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1.
Magn Reson Med ; 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33847012

RESUMO

PURPOSE: A standard MRI system phantom has been designed and fabricated to assess scanner performance, stability, comparability and assess the accuracy of quantitative relaxation time imaging. The phantom is unique in having traceability to the International System of Units, a high level of precision, and monitoring by a national metrology institute. Here, we describe the phantom design, construction, imaging protocols, and measurement of geometric distortion, resolution, slice profile, signal-to-noise ratio (SNR), proton-spin relaxation times, image uniformity and proton density. METHODS: The system phantom, designed by the International Society of Magnetic Resonance in Medicine ad hoc committee on Standards for Quantitative MR, is a 200 mm spherical structure that contains a 57-element fiducial array; two relaxation time arrays; a proton density/SNR array; resolution and slice-profile insets. Standard imaging protocols are presented, which provide rapid assessment of geometric distortion, image uniformity, T1 and T2 mapping, image resolution, slice profile, and SNR. RESULTS: Fiducial array analysis gives assessment of intrinsic geometric distortions, which can vary considerably between scanners and correction techniques. This analysis also measures scanner/coil image uniformity, spatial calibration accuracy, and local volume distortion. An advanced resolution analysis gives both scanner and protocol contributions. SNR analysis gives both temporal and spatial contributions. CONCLUSIONS: A standard system phantom is useful for characterization of scanner performance, monitoring a scanner over time, and to compare different scanners. This type of calibration structure is useful for quality assurance, benchmarking quantitative MRI protocols, and to transition MRI from a qualitative imaging technique to a precise metrology with documented accuracy and uncertainty.

2.
J Alzheimers Dis ; 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33814434

RESUMO

BACKGROUND: Lipid alterations contribute to Alzheimer's disease (AD) pathogenesis. Lipidomics studies could help systematically characterize such alterations and identify potential biomarkers. OBJECTIVE: To identify lipids associated with mild cognitive impairment and amyloid-ß deposition, and to examine lipid correlation patterns within phenotype groupsMethods:Eighty plasma lipids were measured using mass spectrometry for 1,255 non-demented participants enrolled in the Mayo Clinic Study of Aging. Individual lipids associated with mild cognitive impairment (MCI) were first identified. Correlation network analysis was then performed to identify lipid species with stable correlations across conditions. Finally, differential correlation network analysis was used to determine lipids with altered correlations between phenotype groups, specifically cognitively unimpaired versus MCI, and with elevated brain amyloid versus without. RESULTS: Seven lipids were associated with MCI after adjustment for age, sex, and APOE4. Lipid correlation network analysis revealed that lipids from a few species correlated well with each other, demonstrated by subnetworks of these lipids. 177 lipid pairs differently correlated between cognitively unimpaired and MCI patients, whereas 337 pairs of lipids exhibited altered correlation between patients with and without elevated brain amyloid. In particular, 51 lipid pairs showed correlation alterations by both cognitive status and brain amyloid. Interestingly, the lipids central to the network of these 51 lipid pairs were not significantly associated with either MCI or amyloid, suggesting network-based approaches could provide biological insights complementary to traditional association analyses. CONCLUSION: Our attempt to characterize the alterations of lipids at network-level provides additional insights beyond individual lipids, as shown by differential correlations in our study.

3.
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.

4.
J Alzheimers Dis ; 80(3): 991-1002, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33682706

RESUMO

BACKGROUND: Cognitive impairment (CI) is a key feature of late life depression (LLD), but the contribution of underlying neurodegenerative pathology remains unclear. OBJECTIVE: To evaluate cognitive dysfunction in LLD relative to a sample of nondepressed (ND) older adults with matched levels of memory impairment and amyloid-ß (Aß) burden. METHODS: Participants included 120 LLD and 240 ND older adults matched on age, education, sex, Mini-Mental State Exam, mild cognitive impairment diagnosis, and PET Aß burden. RESULTS: LLD showed higher rates of impairment relative to ND with 54.6% of the LLD sample demonstrating impairment in at least one cognitive domain compared to 42.9% of controls (H = 7.13, p = 0.008). LLD had poorer performance and higher rates of impairment on Rey Auditory Verbal Learning Test learning and memory compared to controls. In the overall sample, Aß positivity was associated with worse performance on Logical Memory I (p = 0.044), Logical Memory II (p = 0.011), and Trail Making Test -B (p = 0.032), and APOEɛ4 genotype was associated with worse performance on Logical Memory I (p = 0.022); these relationships did not differ between LLD and ND. CONCLUSION: LLD showed higher rates of CI driven by focal deficits in verbal learning and memory. Alzheimer's disease (AD) biomarkers were associated with worse performance on timed set-shifting and story learning and memory, and these relationships were not impacted by depression status. These findings suggest that AD may account for a portion of previously reported multi-domain CI in LLD and highlight the potential for AD to confound studies of cognition in LLD.

5.
J Neurol ; 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33710456

RESUMO

BACKGROUND: Clinical variants of progressive supranuclear palsy (PSP) include the classic Richardson's syndrome (PSP-RS), as well as cortical presentations such as PSP-speech/language (PSP-SL) and subcortical presentations such as PSP-parkinsonism (PSP-P). Patterns of white matter tract degeneration underlying these variants, and the degree to which white matter patterns could differentiate these variants, is unclear. METHODS: Forty-nine PSP patients (28 PSP-RS, 12 PSP-P, and 9 PSP-SL) were recruited by the Neurodegenerative Research Group and underwent diffusion tensor imaging. Regional diffusion tensor imaging metrics were compared across PSP variants using Bayesian linear mixed-effects models, with inter-variant differentiation assessed using the area under the receiver operator characteristic curve (AUROC). RESULTS: All three variants showed degeneration of the body of the corpus callosum, posterior thalamic radiation, superior cerebellar peduncle, internal and external capsule, and superior fronto-occipital fasciculus. PSP-RS showed greater degeneration of superior cerebellar peduncle compared to PSP-P and PSP-SL, whereas PSP-SL showed greater degeneration of body and genu of the corpus callosum, internal capsule, external capsule, and superior longitudinal fasciculus compared to the other variants. Fractional anisotropy in body of the corpus callosum provided excellent differentiation of PSP-SL from both PSP-P and PSP-RS (AUROC = 0.91 and 0.92, respectively). Moderate differentiation of PSP-RS and PSP-P was achieved with fractional anisotropy in superior fronto-occipital fasciculus (AUROC = 0.68) and mean diffusivity in the superior cerebellar peduncle (AUROC = 0.65). CONCLUSION: In this pilot study, patterns of white matter tract degeneration differed across PSP-RS, PSP-SL, and PSP-P, with the body of the corpus callosum showing some utility in the differentiation of PSP-SL from the other two variants.

6.
Alzheimers Dement ; 17(4): 584-594, 2021 Apr.
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.
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.

8.
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.

9.
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.

10.
Neuroimage ; 232: 117899, 2021 May 15.
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.
J Am Heart Assoc ; 10(5): e014270, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33586464

RESUMO

Background Antiplatelets, anticoagulants, and statins are commonly prescribed for various indications. The associations between these medications and the risk of intracerebral hemorrhage (ICH) and cerebral microbleeds (CMBs) are unclear. Methods and Results We performed a retrospective study of the ARIC (Atherosclerosis Risk in Communities) study cohort, recruited from 4 US communities in 1987 to 1989 with follow-up. In 2011 to 2013, a subset (N=1942) underwent brain magnetic resonance imaging with CMB evaluation. Time-varying and any antiplatelet, anticoagulant, or statin use was evaluated at subsequent study visits in participants not on each medication at baseline. To determine the hazard of ICH and odds of CMB by medication use, logistic and Cox proportional hazard models were built, respectively, adjusting for the propensity to take the medication, concomitant use of other medications, and cognitive, genetic, and radiographic data. Of 15 719 individuals during up to 20 years of follow-up, 130 participants experienced an ICH. The adjusted hazard of ICH was significantly lower among participants taking an antiplatelet at the most recent study visit before ICH versus nonusers (hazard ratio [HR], 0.53; 95% CI, 0.30-0.92). Statin users had a significantly lower hazard of an ICH compared with nonusers (adjusted HR, 0.13; 95% CI, 0.05-0.34). There was no association of CMB and antiplatelet, anticoagulant, or statin use in adjusted models. Conclusions In this US community-based study, antiplatelet and statin use were associated with lower ICH hazard, whereas no association was noted between CMBs and antiplatelets, anticoagulants, and statins. Further study is needed to understand the differential roles of these medications in cerebral microhemorrhages and macrohemorrhages.

13.
Brain Imaging Behav ; 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33439369

RESUMO

Imaging markers of cerebrovascular disease and Alzheimer's disease (AD) are implicated in mobility impairment in older adults, but few studies have examined these relationships longitudinally in a racially-diverse population-based sample. At Visit 5 (2011-13) of the ARIC Study, 1859 participants had usual pace gait speed (cm/s) assessed and brain MRI (mean age = 76.3, 28.5% Black) and PET (n = 343; mean age = 75.9, 42.6% Black) measures including total/regional brain volume (cm3), white matter hyperintensities (WMH; cm3), infarcts (present/absent), microbleeds (count) and global beta-amyloid (Aß). Participants returned at Visit 6 (n = 1264, 2016-17) and Visit 7 (n = 1108, 2018-19) for follow-up gait speed assessments. We used linear regression to estimate effects of baseline infarct presence, higher microbleed count, and a one interquartile range (IQR) poorer measures of continuous predictors (-1 IQR total brain volume, temporal-parietal lobe meta region of interest(ROI); +1 IQR WMH volume, global Aß SUVR) on cross-sectional gait speed and change in gait speed adjusting for age, sex, education, study site, APOE e4, estimated intracranial volume, BMI, and cardiovascular risk factors. Cross-sectionally, slower gait speed outcome was associated with higher WMH volume, -3.38 cm/s (95%CI:-4.71, -2.04), infarct presence, -5.60 cm/s (-7.69, -3.51), microbleed count, -2.20 cm/s (-3.20, -0.91), smaller total brain volume, -9.26 cm/s (-12.1, -6.43), and smaller temporal-parietal lobe ROI -6.28 cm/s (-8.28, -4.28). Longitudinally, faster gait speed outcome decline was associated with higher WMH volume, -0.27 cm/s/year, (-0.51, -0.03) and higher global Aß SUVR, -0.62 cm/s/year (-1.20, -0.03). Both cerebrovascular and AD pathology may contribute to mobility decline commonly seen with aging.

14.
Neurology ; 96(12): e1632-e1645, 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33495373

RESUMO

OBJECTIVE: To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD). METHODS: Mutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease. RESULTS: Three percent of noncarriers and 8% of carriers developed CMHs primarily located in lobar areas. Carriers with CMHs were older, had higher diastolic blood pressure and Hachinski ischemic scores, and more clinical, cognitive, and motor impairments than those without CMHs. APOE ε4 status was not associated with the prevalence or incidence of CMHs. Prevalent or incident CMHs predicted faster change in Clinical Dementia Rating although not composite cognitive measure, cortical thickness, hippocampal volume, or white matter lesions. Critically, the presence of 2 or more CMHs was associated with a significant risk for development of additional CMHs over time (8.95 ± 10.04 per year). CONCLUSION: Our study highlights factors associated with the development of CMHs in individuals with DIAD. CMHs are a part of the underlying disease process in DIAD and are significantly associated with dementia. This highlights that in participants in treatment trials exposed to drugs, which carry the risk of ARIA-H as a complication, it may be challenging to separate natural incidence of CMHs from drug-related CMHs.

15.
Neuroreport ; 32(4): 326-331, 2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33470769

RESUMO

Hormone therapy improves sleep in menopausal women and recent data suggest that transdermal 17ß-estradiol may reduce the accumulation of cortical amyloid-ß. However, how menopausal hormone therapies modify the associations of amyloid-ß accumulation with sleep quality is not known. In this study, associations of sleep quality with cortical amyloid-ß deposition and cognitive function were assessed in a subset of women who had participated in the Kronos early estrogen prevention study. It was a randomized, placebo-controlled trial in which recently menopausal women (age, 42-58; 5-36 months past menopause) were randomized to (1) oral conjugated equine estrogen (n = 19); (2) transdermal 17ß-estradiol (tE2, n = 21); (3) placebo pills and patch (n = 32) for 4 years. Global sleep quality score was calculated using Pittsburgh sleep quality index, cortical amyloid-ß deposition was measured with Pittsburgh compound-B positron emission tomography standard uptake value ratio and cognitive function was assessed in four cognitive domains 3 years after completion of trial treatments. Lower global sleep quality score (i.e., better sleep quality) correlated with lower cortical Pittsburgh compound-B standard uptake value ratio only in the tE2 group (r = 0.45, P = 0.047). Better global sleep quality also correlated with higher visual attention and executive function scores in the tE2 group (r = -0.54, P = 0.02) and in the oral conjugated equine estrogen group (r = -0.65, P = 0.005). Menopausal hormone therapies may influence the effects of sleep on cognitive function, specifically, visual attention and executive function. There also appears to be a complex relationship between sleep, menopausal hormone therapies, cortical amyloid-ß accumulation and cognitive function, and tE2 formulation may modify the relationship between sleep and amyloid-ß accumulation.

16.
Alzheimers Dement ; 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33480178

RESUMO

INTRODUCTION: Machine learning models were used to discover novel disease trajectories for autosomal dominant Alzheimer's disease. METHODS: Longitudinal structural magnetic resonance imaging, amyloid positron emission tomography (PET), and fluorodeoxyglucose PET were acquired in 131 mutation carriers and 74 non-carriers from the Dominantly Inherited Alzheimer Network; the groups were matched for age, education, sex, and apolipoprotein ε4 (APOE ε4). A deep neural network was trained to predict disease progression for each modality. Relief algorithms identified the strongest predictors of mutation status. RESULTS: The Relief algorithm identified the caudate, cingulate, and precuneus as the strongest predictors among all modalities. The model yielded accurate results for predicting future Pittsburgh compound B (R2  = 0.95), fluorodeoxyglucose (R2  = 0.93), and atrophy (R2  = 0.95) in mutation carriers compared to non-carriers. DISCUSSION: Results suggest a sigmoidal trajectory for amyloid, a biphasic response for metabolism, and a gradual decrease in volume, with disease progression primarily in subcortical, middle frontal, and posterior parietal regions.

17.
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.

18.
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
19.
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.

20.
Brain ; 143(11): 3463-3476, 2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-33150361

RESUMO

Alzheimer's disease is characterized by the presence of amyloid-ß and tau deposition in the brain, hippocampal atrophy and increased rates of hippocampal atrophy over time. Another protein, TAR DNA binding protein 43 (TDP-43) has been identified in up to 75% of cases of Alzheimer's disease. TDP-43, tau and amyloid-ß have all been linked to hippocampal atrophy. TDP-43 and tau have also been linked to hippocampal atrophy in cases of primary age-related tauopathy, a pathological entity with features that strongly overlap with those of Alzheimer's disease. At present, it is unclear whether and how TDP-43 and tau are associated with early or late hippocampal atrophy in Alzheimer's disease and primary age-related tauopathy, whether either protein is also associated with faster rates of atrophy of other brain regions and whether there is evidence for protein-associated acceleration/deceleration of atrophy rates. We therefore aimed to model how these proteins, particularly TDP-43, influence non-linear trajectories of hippocampal and neocortical atrophy in Alzheimer's disease and primary age-related tauopathy. In this longitudinal retrospective study, 557 autopsied cases with Alzheimer's disease neuropathological changes with 1638 ante-mortem volumetric head MRI scans spanning 1.0-16.8 years of disease duration prior to death were analysed. TDP-43 and Braak neurofibrillary tangle pathological staging schemes were constructed, and hippocampal and neocortical (inferior temporal and middle frontal) brain volumes determined using longitudinal FreeSurfer. Bayesian bivariate-outcome hierarchical models were utilized to estimate associations between proteins and volume, early rate of atrophy and acceleration in atrophy rates across brain regions. High TDP-43 stage was associated with smaller cross-sectional brain volumes, faster rates of brain atrophy and acceleration of atrophy rates, more than a decade prior to death, with deceleration occurring closer to death. Stronger associations were observed with hippocampus compared to temporal and frontal neocortex. Conversely, low TDP-43 stage was associated with slower early rates but later acceleration. This later acceleration was associated with high Braak neurofibrillary tangle stage. Somewhat similar, but less striking, findings were observed between TDP-43 and neocortical rates. Braak stage appeared to have stronger associations with neocortex compared to TDP-43. The association between TDP-43 and brain atrophy occurred slightly later in time (∼3 years) in cases of primary age-related tauopathy compared to Alzheimer's disease. The results suggest that TDP-43 and tau have different contributions to acceleration and deceleration of brain atrophy rates over time in both Alzheimer's disease and primary age-related tauopathy.

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