Publications by authors named "Susan Resnick"

307 Publications

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

Neurobiol Aging 2021 Apr 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
April 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
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
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 Jul 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
July 2021

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

Int J Obes (Lond) 2021 Apr 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

Outdoor air pollution exposure and inter-relation of global cognitive performance and emotional distress in older women.

Environ Pollut 2021 Feb 14;271:116282. Epub 2020 Dec 14.

University of Southern California, Los Angeles, CA, USA. Electronic address:

The interrelationships among long-term ambient air pollution exposure, emotional distress and cognitive decline in older adulthood remain unclear. Long-term exposure may impact cognitive performance and subsequently impact emotional health. Conversely, exposure may initially be associated with emotional distress followed by declines in cognitive performance. Here we tested the inter-relationship between global cognitive ability, emotional distress, and exposure to PM (particulate matter with aerodynamic diameter <2.5 μm) and NO (nitrogen dioxide) in 6118 older women (aged 70.6 ± 3.8 years) from the Women's Health Initiative Memory Study. Annual exposure to PM (interquartile range [IQR] = 3.37 μg/m) and NO (IQR = 9.00 ppb) was estimated at the participant's residence using regionalized national universal kriging models and averaged over the 3-year period before the baseline assessment. Using structural equation mediation models, a latent factor capturing emotional distress was constructed using item-level data from the 6-item Center for Epidemiological Studies Depression Scale and the Short Form Health Survey Emotional Well-Being scale at baseline and one-year follow-up. Trajectories of global cognitive performance, assessed by the Modified-Mini Mental State Examination (3MS) annually up to 12 years, were estimated. All effects reported were adjusted for important confounders. Increases in PM (β = -0.144 per IQR; 95% CI = -0.261; -0.028) and NO (β = -0.157 per IQR; 95% CI = -0.291; -0.022) were associated with lower initial 3MS performance. Lower 3MS performance was associated with increased emotional distress (β = -0.008; 95% CI = -0.015; -0.002) over the subsequent year. Significant indirect effect of both exposures on increases in emotional distress mediated by exposure effects on worse global cognitive performance were present. No statistically significant indirect associations were found between exposures and 3MS trajectories putatively mediated by baseline emotional distress. Our study findings support cognitive aging processes as a mediator of the association between PM and NO exposure and emotional distress in later-life.
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http://dx.doi.org/10.1016/j.envpol.2020.116282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017598PMC
February 2021

Persistently Elevated mTOR Complex 1-S6 Kinase 1 Disrupts DARPP-32-Dependent D Dopamine Receptor Signaling and Behaviors.

Biol Psychiatry 2020 Oct 27. Epub 2020 Oct 27.

Solomon Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, Maryland; Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, Maryland. Electronic address:

Background: The serine-threonine kinase mTORC1 (mammalian target of rapamycin complex 1) is essential for normal cell function but is aberrantly activated in the brain in both genetic-developmental and sporadic diseases and is associated with a spectrum of neuropsychiatric symptoms. The underlying molecular mechanisms of cognitive and neuropsychiatric symptoms remain controversial.

Methods: The present study examines behaviors in transgenic models that express Rheb, the most proximal known activator of mTORC1, and profiles striatal phosphoproteomics in a model with persistently elevated mTORC1 signaling. Biochemistry, immunohistochemistry, electrophysiology, and behavior approaches are used to examine the impact of persistently elevated mTORC1 on D dopamine receptor (D1R) signaling. The effect of persistently elevated mTORC1 was confirmed using D1-Cre to elevate mTORC1 activity in D1R neurons.

Results: We report that persistently elevated mTORC1 signaling blocks canonical D1R signaling that is dependent on DARPP-32 (dopamine- and cAMP-regulated neuronal phosphoprotein). The immediate downstream effector of mTORC1, ribosomal S6 kinase 1 (S6K1), phosphorylates and activates DARPP-32. Persistent elevation of mTORC1-S6K1 occludes dynamic D1R signaling downstream of DARPP-32 and blocks multiple D1R responses, including dynamic gene expression, D1R-dependent corticostriatal plasticity, and D1R behavioral responses including sociability. Candidate biomarkers of mTORC1-DARPP-32 occlusion are increased in the brain of human disease subjects in association with elevated mTORC1-S6K1, supporting a role for this mechanism in cognitive disease.

Conclusions: The mTORC1-S6K1 intersection with D1R signaling provides a molecular framework to understand the effects of pathological mTORC1 activation on behavioral symptoms in neuropsychiatric disease.
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http://dx.doi.org/10.1016/j.biopsych.2020.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076344PMC
October 2020

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

Neuron 2021 02 26;109(3):448-460.e4. Epub 2020 Nov 26.

Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia 25125, Italy; MAC Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia 25125, Italy.

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.
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http://dx.doi.org/10.1016/j.neuron.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864894PMC
February 2021

Association between brain volumes and patterns of physical activity in community-dwelling older adults.

J Gerontol A Biol Sci Med Sci 2020 Nov 24. Epub 2020 Nov 24.

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

Background: Larger brain volumes are often associated with more free-living physical activity (PA) in cognitively normal older adults. Yet, whether greater brain volumes are associated with more favorable (less fragmented) PA patterns, and whether this association is stronger than with total PA, remains unknown.

Methods: Brain magnetic resonance imaging and wrist-worn accelerometer data were collected in 301 participants (mean age=77[SD=7] years, 59% women) enrolled in the Baltimore Longitudinal Study of Aging. Linear regression models were fit to examine whether brain volumes (cc) were cross-sectionally associated with: 1) total daily PA minutes; and 2) activity fragmentation (mean number of PA bouts / total PA minutes x 100). Sensitivity analyses were conducted by adjusting for counterpart PA variables (e.g., fragmentation covariate included in the PA minutes model).

Results: Greater white matter volumes in the parietal and temporal lobes were associated with higher daily PA minutes (2.6(SE=1.0) and 3.8(0.9)min/day, respectively; p<0.009 for both) after adjusting for demographics, behavioral factors, medical conditions, gait speed, apolipoprotein E e4 status, and intracranial volume. Greater temporal white matter volume was associated with lower fragmentation (-0.16(0.05)%, p=0.003). In sensitivity analyses, observed associations between brain volumes and daily PA minutes remained significant while associations with fragmentation no longer remained significant.

Conclusions: Our results suggest white matter brain structure in cognitively normal older adults is associated with the total amount of PA and, to a lesser extent, the PA accumulation patterns. More work is needed to elucidate the longitudinal relationship between brain structure and function and PA patterns with aging.
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http://dx.doi.org/10.1093/gerona/glaa294DOI Listing
November 2020

PM associated with gray matter atrophy reflecting increased Alzheimers risk in older women.

Neurology 2020 11 18. Epub 2020 Nov 18.

From the Departments of Preventive Medicine (D.Y., J.C.C) and Neurology (X.W., A.J.P., H.C.C., J.C.C.), and the Center for Economic and Social Research (M.G.), University of Southern California, Los Angeles, CA; Departments of Biostatistics and Data Science (R.C., R.B., S.A.G., S.S., D.P.B., M.A.E.), Psychiatry and Behavioral Medicine (S.R.R.), Social Sciences & Health Policy (S.A.S., S.R.R., B.C.S.), and Neurology (B.C.S.), Wake Forest School of Medicine, Winston-Salem, NC; Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD (S.M.R.); Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC (M.L.S., W.V.); Departments of Health Research and Policy (Epidemiology) and Neurology and Neurological Sciences, Stanford University, Stanford, CA (V.W.H.); Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J. E.M.); and Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (J.A.S.).

Objective: To examine whether late-life exposure to PM (particulate matter with aerodynamic diameters <2.5-µm) contributes to progressive brain atrophy predictive of Alzheimer's disease (AD) using a community-dwelling cohort of women (aged 70-89) with up to two brain MRI scans (MRI-1: 2005-6; MRI-2: 2010-11).

Methods: AD pattern similarity (AD-PS) scores, developed by supervised machine learning and validated with MRI data from the AD Neuroimaging Initiative, was used to capture high-dimensional gray matter atrophy in brain areas vulnerable to AD (e.g., amygdala, hippocampus, parahippocampal gyrus, thalamus, inferior temporal lobe areas and midbrain). Based on participants' addresses and air monitoring data, we implemented a spatiotemporal model to estimate 3-year average exposure to PM preceding MRI-1. General linear models were used to examine the association between PM and AD-PS scores (baseline and 5-year standardized change), accounting for potential confounders and white matter lesion volumes.

Results: For 1365 women aged 77.9±3.7 years in 2005-6, there was no association between PM and baseline AD-PS score in cross-sectional analyses (β=-0.004; 95% CI: -0.019, 0.011). Longitudinally, each interquartile range increase of PM (2.82-µg/m) was associated with increased AD-PS scores during the follow-up, equivalent to a 24% (hazard ratio=1.24; 95% CI: 1.14, 1.34) increase in AD risk over 5-years (n=712; aged 77.4±3.5 years). This association remained after adjustment for socio-demographics, intracranial volume, lifestyle, clinical characteristics, and white matter lesions, and was present with levels below US regulatory standards (<12-µg/m).

Conclusions: Late-life exposure to PM is associated with increased neuroanatomical risk of AD, which may not be explained by available indicators of cerebrovascular damage.
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http://dx.doi.org/10.1212/WNL.0000000000011149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055348PMC
November 2020

Air Pollution and the Dynamic Association Between Depressive Symptoms and Memory in Oldest-Old Women.

J Am Geriatr Soc 2021 Feb 17;69(2):474-484. Epub 2020 Nov 17.

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

Background/objectives: Exposure to air pollution may contribute to both increasing depressive symptoms and decreasing episodic memory in older adulthood, but few studies have examined this hypothesis in a longitudinal context. Accordingly, we examined the association between air pollution and changes in depressive symptoms (DS) and episodic memory (EM) and their interrelationship in oldest-old (aged 80 and older) women.

Design: Prospective cohort data from the Women's Health Initiative Memory Study-Epidemiology of Cognitive Health Outcomes.

Setting: Geographically diverse community-dwelling population.

Participants: A total of 1,583 dementia-free women aged 80 and older.

Measurements: Women completed up to six annual memory assessments (latent composite of East Boston Memory Test and Telephone Interview for Cognitive Status) and the 15-item Geriatric Depression Scale (GDS-15). We estimated 3-year average exposures to regional particulate matter with aerodynamic diameter below 2.5 μm (PM ) (interquartile range [IQR] = 3.35 μg/m ) and gaseous nitrogen dioxide (NO ) (IQR = 9.55 ppb) at baseline and during a remote period 10 years earlier, using regionalized national universal kriging.

Results: Latent change structural equation models examined whether residing in areas with higher pollutant levels was associated with annual changes in standardized EM and DS while adjusting for potential confounders. Remote NO (β = .287 per IQR; P = .002) and PM (β = .170 per IQR; P = .019) exposure was significantly associated with larger increases in standardized DS, although the magnitude of the difference, less than 1 point on the GDS-15, is of questionable clinical significance. Higher DS were associated with accelerated EM declines (β = -.372; P = .001), with a significant indirect effect of remote NO and PM exposure on EM declines mediated by DS. There were no other significant indirect exposure effects.

Conclusion: These findings in oldest-old women point to potential adverse effects of late-life exposure to air pollution on subsequent interplay between DS and EM, highlighting air pollution as an environmental health risk factor for older women.
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http://dx.doi.org/10.1111/jgs.16889DOI Listing
February 2021

Pandora: 4-D White Matter Bundle Population-Based Atlases Derived from Diffusion MRI Fiber Tractography.

Neuroinformatics 2020 Nov 16. Epub 2020 Nov 16.

Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA.

Brain atlases have proven to be valuable neuroscience tools for localizing regions of interest and performing statistical inferences on populations. Although many human brain atlases exist, most do not contain information about white matter structures, often neglecting them completely or labelling all white matter as a single homogenous substrate. While few white matter atlases do exist based on diffusion MRI fiber tractography, they are often limited to descriptions of white matter as spatially separate "regions" rather than as white matter "bundles" or fascicles, which are well-known to overlap throughout the brain. Additional limitations include small sample sizes, few white matter pathways, and the use of outdated diffusion models and techniques. Here, we present a new population-based collection of white matter atlases represented in both volumetric and surface coordinates in a standard space. These atlases are based on 2443 subjects, and include 216 white matter bundles derived from 6 different automated state-of-the-art tractography techniques. This atlas is freely available and will be a useful resource for parcellation and segmentation.
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http://dx.doi.org/10.1007/s12021-020-09497-1DOI Listing
November 2020

Microstructural Neuroimaging of Frailty in Cognitively Normal Older Adults.

Front Med (Lausanne) 2020 23;7:546344. Epub 2020 Oct 23.

Longitudinal Studies Section, National Institute on Aging, Baltimore, MD, United States.

Physical frailty is an age-related clinical syndrome that is associated with multiple adverse health outcomes, including cognitive impairment and dementia. Recent studies have shown that frailty is associated with specific volumetric neuroimaging characteristics. Whether brain microstructural characteristics, particularly gray matter, associated with frailty exist and what their spatial distribution is have not been explored. We identified 670 participants of the Baltimore Longitudinal Study of Aging who were aged 60 and older and cognitively normal and who had concurrent data on frailty and regional microstructural neuroimaging markers by diffusion tensor imaging (DTI), including mean diffusivity (MD) of gray matter and fractional anisotropy (FA) of white matter. We identified neuroimaging markers that were associated with frailty status (non-frail, pre-frail, frail) and further examined differences between three groups using multivariate linear regression (non-frail = reference). Models were adjusted for age, sex, race, years of education, body mass index, scanner type, and Apolipoprotein E e4 carrier status. Compared to the non-frail participants, those who were frail had higher MD in the medial frontal cortex, several subcortical regions (putamen, caudate, thalamus), anterior cingulate cortex, and a trend of lower FA in the body of the corpus callosum. Those who were pre-frail also had higher MD in the putamen and a trend of lower FA in the body of the corpus callosum. Our study demonstrates for the first time that the microstructure of both gray and white matter differs by frailty status in cognitively normal older adults. Brain areas were not widespread but mostly localized in frontal and subcortical motor areas and the body of the corpus callosum. Whether changes in brain microstructure precede future frailty development warrants further investigation.
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http://dx.doi.org/10.3389/fmed.2020.546344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645067PMC
October 2020

Cognitive and neuroimaging profiles of older adults with dual decline in memory and gait speed.

Neurobiol Aging 2021 01 9;97:49-55. Epub 2020 Oct 9.

Translational Gerontology Branch Longitudinal Studies Section, National Institute on Aging, Baltimore, MD, USA.

We previously showed that dual decline in memory and gait speed was associated with an increased risk of dementia compared to memory or gait decline only or no decline. We now characterized cognitive and neuroimaging profiles of dual decliners by comparing longitudinal rates of change in various cognitive domains (n = 664) and brain volumes (n = 391; selected frontal, temporal, parietal, subcortical, and cerebellar areas) in Baltimore Longitudinal Study of Aging participants who experienced age-related dual decline to others. Compared to others, dual decliners had steeper declines in verbal fluency, attention, and sensorimotor function by Pegboard nondominant hand performance. Dual decliners had greater brain volume loss in superior frontal gyrus, superior parietal gyrus, precuneus, thalamus, and cerebellum (all p ≤ 0.01). Participants with age-related dual decline experienced steeper declines in multiple cognitive domains and greater brain volume loss in cognitive, sensorimotor, and locomotion areas. Impaired sensorimotor integration and locomotion are underlying features of dual decline. Whether these features contribute to the increased risk of dementia should be investigated.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.10.002DOI Listing
January 2021

The Brain Chart of Aging: Machine-learning analytics reveals links between brain aging, white matter disease, amyloid burden, and cognition in the iSTAGING consortium of 10,216 harmonized MR scans.

Alzheimers Dement 2021 01 13;17(1):89-102. Epub 2020 Sep 13.

Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Introduction: Relationships between brain atrophy patterns of typical aging and Alzheimer's disease (AD), white matter disease, cognition, and AD neuropathology were investigated via machine learning in a large harmonized magnetic resonance imaging database (11 studies; 10,216 subjects).

Methods: Three brain signatures were calculated: Brain-age, AD-like neurodegeneration, and white matter hyperintensities (WMHs). Brain Charts measured and displayed the relationships of these signatures to cognition and molecular biomarkers of AD.

Results: WMHs were associated with advanced brain aging, AD-like atrophy, poorer cognition, and AD neuropathology in mild cognitive impairment (MCI)/AD and cognitively normal (CN) subjects. High WMH volume was associated with brain aging and cognitive decline occurring in an ≈10-year period in CN subjects. WMHs were associated with doubling the likelihood of amyloid beta (Aβ) positivity after age 65. Brain aging, AD-like atrophy, and WMHs were better predictors of cognition than chronological age in MCI/AD.

Discussion: A Brain Chart quantifying brain-aging trajectories was established, enabling the systematic evaluation of individuals' brain-aging patterns relative to this large consortium.
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http://dx.doi.org/10.1002/alz.12178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923395PMC
January 2021

Vestibular function and cortical and sub-cortical alterations in an aging population.

Heliyon 2020 Aug 18;6(8):e04728. Epub 2020 Aug 18.

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

While it is well known that the vestibular system is responsible for maintaining balance, posture and coordination, there is increasing evidence that it also plays an important role in cognition. Moreover, a growing number of epidemiological studies are demonstrating a link between vestibular dysfunction and cognitive deficits in older adults; however, the exact pathways through which vestibular loss may affect cognition are unknown. In this cross-sectional study, we sought to identify relationships between vestibular function and variation in morphometry in brain structures from structural neuroimaging. We used a subset of 80 participants from the Baltimore Longitudinal Study of Aging, who had both brain MRI and vestibular physiological data acquired during the same visit. Vestibular function was evaluated through the cervical vestibular-evoked myogenic potential (cVEMP). The brain structures of interest that we analyzed were the hippocampus, amygdala, thalamus, caudate nucleus, putamen, insula, entorhinal cortex (ERC), trans-entorhinal cortex (TEC) and perirhinal cortex, as these structures comprise or are connected with the putative "vestibular cortex." We modeled the volume and shape of these structures as a function of the presence/absence of cVEMP and the cVEMP amplitude, adjusting for age and sex. We observed reduced overall volumes of the hippocampus and the ERC associated with poorer vestibular function. In addition, we also found significant relationships between the shape of the hippocampus (p = 0.0008), amygdala (p = 0.01), thalamus (p = 0.008), caudate nucleus (p = 0.002), putamen (p = 0.02), and ERC-TEC complex (p = 0.008) and vestibular function. These findings provide novel insight into the multiple pathways through which vestibular loss may impact brain structures that are critically involved in spatial memory, navigation and orientation.
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http://dx.doi.org/10.1016/j.heliyon.2020.e04728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457317PMC
August 2020

Association of Poorer Hearing With Longitudinal Change in Cerebral White Matter Microstructure.

JAMA Otolaryngol Head Neck Surg 2020 Nov;146(11):1035-1042

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

Importance: There is a dearth of studies that examine the association between poorer hearing and change in cerebral white matter (WM) microstructure.

Objective: To examine the association of poorer hearing with baseline and change in WM microstructure among older adults.

Design, Setting, And Participants: This was a prospective cohort study that evaluated speech-in-noise, pure-tone audiometry, and WM microstructure, as measured by mean diffusivity (MD) and fractional anisotropy (FA), both of which were evaluated by diffusion tensor imaging (DTI) in 17 WM regions. Data were collected between October 2012 and December 2018 and analyzed between March 2019 and August 2019 with a mean follow-up time of 1.7 years. The study evaluated responses to the Baltimore Longitudinal Study of Aging among 356 cognitively normal adults who had at least 1 hearing assessment and DTI session. Excluded were those with baseline cognitive impairment, stroke, head injuries, Parkinson disease, and/or bipolar disorder.

Exposures: Peripheral auditory function was measured by pure-tone average in the better-hearing ear. Central auditory function was measured by signal-to-noise ratio score from a speech-in-noise task and adjusted by pure-tone average.

Main Outcomes And Measures: Linear mixed-effects models with random intercepts and slopes were used to examine the association of poorer peripheral and central auditory function with baseline and longitudinal DTI metrics in 17 WM regions, adjusting for baseline characteristics (age, sex, race, hypertension, elevated total cholesterol, and obesity).

Results: Of 356 cognitively normal adults included in the study, the mean (SD) age was 73.5 (8.8) years, and 204 (57.3%) were women. There were no baseline associations between hearing and DTI measures. Longitudinally, poorer peripheral hearing was associated with increases in MD in the inferior fronto-occipital fasciculus (β = 0.025; 95% CI, 0.008-0.042) and the body (β = 0.050; 95% CI, 0.015-0.085) of the corpus callosum, but there were no associations of peripheral hearing with FA changes in these tracts. Poorer central auditory function was associated with longitudinal MD increases (β = 0.031; 95% CI, 0.010-0.052) and FA declines (β = -1.624; 95% CI, -2.511 to -0.738) in the uncinate fasciculus.

Conclusions And Relevance: Findings of this cohort study suggest that poorer hearing is related to change in integrity of specific WM regions involved with auditory processing.
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http://dx.doi.org/10.1001/jamaoto.2020.2497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489397PMC
November 2020

Associations between cognitive and brain volume changes in cognitively normal older adults.

Neuroimage 2020 12 21;223:117289. Epub 2020 Aug 21.

Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224-6825, USA. Electronic address:

Investigation of relationships between age-related changes in regional brain volumes and changes in domain-specific cognition could provide insights into the neural underpinnings of individual differences in cognitive aging. Domain-specific cognition (memory, verbal fluency, visuospatial ability) and tests of executive function and attention (Trail-Making Test Part A and B) and 47 brain volumes of interest (VOIs) were assessed in 836 Baltimore Longitudinal Study of Aging participants with mean follow-up of 4.1 years (maximum 23.1 years). To examine the correlation between changes in domain-specific cognition and changes in brain volumes, we used bivariate linear mixed effects models with unstructured variance-covariance structure to estimate longitudinal trajectories for each variable of interest and correlations among the random effects of these measures. Higher annual rates of memory decline were associated with greater volume loss in 14 VOIs primarily within the temporal and occipital lobes. Verbal fluency decline was associated with greater ventricular enlargement and volume loss in 24 VOIs within the frontal, temporal, and parietal lobes. Decline in visuospatial ability was associated with volume loss in 3 temporal and parietal VOIs. Declines on the attentional test were associated with volume loss in 4 VOIs located within temporal and parietal lobes. Greater declines on the executive function test were associated with greater ventricular enlargement and volume loss in 10 frontal, parietal, and temporal VOIs. Our findings highlight domain-specific patterns of regional brain atrophy that may contribute to individual differences in cognitive aging.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117289DOI Listing
December 2020

Distortion correction of diffusion weighted MRI without reverse phase-encoding scans or field-maps.

PLoS One 2020 31;15(7):e0236418. Epub 2020 Jul 31.

Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, United States of America.

Diffusion magnetic resonance images may suffer from geometric distortions due to susceptibility induced off resonance fields, which cause geometric mismatch with anatomical images and ultimately affect subsequent quantification of microstructural or connectivity indices. State-of-the art diffusion distortion correction methods typically require data acquired with reverse phase encoding directions, resulting in varying magnitudes and orientations of distortion, which allow estimation of an undistorted volume. Alternatively, additional field maps acquisitions can be used along with sequence information to determine warping fields. However, not all imaging protocols include these additional scans and cannot take advantage of state-of-the art distortion correction. To avoid additional acquisitions, structural MRI (undistorted scans) can be used as registration targets for intensity driven correction. In this study, we aim to (1) enable susceptibility distortion correction with historical and/or limited diffusion datasets that do not include specific sequences for distortion correction and (2) avoid the computationally intensive registration procedure typically required for distortion correction using structural scans. To achieve these aims, we use deep learning (3D U-nets) to synthesize an undistorted b0 image that matches geometry of structural T1w images and intensity contrasts from diffusion images. Importantly, the training dataset is heterogenous, consisting of varying acquisitions of both structural and diffusion. We apply our approach to a withheld test set and show that distortions are successfully corrected after processing. We quantitatively evaluate the proposed distortion correction and intensity-based registration against state-of-the-art distortion correction (FSL topup). The results illustrate that the proposed pipeline results in b0 images that are geometrically similar to non-distorted structural images, and more closely match state-of-the-art correction with additional acquisitions. In addition, we show generalizability of the proposed approach to datasets that were not in the original training / validation / testing datasets. These datasets included varying populations, contrasts, resolutions, and magnitudes and orientations of distortion and show efficacious distortion correction. The method is available as a Singularity container, source code, and an executable trained model to facilitate evaluation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236418PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394453PMC
September 2020

Lasting consequences of concussion on the aging brain: Findings from the Baltimore Longitudinal Study of Aging.

Neuroimage 2020 11 20;221:117182. Epub 2020 Jul 20.

Laboratory of Behavioral Neuroscience, National Institute on Aging, 251 Bayview Blvd., Baltimore, MD, 21224-6825, USA. Electronic address:

Studies suggest that concussions may be related to increased risk of neurodegenerative diseases, such as Chronic Traumatic Encephalopathy and Alzheimer's Disease. Most neuroimaging studies show effects of concussions in frontal and temporal lobes of the brain, yet the long-term impacts of concussions on the aging brain have not been well studied. We examined neuroimaging data from 51 participants (mean age at first imaging visit=65.1 ± 11.23) in the Baltimore Longitudinal Study of Aging (BLSA) who reported a concussion in their medical history an average of 23 years prior to the first imaging visit, and compared them to 150 participants (mean age at first imaging visit=66.6 ± 10.97) with no history of concussion. Participants underwent serial structural MRI over a mean of 5.17±6.14 years and DTI over a mean of 2.92±2.22 years to measure brain structure, as well as O-water PET over a mean of 5.33±2.19 years to measure brain function. A battery of neuropsychological tests was also administered over a mean of 11.62±7.41 years. Analyses of frontal and temporal lobe regions were performed to examine differences in these measures between the concussion and control groups at first imaging visit and in change over time. Compared to those without concussion, participants with a prior concussion had greater brain atrophy in temporal lobe white matter and hippocampus at first imaging visit, which remained stable throughout the follow-up visits. Those with prior concussion also showed differences in white matter microstructure using DTI, including increased radial and axial diffusivity in the fornix/stria terminalis, anterior corona radiata, and superior longitudinal fasciculus at first imaging visit. In O-water PET, higher resting cerebral blood flow was seen at first imaging visit in orbitofrontal and lateral temporal regions, and both increases and decreases were seen in prefrontal, cingulate, insular, hippocampal, and ventral temporal regions with longitudinal follow-up. There were no significant differences in neuropsychological performance between groups. Most of the differences observed between the concussed and non-concussed groups were seen at the first imaging visit, suggesting that concussions can produce long-lasting structural and functional alterations in temporal and frontal regions of the brain in older individuals. These results also suggest that many of the reported short-term effects of concussion may still be apparent later in life.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848820PMC
November 2020

Plasma proteomic signatures predict dementia and cognitive impairment.

Alzheimers Dement (N Y) 2020 9;6(1):e12018. Epub 2020 May 9.

Translational Gerontology Branch National Institute on Aging NIH Baltimore Maryland.

Introduction: Biomarker discovery of dementia and cognitive impairment is important to gather insight into mechanisms underlying the pathogenesis of these conditions.

Methods: In 997 adults from the InCHIANTI study, we assessed the association of 1301 plasma proteins with dementia and cognitive impairment. Validation was conducted in two Alzheimer's disease (AD) case-control studies as well as endophenotypes of AD including cognitive decline, brain amyloid burden, and brain volume.

Results: We identified four risk proteins that were significantly associated with increased odds (peptidase inhibitor 3 (PI3), trefoil factor 3 (TFF3), pregnancy associated plasma protein A (PAPPA), agouti-related peptide (AGRP)) and two protective proteins (myostatin (MSTN), integrin aVb5 (ITGAV/ITGB5)) with decreased odds of baseline cognitive impairment or dementia. Of these, four proteins (MSTN, PI3, TFF3, PAPPA) were associated cognitive decline in subjects that were cognitively normal at baseline. ITGAV/ITGB5 was associated with lower brain amyloid burden, MSTN and ITGAV/ITGB5 were associated with larger brain volume and slower brain atrophy, and PI3, PAPPA, and AGRP were associated with smaller brain volume and/or faster brain atrophy.

Discussion: These proteins may be useful as non-invasive biomarkers of dementia and cognitive impairment.
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http://dx.doi.org/10.1002/trc2.12018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210784PMC
May 2020

Psychometric Tests and Spatial Navigation: Data From the Baltimore Longitudinal Study of Aging.

Front Neurol 2020 11;11:484. Epub 2020 Jun 11.

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

Spatial cognition is the process by which individuals interact with their spatial environment. Spatial cognition encompasses the specific skills of spatial memory, spatial orientation, and spatial navigation. Prior studies have shown an association between psychometric tests of spatial ability and self-reported or virtual measures of spatial navigation. In this study, we examined whether psychometric spatial cognitive tests predict performance on a dynamic spatial navigation task that involves movement through an environment. We recruited 151 community-dwelling adult participants [mean () age 69.7 (13.6), range 24.6-93.2] from the Baltimore Longitudinal Study of Aging (BLSA). Spatial navigation ability was assessed using the triangle completion task (TCT), and two quantities, the angle and distance of deviation, were computed. Visuospatial cognitive ability was assessed primarily using the Card Rotations Test. Additional tests of executive function, memory, and attention were also administered. In multiple linear regression analyses adjusting for age, sex, race, and education, cognitive tests of visuospatial ability, executive function, and perceptual motor speed and integration were significantly associated with spatial navigation, as determined by performance on the TCT. These findings suggest that dynamic spatial navigation ability is related to spatial memory, executive function, and motor processing speed.
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http://dx.doi.org/10.3389/fneur.2020.00484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300262PMC
June 2020

Association of hippocampal volume polygenic predictor score with baseline and change in brain volumes and cognition among cognitively healthy older adults.

Neurobiol Aging 2020 10 21;94:81-88. Epub 2020 May 21.

Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.

A high hippocampal volume polygenic predictor score (HV-PPS), computed based on GWAS summary statistics (n = 33,536), could be protective against declines in brain volume and cognition in older adults. Linear mixed-effects models with random intercepts and slopes were used to estimate associations of HV-PPS with baseline and annual rate of change in both brain volumes (n = 508) and cognitive performance (n = 1041) in Caucasian Baltimore Longitudinal Study of Aging participants. Higher HV-PPS was associated with greater baseline volumes of the hippocampus and parahippocampal gyrus, and slower rates of ventricular enlargement and volume loss in frontal and parietal white matter, all adjusted for intracranial volume. In addition, higher HV-PPS was associated with better executive function performance and slower rates of decline in verbal fluency scores over time. Individuals with a genetic predisposition toward larger hippocampal volumes show better baseline executive function, slower decline in verbal fluency performance, and slower rates of longitudinal brain atrophy.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.05.007DOI Listing
October 2020

Longitudinal analysis of regional cerebellum volumes during normal aging.

Neuroimage 2020 10 25;220:117062. Epub 2020 Jun 25.

Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, 20892, USA.

Some cross-sectional studies suggest reduced cerebellar volumes with aging, but there have been few longitudinal studies of age changes in cerebellar subregions in cognitively healthy older adults. In this work, 2,023 magnetic resonance (MR) images of 822 cognitively normal participants from the Baltimore Longitudinal Study of Aging (BLSA) were analyzed. Participants ranged in age from 50 to 95 years (mean 70.7 years) at the baseline assessment. Follow-up intervals were 1-9 years (mean 3.7 years) for participants with two or more visits. We used a recently developed cerebellum parcellation algorithm based on convolutional neural networks to divide the cerebellum into 28 subregions. Linear mixed effects models were applied to the volume of each cerebellar subregion to investigate cross-sectional and longitudinal age effects, as well as effects of sex and their interactions, after adjusting for intracranial volume. Our findings suggest spatially varying atrophy patterns across the cerebellum with respect to age and sex both cross-sectionally and longitudinally.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117062DOI Listing
October 2020

MRI signatures of brain age and disease over the lifespan based on a deep brain network and 14 468 individuals worldwide.

Brain 2020 07;143(7):2312-2324

Center for Biomedical Image Computing and Analytics, Department of Radiology, University of Pennsylvania, Philadelphia, USA.

Deep learning has emerged as a powerful approach to constructing imaging signatures of normal brain ageing as well as of various neuropathological processes associated with brain diseases. In particular, MRI-derived brain age has been used as a comprehensive biomarker of brain health that can identify both advanced and resilient ageing individuals via deviations from typical brain ageing. Imaging signatures of various brain diseases, including schizophrenia and Alzheimer's disease, have also been identified using machine learning. Prior efforts to derive these indices have been hampered by the need for sophisticated and not easily reproducible processing steps, by insufficiently powered or diversified samples from which typical brain ageing trajectories were derived, and by limited reproducibility across populations and MRI scanners. Herein, we develop and test a sophisticated deep brain network (DeepBrainNet) using a large (n = 11 729) set of MRI scans from a highly diversified cohort spanning different studies, scanners, ages and geographic locations around the world. Tests using both cross-validation and a separate replication cohort of 2739 individuals indicate that DeepBrainNet obtains robust brain-age estimates from these diverse datasets without the need for specialized image data preparation and processing. Furthermore, we show evidence that moderately fit brain ageing models may provide brain age estimates that are most discriminant of individuals with pathologies. This is not unexpected as tightly-fitting brain age models naturally produce brain-age estimates that offer little information beyond age, and loosely fitting models may contain a lot of noise. Our results offer some experimental evidence against commonly pursued tightly-fitting models. We show that the moderately fitting brain age models obtain significantly higher differentiation compared to tightly-fitting models in two of the four disease groups tested. Critically, we demonstrate that leveraging DeepBrainNet, along with transfer learning, allows us to construct more accurate classifiers of several brain diseases, compared to directly training classifiers on patient versus healthy control datasets or using common imaging databases such as ImageNet. We, therefore, derive a domain-specific deep network likely to reduce the need for application-specific adaptation and tuning of generic deep learning networks. We made the DeepBrainNet model freely available to the community for MRI-based evaluation of brain health in the general population and over the lifespan.
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http://dx.doi.org/10.1093/brain/awaa160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364766PMC
July 2020

Association Between Common Variants in RBFOX1, an RNA-Binding Protein, and Brain Amyloidosis in Early and Preclinical Alzheimer Disease.

JAMA Neurol 2020 Oct;77(10):1288-1298

Department of Neurology, Columbia University Medical Center, New York, New York.

Importance: Genetic studies of Alzheimer disease have focused on the clinical or pathologic diagnosis as the primary outcome, but little is known about the genetic basis of the preclinical phase of the disease.

Objective: To examine the underlying genetic basis for brain amyloidosis in the preclinical phase of Alzheimer disease.

Design, Setting, And Participants: In the first stage of this genetic association study, a meta-analysis was conducted using genetic and imaging data acquired from 6 multicenter cohort studies of healthy older individuals between 1994 and 2019: the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study, the Berkeley Aging Cohort Study, the Wisconsin Registry for Alzheimer's Prevention, the Biomarkers of Cognitive Decline Among Normal Individuals cohort, the Baltimore Longitudinal Study of Aging, and the Alzheimer Disease Neuroimaging Initiative, which included Alzheimer disease and mild cognitive impairment. The second stage was designed to validate genetic observations using pathologic and clinical data from the Religious Orders Study and Rush Memory and Aging Project. Participants older than 50 years with amyloid positron emission tomographic (PET) imaging data and DNA from the 6 cohorts were included. The largest cohort, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (n = 3154), was the PET screening cohort used for a secondary prevention trial designed to slow cognitive decline associated with brain amyloidosis. Six smaller, longitudinal cohort studies (n = 1160) provided additional amyloid PET imaging data with existing genetic data. The present study was conducted from March 29, 2019, to February 19, 2020.

Main Outcomes And Measures: A genome-wide association study of PET imaging amyloid levels.

Results: From the 4314 analyzed participants (age, 52-96 years; 2478 participants [57%] were women), a novel locus for amyloidosis was noted within RBFOX1 (β = 0.61, P = 3 × 10-9) in addition to APOE. The RBFOX1 protein localized around plaques, and reduced expression of RBFOX1 was correlated with higher amyloid-β burden (β = -0.008, P = .002) and worse cognition (β = 0.007, P = .006) during life in the Religious Orders Study and Rush Memory and Aging Project cohort.

Conclusions And Relevance: RBFOX1 encodes a neuronal RNA-binding protein known to be expressed in neuronal tissues and may play a role in neuronal development. The findings of this study suggest that RBFOX1 is a novel locus that may be involved in the pathogenesis of Alzheimer disease.
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http://dx.doi.org/10.1001/jamaneurol.2020.1760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309575PMC
October 2020

Joint and Individual Representation of Domains of Physical Activity, Sleep, and Circadian Rhythmicity.

Stat Biosci 2019 Jul 15;11(2):371-402. Epub 2019 Apr 15.

Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health.

Developments in wearable technology have enabled researchers to continuously and objectively monitor various aspects and physiological domains of real-life including levels of physical activity, quality of sleep, and strength of circadian rhythm in many epidemiological and clinical studies. Current analytical practice is to summarize each of these three domains individually via a standard inventory of interpretable features, and explore individual associations between the features and clinical variables. However, the features often exhibit significant interaction and correlation both within and between domains. Integration of features across multiple domains remains methodologically challenging. To address this problem, we propose to use joint and individual variation explained (JIVE), a dimension reduction technique that efficiently deals with multivariate data representing multiple domains. In this paper, we review the most frequently used features to characterize the domains of physical activity, sleep, and circadian rhythniicity and illustrate the approach using wrist-worn actigraphy data from 198 participants of the Baltimore Longitudinal Study of Aging.
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http://dx.doi.org/10.1007/s12561-019-09236-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241438PMC
July 2019