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Introduction: Cerebrospinal fluid (CSF) tau phosphorylation at multiple sites is associated with cortical amyloid and other pathologic changes in Alzheimer's disease. These relationships can be non-linear. We used an artificial neural network to assess the ability of 10 different CSF tau phosphorylation sites to predict continuous amyloid positron emission tomography (PET) values., Methods: CSF tau phosphorylation occupancies at 10 sites (including pT181/T181, pT217/T217, pT231/T231 and pT205/T205) were measured by mass spectrometry in 346 individuals (57 cognitively impaired, 289 cognitively unimpaired). We generated synthetic amyloid PET scans using biomarkers and evaluated their performance., Results: Concentration of CSF pT217/T217 had low predictive error (average error: 13%), but also a low predictive range (ceiling 63 Centiloids). CSF pT231/T231 has slightly higher error (average error: 19%) but predicted through a greater range (87 Centiloids)., Discussion: Tradeoffs exist in biomarker selection. Some phosphorylation sites offer greater concordance with amyloid PET at lower levels, while others perform better over a greater range., Highlights: Novel pTau isoforms can predict cortical amyloid burden. pT217/T217 accurately predicts cortical amyloid burden in low-amyloid individuals. Traditional CSF biomarkers correspond with higher levels of amyloid., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Abnormal levels of Alzheimer's disease (AD) biomarkers, measured by positron emission tomography imaging using amyloid-based radiotracers and cerebrospinal fluid, are associated with impaired driving performance in older adults. We examined whether preclinical AD staging, defined using amyloid imaging and tau imaging using the radiotracer T807 (AKA flortaucipir or AV-1451), was associated with receiving a marginal/fail rating on a standardized road test (n = 42). Participants at Stage 2 (positive amyloid and tau scans) of preclinical AD were more likely to receive a marginal/fail rating compared to participants at Stage 0 or 1. Stage 2 preclinical AD may manifest in worse driving performance.

Major imaging biomarkers of Alzheimer's disease include amyloid deposition [imaged with [(11)C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [(18)F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer's disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer's disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease.

Valproic acid (VPA) reduces latent human immunodeficiency virus (HIV) reservoirs by activating resting CD4+ cells. This retrospective case-control study (n = 30) examined effects of VPA on markers of HIV progression. VPA was not associated with changes in cerebrospinal fluid viral loads (VL), plasma VL, or neuropsychological performance. VPA patients had a trend towards lower CD4+ cells (P = .08) at follow-up. Concurrent antiretrovirals did not alter these relationships. VPA does not induce viremia or promote disease progression and may be safe for clinical intervention.

BackgroundIndividuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21.MethodsWe examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ40, Aβ42, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ40, Aβ42, tau, ptau181, and NfL) and amyloid and tau PET data.FindingsFor both cohorts, the prevalence of mosaicism was

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.

BackgroundImportant 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.MethodsIn 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 β42 (Aβ42) to Aβ40 (Aβ42/40) 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 Aβ42/40 was evaluated.Findings192 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 Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p

BackgroundThe need for diagnostic biomarkers of cognitive decline is particularly important among aging adults with Down syndrome (DS). Growing empirical support has identified the utility of plasma derived biomarkers among neurotypical adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD); however, the application of such biomarkers has been limited among the DS population.ObjectiveThis study aimed to investigate the cross-sectional diagnostic performance of plasma neurofilament light chain (Nf-L) and total-tau, individually and in combination among a cohort of DS adults.MethodsPlasma samples were analyzed from n = 305 (n = 225 cognitively stable (CS); n = 44 MCI-DS; n = 36 DS-AD) participants enrolled in the Alzheimer's Biomarker Consortium -Down Syndrome.ResultsIn distinguishing DS-AD participants from CS, Nf-L alone produced an AUC of 90%, total-tau alone reached 74%, and combined reached an AUC of 86%. When age and gender were included, AUC increased to 93%. Higher values of Nf-L, total-tau, and age were all shown to be associated with increased risk for DS-AD. When distinguishing MCI-DS participants from CS, Nf-L alone produced an AUC of 65%, while total-tau alone reached 56%. A combined model with Nf-L, total-tau, age, and gender produced an AUC of 87%. Both higher values in age and total-tau were found to increase risk for MCI-DS; Nf-L levels were not associated with increased risk for MCI-DS.ConclusionAdvanced assay techniques make total-tau and particularly Nf-L useful biomarkers of both AD pathology and clinical status in DS and have the potential to serve as outcome measures in clinical trials for future disease-modifying drugs.

The National Institute on Aging in conjunction with the Alzheimer's Association (NIA-AA) recently proposed a biological framework for defining the Alzheimer's disease (AD) continuum. This new framework is based upon the key AD biomarkers (amyloid, tau, neurodegeneration, AT[N]) instead of clinical symptoms and represents the latest understanding that the pathological processes underlying AD begin decades before the manifestation of symptoms. By using these same biomarkers, individuals with Down syndrome (DS), who are genetically predisposed to developing AD, can also be placed more precisely along the AD continuum. The A/T(N) framework is therefore thought to provide an objective manner by which to select and enrich samples for clinical trials. This new framework is highly flexible and allows the addition of newly confirmed AD biomarkers into the existing AT(N) groups. As biomarkers for other pathological processes are validated, they can also be added to the AT(N) classification scheme, which will allow for better characterization and staging of AD in DS. These biological classifications can then be merged with clinical staging for an examination of factors that impact the biological and clinical progression of the disease. Here, we leverage previously published guidelines for the AT(N) framework to generate such a plan for AD among adults with DS.

BackgroundHuman immunodeficiency virus (HIV) penetrates the brain in early infection. We used neuroimaging to longitudinally examine the impact of HIV and combination antiretroviral therapy (cART) on the brain in treated and untreated HIV-infected participants, starting in primary HIV infection (PHI).MethodsSixty-five participants, enrolled during PHI, underwent longitudinal magnetic resonance imaging, 30 of whom commenced cART during follow-up. Cross-sectional data from 16 patients with chronic HIV infection (CHI) and 19 HIV-uninfected participants were included for comparison. Brain volume and cortical thickness were estimated using tensor-based morphometry and cortical modeling, respectively. Mixed-effects models longitudinally mapped structural brain changes before and after cART. The relationship between brain morphometry estimates and blood and cerebrospinal fluid (CSF) biomarkers were also tested. Region-of-interest analyses were performed to compare brain morphometry estimates between the groups.ResultsPrior to cART, longer duration of untreated infection in PHI correlated with volume loss in the thalamus, caudate, and cerebellum, and with cortical thinning in the frontal and temporal lobes and cingulate cortex. After cART, no further volume loss was observed. However, small increases of cortical thickness in the frontal and temporal lobe correlated with longer cART duration. No correlations were observed with blood or CSF measures. The PHI group did not have different brain morphometric measures compared to the HIV-uninfected group, but had larger volumes in the thalamus, caudate, putamen, and cortical gray matter compared with CHI participants.ConclusionsSubcortical atrophy and cortical thinning occur during untreated infection but may be arrested by cART. These findings emphasize the importance of early cART.

Background: Examination of Alzheimer's disease (AD) related biomarkers among diverse communities has remained limited. Objective: The aim of this study was to expand on prior work to provide a characterization of ptau181 among a diverse community sample. Consideration was taken regarding the impact of comorbidities on ptau181 levels including medical. Methods: 3,228 (n = 770 African American [AA], n = 1,231 Hispanic, and n = 1,227 non-Hispanic white [NHW]) Health and Aging Brain Study- Health Disparities (HABS-HD) participants were included in this study. ANCOVAs were conducted to examine differences in ptau181 levels across race and ethnic groups. Violin plots were also generated stratified by APOEɛ4 carrier status, Amyloid PET positivity status, medical comorbidity (hypertension, dyslipidemia, chronic kidney disease [CKD], and diabetes) and by cognitive diagnosis. Results: Ptau181 levels were found to differ between Hispanics and NHW after covarying for age, sex, and APOEɛ4 status. Amyloid PET positivity was associated with higher ptau181 levels across all groups. APOEɛ4 positivity status was only significantly associated with ptau181 levels among AAs. Across all race and ethnic groups, those with a diagnosis of CKD had higher levels of ptau181. When stratified by cognitive diagnosis, cognitively unimpaired Hispanics had higher ptau181 if they also had a diagnosis of CKD or diabetes. p-values ≤0.01. Conclusions: Differences in ptau181 levels were shown in a diverse community sample. Medical comorbidities had a differing effect on ptau181 levels particularly among Hispanics even without cognitive impairment. Findings support the need for future work to consider comorbid conditions when examining the utility of ptau181. [ABSTRACT FROM AUTHOR]

ObjectiveInflammation and infection within the central nervous system is initiated during primary HIV infection (PHI), but the association of these processes with the integrity of brain white matter during PHI is unknown.DesignWe used diffusion tensor imaging (DTI) in this prospective cross-sectional neuroimaging study to determine the extent of white matter involvement in early HIV infection.MethodsAntiretroviral-naive PHI (defined as

Background While antiretroviral therapy (ART) has improved outcomes for people with HIV (PWH), brain dysfunction is still evident. Immune activation and inflammation remain elevated in PWH receiving ART, thereby contributing to morbidity and mortality. Previous studies demonstrated reduced functional and structural changes in PWH; however, underlying mechanisms remain elusive. Methods Our cohort consisted of PWH with ART adherence and viral suppression (< 50 copies/mL; N = 173). Measurements included immune cell markers of overall immune health (CD4/CD8 T-cell ratio) and myeloid inflammation (CD16+ monocytes), plasma markers of inflammatory status (soluble CD163 and CD14), and structural and functional neuroimaging (volume and cerebral blood flow [CBF], respectively). Results Decreased CD4/CD8 ratios correlated with reduced brain volume, and higher levels of inflammatory CD16+ monocytes were associated with reduced brain volume in total cortex and gray matter. An increase in plasma soluble CD14—a marker of acute peripheral inflammation attributed to circulating microbial products—was associated with reduced CBF within the frontal, parietal, temporal, and occipital cortices and total gray matter. Conclusions CD4/CD8 ratio and number of CD16+ monocytes, which are chronic immune cell markers, are associated with volumetric loss in the brain. Additionally, this study shows a potential new association between plasma soluble CD14 and CBF. [ABSTRACT FROM AUTHOR]

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-β (Aβ)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 Aβ42. 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. [ABSTRACT FROM AUTHOR]

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-β [Aβ] 42/Aβ40 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 Aβ42 and Aβ40 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 Aβ42/Aβ40 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 Aβ42/Aβ40 ratio was significantly lower, and the APS higher, in PWoH_AD than in other groups. A lower Aβ42/Aβ40 ratio and higher APS was associated with smaller hippocampal volumes for PWoH_AD. The Aβ42/Aβ40 ratio and APS were not associated with cognition or HIV clinical measures for PWH. Conclusions The plasma Aβ42/Aβ40 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. [ABSTRACT FROM AUTHOR]

Background: Driving behavior as a digital marker and recent developments in blood-based biomarkers show promise as a widespread solution for the early identification of Alzheimer's disease (AD). Objective: This study used artificial intelligence methods to evaluate the association between naturalistic driving behavior and blood-based biomarkers of AD. Methods: We employed an artificial neural network (ANN) to examine the relationship between everyday driving behavior and plasma biomarker of AD. The primary outcome was plasma Aβ42/Aβ40, where Aβ42/Aβ40 < 0.1013 was used to define amyloid positivity. Two ANN models were trained and tested for predicting the outcome. The first model architecture only includes driving variables as input, whereas the second architecture includes the combination of age, APOE ɛ4 status, and driving variables. Results: All 142 participants (mean [SD] age 73.9 [5.2] years; 76 [53.5%] men; 80 participants [56.3% ] with amyloid positivity based on plasma Aβ42/Aβ40) were cognitively normal. The six driving features, included in the ANN models, were the number of trips during rush hour, the median and standard deviation of jerk, the number of hard braking incidents and night trips, and the standard deviation of speed. The F1 score of the model with driving variables alone was 0.75 [0.023] for predicting plasma Aβ42/Aβ40. Incorporating age and APOE ɛ4 carrier status improved the diagnostic performance of the model to 0.80 [>0.051]. Conclusion: Blood-based AD biomarkers offer a novel opportunity to establish the efficacy of naturalistic driving as an accessible digital marker for AD pathology in driving research. [ABSTRACT FROM AUTHOR]

Background: Virtually all adults with Down syndrome (DS) develop Alzheimer's disease (AD) pathology, but research gaps remain in understanding early signs of AD in DS. Objective: The goal of the present study was to determine if unintentional weight loss is part of AD in DS. The specific aims were to: 1) examine relation between chronological age, weight, AD pathology, and AD-related cognitive decline were assessed in a large cohort of adults with DS, and 2) determine if baseline PET amyloid-β (Aβ) and tau PET status (–versus+) and/or decline in memory and mental status were associated with weight loss prior to AD progression. Methods: Analyses included 261 adults with DS. PET data were acquired using [11C] PiB for Aβ and [18F] AV-1451 for tau. Body mass index (BMI) was calculated from weight and height. Direct measures assessed dementia and memory. Clinical AD status was determined using a case consensus process. Percent weight decline across 16–20 months was assessed in a subset of participants (n = 77). Results: Polynomial regressions indicated an 0.23 kg/m2 decrease in BMI per year beginning at age 36.5 years, which occurs alongside the period during which Aβ and tau increase and memory and mental status decline. At a within-person level, elevated Aβ, decline in memory and mental status were associated with higher percent weight loss across 16–20 months. Conclusion: Unintentional weight loss occurs alongside Aβ deposition and prior to onset of AD dementia, and thus may be a useful sign of AD in DS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Persons with human immunodeficiency virus (PWH) are characterized by altered brain structure and function. As they attain normal lifespans, it has become crucial to understand potential interactions between human immunodeficiency virus (HIV) and aging. However, it remains unclear how brain aging varies with viral load (VL). Methods In this study, we compare magnetic resonance imaging (MRI) biomarkers among PWH with undetectable VL (UVL; ≤50 genomic copies/mL; n = 230), PWH with detectable VL (DVL; >50 copies/mL; n = 93), and HIV-uninfected (HIV–) controls (n = 206). To quantify gray matter cerebral blood flow (CBF), we utilized arterial spin labeling. To measure structural aging, we used a publicly available deep learning algorithm to estimate brain age from T1-weighted MRI. Cognitive performance was measured using a neuropsychological battery covering 5 domains. Results Associations between age and CBF varied with VL. Older PWH with DVL had reduced CBF vs PWH with UVL (P =.02). Structurally predicted brain aging was accelerated in PWH vs HIV– controls regardless of VL (P <.001). Overall, PWH had impaired learning, executive function, psychomotor speed, and language compared to HIV– controls. Structural brain aging was associated with reduced psychomotor speed (P <.001). Conclusions Brain aging in HIV is multifaceted. CBF depends on age and current VL and is improved by medication adherence. By contrast, structural aging is an indicator of cognitive function and reflects serostatus rather than current VL. [ABSTRACT FROM AUTHOR]

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-β42 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-β42 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. [ABSTRACT FROM AUTHOR]

Recent functional magnetic resonance imaging studies have demonstrated that moment-to-moment variability in the blood oxygen level–dependent (BOLD) signal is related to age differences, cognition, and symptomatic Alzheimer's disease (AD). However, no studies have examined BOLD variability in the context of preclinical AD. We tested relationships between resting-state BOLD variability and biomarkers of amyloidosis, tauopathy, and neurodegeneration in a large (N = 321), well-characterized sample of cognitively normal adults (age = 39–93), using multivariate machine learning techniques. Furthermore, we controlled for cardiovascular health factors, which may contaminate resting-state BOLD variability estimates. BOLD variability, particularly in the default mode network, was related to cerebrospinal fluid (CSF) amyloid-β42 but was not related to CSF phosphorylated tau-181. Furthermore, BOLD variability estimates were also related to markers of neurodegeneration, including CSF neurofilament light protein, hippocampal volume, and a cortical thickness composite. Notably, relationships with hippocampal volume and cortical thickness survived correction for cardiovascular health and also contributed to age-related differences in BOLD variability. Thus, BOLD variability may be sensitive to preclinical pathology, including amyloidosis and neurodegeneration in AD-sensitive areas. • BOLD variability in the default mode network is sensitive to CSF amyloid. • BOLD variability is sensitive to hippocampal volume and cortical thickness. • Preclinical neurodegeneration may contribute to age differences in BOLD variability. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Depression is also common with older age. Alzheimer's disease (AD) studies suggest that both cerebrospinal fluid and positron emission tomography (PET) amyloid biomarkers are associated with more depressive symptoms in cognitively normal older adults. The recent availability of tau radiotracers offers the ability to examine in vivo tauopathy. It is unclear if the tau biomarker is associated with depression diagnosis.Objective: We examined if tau and amyloid imaging were associated with a depression diagnosis among cognitively normal adults (Clinical Dementia Rating = 0) and whether antidepressants modified this relationship.Methods: Among 301 participants, logistic regression models evaluated whether in vivo PET tau was associated with depression, while another model tested the interaction between PET tau and antidepressant use. A second set of models substituted PET amyloid for PET tau. A diagnosis of depression (yes/no) was made during an annual clinical assessment by a clinician. Antidepressant use (yes/no) was determined by comparing medications the participants used to a list of 30 commonly used antidepressants. All models adjusted for age, sex, education, race, and apolipoprotein ɛ4. Similar models explored the association between the biomarkers and depressive symptoms.Results: Participants with elevated tau were twice as likely to be depressed. Antidepressant use modified this relationship where participants with elevated tau who were taking antidepressants had greater odds of being depressed. Relatedly, elevated amyloid was not associated with depression.Conclusions: Our results demonstrate that tau, not amyloid, was associated with a depression diagnosis. Additionally, antidepressant use interacts with tau to increase the odds of depression among cognitively normal adults. [ABSTRACT FROM AUTHOR]

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 (Aβ42 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. [ABSTRACT FROM AUTHOR]

Background: Emerging evidence shows that cognitively normal older adults with preclinical Alzheimer's disease (AD) make more errors and are more likely to receive a marginal/fail rating on a standardized road test compared to older adults without preclinical AD, but the extent to which preclinical AD impacts everyday driving behavior is unknown.Objective: To examine self-reported and naturalistic longitudinal driving behavior among persons with and without preclinical AD.Method: We prospectively followed cognitively normal drivers (aged 65 + years) with (n = 10) and without preclinical AD (n = 10) for 2.5 years. Preclinical AD was assessed using amyloid positron emission tomography (PET) with Pittsburgh Compound B. The Driving Habits Questionnaire assessed self-reported driving outcomes. Naturalistic driving was captured using a commercial GPS data logger plugged into the on-board diagnostics II port of each participant's vehicle. Data were sampled every 30 seconds and all instances of speeding, hard braking, and sudden acceleration were recorded.Results: Preclinical AD participants went to fewer places/unique destinations, traveled fewer days, and took fewer trips than participants without preclinical AD. The preclinical AD group reported a smaller driving space, greater dependence on other drivers, and more difficulty driving due to vision difficulties. Persons with preclinical AD had fewer trips with any aggression and showed a greater decline across the 2.5-year follow-up period in the number of days driving per month and the number of trips between 1-5 miles.Conclusion: Changes in driving occur even during the preclinical stage of AD. [ABSTRACT FROM AUTHOR]

Longer periods are needed to examine how biomarker changes occur relative to incident sporadic cognitive impairment. We evaluated molecular (CSF and imaging), structural, and cognitive biomarkers to predict incident cognitive impairment and examined longitudinal biomarker changes before and after symptomatic onset. Data from participants who were cognitively normal, underwent amyloid imaging using Pittsburgh compound B and/or CSF studies, and at least two clinical assessments were used. Stepwise Cox proportional hazards models tested associations of molecular (Pittsburgh compound B; CSF amyloid-β42, tau, ptau181, tau/amyloid-β42, ptau181/amyloid-β42), structural (normalized hippocampal volume, normalized whole brain volume), and cognitive (Animal Naming, Trail Making A, Trail Making B, Selective Reminding Test - Free Recall) biomarkers with time to Clinical Dementia Rating (CDR) > 0. Cognitively normal participants (n = 664), aged 42 to 90 years (mean ± standard deviation = 71.4 ± 9.2) were followed for up to 16.9 years (mean ± standard deviation = 6.2 ± 3.5 years). Of these, 145 (21.8%) participants developed a CDR > 0. At time of incident cognitive impairment, molecular, structural, and cognitive markers were abnormal for CDR > 0 compared to CDR = 0. Linear mixed models indicated rates of change in molecular biomarkers were similar for CDR = 0 and CDR > 0, suggesting that the separation in values between CDR = 0 and CDR > 0 must have occurred prior to the observation period. Rate of decline for structural and cognitive biomarkers was faster for CDR > 0 compared to CDR = 0 (P < 0.0001). Structural and cognitive biomarkers for CDR > 0 diverged from CDR 0 at 9 and 12 years before incident cognitive impairment, respectively. Within those who developed CDR > 0, a natural separation occurred for Pittsburgh compound B values. In particular, CDR > 0 who had at least one APOE ɛ4 allele had higher, and more rapid increase in Pittsburgh compound B, while APOE ɛ2 was observed to have slower increases in Pittsburgh compound B. Of molecular biomarker-positive participants followed for at least 10 years (n = 16-23), ∼70% remained CDR = 0 over the follow-up period. In conclusion, conversion from cognitively normal to CDR > 0 is characterized by not only the magnitude of molecular biomarkers but also rate of change in cognitive and structural biomarkers. Findings support theoretical models of biomarker changes seen during transition to cognitive impairment using longitudinal data and provide a potential time for changes seen during this transition. These findings support the use of molecular biomarkers for trial inclusion and cognitive/structural biomarkers for evaluating trial outcomes. Finally, results support a potential role for APOE ɛ in modulating amyloid accumulation in CDR > 0 with APOE ɛ4 being deleterious and APOE ɛ2 protective. [ABSTRACT FROM AUTHOR]

Converging evidence from structural, metabolic and functional connectivity MRI suggests that neurodegenerative diseases, such as Alzheimer's disease, target specific neural networks. However, age-related network changes commonly co-occur with neuropathological cascades, limiting efforts to disentangle disease-specific alterations in network function from those associated with normal ageing. Here we elucidate the differential effects of ageing and Alzheimer's disease pathology through simultaneous analyses of two functional connectivity MRI datasets: (i) young participants harbouring highly-penetrant mutations leading to autosomal-dominant Alzheimer's disease from the Dominantly Inherited Alzheimer's Network (DIAN), an Alzheimer's disease cohort in which age-related comorbidities are minimal and likelihood of progression along an Alzheimer's disease trajectory is extremely high; and (ii) young and elderly participants from the Harvard Aging Brain Study, a cohort in which imaging biomarkers of amyloid burden and neurodegeneration can be used to disambiguate ageing alone from preclinical Alzheimer's disease. Consonant with prior reports, we observed the preferential degradation of cognitive (especially the default and dorsal attention networks) over motor and sensory networks in early autosomal-dominant Alzheimer's disease, and found that this distinctive degradation pattern was magnified in more advanced stages of disease. Importantly, a nascent form of the pattern observed across the autosomal-dominant Alzheimer's disease spectrum was also detectable in clinically normal elderly with clear biomarker evidence of Alzheimer's disease pathology (preclinical Alzheimer's disease). At the more granular level of individual connections between node pairs, we observed that connections within cognitive networks were preferentially targeted in Alzheimer's disease (with between network connections relatively spared), and that connections between positively coupled nodes (correlations) were preferentially degraded as compared to connections between negatively coupled nodes (anti-correlations). In contrast, ageing in the absence of Alzheimer's disease biomarkers was characterized by a far less network-specific degradation across cognitive and sensory networks, of between- and within-network connections, and of connections between positively and negatively coupled nodes. We go on to demonstrate that formalizing the differential patterns of network degradation in ageing and Alzheimer's disease may have the practical benefit of yielding connectivity measurements that highlight early Alzheimer's disease-related connectivity changes over those due to age-related processes. Together, the contrasting patterns of connectivity in Alzheimer's disease and ageing add to prior work arguing against Alzheimer's disease as a form of accelerated ageing, and suggest multi-network composite functional connectivity MRI metrics may be useful in the detection of early Alzheimer's disease-specific alterations co-occurring with age-related connectivity changes. More broadly, our findings are consistent with a specific pattern of network degradation associated with the spreading of Alzheimer's disease pathology within targeted neural networks. [ABSTRACT FROM AUTHOR]

The two primary molecular pathologies in Alzheimer's disease are amyloid-β plaques and tau-immunoreactive neurofibrillary tangles. Investigations into these pathologies have been restricted to cerebrospinal fluid assays, and positron emission tomography tracers that can image amyloid-β plaques. Tau tracers have recently been introduced into the field, although the utility of the tracer and its relationship to other Alzheimer biomarkers are still unknown. Here we examined tau deposition in 41 cognitively normal and 11 cognitively impaired older adults using the radioactive tau ligand (18)F-AV-1451 (previously known as T807) who also underwent a lumbar puncture to assess cerebrospinal fluid levels of total tau (t-tau), phosphorylated tau181 (p-tau181) and amyloid-β42 Voxel-wise statistical analyses examined spatial patterns of tau deposition associated with cognitive impairment. We then related the amount of tau tracer uptake to levels of cerebrospinal fluid biomarkers. All analyses controlled for age and gender and, when appropriate, the time between imaging and lumbar puncture assessments. Symptomatic individuals (Clinical Dementia Rating > 0) demonstrated markedly increased levels of tau tracer uptake. This elevation was most prominent in the temporal lobe and temporoparietal junction, but extended more broadly into parietal and frontal cortices. In the entire cohort, there were significant relationships among all cerebrospinal fluid biomarkers and tracer uptake, notably for tau-related cerebrospinal fluid markers. After controlling for levels of amyloid-β42, the correlations with tau uptake were r = 0.490 (P < 0.001) for t-tau and r = 0.492 (P < 0.001) for p-tau181 Within the cognitively normal cohort, levels of amyloid-β42, but not t-tau or p-tau181, were associated with elevated tracer binding that was confined primarily to the medial temporal lobe and adjacent neocortical regions. AV-1451 tau binding in the medial temporal, parietal, and frontal cortices is correlated with tau-related cerebrospinal fluid measures. In preclinical Alzheimer's disease, there is focal tauopathy in the medial temporal lobes and adjacent cortices. [ABSTRACT FROM AUTHOR]

We investigated the interactions between human immunodeficiency virus (HIV) infection and aging and their effects on brain function demands by means of functional magnetic resonance imaging (fMRI). A multiple-regression model was used to study the association and interaction between fMRI measures, HIV serostatus, and age for 26 HIV-infected subjects and 25 seronegative subjects. Although HIV serostatus and age independently affected fMRI measures, no interaction occurred. Functional brain demands in HIV-positive subjects were equivalent to those of HIV-negative subjects who were 15-20 years older. Frailty parallels between HIV infection and aging could result from continued immunological challenges depleting resources and triggering increased metabolic demands. In the future, fMRI could be a noninvasive biomarker to assess HIV infection in the brain. [ABSTRACT FROM AUTHOR]

• Drivers with preclinical Alzheimer disease drive more slowly compared to drivers without. • Road diets decrease speed variance between older drivers. • Attentional control partially mediates observed differences in driving speed. The driving populace of the United States is aging. The prevalence of Alzheimer disease (AD) will increase in the coming decades. Road diets (that is, the reallocation of one or more lanes of car traffic to other uses) have been proposed as a modification to increase pedestrian safety, particularly for older adults. In contrast, we considered the impacts of road diets on aging drivers, and on those with early pathological accumulation of AD. We observed naturalistic driving data for 60 cognitively normal older drivers (Age Range = 62–87 years, Median = 75 years) driving across three road segments located in the St. Louis metropolitan area, Missouri, United States. We used neuroimaging and lumbar puncture derived biomarker data to determine which of the drivers had preclinical AD. Since previous AD studies identified a variety of changes in driving behavior among older drivers with preclinical AD, we examined driving speed before and after lane repurposing. We found that drivers with preclinical AD drove at lower speeds compared to those without preclinical AD prior to road diet implementation. After lanes were repurposed, there was no statistical difference in the speed between older drivers with and without preclinical AD. We evaluated cognitive performance and found that attentional control had a mediating effect on driver speed, suggesting that an individual's ability to focus on a specific task and filter out distractions was associated with faster driving. Driving speed after lane repurposing is not mediated by attentional control, suggesting that road diets are impervious to individual driver capacity. We conclude that lane repurposing has potential as an important mobility infrastructure solution that could enhance older driver safety and facilitate aging in place. [ABSTRACT FROM AUTHOR]

• Adults with Down syndrome have a high risk for Alzheimer's disease • There is variability in the age of Alzheimer's disease onset in Down syndrome. • Actigraph accelerometers assessed daytime sedentary behavior and physical activity. • Sedentary behavior and activity related to cognitive functioning and white matter. • Physical activity intervention may help promote healthy aging in Down syndrome. Adults with Down syndrome (DS) are at risk for Alzheimer's disease. Despite sharing trisomy 21, however, there is variability in the age of disease onset. This variability may mean that other factors, such as lifestyle, influence cognitive aging and disease timing. The present study assessed the association between everyday life physical activity using an actigraph accelerometer and cognitive functioning and early Alzheimer's disease pathology via positron emission tomography amyloid-β and tau and diffusion tension imaging measures of white matter integrity in 61 non-demented adults with DS. Percent time in sedentary behavior and in moderate-to-vigorous activity were associated (negatively and positively, respectively) with cognitive functioning (r = -.472 to.572, p < 0.05). Neither sedentary behavior nor moderate-to-vigorous activity were associated with amyloid-β or tau, but both were associated with white matter integrity in the superior and inferior longitudinal fasciculus (Fractional Anisotropy: r = -.397 to -.419, p < 0.05; Mean Diffusivity: r =.400, p < 0.05). Longitudinal studies are needed to determine if physical activity promotes healthy aging in DS. [ABSTRACT FROM AUTHOR]

Background: Models of Alzheimer's disease propose a sequence of amyloid β (Aβ) accumulation, hypometabolism, and structural decline that precedes the onset of clinical dementia. These pathological features evolve both temporally and spatially in the brain. In this study, we aimed to characterise where in the brain and when in the course of the disease neuroimaging biomarkers become abnormal.Methods: Between Jan 1, 2009, and Dec 31, 2015, we analysed data from mutation non-carriers, asymptomatic carriers, and symptomatic carriers from families carrying gene mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) enrolled in the Dominantly Inherited Alzheimer's Network. We analysed 11C-Pittsburgh Compound B (11C-PiB) PET, 18F-Fluorodeoxyglucose (18F-FDG) PET, and structural MRI data using regions of interest to assess change throughout the brain. We estimated rates of biomarker change as a function of estimated years to symptom onset at baseline using linear mixed-effects models and determined the earliest point at which biomarker trajectories differed between mutation carriers and non-carriers. This study is registered at ClinicalTrials.gov (number NCT00869817) FINDINGS: 11C-PiB PET was available for 346 individuals (162 with longitudinal imaging), 18F-FDG PET was available for 352 individuals (175 with longitudinal imaging), and MRI data were available for 377 individuals (201 with longitudinal imaging). We found a sequence to pathological changes, with rates of Aβ deposition in mutation carriers being significantly different from those in non-carriers first (across regions that showed a significant difference, at a mean of 18·9 years [SD 3·3] before expected onset), followed by hypometabolism (14·1 years [5·1] before expected onset), and lastly structural decline (4·7 years [4·2] before expected onset). This biomarker ordering was preserved in most, but not all, regions. The temporal emergence within a biomarker varied across the brain, with the precuneus being the first cortical region for each method to show divergence between groups (22·2 years before expected onset for Aβ accumulation, 18·8 years before expected onset for hypometabolism, and 13·0 years before expected onset for cortical thinning).Interpretation: Mutation carriers had elevations in Aβ deposition, reduced glucose metabolism, and cortical thinning compared with non-carriers which preceded the expected onset of dementia. Accrual of these pathologies varied throughout the brain, suggesting differential regional and temporal vulnerabilities to Aβ, metabolic decline, and structural atrophy, which should be taken into account when using biomarkers in a clinical setting as well as designing and evaluating clinical trials.Funding: US National Institutes of Health, the German Center for Neurodegenerative Diseases, and the Medical Research Council Dementias Platform UK. [ABSTRACT FROM AUTHOR]