Valproic acid is associated with cognitive decline in HIV-infected individuals: a clinical observational study

BACKGROUND: Valproic acid (VPA) is often used to control pain in HIV-related neuropathy. However, the effect of VPA on cognitive functions in advanced HIV-infected individuals is largely unknown. A recent study would suggest that it may have a neuroprotective effect, the doses used were low and the observation period short. METHODS: We used a well studied HIV-infected cohort assessed for a median of 15 (range 6–27 months) to determine whether individuals who were receiving VPA showed any cognitive benefits. Multiple regression procedures allowed us to control for the effects of HAART and HIV disease status as well as numbers of visits and variation in VPA intake over-time. RESULTS: We found a negative effect of VPA (mean dose of 850 mg/d for 18 months on average; range 6–27 months) on cognitive performance in eight advanced HIV-infected individuals compared to 32 advanced HIV-infected individuals on no VPA who had comparable neuropsychological performance at baseline. Control for plasma HIV viral load provided similar results. CONCLUSION: Our results suggest that further studies of VPA in advanced HIV-infection should cautiously include high doses over prolonged periods of at least 18 months in order to more accurately determine whether the posited neuroprotective benefit of VPA still occurs or whether it is replaced by toxicity

Assessment of Neurocognitive Functions, Olfaction, Taste, Mental, and Psychosocial Health in COVID-19 in Adults: Recommendations for Harmonization of Research and Implications for Clinical Practice

Assessment; COVID-19; Guidelines; Neuropsychological functions.Avaluació; COVID 19; Directrius; Funcions neuropsicològiques.Evaluación; COVID-19; Pautas; Funciones neuropsicológicasObjective: To propose a set of internationally harmonized procedures and methods for assessing neurocognitive functions, smell, taste, mental, and psychosocial health, and other factors in adults formally diagnosed with COVID-19 (confirmed as SARS-CoV-2 + WHO definition). Methods: We formed an international and cross-disciplinary NeuroCOVID Neuropsychology Taskforce in April 2020. Seven criteria were used to guide the selection of the recommendations' methods and procedures: (i) Relevance to all COVID-19 illness stages and longitudinal study design; (ii) Standard, cross-culturally valid or widely available instruments; (iii) Coverage of both direct and indirect causes of COVID-19-associated neurological and psychiatric symptoms; (iv) Control of factors specifically pertinent to COVID-19 that may affect neuropsychological performance; (v) Flexibility of administration (telehealth, computerized, remote/online, face to face); (vi) Harmonization for facilitating international research; (vii) Ease of translation to clinical practice. Results: The three proposed levels of harmonization include a screening strategy with telehealth option, a medium-size computerized assessment with an online/remote option, and a comprehensive evaluation with flexible administration. The context in which each harmonization level might be used is described. Issues of assessment timelines, guidance for home/remote assessment to support data fidelity and telehealth considerations, cross-cultural adequacy, norms, and impairment definitions are also described. Conclusions: The proposed recommendations provide rationale and methodological guidance for neuropsychological research studies and clinical assessment in adults with COVID-19. We expect that the use of the recommendations will facilitate data harmonization and global research. Research implementing the recommendations will be crucial to determine their acceptability, usability, and validity

Acceptability and usability of computerized cognitive assessment among Australian Indigenous residents of the Torres Strait Islands

Objectives: This cross-sectional study aimed to investigate the acceptability and usability of the Cogstate Brief Battery (CBB) in a community-based sample of Australian Indigenous people from the Torres Strait region, based on a user experience framework of human-computer interaction. Methods: Two-hundred community participants completed the four subtests of the CBB on an iPad platform, during a free adult health check on two islands in the region, between October and December 2016. Acceptability was defined as completing the learning trial of a task and usability as continuing a task through to completion, determined by examiner acumen and internal Cogstate completion and integrity criteria. These were combined into a single dichotomous completion measure for logistic regression analyses. Performance-measured as reaction times and accuracy of responses-was analyzed using linear regression analyses. Results: CBB completion ranged from 82.0% to 91.5% across the four tasks and the odds of completing decreased with age. After adjusting for age, iPad/tablet familiarity increased the odds of completion for all tasks while level of education and employment increased the odds for some tasks only. These variables accounted for 18.0%-23.8% of the variance in reaction times on speeded tasks. Age and education had the most effect, although semipartial correlations were modest. Conclusions: When administered in a health-screening context, the acceptability and usability of the CBB were greatest in young- to middle-aged participants with some education and iPad/tablet experience. Older and more vulnerable participants may have benefited from additional time and practice on the CBB prior to administration

Using health check data to investigate cognitive function in Aboriginal and Torres Strait Islanders living with diabetes in the Torres Strait, Australia

Background: Type 2 Diabetes (T2DM) has a subtle deleterious effect on cognition and imposes a higher lifetime risk of cognitive impairment and dementia. In populations where both T2DM and dementia are highly prevalent, understanding more about the early effects of T2DM on cognition may provide insights into the lifetime risks of this disease. Methods: In 2016, 186 Australian Aboriginal and/or Torres Strait Islander residents of the Torres Strait (54% female, mean age =8.9 years, SD =15.9, range =15–74) participated in a community health check. The effect of diabetes (Type 1 or Type 2) on speed of thinking and working memory was assessed with the Cogstate Brief Battery (CBB) during the health check. Results: One third of participants had diabetes (n = 56, 30.1%). After adjusting for age, education and previous iPad/Tablet experience, participants with diabetes had a small, yet significant reduction in accuracy on the One Back working memory task (β = −.076, p =.010, r2 =.042). The effect was most pronounced among participants with diabetes aged 20–49 years (n = 20), who also had evidence of poorer diabetes control (eg HbA1c% ≥6.5, 76.6%), relative to participants with diabetes aged 50 years and over (n = 31) (HbA1c% ≥6.5, 32.0%, p =.005). Conclusions: Early and subtle decrements in working memory may be a potential complication of diabetes among Aboriginal and Torres Strait Islander residents of the Torres Strait. Several potentially influential variables were not captured in this study (eg medication and diabetes duration). Greater preventative health resources are required for this population, particularly given the emerging elevated dementia rates linked to chronic disease

Central nervous system antiretroviral efficacy in HIV infection: a qualitative and quantitative review and implications for future research

<p>Abstract</p> <p>Background</p> <p>There is conflicting information as to whether antiretroviral drugs with better central nervous system (CNS) penetration (neuroHAART) assist in improving neurocognitive function and suppressing cerebrospinal fluid (CSF) HIV RNA. The current review aims to better synthesise existing literature by using an innovative two-phase review approach (qualitative and quantitative) to overcome methodological differences between studies.</p> <p>Methods</p> <p>Sixteen studies, all observational, were identified using a standard citation search. They fulfilled the following inclusion criteria: conducted in the HAART era; sample size > 10; treatment effect involved more than one antiretroviral and none had a retrospective design. The qualitative phase of review of these studies consisted of (i) a blind assessment rating studies on features such as sample size, statistical methods and definitions of neuroHAART, and (ii) a non-blind assessment of the sensitivity of the neuropsychological methods to HIV-associated neurocognitive disorder (HAND). During quantitative evaluation we assessed the statistical power of studies, which achieved a high rating in the qualitative analysis. The objective of the power analysis was to determine the studies ability to assess their proposed research aims.</p> <p>Results</p> <p>After studies with at least three limitations were excluded in the qualitative phase, six studies remained. All six found a positive effect of neuroHAART on neurocognitive function or CSF HIV suppression. Of these six studies, only two had statistical power of at least 80%.</p> <p>Conclusions</p> <p>Studies assessed as using more rigorous methods found that neuroHAART was effective in improving neurocognitive function and decreasing CSF viral load, but only two of those studies were adequately statistically powered. Because all of these studies were observational, they represent a less compelling evidence base than randomised control trials for assessing treatment effect. Therefore, large randomised trials are needed to determine the robustness of any neuroHAART effect. However, such trials must be longitudinal, include the full spectrum of HAND, ideally carefully control for co-morbidities, and be based on optimal neuropsychology methods.</p

The comorbidity of depression and neurocognitive disorder in persons with HIV infection: call for investigation and treatment

Depression and neurocognitive disorder continue to be the major neuropsychiatric disorders affecting persons with HIV (PWH). The prevalence of major depressive disorder is two to fourfold higher among PWH than the general population (∼6.7%). Prevalence estimates of neurocognitive disorder among PWH range from 25 to over 47% – depending upon the definition used (which is currently evolving), the size of the test battery employed, and the demographic and HIV disease characteristics of the participants included, such as age range and sex distribution. Both major depressive disorder and neurocognitive disorder also result in substantial morbidity and premature mortality. However, though anticipated to be relatively common, the comorbidity of these two disorders in PWH has not been formally studied. This is partly due to the clinical overlap of the neurocognitive symptoms of these two disorders. Both also share neurobehavioral aspects — particularly apathy — as well as an increased risk for non-adherence to antiretroviral therapy. Shared pathophysiological mechanisms potentially explain these intersecting phenotypes, including neuroinflammatory, vascular, and microbiomic, as well as neuroendocrine/neurotransmitter dynamic mechanisms. Treatment of either disorder affects the other with respect to symptom reduction as well as medication toxicity. We present a unified model for the comorbidity based upon deficits in dopaminergic transmission that occur in both major depressive disorder and HIV-associated neurocognitive disorder. Specific treatments for the comorbidity that decrease neuroinflammation and/or restore associated deficits in dopaminergic transmission may be indicated and merit study

The Influence of HLA on HIV-Associated Neurocognitive Impairment in Anhui, China

HLA-DR*04 was identified as a predictor of HIV-Associated neurocognitive disorder (HAND), low CD4 T-cell responses to HIV, and low plasma HIV RNA levels in a U.S. cohort. We hypothesized that low CD4 T-cell activation leads to poor immune control of HIV in the CNS, predisposing to HAND, but also provided fewer target (activated CD4 T-cells) for HIV replication. To assess the consistency of these HLA Class II associations in a new cohort and extend analysis to HLA Class I, HLA types, neurocognitive, and virologic status were examined in a cohort of former plasma donors in China.178 HIV infected individuals in Anhui China, were HLA typed and underwent neurocognitive evaluations (using locally standardized norms), neuromedical, treatment and virologic assessments at baseline and at 12 months.HLA DR*04 was associated with a higher rate of baseline neurocognitive impairment (p = 0.04), neurocognitive decline (p = 0.04), and lower levels of HIV RNA in plasma (p = 0.05). HLA Class I alleles (B*27,57,58,A*03,33) that specify a CD8 T-cell response to conserved HIV sequences were neuroprotective, associated with less impairment at baseline (p = 0.037), at month 012 (p = 0.013) and less neurocognitive decline (p = 0.023) in the interval. Consistent with the theory that effective CD8 T-cell responses require CD4 T-cell support, the HLA DR*04 allele reduced the neuroprotective effect of the Class I alleles. The presence of HLA-DR*04 and the Alzheimer associated allele ApoE4 in the same individual had a synergistic negative effect on cognition (p = 0.003).Despite major background differences between U.S. and Anhui China cohorts, HLA DR*04 predicted neurocognitive impairment and lower plasma HIV RNA levels in both populations. HLA Class I alleles associated with CD8 T-cell control of HIV were associated with protection from HAND, but protection was reduced in the presence of HLA-DR*04

APOE ε4 moderates abnormal CSF-abeta-42 levels, while neurocognitive impairment is associated with abnormal CSF tau levels in HIV+ individuals – a cross-sectional observational study

Background: Cerebrospinal fluid (CSF) biomarkers Aβ1-42, t-tau and p-tau have a characteristic pattern in Alzheimer’s Disease (AD). Their roles in HIV-associated neurocognitive disorder (HAND) remains unclear. Methods: Adults with chronic treated HIV disease were recruited (n = 43, aged 56.7 ± 7.9; 32% aged 60+; median HIV duration 20 years, \u3e95% plasma and CSF HIV RNA \u3c50 cp/mL, on cART for a median 24 months). All underwent standard neuropsychological testing (61% had HAND), APOE genotyping (30.9% carried APOE ε4 and 7.1% were ε4 homozygotes) and a lumbar puncture. Concentrations of Aβ1-42, t-tau and p-tau were assessed in the CSF using commercial ELISAs. Current neurocognitive status was defined using the continuous Global Deficit Score, which grades impairment in clinically relevant categories. History of HAND was recorded. Univariate correlations informed multivariate models, which were corrected for nadir CD4-T cell counts and HIV duration. Results: Carriage of APOE ε4 predicted markedly lower levels of CSF Aβ1-42 in univariate (r = -.50; p = .001) and multivariate analyses (R2 = .25; p \u3c .0003). Greater levels of neurocognitive impairment were associated with higher CSF levels of p-tau in univariate analyses (r = .32; p = .03) and multivariate analyses (R2 = .10; p = .03). AD risk prediction cut-offs incorporating all three CSF biomarkers suggested that 12.5% of participants had a high risk for AD. Having a CSF-AD like profile was more frequent in those with current (p = .05) and past HIV-associated dementia (p = .03). Conclusions: Similarly to larger studies, APOE ε4 genotype was not directly associated with HAND, but moderated CSF levels of Aβ1-42 in a minority of participants. In the majority of participants, increased CSF p-tau levels were associated with current neurocognitive impairment. Combined CSF biomarker risk for AD in the current HIV+ sample is more than 10 times greater than in the Australian population of the same age. Larger prospective studies are warranted

HIV-associated neurocognitive disorder in Australia: a case of a high-functioning and optimally treated cohort and implications for international neuroHIV research

Abstract The Australian HIV-infected (HIV+) population is largely comprised of high-functioning men who have sex with men (MSM). Like other English-speaking countries, Australia mostly relies on US neuropsychological normative standards to detect and determine the prevalence of neurological disorders. Whether the US neuropsychological (NP) normative standards are appropriate in Australian HIV+ MSM has not been established. Ninety virally suppressed HIV+ and 49 HIV-uninfected (HIV−) men (respectively 86 and 85 % self-reported MSM; mean age 54 and 56 years, mean premorbid verbal IQ estimate 110 and 111) undertook standard NP testing. The raw neuropsychological data were transformed using the following: (1) US standards as uncorrected scaled scores and demographically corrected T scores (US norms); and (2) z scores (without demographic corrections) derived from Australian comparison group scaled scores (local norms). To determine HIV-associated neurocognitive disorder prevalence, we used a standard definition of impairment based upon a battery-wide summary score: the global deficit score (GDS). Impairment classification (GDS≥0.5) based on the local norms was best at discriminating between the two groups (HIV− = 14.3 % vs. HIV+ = 53.3 %; p&lt;0.0001). This definition was significantly associated with age. Impairment classification based on the US norms yielded much lower impairment rate regardless of the HIV status (HIV−=4.1 % vs. HIV+=14.7 %; p= 0.05), but was associated with historical AIDS, and not age. Both types of summary scores were associated with reduced independence in activities of daily living (p≤ 0.03). Accurate neuropsychological classifications of high (or low) functioning individuals may need country-specific norms that correct for performancebased (e.g., reading) estimates of premorbid cognition in addition to the traditional demographic factors