Reporting white matter findings in voxel-wise neuroimaging studies typically lacks specificity in terms of brain connectivity. Therefore, the purpose of this work was to develop an approach for ...rapidly extracting standardized brain connectivity information for white matter regions with significant findings in voxel-wise neuroimaging studies. The new approach was named regionconnect and is based on precalculated average healthy adult brain connectivity information stored in standard space in a fashion that allows fast retrieval and integration. Towards this goal, the present work first generated and evaluated the white matter connectome of the IIT Human Brain Atlas v.5.0. It was demonstrated that the edges of the atlas connectome are representative of those of individual participants of the Human Connectome Project in terms of the spatial organization of streamlines and spatial patterns of track-density. Next, the new white matter connectome was used to develop multi-layer, connectivity-based labels for each white matter voxel of the atlas, consistent with the fact that each voxel may contain axons from multiple connections. The regionconnect algorithm was then developed to rapidly integrate information contained in the multi-layer labels across voxels of a white matter region and to generate a list of the most probable connections traversing that region. Usage of regionconnect does not require high angular resolution diffusion MRI or any MRI data. The regionconnect algorithm as well as the white matter tractogram and connectome, multi-layer, connectivity-based labels, and associated resources developed for the IIT Human Brain Atlas v.5.0 in this work are available at www.nitrc.org/projects/iit. An interactive, online version of regionconnect is also available at www.iit.edu/~mri.
The ageing brain is vulnerable to a wide array of neuropathologies. Prior work estimated that the three most studied of these, Alzheimer's disease, infarcts, and Lewy bodies, account for ∼40% of the ...variation in late life cognitive decline. However, that estimate did not incorporate many other diseases that are now recognized as potent drivers of cognitive decline e.g. limbic predominant age-related TDP-43 encephalopathy (LATE-NC), hippocampal sclerosis, other cerebrovascular conditions. We examined the degree to which person-specific cognitive decline in old age is driven by a wide array of neuropathologies. Deceased participants (n = 1164) from two longitudinal clinical-pathological studies, the Rush Memory and Aging Project and Religious Orders Study, completed up to 24 annual evaluations including 17 cognitive performance tests and underwent brain autopsy. Neuropathological examinations provided 11 pathological indices, including markers of Alzheimer's disease, non- Alzheimer's disease neurodegenerative diseases (i.e. LATE-NC, hippocampal sclerosis, Lewy bodies), and cerebrovascular conditions (i.e. macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis, and arteriolosclerosis). Mixed effects models examined the linear relation of pathological indices with global cognitive decline, and random change point models examined the relation of the pathological indices with the onset of terminal decline and rates of preterminal and terminal decline. Cognition declined an average of about 0.10 unit per year (estimate = -0.101, SE = 0.003, P < 0.001) with considerable heterogeneity in rates of decline (variance estimate for the person-specific slope of decline was 0.0094, P < 0.001). When considered separately, 10 of 11 pathological indices were associated with faster decline and accounted for between 2% and 34% of the variation in decline, respectively. When considered simultaneously, the 11 pathological indices together accounted for 43% of the variation in decline; Alzheimer's disease-related indices accounted for 30-36% of the variation, non-Alzheimer's disease neurodegenerative indices 4-10%, and cerebrovascular indices 3-8%. Finally, the 11 pathological indices combined accounted for less than a third of the variation in the onset of terminal decline (28%) and rates of preterminal (32%) and terminal decline (19%). Although age-related neuropathologies account for a large proportion of the variation in late life cognitive decline, considerable variation remains unexplained even after considering a wide array of neuropathologies. These findings highlight the complexity of cognitive ageing and have important implications for the ongoing effort to develop effective therapeutics and identify novel treatment targets.
Sporadic cerebral small vessel disease (SVD) is a major contributor to vascular cognitive impairment and dementia in the aging human brain. On neuropathology, sporadic SVD is characterized by ...abnormalities to the small vessels of the brain predominantly in the form of cerebral amyloid angiopathy and arteriolosclerosis. These pathologies frequently coexist with Alzheimer disease changes, such as plaques and tangles, in a single brain. Conversely, during life, magnetic resonance imaging (MRI) only captures the larger manifestations of SVD in the form of parenchymal brain abnormalities. There appears to be a major knowledge gap regarding the underlying neuropathology of individual MRI-detectable SVD abnormalities. Ex vivo MRI in postmortem human brain tissue is a powerful tool to bridge this gap. This review summarizes current insights into the histopathologic correlations of MRI manifestations of SVD, their underlying cause, presumed pathophysiology, and associated secondary tissue injury. Moreover, we discuss the advantages and limitations of ex vivo MRI-guided histopathologic investigations and make recommendations for future studies.
Recent reports suggest declines in the age-specific risk of Alzheimer’s dementia in higher income Western countries. At the same time, investigators believe that worldwide trends of increasing ...mid-life modifiable risk factors e.g., cardiovascular disease (CVD) risk factors coupled with the growth of the world's oldest age groups may nonetheless lead to an increase in Alzheimer’s dementia. Thus, understanding the overlap in neuroanatomical profiles associated with CVD risk factors and AD may offer more relevant targets for investigating ways to reduce the growing dementia epidemic than current targets specific to isolated AD-related neuropathology. We hypothesized that a core group of common brain structural alterations exist between CVD risk factors and Alzheimer’s dementia. Two co-authors conducted independent literature reviews in PubMed using search terms for CVD risk factor burden (separate searches for ‘cardiovascular disease risk factors’, ‘hypertension’, and ‘Type 2 diabetes’) and ‘aging’ or ‘Alzheimer’s dementia’ with either ‘grey matter volumes’ or ‘white matter’. Of studies that reported regionally localized results, we found support for our hypothesis, determining 23 regions commonly associated with both CVD risk factors and Alzheimer’s dementia. Within this context, we outline future directions for research as well as larger cerebrovascular implications for these commonalities. Overall, this review supports previous as well as more recent calls for the consideration that both vascular and neurodegenerative factors contribute to the pathogenesis of dementia.
•High quality 0.5 mm T1w and DTI templates of the older adult brain were constructed.•Data from a diverse, community cohort of 400 non-demented older adults were used.•The new templates are ...well-matched in space.•The new templates are most representative of the brain of non-demented older adults.•The new templates showed high performance when used as references for normalization.
High quality, high resolution T1-weighted (T1w) and diffusion tensor imaging (DTI) brain templates located in a common space can enhance the sensitivity and precision of template-based neuroimaging studies. However, such multimodal templates have not been constructed for the older adult brain. The purpose of this work which is part of the MIITRA atlas project was twofold: (A) to develop 0.5 mm isotropic resolution T1w and DTI templates that are representative of the brain of non-demented older adults and are located in the same space, using advanced multimodal template construction techniques and principles of super resolution on data from a large, diverse, community cohort of 400 non-demented older adults, and (B) to systematically compare the new templates to other standardized templates. It was demonstrated that the new MIITRA-0.5mm T1w and DTI templates are well-matched in space, exhibit good definition of brain structures, including fine structures, exhibit higher image sharpness than other standardized templates, and are free of artifacts. The MIITRA-0.5mm T1w and DTI templates allowed higher intra-modality inter-subject spatial normalization precision as well as higher inter-modality intra-subject spatial matching of older adult T1w and DTI data compared to other available templates. Consequently, MIITRA-0.5mm templates allowed detection of smaller inter-group differences for older adult data compared to other templates. The MIITRA-0.5mm templates were also shown to be most representative of the brain of non-demented older adults compared to other templates with submillimeter resolution. The new templates constructed in this work constitute two of the final products of the MIITRA atlas project and are anticipated to have important implications for the sensitivity and precision of studies on older adults.
Investigating the structure of the older adult brain at high spatial resolution is of high significance, and a dedicated older adult structural brain template with sub-millimeter resolution is ...currently lacking. Therefore, the purpose of this work was twofold: (A) to develop a 0.5mm isotropic resolution standardized T1-weighted template of the older adult brain by applying principles of super resolution to high quality MRI data from 222 older adults (65–95 years of age), and (B) to systematically compare the new template to other standardized and study-specific templates in terms of image quality and performance when used as a reference for alignment of older adult data. The new template exhibited higher spatial resolution and improved visualization of fine structural details of the older adult brain compared to a template constructed using a conventional template building approach and the same data. In addition, the new template exhibited higher image sharpness and did not contain image artifacts observed in some of the other templates considered in this work. Due to the above enhancements, the new template provided higher inter-subject spatial normalization precision for older adult data compared to the other templates, and consequently enabled detection of smaller inter-group morphometric differences in older adult data. Finally, the new template was among those that were most representative of older adult brain data. Overall, the new template constructed here is an important resource for studies of aging, and the findings of the present work have important implications in template selection for investigations on older adults.
High-quality T1-weighted (T1w) and diffusion tensor imaging (DTI) brain templates that are representative of the individuals under study enhance the accuracy of template-based neuroimaging ...investigations, and when they are also located in a common space they facilitate optimal integration of information on brain morphometry and diffusion characteristics. However, such multimodal templates have not been constructed for the brain of older adults. The purpose of this work was threefold: (A) to introduce an iterative method for construction of multimodal T1w and DTI templates that aims at maximizing the quality of each template separately as well as the spatial matching between templates, (B) to use this method to develop T1w and DTI templates of the older adult brain in a common space, and (C) to evaluate the performance of the method across iterations and compare it to the performance of state-of-the-art approaches based on multichannel registration. It was demonstrated that more iterations of the proposed method enhanced the characteristics and spatial matching of the resulting T1w and DTI templates. The templates of the older adult brain generated by the final iteration of the proposed method provided better delineation of brain structures, higher discriminability between tissues, and higher image sharpness near the cortex compared to templates generated with approaches employing multichannel registration. In addition, the spatial matching between the T1w and DTI templates constructed by the proposed method approximated the template alignment achieved with methods employing multichannel registration. Finally, when using the templates generated by the proposed method as references for spatial normalization of older adult T1w and DTI data, both the intra-modality inter-subject normalization precision and the inter-modality spatial matching were higher in most metrics than those achieved with templates constructed with other methods. Overall, the present work brought new insights into multimodal template construction, generated much-needed high quality T1w and DTI templates of the older adult brain in a common space, and conducted a thorough, quantitative evaluation of available multimodal template construction methods.
To investigate the contribution of Alzheimer disease (AD) vs non-AD neuropathologies to hippocampal atrophy.
The Religious Orders Study and Rush Memory and Aging Project are clinicopathologic cohort ...studies of aging. The current study included 547 participants who had undergone brain autopsy and postmortem hippocampal volume measurement by November 1, 2018. Hippocampal volume was measured with postmortem MRI via a 3D region of interest applied to the hippocampal formation. Neuropathologies were measured via uniform structured evaluations. Linear regression analyses estimated the proportion of variance of hippocampal volume attributable to AD and non-AD neuropathologies.
The average age at death was 90 years, and the average hippocampal volume was 2.1 mL. AD, transactive response DNA-binding protein 43 (TDP), hippocampal sclerosis (HS), and atherosclerosis were associated with hippocampal volume. After demographics and total hemisphere volume were controlled for, 7.0% of the variance (95% bootstrapped confidence interval CI 4.3%-10.5%) of hippocampal volume was attributable to AD pathology. TDP/HS explained an additional 4.5% (95% CI 2.2%-7.6%). Among individuals with Alzheimer dementia (n = 232), 3.1% (95% CI 0.6%-7.7%) of the variance was attributable to AD pathology, and TDP/HS explained an additional 6.1% (95% CI 2.2%-11.6%). Among those without Alzheimer dementia (n = 307), 3.2% (95% CI 0.9%-7.3%) of the variance was attributable to AD pathology, and TDP/HS explained an additional 1.1%, which did not reach statistical significance. Lewy bodies and vascular diseases had modest contribution to the variance of hippocampal volume.
Both AD and TDP/HS contribute to hippocampal volume loss in older-old persons, with TDP/HS more strongly associated with hippocampal volume than AD in Alzheimer dementia.
Background Individuals with generalized social anxiety disorder (GSAD) exhibit exaggerated amygdala reactivity to aversive social stimuli. These findings could be explained by microstructural ...abnormalities in white matter (WM) tracts that connect the amygdala and prefrontal cortex, which is known to modulate the amygdala's response to threat. The goal of this study was to investigate brain frontal WM abnormalities using diffusion tensor imaging (DTI) in patients with social anxiety disorder. Methods A Turboprop DTI sequence was used to acquire diffusion tensor images in 30 patients with GSAD and 30 matched healthy control subjects. Fractional anisotropy, an index of axonal organization, within WM was quantified in individual subjects, and an automated voxel-based, whole-brain method was used to analyze group differences. Results Compared with healthy control subjects, patients had significantly lower fractional anisotropy localized to the right uncinate fasciculus WM near the orbitofrontal cortex. There were no areas of higher fractional anisotropy in patients than controls. Conclusions These findings point to an abnormality in the uncinate fasciculus, the major WM tract connecting the frontal cortex to the amygdala and other limbic temporal regions, in GSAD, which could underlie the aberrant amygdala-prefrontal interactions resulting in dysfunctional social threat processing in this illness.
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