Zanjbeel Mahmood

Combined effects of HIV and marijuana use on neurocognitive functioning and immune status

ABSTRACT The current study examined the independent and combined effects of HIV and marijuana (MJ) use (no use, light use, and moderate-to-heavy use) on neurocognitive functioning among a convenience sample of HIV-positive (HIV+) and HIV-negative (HIV–) individuals recruited from HIV community care clinics and advertisements in the Greater Los Angeles area. MJ users consisted of individuals who reported regular use of MJ for at least 12 months, with last reported use within the past month. Participants included 89 HIV+ (n = 55) and HIV– (n = 34) individuals who were grouped into non-users, light users, and moderate-to-heavy users based on self-reported MJ use. Participants were administered a brief cognitive test battery and underwent laboratory testing for CD4 count and viral load. HIV+ individuals demonstrated lower performance on neurocognitive testing than controls, and moderate-to-heavy MJ users performed more poorly on neurocognitive testing than light users or non-users. Moderate-to-heavy HIV+ users performed significantly lower on learning/memory than HIV– moderate-to-heavy users (MD = −8.34; 95% CI: −16.11 to −0.56) as well as all other comparison groups. In the domain of verbal fluency, HIV+ light users outperformed HIV– light users (MD = 7.28; 95% CI: 1.62–12.39), but no HIV group differences were observed at other MJ use levels. HIV+ MJ users demonstrated lower viral load (MD = −0.58; 95% CI: −1.30 to 0.14) and higher CD4 count than non-users (MD = 137.67; 95% CI: 9.48–265.85). The current study findings extend the literature by demonstrating the complex relationship between HIV status and MJ use on neurocognitive and clinical outcomes.

An Alzheimer's Disease Genetic Risk Score Predicts Longitudinal Thinning of Hippocampal Complex Subregions in Healthy Older Adults.

Abstract Variants at 21 genetic loci have been associated with an increased risk for Alzheimer’s disease (AD). An important unresolved question is whether multiple genetic risk factors can be combined to increase the power to detect changes in neuroimaging biomarkers for AD. We acquired high-resolution structural images of the hippocampus in 66 healthy, older human subjects. For 45 of these subjects, longitudinal 2-year follow-up data were also available. We calculated an additive AD genetic risk score for each participant and contrasted this with a weighted risk score (WRS) approach. Each score included APOE (apolipoprotein E), CLU (clusterin), PICALM (phosphatidylinositol binding clathrin assembly protein), and family history of AD. Both unweighted risk score (URS) and WRS correlated strongly with the percentage change in thickness across the whole hippocampal complex (URS: r = −0.40; p = 0.003; WRS: r = −0.25, p = 0.048), driven by a strong relationship to entorhinal cortex thinning (URS: r = −0.35; p = 0.009; WRS: r = −0.35, p = 0.009). By contrast, at baseline the risk scores showed no relationship to thickness in any hippocampal complex subregion. These results provide compelling evidence that polygenic AD risk scores may be especially sensitive to structural change over time in regions affected early in AD, like the hippocampus and adjacent entorhinal cortex. This work also supports the paradigm of studying genetic risk for disease in healthy volunteers. Together, these findings will inform clinical trial design by supporting the idea that genetic prescreening in healthy control subjects can be useful to maximize the ability to detect an effect on a longitudinal neuroimaging endpoint, like hippocampal complex cortical thickness.

Marijuana effects on changes in brain structure and cognitive function among HIV+ and HIV- adults.

BACKGROUND The current study examined the independent and interactive effects of HIV and marijuana (MJ) use on brain structure and cognitive function among a sample of HIV-positive (HIV+) and HIV-negative (HIV-) individuals. METHODS Participants (HIV+, n=48; HIV-, n=29) individuals underwent cognitive testing, questionnaires about substance use, and brain MRI. The HIV+ group was clinically stable based upon current plasma CD4 count, 50% had undetectable viral load (i.e.,<20 copies/mL), and all were on a stable regimen of cART. RESULTS For HIV+ and HIV- participants, higher levels of MJ use were associated with smaller volumes in the entorhinal cortex and fusiform gyrus. HIV status (but not MJ use) was associated with cingulate thickness, such that HIV+ participants evidenced smaller thickness of the cingulate, as compared to HIV- controls. Regarding neurocognitive functioning, there was a HIV*MJ interactive effect on global cognition, such that when the amount of MJ use was less than 1.43g per week, the HIV- group displayed significantly better neurocognitive performance than the HIV+ group (t=3.14, p=0.002). However, when MJ use reached 1.43g per week, there were no significant HIV group differences in global cognitive performance (t=1.39, p=0.168). CONCLUSIONS Our results show independent and interactive effects of HIV and MJ on brain structure and cognition. However, our results do not support that HIV+ MJ users are at greater risk for adverse brain or cognitive outcomes compared to HIV- MJ users.

Hippocampal thinning linked to longer TOMM40 poly-T variant lengths in the absence of the APOE ε4 variant

The translocase of outer mitochondrial membrane 40 (TOMM40), which lies in linkage disequilibrium with apolipoprotein E (APOE), has received attention more recently as a promising gene in Alzheimers disease (AD) risk. TOMM40 influences AD pathology through mitochondrial neurotoxicity, and the medial temporal lobe (MTL) is the most likely brain region for identifying early manifestations of AD‐related morphology changes.

Differential relationships between social adversity and depressive symptoms by HIV status and racial/ethnic identity.

Objective: Historically marginalized groups are likely to be exposed to social adversity, which predicts important mental health outcomes (e.g., depression). Despite the well-established relationship between adversity and poor health, few studies have examined how adversity differentially predicts mental health among people living with multiple, co-occurring marginalized identities or statuses. The current study fills this gap by examining whether relationships between social adversity and depressive symptoms differed between those living with or without a stigmatized disease (i.e., HIV) and/or marginalized racial/ethnic identity (i.e., African American). Method: A community sample of men and women (N = 149) completed questionnaires assessing demographics and depressive symptoms. Additionally, a composite index of social adversity was derived from measures of perceived discrimination, socioeconomic status, financial restriction to receiving medical care, and perceived neighborhood characteristics. Multiple regression was used to test whether relationships between adversity and depressive symptoms differed as a function of HIV status and racial/ethnic identity. Results: A significant 3-way interaction between social adversity, HIV status, and racial/ethnic identity indicated that there was a direct relationship between adversity and depressive symptoms for HIV-positive (HIV+) African Americans but not for HIV-negative (HIV–) African Americans, HIV+ Caucasians, or HIV– Caucasians. Further, HIV+ African Americans evidenced a significantly greater relationship between adversity and depressive symptoms compared with HIV– African Americans, but not compared with other groups. Conclusions: The findings suggest that HIV+ African Americans may be at risk for higher depressive symptoms amid adversity, highlighting the importance of evaluating intersectional identities/statuses in the context of mental health.

Longitudinal Intra-Individual Variability in Neuropsychological Performance Relates to White Matter Changes in HIV.

Objectives: Recent studies suggest that intraindividual variability (IIV) of neuropsychological performance may be sensitive to HIV-associated neurologic compromise. IIV may be particularly dependent upon the integrity of frontal-subcortical systems, and therefore may be a meaningful phenotype in HIV. We examined the relationship between change in IIV and white matter integrity among HIV seropositive (HIV+) and HIV seronegative (HIV−) individuals. Method: The sample consisted of 38 HIV+ participants and 26 HIV− control participants who underwent neuroimaging and a neuropsychological evaluation at baseline and at 2-year follow-up evaluation. Results: Among HIV+ participants, increases in IIV (greater dispersion) were related to lower fractional anisotropy (FA) values in the anterior thalamic radiations (ATR) and the superior longitudinal fasciculus (SLF). Changes in mean-level global cognitive functioning were not significantly related to white matter integrity. Additionally, there was a significant Group × IIV interaction effect in the SLF demonstrating that the relationship between IIV and white matter integrity was specific to HIV. Conclusions: Overall, findings suggest that IIV may be more sensitive, relative to mean-level global cognitive functioning, in the detection of neurologic compromise among HIV+ individuals.

CEREBROVASCULAR RISK AND HIPPOCAMPAL THICKNESS IN HEALTHY MIDDLE-AGED AND OLDER ADULTS WITHOUT DEMENTIA

to perform a cross-cultural adaptation of a Brazilian version of Cognitive Function Instrument (CFI). It is an instrument developed by the Alzheimer’s Disease Cooperative Study Group for evaluation of Subjective Cognitive Decline. The project consisted of a cross-sectional study where the original instrument in English was translated and adapted into the Portuguese language. The sample consisted of individuals recruited from among the patients’ caregiver from the Cognitive Neurology outpatient clinic of the Medical School of University of S~ao Paulo.Results:This transcultural translation and adaptation process consisted of six stages: initial translation by two translators, synthesis, back translation by two others translators, review by a committee of experts and pretesting of a draft. The preliminary version was applied in 37 individuals. The mean age was 63.5 years with an average of 10.4 years of schooling. In final review, decisions taken by the committee of experts sought to obtain semantic, idiomatic, experimental and conceptual equivalence between the source and the translated version. Throughout the process, all problems found were solved to ensure the quality of the instrument and its appropriateness to the target population. Conclusions:We elaborated a translated and adapted version of an instrument that can be applied to evaluate Subjective Cognitive Decline in the Brazilian population. This instrument is being validated in a cohort of normal elderly without and with subjective cognitive decline and compared with biomarkers of Alzheimer’s disease.

Vascular and genetic risk factors influence hippocampal thickness

P1⁄40.00153). According to the cognitive impairment level, a moderate positive correlation was observed in the MCI level (FAST stage: 2-3) (r1⁄40.310, t1⁄42.62, P1⁄40.0109), but no correlation was noted in the dementia level ( FAST stage 4) (r1⁄4-0.0771, t1⁄4-0.604, P1⁄40.548). Conclusions: Since the results of this study indicated that the Z score tends to increase with the FAST stage, the degree of atrophy of the medial temporal region is considered to increase with the severity of Alzheimer’s disease. While the Z score increased with the FAST stage in the MCI group, no correlation was observed between the FAST stage and Z score in the Alzheimer’s disease group. Therefore, the VSRAD was suggested to be useful as an index for the follow-up of patients with MCI.

Weighted and unweighted genetic risk scores are associated with longitudinal cortical thinning of hippocampal complex subregions

Background:To date, 21 genetic loci have been identified where specific variants increase an individual’s risk for sporadic, late-onset Alzheimer Disease (AD). An important unresolved question is whether or not polygenic risk scores that use combinations of these risk loci increase power to detect changes in neuroimaging endophenotypes for AD. Furthermore, the optimal method to create polygenic risk scores is an active field of research. Methods: In a preliminary study, we acquired high-resolution structural images of the hippocampus in 47 healthy, older subjects. For 14 of these subjects, longitudinal two-year follow-up datawere also available. Unweighted andweighted genetic AD-risk scores were calculated for each subject. The unweighted risk score (URS)was the sumof family history ofAD (0 if negative history or 1 if positive history),APOE4 alleles (0,1, or 2), CLU risk alleles (0,1, or 2) and PICALM risk alleles (0,1, or 2). The weighted risk scores (WRS) usedpublishedodds ratios (OR) toweight the relative contribution of these risk factors before summing: positive family history OR1⁄42, APOE4 OR1⁄43, CLU minor allele OR1⁄40.9, PICALM minor allele OR1⁄40.9. Results: For the cross-sectional cohort, both URS and WRS showed no relationship to thickness in any hippocampal subregion. For the longitudinal cohort, URS and WRS correlated strongly to percent change in thickness across the whole hippocampus (URS r1⁄4-0.85, p1⁄40.0001; WRS r1⁄4-0.63, p1⁄40.015), driven by strong relationships in the entorhinal cortex (URS r1⁄4-0.66, p1⁄40.01; WRS r1⁄4-0.73, p1⁄40.003) and CA23/dentate gyrus (URS r1⁄4-0.66, p1⁄40.01; WRS r1⁄4-0.65, p1⁄40.01), two anterior subregions. In a multiple regression including age and sex as predictors, models with URS (beta1⁄4-2.16, p1⁄40.0003) and WRS (beta1⁄47.01, p1⁄40.014) predicting percent change in thickness across the whole hippocampus were significant (URS model p1⁄40.009; WRS model p1⁄40.03). Conclusions: These results provide compelling evidence that polygenic AD-risk scores may be especially sensitive to structural change over time in regions affected early in AD, like the hippocampus. Our findings also show that the relationships between our polygenic risk score and hippocampal thinning are not mediated by weighting risk score components with published ORs.