Synopsis

Perivascular spaces are fluid-filled spaces surrounding blood vessels as they penetrate the brain, forming a brain fluid drainage system that facilitates interstitial fluid exchange and clearance of waste products. Enlargement of perivascular spaces is common in aging, and literature has linked enlarged perivascular spaces (EPVS) to increased risk of stroke, lower cognitive function, and vascular dementia. The links of EPVS burden to age-related neuropathologies have not yet been thoroughly investigated. Therefore, the purpose of this work was to assess the neuropathologic correlates of EPVS by combining ex-vivo MRI and pathology data in a large community cohort of 625 older adults.

INTRODUCTION:

METHODS:

Cerebral hemispheres were obtained from 625 deceased participants of the Rush Memory and Aging Project^[14] and Religious Orders Study^[15], two longitudinal, epidemiologic clinical-pathologic cohort studies of aging. All hemispheres were imaged on clinical 3T MRI scanners while immersed in 4% formaldehyde solution, with an average postmortem interval to fixation PMI_f≈9 hours, and an average postmortem interval to imaging PMI_i≈39 days (Fig.1). Following ex-vivo MRI, all hemispheres underwent neuropathologic examination by a board-certified neuropathologist blinded to clinical and imaging findings^[16]-[20]. The pathologies assessed included: gross and microscopic infarcts, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, amyloid plaques, neurofibrillary tangles, hippocampal sclerosis, Lewy bodies, and TDP-43. Two experienced observers blinded to all pathologic and clinical data rated EPVS burden in the basal ganglia and white matter throughout the whole brain based on T2-weighted ex-vivo MRI data, using a semiquantitative four-level scale (none=0, mild=1, moderate=2, severe=3) (Fig.2). Intra-rater and inter-rater reliability were assessed using the intraclass correlation (ICC). Statistical analysis involved a two-step process, including univariate logistic regression where EPVS burden was the dependent variable and each pathology was the independent variable, followed by multivariate logistic regression where EPVS burden was the dependent variable and all pathologies where considered in the same model as independent variables, also controlling for age, sex, education, PMI_f, PMI_i, and scanners.

RESULTS:

Participants’ age at the time of death was [65.9-108.3 years] with a mean of 90.1±6.5 years, and 28% of the participants were male (Fig.1). Both intra-rater (ICC=0.88) and inter-rater reliability (ICC=0.75) for EPVS rating were good^[21]. The distribution of EPVS scores of 0 to 3 among participants of this community cohort was 6 (1%), 281 (45%), 164 (26%) and 174 (28%) participants, respectively. Due to the small number of participants with a score of 0, scores of 0 and 1 were merged into one level. Univariate analyses showed significant association of EPVS burden with gross infarcts (OR=1.66, p-value<0.001) and TDP-43 pathology (OR=0.86, p-value=0.024). Multivariate logistic regression considering all pathologies and covariates showed a significant association of EPVS burden with gross infarcts (OR=1.67, p=0.002).

DISCUSSION:

The present work demonstrated that EPVS burden is associated with gross infarcts in a community cohort of older adults. This suggests that the two abnormalities may share similar neurobiological pathways. It has been suggested that stiffening of the arterioles in small-vessel disease impairs interstitial fluid drainage along PVS and causes EPVS, and that ischemia might occur secondary to endothelial dysfunction and impaired autoregulation in stiffened vessels unable to respond to vasodilatory stimuli during exertion^[22].

The work presented here is the largest investigation on the neuropathologic correlates of EPVS in a community cohort. Other strengths of this work include the combination of MRI with histopathology which provides the gold standard when studying age-related neuropathologies, the comprehensive list of neuropathologies investigated, and the use of ex-vivo MRI which eliminates the possibility of additional pathology developing in the time interval between imaging and autopsy.

CONCLUSION:

Acknowledgements

References

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