p = .340, learning memory, R 2 = .03, p = .680, perception, R 2 = .09, p = .723, and attention/calculation, R 2 = .19, p = .097. Conclusions: Some CAMCOG-R subscale scores were more strongly associated with educational attainment than others. Importantly, however, performance on the recent memory and learning memory subscales was not affected by education. These subscales are sensitive indicators of amnestic mild cognitive impairment (MCI) and early AD. These subscales may therefore remain valid for use as an AD screening tool in resource-poor healthcare settings.

Relationship between apolipoprotein E4 genotype and white matter integrity in HIV-positive young adults in South Africa.

HIV-associated dementia (HAD) is a serious neuropsychiatric disorder affecting people with AIDS. Host genotype may affect the pathogenesis of HIV in the central nervous system (CNS). One gene relevant to the individual variation in acquiring HAD may be Apolipoprotein E (ApoE). We aimed to investigate the relationship of ApoE genotype to neuropsychological function and white matter integrity of the corpus callosum in a region of interest a priori analysis of HIV-positive subjects with clade C HIV. Forty-five subjects underwent ApoE genotyping, neuropsychological testing, and diffusion tensor imaging (DTI). Subjects (n = 24) with at least one ε4 allele when compared to subjects with no ε4 allele (n = 19) had significantly decreased immediate and delayed recall on the Hopkins Verbal Learning test (p = 0.05) and significantly decreased fractional anisotrophy in the corpus callosum (p = 0.007). These data indicate that the ε4 allelic variant of ApoE is associated with memory impairment and white matter damage of the corpus callosum in HIV-positive subjects.

White-Matter damage in Clade C HIV-positive subjects: a diffusion tensor imaging study.

The relationship between cognitive impairment and white-matter integrity in human immunodeficiency virus (HIV) remains poorly understood, particularly in clade C. The authors utilized diffusion tensor imaging (DTI) and a comprehensive neuropsychological evaluation to investigate the relationship between cognitive impairment and white-matter integrity in HIV-positive subjects with clade C HIV. Forty-four HIV-infected individuals and 10 seronegative subjects were compared, using a whole-brain, voxel-based approach to define fractional anisotropy (FA) and mean diffusion (MD). Compared with healthy-control subjects, the HIV-infected group exhibited decreased FA in the corpus callosum, superior longitudinal fasciculus, and cingulum and sagittal stratum. This study provides evidence that white-matter integrity is compromised in individuals infected with clade C HIV.

Characterization of HIV-Associated Neurocognitive Disorders among individuals starting antiretroviral therapy in South Africa.

HIV-Associated Neurocognitive Disorders (HAND) exert an impact on everyday functions, including adherence. The prevalence of and risk factors for HAND in patients commencing anti-retroviral therapy in Southern Africa are unknown. Participants from primary care clinics in Cape Town, South Africa underwent detailed neuropsychological, neuropsychiatric, and neuromedical evaluation. Using the updated American Academy of Neurology (AAN) criteria, participants were classified into categories of HAND, and demographic and clinical risk factors for HIV-dementia (HIV-D) were assessed. The prevalence of mild neurocognitive disorder (MND) and HIV-D were 42.4 and 25.4%, respectively. There were significant associations between lower levels of education and older age with HIV-D, and a trend to association with HIV-D and lower CD4 count. In a regression model, a lower level of education and male gender were predictive of HIV-D. These findings suggest that HAND are highly prevalent in primary care settings in South Africa where clade C HIV is predominant.

Association between apolipoprotein E4 genotype and human immunodeficiency virus-associated dementia in younger adults starting antiretroviral therapy in South Africa.

It is not known whether the apolipoprotein E (ApoE) ε4 allelic variant is associated with human immunodeficiency virus (HIV)-associated dementia (HAD) in a South African population, where HIV clade C is predominant. ApoE genotyping was performed on 144 participants in a larger study of HIV-associated neurocognitive disorders (HAND). There was a lower frequency of the ε2 and ε3 alleles in the HIV-positive group, compared to a group of 300 community-based newborn infants. There were no differences in ApoE genotype across different categories of HAND. The ε4 allelic variant was less common in individuals with HAD than in those without HAD. These findings suggest that the ε4 allelic variant in HIV-positive individuals is not associated with the development of HAD in Southern Africa.

Peripheral reductive capacity is associated with cognitive performance and survival in Alzheimer's disease.

BACKGROUND: Oxidative stress is believed to be an early event and a key factor in Alzheimer's disease (AD) pathogenesis and progression. In spite of an intensive search for surrogate markers to monitor changes related to oxidative stress in the brain, there is as yet no consensus about which markers to use in clinical studies. The measurement of peripheral anti-oxidants is an alternative way of evaluating the involvement of oxidative stress in the course of the disease. Given the complexity of peripheral anti-oxidant defence, variations in the levels of individual anti-oxidant species may not fully reflect the overall capacity to fight oxidant conditions. We therefore chose to evaluate the total reductive capacity (herein defined as anti-oxidant capacity, AOC) in serum from control subjects and AD patients in order to study the association between peripheral anti-oxidant defence, cognitive impairment and patient survival. METHODS: We measured the levels of AOC in serum samples from 26 cognitively normal controls and 25 AD patients (12 post-mortem confirmed) who completed the Cambridge Cognitive Assessment. Cognitive decline was assessed in a subgroup of 19 patients who underwent a second cognitive assessment 2 years after the initial visit. RESULTS: Serum AOC levels were lower in AD patients than in controls and were correlated with their cognitive test scores, although AOC levels were unrelated to cognitive decline assessed two years later. On the other hand, AOC levels were predictive of the length of patients' survival, with higher levels giving longer survival. CONCLUSION: This study indicates that peripheral anti-oxidant defences are depleted in AD patients. The results suggest that serum AOC is a good index of the general health status and prognosis of patients but does not necessarily reflect the extent to which vulnerable neuronal populations are protected from oxidant processes. Further studies are required to establish whether peripheral AOC measurements may be useful in identifying asymptomatic individuals or those with early symptoms at high risk of developing significant cognitive impairment or dementia.

Productive herpes simplex virus in brain of elderly normal subjects and Alzheimer's disease patients.

It was previously shown that herpes simplex virus type 1 (HSV1) DNA resides latently in a high proportion of aged brains and that in carriers of the type 4 allele of the apolipoprotein E gene (APOE-epsilon4), it confers a strong risk of Alzheimer's disease. It was suggested that initial entry of brain by HSV1 and any subsequent reactivation(s) would cause a type of limited encephalitis, the resulting damage being more harmful in APOE-epsilon4 carriers. Reactivation(s) would induce synthesis of intrathecal antibodies; these are long-lived after herpes simplex encephalitis so they were sought in cerebrospinal fluid (CSF) of Alzheimer's disease patients and age-matched normal subjects. Intrathecal antibodies to human herpesvirus 6 (HHV6) were also sought as DNA of this virus has been detected previously in a high proportion of Alzheimer's disease brains. Antibody indices for HSV and HHV6 were measured using indirect ELISA for IgG antibody, and single radial immunodiffusion was used for albumin, in serum and CSF. A raised antibody index (>1.5) indicative of virus-specific intrathecal HSV1 IgG synthesis was found in 14/27 (52%) Alzheimer's disease patients and 9/13 (69%) age-matched normals (difference non-significant). A raised antibody index to HHV6 was detected in 22% of the Alzheimer's disease patients and in no normals, so presumably this virus either did not reactivate in brain or it elicited only short-lived intrathecal antibodies. The HSV1 results confirm the original PCR findings that show the presence of HSV1 DNA sequences in many elderly brains, and indicate also that the whole functional HSV1 genome is present, and that the virus has replicated.

Association between subcortical vascular disease on CT and neuropathological findings.

BACKGROUND: Small vessel cerebrovascular disease (svCVD) causes cognitive impairment and predicts poorer outcomes in elderly persons. The demonstration of svCVD by structural imaging such as computed tomography (CT) is central to the clinical diagnosis but its accuracy is uncertain. OBJECTIVE: The aim of this study was to assess the validity of CT to detect pathologically verified svCVD. METHODS: Leukoaraiosis, patchy lesions, and lacunes were assessed separately in different cerebral regions on CT scans of 87 elderly persons with Mini-Mental State Examination scores between 0 and 30 enrolled in the OPTIMA project. We rated small vessel disease on pathology separately in the white matter and basal ganglia as absent/mild, moderate, and severe. The presence of microinfarcts was also noted. RESULTS: The severity of all types of CT lesions was associated with pathological findings. Subjects with absent/mild leukoaraiosis on CT decreased and those with severe leukoaraiosis increased with increasing severity of subcortical small vessel ratings on pathology (31, 18 and 0%; 17, 23 and 50%, respectively; p = 0.028). A similar association was present for patchy lesions (73, 59 and 17%; 7, 18 and 33%, respectively; p = 0.004) and lacune (83, 77 and 50%; 0, 4 and 17%, respectively; p = 0.023). Leukoaraiosis, patchy lesions, and lacunes on CT were associated also with microinfarcts on pathology (p < 0.05). CONCLUSION: The standardized assessment of svCVD on CT films at the time of the diagnosis correlates with small vessel disease on pathology at death.