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Background: Mild cognitive difficulties and progressive brain atrophy are observed in older people living with HIV (PLWH) despite persistent viral suppression. Whether cerebrovascular disease (CVD) risk factors and white matter hyperintensity (WMH) volume correspond to the observed progressive brain atrophy is not well understood. Methods:Longitudinal structural brain atrophy rates and WMH volume were examined among 57 HIV-infected participants and 40 demographically similar HIV-uninfected controls over an average (SD) of 3.4 (1.7) years. We investigated associations between CVD burden (presence of diabetes, hypertension, hyperlipidemia, obesity, smoking history, and atrial fibrillation) and WMH with atrophy over time. Results:The mean (SD) age was 64.8 (4.3) years for PLWH and 66.4 (3.2) years for controls. Participants and controls were similar in age and sex (P . 0.05). PLWH were persistently suppressed (VL ,375 copies/mL with 93% ,75 copies/mL). The total number of CVD risk factors did not associate with atrophy rates in any regions of interests examined; however, body mass index independently associated with progressive atrophy in the right precentral gyrus (b = 20.30; P = 0.023), parietal lobe (b = 20.28; P = 0.030), and frontal lobe atrophy (b = 20.27; P = 0.026) of the HIV-infected group. No associations were found in the HIV-uninfected group. In both groups, baseline WMH was associated with progressive atrophy rates bilaterally in the parietal gray in the HIV-infected group (b = 20.30; P = 0.034) and the HIV-uninfected participants (b = 20.37; P = 0.033).Conclusions: Body mass index and WMH are associated with atrophy in selective brain regions. However, CVD burden seems to partially contribute to progressive brain atrophy in older individuals regardless of HIV status, with similar effect sizes. Thus, CVD alone is unlikely to explain accelerated atrophy rates observed in virally suppressed PLWH. In older individuals, addressing modifiable CVD risk factors remains important to optimize brain health.

Background: clinically relevant methods to identify individuals at risk for impaired daily living abilities secondary to neurocognitive impairment (ADLs) remain elusive. This is especially true for complex clinical conditions such as HIV-Associated Neurocognitive Disorders (HAND). The aim of this study was to identify novel and modifiable factors that have potential to improve diagnostic accuracy of ADL risk, with the long-term goal of guiding future interventions to minimize ADL disruption. Methods: study participants included 79 people with HIV (PWH; mean age = 63; range = 55À80) enrolled in neuroHIV studies at University California San Francisco (UCSF) between 2016 and 2019. All participants were virally suppressed and exhibited objective evidence of neurocognitive impairment. ADL status was defined as either normative (n = 39) or at risk (n = 40) based on a task-based protocol. Gradient boosted multivariate regression (GBM) was employed to identify the combination of variables that differentiated ADL subgroup classification. Predictor variables included demographic factors, HIV disease severity indices, brain white matter integrity quantified using diffusion tensor imaging, cognitive test performance, and health co-morbidities. Model performance was examined using average Area Under the Curve (AUC) with repeated fivefold cross validation. Findings: the univariate GBM yielded an average AUC of 83% using Wide Range Achievement test 4 (WRAT-4) reading score, self-reported thought confusion and difficulty reading, radial diffusivity (RD) in the left external capsule, fractional anisotropy (FA) in the left cingulate gyrus, and Stroop performance. The model allowing for two-way interactions modestly improved classification performance (AUC of 88%) and revealed synergies between race, reading ability, cognitive performance, and neuroimaging metrics in the genu and uncinate fasciculus. Conversion of Neuropsychological Assessment Battery Daily Living Module (NAB-DLM) performance from raw scores into T scores amplified differences between White and non-White study participants. Interpretation: demographic and sociocultural factors are critical determinants of ADL risk status among older PWH who meet diagnostic criteria for neurocognitive impairment. Task-based ADL assessment that relies heavily on reading proficiency may artificially inflate the frequency/severity of ADL impairment among diverse clinical populations. Culturally relevant measures of ADL status are needed for individuals with acquired neurocognitive disorders, including HAND.

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BackgroundCerebral blood flow (CBF) is disrupted in Alzheimer’s disease (AD) and associated with worse cognition, including episodic memory performance. Sex differences have been noted in both CBF and memory performance in AD; women demonstrate higher global CBF and memory performance than men. However, the effect of sex on the association between CBF and memory performance has not been explored. This study examined whether there were sex differences in the association between memory performance and CBF in AD‐related regions in typically aging older adults.MethodThe study included 119 functionally intact (CDR=0) older adults from the UCSF Hillblom Aging Network (mean age 74.9 (5.7), 51.2% females) who completed a cognitive assessment with brain MRI including T1‐weighted and arterial spin labeling (ASL) in hippocampal and precentral gyrus (as control) regions. Episodic memory was assessed by the California Verbal Learning Test and Benson figure delayed recall. Mean Z‐scores estimated a memory composite score. Memory composites were the dependent variable in regression models testing the interaction between regional ASL and sex as predictors, and age, education, APOE‐ε4, hippocampal volume, and vascular burden composite as covariates.ResultThere were no significant sex differences in levels of hippocampal CBF, but females performed better on the memory composite (p<0.001) than males after adjustment for age and education. We found that sex modified the association between hippocampal CBF and memory performance (figure 1) (p=0.04). Specifically, the positive association between hippocampal CBF and memory performances was stronger in men compared to women. This interaction remained significant after further adjusting for APOE‐ε4, hippocampal volume, and vascular burden. There was no significant sex by CBF interaction on memory performance when examining precentral CBF (p=0.79).ConclusionOur result suggests that sex modifies the association between memory performance and perfusion in brain regions vulnerable to pathological changes in preclinical AD. Specifically, greater hippocampal CBF is positively associated with memory performance in men but not women. Men may benefit more from increased blood flow, possibly reflecting vascular integrity, in hippocampal regions in memory performance than women. This work highlights mechanisms that may be differentially vulnerable by sex differences and inform risk for neurodegenerative diseases.

ImportancePlasma phosphorylated tau217 (p-tau217), a biomarker of Alzheimer disease (AD), is of special interest in corticobasal syndrome (CBS) because autopsy studies have revealed AD is the driving neuropathology in up to 40% of cases. This differentiates CBS from other 4-repeat tauopathy (4RT)–associated syndromes, such as progressive supranuclear palsy Richardson syndrome (PSP-RS) and nonfluent primary progressive aphasia (nfvPPA), where underlying frontotemporal lobar degeneration (FTLD) is typically the primary neuropathology.ObjectiveTo validate plasma p-tau217 against positron emission tomography (PET) in 4RT-associated syndromes, especially CBS.Design, Setting, and ParticipantsThis multicohort study with 6, 12, and 24-month follow-up recruited adult participants between January 2011 and September 2020 from 8 tertiary care centers in the 4RT Neuroimaging Initiative (4RTNI). All participants with CBS (n = 113), PSP-RS (n = 121), and nfvPPA (n = 39) were included; other diagnoses were excluded due to rarity (n = 29). Individuals with PET-confirmed AD (n = 54) and PET-negative cognitively normal control individuals (n = 59) were evaluated at University of California San Francisco. Operators were blinded to the cohort.Main Outcome and MeasuresPlasma p-tau217, measured by Meso Scale Discovery electrochemiluminescence, was validated against amyloid-β (Aβ) and flortaucipir (FTP) PET. Imaging analyses used voxel-based morphometry and bayesian linear mixed-effects modeling. Clinical biomarker associations were evaluated using longitudinal mixed-effect modeling.ResultsOf 386 participants, 199 (52%) were female, and the mean (SD) age was 68 (8) years. Plasma p-tau217 was elevated in patients with CBS with positive Aβ PET results (mean [SD], 0.57 [0.43] pg/mL) or FTP PET (mean [SD], 0.75 [0.30] pg/mL) to concentrations comparable to control individuals with AD (mean [SD], 0.72 [0.37]), whereas PSP-RS and nfvPPA showed no increase relative to control. Within CBS, p-tau217 had excellent diagnostic performance with area under the receiver operating characteristic curve (AUC) for Aβ PET of 0.87 (95% CI, 0.76-0.98; P &amp;lt; .001) and FTP PET of 0.93 (95% CI, 0.83-1.00; P &amp;lt; .001). At baseline, individuals with CBS-AD (n = 12), defined by a PET-validated plasma p-tau217 cutoff 0.25 pg/mL or greater, had increased temporoparietal atrophy at baseline compared to individuals with CBS-FTLD (n = 39), whereas longitudinally, individuals with CBS-FTLD had faster brainstem atrophy rates. Individuals with CBS-FTLD also progressed more rapidly on a modified version of the PSP Rating Scale than those with CBS-AD (mean [SD], 3.5 [0.5] vs 0.8 [0.8] points/year; P = .005).Conclusions and RelevanceIn this cohort study, plasma p-tau217 had excellent diagnostic performance for identifying Aβ or FTP PET positivity within CBS with likely underlying AD pathology. Plasma P-tau217 may be a useful and inexpensive biomarker to select patients for CBS clinical trials.

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