Postmortem MRI: a novel window into the neurobiology of late life cognitive decline

Behavioural Brain Research

Buchman

et al. 2017

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Alterations of the transverse relaxation rate, R2, measured using MRI, are observed in older persons with Alzheimer’s (AD) dementia. However, the spatial pattern of these alterations and the degree to which they reflect the accumulation of common age-related neuropathologies are unknown. In this study, we characterized the profile of R2 alterations in post-mortem brains of persons with clinical diagnosis of AD dementia and investigated how the profile differs after accounting for neuropathologic indices of AD, cerebral infarcts, Lewy body disease, hippocampal sclerosis and transactive response DNA-binding protein 43. Data came from 567 post-mortem brains donated by participants in two cohort studies of aging and dementia. R2 was quantified using fast spin echo imaging. Voxelwise linear regression examined R2 alterations between subjects diagnosed with AD dementia at death and those with no cognitive impairment. Voxels showing significant R2 alterations were clustered into regions of interest (ROIs). Three R2 profiles were compared, which were adjusted for (1) demographics only; (2) demographics and AD pathology; (3) demographics, AD pathology and other common neuropathologies. R2 alterations were observed throughout the hemisphere, most commonly in white matter. Of the distinct ROIs identified, the largest region encompassed large portions of white matter in all lobes. This ROI became smaller in size but remained largely intact after adjusting for AD and other neuropathologic indices. Further, R2 alterations identify AD dementia with improved accuracy, above and beyond demographics and neuropathologic indices (p<0.0001). In conclusion, R2 alterations in AD dementia are not solely reflective of common age-related neuropathologies, suggesting that other mechanisms are at work.

“…This current study extends our previous work (Dawe, et al, 2014, Dawe, et al, 2016) in three important ways. First, we focus on a complementary clinical outcome, i.e.…”

Section: Introductionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 84%

Ex vivo MRI transverse relaxation in community based older persons with and without Alzheimer’s dementia

Behavioural Brain Research

Buchman

et al. 2017

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“…Therefore, we focused on a composite R 2 measure that captures the overall relaxation associated with cognitive decline above and beyond the influence of commonly measured neuropathologic conditions. 11 …”

Section: Methodsmentioning

confidence: 99%

Association Between Brain Gene Expression, DNA Methylation, and Alteration of Ex Vivo Magnetic Resonance Imaging Transverse Relaxation in Late-Life Cognitive Decline

Boyle

et al. 2017

JAMA Neurol

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vivo magnetic resonance imaging transverse relaxation is associated with late-life cognitive decline even after controlling for common neuropathologic conditions. However, the underlying neurobiology of this association is unknown.OBJECTIVE To investigate the association between brain gene expression, DNA methylation, and alteration of magnetic resonance imaging transverse relaxation in late-life cognitive decline.DESIGN, SETTING, AND PARTICIPANTS Data came from 2 community-based longitudinal cohort studies of aging and dementia, the Religious Orders Study, which began in 1993, and the Rush Memory and Aging Project, which began in 1997. All participants agreed to undergo annual clinical evaluations and to donate their brains after death. By October 24, 2016, a total of 1358 individuals had died and had brain autopsies that were approved by board-certified neuropathologists. Of those, 552 had undergone ex vivo imaging. The gene expression analysis was limited to 174 individuals with both imaging and brain RNA sequencing data. The DNA methylation analysis was limited to 225 individuals with both imaging and brain methylation data. MAIN OUTCOMES AND MEASURESMaps of ex vivo magnetic resonance imaging transverse relaxation were generated using fast spin echo imaging. The target was a composite measure of the transverse relaxation rate (R 2 ) that was associated with cognitive decline after controlling for common neuropathologic conditions. Next-generation RNA sequencing and DNA methylation data were generated using frozen tissue from the dorsolateral prefrontal cortex. Genome-wide association analysis was used to investigate gene expression and, separately, DNA methylation for signals associated with the R 2 measure. RESULTSOf the 552 individuals with ex vivo imaging data, 394 were women and 158 were men, and the mean (SD) age at death was 90.4 (6.0) years. Four co-expressed genes (PADI2 [Ensembl ENSG00000117115], ZNF385A [Ensembl ENSG00000161642], PSD2 [Ensembl ENSG00000146005], and A2ML1 [Ensembl ENSG00000166535]) were identified, of which higher expressions were associated with slower R 2 . The association of R 2 with cognitive decline was attenuated when the gene expression signals were added to the model, such that the mean (SE) coefficient of association was reduced from 0.028 (0.008) (P < .001) to 0.019 (0.009) (P = .03). The DNA methylation scan did not detect a genome-wide significant signal, but it revealed an anticorrelation between R 2 and DNA methylation in many of the cytosine-guanine dinucleotides.CONCLUSIONS AND RELEVANCE Brain gene expression and DNA methylation dysregulations are implicated in the alteration of brain tissue properties associated with late-life cognitive decline above and beyond the influence of common neuropathologic conditions.

“…Ex-vivo MRI scans show high correlation with antemortem imaging (Dawe et al 2016) and were conducted on a 3 Tesla MRI scanner using a 2D fast spin-echo sequence with multiple echo-times (TEs), producing estimates of relaxation rates (R 2 ) for each voxel. R 2 values are the inverse of T 2 values.…”

Section: Neuroimaging Data Processingmentioning

confidence: 99%

“…We followed an imaging omics approach to discover relationships between omics and neuroimaging, using~200 brains with paired omics and ex-vivo neuroimaging Dawe et al 2009;Dawe et al 2016;Kotrotsou et al 2014;Kotrotsou et al 2015), from two longitudinal cohort studies of aging Bennett et al 2005). Our approach to finding relationships between brain omics and structure is analogous to typical neuroimaging studies and imaging genetics studies (Fig.…”

Section: Introductionmentioning

confidence: 99%

Gene expression and DNA methylation are extensively coordinated with MRI-based brain microstructural characteristics

Gaiteri

Brain Imaging and Behavior

Mostafavi

et al. 2018

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Cognitive function relies on both molecular levels and cellular structures. However, systematic relationships between these two components of cognitive function, and their joint contribution to disease, are largely unknown. We utilize postmortem neuroimaging in tandem with gene expression and DNA methylation, from 222 deeply-phenotyped persons in a longitudinal aging cohort. Expression of hundreds of genes and methylation at thousands of loci are related to the microstructure of extensive regions of this same set of brains, as assessed by MRI. The genes linked to brain microstructure perform functions related to cell motility, transcriptional regulation and nuclear processes, and are selectively associated with Alzheimer's phenotypes. Similar methodology can be applied to other diseases to identify their joint molecular and structural basis, or to infer molecular levels in the brain on the basis of neuroimaging for precision medicine applications.