Enlarged perivascular spaces are associated with white matter injury, cognition and inflammation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Enlarged perivascular spaces have been previously reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, but their significance and pathophysiology remains unclear. We investigated associations of white matter enlarged perivascular spaces with classical imaging measures, cognitive measures and plasma proteins to better understand what enlarged perivascular spaces represent in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and whether radiographic measures of enlarged perivascular spaces would be of value in future therapeutic discovery studies for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Twenty-four individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and 24 age- and sex-matched controls were included. Disease status was determined based on the presence of NOTCH3 mutation. Brain imaging measures of white matter hyperintensity, brain parenchymal fraction, white matter enlarged perivascular space volumes, clinical and cognitive measures as well as plasma proteomics were used in models. White matter enlarged perivascular space volumes were calculated via a novel, semiautomated pipeline, and levels of 7363 proteins were quantified in plasma using the SomaScan assay. The relationship of enlarged perivascular spaces with global burden of white matter hyperintensity, brain atrophy, functional status, neurocognitive measures and plasma proteins was modelled with linear regression models. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and control groups did not exhibit differences in mean enlarged perivascular space volumes. However, increased enlarged perivascular space volumes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy were associated with increased white matter hyperintensity volume (ß = 0.57, P = 0.05), Clinical Dementia Rating Sum-of-Boxes score (ß = 0.49, P = 0.04) and marginally with decreased brain parenchymal fraction (ß = -0.03, P = 0.10). In interaction term models, the interaction term between cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease status and enlarged perivascular space volume was associated with increased white matter hyperintensity volume (ß = 0.57, P = 0.02), Clinical Dementia Rating Sum-of-Boxes score (ß = 0.52, P = 0.02), Mini-Mental State Examination score (ß = -1.49, P = 0.03) and marginally with decreased brain parenchymal fraction (ß = -0.03, P = 0.07). Proteins positively associated with enlarged perivascular space volumes were found to be related to leukocyte migration and inflammation, while negatively associated proteins were related to lipid metabolism. Two central hub proteins were identified in protein networks associated with enlarged perivascular space volumes: CXC motif chemokine ligand 8/interleukin-8 and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. The levels of CXC motif chemokine ligand 8/interleukin-8 were also associated with increased white matter hyperintensity volume (ß = 42.86, P = 0.03), and levels of C-C motif chemokine ligand 2/monocyte chemoattractant protein 1 were further associated with decreased brain parenchymal fraction (ß = -0.0007, P < 0.01) and Mini-Mental State Examination score (ß = -0.02, P < 0.01) and increased Trail Making Test B completion time (ß = 0.76, P < 0.01). No proteins were associated with all three studied imaging measures of pathology (brain parenchymal fraction, enlarged perivascular spaces, white matter hyperintensity). Based on associations uncovered between enlarged perivascular space volumes and cognitive functions, imaging and plasma proteins, we conclude that white matter enlarged perivascular space volumes may capture pathologies contributing to chronic brain dysfunction and degeneration in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Mindfulness-Based Stress Reduction for Symptom Management in Older Individuals with HIV-Associated Neurocognitive Disorder.

The growing number of people aging with HIV represents a group vulnerable to the symptom burdens of HIV-associated neurocognitive disorder (HAND). Among younger groups, Mindfulness-Based Stress Reduction (MBSR) has been shown to help people living with HIV manage HIV-related and other life stress, and although there is some theoretical and empirical evidence that it may be effective among those with cognitive deficits, the approach has not been studied in older populations with HAND. Participants (n = 180) 55 years or older with HIV and cognitive impairment were randomly assigned to either an 8-week MBSR arm or a waitlist control. We assessed the impact of MBSR compared to a waitlist control on psychological outcomes [stress, anxiety, depression, and quality of life (QOL)] and cognitive metrics (e.g., speed of information processing, working memory, attention, impulsivity) measured at baseline, immediately post intervention (8 weeks) and one month later (16 weeks). Intent to treat analyses showed significant improvement in the MBSR group compared to control on symptoms of depression from baseline to 8 weeks, however, the difference was not sustained at 16 weeks. The MBSR group also showed improvement in perceived QOL from baseline to 16 weeks compared to the waitlist control group. Cognitive performance did not differ between the two treatment arms. MBSR shows promise as a tool to help alleviate the symptom burden of depression and low QOL in older individuals living with HAND and future work should address methods to better sustain the beneficial impact on depression and QOL.

Data-driven physical actigraphy patterns relate to cognitive and vascular health in older adults.

Health benefits of physical activity (PA) are well known; however, specific PA patterns that relate most strongly to cognitive aging outcomes are poorly understood. We characterized latent profiles of PA among older adults and examined associations with cognition and vascular burden. 124 functionally normal older adults wore a Fitbit™ for 30 days. Daily average step count, sedentary time (0 steps/min), and high-intensity time (≥120 steps/min) were calculated. Participants completed neurocognitive testing assessing cognitive domains of executive functioning and memory; medical history, from which vascular burden (i.e., a count of cardiovascular conditions) was calculated; and brain MRI (n = 44). Subgroups with similar PA patterns were identified via latent profile analysis. Three latent PA classes emerged: Class 1Low PA (n = 49), Class 2Average PA (n = 59), and Class 3High-intensity PA (n = 16). PA class related to executive functioning and vascular burden, driven by better outcomes in Class 3 than Class 1. Sex-stratified analyses revealed these associations were strongest in males. Post hoc analyses showed a positive association between high-intensity PA and white matter integrity among males. High-intensity PA related to better cognitive and vascular health, particularly among males. Findings inform physical activity-specific and person-specific recommendations for optimal cognitive aging.

Evaluation of Plasma Phosphorylated Tau217 for Differentiation Between Alzheimer Disease and Frontotemporal Lobar Degeneration Subtypes Among Patients With Corticobasal Syndrome.

Importance: Plasma 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. Objective: To validate plasma p-tau217 against positron emission tomography (PET) in 4RT-associated syndromes, especially CBS. Design, Setting, and Participants: This 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 Measures: Plasma p-tau217, measured by Meso Scale Discovery electrochemiluminescence, was validated against amyloid-ß (Aß) 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. Results: Of 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 Aß 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 Aß PET of 0.87 (95% CI, 0.76-0.98; P < .001) and FTP PET of 0.93 (95% CI, 0.83-1.00; P < .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 Relevance: In this cohort study, plasma p-tau217 had excellent diagnostic performance for identifying Aß 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.

Multi-Modal Biomarkers of Repetitive Head Impacts and Traumatic Encephalopathy Syndrome: A Clinicopathological Case Series.

Traumatic encephalopathy syndrome (TES) criteria were developed to aid diagnosis of chronic traumatic encephalopathy (CTE) pathology during life. Interpreting clinical and biomarker findings in patients with TES during life necessitates autopsy-based determination of the neuropathological profile. We report a clinicopathological series of nine patients with previous repetitive head impacts (RHI) classified retrospectively using the recent TES research framework (100% male and white/Caucasian, age at death 49-84) who completed antemortem neuropsychological evaluations, T1-weighted magnetic resonance imaging, diffusion tensor imaging (n = 6), (18)F-fluorodeoxyglucose-positron emission tomography (n = 5), and plasma measurement of neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and total tau (n = 8). Autopsies were performed on all patients. Cognitively, low test scores and longitudinal decline were relatively consistent for memory and executive function. Medial temporal lobe atrophy was observed in all nine patients. Poor white matter integrity was consistently found in the fornix. Glucose hypometabolism was most common in the medial temporal lobe and thalamus. Most patients had elevated plasma GFAP, NfL, and total tau at their initial visit and a subset showed longitudinally increasing concentrations. Neuropathologically, five of the nine patients had CTE pathology (n = 4 "High CTE"/McKee Stage III-IV, n = 1 "Low CTE"/McKee Stage I). Primary neuropathological diagnoses (i.e., the disease considered most responsible for observed symptoms) were frontotemporal lobar degeneration (n = 2 FTLD-TDP, n = 1 FTLD-tau), Alzheimer disease (n = 3), CTE (n = 2), and primary age-related tauopathy (n = 1). In addition, hippocampal sclerosis was a common neuropathological comorbidity (n = 5) and associated with limbic-predominant TDP-43 proteinopathy (n = 4) or FTLD-TDP (n = 1). Memory and executive function decline, limbic system brain changes (atrophy, decreased white matter integrity, hypometabolism), and plasma biomarker alterations are common in RHI and TES but may reflect multiple neuropathologies. In particular, the neuropathological differential for patients with RHI or TES presenting with medial temporal atrophy and memory loss should include limbic TDP-43. Researchers and clinicians should be cautious in attributing cognitive, neuroimaging, or other biomarker changes solely to CTE tau pathology based on previous RHI or a TES diagnosis alone.

Cerebrovascular Disease Correlates With Longitudinal Brain Atrophy in Virally Suppressed Older People Living With HIV.

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 (ß = -0.30; P = 0.023), parietal lobe (ß = -0.28; P = 0.030), and frontal lobe atrophy (ß = -0.27; 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 (ß = -0.30; P = 0.034) and the HIV-uninfected participants (ß = -0.37; 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.

Ensemble machine learning classification of daily living abilities among older people with HIV.

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 = 55-80) 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 five-fold 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.

Foreign- vs US-born Asians and the association of type I uterine cancer.

OBJECTIVE: The purpose of this study was to determine the association of type I endometrioid uterine cancer in US-born vs immigrant Asian women. STUDY DESIGN: Data were obtained from the Surveillance, Epidemiology, and End Results Program from 2001-2009. Chi-squared, Kaplan-Meier, and binomial logistic regression analyses were used for statistics. RESULTS: Of 4834 Asian women with uterine cancer, 62% were US-born and 38% were immigrants. Of these women, 2972 (61%) had type I (grade 1 or 2, endometrioid histologic type) uterine cancer. Compared with patients with type II disease (grade 3, clear cell and serous histologic type), patients with type I disease were younger (age 55 vs 59 years; P < .01) and had lower stage disease (90% vs 71%; P < .01). US-born Asian women had a significantly higher proportion of type I uterine cancers in contrast to their immigrant counterparts (65% vs 56%; P < .01). Of all immigrants, the proportion of type I cancers was lowest in Japanese women followed by Chinese and Filipino women, respectively (48% vs 52% vs 58%; P < .01). The 5-year disease-specific survivals of US-born vs immigrant Asian women with type I cancer was 92% for both groups. Over 3 time periods (2001-2003, 2004-2006, and 2007-2009), there was an increase in type I cancers among US-born Asian women (61% to 65% to 68%; P < .01). CONCLUSION: US-born Asian women are more likely to be diagnosed with type I uterine cancer compared with immigrants. Over the study period, there was a trend towards an increase in type I cancers among US-born Asian women.