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.

Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease.

BACKGROUND: "Brain-predicted age" estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology. METHODS: We modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-ß-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE Îµ4 carrier status, sex, and education. RESULTS: Advanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG. CONCLUSIONS: We extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI.

Precipitating Mechanisms of Falls in Preclinical Alzheimer's Disease.

Background: Individuals with Alzheimer's disease (AD) are more than twice as likely to incur a serious fall as the general population of older adults. Although AD is commonly associated with cognitive changes, impairments in other clinical measures such as strength or functional mobility (i.e., gait and balance) may precede symptomatic cognitive impairment in preclinical AD and lead to increased fall risk. Objective: To examine mechanisms (i.e., functional mobility, cognition, AD biomarkers) associated with increased falls in cognitively normal older adults. Methods: This 1-year study was part of an ongoing longitudinal cohort study. We examined the relationships among falls, clinical measures of functional mobility and cognition, and neuroimaging AD biomarkers in cognitively normal older adults. We also investigated which domain(s) best predicted fall propensity and severity through multiple regression models. Results: A total of 182 older adults were included (mean age 75 years, 53% female). A total of 227 falls were reported over the year; falls per person ranged from 0-16 with a median of 1. Measures of functional mobility were the best predictors of fall propensity and severity. Cognition and AD biomarkers were associated with each other but not with the fall outcome measures. Conclusion: These results suggest that, although subtle changes in cognition may be more closely associated with AD neuropathology, functional mobility indicators better predict falls in cognitively normal older adults. This study adds to our understanding of the mechanisms underlying falls in older adults and could lead to the development of targeted fall prevention strategies.

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.

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.

Adverse driving behaviors increase over time as a function of preclinical Alzheimer's disease biomarkers.

INTRODUCTION: We investigated the relationship between preclinical Alzheimer's disease (AD) biomarkers and adverse driving behaviors in a longitudinal analysis of naturalistic driving data. METHODS: Naturalistic driving data collected using in-vehicle dataloggers from 137 community-dwelling older adults (65+) were used to model driving behavior over time. Cerebrospinal fluid (CSF) biomarkers were used to identify individuals with preclinical AD. Additionally, hippocampal volume and cognitive biomarkers for AD were investigated in exploratory analyses. RESULTS: CSF biomarkers predicted the longitudinal trajectory of the incidence of adverse driving behavior. Abnormal amyloid beta (Aß42 /Aß40 ) ratio was associated with an increase in adverse driving behaviors over time compared to ratios in the normal/lower range. DISCUSSION: Preclinical AD is associated with increased adverse driving behavior over time that cannot be explained by cognitive changes. Driving behavior as a functional, neurobehavioral marker may serve as an early detection for decline in preclinical AD. Screening may also help prolong safe driving as older drivers age.

Assessment of Pretreatment and Posttreatment Evolution of Neurofilament Light Chain Levels in Patients Who Develop Immune Effector Cell-Associated Neurotoxicity Syndrome.

Importance: Determining whether neurofilament light chain (NfL) elevations in patients who develop immune effector cell-associated neurotoxicity syndrome (ICANS) occur before or after infusion of cellular product is important to identify high-risk patients and inform whether neuroaxonal injury is latent or a consequence of treatment. Objective: To quantify serial NfL levels in patients undergoing cellular therapy. Design, Setting, and Participants: This retrospective 2-center study examined plasma NfL levels in 30 patients with detailed medical and treatment history, including all major pretreatment and posttreatment risk factors. Exclusion criteria included dementia and severe, symptomatic central nervous system (CNS) involvement. Main Outcomes and Measures: Patients' NfL levels were measured at 7 time points: baseline (prelymphodepletion), during lymphodepletion, postinfusion day (D) 1, D3, D7, D14, and D30. Prediction accuracy for the development of ICANS was next modeled using receiver operating characteristic (ROC) classification. Finally, univariate and multivariate modeling examined the association between NfL levels, ICANS, and potential risk factors including demographic (age, sex), oncologic (tumor burden, history of CNS involvement), neurologic (history of nononcologic CNS disease or neuropathy), and neurotoxic exposure histories (vincristine, cytarabine, methotrexate, or CNS radiotherapy). Results: A total of 30 patients (median [range] age, 64 [22-80] years; 12 women [40%] and 18 men [60%]) were included. Individuals who developed ICANS had elevations in NfL prior to lymphodepletion and chimeric antigen receptor T-cell infusion compared with those who did not develop ICANS (no ICANS: 29.4 pg/mL, vs any ICANS: 87.6 pg/mL; P < .001). Baseline NfL levels further predicted ICANS development with high accuracy (area under the ROC curve, 0.96), sensitivity (0.91), and specificity (0.95). Levels of NfL remained elevated across all time points, up to 30 days postinfusion. Baseline NfL levels correlated with ICANS severity but not demographic factors, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies. Conclusions and Relevance: In a subset of patients in this cross-sectional study, the risk of developing ICANS was associated with preexisting neuroaxonal injury that was quantifiable with plasma NfL level. This latent neuroaxonal injury was present prior to drug administration but was not associated with historic neurotoxic therapies or nononcologic neurologic disease. Preinfusion NfL may further permit early screening and identification of patients most at risk for ICANS. Additional studies are needed to determine NfL's utility as a predictive biomarker for early (preemptive or prophylactic) intervention and to delineate the origin of this underlying neural injury.

Socioeconomic status largely explains integrase inhibitors-related body composition differences in chronically infected men living with HIV.

BACKGROUND: Substantial body composition alterations have been reported after starting combined antiretroviral therapy (cART). We characterized a cohort of chronically infected and virologically suppressed (VL < 50 copies/ml) men (≥50 years old) living with HIV (MLWH) who were switched to integrase inhibitors (INSTI), and compared their body composition parameters and proinflammatory/endocrine profiles to age-matched MLWH on integrase inhibitor free (non-INSTI) regimens, taking into account neighborhood-level measures of socioeconomic status (SES). In addition, we used previously published HIV-seronegative men of the same age as controls. METHODS: We used dual energy X-ray absorptiometry to quantify body composition parameters, and measured plasma proinflammatory/endocrine markers in 56 MLWH. We compared body composition to a publicly available dataset of 450 HIV-seronegative men of similar age. Within the MLWH group, body composition and plasma proinflammatory/endocrine markers were compared between individuals on INSTI and non-INSTI regimens, accounting for SES. RESULTS: Men living with HIV tended to have a greater android/gynoid ratio compared to HIV-seronegative men (p < 0.001). INSTI usage in MLWH was associated with lower adiposity measures when compared to non-INSTI, although these differences largely disappeared after controlling for SES. Proinflammatory/endocrine markers were similar for INSTI and non-INSTI MLWH. CONCLUSIONS: Among cART-experienced MLWH, those receiving INSTI-containing regimens had modestly lower adiposity compared to non-INSTI MLWH, although these differences were explained by SES. Future studies examining the relationship between INSTI use and body composition should consider the impact of SES.

Assessment of Instrumental Activities of Daily Living in Preclinical Alzheimer Disease.

Questionnaires are used to assess instrumental activities of daily living (IADL) among individuals with preclinical Alzheimer disease (AD). They have indicated no functional impairment among this population. We aim to determine among cognitively normal (CN) older adults with and without preclinical AD whether: (a) performance-based IADL assessment measures a wider range of function than an IADL questionnaire and (b) biomarkers of AD are associated with IADL performance. In this cross-sectional analysis of 161 older adults, participants in studies of AD completed an IADL questionnaire, performance-based IADL assessment, cognitive assessments, and had biomarkers of AD (amyloid, hippocampal volume, brain network strength) assessed within 2 to 3 years. Performance-based IADL scores were more widely distributed compared with the IADL questionnaire. Smaller hippocampal volumes and reduced brain network connections were associated with worse IADL performance. A performance-based IADL assessment demonstrates functional impairment associated with neurodegeneration among CN older adults.

Naturalistic driving measures of route selection associate with resting state networks in older adults.

Our objective was to identify functional brain changes that associate with driving behaviors in older adults. Within a cohort of 64 cognitively normal adults (age 60+), we compared naturalistic driving behavior with resting state functional connectivity using machine learning. Functional networks associated with the ability to interpret and respond to external sensory stimuli and the ability to multi-task were associated with measures of route selection. Maintenance of these networks may be important for continued preservation of driving abilities.

Network dysfunction in cognitively normal APOE ε4 carriers is related to subclinical tau.

INTRODUCTION: Apolipoprotein E (APOE) ε4 allele status is associated with amyloid and tau-related pathological changes related to Alzheimer's disease (AD). However, it is unknown whether brain network changes are related to amyloid beta (Aß) and/or tau-related pathology in cognitively normal APOE ε4 carriers with subthreshold Aß accumulation. METHODS: Resting state functional connectivity measures of network integrity were evaluated in cognitively normal individuals (n = 121, mean age 76.6 ± 7.8 years, 15% APOE ε4 carriers, 65% female) with minimal Aß per cerebrospinal fluid (CSF) or amyloid positron emission tomography. RESULTS: APOE ε4 carriers had increased lateralized connections relative to callosal connections within the default-mode, memory, and salience networks (P = .02), with significant weighting on linear regression toward CSF total tau (P = .03) and CSF phosphorylated tau at codon 181 (P = .03), but not CSF Aß42 . DISCUSSION: Cognitively normal APOE ε4 carriers with subthreshold amyloid accumulation may have network reorganization associated with tau.

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.

Socioeconomic Status Mediates Racial Differences Seen Using the AT(N) Framework.

OBJECTIVES: African Americans are at greater risk for developing Alzheimer's disease (AD) dementia than non-Hispanic whites. In addition to biological considerations (eg, genetic influences and comorbid disorders), social and environmental factors may increase the risk of AD dementia. This paper (1) assesses neuroimaging biomarkers of amyloid (A), tau (T), and neurodegeneration (N) for potential racial differences and (2) considers mediating effects of socioeconomic status (SES) and measures of small vessel and cardiovascular disease on observed race differences. METHODS: Imaging measures of AT(N) (amyloid and tau positron emission tomography [PET]) structural magnetic resonance imaging (MRI), and resting state functional connectivity (rs-fc) were collected from African American (n = 131) and white (n = 685) cognitively normal participants age 45 years and older. Measures of small vessel and cardiovascular disease (white matter hyperintensities [WMHs] on MRI, blood pressure, and body mass index [BMI]) and area-based SES were included in mediation analyses. RESULTS: Compared to white participants, African American participants had greater neurodegeneration, as measured by decreased cortical volumes (Cohen's f2 = 0.05, p < 0.001). SES mediated the relationship between race and cortical volumes. There were no significant race effects for amyloid, tau, or rs-fc signature. INTERPRETATION: Modifiable factors, such as differences in social contexts and resources, particularly area-level SES, may contribute to observed racial differences in AD. Future studies should emphasize collection of relevant psychosocial factors in addition to the development of intentional diversity and inclusion efforts to improve the racial/ethnic and socioeconomic representativeness of AD studies. ANN NEUROL 2021;89:254-265.

Sex-related Differences in Tau Positron Emission Tomography (PET) and the Effects of Hormone Therapy (HT).

IMPORTANCE: Female sex is a major risk factor for late-onset Alzheimer disease (AD), and sex hormones have been implicated as a possible protective factor. Neuroimaging studies that evaluated the effects of sex hormones on brain integrity have primarily emphasized neurodegenerative measures rather than amyloid and tau burden. OBJECTIVE: We compared cortical amyloid and regional tau positron emission tomography (PET) deposition between cognitively normal males and females. We also compared preclinical AD pathology between females who have and have not used hormone therapy (HT). Finally, we compared the effects of amyloid and tau pathology on cognition, testing for both sex and HT effects. DESIGN, SETTING, AND PARTICIPANTS: We analyzed amyloid, tau, and cognition in a cognitively normal cross-sectional cohort of older individuals (n=148) followed at the Knight Alzheimer Disease Research Center. Amyloid and tau PET, medication history, and neuropsychological testing were obtained for each participant. RESULTS: Within cognitively normal individuals, there was no difference in amyloid burden by sex. Whether or not we controlled for amyloid burden, female participants had significantly higher tau PET levels than males in multiple regions, including the rostral middle frontal and superior and middle temporal regions. HT accounted for a small reduction in tau PET; however, males still had substantially lower tau PET compared with females. Amyloid PET and tau PET burden were negatively associated with cognitive performance, although increasing amyloid PET did not have a deleterious effect on cognitive performance for women with a history of HT. CONCLUSIONS AND RELEVANCE: Regional sex-related differences in tau PET burden may contribute to the disparities in AD prevalence between males and females. The observed decreases tau PET burden in HT users has important implications for clinical practice and trials and deserves future consideration in longitudinal studies.

Falls Associate with Neurodegenerative Changes in ATN Framework of Alzheimer's Disease.

BACKGROUND: Behavioral markers for Alzheimer's disease (AD) are not included within the widely used amyloid-tau-neurodegeneration framework. OBJECTIVE: To determine when falls occur among cognitively normal (CN) individuals with and without preclinical AD. METHODS: This cross-sectional study recorded falls among CN participants (n = 83) over a 1-year period. Tailored calendar journals recorded falls. Biomarkers including amyloid positron emission tomography (PET) and structural and functional magnetic resonance imaging were acquired within 2 years of fall evaluations. CN participants were dichotomized by amyloid PET (using standard cutoffs). Differences in amyloid accumulation, global resting state functional connectivity (rs-fc) intra-network signature, and hippocampal volume were compared between individuals who did and did not fall using Wilcoxon rank sum tests. Among preclinical AD participants (amyloid-positive), the partial correlation between amyloid accumulation and global rs-fc intra-network signature was compared for those who did and did not fall. RESULTS: Participants who fell had smaller hippocampal volumes (p = 0.04). Among preclinical AD participants, those who fell had a negative correlation between amyloid uptake and global rs-fc intra-network signature (R = -0.75, p = 0.012). A trend level positive correlation was observed between amyloid uptake and global rs-fc intra-network signature (R = 0.70, p = 0.081) for preclinical AD participants who did not fall. CONCLUSION: Falls in CN older adults correlate with neurodegeneration biomarkers. Participants without falls had lower amyloid deposition and preserved global rs-fc intra-network signature. Falls most strongly correlated with presence of amyloid and loss of brain connectivity and occurred in later stages of preclinical AD.

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.

Resting State Functional Connectivity Signature Differentiates Cognitively Normal from Individuals Who Convert to Symptomatic Alzheimer's Disease.

BACKGROUND: Changes in resting state functional connectivity (rs-fc) occur in Alzheimer's disease (AD), but few longitudinal rs-fc studies have been performed. Most studies focus on single networks and not a global measure of rs-fc. Although the amyloid tau neurodegeneration (AT(N)) framework is increasingly utilized by the AD community, few studies investigated when global rs-fc signature changes occur within this model. OBJECTIVE: 1) Identify a global rs-fc signature that differentiates cognitively normal (CN) individuals from symptomatic AD. 2) Assess when longitudinal changes in rs-fc occur relative to conversion to symptomatic AD. 3) Compare rs-fc with amyloid, tau, and neurodegeneration biomarkers. METHODS: A global rs-fc signature composed of intra-network connections was longitudinally evaluated in a cohort of cognitively normal participants at baseline (n = 335). Biomarkers, including cerebrospinal fluid (Aß42 and tau), structural magnetic resonance imaging, and positron emission tomography were obtained. RESULTS: Global rs-fc signature distinguished CN individuals from individuals who developed symptomatic AD. Changes occurred nearly four years before conversion to symptomatic AD. The global rs-fc signature most strongly correlated with markers of neurodegeneration. CONCLUSION: The global rs-fc signature changes near symptomatic onset and is likely a neurodegenerative biomarker. Rs-fc changes could serve as a biomarker for evaluating potential therapies for symptomatic conversion to AD.