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1.  Changes in Aβ biomarkers and associations with APOE genotype in two longitudinal cohorts 
Neurobiology of aging  2015;36(8):2333-2339.
Apolipoprotein E (APOE) genotype influences onset age of Alzheimer’s disease but effects on disease progression are less clear. We investigated amyloid-β (Aβ) levels and change in relationship to APOE genotype, using two different measures of Aβ in two different longitudinal cohorts. Aβ accumulation was measured using PET imaging and 11C-Pittsburgh compound-B (PiB) in 113 Baltimore Longitudinal Study of Aging (BLSA) participants (mean age 77.3 years; 107 normal, 6 cognitively impaired) and CSF Aβ1–42 assays in 207 BIOCARD study participants (mean age 62 years; 195 normal,12 cognitively impaired). Participants in both cohorts had up to 7 serial assessments (mean 2.3–2.4). PET-PiB retention increased and CSF Aβ1–42 declined longitudinally. APOE ε4 was significantly associated with higher PET-PiB retention and lower CSF Aβ1–42, independent of age and sex, but APOE genotype did not significantly affect Aβ change over time. APOE ε4 carriers may be further along in the disease process, consistent with earlier brain Aβ deposition and providing a biological basis for APOE genotype effects on onset age of Alzheimer’s disease.
PMCID: PMC5084914  PMID: 26004017
PET amyloid imaging; CSF Aβ1–42; biomarkers; Apolipoprotein E genotype; longitudinal
2.  Relationship between APOE genotype and structural MRI measures throughout adulthood in the SHIP population-based cohort 
Background and Purpose
The presence of the apolipoprotein E (APOE) ε4 allele is the strongest sporadic Alzheimer disease (AD) genetic risk factor. We hypothesized that APOE ε4 carriers and non-carriers may differ in imaging patterns already in the midlife. We therefore sought to identify the effect of APOE genotype on brain atrophy across almost the entire adult age span using advanced magnetic resonance imaging-based pattern analysis.
Materials and Methods
We analyzed MRI scans of 1,472 participants form the Study of Health in Pomerania (aged 22–90 years). We studied the association between age, APOE ε4 carrier status and brain atrophy, which was quantified using two magnetic resonance imaging-based indices: Spatial Pattern of Atrophy for Recognition of Brain Aging SPARE-BA (summarizing age-related brain atrophy) and SPARE-AD (summarizing AD-like brain atrophy patterns), as well as the gray matter volumes in several AD- and APOE-related regions of interest (lateral frontal, lateral temporal, medial frontal and hippocampus).
No significant association was found between APOE ε4 carrier status and the studied regions of interest or the SPARE indices in linear regression models adjusted for age, gender, and education and including an interaction term between APOE and age.
Our study indicates that measurable APOE related brain atrophy does not occur in early adulthood and midlife and suggests that such atrophy may only occur more proximal to the onset of clinical symptoms of dementia.
PMCID: PMC5154957  PMID: 27173368
3.  Impact of Type 2 Diabetes and Postmenopausal Hormone Therapy on Incidence of Cognitive Impairment in Older Women 
Diabetes Care  2015;38(12):2316-2324.
In older women, higher levels of estrogen may exacerbate the increased risk for cognitive impairment conveyed by diabetes. We examined whether the effect of postmenopausal hormone therapy (HT) on cognitive impairment incidence differs depending on type 2 diabetes.
The Women’s Health Initiative (WHI) randomized clinical trials assigned women to HT (0.625 mg/day conjugated equine estrogens with or without [i.e., unopposed] 2.5 mg/day medroxyprogesterone acetate) or matching placebo for an average of 4.7–5.9 years. A total of 7,233 women, aged 65–80 years, were classified according to type 2 diabetes status and followed for probable dementia and cognitive impairment (mild cognitive impairment or dementia).
Through a maximum of 18 years of follow-up, women with diabetes had increased risk of probable dementia (hazard ratio [HR] 1.54 [95% CI 1.16–2.06]) and cognitive impairment (HR 1.83 [1.50–2.23]). The combination of diabetes and random assignment to HT increased their risk of dementia (HR 2.12 [1.47–3.06]) and cognitive impairment (HR 2.20 [1.70–2.87]) compared with women without these conditions, interaction P = 0.09 and P = 0.08. These interactions appeared to be limited to women assigned to unopposed conjugated equine estrogens.
These analyses provide additional support to a prior report that higher levels of estrogen may exacerbate risks that type 2 diabetes poses for cognitive function in older women. The role estrogen plays in suppressing non–glucose-based energy sources in the brain may explain this interaction.
PMCID: PMC4657616  PMID: 26486190
4.  Intra-individual lap time variation of the 400-m walk, an early mobility indicator of executive function decline in high-functioning older adults? 
Age  2015;37(6):115.
Higher intra-individual lap time variation (LTV) of the 400-m walk is cross-sectionally associated with poorer attention in older adults. Whether higher LTV predicts decline in executive function and whether the relationship is accounted for by slower walking remain unanswered. The main objective of this study was to examine the relationship between baseline LTV and longitudinal change in executive function. We used data from 347 participants aged 60 years and older (50.7 % female) from the Baltimore Longitudinal Study of Aging. Longitudinal assessments of executive function were conducted between 2007 and 2013, including attention (Trails A, Digit Span Forward Test), cognitive flexibility and set shifting (Trails B, Delta TMT: Trials B minus Trials A), visuoperceptual speed (Digit Symbol Substitution Test), and working memory (Digit Span Backward Test). LTV and mean lap time (MLT) were obtained from the 400-m walk test concurrent with the baseline executive function assessment. LTV was computed as variability of lap time across ten 40-m laps based on individual trajectories. A linear mixed-effects model was used to examine LTV in relation to changes in executive function, adjusted for age, sex, education, and MLT. Higher LTV was associated with greater decline in performance on Trails B (β = 4.322, p < 0.001) and delta TMT (β = 4.230, p < 0.001), independent of covariates. Findings remained largely unchanged after further adjustment for MLT. LTV was not associated with changes in other executive function measures (all p > 0.05). In high-functioning older adults, higher LTV in the 400-m walk predicts executive function decline involving cognitive flexibility and set shifting over a long period of time. High LTV may be an early indicator of executive function decline independent of MLT.
PMCID: PMC5005853  PMID: 26561401
Lap time variation; Executive function; Longitudinal study; Aging
5.  Deformation field correction for spatial normalization of PET images 
NeuroImage  2015;119:152-163.
Spatial normalization of positron emission tomography (PET) images is essential for population studies, yet the current state of the art in PET-to-PET registration is limited to the application of conventional deformable registration methods that were developed for structural images. A method is presented for the spatial normalization of PET images that improves their anatomical alignment over the state of the art. The approach works by correcting the deformable registration result using a model that is learned from training data having both PET and structural images. In particular, viewing the structural registration of training data as ground truth, correction factors are learned by using a generalized ridge regression at each voxel given the PET intensities and voxel locations in a population-based PET template. The trained model can then be used to obtain more accurate registration of PET images to the PET template without the use of a structural image. A cross validation evaluation on 79 subjects shows that the proposed method yields more accurate alignment of the PET images compared to deformable PET-to-PET registration as revealed by 1) a visual examination of the deformed images, 2) a smaller error in the deformation fields, and 3) a greater overlap of the deformed anatomical labels with ground truth segmentations.
PMCID: PMC4564310  PMID: 26142272
PET registration; deformation field; ridge regression; Pittsburgh compound B (PiB)
6.  Lap time variation and executive function in older adults: the Baltimore Longitudinal Study of Aging 
Age and Ageing  2015;44(5):796-800.
Background: poor cognitive and motor performance predicts neurological dysfunction. Variable performance may be a subclinical indicator of emerging neurological problems.
Objective: examine the cross-sectional association between a clinically accessible measure of variable walking and executive function.
Methods: older adults aged 60 or older from the Baltimore Longitudinal Study of Aging (n = 811) with data on the 400-m walk test and cognition. Based on ten 40-m laps, we calculated mean lap time (MLT) and variation in time across ten 40-m laps (lap time variation, LTV). Executive function tests assessed attention and short-term memory (digit span forward and backward), psychomotor speed [Trail Making Test (TMT) part A] and multicomponent tasks requiring cognitive flexibility [TMT part B, part B-A (Delta TMT) and digit symbol substitution test (DSST)]. Multivariate linear regression analysis examined the cross-sectional association between LTV and executive function, adjusted for MLT, age, sex and education, as well as the LTV × MLT interaction.
Results: the LTV was univariately associated with all executive function tests except digit span (P < 0.001); after adjustment, the association with TMT part A remained (standardised β = 0.142, P = 0.002). There was an interaction between MLT and LTV; among fast walkers, greater LTV was associated with a greater Delta TMT (β for LTV × MLT = −1.121, P = 0.016) after adjustment.
Conclusion: at any walking speed, greater LTV is associated with psychomotor slowing. Among persons with faster walking speed, variation is associated with worse performance on a complex measure of cognitive flexibility. A simple measure of variability in walking time is independently associated with psychomotor slowing.
PMCID: PMC4547927  PMID: 26082177
lap time variation; psychomotor speed; cognitive flexibility; older people
7.  Recruitment and Screening for the Testosterone Trials 
We describe the recruitment of men for The Testosterone (T) Trials, which were designed to determine the efficacy of T treatment.
Men were eligible if they were ≥65 years, had an average of two morning total T values <275ng/dL with neither value >300ng/mL, and had symptoms and objective evidence of mobility limitation, sexual dysfunction, and/or low vitality. Men had to be eligible for and enroll in at least one of these three main trials (physical function, sexual function, vitality).
Men were recruited primarily through mass mailings in 12 U.S. communities: 82% of men who contacted the sites did so in response to mailings. Men who responded were screened by telephone to ascertain eligibility. Of 51,085 telephone screens, 53.5% were eligible for further screening. Of 23,889 initial screening visits (SV1), 2,781 (11.6%) men were eligible for the second screening visit (SV2), which 2,261 (81.3%) completed. At SV2, 931 (41.2%) men met the criteria for one or more trials, the T level criterion and had no other exclusions. Of these, 790 (84.6%) were randomized; 99 (12.5%) in all three trials and 348 (44%) in two trials. Their mean age was 72 years and mean body mass index (BMI) was 31.0kg/m2. Mean (standard deviation) total T (ng/dL) was 212.0 (40.0).
Despite the telephone screening to enrollment ratio of 65 to 1, we met the recruitment goals for each trial. Recruitment of symptomatic older men with low testosterone levels is difficult but feasible.
PMCID: PMC4861649  PMID: 25878029
Testosterone treatment; Recruitment; Hypogonadal men; Physical function; Vitality; Sexual function; Randomized clinical trials.
8.  Postmenopausal hormone therapy and cognition 
Hormones and behavior  2015;74:167-172.
Prior to the publication of findings from the Women’s Health Initiative (WHI) in 2002, estrogen-containing hormone therapy (HT) was used to prevent age-related disease, especially cardiovascular disease, and to treat menopausal symptoms such as hot flushes and sleep disruptions. Some observational studies of HT in midlife and aging women suggested that HT might also benefit cognitive function, but randomized clinical trials have produced mixed findings in terms of health and cognitive outcomes. This review focuses on hormone effects on cognition and risk for dementia in naturally menopausal women as well as surgically induced menopause, and highlights findings from the large-scale WHI Memory Study (WHIMS) which, contrary to expectation, showed increased dementia risk and poorer cognitive outcomes in older postmenopausal women randomized to HT versus placebo. We consider the ‘critical window hypothesis’, which suggests that a window of opportunity may exist shortly after menopause during which estrogen treatments are most effective. In addition, we highlight emerging evidence that potential adverse effects of HT on cognition are most pronounced in women who have other health risks, such as cerebrovascular disease or diabetes. Lastly, we point towards implications for future research and clinical treatments.
PMCID: PMC4573348  PMID: 25935728
9.  Association Between Visuospatial Ability and Vestibular Function in the Baltimore Longitudinal Study of Aging 
To investigate the relationship between vestibular loss associated with aging and age-related decline in visuospatial function.
Cross-sectional analysis within a prospective cohort study.
Baltimore Longitudinal Study of Aging (BLSA).
Community-dwelling BLSA participants with a mean age of 72 (range 26–91) (N = 183).
Vestibular function was measured using vestibular-evoked myogenic potentials. Visuospatial cognitive tests included Card Rotations, Purdue Pegboard, Benton Visual Retention Test, and Trail-Making Test Parts A and B. Tests of executive function, memory, and attention were also considered.
Participants underwent vestibular and cognitive function testing. In multiple linear regression analyses, poorer vestibular function was associated with poorer performance on Card Rotations (P = .001), Purdue Pegboard (P = .005), Benton Visual Retention Test (P = 0.008), and Trail-Making Test Part B (P = .04). Performance on tests of executive function and verbal memory were not significantly associated with vestibular function. Exploratory factor analyses in a subgroup of participants who underwent all cognitive tests identified three latent cognitive abilities: visuospatial ability, verbal memory, and working memory and attention. Vestibular loss was significantly associated with lower visuospatial and working memory and attention factor scores.
Significant consistent associations between vestibular function and tests of visuospatial ability were observed in a sample of community-dwelling adults. Impairment in visuospatial skills is often one of the first signs of dementia and Alzheimer’s disease. Further longitudinal studies are needed to evaluate whether the relationship between vestibular function and visuospatial ability is causal.
PMCID: PMC4883683  PMID: 26311169
vestibular function; cognition; aging; visuospatial ability
10.  Depressive symptoms and longitudinal changes in cognition: Women's Health Initiative Study of Cognitive Aging 
Elevated Depressive symptoms (DS) are associated with incident mild cognitive impairment and probable dementia in postmenopausal women. We examined the association of elevated DS with domain-specific cognitive changes, and the moderating role of cardiovascular risk factor (CVRF) severity and cardiovascular disease (CVD). 2221 elderly women who participated in the Women's Health Initiative Study of Cognitive Aging were separated into those with (N = 204) and without (N = 2017) elevated DS. DS and multi-domain cognitive outcomes were measured annually for an average follow-up of 5.04 years. Women with elevated DS showed baseline multi-domain cognitive deficits, but longitudinal declines in global cognition only. Persistent DS was related to greater global cognition, and verbal knowledge and fluency, and memory declines. Significant DS-CVD interactions were observed cross-sectionally (but not longitudinally) for figural memory and fine motor speed. Future studies should investigate the role of nonvascular mechanisms linking DS and cognitive decline.
PMCID: PMC4433445  PMID: 24584465
Depression; Cognitive decline; Vascular risk factors; Cardiovascular disease; Women; Dementia; Depressive symptoms; Elderly; Cognitive decline
11.  Combining Multi-atlas Segmentation with Brain Surface Estimation 
Whole brain segmentation (with comprehensive cortical and subcortical labels) and cortical surface reconstruction are two essential techniques for investigating the human brain. The two tasks are typically conducted independently, however, which leads to spatial inconsistencies and hinders further integrated cortical analyses. To obtain self-consistent whole brain segmentations and surfaces, FreeSurfer segregates the subcortical and cortical segmentations before and after the cortical surface reconstruction. However, this “segmentation to surface to parcellation” strategy has shown limitations in various situations. In this work, we propose a novel “multi-atlas segmentation to surface” method called Multi-atlas CRUISE (MaCRUISE), which achieves self-consistent whole brain segmentations and cortical surfaces by combining multi-atlas segmentation with the cortical reconstruction method CRUISE. To our knowledge, this is the first work that achieves the reliability of state-of-the-art multi-atlas segmentation and labeling methods together with accurate and consistent cortical surface reconstruction. Compared with previous methods, MaCRUISE has three features: (1) MaCRUISE obtains 132 cortical/subcortical labels simultaneously from a single multi-atlas segmentation before reconstructing volume consistent surfaces; (2) Fuzzy tissue memberships are combined with multi-atlas segmentations to address partial volume effects; (3) MaCRUISE reconstructs topologically consistent cortical surfaces by using the sulci locations from multi-atlas segmentation. Two data sets, one consisting of five subjects with expertly traced landmarks and the other consisting of 100 volumes from elderly subjects are used for validation. Compared with CRUISE, MaCRUISE achieves self-consistent whole brain segmentation and cortical reconstruction without compromising on surface accuracy. MaCRUISE is comparably accurate to FreeSurfer while achieving greater robustness across an elderly population.
PMCID: PMC4845967  PMID: 27127332
Multi-atlas Segmentation; Magnetic Resonance Imaging; Cerebral Cortex; Cortical Reconstruction
12.  Interleukin-6 is linked to longitudinal rates of cortical thinning in aging 
Translational neuroscience  2014;5(1):1-7.
Interleukin-6 (IL-6) is a pro-inflammatory cytokine produced by immune cells and other cell types such as microglia throughout the brain. Higher levels of IL-6 in older adults have been cross-sectionally and longitudinally associated with physical and cognitive impairment, as well as increased dementia risk. The association between IL-6 levels and structural and functional brain changes is less clear. In the present study, we investigated the relationship between IL-6 concentrations and cortical thinning with aging. Magnetic Resonance Imaging (MRI) scans from the Baltimore Longitudinal Study of Aging were analyzed for 121 older subjects (M = 69.3; SD = 7.3; range = 56.1 – 85.9 yrs) who were repeatedly tested over an average period of 7.5 yrs, and who remained non-demented for the entire follow-up period. The Freesurfer longitudinal processing stream was utilized for image processing, and IL-6 measures were based on serum ELISA assays averaged across time points. Results showed that higher mean IL-6 concentrations were associated with accelerated annual rates of cortical thinning in the inferior temporal poles bilaterally. Additional pronounced regions of IL-6 -accelerated thinning included the transverse frontopolar gyri within the left hemisphere, and subcentral gyrus and sulcus within the right hemisphere. Our results indicate that sustained high levels of the inflammatory biomarker IL-6 are associated with regionally increased rates of age-related cortical thinning. These data build on previous findings that link IL-6 to chronic disease and demonstrate one mechanism through which high levels of inflammation may have adverse effects on physical and cognitive function.
PMCID: PMC4824945  PMID: 27066268
Aging; MRI; Biomarker; Inflammation
13.  Effects of Hormone Therapy on Brain Volumes Changes of Postmenopausal Women Revealed by Optimally-Discriminative Voxel-Based Morphometry 
PLoS ONE  2016;11(3):e0150834.
The Women's Health Initiative Memory Study Magnetic Resonance Imaging (WHIMS-MRI) provides an opportunity to evaluate how menopausal hormone therapy (HT) affects the structure of older women’s brains. Our earlier work based on region of interest (ROI) analysis demonstrated potential structural changes underlying adverse effects of HT on cognition. However, the ROI-based analysis is limited in statistical power and precision, and cannot provide fine-grained mapping of whole-brain changes.
We aimed to identify local structural differences between HT and placebo groups from WHIMS-MRI in a whole-brain refined level, by using a novel method, named Optimally-Discriminative Voxel-Based Analysis (ODVBA). ODVBA is a recently proposed imaging pattern analysis approach for group comparisons utilizing a spatially adaptive analysis scheme to accurately locate areas of group differences, thereby providing superior sensitivity and specificity to detect the structural brain changes over conventional methods.
Women assigned to HT treatments had significant Gray Matter (GM) losses compared to the placebo groups in the anterior cingulate and the adjacent medial frontal gyrus, and the orbitofrontal cortex, which persisted after multiple comparison corrections. There were no regions where HT was significantly associated with larger volumes compared to placebo, although a trend of marginal significance was found in the posterior cingulate cortical area. The CEE-Alone and CEE+MPA groups, although compared with different placebo controls, demonstrated similar effects according to the spatial patterns of structural changes.
HT had adverse effects on GM volumes and risk for cognitive impairment and dementia in older women. These findings advanced our understanding of the neurobiological underpinnings of HT effects.
PMCID: PMC4790922  PMID: 26974440
14.  Finding Imaging Patterns of Structural Covariance via Non-Negative Matrix Factorization 
NeuroImage  2014;108:1-16.
In this paper, we investigate the use of Non-Negative Matrix Factorization (NNMF) for the analysis of structural neuroimaging data. The goal is to identify the brain regions that co-vary across individuals in a consistent way, hence potentially being part of underlying brain networks or otherwise influenced by underlying common mechanisms such as genetics and pathologies. NNMF offers a directly data-driven way of extracting relatively localized co-varying structural regions, thereby transcending limitations of Principal Component Analysis (PCA), Independent Component Analysis (ICA) and other related methods that tend to produce dispersed components of positive and negative loadings. In particular, leveraging upon the well known ability of NNMF to produce parts-based representations of image data, we derive decompositions that partition the brain into regions that vary in consistent ways across individuals. Importantly, these decompositions achieve dimensionality reduction via highly interpretable ways and generalize well to new data as shown via split-sample experiments. We empirically validate NNMF in two data sets: i) a Diffusion Tensor (DT) mouse brain development study, and ii) a structural Magnetic Resonance (sMR) study of human brain aging. We demonstrate the ability of NNMF to produce sparse parts-based representations of the data at various resolutions. These representations seem to follow what we know about the underlying functional organization of the brain and also capture some pathological processes. Moreover, we show that these low dimensional representations favorably compare to descriptions obtained with more commonly used matrix factorization methods like PCA and ICA.
PMCID: PMC4357179  PMID: 25497684
Data Analysis; Structural Covariance; Non-Negative Matrix Factorization; Principal Component Analysis; Independent Component Analysis; Diffusion Tensor Imaging; Fractional Anisotropy; structural Magnetic Resonance Imaging; Gray Matter; RAVENS
15.  Temporal filtering of longitudinal brain magnetic resonance images for consistent segmentation 
NeuroImage : Clinical  2016;11:264-275.
Longitudinal analysis of magnetic resonance images of the human brain provides knowledge of brain changes during both normal aging as well as the progression of many diseases. Previous longitudinal segmentation methods have either ignored temporal information or have incorporated temporal consistency constraints within the algorithm. In this work, we assume that some anatomical brain changes can be explained by temporal transitions in image intensities. Once the images are aligned in the same space, the intensities of each scan at the same voxel constitute a temporal (or 4D) intensity trend at that voxel. Temporal intensity variations due to noise or other artifacts are corrected by a 4D intensity-based filter that smooths the intensity values where appropriate, while preserving real anatomical changes such as atrophy. Here smoothing refers to removal of sudden changes or discontinuities in intensities. Images processed with the 4D filter can be used as a pre-processing step to any segmentation method. We show that such a longitudinal pre-processing step produces robust and consistent longitudinal segmentation results, even when applying 3D segmentation algorithms. We compare with state-of-the-art 4D segmentation algorithms. Specifically, we experimented on three longitudinal datasets containing 4–12 time-points, and showed that the 4D temporal filter is more robust and has more power in distinguishing between healthy subjects and those with dementia, mild cognitive impairment, as well as different phenotypes of multiple sclerosis.
•Longitudinal analysis of MR images of the human brain provides knowledge about brain changes during aging and diseases.•Unlike previous methods, some temporal anatomical changes in the brain has been modeled by MR intensity change.•A 4D intensity based filter is proposed as a pre-processing step to 3D segmentation methods.•The 4D filter ensures consistency in segmentation while retaining sensitivity to true anatomical changes.•Experiments show improved atrophy detection in presence of dementia, cognitive impairment and different phenotypes of multiple sclerosis.
PMCID: PMC4773508  PMID: 26958465
16.  Factors affecting longitudinal trajectories of plasma sphingomyelins: the Baltimore Longitudinal Study of Aging 
Aging cell  2014;14(1):112-121.
Sphingomyelin metabolism has been linked to several diseases and to longevity. However, few epidemiological studies have quantified individual plasma sphingomyelin species (identified by acyl chain length and saturation) or their relationship to demographic factors and disease processes. In this study we determined plasma concentrations of distinct sphingomyelin species in 992 individuals, aged 55 and older, enrolled in the Baltimore Longitudinal Study of Aging. Participants were followed, with serial measures, up to 6 visits and 38 years (3,972 total samples). Quantitative analyses were performed on a high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometer. Linear mixed models were used to assess variation in specific sphingomyelin species and associations with demographics, diseases, medications or lifestyle factors, and plasma cholesterol and triglyceride levels. We found that most sphingomyelin species increased with age. Women had higher plasma levels of all sphingomyelin species and showed steeper trajectories of age-related increases compared to men. African Americans also showed higher circulating sphingomyelin concentrations compared to Caucasians. Diabetes, smoking, and plasma triglycerides were associated with lower levels of many sphingomyelins and dihydrosphingomyelins. Notably, these associations showed specificity to sphingomyelin acyl chain length and saturation. These results demonstrate that longitudinal changes in circulating sphingomyelin levels are influenced by age, sex, race, lifestyle factors, and diseases. It will be important to further establish the intra-individual age- and sex-specific changes in each sphingomyelin species in relation to disease onset and progression.
PMCID: PMC4310757  PMID: 25345489
aging; sphingomyelin; dihydrosphingomyelin; human; longitudinal; sex differences
17.  Greater cortical thinning in normal older adults predicts later cognitive impairment 
Neurobiology of aging  2014;36(2):903-908.
Cross-sectional studies have shown regional differences in cortical thickness between healthy older adults and patients with Alzheimer’s disease (AD) or mild cognitive impairment (MCI). We now demonstrate that participants who subsequently develop cognitive impairment leading to a diagnosis of MCI or AD (n=25) experience greater cortical thinning in specific neuroanatomical regions compared to control participants who remained cognitively normal (n=96). Based on 8 years of annual MRI scans beginning an average of 11 years prior to onset of cognitive impairment, participants who developed cognitive impairment subsequent to the scanning period had greater longitudinal cortical thinning in the temporal poles and left medial temporal lobe compared to controls. No significant regional cortical thickness differences were found at baseline between the two study groups indicating that we are capturing a critical time when brain changes occur before behavioral manifestations of impairment are detectable. Our findings suggest that early events of the pathway that leads to cognitive impairment may involve the temporal lobe, and that this increased atrophy could be considered an early biomarker of neurodegeneration predictive of cognitive impairment years later.
PMCID: PMC4315712  PMID: 25311277
Alzheimer’s disease; cortical thinning; early detection; longitudinal; mild cognitive impairment
18.  Self-Reported Sleep and β-Amyloid Deposition in Community-Dwelling Older Adults 
JAMA neurology  2013;70(12):1537-1543.
Older adults commonly report disturbed sleep, and recent studies in humans and animals suggest links between sleep and Alzheimer disease biomarkers. Studies are needed that evaluate whether sleep variables are associated with neuroimaging evidence of β-amyloid deposition.
To determine the association between self-reported sleep parameters and β-amyloid deposition in community-dwelling older adults.
Baltimore Longitudinal Study of Aging, a prospective study of normative aging
70 adults (mean age = 76; range 53 - 91) in the BLSA neuroimaging study
Main Outcome Measure
β-amyloid burden, measured by [11C] Pittsburgh compound B (PiB) positron emission tomography (PET) distribution volume ratios (DVR)
After adjustment for potential confounders, reports of shorter sleep duration were associated with greater β-amyloid burden, measured by mean cortical DVR (cDVR; B = 0.08, 95% confidence interval (CI) 0.03, 0.14, p = 0.005) and precuneus DVR (B = 0.11, 95% CI 0.03, 0.18, p = 0.007). Reports of lower sleep quality were associated with greater β-amyloid burden measured by precuneus DVR (B = 0.08, 95% CI 0.01, 0.15, p = 0.025).
Among community-dwelling older adults, reports of shorter sleep duration and lower sleep quality are associated with greater β-amyloid burden. Further studies with objective sleep measures are needed to determine whether sleep disturbance causes or accelerates Alzheimer disease.
PMCID: PMC3918480  PMID: 24145859
19.  A Voxel-Based Morphometry Study Reveals Local Brain Structural Alterations Associated with Ambient Fine Particles in Older Women 
Objective: Exposure to ambient fine particulate matter (PM2.5: PM with aerodynamic diameters < 2.5 μm) has been linked with cognitive deficits in older adults. Using fine-grained voxel-wise analyses, we examined whether PM2.5 exposure also affects brain structure.
Methods: Brain MRI data were obtained from 1365 women (aged 71–89) in the Women's Health Initiative Memory Study and local brain volumes were estimated using RAVENS (regional analysis of volumes in normalized space). Based on geocoded residential locations and air monitoring data from the U.S. Environmental Protection Agency, we employed a spatiotemporal model to estimate long-term (3-year average) exposure to ambient PM2.5 preceding MRI scans. Voxel-wise linear regression models were fit separately to gray matter (GM) and white matter (WM) maps to analyze associations between brain structure and PM2.5 exposure, with adjustment for potential confounders.
Results: Increased PM2.5 exposure was associated with smaller volumes in both cortical GM and subcortical WM areas. For GM, associations were clustered in the bilateral superior, middle, and medial frontal gyri. For WM, the largest clusters were in the frontal lobe, with smaller clusters in the temporal, parietal, and occipital lobes. No statistically significant associations were observed between PM2.5 exposure and hippocampal volumes.
Conclusions: Long-term PM2.5 exposures may accelerate loss of both GM and WM in older women. While our previous work linked smaller WM volumes to PM2.5, this is the first neuroimaging study reporting associations between air pollution exposure and smaller volumes of cortical GM. Our data support the hypothesized synaptic neurotoxicity of airborne particles.
PMCID: PMC5061768  PMID: 27790103
air pollution; brain; MRI; PM2.5; VBM
20.  Demographic and clinical variables affecting mid‐ to late‐life trajectories of plasma ceramide and dihydroceramide species 
Aging Cell  2015;14(6):1014-1023.
It has been increasingly recognized at the basic science level that perturbations in ceramide metabolism are associated with the development and progression of many age‐related diseases. However, the translation of this work to the clinic has lagged behind. Understanding the factors longitudinally associated with plasma ceramides and dihydroceramides (DHCer) at the population level and how these lipid levels change with age, and by sex, is important for the clinical development of future therapeutics and biomarkers focused on ceramide metabolism. We, therefore, examined factors cross‐sectionally and longitudinally associated with plasma concentrations of ceramides and DHCer among Baltimore Longitudinal Study of Aging participants (n = 992; 3960 total samples), aged 55 years and older, with plasma at a mean of 4.1 visits (range 2–6). Quantitative analyses were performed on a high‐performance liquid chromatography‐coupled electrospray ionization tandem mass spectrometer. Linear mixed models were used to assess the relationships between plasma ceramide and DHCer species and demographics, diseases, medications, and lifestyle factors. Women had higher plasma concentrations of most ceramide and DHCer species and showed steeper trajectories of age‐related increases compared to men. Ceramides and DHCer were more associated with waist–hip ratio than body mass index. Plasma cholesterol and triglycerides, prediabetes, and diabetes were associated with ceramides and DHCer, but the relationship showed specificity to the acyl chain length and saturation. These results demonstrate the importance of examining the individual species of ceramides and DHCer, and of establishing whether intra‐individual age‐ and sex‐specific changes occur in synchrony to disease onset and progression.
PMCID: PMC4693456  PMID: 26193443
aging; ceramide; dihydroceramide; human; longitudinal; sex differences
21.  Depressive Symptoms, Symptom Dimensions and White Matter Lesion Volume in Older Adults: A Longitudinal Study 
White matter lesions (WMLs) are associated with depressive symptoms in older adults. However, it is not clear whether different symptom dimensions of depression have distinct associations with WMLs. We assessed the longitudinal relationships of the Center for Epidemiologic Studies Depression Scale (CES-D) total score and subscale scores with WML volume in the Baltimore Longitudinal Study of Aging (BLSA).
Prospective observational design with examination of WML volume and depressive symptoms at 1–2 year intervals for up to 9 years.
Neuroimaging substudy of the BLSA.
116 dementia-free participants (mean age = 68.78 ± 7.68).
At each visit, depressive symptoms were measured with the CES-D and WML volumes were quantified from structural magnetic resonance imaging scans.
Higher CES-D full scale scores were associated with greater WML volume and with a faster rate of volume increases over time in women, especially at older ages. Higher depressed mood and somatic symptoms subscale scores were associated with greater increases in WML volume over time at older ages. In men, depressed mood and somatic symptoms were associated with larger WML volume at baseline.
Findings confirm an association between WMLs and depressive symptoms and suggest that depressed mood and somatic symptoms may be stronger predictors of depression-related brain changes than lack of well-being. Age and sex may moderate the relationships between depressive symptoms and WMLs. Understanding particular symptom dimensions of depressive symptoms has implications for treatment and may lead to targeted interventions and more precise knowledge of mechanisms underlying depression.
PMCID: PMC3984387  PMID: 24211028
depression; WML; symptom dimensions; aging; MRI
22.  Trajectories of Alzheimer disease-related cognitive measures in a longitudinal sample 
Delineation of the relative temporal trajectories of specific cognitive measures associated with Alzheimer’s disease (AD) is important for evaluating preclinical markers and monitoring disease progression.
We characterized the temporal trajectories of measures of verbal episodic memory, short-term visual memory, and mental status using data from 895 participants in the Baltimore Longitudinal Study of Aging.
The California Verbal Learning Test (CVLT) immediate recall was the first measure to decline, followed by CVLT delayed recall. However, further along the disease progression scale, CVLT delayed recall and visual memory changed more rapidly than CVLT immediate recall.
Our findings reconcile reports of early changes in immediate recall with greater reliance on delayed recall performance in clinical settings. Moreover, the utility of cognitive markers in evaluating AD progression depends on the stage of cognitive decline, suggesting that optimal endpoints in therapeutic trials may vary across different stages of the disease process.
PMCID: PMC4253313  PMID: 25035155
Disease progression score; California Verbal Learning Test; Alzheimer’s disease; Memory
23.  Temporal trajectory and progression score estimation from voxelwise longitudinal imaging measures: Application to amyloid imaging 
Cortical β-amyloid deposition begins in Alzheimer’s disease (AD) years before the onset of any clinical symptoms. It is therefore important to determine the temporal trajectories of amyloid deposition in these earliest stages in order to better understand their associations with progression to AD. A method for estimating the temporal trajectories of voxelwise amyloid as measured using longitudinal positron emission tomography (PET) imaging is presented. The method involves the estimation of a score for each subject visit based on the PET data that reflects their amyloid progression. This amyloid progression score allows subjects with similar progressions to be aligned and analyzed together. The estimation of the progression scores and the amyloid trajectory parameters are performed using an expectation-maximization algorithm. The correlations among the voxel measures of amyloid are modeled to reflect the spatial nature of PET images. Simulation results show that model parameters are captured well at a variety of noise and spatial correlation levels. The method is applied to longitudinal amyloid imaging data considering each cerebral hemisphere separately. The results are consistent across the hemispheres and agree with a global index of brain amyloid known as mean cortical DVR. Unlike mean cortical DVR, which depends on a priori defined regions, the progression score extracted by the method is data-driven and does not make assumptions about regional longitudinal changes. Compared to regressing on age at each voxel, the longitudinal trajectory slopes estimated using the proposed method show better localized longitudinal changes.
PMCID: PMC4591058  PMID: 26221692
Progression score; amyloid; Pittsburgh compound B; PiB; longitudinal image analysis
Clinical trials (London, England)  2014;11(3):362-375.
The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and glucose tolerance, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of testosterone treatment in elderly men, however, have produced equivocal results.
To describe a coordinated set of clinical trials designed to avoid the pitfalls of prior studies and determine definitively if testosterone treatment of elderly men with low testosterone is efficacious in improving symptoms and objective measures of age-associated conditions.
We present the scientific and clinical rationale for the decisions made in the design of this trial.
We designed The Testosterone Trials as a coordinated set of seven trials to determine if testosterone treatment of elderly men with low serum testosterone concentrations and also symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be efficacious in improving mobility (Physical Function Trial), sexual function (Sexual Function Trial), fatigue (Vitality Trial), cognitive function (Cognitive Function Trial), hemoglobin (Anemia Trial), bone density (Bone Trial), and coronary artery plaque volume (Cardiovascular Trial). The scientific advantages of this coordination were common eligibility criteria, treatment and monitoring and the ability to pool safety data. The logistical advantages were a single steering committee, data coordinating center and data safety monitoring board (DSMB), the same clinical trial sites, and the possibility of men participating in multiple trials. The major consideration in subject selection was setting the eligibility criterion for serum testosterone low enough to ensure that the men were unequivocally testosterone deficient, but not so low as to preclude sufficient enrollment or eventual generalizability of the results. The major considerations in choosing primary end points for each trial were identifying those of the highest clinical importance and identifying the minimum clinically important differences between treatment arms for sample size estimation.
Potential Limitations
Setting the serum testosterone concentration sufficiently low to ensure that most men would be unequivocally testosterone deficient, as well as many other entry criteria, resulted in screening approximately 30 men in person to randomize one subject.
The Testosterone Trials were designed to determine definitively if testosterone treatment of elderly men with low testosterone would have any clinical benefit. Designing The Testosterone Trials as a coordinated set of seven trials afforded many important scientific and logistical advantages but required an intensive recruitment and screening effort.
PMCID: PMC4182174  PMID: 24686158
clinical trial; testosterone; hypogonadism; aging; mobility; sexual function; vitality; cognitive function; anemia; CT angiography; volumetric BMD; bone strength
25.  Cortical surface segmentation and mapping 
NeuroImage  2004;23(0 1):S108-S118.
Segmentation and mapping of the human cerebral cortex from magnetic resonance (MR) images plays an important role in neuro-science and medicine. This paper describes a comprehensive approach for cortical reconstruction, flattening, and sulcal segmentation. Robustness to imaging artifacts and anatomical consistency are key achievements in an overall approach that is nearly fully automatic and computationally fast. Results demonstrating the application of this approach to a study of cortical thickness changes in aging are presented.
PMCID: PMC4587756  PMID: 15501080
Cerebral cortex; Cortical surface; Cortical thickness; Surface flattening

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