Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is associated with abnormalities in white matter structural integrity and connectivity: An ex-vivo diffusion MRI and pathology investigation.

Limbic predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is common in older adults and is associated with neurodegeneration, cognitive decline and dementia. In this MRI and pathology investigation we tested the hypothesis that LATE-NC is associated with abnormalities in white matter structural integrity and connectivity of a network of brain regions typically harboring TDP-43 inclusions in LATE, referred to here as the "LATE-NC network". Ex-vivo diffusion MRI and detailed neuropathological data were collected on 184 community-based older adults. Linear regression revealed an independent association of higher LATE-NC stage with lower diffusion anisotropy in a set of white matter connections forming a pattern of connectivity that is consistent with the stereotypical spread of this pathology in the brain. Graph theory analysis revealed an association of higher LATE-NC stage with weaker integration and segregation in the LATE-NC network. Abnormalities were significant in stage 3, suggesting that they are detectable in later stages of the disease. Finally, LATE-NC network abnormalities were associated with faster cognitive decline, specifically in episodic and semantic memory.

High resolution 0.5mm isotropic T1-weighted and diffusion tensor templates of the brain of non-demented older adults in a common space for the MIITRA atlas.

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.

Development of high quality T1-weighted and diffusion tensor templates of the older adult brain in a common space.

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.

Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is associated with lower R2 relaxation rate: an ex-vivo MRI and pathology investigation.

Limbic predominant age-related transactive response DNA binding protein 43 (TDP-43) encephalopathy neuropathological change (LATE-NC) is common in persons older than 80 years of age and is associated with cognitive decline and increased likelihood of dementia. The MRI signature of LATE-NC has not been fully determined. In this study, the association of LATE-NC with the transverse relaxation rate, R2, was investigated in a large number of community-based older adults. Cerebral hemispheres from 738 participants of the Rush Memory and Aging Project, Religious Orders Study, and Minority Aging Research Study, were imaged ex-vivo with multi-echo spin-echo MRI and underwent detailed neuropathologic examination. Voxel-wise analysis revealed a novel spatial pattern of lower R2 for higher LATE-NC stage, controlling for other neuropathologies and demographics. This pattern was consistent with the distribution of LATE-NC in gray matter, and also involved white matter providing temporo-temporal, fronto-temporal, and temporo-basal ganglia connectivity. Furthermore, analysis at different LATE-NC stages showed that R2 imaging may capture the general progression of LATE-NC, but only when TDP-43 inclusions extend beyond the amygdala.

Development and evaluation of a high resolution 0.5mm isotropic T1-weighted template of the older adult brain.

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.

Development and evaluation of a high performance T1-weighted brain template for use in studies on older adults.

Τhe accuracy of template-based neuroimaging investigations depends on the template's image quality and representativeness of the individuals under study. Yet a thorough, quantitative investigation of how available standardized and study-specific T1-weighted templates perform in studies on older adults has not been conducted. The purpose of this work was to construct a high-quality standardized T1-weighted template specifically designed for the older adult brain, and systematically compare the new template to several other standardized and study-specific templates in terms of image quality, performance in spatial normalization of older adult data and detection of small inter-group morphometric differences, and representativeness of the older adult brain. The new template was constructed with state-of-the-art spatial normalization of high-quality data from 222 older adults. It was shown that the new template (a) exhibited high image sharpness, (b) provided higher inter-subject spatial normalization accuracy and (c) allowed detection of smaller inter-group morphometric differences compared to other standardized templates, (d) had similar performance to that of study-specific templates constructed with the same methodology, and (e) was highly representative of the older adult brain.

Exploring the unknown: electrophysiological and behavioural measures of visuospatial learning.

Visuospatial memory describes our ability to temporarily store and manipulate visual and spatial information and is employed for a wide variety of complex cognitive tasks. Here, a visuospatial learning task requiring fine motor control is employed to investigate visuospatial learning in a group of typically developing adults. Electrophysiological and behavioural data are collected during a target location task under two experimental conditions: Target Learning and Target Cued. Movement times (MTs) are employed as a behavioural metric of performance, while dynamic P3b amplitudes and power in the alpha band (approximately 10 Hz) are explored as electrophysiological metrics during visuospatial learning. Results demonstrate that task performance, as measured by MT, is highly correlated with P3b amplitude and alpha power at a consecutive trial level (trials 1-30). The current set of results, in conjunction with the existing literature, suggests that changes in P3b amplitude and alpha power could correspond to different aspects of the learning process. Here it is hypothesized that changes in P3b correspond to a diminishing inter-stimulus interval and reduced stimulus relevance, while the corresponding changes in alpha power represent an automation of response as habituation occurs in participants. The novel analysis presented in the current study demonstrates how gradual electrophysiological changes can be tracked during the visuospatial learning process under the current paradigm.