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1.  Aging, the Central Nervous System, and Mobility 
Mobility limitations are common and hazardous in community-dwelling older adults but are largely understudied, particularly regarding the role of the central nervous system (CNS). This has limited development of clearly defined pathophysiology, clinical terminology, and effective treatments. Understanding how changes in the CNS contribute to mobility limitations has the potential to inform future intervention studies.
A conference series was launched at the 2012 conference of the Gerontological Society of America in collaboration with the National Institute on Aging and the University of Pittsburgh. The overarching goal of the conference series is to facilitate the translation of research results into interventions that improve mobility for older adults.
Evidence from basic, clinical, and epidemiological studies supports the CNS as an important contributor to mobility limitations in older adults without overt neurologic disease. Three main goals for future work that emerged were as follows: (a) develop models of mobility limitations in older adults that differentiate aging from disease-related processes and that fully integrate CNS with musculoskeletal contributors; (b) quantify the contribution of the CNS to mobility loss in older adults in the absence of overt neurologic diseases; (c) promote cross-disciplinary collaboration to generate new ideas and address current methodological issues and barriers, including real-world mobility measures and life-course approaches.
In addition to greater cross-disciplinary research, there is a need for new approaches to training clinicians and investigators, which integrate concepts and methodologies from individual disciplines, focus on emerging methodologies, and prepare investigators to assess complex, multisystem associations.
PMCID: PMC3805295  PMID: 23843270
Motor control; Central nervous system; Mobility.
2.  Frontal Gray Matter Atrophy in Middle Aged Adults with Type 1 Diabetes is Independent of Cardiovascular Risk Factors and Diabetes Complications 
Journal of diabetes and its complications  2013;27(6):10.1016/j.jdiacomp.2013.07.001.
To determine if regional gray matter volume (GMV) differences in middle-aged adults with and without type-1 diabetes (T1D) are localized in areas most vulnerable to aging, e.g. fronto-subcortical networks; and if these differences are explained by cardiovascular risk factors and diabetes complications.
Regional GMV was computed using 3 Tesla MRI of 104 adults with a childhood onset of T1D (mean age: 49+7 and duration: 41±6 years) and 151 adults without diabetes (mean age: 40+6). A Bonferroni threshold (n=45, p≤0.001) was applied to account for multiple between-group comparisons and analyses were repeated in an age- and gender-matched subset of participants with T1D and controls (n=44 in each group, mean age [SD] and range: 44.0, [4.3], 17.4 and 44.6 [4.3], 17.0, respectively).
Compared to controls, T1D patients had smaller GMV in the frontal lobe (6 to 19% smaller) and adjacent supramarginal and postcentral gyri (8 to 13% smaller). Between-group differences were independent of age, waist circumference, systolic blood pressure, fasting total cholesterol and smoking status and were similar in sensitivity analyses restricted to age- and gender-matched participants. Associations between GMV and diabetes complications were not significant.
These findings extend the notion of accelerated brain aging in T1D to middle-aged adults. The pathophysiology of frontal gray matter atrophy and its impact on future development of disability and dementia need further study, especially as middle-aged T1D patients progress to older age.
PMCID: PMC3818288  PMID: 23994432
Brain; Imaging (MRI); Complications; Retinopathy; Nephropathy; Hypertension
3.  Neuroprogressive effects of lifetime illness duration in older adults with bipolar disorder 
Bipolar disorders  2014;16(6):617-623.
The aim of the present study was to examine the long-term effects of bipolar disorder (BD) on brain structure (gray matter volumes).
Fifty-four adults with BD [mean (standard deviation) age = 64.4 (5.4) years] underwent brain MR imaging along with comprehensive clinical assessment. Total gray matter, hippocampal, and amygdala volumes were extracted using methods developed through the Geriatric Neuroimaging Laboratory at the University of Pittsburgh (Pittsburgh, PA, USA).
Lower total gray matter volumes were related to longer duration of BD, even when controlling for current age and cerebrovascular accident (CVA) risk/burden. Additionally, longer exposure to antipsychotic medication was related to lower gray matter volumes. Lower hippocampal volumes were related to total years of antipsychotic agent exposure and CVA risk/burden scores. Older age was related to lower total gray matter, hippocampal, and amgydala volumes.
Our study of older adults with BD supports the understanding that BD is a neuroprogressive disorder with a longer duration of illness and more antipsychotic agent exposure related to lower gray matter volume.
PMCID: PMC4149863  PMID: 24716786
amygdala; bipolar disorder; brain; hippocampus; lithium; neuroimaging; neuroprogression
4.  Cognitive aging in persons with minimal amyloid-beta and white matter hyperintensities 
Neuropsychologia  2013;51(11):2202-2209.
Substantial individual differences exist in the magnitude of the cognitive decline associated with normal aging. Potential contributors to this intersubject variability include white matter hyperintensities (WMH) and preclinical Alzheimer’s disease, evident as increased brain amyloid. This study examined whether older individuals with minimal evidence of WMH and/or brain amyloid-beta (seen on positron emission tomography with the Pittsburgh compound B radiotracer - PiB) still showed significant cognitive decrements compared to the young. Older individuals, conservatively screened for normal range performance on an extensive neuropsychological battery, underwent structural magnetic resonance imaging (MRI) and PiB scans and performed tests of information processing speed, working memory and inhibitory function. The elderly were divided into PiB(+) and PiB(−) groups based on radiotracer retention. There were no significant differences in cognitive performance between PiB(+) and PiB(−) elderly. However, both PiB groups performed significantly worse than did the young on cognitive testing. WMH burden in the same individuals was quantified by consensus ratings using a 10 point scale with a median split defining two groups, WMH(+) and WMH(−). There were no differences in cognitive performance between WMH(+) and WMH(−) individuals, but both WMH groups performed significantly worse than did the young. Older participants who were both PiB(−) and WMH(−) also performed significantly worse than did the young in all three cognitive domains. The present results suggest that normal-elderly individuals whose brain scans show minimal evidence of amyloid deposition or WMH, still demonstrate a major decrement in comparison to younger persons on measures of processing resources and inhibitory efficiency.
PMCID: PMC3807130  PMID: 23911776
amyloid; white matter hyperintensities; normal aging; cognition
5.  Long-term Survival in Adults Aged 65 and Older With White Matter Hyperintensity: Association With Performance on the Digit Symbol Substitution Test 
Psychosomatic medicine  2013;75(7):10.1097/PSY.0b013e31829c1df2.
White matter hyperintensity (WMH) confers increased mortality risk in patients with cardiovascular diseases. However, little is known about differences in survival times among adults 65 years and older who have WMH and live in the community. To characterize the factors that may reduce mortality risk in the presence of WMH, measures of race, sex, ApoE4, neuroimaging, cardiometabolic, physiological and psychosocial characteristics were examined, with a particular focus on information processing as measured by the Digit Symbol Substitution Test(DSST).
Cox-proportional models were used to estimate mortality risks in a cohort of 3513 adults (74.8years, 58%women, 84%white) with WMH (0–9 points), DSST (0–90 points), risk factor assessment in 1992–94 and data on mortality and incident stroke to 2009 (median follow-up [range]:14.2[0.5–18.1]years).
WMH predicted a 48% greater mortality risk (age-adjusted hazard ratio (HR)[95% confidence interval(CI)] for WMH>3 points=1.48[1.35–1.62]). This association was attenuated after adjustment for DSST (HR[CI]: 1.38[1.27–1.51]) or lacunar infarcts (HR[CI]: 1.37[1.25,1.50]) but not after adjustment for other factors. The interaction between DSST and WMH was significant (p=0.011). In fully adjusted models stratified by WMH>3, participants with DSST>median had a 34% lower mortality risk among those with WMH>3 (n=532/1217) and a 28% lower mortality risk among those with WMH<3 (n=1364/2296), compared to participants with DSST
WMH is associated with increased long-term mortality risk in community-dwelling adults aged 65 and older. The increased risk is attenuated for those with higher DSST. Assessment of cognitive function with DSST may improve risk stratification of individuals with WMH.
PMCID: PMC3809761  PMID: 23886735
mortality; information processing; white matter hyperintensity
In older adults, depression not only results in more years lived with disability than any other disease, but it also carries additional risk for suicide, medical comorbidities, and family care-giving burden. Because it can take many months to identify an effective treatment regimen, it is of upmost importance to shorten the window of time and identify early on what medication(s) and dosages will work effectively for individuals suffering from depression. Late-life depression (LLD) has been associated with greater burden of age-related changes, including atrophy, white matter ischemic changes, and alterations in functional connectivity (FC). Depression in midlife has been shown to alter affective reactivity and regulation, and functional magnetic resonance imaging (fMRI) studies in LLD have replicated the same abnormalities. Effective treatment can normalize these alterations. This article provides a review of the current literature using structural and functional neuroimaging to identify magnetic resonance imaging (MRI) predictors of treatment response in LLD. The majority of the literature on structural MRI has focused on the vascular depression hypothesis, and studies support the view that loss of brain volume and white matter integrity is associated with poorer treatment outcomes. Studies using fMRI have reported that lower task-based activity in the prefrontal cortex (PFC) and limbic regions is associated with poorer outcome. These imaging markers may be integrated into clinical decision-making to better treatment outcomes in the future.
PMCID: PMC4103612  PMID: 24381231
Current psychiatry reports  2013;15(6):360.
Neuroimaging, both structural and functional, serve as useful adjuncts to clinical assessment, and can provide objective, reliable means of assessing disease presence and process in the aging population. In the following review we briefly explain current imaging methodologies. Then, we analyze recent developments in developing neuroimaging biomarkers for two highly prevalent disorders in the elderly population- Alzheimer's disease (AD) and late-life depression (LLD). In AD, efforts are focused on early diagnosis through in vivo visualization of disease pathophysiology. In LLD, recent imaging evidence supports the role of white matter ischemic changes in the pathogenesis of depression in the elderly, the “vascular hypothesis.” Finally, we discuss potential roles for neuroimaging biomarkers in geriatric psychiatry in the future.
PMCID: PMC3667151  PMID: 23636984
Geriatric; Psychiatry; Neuroimaging; Biomarkers; Dementia; Alzheimer's disease (AD); Late-life depression (LLD); MRI; DTI; fMRI; PET; FDG-PET; Pittsburgh Compound B (PiB); White matter lesions (WML); Resting-state network; Vascular hypothesis
Annals of neurology  2013;73(6):751-761.
This study examined amyloid-β (Aβ) deposition in 190 non-demented subjects aged 82 and older to determine the proportion of Aβ-positive scans and associations with cognition, APOE status, brain volume, and Ginko biloba (Gb) treatment.
Subjects who agreed to participate had a brain MRI and positron emission tomography scan with 11C-labeled Pittsburgh compound B (PiB) following completion of a Gb treatment clinical trial. The youngest subject in this imaging study was 82, and the mean age of the subjects was 85.5 at the time of the scans;152 (80%) were cognitively normal and 38 (20%) were diagnosed with mild cognitive impairment (MCI)at the time of the PiB study.
A high proportion of the cognitively normal subjects (51%) and MCI subjects (68%) were PiB-positive. The APOE*4 allele was more prevalent in PiB-positive than in PiB-negative subjects (30% vs 6%). Measures of memory, language and attentional functions were worse in PiB-positive than in PiB-negative subjects, when both normal and MCI cases were analyzed together; however no significant associations were observed within either normal or MCI subject groups alone. There was no relationship between Gb treatment and Aβ deposition as determined by PiB.
The data revealed a 55% prevalence of PiB-positivity in non-demented subjects age >80 and 85% PiB-positivity in the APOE*4 non-demented elderly subjects. The findings also showed that long-term exposure to Gb did not affect the prevalence of cerebral Aβ deposition.
PMCID: PMC3725727  PMID: 23596051
NeuroImage  2013;71:207-215.
An important research application of amyloid imaging with positron emission tomography (PET) is detection of the earliest evidence of fibrillar amyloid-beta (Aβ) deposition. Use of amyloid PET for this purpose, requires a reproducible method for defining a cutoff that separates individuals with no significant Aβ deposition from those in which Aβ deposition has begun. We previously reported the iterative outlier approach (IO) for the analysis of Pittsburgh Compound-B (PiB) PET data. Developments in amyloid imaging since the initial report of IO have led us to re-examine the generalizability of this method. IO was developed using full-dynamic atrophy-corrected PiB PET data obtained from a group of control subjects with a fairly distinct separation between PiB-positive [PiB(+)] and PiB-negative [PiB(−)] subjects.
We tested the performance of IO using late-summed tissue ratio data with atrophy correction or with an automated template method without atrophy correction and tested the robustness of the method when applied to a cohort of older subjects in which separation between PiB(+) and PiB(−) subjects was not so distinct.
The IO method did not perform consistently across analyses and performed particularly poorly when separation was less clear. We found that a sparse k-means (SKM) cluster analysis approach performed significantly better; performing more consistently across methods and subject cohorts. We also compared SKM to a consensus visual read approach and found very good correspondence.
The visual read and SKM methods, applied together, may optimize the identification of early Aβ deposition. These methods have the potential to provide a standard approach to the detection of PiB-positivity that is generalizable across centers.
PMCID: PMC3605888  PMID: 23353602
Amyloid; Positron Emission Tomography; Pittsburgh Compound B; Visual Read; Cluster analysis
Cognitive dysfunction is prevalent in older adults with bipolar disorder (BD). High white matter hyperintensity (WMH) burden, a marker of white matter disease, detected on T2/fluid-attenuated inversion recovery brain magnetic resonance imaging (MRI) has been consistently reported in BD across all age ranges, including older adults. Yet, whether high WMH burden is related to the excess cognitive impairment present in older adults with BD is unknown. Therefore, we examine whether higher WMH burden is related to worse cognitive function in older adults with BD.
This is a cross-sectional study of 27 non-demented BD patients aged ≥50 years and 12 similarly aged mentally healthy comparators (controls). Subjects underwent both brain MRI and comprehensive neurocognitive assessment. We employed correlational analyses to evaluate the burden of WMH and the relationship between WMH and cognitive function.
Although BD subjects had worse performance in all cognitive domains, BD subjects had less total WMH burden (t[13.4] = −3.57, p = 0.003). In control subjects, higher WMH was related to lower global cognitive function (ρ= −0.57, n= 12, p = 0.05). However, WMH did not correlate with neuropsychological performance in BD subjects. Further, BD and control subjects did not differ with respect to total gray and hippocampal volumes.
Cognitive dysfunction in late-life BD does not appear to be due primarily to processes related to increased WMH or reduced gray matter volume. Future longitudinal studies should examine other potential neuroprogressive pathways such as inflammation, mitochondrial dysfunction, serum anticholinergic burden, and altered neurogenesis.
PMCID: PMC3947373  PMID: 24006234
bipolar disorder; cognition; aging; neuroimaging
Molecular psychiatry  2013;18(9):963-974.
The ‘Vascular Depression’ hypothesis posits that cerebrovascular disease may predispose, precipitate, or perpetuate some geriatric depressive syndromes. This hypothesis stimulated much research that has improved our understanding of the complex relationships between late-life depression (LLD), vascular risk factors, and cognition. Succinctly, there are well-established relationships between late-life depression, vascular risk factors, and cerebral hyperintensities, the radiological hallmark of vascular depression. Cognitive dysfunction is common in late-life depression, particularly executive dysfunction, a finding predictive of poor antidepressant response. Over time, progression of hyperintensities and cognitive deficits predicts a poor course of depression and may reflect underlying worsening of vascular disease. This work laid the foundation for examining the mechanisms by which vascular disease influences brain circuits and influences the development and course of depression. We review data testing the vascular depression hypothesis with a focus on identifying potential underlying vascular mechanisms. We propose a disconnection hypothesis, wherein focal vascular damage and white matter lesion location is a crucial factor influencing neural connectivity that contributes to clinical symptomatology. We also propose inflammatory and hypoperfusion hypotheses, concepts that link underlying vascular processes with adverse effects on brain function that influence the development of depression. Testing such hypotheses will not only inform the relationship between vascular disease and depression but also provide guidance on the potential repurposing of pharmacological agents that may improve late-life depression outcomes.
PMCID: PMC3674224  PMID: 23439482
Depression; geriatrics; cerebrovascular; review; neuroimaging; cognition
Hypertension  2012;61(1):160-165.
While the cross-sectional relationship of arterial stiffness with cerebral small vessel disease is consistently shown in middle-aged and young-old adults, its less clear if these associations remain significant over time in very old adults. We hypothesize that arterial stiffness is longitudinally associated with white matter characteristics and associations are stronger within watershed areas.
Neuroimaging was obtained in 2006–08 from 303 elderly (mean age 82.9 years, 59% women, 41% black) with pulse wave velocity measures in 1997–98. Multivariable regression models estimated the coefficients for pulse wave velocity (cm/sec) in relationship to presence, severity and spatial distribution of white matter hyperintensities, gray matter volume and fractional anisotropy from diffusion tensor, adjusting for demographic, cardiovascular risk factors and diseases from 1997–98 to 2006–08.
Higher pulse wave velocity in 1997–98 was associated with greater white matter hyperintensities volume in 2006–08 within the left superior longitudinal fasciculus (age and total brain white matter hyperintensities-adjusted p=0.023), but not with white matter hyperintensities in other tracts, or with fractional anisotropy or gray matter volume from total brain (p>0.2). Associations were stronger in blacks than in whites remaining significant in fully adjusted models.
Elderly with white matter hyperintensities in tracts related to processing speed and memory are more likely to have had higher pulse wave velocity values ten years prior, before neuroimaging data being available. Future studies should address whether arterial stiffness can serve as an early biomarker of covert brain structural abnormalities and whether early arterial stiffness control can promote successful brain aging, especially in black elderly.
PMCID: PMC3521843  PMID: 23172923
pulse wave velocity; small vessel disease; longitudinal; fractional anisotropy; community-dwelling elderly
Journal of the American Geriatrics Society  2013;61(5):10.1111/jgs.12211.
Background and Objectives
White matter hyperintensities (WMH) on brain MRI are associated with cognitive and mobility impairment in older adults. We examined whether WMH in tracts in older adults with mobility impairment are linked to outcomes of gait rehabilitation interventions.
A 12-week randomized controlled single-blind trial.
University-based mobility research laboratory.
Ambulatory adults aged 65 and older with mobility impairment.
A conventional gait intervention focusing on walking, endurance, balance, and strength (WEBS, n=21) compared to a task-oriented intervention focused on timing and coordination of gait (TC, n=23).
We measured self-paced gait speed over an instrumented walkway, pre and post intervention, and quantified WMH and brain volumes on pre-intervention brain MRI using an automated segmentation process. We overlaid a white matter tract atlas on the segmented images to measure tract WMH volumes and normalized WMH volumes to total brain volume. Aggregate WMH volumes in all white matter tracts and individual WMH volumes in specific longitudinal tracts (the superior longitudinal fasciculus, inferior longitudinal fasciculus and the fronto-occipital fasciculus) and cingulum were obtained.
Gait speed gains in the TC group were of the same magnitude, independent of the WMH volume measures in all except the cingulum. However, in the WEBS group, gain in gait speed was smaller with greater overall tract WMH volumes (P<0.001) and with greater WMH volume in the three longitudinal tracts (P< 0.001 to 0.025).
Gains in gait speed with two types of gait rehabilitation are associated with individual differences in WMH. Task-oriented therapy that targets timing and coordination of gait may particularly benefit older adults with WMH in brain tracts that influence gait and cognition.
PMCID: PMC3874589  PMID: 23590257
Psychiatry research  2012;204(2-3):117-122.
White matter hyperintensities (WMHs) are often identified on T2-weighted magnetic resonance (MR) images in the elderly. The WMHs are generally associated with small vessel ischemic or pre-ischemic changes. However, the association of WMHs with blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal is understudied. In this study, we evaluate how the BOLD signal change is related to the presence of WMHs in the elderly. Data were acquired as part of a study of late-life depression and included elderly individuals with and without major depression. The subjects were pooled because the presence of depression was not significantly associated with task-related BOLD changes, task performance, and WMH distribution. A whole brain voxel-wise regression analysis revealed a significant negative correlation between WMH burden and BOLD signal change during finger-tapping in the parietal white matter. Our observation that WMHs are associated with a significant diminution of the BOLD signal change underscores the importance of considering cerebrovascular burden when interpreting fMRI studies in the elderly. The mechanism underlying the association of WMH and BOLD signal change remains unclear: the association may be mediated by changes in neural activation, changes in coupling between neuronal activity and hemodynamics, or, perhaps, secondary to the effect of the ischemic changes on the sensitivity of the T2* BOLD MR signal.
PMCID: PMC3518674  PMID: 23131524
Functional imaging; structural imaging; white matter hyperintensities; BOLD; aging
Neuroscience letters  2012;522(2):113-117.
While our previous work suggests that the midazolam-induced memory impairment results from the inhibition of new association formation, little is known about the neural correlates underlying these effects beyond the effects of GABA agonists on the brain. We used arterial spin-labeling perfusion MRI to measure cerebral blood flow changes associated with the effects of midazolam on ability to learn arbitrary word-pairs. Using a double-blind, within-subject cross-over design, subjects studied word-pairs for a later cued-recall test while they were scanned. Lists of different word-pairs were studied both before and after an injection of either saline or midazolam. As expected, recall was severely impaired under midazolam. The contrast of MRI signal before and after midazolam administration revealed a decrease in CBF in the left dorsolateral prefrontal cortex (DLPFC), left cingulate gyrus and left posterior cingulate gyrus/precuneus. These effects were observed even after controlling for any effect of injection. A strong correlation between the midazolam-induced changes in neural activity and memory performance was found in the left DLPFC. These findings provide converging evidence that this region plays a critical role in the formation of new associations and that low functioning of this region is associated with anterograde amnesia.
PMCID: PMC3780778  PMID: 22710004
associative memory; arterial spin labeling; dorsolateral prefrontal cortex
Brain imaging and behavior  2012;6(3):366-373.
There is need for a valid and reliable biomarker for HIV Associated Neurocognitive Disorder (HAND). The purpose of the present study was to provide preliminary evidence of the potential utility of neuronal functional connectivity measures obtained using magnetoencephalography (MEG) to identify HIV-associated changes in brain function. Resting state, eyes closed, MEG data from 10 HIV-infected individuals and 8 seronegative controls were analyzed using mutual information (MI) between all pairs of MEG sensors to determine whether there were functional brain networks that distinguished between subject groups based on cognition (global and learning) or on serostatus.
Three networks were identified across all subjects, but after permutation testing (at α < .005) only the one related to HIV serostatus was significant. The network included MEG sensors (planar gradiometers) above the right anterior region connecting to sensors above the left posterior region. A mean MI value was calculated across all connections from the anterior to the posterior groupings; that score distinguished between the serostatus groups with only one error (sensitivity = 1.00, specificity = .88 (X2 = 15.4, df = 1, p < .01, Relative Risk = .11). There were no significant associations between the MI value and the neuropsychological Global Impairment rating, substance abuse, mood disorder, age, education, CD4+ cell counts or HIV viral load.
We conclude that using a measure of functional connectivity, it may be possible to distinguish between HIV-infected and uninfected individuals, suggesting that MEG may have the potential to serve as a sensitive, non-invasive biomarker for HAND.
PMCID: PMC3351549  PMID: 22328062
HIV Disease; Cognition; Magnetoencephalography; Functional Connectivity
Identify the neuroimaging correlates of parkinsonian signs in older adults living in the community.
Magnetic resonance imaging was obtained in 307 adults (82.9 years, 55% women, 39% blacks) concurrently with the Unified Parkinson Disease Rating scale—motor part. Magnetic resonance imaging measures included volume of whole-brain white matter hyperintensities and of gray matter for primary sensorimotor, supplementary motor, medial temporal areas, cerebellum, prefronto-parietal cortex, and basal ganglia.
About 25% of the participants had bradykinesia, 26% had gait disturbances, and 12% had tremor. Compared with those without, adults with any one of these signs were older, walked more slowly, had worse scores on tests of cognition, mood and processing speed, and higher white matter hyperintensities volume (all p ≤ .002). Gray matter volume of primary sensorimotor area was associated with bradykinesia (standardized odds ratio [95% confidence interval]: 0.46 [0.31, 0.68], p < .0001), and gray matter volume of medial temporal area was associated with gait disturbances (0.56 [0.42, 0.83], p < .0001), independent of white matter hyperintensities volume and age. Further adjustment for measures of muscle strength, cardiovascular health factors, cognition, processing speed, and mood or for gait speed did not substantially change these results.
Atrophy within primary sensorimotor and medial temporal areas might be important for development of bradykinesia and of gait disturbances in community-dwelling elderly adults. The pathways underlying these associations may not include changes in white matter hyperintensities volume, cognition, information processing speed, mood, or gait speed.
PMCID: PMC3436092  PMID: 22367436
Bradykinesia; Gait disturbances; Brain MRI
Background: Slowing information processing is common among community-dwelling elderly and it predicts greater mortality and disability risk. Slowing information processing is related to brain macro-structural abnormalities. Specifically, greater global atrophy and greater small vessel disease of the white matter (WM) have been associated with slower processing speed. However, community-dwelling elderly with such macro-structural abnormalities can maintain processing speed. The roles of brain micro-structure for slow processing in very old adults living in the community is uncertain, as epidemiological studies relating these brain markers to cognition and in the context of other health characteristics are sparse. Hypothesis: Information processing is cross-sectionally associated with WM micro-structure independent of overt macro-structural abnormalities and also independent of health related characteristics. Methods: Imaging indices of micro-structure diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI), macro-structure white matter hyperintensities (WMH), gray matter (GM) volume, digit symbol substitution test (DSST), and health characteristics were measured in 272 elderly (mean age 83 years old, 43% men, 40% black) living in the community. Results: The DTI- and MTI-indices of micro-structure from the normal appearing WM and not from the normal appearing GM were associated with DSST score independent of WMH and GM volumes. Associations were also independent of age, race, gender, mini-mental score, systolic blood pressure, and prevalent myocardial infarction. Interpretation: DTI and MTI-indices of normal appearing WM are indicators of information processing speed in this cohort of very old adults living in the community. Since processing slowing is a potent index of mortality and disability, these indices may serve as biomarkers in prevention or treatment trials of disability.
PMCID: PMC3180637  PMID: 21991255
digit symbol substitution score; oldest old; magnetization transfer; diffusion tensor imaging; white matter
NeuroImage  2012;62(1):307-313.
Maintaining cognitive function protects older adults from developing functional decline. This study aims to identify the neuroimaging correlates of maintenance of higher global cognition as measured by the Modified Mini Mental State Test (3MS) score.
Repeated 3MS measures from 1997–98 through 2006–07 and magnetic resonance imaging with diffusion tensor in 2006–07 were obtained in a biracial cohort of 258 adults free from dementia (mean age 82.9 years, 56% women, 42% blacks). Participants were classified as having shown either maintenance (3MS slope>0) or decline (3MS slopeb1 SD below the mean) of cognition using linear mixed models. Measures of interest were white matter hyperintensity volume (WMHv) from total brain, volume of the gray matter (GMv) and microstructure (mean diffusivity, MD) for total brain and for brain areas known to be related to memory and executive control function: medial temporal area (hippocampus, parahippocampus and entorhinal cortex), cingulate cortex, dorsolateral prefrontal and posterior parietal cortex.
Differences between cognitive maintainers (n=153) and non-maintainers (n=107) were significant for GMv of the medial temporal area (35.8%, p=0.004) and lower MD of the cingulate cortex (37.9%, p=0.008), but not for other neuroimaging markers. In multivariable regression models adjusted for age, race, WMHv and GMV from the total brain and vascular conditions, each standard deviation of GMv of the medial temporal area and each standard deviation of MD of the cingulate cortex were associated with a nearly 4 times greater probability (odds ratio [standard deviation]: 3.80 [1.16, 12.44]) and a 34% lower probability (0.66, [0.46, 0.97]) of maintaining cognitive function, respectively. In these models neither WMHv nor GMv from total brain were significantly associated with probability of maintaining cognitive function.
Preserving the volume of the medial temporal area and the microstructure of the cingulate cortex may contribute to maintaining cognitive function late in life.
PMCID: PMC3690545  PMID: 22542701
Human brain mapping  2006;27(9):747-754.
Typical packages used for coregistration in functional image analyses include automated image registration (AIR) and statistical parametric mapping (SPM). However, both methods have limited-dimension deformation models. A fully deformable model, which combines the piecewise linear registration for coarse alignment with demons algorithm for voxel-level refinement, allows a higher degree of spatial deformation. This leads to a more accurate colocalization of the functional signal from different subjects and therefore can produce a more reliable group average signal. We quantitatively compared the performance of the three different registration approaches through a series of experiments and we found that the fully deformable model consistently produces a more accurate structural segmentation and a more reliable functional signal colocalization than does AIR or SPM.
PMCID: PMC2886594  PMID: 16463385
deformable model; atlas-based segmentation; image registration; fMRI
The American journal of psychiatry  2011;168(10):1075-1082.
This study tests whether or not the structural white matter lesions that are characteristic of late-life depression are associated with alterations in the functional affective circuits of late-life depression. This study used an emotional faces paradigm that has been shown to engage the affective limbic brain regions.
Thirty-three elderly depressed patients and 27 nondepressed comparison subjects participated in this study. The patients were recruited through the NIMH-sponsored Advanced Center for Interventions and Services Research for the Study of Late-Life Mood Disorders at the University of Pittsburgh Center for Bioethics and Health Law. Structural and functional MRI was used to assess white matter hyperintensity (WMH) burden and functional magnetic resonance imaging (fMRI) blood-oxygen-level-dependent (BOLD) response on a facial expression affective-reactivity task in both elderly participants with nonpsychotic and non-bipolar major depression (unmedicated) and nondepressed elderly comparison subjects.
As expected, greater subgenual cingulate activity was observed in the depressed patients relative to the nondepressed comparison subjects. This same region showed greater task-related activity associated with a greater burden of cerebrovascular white matter change in the depressed group. Moreover, the depressed group showed a significantly greater interaction of WMH by fMRI activity effect than the nondepressed group.
The observation that high WMH burden in late-life depression is associated with greater BOLD response on the affective-reactivity task supports the model that white matter ischemia in elderly depressed patients disrupts brain mechanisms of affective regulation and leads to limbic hyperactivation.
PMCID: PMC3656408  PMID: 21799066
Journal of Neuroscience Methods  2012;206(2):176-182.
There is a lack of a neuroimaging biomarker for HIV-Associated Neurocognitive Disorder. We report magnetoencephalography (MEG) data from patients with HIV disease and risk-group appropriate controls that were collected to determine the MEG frequency profile during the resting state, and the stability of the profile over 24 weeks. 17 individuals (10 HIV+, 7 HIV−) completed detailed neurobehavioral evaluations and 10 minutes of resting-state MEG acquisition with a 306-channel whole-head system. The entire evaluation and MEG measurement were repeated 24 weeks later. Relative MEG power in the delta (0–4 Hz), theta (4–7 Hz), alpha (8–12 Hz), beta (12–30 Hz) and low gamma (30–50 Hz) bands was computed for 8 predefined sensor groups. The median stability of resting-state relative power over 24 weeks of follow-up was 0.80 with eyes closed, and 0.72 with eyes open. The relative gamma power in the right occipital (t(15) = 1.99, p < .06, r = −.46) and right frontal (t(15t) = 2.15, p < .05, r = −.48) regions was associated with serostatus. The effect of age on delta power was greater in the seropositive subjects (r2 = .51) than in the seronegative subjects (r2 = .11). Individuals with high theta-to-gamma ratios tended to have lower cognitive test performance, regardless of serostatus. The stability of the wide-band MEG frequency profiles over 24 weeks supports the utility of MEG as a biomarker. The links between the MEG profile, serostatus, and cognition suggest further research on its potential in HAND is needed.
PMCID: PMC3327782  PMID: 22414786
HIV; HIV-Associated Neurocognitive Disorder; Magnetoencephalography (MEG); Magnetic Source Imaging (MSI); Cognition; Reliability; Biomarker
To characterize the functional neuroanatomy of late-life depression (LLD) by probing for both episodic and persistent alterations in the executive-control circuit of elderly adults.
Event-related fMRI data were collected while participants performed an executive-control task.
Participants were recruited through a depression-treatment study within the Pittsburgh Intervention Research Center for Late-Life Mood Disorders.
13 non-depressed elderly comparison participants and 13 LLD patients.
The depressed patients underwent imaging before initiating and after completing 12 weeks of paroxetine.
Regional fMRI activity was assessed in the dorsolateral prefrontal cortex (dLPFC: BA9 and BA46 bilaterally) and the dorsal anterior cingulate cortex (dACC). Functional connectivity was assessed by correlating the fMRI time-series in the dLPFC and dACC.
Both depressed and comparison participants performed the task as expected, with greater response latency during high versus low-load trials. The response-latency load-effect did not differ between groups. In contrast to the null findings for behavioral data, pre-treatment, depressed patients showed diminished activity in the dLPFC (BA46 left, t(25)=1.9, p=.035) and diminished functional connectivity between the dLPFC and dACC. Moreover, right dLPFC (BA46 right, t(25)=2.17, p<.02) showed increased activity after treatment.
These results support a model of both episodic and persistent neurobiologic components of LLD. The altered functional connectivity, perhaps due to vascular damage to frontal white matter, appears to be persistent. Further, at least some of the pre-frontal hypoactivity (in the right dLPFC) appears to be an episodic characteristic of acute depression amenable to treatment.
PMCID: PMC2626170  PMID: 19001356
fMRI; Geriatric depression; Cognitive control
Disability and rehabilitation  2012;34(21):1848-1852.
Mild cognitive deficits associated with HIV disease can affect activities of daily living, so interventions that reduce them may have a long-term effect on quality of life. We evaluated the feasibility of a cognitive stimulation program (CSP) to improve neuropsychological test performance in HIV disease.
60 volunteers (30 HIV-infected) participated. The primary outcome was the change in neuropsychological test performance as indexed by the Global Impairment Rating; secondary outcomes included mood (Brief Symptom Inventory subscales) and quality of life rating (Medical Outcomes Survey-HIV) scales.
52 participants completed all 24 weeks of the study, and 54% of the participants in the CSP group successfully used the system via internet access from their home or other location. There was a significant interaction between usage and study visit such that the participants who used the program most frequently showed significantly greater improvements in cognitive functioning (F(3,46.4)=3.26, p =.030); none of the secondary outcomes were affected by the dose of CSP.
We found it possible to complete an internet-based CSP in HIV-infected individuals; ease of internet access was a key component for success. Participants who used the program most showed improvements in cognitive function over the 24-week period, suggesting that a larger clinical trial of CSP may be warranted.
PMCID: PMC3394884  PMID: 22458375
HIV; Cognition; Internet

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