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.
Functional imaging; structural imaging; white matter hyperintensities; BOLD; aging
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.
associative memory; arterial spin labeling; dorsolateral prefrontal cortex
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.
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.
Bradykinesia; Gait disturbances; Brain MRI
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.
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.
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.
HIV; HIV-Associated Neurocognitive Disorder; Magnetoencephalography (MEG); Magnetic Source Imaging (MSI); Cognition; Reliability; Biomarker
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.
HIV; Cognition; Internet
Background: slower gait in older adults is related to smaller volume of the prefrontal area (PFAv). The pathways underlying this association have not yet been explored. Understanding slowing gait could help improve function in older age. We examine whether the association between smaller PFAv and slower gait is explained by lower performance on numerous neuropsychological tests.
Hypothesis: we hypothesise that slower information processing explains this association, while tests of language or memory will not.
Methods: data on brain imaging, neuropsychological tests (information processing speed, visuospatial attention, memory, language, mood) and time to walk 15 feet were obtained in 214 adults (73.3 years, 62% women) free from stroke and dementia. Covariates included central (white matter hyperintensities, vision) and peripheral contributors of gait (vibration sense, muscle strength, arthritis, body mass index), demographics (age, race, gender, education), as well as markers of prevalent vascular diseases (cardiovascular disease, diabetes and ankle arm index).
Results: in linear regression models, smaller PFAv was associated with slower time to walk independent of covariates. This association was no longer significant after adding information processing speed to the model. None of the other neuropsychological tests significantly attenuated this association.
Conclusions: we conclude that smaller PFAv may contribute to slower gait through slower information processing. Future longitudinal studies are warranted to examine the casual relationship between focal brain atrophy with slowing in information processing and gait.
prefrontal volume; gait speed; information processing; elderly
The aim of this exploratory study is to examine the default-mode network (DMN) functional connectivity pattern in elderly depressed subjects with and without comorbid anxiety.
Functional MRI data were collected for 11 elderly depressed subjects with high comorbid anxiety and 8 elderly depressed subjects with low anxiety. We analyzed the resting connectivity patterns of the posterior cingulate cortex. We compared the DMN activity in the elderly depressed subjects with high versus low comorbid anxiety.
Depressed elderly with high comorbid anxiety had increased functional connectivity in the posterior regions of the DMN and decreased functional connectivity in the anterior regions of the DMN.
Elderly depressed subjects with high anxiety display a dissociative pattern of connectivity in the DMN when compared with elderly depressed subjects with low anxiety. These results suggest a unique biological signature of the anxiety symptoms in the context of late-life depression.
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.
deformable model; atlas-based segmentation; image registration; fMRI
As the incidence of HIV-associated dementia has decreased, the survival of HIV-infected individuals with milder forms of cognitive impairment has increased. Detecting this milder impairment in its earliest stages has great clinical and research importance. We report here the results of an initial evaluation of the Computer Assessment of Mild Cognitive Impairment (CAMCI®), a computerized screening tool designed to assess abnormal cognitive decline with reduced respondent and test administrator burden. Fifty-nine volunteers (29 HIV infected; age=50.9 years; education=14.9 years; 36/59 males) completed the CAMCI® and a battery of neuropsychological tests. The CAMCI was repeated 12 and 24 weeks later. The results from the CAMCI were compared to Global and Domain Impairment scores derived from the full neuropsychological test battery. The CAMCI detected mild impairment (compared with normal and borderline test performance) with a sensitivity of 0.72, specificity of 0.97, positive predictive rate of 0.93, and a negative predictive rate of 0.89. Median stability over 12 and 24 weeks of follow-up was 0.32 and 0.46, respectively. These rates did not differ as a function of serostatus. A discriminant function analysis correctly classified 90% of the subjects with respect to their overall Global Impairment Rating from six of the CAMCI scores. This preliminary study demonstrates that the CAMCI is sensitive to mild forms of cognitive impairment, and is stable over 24 weeks of follow-up. A larger trial to obtain risk-group appropriate normative data will be necessary to make the instrument useful in both clinical practice and research (e.g., clinical trials).
White matter hyperintensities (WMH), commonly found on T2-weighted FLAIR brain MR images in the elderly, are associated with a number of neuropsychiatric disorders, including vascular dementia, Alzheimer’s disease, and late-life depression. Previous MRI studies of WMHs have primarily relied on the subjective and global (i.e., full-brain) ratings of WMH grade. In the current study we implement and validate an automated method for quantifying and localizing WMHs. We adapt a fuzzy connected algorithm to automate the segmentation of WMHs and use a demons-based image registration to automate the anatomic localization of the WMHs using the Johns Hopkins University White Matter Atlas. The method is validated using the brain MR images acquired from eleven elderly subjects with late-onset late-life depression (LLD) and eight elderly controls. This dataset was chosen because LLD subjects are known to have significant WMH burden. The volumes of WMH identified in our automated method are compared with the accepted gold standard (manual ratings). A significant correlation of the automated method and the manual ratings is found (P<0.0001), thus demonstrating similar WMH quantifications of both methods. As has been shown in other studies e.g. (Taylor, et al. 2003)), we found there was a significantly greater WMH burden in the LLD subjects versus the controls for both the manual and automated method. The effect size was greater for the automated method, suggesting that it is a more specific measure. Additionally, we describe the anatomic localization of the WMHs in LLD subjects as well as in the control subjects, and detect the regions of interest (ROIs) specific for the WMH burden of LLD patients. Given the emergence of large neuroimage databases, techniques, such as that described here, will allow for a better understanding of the relationship between WMHs and neuropsychiatric disorders.
White matter hyperintensity; late-onset late-life depression
To evaluate the cause of diagnostic errors in the visual interpretation of positron emission tomography scans with 18F-fluorodeoxyglucose (FDG-PET) in patients with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD).
Twelve trained raters unaware of clinical and autopsy information independently reviewed FDG-PET scans and provided their diagnostic impression and confidence of either FTLD or AD. Six of these raters also recorded whether metabolism appeared normal or abnormal in 5 predefined brain regions in each hemisphere – frontal cortex, anterior cingulate cortex, anterior temporal cortex, temporoparietal cortex and posterior cingulate cortex. Results were compared to neuropathological diagnoses.
Academic medical centers
45 patients with pathologically confirmed FTLD (n=14) or AD (n=31)
Raters had a high degree of diagnostic accuracy in the interpretation of FDG-PET scans; however, raters consistently found some scans more difficult to interpret than others. Unanimity of diagnosis among the raters was more frequent in patients with AD (27/31, 87%) than in patients with FTLD (7/14, 50%) (p = 0.02). Disagreements in interpretation of scans in patients with FTLD largely occurred when there was temporoparietal hypometabolism, which was present in 7 of the 14 FTLD scans and 6 of the 7 lacking unanimity. Hypometabolism of anterior cingulate and anterior temporal regions had higher specificities and positive likelihood ratios for FTLD than temporoparietal hypometabolism had for AD.
Temporoparietal hypometabolism in FTLD is common and may cause inaccurate interpretation of FDG-PET scans. An interpretation paradigm that focuses on the absence of hypometabolism in regions typically affected in AD before considering FTLD is likely to misclassify a significant portion of FTLD scans. Anterior cingulate and/or anterior temporal hypometabolism indicates a high likelihood of FTLD, even when temporoparietal hypometabolism is present. Ultimately, the accurate interpretation of FDG-PET scans in patients with dementia cannot rest on the presence or absence of a single region of hypometabolism, but must take into account the relative hypometabolism of all brain regions.
Population-based brain mapping provides great insight into the trajectory of aging and dementia, as well as brain changes that normally occur over the human life span. We describe three novel brain mapping techniques, cortical thickness mapping, tensor-based morphometry (TBM), and hippocampal surface modeling, which offer enormous power for measuring disease progression in drug trials, and shed light on the neuroscience of brain degeneration in Alzheimer’s disease (AD) and mild cognitive impairment (MCI).We report the first time-lapse maps of cortical atrophy spreading dynamically in the living brain, based on averaging data from populations of subjects with Alzheimer’s disease and normal subjects imaged longitudinally with MRI. These dynamic sequences show a rapidly advancing wave of cortical atrophy sweeping from limbic and temporal cortices into higher-order association and ultimately primary sensorimotor areas, in a pattern that correlates with cognitive decline. A complementary technique, TBM, reveals the 3D profile of atrophic rates, at each point in the brain. A third technique, hippocampal surface modeling, plots the profile of shape alterations across the hippocampal surface. The three techniques provide moderate to highly automated analyses of images, have been validated on hundreds of scans, and are sensitive to clinically relevant changes in individual patients and groups undergoing different drug treatments. We compare time-lapse maps of AD, MCI, and other dementias, correlate these changes with cognition, and relate them to similar time-lapse maps of childhood development, schizophrenia, and HIV-associated brain degeneration. Strengths and weaknesses of these different imaging measures for basic neuroscience and drug trials are discussed.
MRI; Alzheimer’s disease; aging; MCI; dementia; brain degeneration; PET
35% of HIV-infected patients have cognitive impairment, but the profile of HIV-induced brain damage is still not well understood. Here we used tensor-based morphometry (TBM) to visualize brain deficits and clinical/anatomical correlations in HIV/AIDS. To perform TBM, we developed a new MRI-based analysis technique that uses fluid image warping, and a new α-entropy-based information-theoretic measure of image correspondence, called the Jensen–Rényi divergence (JRD).
3D T1-weighted brain MRIs of 26 AIDS patients (CDC stage C and/or 3 without HIV-associated dementia; 47.2 ± 9.8 years; 25M/1F; CD4+ T-cell count: 299.5 ± 175.7/µl; log10 plasma viral load: 2.57 ± 1.28 RNA copies/ml) and 14 HIV-seronegative controls (37.6 ± 12.2 years; 8M/6F) were fluidly registered by applying forces throughout each deforming image to maximize the JRD between it and a target image (from a control subject). The 3D fluid registration was regularized using the linearized Cauchy–Navier operator. Fine-scale volumetric differences between diagnostic groups were mapped. Regions were identified where brain atrophy correlated with clinical measures.
Severe atrophy (~15–20% deficit) was detected bilaterally in the primary and association sensorimotor areas. Atrophy of these regions, particularly in the white matter, correlated with cognitive impairment (P=0.033) and CD4+ T-lymphocyte depletion (P=0.005).
TBM facilitates 3D visualization of AIDS neuropathology in living patients scanned with MRI. Severe atrophy in frontoparietal and striatal areas may underlie early cognitive dysfunction in AIDS patients, and may signal the imminent onset of AIDS dementia complex.
Evidence from longitudinal studies in community-dwelling elderly links complaints of urgency and urinary incontinence with structural white matter changes known as white matter hyperintensities (WMH). How WMH might lead to incontinence remains unknown, since information about how they relate to neural circuits involved in continence control is lacking. The aim of this study was to investigate the role of WMH in altered brain activity in older women with urgency incontinence. In a cross-sectional study, we measured WMH, globally and in specific white matter tracts, and correlated them with regional brain activity measured by fMRI (combined with simultaneous urodynamic monitoring) during bladder filling and reported 'urgency'. We postulated that increase in global WMH burden would be associated with changes (either attenuation or reinforcement) in responses to bladder filling in brain regions involved in bladder control. Secondly, we proposed that such apparent effects of global WMH burden might be specifically related to the burden in a few critical white matter pathways. The results showed that regional activations (e.g. medial/superior frontal gyrus adjacent to dorsal ACG) and deactivations (e.g. perigenual ACG adjacent to ventromedial prefrontal cortex) became more prominent with increased global WMH burden, suggesting that activity aimed at suppressing urgency was augmented. Secondary analyses confirmed that the apparent effect of global WMH burden might reflect the presence of WMH in specific pathways (anterior thalamic radiation and superior longitudinal fasciculus), thus affecting connections between key regions and suggesting possible mechanisms involved in continence control.
Phan et al. (2008) recently reported that an acute dose of oral THC is associated with a decrease in threat-related amygdala reactivity during a social threat stimulus task. However, to date, those findings have not been replicated, and have not been extended to clinical studies involving smoked rather than oral cannabis. In this study, we hypothesized that level of cannabis smoked by participants in our treatment study would be inversely related to the level of threat-related amygdala reactivity. Subjects were recruited from among participants in our double-blind, placebo-controlled trial of fluoxetine in comorbid youth with cannabis dependence/major depression. The threat-related amygdala reactivity task used by Hariri et al. (2009) was completed during BOLD fMRI scans at study baseline and then again 12 weeks later at the end of the trial. Data are available from six subjects with pre-and post-treatment fMRI data. During the course of the study, five of the six subjects demonstrated a decrease in their level of cannabis use, with a mean decrease of 64%, and those persons all demonstrated an increase in their level of amygdala reactivity. One subject demonstrated an increase in their level of cannabis use (a 79% increase) during the treatment trial, and that person demonstrated a decrease in their level of amygdala reactivity. Thus, a higher level of cannabis use was consistently associated with a lower level of amygdala reactivity across all subjects (matched pairs t=2.70, df=5, p<0.05, two-tailed). These findings are consistent with the reports by Phan et al. (Phan et al., 2008) and Hariri et al. (Hariri et al., 2009) suggesting that cannabinoids have an inhibitory effect on threat-related amygdala reactivity.
Dual process theories of recognition memory posit that recollection and familiarity represent dissociable processes. Animal studies and human functional imaging experiments support an anatomic dissociation of these processes in the medial temporal lobes (MTL). By this hypothesis, recollection may be dependent on the hippocampus; while familiarity appears to rely on extrahippocampal MTL (ehMTL) structures, particularly perirhinal and lateral entorhinal cortices. Despite these findings, the dual process model and these anatomic mappings remain controversial, in part because the study of patients with lesions to the MTL has been limited and has revealed predominantly single dissociations. We examined measures of recollection and familiarity in three groups (normal older adults, amnesic-Mild Cognitive Impairment, Alzheimer’s Disease) in which these memory measures and the relative integrity of MTL structures are variable, thus enhancing our power to detect MTL-memory relationships. Recollection and familiarity and volumes of hippocampus and ehMTL, defined as a region including entorhinal/perirhinal cortices and parahippocampus, were measured. Regression analyses revealed a stronger relationship of recollection with the hippocampus compared to ehMTL, while familiarity was more highly related to ehMTL compared to hippocampus. These results are consistent with a division of labor in the MTL and the dual process model.
Here we developed a new method, called multivariate tensor-based surface morphometry (TBM), and applied it to study lateral ventricular surface differences associated with HIV/AIDS. Using concepts from differential geometry and the theory of differential forms, we created mathematical structures known as holomorphic one-forms, to obtain an efficient and accurate conformal parameterization of the lateral ventricular surfaces in the brain. The new meshing approach also provides a natural way to register anatomical surfaces across subjects, and improves on prior methods as it handles surfaces that branch and join at complex 3D junctions. To analyze anatomical differences, we computed new statistics from the Riemannian surface metrics - these retain multivariate information on local surface geometry. We applied this framework to analyze lateral ventricular surface morphometry in 3D MRI data from 11 subjects with HIV/AIDS and 8 healthy controls. Our method detected a 3D profile of surface abnormalities even in this small sample. Multivariate statistics on the local tensors gave better effect sizes for detecting group differences, relative to other TBM-based methods including analysis of the Jacobian determinant, the largest and smallest eigenvalues of the surface metric, and the pair of eigenvalues of the Jacobian matrix. The resulting analysis pipeline may improve the power of surface-based morphometry studies of the brain.
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.
digit symbol substitution score; oldest old; magnetization transfer; diffusion tensor imaging; white matter
To compare the volumes of the caudate nucleus, using traditional volumetry and a three-dimensional brain mapping technique, in a group of individuals with late-life depression and a group of age- and education-equated nondepressed comparison subjects.
University Medical Center
Twenty-three nondemented subjects with late-life depression and 15 age- and education-equated elderly comparison subjects (depressed mean years of age: 70.5 ± 5.7 SD, comparison subjects = 69.9 years ± 6.4) with no history of psychiatric or neurologic disease.
Structural magnetic resonance imaging. Three-dimensional (3-D) surface models were created from manually traced outlines of the caudate nucleus from spoiled gradient echo images. Models were geometrically averaged across subjects and statistical maps created to localize any regional volume differences between groups.
Relative to comparison subjects, depressed subjects had significantly lower mean volumes for both the left (p = 0.029) and right (p = 0.052) caudate nucleus as well as total caudate volume (p = 0.032). Total volumes were 13.1% less in the depressed group (13.5% on the left and 12.6% on the right). 3-D maps further localized these reductions to the caudate head. Volume reductions were correlated with depression severity, as measured by the 17-item Hamilton Depression Rating Scale.
Late-life depression is associated with left and right caudate nucleus reduction especially in anterior portions. Among depressed subjects, greater caudate reduction was associated with more severe depression. These results are consistent with growing evidence that the anterior caudate nucleus, especially the head, may be structurally and functionally abnormal in affective disorders.
Geriatric depression; late-life depression; caudate nucleus
Objective and Methods
The neurobiology of late-life anxious depression (LLAD) is poorly characterized despite evidence that this is a common and severe subtype of late-life depression. To identify the neuroanatomical substrate of late-life anxious depression, we examined event-related fMRI data collected in 8 subjects with late-life depression, half of whom had high levels of comorbid anxiety. Subjects were trained on the Preparing to Overcome Prepotency (POP) task, which is an executive control task that reliably activates the lateral prefrontal cortex - anterior cingulate cortex cognitive control circuit.
Time series analysis showed that, when compared with elderly depressed subjects, elderly subjects with anxious depression performing the POP task produced a significantly greater and more sustained signal in three regions: BA 24 (dorsal anterior cingulate), BA31 (posterior cingulate) and BA6 (prefrontal cortex). While elderly subjects with pure depression presented a bimodal activation curve in the dorsal anterior cingulate and the posterior cingulate, elderly subjects with anxious depression presented a sustained unimodal activation pattern.
Our preliminary results suggest specific activation patterns unique to anxious depression that may suggest greater and more sustained efforts of the ACC to carry out cognitive control tasks. Further research is needed to clarify the neuroanatomical basis of late-life anxious depression.
Late-life anxious depression; fMRI; cognitive control
The amygdalae have been a focus of mood disorder research due to their key role in processing emotional information. It has been long known that depressed individuals demonstrate impaired functional performance while engaged in emotional tasks. The structural basis for these functional differences has been investigated via volumetric analysis with mixed findings. In this study, we examined the morphometric basis for these functional changes in late-life depression (LLD) by analyzing both the size and shape of the amygdalae with the hypothesis that shape differences may be apparent even when overall volume differences are inconsistent.
Magnetic resonance imaging data were acquired from 11 healthy, elderly individuals and 14 depressed, elderly individuals. Amygdalar size was quantified by computing total volume and amygdalar shape was quantified with a shape analysis method that we have developed.
No significant volumetric differences were found for either amygdala. Nevertheless, localized regions of significant shape variation were detected for the left and right amygdalae. The most significant difference was contraction (LLD subjects as compared to control subjects) in a region typically associated with the basolateral nucleus, which plays a key role in emotion recognition in neurobiologic models of depression.
In this LLD study, we have shown that, despite insignificant amygdalar volumetric findings, variations of amygdalar shape can be detected and localized. With further investigation, morphometric analysis of various brain structures may help elucidate the neurobiology associated with LLD and other mood disorders.
morphometry; late-life depression; amygdala; shape analysis; volumetrics
Expansion of the cerebral ventricles may occur at an accelerated rate in subjects with dementia, but the time course of expansion during transitions between normal cognitive function, mild cognitive impairment (MCI), and dementia is not well understood. Furthermore, the effects of cardiovascular risk factors on rate of ventricular expansion are unclear. We used a fully automated segmentation technique to measure change rate in lateral ventricle-to-brain ratio (VBR) on 145 longitudinal pairs of magnetic resonance images of subjects in the Cardiovascular Health Study Cognition Study from the Pittsburgh Center. A multivariate model analyzed VBR change rate, accounting for dementia statuses at both imaging times (normal, MCI, or dementia), age, sex, education, race, magnetic resonance-defined infarcts, Center for Epidemiology Studies Depression Scale, baseline ventricular volume, and cardiovascular risk factors. VBR change was faster in subjects who were demented or transitioned from MCI to dementia, compared with subjects normal at both images and subjects who transitioned from normal to MCI or dementia. Patients with diabetes had faster VBR change. Ventricular expansion may accelerate late in the progression from normal cognitive function to dementia, and may be modulated by diabetes.
dementia; mild cognitive impairment; magnetic resonance imaging; lateral ventricles; automated segmentation