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1.
Neurology ; 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33827960

RESUMO

OBJECTIVE: We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression. METHODS: Baseline plasma NfL concentrations were measured with Simoa in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN and MAPT mutation carriers and non-carriers from the same families were classified by disease severity [asymptomatic, prodromal and full phenotype] using the CDR® Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR®+NACC-FTLD). Linear mixed effect models related NfL to clinical variables. RESULTS: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to non-progressors (original: 11.4 ± 7 pg/mL vs. 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs. 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR®+NACC-FTLD sum of boxes scores, neuropsychological function and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers. CONCLUSIONS: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression, and is a potential tool to select participants for prevention clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.

2.
Acta Neuropathol Commun ; 9(1): 48, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33757599

RESUMO

Although abnormal accumulation of amyloid in the brain is an early biomarker of Alzheimer's disease (AD), wide variation in cognitive trajectories during life can be seen in the setting of brain amyloidosis, ranging from maintenance of normal function to progression to dementia. It is widely presumed that cognitive resilience (i.e., coping) to amyloidosis may be influenced by environmental, lifestyle, and inherited factors, but relatively little in specifics is known about this architecture. Here, we leveraged multimodal longitudinal data from a large, population-based sample of older adults to discover genetic factors associated with differential cognitive resilience to brain amyloidosis determined by positron emission tomography (PET). Among amyloid-PET positive older adults, the AD risk allele APOE ɛ4 was associated with worse longitudinal memory trajectories as expected, and was thus covaried in the main analyses. Through a genome-wide association study (GWAS), we uncovered a novel association with cognitive resilience on chromosome 8 at the MTMR7/CNOT7/ZDHHC2/VPS37A locus (p = 4.66 × 10-8, ß = 0.23), and demonstrated replication in an independent cohort. Post-hoc analyses confirmed this association as specific to the setting of elevated amyloid burden and not explained by differences in tau deposition or cerebrovascular disease. Complementary gene-based analyses and publically available functional data suggested that the causative variant at this locus may tag CNOT7 (CCR4-NOT Transcription Complex Subunit 7), a gene linked to synaptic plasticity and hippocampal-dependent learning and memory. Pathways related to cell adhesion and immune system activation displayed enrichment of association in the GWAS. Our findings, resulting from a unique study design, support the hypothesis that genetic heterogeneity is one of the factors that explains differential cognitive resilience to brain amyloidosis. Further characterization of the underlying biological mechanisms influencing cognitive resilience may facilitate improved prognostic counseling, therapeutic application, and trial enrollment in AD.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33724517

RESUMO

OBJECTIVE: Neuropsychiatric symptoms (NPS) are associated with the risk of incident mild cognitive impairment (MCI) and dementia. We examined associations between NPS and the outcomes of global and domain-specific cognitive trajectories. METHODS: In this longitudinal study conducted in the setting of the population-based Mayo Clinic Study of Aging, 5081 community-dwelling, nondemented individuals aged ≥50 years (51% males) underwent NPS assessment using Neuropsychiatric Inventory Questionnaire (NPI-Q), and Beck Depression and Anxiety Inventories (BDI-II, BAI). Global and domain-specific (memory, language, attention, and visuospatial skills) cognitive performance was assessed through neuropsychological testing every 15 months. Associations between baseline NPS and trajectories for individual yearly change in cognitive z-scores were calculated using linear mixed-effect models. RESULTS: Cognition declined regardless of NPS status over the median follow-up of 4.5 years. Presence of NPS was associated with increased cognitive decline. Differences in annualized change in global cognition z-scores for participants with NPS compared to without NPS ranged from -0.018 (95% CI -0.032, -0.004; p = 0.011) for irritability to -0.159 (-0.254, -0.065; p = 0.001) for hallucinations. Associations between NPS and annual decline in global cognition were significant for most NPI-Q-assessed NPS and clinical depression (BDI-II≥13). Participants with NPI-Q-assessed depression, apathy, nighttime behavior, and clinical depression had greater decline in all domain-specific z-scores; presence of delusions and anxiety was associated with more pronounced decline in language, attention and visuospatial skills. CONCLUSION: NPS were associated with a more accelerated cognitive decline. Clinical assessment and potential treatment of NPS is warranted even in a community setting as NPS may impact cognitive decline in nondemented individuals.

4.
Ann Neurol ; 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33772866

RESUMO

BACKGROUND: To operationalize the National Institute on Aging - Alzheimer's Association (NIA-AA) Research Framework for Alzheimer's Disease 6-stage continuum of clinical progression for persons with abnormal amyloid. METHODS: The Mayo Clinic Study of Aging is a population-based longitudinal study of aging and cognitive impairment in Olmsted County, Minnesota. We evaluated persons without dementia having 3 consecutive clinical visits. Measures for cross-sectional categories included objective cognitive impairment (OBJ) and function (FXN). Measures for change included subjective cognitive impairment (SCD), objective cognitive change (ΔOBJ), and new onset of neurobehavioral symptoms (ΔNBS). We calculated frequencies of the stages using different cutoff points and assessed stability of the stages over 15 months. RESULTS: Among 243 abnormal amyloid participants, the frequencies of the stages varied with age: 66 to 90% were classified as stage 1 at age 50 but at age 80, 24 to 36% were stage 1, 32 to 47% were stage 2, 18 to 27% were stage 3, 1 to 3% were stage 4 to 6, and 3 to 9% were indeterminate. Most stage 2 participants were classified as stage 2 because of abnormal ΔOBJ only (44-59%), whereas 11 to 21% had SCD only, and 9 to 13% had ΔNBS only. Short-term stability varied by stage and OBJ cutoff points but the most notable changes were seen in stage 2 with 38 to 63% remaining stable, 4 to 13% worsening, and 24 to 41% improving (moving to stage 1). INTERPRETATION: The frequency of the stages varied by age and the precise membership fluctuated by the parameters used to define the stages. The staging framework may require revisions before it can be adopted for clinical trials. ANN NEUROL 2021.

5.
Alzheimers Dement ; 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33663022

RESUMO

INTRODUCTION: We determined whether cerebrospinal fluid (CSF) neurofilament light (NfL), neurogranin (Ng), and total-tau (t-tau) differentially mapped to magnetic resonance imaging (MRI) measures of cortical thickness, microstructural integrity (corpus callosum and cingulum fractional anisotropy [FA]), and white matter hyperintensities (WMH). METHODS: Analyses included 536 non-demented Mayo Clinic Study of Aging participants with CSF NfL, Ng, t-tau, amyloid beta (Aß)42 and longitudinal MRI scans. Linear mixed models assessed longitudinal associations between CSF markers and MRI changes. RESULTS: Higher CSF NfL was associated with decreasing microstructural integrity and WMH. Higher t-tau was associated with decreasing temporal lobe and Alzheimer's disease (AD) meta region of interest (ROI) cortical thickness. There was no association between Ng and any MRI measure. CSF Aß42 interacted with Ng for declines in temporal lobe and AD meta ROI cortical thickness and cingulum FA. DISCUSSION: CSF NfL predicts changes in white matter integrity, t-tau reflects non-specific changes in cortical thickness, and Ng reflects AD-specific synaptic and neuronal degeneration.

6.
Alzheimers Dement ; 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33650308

RESUMO

INTRODUCTION: This study evaluated the diagnostic accuracy of the Cogstate Brief Battery (CBB) for mild cognitive impairment (MCI) and prodromal Alzheimer's disease (AD) in a population-based sample. METHODS: Participants included adults ages 50+ classified as cognitively unimpaired (CU, n = 2866) or MCI (n = 226), and a subset with amyloid (A) and tau (T) positron emission tomography who were AD biomarker negative (A-T-) or had prodromal AD (A+T+). RESULTS: Diagnostic accuracy of the Learning/Working Memory Composite (Lrn/WM) for discriminating all CU and MCI was moderate (area under the curve [AUC] = 0.75), but improved when discriminating CU A-T- and MCI A+T+ (AUC = 0.93) and when differentiating MCI participants without AD biomarkers from those with prodromal AD (AUC = 0.86). Conventional cut-offs yielded lower than expected sensitivity for both MCI (38%) and prodromal AD (73%). DISCUSSION: Clinical utility of the CBB for detecting MCI in a population-based sample is lower than expected. Caution is needed when using currently available CBB normative data for clinical interpretation.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33650631

RESUMO

BACKGROUND: Hospitalization can impair physical and functional status of older adults, but it is unclear whether these deficits are transient or chronic. This study determined the association between hospitalization of older adults and changes in long-term longitudinal trajectories of two measures of physical and functional status: gait speed (GS) and Instrumental Activities of Daily Living measured with Functional Activities Questionnaire (FAQ). METHODS: Linear mixed effects models assessed the association between hospitalization (non-elective vs. elective, and surgical vs. medical) and outcomes of GS and FAQ score in participants (>60 years old) enrolled in the Mayo Clinic Study of Aging who had longitudinal assessments. RESULTS: Of 4,902 participants, 1,879 had ≥1 hospital admission. Median GS at enrollment was 1.1 m/s. The slope of the annual decline in GS before hospitalization was -0.015 m/s. The parameter estimate [95%CI] for additional annual change in GS trajectory after hospitalization was -0.009 [-0.011 to -0.006] m/s, P<0.001. The accelerated GS decline was greater for medical vs. surgical hospitalizations (-0.010 vs. -0.003 m/s, P=0.005), and non-elective vs. elective hospitalizations (-0.011 vs -0.006 m/s, P=0.067). The odds of a worsening FAQ-score increased on average by 4% per year. Following hospitalization, odds of FAQ-score worsening further increased (multiplicative annual increase in odds ratio per year [95%C] following hospitalization was 1.05 [1.03, 1.07], P<0.001). CONCLUSIONS: Hospitalization of older adults is associated with accelerated long-term decline in GS and functional limitations, especially after non-elective admissions and those for medical indications. However, for most well-functioning participants these changes have little clinical significance.

8.
J Alzheimers Dis ; 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33720897

RESUMO

BACKGROUND: The relationship between cerebral microbleeds (CMBs) on hemosiderin-sensitive MRI sequences and cerebral amyloid angiopathy (CAA) remains unclear in population-based participants or in individuals with dementia. OBJECTIVE: To determine whether CMBs on antemortem MRI correlate with CAA. METHODS: We reviewed 54 consecutive participants with antemortem T2 *GRE-MRI sequences and subsequent autopsy. CMBs were quantified on MRIs closest to death. Autopsy CAA burden was quantified in each region including leptomeningeal/cortical and capillary CAA. By clustering approach, we examined the relationship among CAA variables and performed principal component analysis (PCA) for dimension reduction to produce two scores from these 15 interrelated predictors. Hurdle models assessed relationships between principal components and lobar CMBs. RESULTS: MRI-based CMBs appeared in 20/54 (37%). 10 participants had ≥2 lobar-only CMBs. The first two components of the PCA analysis of the CAA variables explained 74% variability. The first rotated component (RPC1) consisted of leptomeningeal and cortical CAA and the second rotated component of capillary CAA (RPC2). Both the leptomeningeal and cortical component and the capillary component correlated with lobar-only CMBs. The capillary CAA component outperformed the leptomeningeal and cortical CAA component in predicting lobar CMBs. Both capillary and the leptomeningeal and cortical components correlated with number of lobar CMBs. CONCLUSION: Capillary and leptomeningeal/cortical scores correlated with lobar CMBs on MRI but lobar CMBs were more closely associated with the capillary component. The capillary component correlated with APOEɛ4, highlighting lobar CMBs as one aspect of CAA phenotypic diversity. More CMBs also increase the probability of underlying CAA.

9.
J Alzheimers Dis ; 80(2): 683-693, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33579840

RESUMO

BACKGROUND: Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with memory impairment and overall cognitive decline. It is unclear how TDP-43 contributes to the rate of clinical decline. OBJECTIVE: To determine whether cross-sectional and longitudinal cognitive and functional decline are associated with anatomical distribution of TDP-43 in the brain. METHODS: Longitudinal clinical-neuropathologic autopsy cohort study of 385 initially cognitively normal/mildly impaired older adults prospectively followed until death. We investigated how TDP-43, amyloid-ß (Aß), tau neurofibrillary tangles (NFT), Lewy body disease (LBD), age, sex, and genetics are associated with clinical scores and rates of their longitudinal decline. RESULTS: Of 385 participants, 260 (68%) had no TDP-43, 32 (8%) had TDP-43 limited to amygdala, and 93 (24%) had TDP-43 in the hippocampus and beyond. Higher TDP-43 and Braak NFT stages independently were associated with faster decline in global cognition, functional performance measured by Clinical Dementia Rating scale, and naming and episodic memory, whereas older age was associated with slower rate of cognitive, psychiatric, and functional decline. Cross-sectionally the following associations were found: higher TDP-43 and Braak NFT - worse performance; higher Aß burden - worse global cognition, more behavioral changes, the latter also with higher LBD; older age - worse naming, lower frequency of behavioral changes; female sex - more impaired naming and better preserved episodic memory. There were no genetic associations. CONCLUSION: The association of TDP-43 distribution with decline in cognitive and functional performance suggests that TDP-43 is playing a role in the clinical progression to dementia. Further characterization of clinical features associated with TDP-43 can facilitate establishment of antemortem diagnosis.

10.
Neuroimage ; 232: 117899, 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33631332

RESUMO

Disproportionately enlarged subarachnoid-space hydrocephalus (DESH), characterized by tight high convexity CSF spaces, ventriculomegaly, and enlarged Sylvian fissures, is thought to be an indirect marker of a CSF dynamics disorder. The clinical significance of DESH with regard to cognitive decline in a community setting is not yet well defined. The goal of this work is to determine if DESH is associated with cognitive decline. Participants in the population-based Mayo Clinic Study of Aging (MCSA) who met the following criteria were included: age ≥ 65 years, 3T MRI, and diagnosis of cognitively unimpaired or mild cognitive impairment at enrollment as well as at least one follow-up visit with cognitive testing. A support vector machine based method to detect the DESH imaging features on T1-weighted MRI was used to calculate a "DESH score", with positive scores indicating a more DESH-like imaging pattern. For the participants who were cognitively unimpaired at enrollment, a Cox proportional hazards model was fit with time defined as years from enrollment to first diagnosis of mild cognitive impairment or dementia, or as years to last known cognitively unimpaired diagnosis for those who did not progress. Linear mixed effects models were fit among all participants to estimate annual change in cognitive z scores for each domain (memory, attention, language, and visuospatial) and a global z score. For all models, covariates included age, sex, education, APOE genotype, cortical thickness, white matter hyperintensity volume, and total intracranial volume. The hazard of progression to cognitive impairment was an estimated 12% greater for a DESH score of +1 versus -1 (HR 1.12, 95% CI 0.97-1.31, p = 0.11). Global and attention cognition declined 0.015 (95% CI 0.005-0.025) and 0.016 (95% CI 0.005-0.028) z/year more, respectively, for a DESH score of +1 vs -1 (p = 0.01 and p = 0.02), with similar, though not statistically significant DESH effects in the other cognitive domains. Imaging features of disordered CSF dynamics are an independent predictor of subsequent cognitive decline in the MCSA, among other well-known factors including age, cortical thickness, and APOE status. Therefore, since DESH contributes to cognitive decline and is present in the general population, identifying individuals with DESH features may be important clinically as well as for selection in clinical trials.

11.
Neuroimage ; 231: 117845, 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33582276

RESUMO

Recent advances in automated face recognition algorithms have increased the risk that de-identified research MRI scans may be re-identifiable by matching them to identified photographs using face recognition. A variety of software exist to de-face (remove faces from) MRI, but their ability to prevent face recognition has never been measured and their image modifications can alter automated brain measurements. In this study, we compared three popular de-facing techniques and introduce our mri_reface technique designed to minimize effects on brain measurements by replacing the face with a population average, rather than removing it. For each technique, we measured 1) how well it prevented automated face recognition (i.e. effects on exceptionally-motivated individuals) and 2) how it altered brain measurements from SPM12, FreeSurfer, and FSL (i.e. effects on the average user of de-identified data). Before de-facing, 97% of scans from a sample of 157 volunteers were correctly matched to photographs using automated face recognition. After de-facing with popular software, 28-38% of scans still retained enough data for successful automated face matching. Our proposed mri_reface had similar performance with the best existing method (fsl_deface) at preventing face recognition (28-30%) and it had the smallest effects on brain measurements in more pipelines than any other, but these differences were modest.

12.
Neurology ; 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33408148

RESUMO

OBJECTIVE: To determine the clinical phenotypes associated with the amyloid-ß PET and dopamine transporter imaging (123I-FP-CIT SPECT) findings in mild cognitive impairment (MCI) with the core clinical features of dementia with Lewy bodies (DLB; MCI-LB). METHODS: Patients with MCI who had at least one core clinical feature of DLB (n=34) were grouped into ß-amyloid A+ or A- and 123I-FP-CIT SPECT D+ or D- groups based on previously established abnormality cut points for A+ with Pittsburgh compound-B PET standardized uptake value ratio (PiB SUVR) ≥1.48 and D+ with putamen z-score with DATQUANT < -0.82 on 123I-FP-CIT SPECT. Individual MCI-LB patients fell into one of four groups: A+D+, A+D-, A-D+, or A-D-. Log transformed PiB SUVR and putamen z-score were tested for associations with patient characteristics. RESULTS: The A-D+ biomarker profile was most common (38.2%) followed by A+D+ (26.5%) and A-D- (26.5%). Least common was A+D- biomarker profile (8.8 %). The A+ group was older, had a higher frequency of APOE ε4 carriers, and a lower MMSE score than the A- group. The D+ group was more likely to have probable rapid eye movement sleep behavior disorder. Lower putamen DATQUANT z-scores and lower PiB SUVRs were independently associated with higher Unified Parkinson Disease Rating Scale (UPDRS)-III scores. CONCLUSIONS: A majority of MCI-LB patients are characterized by low amyloid-ß deposition and reduced dopaminergic activity. Amyloid-ß PET and 123I-FP-CIT SPECT are complementary in characterizing clinical phenotypes of patients with MCI-LB.

13.
Neurology ; 96(7): e964-e974, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33408144

RESUMO

OBJECTIVE: To test the hypothesis that greater levels of leisure-time moderate to vigorous intensity physical activity (MVPA) in midlife or late life are associated with larger gray matter volumes, less white matter disease, and fewer cerebrovascular lesions measured in late life, we utilized data from 1,604 participants enrolled in the Atherosclerosis Risk in Communities study. METHODS: Leisure-time MVPA was quantified using a past-year recall, interviewer-administered questionnaire at baseline and 25 years later and classified as none, low, middle, and high at each time point. The presence of cerebrovascular lesions, white matter hyperintensities (WMH), white matter integrity (mean fractional anisotropy [FA] and mean diffusivity [MD]), and gray matter volumes were quantified with 3T MRI in late life. The odds of cerebrovascular lesions were estimated with logistic regression. Linear regression estimated the mean differences in WMH, mean FA and MD, and gray matter volumes. RESULTS: Among 1,604 participants (mean age 53 years, 61% female, 27% Black), 550 (34%), 176 (11%), 250 (16%), and 628 (39%) reported no, low, middle, and high MVPA in midlife, respectively. Compared to no MVPA in midlife, high MVPA was associated with more intact white matter integrity in late life (mean FA difference 0.13 per SD [95% confidence interval (CI) 0.004, 0.26]; mean MD difference -0.11 per SD [95% CI -0.21, -0.004]). High MVPA in midlife was also associated with a lower odds of lacunar infarcts (odds ratio 0.68, 95% CI 0.46, 0.99). High MVPA was not associated with gray matter volumes. High MVPA compared to no MVPA in late life was associated with most brain measures. CONCLUSION: Greater levels of physical activity in midlife may protect against cerebrovascular sequelae in late life.


Assuntos
Encéfalo/diagnóstico por imagem , Exercício Físico/fisiologia , Substância Cinzenta/diagnóstico por imagem , Atividades de Lazer , Substância Branca/diagnóstico por imagem , Feminino , Humanos , Leucoencefalopatias/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Tamanho do Órgão/fisiologia
14.
J Crit Care ; 62: 117-123, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33340966

RESUMO

PURPOSE: To investigate the association between episodes of critical care hospitalizations and delirium with structural brain changes in older adults. MATERIALS AND METHODS: We included Mayo Clinic Study of Aging participants ≥60 years old at the time of study enrollment (October 29, 2004, through September 11, 2017) with available brain MRI and 'amyloid' positron emission tomography (PET) scans. We tested the hypothesis that a) intensive care unit (ICU) admission is associated with greater cortical thinning and atrophy in entorhinal cortex, inferior temporal cortex, middle temporal cortex, and fusiform cortex (Alzheimer''s disease-signature regions); b) atrophy in hippocampus and corpus callosum; c) delirium accelerates these changes; and d) ICU admission is not associated with increased deposition of cortical amyloid. RESULTS: ICU admission was associated with cortical thinning in temporal, frontal, and parietal cortices, and decreases in hippocampal/corpus callosum volumes, but not Alzheimer''s disease-signature regions. For hippocampal volume, and 10 of 14 cortical thickness measurements, the change following ICU admission was significantly more pronounced for those who experienced delirium. ICU admission was not associated with an increased amyloid burden. CONCLUSIONS: Critical care hospitalization is associated with accelerated brain atrophy in selected brain regions, without increases in amyloid deposition, suggesting a pathogenesis based on neurodegeneration unrelated to Alzheimer''s pathway.

16.
J Am Heart Assoc ; : e018399, 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33289449

RESUMO

Background Atrial fibrillation (AF) is a risk factor for cognitive decline, possibly from silent brain infarction. Left atrial changes in structure or function (atrial cardiopathy) can lead to AF but may impact cognition independently. It is unknown if AF or atrial cardiopathy also acts on Alzheimer disease-specific mechanisms, such as deposition of ß-amyloid. Methods and Results A total of 316 dementia-free participants from the ARIC (Atherosclerosis Risk in Communities) study underwent florbetapir positron emission tomography, electrocardiography, and 2-dimensional echocardiography. Atrial cardiopathy was defined as ≥1: (1) left atrial volume index >34 mL/m2; (2) P-wave terminal force >5000 µV×ms; and (3) serum NT-proBNP (N-terminal pro-B-type natriuretic peptide) >250 pg/mL. Cross-sectional associations between global cortical ß-amyloid (>1.2 standardized uptake value ratio) and adjudicated history of AF and atrial cardiopathy, each, were evaluated using multivariable logistic regression. Participants (mean age, 76 years) were 56% women and 42% Black individuals. Odds of elevated florbetapir standardized uptake value ratio were significantly increased among those with atrial cardiopathy (odds ratio, 1.81; 95% CI, 1.02-3.22) and doubled for those with enlarged left atrial volume index after adjustment for demographics/risk factors (95% CI, 1.04-4.61). There was no association between P-wave terminal force or NT-proBNP and elevated florbetapir standardized uptake value ratio, nor between AF and elevated standardized uptake value ratio. Conclusions Among healthy, nondemented community-dwelling older individuals, we report an association between atrial cardiopathy, left atrial volume index, and elevated brain amyloid, by positron emission tomography, without a similar association in individuals with AF. Potential limitations include reverse causation and survival bias. Ongoing work will help determine if changes in cardiac structure and function precede or occur simultaneously with amyloid deposition.

17.
Nat Commun ; 11(1): 6285, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33293549

RESUMO

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

18.
Artigo em Inglês | MEDLINE | ID: mdl-33247623

RESUMO

OBJECTIVE: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach. METHODS: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype. RESULTS: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers. INTERPRETATION: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.

19.
J Alzheimers Dis ; 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33216032

RESUMO

BACKGROUND: Little is known about the association between physical activity (PA) and cognitive trajectories in older adults. OBJECTIVE: To examine the association between PA and change in memory, language, attention, visuospatial skills, and global cognition, and a potential impact of sex or Apolipoprotein E (APOE) ɛ4 status. METHODS: Longitudinal study derived from the population-based Mayo Clinic Study of Aging, including 2,060 cognitively unimpaired males and females aged ≥70 years. Engagement in midlife (ages 50-65) and late-life (last year) PA was assessed using a questionnaire. Neuropsychological testing was done every 15 months (mean follow-up 5.8 years). We ran linear mixed-effect models to examine whether mid- or late-life PA at three intensities (mild, moderate, vigorous) was associated with cognitive z-scores. RESULTS: Light intensity midlife PA was associated with less decline in memory function compared to the no-PA reference group (time x light PA; estimate [standard error] 0.047 [0.016], p = 0.004). Vigorous late-life PA was associated with less decline in language (0.033 [0.015], p = 0.030), attention (0.032 [0.017], p = 0.050), and global cognition (0.039 [0.016], p = 0.012). Females who were physically inactive in midlife experienced more pronounced cognitive decline than females physically active in midlife and males regardless of PA (p-values for time interaction terms with midlife PA levels and sex were all p <  0.05 for global cognition). APOE ɛ4 carriership did not moderate the association between PA and cognition. CONCLUSION: Engaging in PA, particularly of vigorous intensity in late-life, was associated with less pronounced decline in global and domain-specific cognition. This association may differ by sex.

20.
Artigo em Inglês | MEDLINE | ID: mdl-33185118

RESUMO

Background - An artificial intelligence (AI) algorithm applied to electrocardiography (ECG) during sinus rhythm (SR) has recently been shown to detect concurrent episodic atrial fibrillation (AF). We sought to characterize the value of AI-ECG as a predictor of future AF and assess its performance compared to the CHARGE-AF score in a population-based sample. Methods - We calculated the probability of AF using AI-ECG, among participants in the population-based Mayo Clinic Study of Aging who had no history of AF at the time of the baseline study visit. Cox proportional hazards models were fit to assess the independent prognostic value and interaction between AI-ECG AF model output and CHARGE-AF score. Concordance (C) statistics were calculated for AI-ECG AF model output, CHARGE-AF score and combined AI-ECG and CHARGE-AF score. Results - A total of 1,936 participants with median age 75.8 (interquartile range [IQR] 70.4, 81.8) years and median CHARGE-AF score 14.0 (IQR 13.2, 14.7) were included in the analysis. Participants with AI-ECG AF model output of >0.5 at the baseline visit had cumulative incidence of AF 21.5% at 2 years and 52.2% at 10 years. When included in the same model, both AI-ECG AF model output (hazard ratio [HR] 1.76 per standard deviation (SD) after logit transformation, 95% confidence interval [CI] 1.51, 2.04) and CHARGE-AF score (HR 1.90 per SD, 95% CI 1.58, 2.28) independently predicted future AF without significant interaction (p=0.54). C statistics were 0.69 (95% CI 0.66, 0.72) for AI-ECG AF model output, 0.69 (95% CI 0.66, 0.71) for CHARGE-AF and 0.72 (95% CI 0.69, 0.75) for combined AI-ECG and CHARGE-AF score. Conclusions - In the present study, both the AI-ECG AF model output and CHARGE-AF score independently predicted incident AF. The AI-ECG may offer a means to assess risk with a single test and without requiring manual or automated clinical data abstraction.

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