Marc Combrinck

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.

The Validity and Reliability of 6 Sets of Clinical Criteria to Classify Alzheimer’s Disease and Vascular Dementia in Cases Confirmed Post-Mortem: Added Value of a Decision Tree Approach

Data from 204 participants from the Oxford Project to Investigate Memory and Ageing, who were diagnosed post-mortem using the histopathological criteria of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), were used to assess the validity of the clinical criteria for Alzheimer’s disease (AD) of the ‘National Institute of Neurological and Communicative Disorders and Stroke/the Alzheimer’s Disease and Related Disorders Association’ (NINCDS/ADRDA). Cases who had been diagnosed as NINCDS/ADRDA ‘probable AD’ in life were usually confirmed at autopsy, but half of the NINCDS/ADRDA ‘negative’ cases were not (low specificity). It was hypothesized that the overall clinical impression may have taken precedence over the use of the actual criteria. We therefore investigated the validity and reliability of the clinical criteria using a computerized ‘dementia diagnosis system’ for each of 6 sets of criteria [Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), NINCDS/ADRDA and three sets of criteria specifically for vascular dementia (VaD): NINCDS-AIREN, State of California Alzheimer’s Disease Diagnostic and Treatment Centers (ADDTC), and Vascular Cognitive Impairment (VCI)] to classify a subset (n = 96) of the cases confirmed post-mortem. The use of the computerized system significantly (p = 0.01) increased the specificity (81%, similar to sensitivity) of the NINCDS/ADRDA diagnoses, which were shown to have ‘moderate’ inter-rater reliability. The DSM-IV criteria had good validity for AD when compared with post-mortem confirmation and showed ‘substantial’ inter-rater reliability. The ADDTC and VCI criteria for VaD had good specificity (88%) and sensitivity (75%), but only for one rater. The DSM-IV and NINCDS-AIREN criteria for VaD showed poor validity and inter-rater reliability. We conclude that the forced use of decision trees through a computerized system enhances the accuracy of the clinical diagnoses of dementia.

Association of the androgen receptor CAG repeat polymorphism with Alzheimer's disease in men

We examined the CAG repeat polymorphism in exon 1 of the androgen receptor (AR) in an Oxford cohort of 150 cases (101 men) of definite or probable Alzheimers disease (AD) and 190 elderly controls (140 men). We found that short alleles (< or = 20 CAG repeats) were associated with AD (adjusted odds ratio = 2.5, 95% confidence intervals: 1.2-5.0) in men, but not in women. This association appeared stronger in early-onset AD (< 65 years). We conclude that this AR polymorphism is of potential relevance to the risk of AD in men.

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.

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.

Cerebrospinal Fluid Biomarkers Distinguish Postmortem-Confirmed Alzheimer's Disease from Other Dementias and Healthy Controls in the OPTIMA Cohort

Cerebrospinal fluid (CSF) amyloid-β (Aβ) and tau have been studied as markers of Alzheimers disease (AD). Combined Aβ42 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 Aβ42 and higher t-tau, p-tau, t-tau/Aβ42, and t-tau/Aβ40 compared to CTLs, with MCI intermediate. CTL and MCI participants who progressed to AD demonstrated more AD-like profiles. Aβ40, sAβPPα, and sAβPPβ were lower in AD compared to CTL. High-level discriminators of AD from CTL were t-tau/Aβ40 (AUROC 0.986, sens/spec of 92%/94%), p-tau/Aβ42 (AUROC 0.972, sens/spec of 94%/90%), and Aβ42 (AUROC 0.941, sens/spec of 88%). For discriminating AD from ODS, p-tau/Aβ42 demonstrated sens/spec of 88%/100% (95%/86% at the AD versus CTL cutoff) and Aβ42 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 Aβ 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.

HIV-associated neurocognitive disorders: Antiretroviral regimen, central nervous system penetration effectiveness, and cognitive outcomes

BACKGROUND The human immunodeficiency virus (HIV) can give rise to a spectrum of neuropsychological impairments known collectively as HIV-associated neurocognitive disorders (HAND). Although antiretroviral therapy (ART) has reduced the incidence of HIV dementia, the prevalence of milder forms of HAND has increased. It has been postulated that incomplete central nervous system (CNS) viral suppression or potential drug toxicity, both of which could be related to the CNS penetration effectiveness (CPE) of ART regimens, may contribute to this phenomenon. OBJECTIVE This study compared cognitive outcomes in clade C-infected HIV patients in South Africa treated for 1 year with ART regimens with differing CPE scores. METHODS We assessed 111 HIV-positive patients with varying levels of cognitive function at baseline (pre-ART) and then a year later. A neuropsychological battery was administered at both visits to derive global deficit scores. ART regimen data were collected at the follow-up visit. Some participants remained ART-naïve during this period, thus providing a non-treatment control group. RESULTS Significantly more ART recipients maintained or improved cognitive function compared with patients not on ART (p=0.017). There was no significant difference in cognitive outcomes between higher and lower CPE regimen groups (p=0.473). CONCLUSIONS ART preserves or improves cognition in HIV-infected patients after 1 year, irrespective of the regimens CPE. South Africas current low CPE-scored first-line regimen performed as well as higher CPE-scored regimens. These findings are reassuring for South Africa, but larger, longer-term studies would be more definitive.

Dementia in rural South Africa: A pressing need for epidemiological studies.

Dementia is one of the biggest challenges to society today, with an increasing prevalence as the global population ages. The 2013 worldwide estimate was 44 million persons with dementia, with predictions that about 70% of new cases will occur in low- and middle-income countries (LMICs). With negligible published prevalence data for South Africa, little is known about the impact of dementia, especially in poorer communities. Successful community dementia prevalence screening has been conducted in ten LMICs worldwide, using a one-step diagnostic procedure developed in the UK by the 10/66 group. The prevalence of dementia needs to be established locally across various communities. Awareness, education, training and skilled resources for diagnosis and care are minimal. Only once prevalence data and an assessment of care needs are available will it be possible to propose improving health services for the growing aged population, especially those with dementia in poorer rural communities.

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.

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 Alzheimers 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.