Publications by authors named "Susan M Resnick"

311 Publications

Association of Combined Slow Gait and Low Activity Fragmentation With Later Onset of Cognitive Impairment.

JAMA Netw Open 2021 Nov 1;4(11):e2135168. Epub 2021 Nov 1.

Translational Gerontology Branch Longitudinal Studies Section, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.

Importance: Among older people, slow walking is an early indicator of risk for Alzheimer disease (AD). However, studies that have assessed this association have not considered that slow walking may have different causes, some of which are not necessarily associated with higher AD risk.

Objective: To evaluate whether low activity fragmentation among older adults with slow gait speed indicates neurological causes of slow walking that put these individuals at higher risk of AD.

Design, Setting, And Participants: This prospective cohort study performed survival analyses using data from the Baltimore Longitudinal Study of Aging. Participants included 520 initially cognitively normal persons aged 60 years or older. New diagnoses of mild cognitive impairment (MCI) or AD were adjudicated during a mean (SD) follow-up of 7.3 (2.7) years. Initial assessment of gait speed and activity fragmentation occurred from January 3, 2007, to May 11, 2015, with follow-up completed on December 31, 2020. Data were analyzed from February 1 to May 15, 2021.

Exposures: Gait speed for 6 m and activity fragmentation assessed by accelerometry.

Main Outcomes And Measures: Associations of gait speed, activity fragmentation, and their interaction with incident MCI/AD were evaluated using Cox proportional hazards models, adjusted for covariates.

Results: Among the 520 participants (265 women [51.0%]; 125 Black participants [24.0%]; 367 White participants [70.6%]; mean [SD] age, 73 [8] years), MCI/AD developed in 64 participants. Each 0.05-m/s slower gait was associated with a 7% increase in risk of developing MCI/AD (hazard ratio [HR], 1.07 [95% CI, 1.00-1.15]; P = .04). Activity fragmentation alone was not associated with MCI/AD risk (HR, 0.83 [95% CI, 0.56-1.23]; P = .35), but there was a significant interaction between gait speed and activity fragmentation (HR, 0.92 [95% CI, 0.87-0.98]; P = .01). At low activity fragmentation (-1 SD), each 0.05-m/s slower gait speed was associated with a 19% increase in hazard of developing MCI/AD (HR, 1.19 [95% CI, 1.07-1.32]), whereas at higher activity fragmentation (+1 SD), gait speed was not associated with MCI/AD (HR, 1.01 [95% CI, 0.93-1.10]). Among participants with slow gait, higher activity fragmentation was associated with higher odds of having lower extremity osteoarthritis (odds ratio, 1.31 [95% CI, 1.01-1.69]) and less decline in pegboard dominant hand performance (β = 0.026 [SE, 0.009]; P > .05).

Conclusions And Relevance: These findings suggest that frequent rests among older adults with slow gait speed are associated with lower risk of future MCI/AD and that this behavioral strategy is associated with a lower likelihood of subclinical neurological impairment.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.35168DOI Listing
November 2021

Associations Between Air Pollution Exposure and Empirically Derived Profiles of Cognitive Performance in Older Women.

J Alzheimers Dis 2021 Oct 30. Epub 2021 Oct 30.

University of Southern California, Department of Neurology, Los Angeles, CA, USA.

Background: Elucidating associations between exposures to ambient air pollutants and profiles of cognitive performance may provide insight into neurotoxic effects on the aging brain.

Objective: We examined associations between empirically derived profiles of cognitive performance and residential concentrations of particulate matter of aerodynamic diameter < 2.5 (PM2.5) and nitrogen dioxide (NO2) in older women.

Method: Women (N = 2,142) from the Women's Health Initiative Study of Cognitive Aging completed a neuropsychological assessment measuring attention, visuospatial, language, and episodic memory abilities. Average yearly concentrations of PM2.5 and NO2 were estimated at the participant's addresses for the 3 years prior to the assessment. Latent profile structural equation models identified subgroups of women exhibiting similar profiles across tests. Multinomial regressions examined associations between exposures and latent profile classification, controlling for covariates.

Result: Five latent profiles were identified: low performance across multiple domains (poor multi-domain; n = 282;13%), relatively poor verbal episodic memory (poor memory; n = 216; 10%), average performance across all domains (average multi-domain; n = 974; 45%), superior memory (n = 381; 18%), and superior attention (n = 332; 15%). Using women with average cognitive ability as the referent, higher PM2.5 (per interquartile range [IQR] = 3.64μg/m3) was associated with greater odds of being classified in the poor memory (OR = 1.29; 95% Confidence Interval [CI] = 1.10-1.52) or superior attention (OR = 1.30; 95% CI = 1.10-1.53) profiles. NO2 (per IQR = 9.86 ppb) was associated with higher odds of being classified in the poor memory (OR = 1.38; 95% CI = 1.17-1.63) and lower odds of being classified with superior memory (OR = 0.81; 95% CI = 0.67-0.97).

Conclusion: Exposure to PM2.5 and NO2 are associated with patterns of cognitive performance characterized by worse verbal episodic memory relative to performance in other domains.
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http://dx.doi.org/10.3233/JAD-210518DOI Listing
October 2021

TractEM: Evaluation of protocols for deterministic tractography white matter atlas.

Magn Reson Imaging 2022 Jan 16;85:44-56. Epub 2021 Oct 16.

Electrical Engineering, Vanderbilt University, Nashville, TN, USA; Vanderbilt University Institute of Imaging Science, Nashville, TN, USA; Computer Science, Vanderbilt University, Nashville, TN, USA; Department of Radiology and Radiological Sciences, Vanderbilt University, Nashville, TN, USA.

Reproducible identification of white matter pathways across subjects is essential for the study of structural connectivity of the human brain. One of the key challenges is anatomical differences between subjects and human rater subjectivity in labeling. Labeling white matter regions of interest presents many challenges due to the need to integrate both local and global information. Clearly communicating the manual processes to capture this information is cumbersome, yet essential to lay a solid foundation for comprehensive atlases. Segmentation protocols must be designed so the interpretation of the requested tasks as well as locating structural landmarks is anatomically accurate, intuitive and reproducible. In this work, we quantified the reproducibility of a first iteration of an open/public multi-bundle segmentation protocol. This allowed us to establish a baseline for its reproducibility as well as to identify the limitations for future iterations. The protocol was tested/evaluated on both typical 3 T research acquisition Baltimore Longitudinal Study of Aging (BLSA) and high-acquisition quality Human Connectome Project (HCP) datasets. The results show that a rudimentary protocol can produce acceptable intra-rater and inter-rater reproducibility. However, this work highlights the difficulty in generalizing reproducible results and the importance of reaching consensus on anatomical description of white matter pathways. The protocol has been made available in open source to improve generalizability and reliability in collaboration. The goal is to improve upon the first iteration and initiate a discussion on the anatomical validity (or lack thereof) of some bundle definitions and the importance of reproducibility of tractography segmentation.
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http://dx.doi.org/10.1016/j.mri.2021.10.017DOI Listing
January 2022

Personality Associations With Amyloid and Tau: Results From the Baltimore Longitudinal Study of Aging and Meta-analysis.

Biol Psychiatry 2021 Sep 3. Epub 2021 Sep 3.

Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.

Background: Higher neuroticism and lower conscientiousness are risk factors for Alzheimer's disease and related dementias, but the underlying neuropathological correlates remain unclear. Our aim was to examine whether personality traits are associated with amyloid and tau neuropathology in a new sample and meta-analyses.

Methods: Participants from the BLSA (Baltimore Longitudinal Study of Aging) completed the Revised NEO Personality Inventory and underwent amyloid (C-labeled Pittsburgh compound B) and tau (F-flortaucipir) positron emission tomography.

Results: Among cognitively normal BLSA participants, neuroticism was associated with higher cortical amyloid burden (odds ratio 1.68, 95% confidence interval 1.20-2.34), and conscientiousness was associated with lower cortical amyloid burden (odds ratio 0.61, 95% confidence interval 0.44-0.86). These associations remained significant after accounting for age, sex, education, depressive symptoms, hippocampal volume, and APOE ε4. Similar associations were found with tau in the entorhinal cortex. Random-effects meta-analyses of 12 studies found that higher neuroticism (N = 3015, r = 0.07, p = .008) and lower conscientiousness (N = 2990, r = -0.11, p < .001) were associated with more amyloid deposition. Meta-analyses of 8 studies found that higher neuroticism (N = 2231, r = 0.15, p < .001) and lower conscientiousness (N = 2206, r = -0.14, p < .001) were associated with more tau pathology. The associations were moderated by cognitive status, with stronger effects in cognitively normal compared with heterogeneous samples, suggesting that the associations between personality and proteopathies are not phenomena that emerge with neuropsychiatric clinical symptoms.

Conclusions: By aggregating results across samples, this study advances knowledge on the association between personality and neuropathology. Neuroticism and conscientiousness may contribute to resistance against amyloid and tau neuropathology.
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http://dx.doi.org/10.1016/j.biopsych.2021.08.021DOI Listing
September 2021

Energetic cost of walking and Brain Atrophy in Mid-to-Late Life.

J Gerontol A Biol Sci Med Sci 2021 Oct 10. Epub 2021 Oct 10.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Background: Higher energetic costs for mobility are associated with declining gait speed and slow gait is linked to cognitive decline and Alzheimer's disease. However, the physiological underpinnings of gait and brain health have not been well explored. We examined the associations of the energetic cost of walking with brain volume in cognitively unimpaired adults from the Baltimore Longitudinal Study of Aging.

Methods: We used brain MRI data from 850 participants (mean baseline age 66.3±14.5 years), of whom 451 had longitudinal MRI data (2.8±1.0 MRI scans over 4.0±2.0 years). The energetic cost of walking was assessed as the average energy expended (V̇O2) during 2.5 minutes of customary-paced overground walking. Multivariable linear mixed effects models examined the associations between baseline energetic cost of walking and regional brain volumes adjusting for covariates.

Results: At baseline, higher energetic cost of walking was cross-sectionally associated with lower gray and white matter volumes within the frontal, parietal, and temporal lobes, as well as hippocampal, total brain, and larger ventricular volumes (all FDR p< 0.05). A baseline energetic cost of walking × time interaction demonstrated that participants with higher energetic cost of walking had faster annual decline in hippocampal volume (FDR p= 0.01) and accelerated annual increase in ventricular volumes (FDR p= 0.01).

Conclusions: The energetic cost of walking is associated with gray and white matter volumes and subsequent hippocampal atrophy and ventricular enlargement. Collectively, these data suggest the energetic cost of walking may be an early marker of neurodegeneration that contributes to the gait brain connection.
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http://dx.doi.org/10.1093/gerona/glab309DOI Listing
October 2021

Patterns of Prevalence of Multiple Sensory Impairments among Community-Dwelling Older Adults.

J Gerontol A Biol Sci Med Sci 2021 Oct 5. Epub 2021 Oct 5.

Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Much is known about individual sensory deficits among older adults, but there is a dearth of information about the prevalence of multiple concurrent sensory deficits in this population.

Methods: We evaluated the prevalence of individual and multiple sensory impairments at the most recent clinic visit among participants aged 24 years and older in the Baltimore Longitudinal Study of Aging (BLSA) (hearing, vision, olfaction, proprioception, and vestibular function) and Atherosclerosis Risk in Communities Study (ARIC) (hearing, vision, olfaction). We compared observed prevalence of multiple sensory impairments with expected prevalence based on compounded probabilities of multiple impairments using Fisher Exact Tests. Also, we evaluated the comparability of different measures used between these two studies.

Results: In both studies, the prevalence of each individual sensory impairment was common (>10%), and higher with older age, and the most common pattern of co-occurring sensory impairments was hearing and visual impairments (17.4% [BLSA]; 50.2% [ARIC]). In BLSA, the pattern that differed the most between observed and expected prevalence was combined hearing, vision, and olfactory impairments (observed 5.2% vs. 1.4% expected, p=0.01). In ARIC, this difference was much smaller (observed 8.1% vs. 7.2% expected, p=0.49).

Conclusions: Although concurrent hearing and vision impairments were the most common co-occurring deficits, combined hearing, vision and olfactory impairments are most likely to co-occur above chance, especially at older ages.
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http://dx.doi.org/10.1093/gerona/glab294DOI Listing
October 2021

Deep Generative Medical Image Harmonization for Improving Cross-Site Generalization in Deep Learning Predictors.

J Magn Reson Imaging 2021 Sep 25. Epub 2021 Sep 25.

Artificial Intelligence in Biomedical Imaging Lab, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: In the medical imaging domain, deep learning-based methods have yet to see widespread clinical adoption, in part due to limited generalization performance across different imaging devices and acquisition protocols. The deviation between estimated brain age and biological age is an established biomarker of brain health and such models may benefit from increased cross-site generalizability.

Purpose: To develop and evaluate a deep learning-based image harmonization method to improve cross-site generalizability of deep learning age prediction.

Study Type: Retrospective.

Population: Eight thousand eight hundred and seventy-six subjects from six sites. Harmonization models were trained using all subjects. Age prediction models were trained using 2739 subjects from a single site and tested using the remaining 6137 subjects from various other sites.

Field Strength/sequence: Brain imaging with magnetization prepared rapid acquisition with gradient echo or spoiled gradient echo sequences at 1.5 T and 3 T.

Assessment: StarGAN v2, was used to perform a canonical mapping from diverse datasets to a reference domain to reduce site-based variation while preserving semantic information. Generalization performance of deep learning age prediction was evaluated using harmonized, histogram matched, and unharmonized data.

Statistical Tests: Mean absolute error (MAE) and Pearson correlation between estimated age and biological age quantified the performance of the age prediction model.

Results: Our results indicated a substantial improvement in age prediction in out-of-sample data, with the overall MAE improving from 15.81 (±0.21) years to 11.86 (±0.11) with histogram matching to 7.21 (±0.22) years with generative adversarial network (GAN)-based harmonization. In the multisite case, across the 5 out-of-sample sites, MAE improved from 9.78 (±6.69) years to 7.74 (±3.03) years with histogram normalization to 5.32 (±4.07) years with GAN-based harmonization.

Data Conclusion: While further research is needed, GAN-based medical image harmonization appears to be a promising tool for improving cross-site deep learning generalization.

Level Of Evidence: 4 TECHNICAL EFFICACY: Stage 1.
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http://dx.doi.org/10.1002/jmri.27908DOI Listing
September 2021

Validation of Group-wise Registration for Surface-based Functional MRI Analysis.

Proc SPIE Int Soc Opt Eng 2021 Feb;11596

Department of Computer Science, Vanderbilt University, Nashville, TN, USA.

Resting-state functional MRI (rsfMRI) provides important information for studying and mapping the activities and functions of the brain. Conventionally, rsfMRIs are often registered to structural images in the Euclidean space without considering cortical geometry. Meanwhile, a surface-based representation offers a relaxed coordinate chart, but this still requires surface registration for group-wise data analysis. In this work, we investigate the performance of two existing surface registration methods in a surface-based rsfMRI analysis framework: FreeSurfer and Hierarchical Spherical Deformation (HSD). To minimize registration bias, we establish shape correspondence using both methods in a group-wise manner that estimates the unbiased average of a given cohort. To evaluate their performance, we focus on neuroanatomical alignment as well as the amount of distortion that can potentially bias surface tessellation for secondary level rsfMRI data analyses. In the pilot analysis, we examine a single timepoint of imaging data from 100 subjects out of an aging cohort. Overall, HSD establishes improved shape correspondence with reduced mean curvature deviation (10.94% less on average per subject, paired t-test: p <10) and reduced registration distortion (FreeSurfer: average 41.91% distortion per subject, HSD: 18.63%, paired t-test: p <10). Furthermore, HSD introduces less distortion than FreeSurfer in the areas identified in the individual components that were extracted by surface-based independent component analysis (ICA) after spatial smoothing and time series normalization. Consequently, we show that FreeSurfer capture individual components with globally similar but locally different patterns in ICA in visual inspection.
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http://dx.doi.org/10.1117/12.2580771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442945PMC
February 2021

Longitudinal associations of subclinical hearing loss with cognitive decline.

J Gerontol A Biol Sci Med Sci 2021 Sep 13. Epub 2021 Sep 13.

Department of Otolaryngology-Head and Neck Surgery, Columbia University Vagelos College of Physicians and Surgeons, NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY, USA.

Background: Several studies have demonstrated that age-related hearing loss is associated with cognitive decline. We investigated whether subclinical hearing loss (SCHL), or imperfect hearing traditionally categorized as normal (pure tone average ≤25 dB), may be similarly linked to cognitive decline and risk of incident mild cognitive impairment (MCI)/dementia.

Methods: Participants from the Baltimore Longitudinal Study of Aging were cognitively normal adults ≥50 years old with cognitive assessments from 1991-2019 and pure-tone average ≤25 dB measured between 1991-1994 (n=263). The exposure was hearing based on the better ear pure-tone average. Outcomes were test scores in various cognitive domains. Multivariable linear-mixed effects models modeled the association between hearing and change in cognition over time, adjusting for age, sex, education, vascular burden, and race. Kaplan-Meier survival curves and Cox proportional hazards models portrayed associations between hearing and incident MCI/dementia diagnosis based on predefined criteria.

Results: Of 263 participants, 145 (55.1%) were female; mean age was 68.3 years (standard deviation, SD=8.9). Follow-up ranged up to 27.7 years (mean=11.7 years). Adjusting for multiple comparisons, a 10-dB increase in hearing loss was associated with an annual decline of -0.02 SDs (95% confidence interval, [CI]: -0.03, -0.01) in Letter Fluency. No significant relationships were observed between hearing and incident MCI/dementia.

Conclusions: A relationship between SCHL and cognitive decline was observed for the Letter Fluency test. Further studies are necessary to determine when in the spectrum of hearing loss there begins to be an observable relationship between hearing and cognitive decline.
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http://dx.doi.org/10.1093/gerona/glab263DOI Listing
September 2021

Ambient Air Pollution and Long-Term Trajectories of Episodic Memory Decline among Older Women in the WHIMS-ECHO Cohort.

Environ Health Perspect 2021 Sep 13;129(9):97009. Epub 2021 Sep 13.

Department of Neurology, University of Southern California, Los Angeles, California, USA.

Background: Episodic memory decline varies by age and underlying neuropathology. Whether ambient air pollution contributes to the heterogeneity of episodic memory decline in older populations remains unclear.

Objectives: We estimated associations between air pollution exposures and episodic memory decline according to pollutant, exposure time window, age, and latent class subgroups defined by episodic memory trajectories.

Methods: Participants were from the Women's Health Initiative Memory Study-Epidemiology of Cognitive Health Outcomes. Older women (; 74-92 years of age) completed annual (2008-2018) episodic memory assessments using the telephone-based California Verbal Learning Test (CVLT). We estimated 3-y average fine particulate matter [PM with an aerodynamic diameter of ()] and nitrogen dioxide () exposures at baseline and 10 y earlier (recent and remote exposures, respectively), using regionalized national universal kriging. Separate latent class mixed models were used to estimate associations between interquartile range increases in exposures and CVLT trajectories in women and , adjusting for covariates.

Results: Two latent classes were identified for women (), "slow-decliners" { [95% confidence interval (CI): , ] and "fast-decliners" [ (95% CI: , )]}. In the slow-decliner class, but not the fast-decliner class, exposures were associated with a greater decline in CVLT scores over time, with a stronger association for recent vs. remote exposures [ (95% CI: , ) per and (95% CI: , 0.01) per , respectively]. Among women (), the largest latent class comprised "steady-decliners" [ (95% CI: , )], whereas the second class, "cognitively resilient", had no decline in CVLT on average. was not associated with episodic memory decline in either class. A increase in recent was associated with nonsignificant acceleration of episodic memory decline in the -y-old fast-decliner class [ (95% CI: , 0.04)], and in the cognitively resilient class [ (95% CI: , 0.03)] and steady-decliner class [ (95% CI: , 0.05)]. Associations with recent exposure in women were stronger and statistically significant when 267 women with incident probable dementia were excluded [e.g., (95% CI: , ) for the cognitively resilient class]. In contrast with changes in CVLT over time, there were no associations between exposures and CVLT scores during follow-up in any subgroup.

Discussion: In a community-dwelling U.S. population of older women, associations between late-life exposure to ambient air pollution and episodic memory decline varied by age-related cognitive trajectories, exposure time windows, and pollutants. https://doi.org/10.1289/EHP7668.
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http://dx.doi.org/10.1289/EHP7668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437247PMC
September 2021

Unsupervised MR harmonization by learning disentangled representations using information bottleneck theory.

Neuroimage 2021 11 8;243:118569. Epub 2021 Sep 8.

Department of Electrical and Computer Engineering, The Johns Hopkins University, Baltimore, MD 21218 USA.

In magnetic resonance (MR) imaging, a lack of standardization in acquisition often causes pulse sequence-based contrast variations in MR images from site to site, which impedes consistent measurements in automatic analyses. In this paper, we propose an unsupervised MR image harmonization approach, CALAMITI (Contrast Anatomy Learning and Analysis for MR Intensity Translation and Integration), which aims to alleviate contrast variations in multi-site MR imaging. Designed using information bottleneck theory, CALAMITI learns a globally disentangled latent space containing both anatomical and contrast information, which permits harmonization. In contrast to supervised harmonization methods, our approach does not need a sample population to be imaged across sites. Unlike traditional unsupervised harmonization approaches which often suffer from geometry shifts, CALAMITI better preserves anatomy by design. The proposed method is also able to adapt to a new testing site with a straightforward fine-tuning process. Experiments on MR images acquired from ten sites show that CALAMITI achieves superior performance compared with other harmonization approaches.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118569DOI Listing
November 2021

Association of walking energetics with amyloid beta status: Findings from the Baltimore Longitudinal Study of Aging.

Alzheimers Dement (Amst) 2021 20;13(1):e12228. Epub 2021 Aug 20.

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore Maryland USA.

Introduction: Higher energetic costs for mobility predict gait speed decline. Slow gait is linked to cognitive decline and Alzheimer's disease (AD). Whether the energetic cost of walking is linked to AD pathology is unknown. We investigated the cross-sectional association between the energetic cost of walking, gait speed, and amyloid beta (Aβ) status (+/-) in older adults.

Methods: One hundred forty-nine cognitively normal adults (56% women, mean age 77.5 ± 8.4 years) completed customary-paced walking assessments with indirect calorimetry and C-Pittsburgh compound B positron emission tomography. Logistic regression models examined associations adjusted for demographics, body composition, comorbid conditions, and apolipoprotein E ε4.

Results: Each 0.01 mL/kg/m greater energy cost was associated with 18% higher odds of being Aβ+ (odds ratio [OR] = 1.18; 95% confidence interval [CI]: 1.04 to 1.34; = .011). These findings were not observed when investigating gait speed (OR = 0.99; 95% CI: 0.97 to 1.01; = .321).

Discussion: High energetic cost of walking is linked to AD pathology and may be a potential target for therapeutic intervention.
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http://dx.doi.org/10.1002/dad2.12228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377776PMC
August 2021

Recognition Memory is Associated with Distinct Patterns of Regional Gray Matter Volumes in Young and Aged Monkeys.

Cereb Cortex 2021 Aug 27. Epub 2021 Aug 27.

Neurocognitive Aging Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD 21224, United States.

Cognitive aging varies tremendously across individuals and is often accompanied by regionally specific reductions in gray matter (GM) volume, even in the absence of disease. Rhesus monkeys provide a primate model unconfounded by advanced neurodegenerative disease, and the current study used a recognition memory test (delayed non-matching to sample; DNMS) in conjunction with structural imaging and voxel-based morphometry (VBM) to characterize age-related differences in GM volume and brain-behavior relationships. Consistent with expectations from a long history of neuropsychological research, DNMS performance in young animals prominently correlated with the volume of multiple structures in the medial temporal lobe memory system. Less anticipated correlations were also observed in the cingulate and cerebellum. In aged monkeys, significant volumetric correlations with DNMS performance were largely restricted to the prefrontal cortex and striatum. Importantly, interaction effects in an omnibus analysis directly confirmed that the associations between volume and task performance in the MTL and prefrontal cortex are age-dependent. These results demonstrate that the regional distribution of GM volumes coupled with DNMS performance changes across the lifespan, consistent with the perspective that the aged primate brain retains a substantial capacity for structural reorganization.
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http://dx.doi.org/10.1093/cercor/bhab257DOI Listing
August 2021

Association of Epigenetic Age Acceleration with Incident Mild Cognitive Impairment and Dementia Among Older Women.

J Gerontol A Biol Sci Med Sci 2021 Aug 21. Epub 2021 Aug 21.

Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA, USA.

Background: Epigenetic age acceleration (AgeAccel), which indicates faster biological aging relative to chronological age, has been associated with lower cognitive function. However, the association of AgeAccel with mild cognitive impairment (MCI) or dementia is not well-understood. We examined associations of four AgeAccel measures with incident MCI and dementia.

Methods: This prospective analysis included 578 older women from the Women's Health Initiative Memory Study selected for a case-cohort study of coronary heart disease (CHD). Women were free of CHD and cognitive impairment at baseline. Associations of AgeAccel measures (intrinsic AgeAccel [IEAA], extrinsic AgeAccel [EEAA], AgeAccelPheno, and AgeAccelGrim) with risks for incident adjudicated diagnoses of MCI and dementia overall and stratified by incident CHD status were evaluated.

Results: IEAA was not significantly associated with MCI (HR 1.23; 95% CI 0.99-1.53), dementia (HR 1.10; 95% CI 0.88-1.38), or cognitive impairment (HR 1.18; 95% CI 0.99-1.40). In stratified analysis by incident CHD status, there was a 39% (HR 1.39; 95% CI 1.07-1.81) significantly higher risk of MCI for every 5-year increase in IEAA among women who developed CHD during follow-up. Other AgeAccel measures were not significantly associated with MCI or dementia.

Conclusion: IEAA was not significantly associated with cognitive impairment overall but was associated with impairment among women who developed CHD. Larger studies designed to examine associations of AgeAccel with cognitive impairment are needed, including exploration of whether associations are stronger in the setting of underlying vascular pathologies.
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http://dx.doi.org/10.1093/gerona/glab245DOI Listing
August 2021

Joint cortical surface and structural connectivity analysis of Alzheimer's Disease.

Proc SPIE Int Soc Opt Eng 2021 15;11596. Epub 2021 Feb 15.

Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.

Prior neuroimaging studies have demonstrated isolated structural and connectivity changes in the brain due to Alzheimer's Disease (AD). However, how these changes relate to each other is not well understood. We present a preliminary study to begin to fill this gap by leveraging joint independent component analysis (jICA). We explore how jICA performs in an analysis of T1 and diffusion weighted MRI by characterizing the joint changes of complex cortical surface and structural connectivity metrics in AD in subjects from the Baltimore Longitudinal Study of Aging. We calculate 588 region-based cortical metrics and 4,753 fractional anisotropy-based connectivity metrics and project them into a low-dimensional manifold with principal component analysis. We perform jICA on the manifold and subsequently backproject the independent components to the original data space. We demonstrate component stability with 3-fold cross validation and find differential component loadings between 776 cognitively unimpaired control subjects and 23 with AD that generalizes across folds. In addition, we perform the same analysis on the surface and connectivity metrics separately and find that the joint approach identifies both novel and similar components to the separate approaches. To illustrate the joint approach's primary utility, we provide an example hypothesis for how surface and connectivity components may vary together with AD. These preliminary results suggest jointly varying independent cortical surface and structural connectivity components can be consistently extracted from MRI data and provide a data-driven way for generating novel hypotheses about AD that may not be captured by separate analyses.
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http://dx.doi.org/10.1117/12.2580956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336655PMC
February 2021

Disease Burden Affects Aging Brain Function.

J Gerontol A Biol Sci Med Sci 2021 Jul 30. Epub 2021 Jul 30.

Intramural Research Program, National Institute on Aging, NIH.

Background: Most older adults live with multiple chronic disease conditions, yet the effect of multiple diseases on brain function remains unclear.

Methods: We examine the relationship between disease multimorbidity and brain activity using regional cerebral blood flow (rCBF) 15O-water PET scans from 97 cognitively normal participants (mean baseline age 76.5) in the Baltimore Longitudinal Study of Aging (BLSA). Multimorbidity index scores, generated from the presence of 13 health conditions, were correlated with PET data at baseline and in longitudinal change (n=74) over 5.05 (2.74 SD) years.

Results: At baseline, voxel-based analysis showed that higher multimorbidity scores were associated with lower relative activity in orbitofrontal, superior frontal, temporal pole and parahippocampal regions, and greater activity in lateral temporal, occipital and cerebellar regions. Examination of the individual health conditions comprising the index score showed hypertension and chronic kidney disease individually contributed to the overall multimorbidity pattern of altered activity. Longitudinally, both increases and decreases in activity were seen in relation to increasing multimorbidity over time. These associations were identified in orbitofrontal, lateral temporal, brainstem, and cerebellar areas.

Conclusion: Together, these results show that greater multimorbidity is associated with widespread areas of altered brain activity, supporting a link between health and changes in aging brain function.
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http://dx.doi.org/10.1093/gerona/glab218DOI Listing
July 2021

Association of Vision Impairment With Cognitive Decline Across Multiple Domains in Older Adults.

JAMA Netw Open 2021 Jul 1;4(7):e2117416. Epub 2021 Jul 1.

Johns Hopkins Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Importance: Associations between visual and global cognitive impairments have been previously documented, but there is limited research examining these associations between multiple measures of vision across cognitive domains.

Objective: To examine the association between vision and cognitive across multiple cognitive domains using multiple measures of vision.

Design, Setting, And Participants: This longitudinal cohort study used data from the Baltimore Longitudinal Study of Aging for 2003 to 2019. Participants in the current study were aged 60 to 94 years with vision and cognitive measures. Data analysis was performed from May 2020 to May 2021.

Main Outcomes And Measures: Cognitive function was measured across multiple domains, including language, memory, attention, executive function, and visuospatial ability. Cognitive domain scores were calculated as the mean of standardized cognitive test scores within each domain. Visual function was assessed using measures of visual acuity, contrast sensitivity, and stereo acuity at baseline.

Results: Analyses included 1202 participants (610 women [50.8%]; 853 White participants [71.0%]) with a mean (SD) age of 71.1 (8.6) years who were followed up for a mean (SD) of 6.9 (4.7) years. Worse visual acuity (per 0.1 logarithm of the minimal angle of resolution) at baseline was associated with greater declines in language (β, -0.0035; 95% CI, -0.007 to -0.001) and memory (β, -0.0052; 95% CI, -0.010 to -0.001) domain scores. Worse contrast sensitivity (per 0.1 log units) at baseline was associated with greater declines in language (β, -0.010; 95% CI, -0.014 to -0.006), memory (β, -0.009; 95% CI, -0.015 to -0.003), attention (β, -0.010; 95% CI, -0.017 to -0.003), and visuospatial ability (β, -0.010; 95% CI, -0.017 to -0.002) domain scores. Over the follow-up period, declines on tests of language (β, -0.019; 95% CI, -0.034 to -0.005) and memory (β, -0.032; 95% CI, -0.051 to -0.012) were significantly greater for participants with impaired stereo acuity compared with those without such impairment.

Conclusions And Relevance: These findings suggest that the association between vision and cognition differs between visual acuity, contrast sensitivity, and stereo acuity and that patterns of cognitive decline may differ by type of vision impairment, with impaired contrast sensitivity being associated with declines across more cognitive domains than other measures of visual functioning.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.17416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285732PMC
July 2021

Deconvolution-based partial volume correction of PET images with parallel level set regularization.

Phys Med Biol 2021 Jul 9;66(14). Epub 2021 Jul 9.

Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States of America.

The partial volume effect (PVE), caused by the limited spatial resolution of positron emission tomography (PET), degrades images both qualitatively and quantitatively. Anatomical information provided by magnetic resonance (MR) images has the potential to play an important role in partial volume correction (PVC) methods. Post-reconstruction MR-guided PVC methods typically use segmented MR tissue maps, and further, assume that PET activity distribution is uniform in each region, imposing considerable constraints through anatomical guidance. In this work, we present a post-reconstruction PVC method based on deconvolution with parallel level set (PLS) regularization. We frame the problem as an iterative deconvolution task with PLS regularization that incorporates anatomical information without requiring MR segmentation or assuming uniformity of PET distributions within regions. An efficient algorithm for non-smooth optimization of the objective function (invoking split Bregman framework) is developed so that the proposed method can be feasibly applied to 3D images and produces sharper images compared to PLS method with smooth optimization. The proposed method was evaluated together with several other PVC methods using both realistic simulation experiments based on the BrainWeb phantom as well ashuman data. Our proposed method showed enhanced quantitative performance when realistic MR guidance was provided. Further, the proposed method is able to reduce image noise while preserving structure details onhuman data, and shows the potential to better differentiate amyloid positive and amyloid negative scans. Overall, our results demonstrate promise to provide superior performance in clinical imaging scenarios.
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http://dx.doi.org/10.1088/1361-6560/ac0d8fDOI Listing
July 2021

Investigation of the association between cerebral iron content and myelin content in normative aging using quantitative magnetic resonance neuroimaging.

Neuroimage 2021 10 15;239:118267. Epub 2021 Jun 15.

Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, 21224 MD, United States. Electronic address:

Myelin loss and iron accumulation are cardinal features of aging and various neurodegenerative diseases. Oligodendrocytes incorporate iron as a metabolic substrate for myelin synthesis and maintenance. An emerging hypothesis in Alzheimer's disease research suggests that myelin breakdown releases substantial stores of iron that may accumulate, leading to further myelin breakdown and neurodegeneration. We assessed associations between iron content and myelin content in critical brain regions using quantitative magnetic resonance imaging (MRI) on a cohort of cognitively unimpaired adults ranging in age from 21 to 94 years. We measured whole-brain myelin water fraction (MWF), a surrogate of myelin content, using multicomponent relaxometry, and whole-brain iron content using susceptibility weighted imaging in all individuals. MWF was negatively associated with iron content in most brain regions evaluated indicating that lower myelin content corresponds to higher iron content. Moreover, iron content was significantly higher with advanced age in most structures, with men exhibiting a trend towards higher iron content as compared to women. Finally, relationship between MWF and age, in all brain regions investigated, suggests that brain myelination continues until middle age, followed by degeneration at older ages. This work establishes a foundation for further investigations of the etiology and sequelae of myelin breakdown and iron accumulation in neurodegeneration and may lead to new imaging markers for disease progression and treatment.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370037PMC
October 2021

A multicentre validation study of the diagnostic value of plasma neurofilament light.

Nat Commun 2021 06 7;12(1):3400. Epub 2021 Jun 7.

Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Montreal, QC, Canada.

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.
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http://dx.doi.org/10.1038/s41467-021-23620-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185001PMC
June 2021

Bile acid synthesis, modulation, and dementia: A metabolomic, transcriptomic, and pharmacoepidemiologic study.

PLoS Med 2021 05 27;18(5):e1003615. Epub 2021 May 27.

Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, Maryland, United States of America.

Background: While Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pathogenesis.

Methods And Findings: We used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an average of 2.5 follow-up magnetic resonance imaging (MRI) visits. We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 1,666) to validate longitudinal neuroimaging results in BLSA. ADNI is an ongoing, community-based cohort study that began in 2003. Participants were approximately 55% male with a mean age of 74 years; longitudinal analyses included an average of 5.2 follow-up MRI visits. Lower serum concentrations of 7α-OHC, CA, and CDCA were associated with higher brain amyloid deposition (p = 0.041), faster WML accumulation (p = 0.050), and faster brain atrophy mainly (false discovery rate [FDR] p = <0.001-0.013) in males in BLSA. In ADNI, we found a modest sex-specific effect indicating that lower serum concentrations of CA and CDCA were associated with faster brain atrophy (FDR p = 0.049) in males.Step 2: In the Clinical Practice Research Datalink (CPRD) dataset, covering >4 million registrants from general practice clinics in the United Kingdom, we tested whether patients using BAS (BAS users; 3,208 with ≥2 prescriptions), which reduce circulating BAs and increase cholesterol catabolism, had altered dementia risk compared to those on non-statin lipid-modifying therapies (LMT users; 23,483 with ≥2 prescriptions). Patients in the study (BAS/LMT) were approximately 34%/38% male and with a mean age of 65/68 years; follow-up time was 4.7/5.7 years. We found that BAS use was not significantly associated with risk of all-cause dementia (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 0.72-1.46, p = 0.88) or its subtypes. We found a significant difference between the risk of VaD in males compared to females (p = 0.040) and a significant dose-response relationship between BAS use and risk of VaD (p-trend = 0.045) in males.Step 3: We assayed brain tissue concentrations of CA and CDCA comparing AD and control (CON) samples in the BLSA autopsy cohort (N = 29). Participants in the BLSA autopsy cohort (AD/CON) were approximately 50%/77% male with a mean age of 87/82 years. We analyzed single-cell RNA sequencing (scRNA-Seq) data to compare brain BA receptor gene expression between AD and CON samples from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 46). ROSMAP is an ongoing, community-based cohort study that began in 1994. Participants (AD/CON) were approximately 56%/36% male with a mean age of 85/85 years. In BLSA, we found that CA and CDCA were detectable in postmortem brain tissue samples and were marginally higher in AD samples compared to CON. In ROSMAP, we found sex-specific differences in altered neuronal gene expression of BA receptors in AD. Study limitations include the small sample sizes in the BLSA cohort and likely inaccuracies in the clinical diagnosis of dementia subtypes in primary care settings.

Conclusions: We combined targeted metabolomics in serum and amyloid positron emission tomography (PET) and MRI of the brain with pharmacoepidemiologic analysis to implicate dysregulation of cholesterol catabolism in dementia pathogenesis. We observed that lower serum BA concentration mainly in males is associated with neuroimaging markers of dementia, and pharmacological lowering of BA levels may be associated with higher risk of VaD in males. We hypothesize that dysregulation of BA signaling pathways in the brain may represent a plausible biologic mechanism underlying these results. Together, our observations suggest a novel mechanism relating abnormalities in cholesterol catabolism to risk of dementia.
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http://dx.doi.org/10.1371/journal.pmed.1003615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158920PMC
May 2021

Default mode network connectivity and cognition in the aging brain: the effects of age, sex, and APOE genotype.

Neurobiol Aging 2021 08 2;104:10-23. Epub 2021 Apr 2.

Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD. Electronic address:

The default mode network (DMN) overlaps with regions showing early Alzheimer's Disease (AD) pathology. Age, sex, and apolipoprotein E ɛ4 are the predominant risk factors for developing AD. How these risk factors interact to influence DMN connectivity and connectivity-cognition relationships before the onset of impairment remains unknown. Here, we examined these issues in 475 cognitively normal adults, targeting total DMN connectivity, its anticorrelated network (acDMN), and the DMN-hippocampal component. There were four main findings. First, in the ɛ3 homozygous group, lower DMN and acDMN connectivity was observed with age. Second, sex and ɛ4 modified the relationship between age and connectivity for the DMN and hippocampus with ɛ4 vs. ɛ3 males showing sustained or higher connectivity with age. Third, in the ɛ3 group, age and sex modified connectivity-cognition relationships with the oldest participants having the most differential patterns due to sex. Fourth, ɛ4 carriers with lower connectivity had poorer cognitive performance. Taken together, our results show the three predominant risk factors for AD interact to influence brain function and function-cognition relationships.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.03.013DOI Listing
August 2021

Prognostic Value of Learning and Retention Measures from the Free and Cued Selective Reminding Test to Identify Incident Mild Cognitive Impairment.

J Int Neuropsychol Soc 2021 Mar 22:1-8. Epub 2021 Mar 22.

Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA.

Objective: To compare the predictive validity of learning and retention measures from the picture version of the Free and Cued Selective Reminding Test with Immediate Recall (pFCSRT + IR) for identifying incident mild cognitive impairment (MCI).

Methods: Learning was defined by the sum of free recall (FR) and retention by delayed free recall (DFR) tested 15-20 min later. Totally, 1422 Baltimore Longitudinal Study of Aging (BLSA) participants (mean age 69.6 years, 54% male, mean 16.7 years of education) without dementia or MCI received the pFCSRT + IR at baseline and were followed longitudinally. Cox proportional hazards models were used to evaluate the effect of baseline learning and retention on risk of MCI.

Results: In total, 187 participants developed MCI over a median of 8.1 years of follow-up. FR and DFR each predicted incident MCI adjusting for age, sex, and education. Also, each independently predicted incident MCI in the presence of the other with similar effect sizes: around 20% decrease in the hazard of MCI corresponding to one standard deviation increase in FR or DFR.

Conclusion: The practice of preferring retention over learning to predict incident MCI should be reconsidered. The decision to include retention should be guided by time constraints and patient burden.
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http://dx.doi.org/10.1017/S1355617721000291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455713PMC
March 2021

Association of cerebral blood flow with myelin content in cognitively unimpaired adults.

BMJ Neurol Open 2020 1;2(1):e000053. Epub 2020 Jul 1.

National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.

Background: Myelin loss and cerebral blood flow (CBF) decline are central features of several neurodegenerative diseases. Myelin maintenance through oligodendrocyte metabolism is an energy-demanding process, so that myelin homeostasis is particularly sensitive to hypoxia, hypoperfusion or ischaemia. However, in spite of its central importance, little is known about the association between blood supply and myelin integrity.

Objective: To assess associations between cortical and subcortical CBF, and subcortical myelin content, in critical brain white matter regions.

Materials And Methods: MRI was performed on a cohort of 67 cognitively unimpaired adults. Using advanced MRI methodology, we measured whole-brain longitudinal and transverse relaxation rates ( ), sensitive but non-specific markers of myelin content, and myelin water fraction (MWF), a direct surrogate of myelin content, as well as regional CBF, from each of these participants.

Results: All quantitative relaxometry metrics were positively associated with CBF in all brain regions evaluated. These associations between MWF or and CBF, and, to a lesser extent, between and CBF, were statistically significant in most brain regions examined, indicating that lower regional cortical or subcortical CBF corresponds to a decrease in local subcortical myelin content. Finally, all relaxometry metrics exhibited a quadratic, inverted U-shaped, association with age; this is attributed to the development of myelination from young to middle age, followed by progressive loss of myelin in later years.

Conclusions: In this first study examining the association between local blood supply and myelin integrity, we found that myelin content declines with CBF across a wide age range of cognitively normal subjects.
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http://dx.doi.org/10.1136/bmjno-2020-000053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903181PMC
July 2020

Sex and age-related differences in cerebral blood flow investigated using pseudo-continuous arterial spin labeling magnetic resonance imaging.

Aging (Albany NY) 2021 02 17;13(4):4911-4925. Epub 2021 Feb 17.

Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 20892, USA.

Adequate cerebral blood flow (CBF) is essential to a healthy central nervous system (CNS). Previous work suggests that CBF differs between men and women, and declines with age and certain pathologies, but a highly controlled systematic study across a wide age range, and incorporating white matter (WM) regions, has not been undertaken. Here, we investigate age- and sex-related differences in CBF in gray matter (GM) and WM regions in a cohort ( = 80) of cognitively unimpaired individuals over a wide age range. In agreement with literature, we find that GM regions exhibited lower CBF with age. In contrast, WM regions exhibited higher CBF with age in various cerebral regions. We attribute this new finding to increased oligodendrocyte metabolism to maintain myelin homeostasis in the setting of increased myelin turnover with age. Further, consistent with prior studies, we found that CBF was higher in women than in men in all brain structures investigated. Our work provides new insights into the effects of age and sex on CBF. In addition, our results provide reference CBF values for the standard ASL protocol recommended by the ISMRM Perfusion Study Group and the European ASL in Dementia consortium. Thus, these results provide a foundation for further investigations of CNS perfusion in a variety of settings, including aging, cerebrovascular diseases, and dementias.
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http://dx.doi.org/10.18632/aging.202673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950235PMC
February 2021

Age-related estimates of aggregate g-ratio of white matter structures assessed using quantitative magnetic resonance neuroimaging.

Hum Brain Mapp 2021 Jun 17;42(8):2362-2373. Epub 2021 Feb 17.

Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.

The g-ratio, defined as the inner-to-outer diameter of a myelinated axon, is associated with the speed of nerve impulse conduction, and represents an index of axonal myelination and integrity. It has been shown to be a sensitive and specific biomarker of neurodevelopment and neurodegeneration. However, there have been very few magnetic resonance imaging studies of the g-ratio in the context of normative aging; characterizing regional and time-dependent cerebral changes in g-ratio in cognitively normal subjects will be a crucial step in differentiating normal from abnormal microstructural alterations. In the current study, we investigated age-related differences in aggregate g-ratio, that is, g-ratio averaged over all fibers within regions of interest, in several white matter regions in a cohort of 52 cognitively unimpaired participants ranging in age from 21 to 84 years. We found a quadratic, U-shaped, relationship between aggregate g-ratio and age in most cerebral regions investigated, suggesting myelin maturation until middle age followed by a decrease at older ages. As expected, we observed that these age-related differences vary across different brain regions, with the frontal lobes and parietal lobes exhibiting slightly earlier ages of minimum aggregate g-ratio as compared to more posterior structures such as the occipital lobes and temporal lobes; this agrees with the retrogenesis paradigm. Our results provide evidence for a nonlinear association between age and aggregate g-ratio in a sample of adults from a highly controlled population. Finally, sex differences in aggregate g-ratio were observed in several cerebral regions, with women exhibiting overall lower values as compared to men; this likely reflects the greater myelin content in women's brain, in agreement with recent investigations.
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http://dx.doi.org/10.1002/hbm.25372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090765PMC
June 2021

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Nat Genet 2021 03 15;53(3):294-303. Epub 2021 Feb 15.

Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946812PMC
March 2021

PreQual: An automated pipeline for integrated preprocessing and quality assurance of diffusion weighted MRI images.

Magn Reson Med 2021 07 3;86(1):456-470. Epub 2021 Feb 3.

Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.

Purpose: Diffusion weighted MRI imaging (DWI) is often subject to low signal-to-noise ratios (SNRs) and artifacts. Recent work has produced software tools that can correct individual problems, but these tools have not been combined with each other and with quality assurance (QA). A single integrated pipeline is proposed to perform DWI preprocessing with a spectrum of tools and produce an intuitive QA document.

Methods: The proposed pipeline, built around the FSL, MRTrix3, and ANTs software packages, performs DWI denoising; inter-scan intensity normalization; susceptibility-, eddy current-, and motion-induced artifact correction; and slice-wise signal drop-out imputation. To perform QA on the raw and preprocessed data and each preprocessing operation, the pipeline documents qualitative visualizations, quantitative plots, gradient verifications, and tensor goodness-of-fit and fractional anisotropy analyses.

Results: Raw DWI data were preprocessed and quality checked with the proposed pipeline and demonstrated improved SNRs; physiologic intensity ratios; corrected susceptibility-, eddy current-, and motion-induced artifacts; imputed signal-lost slices; and improved tensor fits. The pipeline identified incorrect gradient configurations and file-type conversion errors and was shown to be effective on externally available datasets.

Conclusions: The proposed pipeline is a single integrated pipeline that combines established diffusion preprocessing tools from major MRI-focused software packages with intuitive QA.
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http://dx.doi.org/10.1002/mrm.28678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387107PMC
July 2021

Evidence of association between obesity and lower cerebral myelin content in cognitively unimpaired adults.

Int J Obes (Lond) 2021 04 22;45(4):850-859. Epub 2021 Jan 22.

Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.

Background: Myelin loss is a central feature of several neurodegenerative diseases, including Alzheimer's disease (AD). In animal studies, a link has been established between obesity and impairment of oligodendrocyte maturation, the cells that produce and maintain myelin. Although clinical magnetic resonance imaging (MRI) studies have revealed microstructural alterations of cerebral white matter tissue in subjects with obesity, no specific myelin vs. obesity correlation studies have been performed in humans using a direct myelin content metric.

Objectives: To assess the association between obesity and myelin integrity in cerebral white matter using advanced MRI methodology for myelin content imaging.

Methods: Studies were performed in the clinical unit of the National Institute on Aging on a cohort of 119 cognitively unimpaired adults. Using advanced MRI methodology, we measured whole-brain myelin water fraction (MWF), a marker of myelin content. Automated brain mapping algorithms and statistical models were used to evaluate the relationships between MWF and obesity, measured using the body mass index (BMI) or waist circumference (WC), in various white matter brain regions.

Results: MWF was negatively associated with BMI or WC in all brain regions evaluated. These associations, adjusted for sex, ethnicity, and age, were statistically significant in most brain regions examined (p < 0.05), with higher BMI or WC corresponding to lower myelin content. Finally, in agreement with previous work, MWF exhibited a quadratic, inverted U-shaped, association with age; this is attributed to the process of myelination from youth through middle age, followed by demyelination afterward.

Conclusions: These findings suggest that obesity was significantly associated with white matter integrity, and in particular myelin content. We expect that this work will lay the foundation for further investigations to clarify the nature of myelin damage in neurodegeneration, including AD, and the effect of lifestyle factors such as diet and physical activity on myelination.
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http://dx.doi.org/10.1038/s41366-021-00749-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009848PMC
April 2021
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