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1.
Neurobiol Aging ; 85: 131-139, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31735379

RESUMO

The relationship between regional brain myelination and aging has been the subject of intense study, with magnetic resonance imaging perhaps the most effective modality for elucidating this. However, most of these studies have used nonspecific methods to probe myelin content, including diffusion tensor imaging, magnetization transfer ratio, and relaxation times. In the present study, we used the BMC-mcDESPOT analysis, a direct and specific method for imaging of myelin water fraction (MWF), a surrogate of myelin content. We investigated age-related differences in MWF in several brain regions in a large cohort of cognitively unimpaired participants, spanning a wide age range. Our results indicate a quadratic, inverted U-shape, relationship between MWF and age in all brain regions investigated, suggesting that myelination continues until middle age followed by decreases at older ages. We also observed that these age-related differences vary across different brain regions, as expected. Our results provide evidence for nonlinear associations between age and myelin in a large sample of well-characterized adults, using a direct myelin content imaging method.

2.
Neuroimage ; : 116450, 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31821869

RESUMO

As medical imaging enters its information era and presents rapidly increasing needs for big data analytics, robust pooling and harmonization of imaging data across diverse cohorts with varying acquisition protocols have become critical. We describe a comprehensive effort that merges and harmonizes a large-scale dataset of 10,477 structural brain MRI scans from participants without a known neurological or psychiatric disorder from 18 different studies that represent geographic diversity. We use this dataset and multi-atlas-based image processing methods to obtain a hierarchical partition of the brain from larger anatomical regions to individual cortical and deep structures and derive age trends of brain structure through the lifespan (3-96 years old). Critically, we present and validate a methodology for harmonizing this pooled dataset in the presence of nonlinear age trends. We provide a web-based visualization interface to generate and present the resulting age trends, enabling future studies of brain structure to compare their data with this reference of brain development and aging, and to examine deviations from ranges, potentially related to disease.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31828289

RESUMO

BACKGROUND: Cognitive decline is consistently associated with diminished life satisfaction and inability to live independently. Identifying early, novel markers of cognitive decline is imperative for improving clinical detection and promoting long-term quality of life. Fatigability, one's perceived exertion after a standardized walking task, has been associated with declines in physical function; however, it remains unclear as to whether these effects may also extend to cognitive function. METHODS: We examined whether perceived fatigability, assessed as the rating of perceived exertion (RPE) after a 5-minute slow-paced treadmill walk (0.67 m/s, 0% grade), is longitudinally associated with cognitive performance in the domains of memory, executive functions, language, and attention among 934 cognitively intact individuals aged > 50 years participating in the Baltimore Longitudinal Study of Aging (BLSA) (Mage=69.6±10.1, 51.9% female). Continuous associations between RPE and each domain (individual test and composite scores) were assessed using linear mixed effect models adjusted for demographics and comorbid conditions. RESULTS: In fully adjusted models, higher fatigability at baseline was associated with declines in all cognitive domains over an average 2.2 years of follow up (p<0.04 for all). Longitudinally, increased fatigability over time was associated with worsened executive functions (ß=-0.01, p=0.002). DISCUSSION: These findings suggest that perceived fatigability after a standardized walking task may aid in identification of individuals at a higher risk of future cognitive decline. Future research should examine underlying biological mechanisms contributing to this relationship as well as whether future interventions may target fatigability in mid-life to attenuate age-related cognitive decline.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31714574

RESUMO

BACKGROUND: Cortisol is a key stress hormone implicated in the pathogenesis of many age-related diseases. Longitudinal information on cortisol exposure has been restricted to animal models and a small number of human studies. The purpose of the present study was to quantify longitudinal change in cortisol across the adult life span. METHODS: We conducted a prospective longitudinal study of 24-hour urinary free cortisol excretion from ages 20 to 90 years and older. Participants were 1,814 men and women from the Baltimore Longitudinal Study of Aging who provided a total of 5,527 urine specimens for analysis. The average duration of longitudinal follow-up was 6.6 years. The primary outcome measure was 24-hour urinary free cortisol to creatinine ratio (UFC/Cr) as determined by liquid chromatography/mass spectrometry. RESULTS: UFC/Cr follows a U-shaped pattern across the life span with decreases in UFC/Cr in the 20s and 30s, relative stability in the 40s and 50s, and increases thereafter. This pattern of change was robust with respect to adjustment for several potential confounding factors. CONCLUSIONS: Age-related changes in cortisol exposure raise important questions about the potential protective or exacerbating role of cortisol exposure in predicting medical, physiological, and behavioral outcomes.

5.
PLoS One ; 14(11): e0225495, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31774837

RESUMO

Increasing reliance on electronic medical records at large medical centers provides unique opportunities to perform population level analyses exploring disease progression and etiology. The massive accumulation of diagnostic, procedure, and laboratory codes in one place has enabled the exploration of co-occurring conditions, their risk factors, and potential prognostic factors. While most of the readily identifiable associations in medical records are (now) well known to the scientific community, there is no doubt many more relationships are still to be uncovered in EMR data. In this paper, we introduce a novel finding index to help with that task. This new index uses data mined from real-time PubMed abstracts to indicate the extent to which empirically discovered associations are already known (i.e., present in the scientific literature). Our methods leverage second-generation p-values, which better identify associations that are truly clinically meaningful. We illustrate our new method with three examples: Autism Spectrum Disorder, Alzheimer's Disease, and Optic Neuritis. Our results demonstrate wide utility for identifying new associations in EMR data that have the highest priority among the complex web of correlations and causalities. Data scientists and clinicians can work together more effectively to discover novel associations that are both empirically reliable and clinically understudied.

6.
Brain ; 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31746986

RESUMO

Evidence suggests exposure to particulate matter with aerodynamic diameter <2.5 µm (PM2.5) may increase the risk for Alzheimer's disease and related dementias. Whether PM2.5 alters brain structure and accelerates the preclinical neuropsychological processes remains unknown. Early decline of episodic memory is detectable in preclinical Alzheimer's disease. Therefore, we conducted a longitudinal study to examine whether PM2.5 affects the episodic memory decline, and also explored the potential mediating role of increased neuroanatomic risk of Alzheimer's disease associated with exposure. Participants included older females (n = 998; aged 73-87) enrolled in both the Women's Health Initiative Study of Cognitive Aging and the Women's Health Initiative Memory Study of Magnetic Resonance Imaging, with annual (1999-2010) episodic memory assessment by the California Verbal Learning Test, including measures of immediate free recall/new learning (List A Trials 1-3; List B) and delayed free recall (short- and long-delay), and up to two brain scans (MRI-1: 2005-06; MRI-2: 2009-10). Subjects were assigned Alzheimer's disease pattern similarity scores (a brain-MRI measured neuroanatomical risk for Alzheimer's disease), developed by supervised machine learning and validated with data from the Alzheimer's Disease Neuroimaging Initiative. Based on residential histories and environmental data on air monitoring and simulated atmospheric chemistry, we used a spatiotemporal model to estimate 3-year average PM2.5 exposure preceding MRI-1. In multilevel structural equation models, PM2.5 was associated with greater declines in immediate recall and new learning, but no association was found with decline in delayed-recall or composite scores. For each interquartile increment (2.81 µg/m3) of PM2.5, the annual decline rate was significantly accelerated by 19.3% [95% confidence interval (CI) = 1.9% to 36.2%] for Trials 1-3 and 14.8% (4.4% to 24.9%) for List B performance, adjusting for multiple potential confounders. Long-term PM2.5 exposure was associated with increased Alzheimer's disease pattern similarity scores, which accounted for 22.6% (95% CI: 1% to 68.9%) and 10.7% (95% CI: 1.0% to 30.3%) of the total adverse PM2.5 effects on Trials 1-3 and List B, respectively. The observed associations remained after excluding incident cases of dementia and stroke during the follow-up, or further adjusting for small-vessel ischaemic disease volumes. Our findings illustrate the continuum of PM2.5 neurotoxicity that contributes to early decline of immediate free recall/new learning at the preclinical stage, which is mediated by progressive atrophy of grey matter indicative of increased Alzheimer's disease risk, independent of cerebrovascular damage.

7.
Brain ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31755958

RESUMO

Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson's disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson's disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson's disease cases, 13 431 Parkinson's disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson's disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson's disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson's disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson's disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.

8.
Neurobiol Aging ; 83: 130-134, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31732016

RESUMO

The structure and function of the brain change over the life span. Aged brains often accumulate pathologic lesions, such as amyloid plaques and tau tangles, which lead to diminished cognitive ability in some, but not all, individuals. The basis of this vulnerability and resilience is unclear. Age-related changes can alter neural firing patterns and ability to form new memories. Risk factors for cognitive decline include male sex and apolipoprotein E genotype. Physical activity seems to be protective against cognitive decline. Longitudinal studies have shown that, although the onset of amyloid pathology and associated cognitive decline can vary greatly, once it begins, the rate of deposition is similar among affected individuals. This session of the Cognitive Aging Summit III explored fixed and modifiable factors that can threaten cognitive function in aging adults and approaches to modulate at least some of these risks.

10.
Brain ; 142(9): 2581-2589, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31497858

RESUMO

Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10-8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10-8) but not females (P = 0.85, sex-interaction P = 2.9 × 10-4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.

11.
Alzheimers Dement (Amst) ; 11: 637-645, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31517026

RESUMO

Introduction: Tau pathology, a hallmark of Alzheimer's disease, is observed in the brains of virtually all individuals over 70 years. Methods: Using 18F-AV-1451 (18F-flortaucipir) positron emission tomography, we evaluated tau pathology in 54 cognitively normal participants (mean age: 77.5 years, SD: 8.9) from the Baltimore Longitudinal Study of Aging. We assessed associations between positron emission tomography signal and age, sex, race, and amyloid positivity. We investigated relationships between regional signal and retrospective rates of change in regional volumes and cognitive function adjusting for age, sex, and amyloid status. Results: Greater age, male sex, black race, and amyloid positivity were associated with higher 18F-AV-1451 retention in distinct brain regions. Retention in the entorhinal cortex was associated with lower entorhinal volume (ß = -1.124, SE = 0.485, P = .025) and a steeper decline in memory performance (ß = -0.086, SE = 0.039, P = .029). Discussion: Assessment of medial temporal tau pathology will provide insights into early structural brain changes associated with later cognitive impairment and Alzheimer's disease.

12.
Alzheimers Dement ; 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31561966

RESUMO

INTRODUCTION: Questions remain about whether apolipoprotein E (APOE)-ε4 effects on cognitive decline are similar in men and women and how APOE-ε4 and age interact to influence decline in different cognitive domains. METHODS: In sex-stratified analyses, baseline age-dependent associations between APOE-ε4 status and longitudinal cognitive trajectories were examined in cognitively normal Caucasian older adults (631 men, 561 women, baseline age range: 50-93, 6733 assessments). RESULTS: In men, older baseline age was associated with greater effects of APOE-ε4 on longitudinal decline in memory and executive function, detectible from baseline age of 64 and 68, respectively. In women, older baseline age was associated with greater APOE-ε4 effects on longitudinal decline in attention, detectible at baseline age of 66. No significant APOE-ε4 effects were found for language, visual-spatial ability, or processing speed. DISCUSSION: Results highlight the importance of considering sex and age when assessing APOE-ε4-associated vulnerability to cognitive decline.

13.
Int J Geriatr Psychiatry ; 34(12): 1833-1844, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31418472

RESUMO

OBJECTIVES: Relatively few APOE ε4+ carriers survive to old age (age 80+) without cognitive impairment (CI); thus, little is known about distinguishing characteristics of resilient APOE ε4+ carriers. Herein, we describe the sociodemographic characteristics of a large sample of resilient APOE ε4+ women from the Women's Health Initiative Memory Study (WHIMS) and compare them to noncarriers and APOE ε4+ women who developed CI before age 80. METHODS: Women were recruited for clinical trials evaluating postmenopausal hormone therapy and incidence of dementia. During posttrial follow-up, cognitive status was adjudicated annually. Among 5716 women, we compared groups by APOE ε4 status using logistic regression, covarying for treatment, demographics, lifestyle, cardiovascular and physical function, well-being, and self-rated general health. RESULTS: Among 557 APOE ε4+ women, those who survived to age 80+ without CI had higher baseline self-rated general health (odds ratio [OR]: 1.02; 95% confidence interval [CI], 1.01-1.04) and cognitive scores (OR: 1.18; 95% CI, 1.12-1.25) than those who did not reach age 80 without CI. Baseline high total cholesterol and low-density lipoprotein (LDL) levels were similar across APOE ε4+ groups but were higher compared with APOE ε4- women. Among women who survived to 80+ without CI, more APOE ε4+ women had a history of high total cholesterol (P = .003) and LDL cholesterol (OR: 1.01; 95% CI, 1.00-1.01). There were no differences in hypertension, diabetes, or other vascular risk factors in APOE ε4+ women compared with noncarriers. CONCLUSIONS: Results highlight the importance of baseline cognitive function and general health for late-life cognition among ε4+ women.

14.
J Am Geriatr Soc ; 67(12): 2581-2586, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31441513

RESUMO

OBJECTIVES: Given the need to detect subclinical changes in brain health that sometimes occur with aging in apparently healthy older adults, we assessed whether bimanual gesture imitation performance, simple to assess clinically, can detect age effects and alterations in cognition, olfaction, and movement. DESIGN: Cross-sectional study. SETTING: Baltimore Longitudinal Study of Aging. PARTICIPANTS: Men and women, aged 22 to 101 years, without cognitive impairment, dementia, stroke, Parkinson disease, resting tremor, abnormal muscle tone, or abnormal coordination (N = 507). MEASUREMENTS: Bimanual gesture imitation was measured using a test validated in older adults. We assessed (1) cognition, including verbal memory, executive function, attention, visuospatial ability, visuoperceptual speed, and language; (2) manual dexterity with the Purdue Pegboard Test; (3) olfaction, using the 16-item Sniffin' Sticks Identification Test; (4) upper extremity motor function, using a computer-based finger tapping test; and (5) lower extremity motor function, including 6-meter usual and rapid gait speeds, 400-meter walk time, Health ABC Physical Performance Battery, and total standing balance time. Cross-sectional associations between bimanual gesture imitation performance and each measure were examined using linear regression after adjustment for age, sex, race, education, and body mass index. Models with mobility measures also adjusted for height. RESULTS: Higher gesture imitation performance was associated with younger age. After adjustment, a worse score was associated with worse olfaction, executive function, and visuospatial ability. Gesture imitation score was not associated with other cognitive measures or motor function. CONCLUSION: In persons without clinically detectable neurological conditions, poor bimanual gesture imitation is associated with other indicators of brain health, including olfaction and selected cognitive function domains. Bimanual gesture imitation may be useful clinically to detect subtle brain changes in apparently healthy older adults. J Am Geriatr Soc 67:2581-2586, 2019.

15.
Artigo em Inglês | MEDLINE | ID: mdl-31326978

RESUMO

BACKGROUND: Hearing loss (HL) and menopausal hormone (conjugated equine estrogens [CEE] and/or medroxyprogesterone acetate [MPA]) are separately associated with cognitive decline and increased risk of incident cognitive impairment. Joint effects of HL and HT could be associated with additive or synergistic decline in global cognition and risk of incident cognitive impairment among postmenopausal women. METHODS: Using the Women's Health Initiative (WHI) Memory Study, 7,220 postmenopausal women with measures of HL, global cognition (Modified Mini- Mental State Examination score), and cognitive impairment (centrally-adjudicated diagnoses of mild cognitive impairment and dementia) from 1996-2009. Multivariable linear mixed effects models were used to analyze rate of change in global cognition. Accelerated failure time models were used to evaluate time to incident cognitive impairment, stratified by HT. RESULTS: Within the CEE-Alone trial, observed adverse effects of CEE-Alone on change in global cognition did not differ by HL, and estimated joint effects of HL and CEE-Alone were not associated with incident cognitive impairment. Within the CEE+MPA trial, HL did not independently accelerate time to cognitive impairment, the adverse effect of CEE+MPA was heightened in older women with HL. Older women on CEE+MPA either with HL (Time Ratio, [TR]=0.82, 95% Confidence Interval, [CI]: 0.71, 0.94) or with normal hearing (TR=0.86, 95% CI: 0.76, 0.97) had faster time to cognitive impairment than those with normal hearing and placebo. CONCLUSIONS: HL may accentuate the adverse effect of CEE+MPA, not CEE-Alone, on global cognitive decline, not incident cognitive impairment, among postmenopausal women on HT.

16.
Neurobiol Aging ; 81: 146-156, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31280118

RESUMO

We evaluated sex differences in MRI-based volume loss and differences in predictors of this neurodegeneration in cognitively healthy older adults. Mixed-effects regression was used to compare regional brain volume trajectories of 295 male and 328 female cognitively healthy Baltimore Longitudinal Study of Aging participants, aged 55-92 years, with up to 20 years of follow-up and to assess sex differences in the associations of age, hypertension, obesity, APOE e4 carrier status, and high-density lipoprotein cholesterol with regional brain volume trajectories. For both sexes, older age was associated with steeper volumetric declines in many brain regions, with sex differences in volume loss observed in frontal, temporal, and parietal regions. In males, hypertension and higher high-density lipoprotein cholesterol were protective against volume loss in the hippocampus, entorhinal cortex, and parahippocampal gyrus. In females, hypertension was associated with steeper volumetric decline in gray matter, and obesity was protective against volume loss in temporal gray matter. Predictors of volume change may affect annual rates of volume change differently between men and women.

17.
Artigo em Inglês | MEDLINE | ID: mdl-31268512

RESUMO

Importance: Hearing impairment (HI) in midlife (45-65 years of age) may be associated with longitudinal neurodegeneration of temporal lobe structures, a biomarker of early Alzheimer disease. Objective: To evaluate the association of midlife HI with brain volume trajectories in later life (≥65 years of age). Design, Setting, and Participants: This prospective cohort study used data from the Baltimore Longitudinal Study of Aging to evaluate hearing from November 5, 1990, to October 3, 1994, and late-life volume change from July 10, 2008, to January 29, 2015, using magnetic resonance imaging (MRI) (mean follow-up time, 19.3 years). Data analysis was performed from September 22, 2017, to August 27, 2018. A total of 194 community-dwelling older adults who had midlife measures of peripheral hearing at a mean age of 54.5 years and late-life volume change of up to 6 years between the first and most recent MRI assessment were studied. Excluded were those with baseline cognitive impairment, stroke, head injuries, Parkinson disease, and bipolar disorder. Exposures: Hearing as measured with pure tone audiometry in each ear from November 5, 1990, to October 3, 1994, and late-life temporal lobe volume change measured by MRI. Main Outcomes and Measures: Linear mixed-effects models with random intercepts were used to examine the association of midlife hearing (pure tone average of 0.5-4 kHz tones in the better ear and each ear separately) with longitudinal late-life MRI-based measures of temporal lobe structures (hippocampus, entorhinal cortex, parahippocampal gyrus, and superior, middle, and inferior temporal gyri) in the left and right hemispheres, in addition to global and lobar regions, adjusting for baseline demographic characteristics (age, sex, subsequent cognitive impairment status, and educational level) and intracranial volume. Results: A total of 194 patients (mean [SD] age at hearing assessment, 54.5 [10.0] years; 106 [54.6%] female; 169 [87.1%] white) participated in the study. After Bonferroni correction, poorer midlife hearing in the better ear was associated with steeper late-life volumetric declines in the right temporal gray matter (ß = -0.113; 95% CI, -0.182 to -0.044), right hippocampus (ß = -0.008; 95% CI, -0.012 to -0.004), and left entorhinal cortex (ß = -0.009; 95% CI, -0.015 to -0.003). Poorer midlife hearing in the right ear was associated with steeper late-life volumetric declines in the right temporal gray matter (ß = -0.136; 95% CI, -0.197 to -0.075), right hippocampus (ß = -0.008; 95% CI, -0.012 to -0.004), and left entorhinal cortex (ß = -0.009; 95% CI, -0.015 to -0.003), whereas there were no associations between poorer midlife hearing in the left ear with late-life volume loss. Conclusions and Relevance: The findings suggest that midlife HI is a risk factor for temporal lobe volume loss. Poorer midlife hearing, particularly in the right ear, was associated with declines in hippocampus and entorhinal cortex.

18.
JAMA Neurol ; 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31305918

RESUMO

Importance: Blood biomarkers able to diagnose Alzheimer disease (AD) at the preclinical stage would enable trial enrollment when the disease is potentially reversible. Plasma neuronal-enriched extracellular vesicles (nEVs) of patients with AD were reported to exhibit elevated levels of phosphorylated (p) tau, Aß42, and phosphorylated insulin receptor substrate 1 (IRS-1). Objective: To validate nEV biomarkers as AD predictors. Design, Setting, Participants: This case-control study included longitudinal plasma samples from cognitively normal participants in the Baltimore Longitudinal Study of Aging (BLSA) cohort who developed AD up to January 2015 and age- and sex-matched controls who remained cognitively normal over a similar length of follow-up. Repeated samples were blindly analyzed over 1 year from participants with clinical AD and controls from the Johns Hopkins Alzheimer Disease Research Center (JHADRC). Data were collected from September 2016 to January 2018. Analyses were conducted in March 2019. Main Outcomes and Measures: Neuronal-enriched extracellular vesicles were immunoprecipitated; tau, Aß42, and IRS-1 biomarkers were quantified by immunoassays; and nEV concentration and diameter were determined by nanoparticle tracking analysis. Levels and longitudinal trajectories of nEV biomarkers between participants with future AD and control participants were compared. Results: Overall, 887 longitudinal plasma samples from 128 BLSA participants who eventually developed AD and 222 age and sex-matched controls who remained cognitively normal were analyzed. Participants were followed up (from earliest sample to AD symptom onset) for a mean (SD) of 3.5 (2.31) years (range, 0-9.73 years). Overall, 161 participants were included in the training set, and 80 were in the test set. Participants in the BLSA cohort with future AD (mean [SD] age, 79.09 [7.02] years; 68 women [53.13%]) had longitudinally higher p-tau181, p-tau231, pSer312-IRS-1, pY-IRS-1, and nEV diameter than controls (mean [SD] age, 76.2 [7.36] years; 110 women [50.45%]) but had similar Aß42, total tau, TSG101, and nEV concentration. In the training BLSA set, a model combining preclinical longitudinal data achieved 89.6% area under curve (AUC), 81.8% sensitivity, and 85.8% specificity for predicting AD. The model was validated in the test BLSA set (80% AUC, 55.6% sensitivity, 88.7% specificity). Preclinical levels of nEV biomarkers were associated with cognitive performance. In addition, 128 repeated samples over 1 year from 64 JHADRC participants with clinical AD and controls were analyzed. In the JHADRC cohort (35 participants with AD: mean [SD] age, 74.03 [8.73] years; 18 women [51.43%] and 29 controls: mean [SD] age, 72.14 [7.86] years; 23 women [79.31%]), nEV biomarkers achieved discrimination with 98.9% AUC, 100% sensitivity, and 94.7% specificity in the training set and 76.7% AUC, 91.7% sensitivity, and 60% specificity in the test set. Conclusions and Relevance: We validated nEV biomarker candidates and further demonstrated that their preclinical longitudinal trajectories can predict AD diagnosis. These findings motivate further development of nEV biomarkers toward a clinical blood test for AD.

19.
J Neurosci Methods ; 324: 108311, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31201823

RESUMO

BACKGROUND: Human cortical primary sulci are relatively stable landmarks and commonly observed across the population. Despite their stability, the primary sulci exhibit phenotypic variability. NEW METHOD: We propose a fully automated pipeline that integrates both sulcal curve extraction and labeling. In this study, we use a large normal control population (n = 1424) to train neural networks for accurately labeling the primary sulci. Briefly, we use sulcal curve distance map, surface parcellation, mean curvature and spectral features to delineate their sulcal labels. We evaluate the proposed method with 8 primary sulcal curves in the left and right hemispheres compared to an established multi-atlas curve labeling method. RESULTS: Sulcal labels by the proposed method reasonably well agree with manual labeling. The proposed method outperforms the existing multi-atlas curve labeling method. COMPARISON WITH EXISTING METHOD: Significantly improved sulcal labeling results are achieved with over 12.5 and 20.6 percent improvement on labeling accuracy in the left and right hemispheres, respectively compared to that of a multi-atlas curve labeling method in eight curves (p≪0.001, two-sample t-test). CONCLUSION: The proposed method offers a computationally efficient and robust labeling of major sulci.

20.
J Am Med Dir Assoc ; 20(12): 1535-1539.e3, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31227471

RESUMO

OBJECTIVES: To determine whether the trajectory of preclinical lap time variability from a 400-m walk differentiates participants with future mild cognitive impairment (MCI)/Alzheimer's disease (AD) from matched controls. DESIGN: A case-control retrospective study embedded in a large longitudinal cohort study, the Baltimore Longitudinal Study of Aging (BLSA). SETTING: In the BLSA, participants were scheduled for clinical visits, including mobility and cognitive assessments. Data reported here were collected between April 2007 and September 2017 (average follow-up 5.2 ± 2.4 years). PARTICIPANTS: 67 participants developed MCI/AD and 134 age- and sex-matched controls remained cognitively normal. MEASUREMENTS: Diagnoses of MCI and AD were adjudicated at a consensus conference. The rate of change in lap time variability between MCI/AD cases prior to symptom onset and controls were compared using mixed effects linear regression, and adjusted for baseline executive function, memory, gait speed, and changes in gait speed. RESULTS: Compared to controls, eventual MCI/AD cases had a greater rate of increase in lap time variability prior to symptom onset (ß = 0.59, P = .009). This association was independent of baseline cognition, gait speeds at baseline or change over time from a 6-m or 400-m walk. CONCLUSION/IMPLICATIONS: Independent of other early indicators and gait slowing, a greater rate of increase in lap time variability from a 400-m walk differentiates individuals who eventually develop MCI/AD from controls, suggesting that early pathology affects the automaticity of walking. Lap time variability can be assessed during routine clinical practice over time and might help identify individuals at risk for future MCI/AD.

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