Minjie Wu

A fully automated method for quantifying and localizing white matter hyperintensities on MR images

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, Alzheimers 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, W.D., MacFall, J.R., Steffens, D.C., Payne, M.E., Provenzale, J.M., Krishnan, K.R., 2003. Localization of age-associated white matter hyperintensities in late-life depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 27 (3), 539-544.]), 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.

Altered Functioning of The Executive Control Circuit in Late-Life Depression: Episodic and Persistent Phenomena

OBJECTIVE 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. DESIGN Event-related functional magnetic resonance imaging (fMRI) data were collected while participants performed an executive-control task. SETTING Participants were recruited through a depression-treatment study within the Pittsburgh, PA, Intervention Research Center for Late-Life Mood Disorders. PARTICIPANTS Thirteen nondepressed elderly comparison participants and 13 LLD patients. INTERVENTION The depressed patients underwent imaging before initiating and after completing 12 weeks of paroxetine. MEASUREMENTS 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. RESULTS 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, pretreatment, depressed patients showed diminished activity in the dLPFC (BA46 left, t(25)=1.9, p = 0.035) and diminished functional connectivity between the dLPFC and dACC. Moreover, right dLPFC (BA46 right, t(25)=2.17, p < 0.02) showed increased activity after treatment. CONCLUSIONS 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 prefrontal hypoactivity (in the right dLPFC) seems to be an episodic characteristic of acute depression amenable to treatment.

Gray Matter Changes in Late Life Depression—a Structural MRI Analysis

Multiple brain morphometric changes have been reported in late-life depression (LLD), mostly in studies comparing volumes of circumscribed brain areas. The aim of our study is to characterize the volumetric changes of multiple gray matter regions in relation to age of onset/duration of illness. We predicted that the association of gray matter volumes with total duration of illness and age of onset would differ depending on whether the region was susceptible to the toxic effects of chronic exposure to cortisol or to the vascular/neurodegenerative changes accompanying prodromal dementia. Seventy-one elderly depressed subjects were studied along with thirty-two comparison subjects. High-resolution T1-weighted brain MRIs were processed using an automated labeling pathway technique. To protect against type-I error, we combined the right and left hemisphere volume data. We sampled 24 regions of interest (ROIs). We used the primary visual cortex volume to normalize for individual variations in brain size. LLD Subjects had smaller volumes than non-depressed subjects in 17 of the 24 examined ROIs. Shorter duration of illness and later age of onset was correlated with smaller volumes of parahippocampal area and parietal inferior area. A later age of onset was also correlated with smaller volumes of several frontal and temporal areas, cingulum, and putamen. Our findings support a dementia prodrome model more strongly than a toxic stress model in this group of subjects. However, it remains likely that both processes as well as other factors contribute to the heterogeneity of volumetric brain changes in LLD.

Default-mode network connectivity and white matter burden in late-life depression

The brains default-mode network has been the focus of intense research. This study characterizes the default-mode network activity in late-life depression and the correlation of the default-mode network activity changes with the white-matter hyperintensities burden. We hypothesized that elderly depressed subjects would have altered default-mode network activity, which would correlate with the increased white-matter hyperintensities burden. Twelve depressed subjects (mean Hamilton Depression Rating Scale 19.8±4.1, mean age 70.5±4.9) and 12 non-depressed, comparison subjects (mean age 69±6.5) were included. Functional magnetic resonance imaging (fMRI) data were collected while subjects performed a low cognitive load, event-related task. We compared the default-mode network activity in these groups (including depressed subjects pre- and post-antidepressant treatment). We analyzed the resting connectivity patterns of the posterior cingulate cortex. Deconvolution was used to evaluate the correlation of resting-state connectivity scores with the white-matter hyperintensities burden. Compared with non-depressed elderly, depressed subjects pretreatment had decreased connectivity in the subgenual anterior cingulate cortex and increased connectivity in the dorsomedial prefrontal cortex and the orbito-frontal cortex. The abnormal connectivity was significantly correlated with the white-matter hyperintensities burden. Remitted elderly depressed subjects had improved functional connectivity compared to pretreatment, although alterations persisted in the anterior cingulate and the prefrontal cortex when remitted elderly depressed subjects were compared with non-depressed elderly. Our study provides evidence for altered default-mode network connectivity in late-life depression. The correlation between white-matter hyperintensities burden and default-mode network connectivity emphasizes the role of vascular changes in late-life depression etiopathogenesis.

Quantitative comparison of AIR, SPM, and the fully deformable model for atlas-based segmentation of functional and structural MR images

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. Hum Brain Mapp, 2006.

The Default Mode Network In Late-Life Anxious Depression

OBJECTIVE 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. METHODS Functional magnetic resonance imaging data were collected for 11 elderly depressed subjects with high comorbid anxiety and eight 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. RESULTS 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. CONCLUSIONS 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 biologic signature of the anxiety symptoms in the context of late-life depression.

Focal Atrophy and Cerebrovascular Disease Increase Dementia Risk among Cognitively Normal Older Adults

Background and Purpose. This study investigated the association of medial temporal lobe (MTL) atrophy and cerebrovascular disease (white matter hyperintensities [WMH], subclinical infarcts) with the risk of developing Alzheimers disease (AD) among cognitively normal older adults. Methods. Risk of developing AD was examined for 155 cognitively normal older adults (77.4 years, 60% women, 81% white). The MTL volumes and the presence of WMH and of subclinical infarcts were determined from brain magnetic resonance imaging (MRI) at the beginning of the study. Follow‐up cognitive evaluations (average 4.3 years) identified those who developed AD. Results. The presence of either MTL atrophy or subclinical infarcts was independently and significantly associated with a greater risk to develop AD (OR [95% CI]: 4.4 [1.5, 12.3] and 2.7 [1.0, 7.1], respectively). In addition, those participants with both MTL atrophy and at least one brain infarct had a 7‐fold increase in the risk of developing AD (OR [95% CI]: 7.0 [1.5, 33.1]), compared to those who had neither of these conditions. Conclusions. In cognitively normal older adults, markers of neurodegeneration (as reflected by MTL atrophy) and of cerebrovascular disease (as reflected by infarcts on MRI) independently contribute to the risk to develop AD.