Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer's disease: a cross-sectional study.

BACKGROUND: In people with genetic forms of Alzheimer's disease, such as in Down syndrome and autosomal-dominant Alzheimer's disease, pathological changes specific to Alzheimer's disease (ie, accumulation of amyloid and tau) occur in the brain at a young age, when comorbidities related to ageing are not present. Studies including these cohorts could, therefore, improve our understanding of the early pathogenesis of Alzheimer's disease and be useful when designing preventive interventions targeted at disease pathology or when planning clinical trials. We compared the magnitude, spatial extent, and temporal ordering of tau spread in people with Down syndrome and autosomal-dominant Alzheimer's disease. METHODS: In this cross-sectional observational study, we included participants (aged ≥25 years) from two cohort studies. First, we collected data from the Dominantly Inherited Alzheimer's Network studies (DIAN-OBS and DIAN-TU), which include carriers of autosomal-dominant Alzheimer's disease genetic mutations and non-carrier familial controls recruited in Australia, Europe, and the USA between 2008 and 2022. Second, we collected data from the Alzheimer Biomarkers Consortium-Down Syndrome study, which includes people with Down syndrome and sibling controls recruited from the UK and USA between 2015 and 2021. Controls from the two studies were combined into a single group of familial controls. All participants had completed structural MRI and tau PET (18F-flortaucipir) imaging. We applied Gaussian mixture modelling to identify regions of high tau PET burden and regions with the earliest changes in tau binding for each cohort separately. We estimated regional tau PET burden as a function of cortical amyloid burden for both cohorts. Finally, we compared the temporal pattern of tau PET burden relative to that of amyloid. FINDINGS: We included 137 people with Down syndrome (mean age 38·5 years [SD 8·2], 74 [54%] male, and 63 [46%] female), 49 individuals with autosomal-dominant Alzheimer's disease (mean age 43·9 years [11·2], 22 [45%] male, and 27 [55%] female), and 85 familial controls, pooled from across both studies (mean age 41·5 years [12·1], 28 [33%] male, and 57 [67%] female), who satisfied the PET quality-control procedure for tau-PET imaging processing. 134 (98%) people with Down syndrome, 44 (90%) with autosomal-dominant Alzheimer's disease, and 77 (91%) controls also completed an amyloid PET scan within 3 years of tau PET imaging. Spatially, tau PET burden was observed most frequently in subcortical and medial temporal regions in people with Down syndrome, and within the medial temporal lobe in people with autosomal-dominant Alzheimer's disease. Across the brain, people with Down syndrome had greater concentrations of tau for a given level of amyloid compared with people with autosomal-dominant Alzheimer's disease. Temporally, increases in tau were more strongly associated with increases in amyloid for people with Down syndrome compared with autosomal-dominant Alzheimer's disease. INTERPRETATION: Although the general progression of amyloid followed by tau is similar for people Down syndrome and people with autosomal-dominant Alzheimer's disease, we found subtle differences in the spatial distribution, timing, and magnitude of the tau burden between these two cohorts. These differences might have important implications; differences in the temporal pattern of tau accumulation might influence the timing of drug administration in clinical trials, whereas differences in the spatial pattern and magnitude of tau burden might affect disease progression. FUNDING: None.

Comparison of Resting State Functional Connectivity in Persons With and Without HIV: A Cross-sectional Study.

BACKGROUND: This study examined the effects of human immunodeficiency virus (HIV) on resting state functional connectivity (RSFC) in a large cohort of people with HIV (PWH) and healthy controls without HIV (PWoH). Within PWH analyses focused on the effects of viral suppression and cognitive impairment on RSFC. METHODS: A total of 316 PWH on stable combination antiretroviral therapy and 209 demographically matched PWoH were scanned at a single institution. Effects of the virus were examined by grouping PWH by detectable (viral load > 20 copies/mL; VLD) and undetectable (VLU) viral loads and as being cognitively impaired (CI) (Global Deficit Score ≥ 0.5) or cognitively normal (CN). Regression analysis, object oriented data analysis, and spring embedded graph models were applied to RSFC measures from 298 established brain regions of interest comprising 13 brain networks to examine group differences. RESULTS: No significant RSFC differences were observed between PWH and PWoH. Within PWH, there were no significant differences in RSFC between VLD and VLU subgroups and CI and CN subgroups. CONCLUSIONS: There were no significant effects of HIV on RSFC in our relatively large cohort of PWH and PWoH. Future studies could increase the sample size and combine with other imaging modalities.

Predicting continuous amyloid PET values with CSF and plasma Aß42/Aß40.

Introduction: Continuous measures of amyloid burden as measured by positron emission tomography (PET) are being used increasingly to stage Alzheimer's disease (AD). This study examined whether cerebrospinal fluid (CSF) and plasma amyloid beta (Aß)42/Aß40 could predict continuous values for amyloid PET. Methods: CSF Aß42 and Aß40 were measured with automated immunoassays. Plasma Aß42 and Aß40 were measured with an immunoprecipitation-mass spectrometry assay. Amyloid PET was performed with Pittsburgh compound B (PiB). The continuous relationships of CSF and plasma Aß42/Aß40 with amyloid PET burden were modeled. Results: Most participants were cognitively normal (427 of 491 [87%]) and the mean age was 69.0 ± 8.8 years. CSF Aß42/Aß40 predicted amyloid PET burden until a relatively high level of amyloid accumulation (69.8 Centiloids), whereas plasma Aß42/Aß40 predicted amyloid PET burden until a lower level (33.4 Centiloids). Discussion: CSF Aß42/Aß40 predicts the continuous level of amyloid plaque burden over a wider range than plasma Aß42/Aß40 and may be useful in AD staging. Highlights: Cerebrospinal fluid (CSF) amyloid beta (Aß)42/Aß40 predicts continuous amyloid positron emission tomography (PET) values up to a relatively high burden.Plasma Aß42/Aß40 is a comparatively dichotomous measure of brain amyloidosis.Models can predict regional amyloid PET burden based on CSF Aß42/Aß40.CSF Aß42/Aß40 may be useful in staging AD.

A practitioner's guide to geospatial analysis in a neuroimaging context.

Introduction: Health disparities arise from biological-environmental interactions. Neuroimaging cohorts are reaching sufficiently large sample sizes such that analyses could evaluate how the environment affects the brain. We present a practical guide for applying geospatial methods to a neuroimaging cohort. Methods: We estimated brain age gap (BAG) from structural magnetic resonance imaging (MRI) from 239 city-dwelling participants in St. Louis, Missouri. We compared these participants to population-level estimates from the American Community Survey (ACS). We used geospatial analysis to identify neighborhoods associated with patterns of altered brain structure. We also evaluated the relationship between Area Deprivation Index (ADI) and BAG. Results: We identify areas in St. Louis, Missouri that were significantly associated with higher BAG from a spatially representative cohort. We provide replication code. Conclusion: We observe a relationship between neighborhoods and brain health, which suggests that neighborhood-based interventions could be appropriate. We encourage other studies to geocode participant information to evaluate biological-environmental interaction.

Plasma Aß42/Aß40 Ratios in Older People With Human Immunodeficiency Virus.

BACKGROUND: As people with human immunodeficiency virus (HIV) (PWH) age, it remains unclear whether they are at higher risk for age-related neurodegenerative disorders-for example, Alzheimer disease (AD)-and, if so, how to differentiate HIV-associated neurocognitive impairment from AD. We examined a clinically available blood biomarker test for AD (plasma amyloid-ß [Aß] 42/Aß40 ratio) in PWH who were cognitively normal (PWH_CN) or cognitively impaired (PWH_CI) and people without HIV (PWoH) who were cognitively normal (PWoH_CN) or had symptomatic AD (PWoH_AD). METHODS: A total of 66 PWH (age >40 years) (HIV RNA <50 copies/mL) and 195 PWoH provided blood samples, underwent magnetic resonance imaging, and completed a neuropsychological battery or clinical dementia rating scale. Participants were categorized by impairment (PWH_CN, n = 43; PWH_CI, n = 23; PWoH_CN, n = 138; PWoH_AD, n = 57). Plasma Aß42 and Aß40 concentrations were obtained using a liquid chromatography-tandem mass spectrometry method to calculate the PrecivityAD amyloid probability score (APS). The APS incorporates age and apolipoprotein E proteotype into a risk score for brain amyloidosis. Plasma Aß42/Aß40 ratios and APSs were compared between groups and assessed for relationships with hippocampal volumes or cognition and HIV clinical characteristics (PWH only). RESULTS: The plasma Aß42/Aß40 ratio was significantly lower, and the APS higher, in PWoH_AD than in other groups. A lower Aß42/Aß40 ratio and higher APS was associated with smaller hippocampal volumes for PWoH_AD. The Aß42/Aß40 ratio and APS were not associated with cognition or HIV clinical measures for PWH. CONCLUSIONS: The plasma Aß42/Aß40 ratio can serve as a screening tool for AD and may help differentiate effects of HIV from AD within PWH, but larger studies with older PWH are needed.

Comparison of amyloid burden in individuals with Down syndrome versus autosomal dominant Alzheimer's disease: a cross-sectional study.

BACKGROUND: Important insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people. METHODS: In this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25-73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid ß42 (Aß42) to Aß40 (Aß42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aß42/40 was evaluated. FINDINGS: 192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aß42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p<0·0001) and in people with Down syndrome (n=32; r=-0·801; p<0·0001). There was no difference in global PET amyloid burden between asymptomatic people with Down syndrome (mean 18·80 centiloids [SD 28·33]) versus asymptomatic mutation carriers (24·61 centiloids [30·27]; p=0·11) and between symptomatic people with Down syndrome (77·25 centiloids [41·76]) versus symptomatic mutation carriers (69·15 centiloids [51·10]; p=0·34). APOE ɛ4 status and sex had no effect on global amyloid PET deposition. Amyloid deposition was elevated significantly earlier in mutation carriers than in participants with Down syndrome (estimated years to symptom onset -23·0 vs -17·5; p=0·0002). PSEN1 mutations primarily drove this difference. Early amyloid accumulation occurred in striatal and cortical regions for both mutation carriers (n=265) and people with Down syndrome (n=128). Although mutation carriers had widespread amyloid accumulation in all cortical regions, the medial occipital regions were spared in people with Down syndrome. INTERPRETATION: Despite minor differences, amyloid PET changes were similar between people with autosomal dominant Alzheimer's disease versus Down syndrome and strongly supported early amyloid dysregulation in individuals with Down syndrome. Individuals with Down syndrome aged at least 35 years might benefit from early intervention and warrant future inclusion in clinical trials, particularly given the relatively high incidence of Down syndrome. FUNDING: The National Institute on Aging, Riney and Brennan Funds, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the German Center for Neurodegenerative Diseases, and the Japan Agency for Medical Research and Development.

Proteomic clusters underlie heterogeneity in preclinical Alzheimer's disease progression.

Heterogeneity in progression to Alzheimer's disease (AD) poses challenges for both clinical prognosis and clinical trial implementation. Multiple AD-related subtypes have previously been identified, suggesting differences in receptivity to drug interventions. We identified early differences in preclinical AD biomarkers, assessed patterns for developing preclinical AD across the amyloid-tau-(neurodegeneration) [AT(N)] framework, and considered potential sources of difference by analysing the CSF proteome. Participants (n = 10) enrolled in longitudinal studies at the Knight Alzheimer Disease Research Center completed four or more lumbar punctures. These individuals were cognitively normal at baseline. Cerebrospinal fluid measures of amyloid-ß (Aß)42, phosphorylated tau (pTau181), and neurofilament light chain (NfL) as well as proteomics values were evaluated. Imaging biomarkers, including PET amyloid and tau, and structural MRI, were repeatedly obtained when available. Individuals were staged according to the amyloid-tau-(neurodegeneration) framework. Growth mixture modelling, an unsupervised clustering technique, identified three patterns of biomarker progression as measured by CSF pTau181 and Aß42. Two groups (AD Biomarker Positive and Intermediate AD Biomarker) showed distinct progression from normal biomarker status to having biomarkers consistent with preclinical AD. A third group (AD Biomarker Negative) did not develop abnormal AD biomarkers over time. Participants grouped by CSF trajectories were re-classified using only proteomic profiles (AUCAD Biomarker Positive versus AD Biomarker Negative = 0.857, AUCAD Biomarker Positive versus Intermediate AD Biomarkers = 0.525, AUCIntermediate AD Biomarkers versus AD Biomarker Negative = 0.952). We highlight heterogeneity in the development of AD biomarkers in cognitively normal individuals. We identified some individuals who became amyloid positive before the age of 50 years. A second group, Intermediate AD Biomarkers, developed elevated CSF ptau181 significantly before becoming amyloid positive. A third group were AD Biomarker Negative over repeated testing. Our results could influence the selection of participants for specific treatments (e.g. amyloid-reducing versus other agents) in clinical trials. CSF proteome analysis highlighted additional non-AT(N) biomarkers for potential therapies, including blood-brain barrier-, vascular-, immune-, and neuroinflammatory-related targets.

Abnormal Magnetic Resonance Image Signature in Virologically Stable HIV Individuals.

BACKGROUND: With implementation of combination antiretroviral therapy (cART), changes to brain integrity in people with HIV (PWH) are subtle compared to those observed in the pre-cART era. T1-weighted/T2-weighted (T1w/T2w) ratio has been proposed as a measure of cortical myelin. This study examines T1w/T2w values between virologically controlled PWH and persons without HIV (PWoH). METHODS: Virologically well-controlled PWH (n = 164) and PWoH (n = 120) were compared on global and regional T1w/T2w values. T1w/T2w values were associated with HIV disease variables (nadir and current CD4 T-cell count, and CNS penetration effectiveness of cART regimen) in PWH, and as a function of age for both PWoH and PWH. RESULTS: PWH had reduced global and regional T1w/T2w values compared to PWoH in the posterior cingulate cortex, caudal anterior cingulate cortex, and insula. T1w/T2w values did not correlate with HIV variables except for a negative relationship with CNS penetration effectiveness. Greater cardiovascular disease risk and older age were associated with lower T1w/T2w values only for PWH. CONCLUSIONS: T1w/T2w values obtained from commonly acquired MRI protocols differentiates virologically well-controlled PWH from PWoH. Changes in T1w/T2w ratio do not correlate with typical HIV measures. Future studies are needed to determine the biological mechanisms underlying this measure.

Effects of Framingham 10-Year Cardiovascular Risk Score and Viral Load on Brain Integrity in Persons With HIV.

BACKGROUND: Combination antiretroviral therapy (cART) has allowed for viral load (VL) suppression and increased life expectancy for persons with HIV (PWH). Altered brain integrity, measured by neuropsychological (NP) performance and neuroimaging, is still prevalent among virally suppressed PWH. Age-related conditions such as cardiovascular disease may also affect brain integrity. This study investigated the effects of cardiovascular risk, VL, and HIV serostatus on cerebral blood flow (CBF), brain volumetrics, and cognitive function in PWH and persons without HIV (PWoH). METHODS: Ten-year cardiovascular risk, using the Framingham Heart Study criteria, was calculated in PWH (n = 164) on cART with undetectable (≤20 copies/mL; n = 134) or detectable (>20 copies/mL; n = 30) VL and PWoH (n = 66). The effects of cardiovascular risk on brain integrity (CBF, volume, and cognition) were compared for PWH (undetectable and detectable VL) and PWoH. RESULTS: PWH had smaller brain volumes and worse NP scores than PWoH. PWH with detectable and undetectable VL had similar brain integrity measures. Higher cardiovascular risk was associated with smaller volumes and lower CBF in multiple brain regions for PWH and PWoH. Significant interactions between HIV serostatus and cardiovascular risk on brain volumes were observed in frontal, orbitofrontal, and motor regions. Cardiovascular risk was not associated with cognition for PWH or PWoH. CONCLUSIONS: Neuroimaging, but not cognitive measures, was associated with elevated cardiovascular risk. HIV serostatus was associated with diminished brain volumes and worse cognition while CBF remained unchanged, reflecting potential protective effects of cART. Neuroimaging measures of structure (volume) and function (CBF) may identify contributions of comorbidities, but future longitudinal studies are needed.

Sleep and longitudinal cognitive performance in preclinical and early symptomatic Alzheimer's disease.

Sleep monitoring may provide markers for future Alzheimer's disease; however, the relationship between sleep and cognitive function in preclinical and early symptomatic Alzheimer's disease is not well understood. Multiple studies have associated short and long sleep times with future cognitive impairment. Since sleep and the risk of Alzheimer's disease change with age, a greater understanding of how the relationship between sleep and cognition changes over time is needed. In this study, we hypothesized that longitudinal changes in cognitive function will have a non-linear relationship with total sleep time, time spent in non-REM and REM sleep, sleep efficiency and non-REM slow wave activity. To test this hypothesis, we monitored sleep-wake activity over 4-6 nights in 100 participants who underwent standardized cognitive testing longitudinally, APOE genotyping, and measurement of Alzheimer's disease biomarkers, total tau and amyloid-ß42 in the CSF. To assess cognitive function, individuals completed a neuropsychological testing battery at each clinical visit that included the Free and Cued Selective Reminding test, the Logical Memory Delayed Recall assessment, the Digit Symbol Substitution test and the Mini-Mental State Examination. Performance on each of these four tests was Z-scored within the cohort and averaged to calculate a preclinical Alzheimer cognitive composite score. We estimated the effect of cross-sectional sleep parameters on longitudinal cognitive performance using generalized additive mixed effects models. Generalized additive models allow for non-parametric and non-linear model fitting and are simply generalized linear mixed effects models; however, the linear predictors are not constant values but rather a sum of spline fits. We found that longitudinal changes in cognitive function measured by the cognitive composite decreased at low and high values of total sleep time (P < 0.001), time in non-REM (P < 0.001) and REM sleep (P < 0.001), sleep efficiency (P < 0.01) and <1 Hz and 1-4.5 Hz non-REM slow wave activity (P < 0.001) even after adjusting for age, CSF total tau/amyloid-ß42 ratio, APOE ε4 carrier status, years of education and sex. Cognitive function was stable over time within a middle range of total sleep time, time in non-REM and REM sleep and <1 Hz slow wave activity, suggesting that certain levels of sleep are important for maintaining cognitive function. Although longitudinal and interventional studies are needed, diagnosing and treating sleep disturbances to optimize sleep time and slow wave activity may have a stabilizing effect on cognition in preclinical or early symptomatic Alzheimer's disease.

Modeling the Effects of HIV and Aging on Resting-State Networks Using Machine Learning.

BACKGROUND: The relationship between HIV infection, the functional organization of the brain, cognitive impairment, and aging remains poorly understood. Understanding disease progression over the life span is vital for the care of people living with HIV (PLWH). SETTING: Virologically suppressed PLWH (n = 297) on combination antiretroviral therapy and 1509 HIV-uninfected healthy controls were evaluated. PLWH were further classified as cognitively normal (CN) or cognitively impaired (CI) based on neuropsychological testing. METHODS: Feature selection identified resting-state networks (RSNs) that predicted HIV status and cognitive status within specific age bins (younger than 35 years, 35-55 years, and older than 55 years). Deep learning models generated voxelwise maps of RSNs to identify regional differences. RESULTS: Salience (SAL) and parietal memory networks (PMNs) differentiated individuals by HIV status. When comparing controls with PLWH CN, the PMN and SAL had the strongest predictive strength across all ages. When comparing controls with PLWH CI, the SAL, PMN, and frontal parietal network (FPN) were the best predictors. When comparing PLWH CN with PLWH CI, the SAL, FPN, basal ganglia, and ventral attention were the strongest predictors. Only minor variability in predictive strength was observed with aging. Anatomically, differences in RSN topology occurred primarily in the dorsal and rostral lateral prefrontal cortex, cingulate, and caudate. CONCLUSION: Machine learning identified RSNs that classified individuals by HIV status and cognitive status. The PMN and SAL were sensitive for discriminating HIV status, with involvement of FPN occurring with cognitive impairment. Minor differences in RSN predictive strength were observed by age. These results suggest that specific RSNs are affected by HIV, aging, and HIV-associated cognitive impairment.

Comparison of CSF biomarkers in Down syndrome and autosomal dominant Alzheimer's disease: a cross-sectional study.

BACKGROUND: Due to trisomy of chromosome 21 and the resultant extra copy of the amyloid precursor protein gene, nearly all adults with Down syndrome develop Alzheimer's disease pathology by the age of 40 years and are at high risk for dementia given their increased life expectancy compared with adults with Down syndrome in the past. We aimed to compare CSF biomarker patterns in Down syndrome with those of carriers of autosomal dominant Alzheimer's disease mutations to enhance our understanding of disease mechanisms in these two genetic groups at high risk for Alzheimer's disease. METHODS: We did a cross-sectional study using data from adults enrolled in the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study, a multisite longitudinal study of Alzheimer's disease in Down syndrome, as well as a cohort of carriers of autosomal dominant Alzheimer's disease mutations and non-carrier sibling controls enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study. For ABC-DS, participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of Jan 31, 2019, were included in the analysis. DIAN participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of June 30, 2018, were evaluated as comparator groups. CSF samples obtained from adults with Down syndrome, similarly aged carriers of autosomal dominant Alzheimer's disease mutations, and non-carrier siblings (aged 30-61 years) were analysed for markers of amyloid ß (Aß1-40, Aß1-42); tau phosphorylated at threonine 181-related processes; neuronal, axonal, or synaptic injury (total tau, visinin-like protein 1, neurofilament light chain [NfL], synaptosomal-associated protein 25); and astrogliosis and neuroinflammation (chitinase-3-like protein 1 [YKL-40]) via immunoassay. Biomarker concentrations were compared as a function of dementia status (asymptomatic or symptomatic), and linear regression was used to evaluate and compare the relationship between biomarker concentrations and age among groups. FINDINGS: We assessed CSF samples from 341 individuals (178 [52%] women, 163 [48%] men, aged 30-61 years). Participants were adults with Down syndrome (n=41), similarly aged carriers of autosomal dominant Alzheimer's disease mutations (n=192), and non-carrier siblings (n=108). Individuals with Down syndrome had patterns of Alzheimer's disease-related CSF biomarkers remarkably similar to carriers of autosomal dominant Alzheimer's disease mutations, including reductions (all p<0·0080) in Aß1-42 to Aß1-40 ratio and increases in markers of phosphorylated tau-related processes; neuronal, axonal, and synaptic injury (p<0·080); and astrogliosis and neuroinflammation, with greater degrees of abnormality in individuals with dementia. Differences included overall higher concentrations of Aß and YKL-40 (both p<0·0008) in Down syndrome and potential elevations in CSF tau (p<0·010) and NfL (p<0·0001) in the asymptomatic stage (ie, no dementia symptoms). FUNDING: National Institute on Aging, Eunice Kennedy Shriver National Institute of Child Health and Human Development, German Center for Neurodegenerative Diseases, and Japan Agency for Medical Research and Development.

Temporal Correlation of CSF and Neuroimaging in the Amyloid-Tau-Neurodegeneration Model of Alzheimer Disease.

OBJECTIVE: To evaluate temporal correlations between CSF and neuroimaging (PET and MRI) measures of amyloid, tau, and neurodegeneration in relation to Alzheimer disease (AD) progression. METHODS: A total of 371 cognitively unimpaired and impaired participants enrolled in longitudinal studies of AD had both CSF (ß-amyloid [Aß]42, phosphorylated tau181, total tau, and neurofilament light chain) and neuroimaging (Pittsburgh compound B [PiB] PET, flortaucipir PET, and structural MRI) measures. The pairwise time interval between CSF and neuroimaging measures was binned into 2-year periods. Spearman correlations identified the time bin when CSF and neuroimaging measures most strongly correlated. CSF and neuroimaging measures were then binarized as biomarker-positive or biomarker-negative using Gaussian mixture modeling. Cohen kappa coefficient identified the time bin when CSF measures best agreed with corresponding neuroimaging measures when determining amyloid, tau, and neurodegeneration biomarker positivity. RESULTS: CSF Aß42 and PiB PET showed maximal correlation when collected within 6 years of each other (R ≈ -0.5). CSF phosphorylated tau181 and flortaucipir PET showed maximal correlation when CSF was collected 4 to 8 years prior to PET (R ≈ 0.4). CSF neurofilament light chain and cortical thickness showed low correlation, regardless of time interval (R avg ≈ -0.3). Similarly, CSF total tau and cortical thickness had low correlation, regardless of time interval (R avg < -0.2). CONCLUSIONS: CSF Aß42 and PiB PET best agree when acquired in close temporal proximity, whereas CSF phosphorylated tau precedes flortaucipir PET by 4 to 8 years. CSF and neuroimaging measures of neurodegeneration have low correspondence and are not interchangeable at any time interval.

Relationships Between Viral Load, Neuroimaging, and NP in Persons Living With HIV.

BACKGROUND: This study examined whether recommended viral load (VL) classifications by the Department of Health and Human Services map onto changes in brain integrity observed in people living with HIV (PLWH). METHODS: Three hundred forty-nine PLWH on combination antiretroviral therapy meeting criteria for virologic suppression (VS) (VL ≤ 20 copies/mL; n = 206), "low-level viremia" (20-200 copies/mL; n = 63), or virologic failure (VF) (>200 copies/mL; n = 80) and 195 demographically similar HIV-negative controls were compared for cognition and brain volumes from 10 regions of interest that are sensitive to HIV. Changes in cognition and brain volumes were examined in a subset of PLWH (n = 132) who completed a follow-up evaluation (mean interval = 28 months) and had no change in treatment regimen. RESULTS: Significant differences in cognition and brain volumes were observed between the HIV-negative control and VS groups compared with those in the VF groups, with few differences observed between the 3 PLWH subgroups. Longitudinally, PLWH who continued to have VF exhibited a greater decline in cognition and brain volumes compared with PLWH who remained with VS. Observed longitudinal changes in cognition correlated with brain volume changes. CONCLUSION: PLWH with continued VF (consecutive VL measurements of >200 copies/mL) represent a cause for clinical concern and may benefit from change in treatment in addition to consideration of other potential etiologies of VF to reduce loss of brain integrity.

Neuroimaging the Neuropathogenesis of HIV.

PURPOSE OF REVIEW: This review highlights neuroimaging studies of HIV conducted over the last 2 years and discusses how relevant findings further our knowledge of the neuropathology of HIV. Three major avenues of neuroimaging research are covered with a particular emphasis on inflammation, aging, and substance use in persons living with HIV (PLWH). RECENT FINDINGS: Neuroimaging has been a critical tool for understanding the neuropathological underpinnings observed in HIV. Recent studies comparing levels of neuroinflammation in PLWH and HIV-negative controls show inconsistent results but report an association between elevated neuroinflammation and poorer cognition in PLWH. Other recent neuroimaging studies suggest that older PLWH are at increased risk for brain and cognitive compromise compared to their younger counterparts. Finally, recent findings also suggest that the effects of HIV may be exacerbated by alcohol and drug abuse. These neuroimaging studies provide insight into the structural, functional, and molecular changes occurring in the brain due to HIV. HIV triggers a strong neuroimmune response and may lead to a cascade of events including increased chronic inflammation and cognitive decline. These outcomes are further exacerbated by age and age-related comorbidities, as well as lifestyle factors such as drug use/abuse.

Effects of anticholinergic medication use on brain integrity in persons living with HIV and persons without HIV.

OBJECTIVE: This study examined relationships between anticholinergic medication burden and brain integrity in people living with HIV (PLWH) and people without HIV (HIV-). METHODS: Neuropsychological performance z-scores (learning, retention, executive function, motor/psychomotor speed, language domains, and global cognition), and neuroimaging measures (brain volumetrics and white matter fractional anisotropy) were analyzed in PLWH (n = 209) and HIV- (n = 95) grouped according to the Anticholinergic Cognitive Burden (ACB) scale (0 = no burden, 1-3 = low burden, >3 = high burden). Neuropsychological performance and neuroimaging outcomes were compared between HIV- and PLWH with high anticholinergic burden. Within a cohort of PLWH (n = 90), longitudinal change in ACB score over ∼2 years was correlated to the rate of change per month of study interval in neuropsychological performance and neuroimaging measures. RESULTS: A higher number of anticholinergic medications and ACB was observed in PLWH compared with HIV- (P < 0.05). A higher ACB was associated with worse motor/psychomotor performance, smaller occipital lobe, putamen, subcortical gray matter and total gray matter volumes in HIV-; and poorer executive function, retention and global cognition, smaller brain volumes (frontal, parietal and temporal lobes, hippocampus, amygdala, cortex, subcortical gray matter and total gray matter), and reduced fractional anisotropy (posterior corpus callosum, perforant pathway) in PLWH. PLWH with high anticholinergic burden performed worse on tests of learning and executive function compared with HIV- with high anticholinergic burden. Longitudinally, PLWH who reduced their ACB over time had better neuropsychological performance and neuroimaging measures. CONCLUSION: Anticholinergic medications were associated with worse neuropsychological performance and reduced structural brain integrity, and these effects were more widespread in PLWH. Use of anticholinergic medications should be carefully monitored in older adults with deprescription considered whenever possible.

Comparison of [11C]-PBR28 Binding Between Persons Living With HIV and HIV-Uninfected Individuals.

OBJECTIVE: Despite combined antiretroviral therapy, neuroinflammation may persist in persons living with HIV (PLWH) and contribute to cognitive impairment in this population. Positron emission tomography (PET) imaging targeting 18 kDa translocator protein (TSPO) has been used to localize neuroinflammation. We aimed to use TSPO-PET imaging to evaluate neuroinflammation in PLWH. DESIGN: Twenty-four virologically suppressed PLWH on combined antiretroviral therapy and 13 HIV-negative (HIV-) controls completed TSPO-PET imaging using the radiotracer [C]PBR28. Because of tracer complexity and differing procedures used in previous studies, we employed an expansive methodological approach, using binding potential (BP) and standard uptake value ratio and multiple different reference regions to estimate [C]PBR28 binding. METHODS: [C]PBR28 binding was measured in 30 cortical and subcortical regions and compared between PLWH and HIV- controls. Pearson correlation evaluated the association between [C]PBR28 binding and cognition and clinical measures of HIV. RESULTS: Analyses conducted using multiple reference regions and measures of tracer uptake revealed no significant differences between [C]PBR28 binding in PLWH compared with HIV- controls. In addition, [C]PBR28 binding in PLWH was not significantly associated with clinical measures of HIV or plasma biomarkers of inflammation. [C]PBR28 binding was not significantly elevated in cognitively impaired PLWH compared with unimpaired PLWH, but there were inverse relationships between cognitive performance (executive and global function) and [C]PBR28 binding in PLWH. CONCLUSIONS: Our results suggest that neuroinflammation may play a role in cognitive deficits, but overall neuroinflammatory levels as measured by TSPO-PET imaging in PLWH are not significantly different from those seen in HIV- controls.

Machine Learning Analysis Reveals Novel Neuroimaging and Clinical Signatures of Frailty in HIV.

BACKGROUND: Frailty is an important clinical concern for the aging population of people living with HIV (PLWH). The objective of this study was to identify the combination of risk features that distinguish frail from nonfrail individuals. SETTING: Machine learning analysis of highly dimensional risk features was performed on a clinical cohort of PLWH. METHODS: Participants included 105 older (average age = 55.6) PLWH, with at least a 3-month history of combination antiretroviral therapy (median CD4 = 546). Predictors included demographics, HIV clinical markers, comorbid health conditions, cognition, and neuroimaging (ie, volumetrics, resting-state functional connectivity, and cerebral blood flow). Gradient-boosted multivariate regressions were implemented to establish linear and interactive classification models. Model performance was determined by sensitivity/specificity (F1 score) with 5-fold cross validation. RESULTS: The linear gradient-boosted multivariate regression classifier included lower current CD4 count, lower psychomotor performance, and multiple neuroimaging indices (volumes, network connectivity, and blood flow) in visual and motor brain systems (F1 score = 71%; precision = 84%; and sensitivity = 66%). The interactive model identified novel synergies between neuroimaging features, female sex, symptoms of depression, and current CD4 count. CONCLUSIONS: Data-driven algorithms built from highly dimensional clinical and brain imaging features implicate disruption to the visuomotor system in older PLWH designated as frail individuals. Interactions between lower CD4 count, female sex, depressive symptoms, and neuroimaging features suggest potentiation of risk mechanisms. Longitudinal data-driven studies are needed to guide clinical strategies capable of preventing the development of frailty as PLWH reach advanced age.

Deep Learning Analysis of Cerebral Blood Flow to Identify Cognitive Impairment and Frailty in Persons Living With HIV.

BACKGROUND: Deep learning algorithms of cerebral blood flow were used to classify cognitive impairment and frailty in people living with HIV (PLWH). Feature extraction techniques identified brain regions that were the strongest predictors. SETTING: Virologically suppressed (<50 copies/mL) PLWH (n = 125) on combination antiretroviral therapy were enrolled. Participants averaged 51.4 (11.4) years of age and 13.7 (2.8) years of education. Participants were administered a neuropsychological battery, assessed for frailty, and completed structural neuroimaging. METHODS: Deep neural network (DNN) models were trained to classify PLWH as cognitively unimpaired or impaired based on neuropsychological tests (Hopkins Verbal Learning Test-Revised and Brief Visuospatial Memory Test-Revised, Trail making, Letter-Number Sequencing, Verbal Fluency, and Color Word Interference), as well as frail, prefrail, or nonfrail based on the Fried phenotype criteria (at least 3 of the following 5: weight loss, physical inactivity, exhaustion, grip strength, walking time). RESULTS: DNNs classified individuals with cognitive impairment in the learning, memory, and executive domains with 82%-86% accuracy (0.81-0.87 AUC). Our model classified nonfrail, prefrail, and frail PLWH with 75% accuracy. The strongest predictors of cognitive impairment were cortical (parietal, occipital, and temporal) and subcortical (amygdala, caudate, and hippocampus) regions, whereas the strongest predictors of frailty were subcortical (amygdala, caudate, hippocampus, thalamus, pallidum, and cerebellum). CONCLUSIONS: DNN models achieved high accuracy in classifying cognitive impairment and frailty status in PLWH. Feature selection algorithms identified predictive regions in each domain and identified overlapping regions between cognitive impairment and frailty. Our results suggest frailty in HIV is primarily subcortical, whereas cognitive impairment in HIV involves subcortical and cortical brain regions.

Altered neuropsychological performance and reduced brain volumetrics in people living with HIV on integrase strand transfer inhibitors.

OBJECTIVES: Neuropsychiatric symptoms have been reported in people living with HIV (PLWH) on integrase strand transfer inhibitors (INSTIs) in postmarketing analysis. Limited data exist regarding brain integrity (function and structure) in PLWH prescribed INSTIs compared with other HIV treatment regimens. DESIGN: A cross-sectional analysis of PLWH on combined antiretroviral therapy aged more than 18 years at a single institution. METHODS: Neuropsychological tests were administered to calculate domain deficit scores in learning/memory, executive function and motor/psychomotor domains. Cortical and subcortical volumes from MRI were obtained using the FreeSurfer software suite (v5.3). RESULTS: Of 202 participants, median age 55 (48, 60) years old, 49% were on INSTI-based combined antiretroviral therapy. PLWH on INSTIs were similar to individuals on non-INSTIs in terms of age, sex, race, education years, smoking history, depression scores, psychiatric medication use, presence of hepatitis C infection, history of substance use, HIV infection duration and recent or nadir CD4 T-cell count. Participants in the INSTI group performed worse than non-INSTI users in the verbal learning and memory domain [1.5 (interquartile range 0, 2.5) versus 1 (0, 2); P = 0.016]. The INSTI and non-INSTI groups were similar for other cognitive domains. Frontal, brain stem and cerebellar volumes were reduced in INSTI compared with non-INSTI users (all P = <0.05). CONCLUSION: We demonstrated modest differences in learning/memory performance and smaller brain volumes in PLWH on INSTI-based regimens compared with non-INSTI users. Prospective studies are needed to define mechanisms and the clinical significance of reduced brain integrity in PLWH on INSTIs.