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.
BackgroundLimbic predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is now recognized as a common neuropathological disorder of the aging brain and is associated with accelerated cognitive decline. However, the MRI signature of LATE‐NC has not been fully determined. In this work, we hypothesized that abnormalities in white matter (WM) structural integrity caused by LATE‐NC may be detected by means of diffusion tensor imaging (DTI).MethodThis study included 148 individuals participating in Rush Memory and Aging Project, and Religious Orders Study (Fig.1). Ex‐vivo DTI images were acquired using 3T scanners, followed by detailed histopathologic examination by a board‐certified neuropathologist (Fig.2). As a post‐processing step, fractional anisotropy (FA) maps generated from DTI images were aligned to an ex‐vivo FA template and projected onto the corresponding WM skeleton.Voxel‐wise analysis was performed on the WM skeleton to investigate the association of FA with LATE‐NC, controlling for Alzheimer’s disease, Lewy bodies, cerebral amyloid angiopathy, cerebral infarcts, atherosclerosis, arteriolosclerosis, age at death, sex, years of education, postmortem interval to fixation and imaging, total white matter hyperintensity volume, and scanner. Statistical significance was set at p<0.05. Using the voxels that showed significance in this analysis, (1) probable WM connections passing through them were extracted, (2) FA values were compared between LATE‐NC stages 1, 2, 3 and stage 0 (after adjusting for covariates).ResultVoxel‐wise analysis revealed lower FA for greater LATE‐NC burden in medial temporal lobe WM (Fig.3). The connections traversing this WM region included fibers connecting amygdala, temporal pole, hippocampus, entorhinal cortex, fusiform, insula, and putamen (Fig.4). No voxel showed positive association between FA and LATE‐NC. Comparison of adjusted FA values in medial temporal lobe WM across LATE‐NC stages revealed significant FA anomalies between stages 0 and 3 (ΔFA=‐0.06, FDR‐corrected p<10‐6) (Fig.5).ConclusionThe present study in autopsied brains of community‐based older adults showed lower diffusion anisotropy with greater LATE‐NC burden involving WM connections between regions consistent with the known distribution of LATE‐NC. Overall, this pattern may potentially contribute towards the development of an in‐vivo tool for the prediction of this devastating, recently recognized disease entity.
BackgroundNeurofibrillary tangles, one of the hallmark pathologies of Alzheimer’s disease, are closely related to brain atrophy and cognitive decline. The purpose of this work was to develop an MRI‐based classifier of neurofibrillary tangles by combining ex‐vivo MRI and neuropathology in brain autopsies from a large number of community‐based older adults.MethodCerebral hemispheres from 878 older adults participating in three longitudinal, clinical pathologic cohort studies of aging: the Rush Memory and Aging Project (MAP), the Religious Orders Study (ROS), and the Minority Aging Research Study (MARS) (Fig. 1) were included in this work. All hemispheres were imaged at room temperature while immersed in 4% formaldehyde solution using clinical 3T MRI scanners, once within 24 hours postmortem and a second time approximately 30 days postmortem followed by detailed neuropathologic examination.An SVM classifier with l2 regularization was trained to distinguish participants at a Braak stage of V‐VI from those at a Braak stage of 0‐IV, based on features extracted from ex‐vivo MRI as well as demographic information (age, sex). The MRI features included volumetric, cortical thickness, subcortical shape, diffusion, and R2 measurements. When a feature contained multiple measurements per person, they were used to train a separate model that generated a separate risk score which was used as a feature in the final model. Because different groupings of features were available on different subgroups of the participants, the performance of the classifier was tested in a total of 74 participants (Fig. 2) that had measurements on all features.ResultThe average AUC of the classifier based on all MRI and demographic features was 0.87 with 82% mean sensitivity and 77% mean specificity (Fig. 3). In comparison, recently published work combining in‐vivo MRI and pathology data trained an MRI‐based classifier of people at Braak stage V‐VI vs. 0‐II and achieved an AUC=0.69 [1].ConclusionSuccessful completion of ex‐vivo to in‐vivo translation of our work may result in a non‐invasive classifier of neurofibrillary tangles aiding in refined participant selection and targeted therapies. Reference: [1] Dallaire‐Théroux, Caroline et al., Braak neurofibrillary tangle staging prediction from in vivo MRI metrics, Alzheimer's & dementia, vol. 11, 2019.
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