Validation of external and internal exposome of the findings associated to cerebral small vessel disease: A Mendelian randomization study

The exposome characterizes all environmental exposures and their impact on a disease. To determine the causally-associated components of the exposome for cerebral small vessel disease (CSVD), we performed mendelian randomization analysis of 5365 exposures on six clinical and subclinical CSVD measures. We found statistically significant evidence (FDR-corrected P < 0.05) that hypertension, high cholesterol, longer television-watching time, lower educational qualifications, younger age of first sexual intercourse, smoking, reduced pulmonary function, higher subjective overall health rating, and frequent tiredness were associated with increased risk of intracerebral hemorrhage or small vessel stroke. Adiposity, diabetes, frequent alcoholic drinks, higher white blood cell count and neutrophil count were significantly associated with higher risk of non-lobar hemorrhage or small vessel stroke, but not lobar hemorrhage. Hypertension, higher arm or leg fat-free mass and higher sitting height were significantly associated with higher white matter hyperintensities. The results were robust to sensitivity analyses and showed no evidence of horizontal pleiotropy. We also identified 41 exposures suggestively associated (uncorrected P < 0.05) with multiple CSVD measures as the “the CSVD exposome”. This exposome-wide association study provides insight into CSVD development and prevention.

Theta Oscillation and Functional Connectivity Alterations Related to Cerebral Small Vessel Disease with Working Memory Impairment

Background Impaired working memory (WM) is an important clinical symptom of cognitive dysfunction associated with cerebral small vessel disease (CSVD). Theta oscillations play an important role in the regulation of learning, WM and synaptic plasticity. Therefore, we speculate that theta oscillation may play an important role in the process of working memory impairment in CSVD. Methods Seventy-eight patients with CSVD (mean age 66.18 ± 1.42) and 49 healthy controls (HCs) (mean age 66.53 ± 1.3) were recruited to perform the WM task. Neural oscillations and functional connectivity during the encoding, maintenance, and retrieval phases of WM were evaluated during performance of WM test. Results Compared with the control group, the working memory behavior of the CSVD group showed a significantly longer reaction time and lower accuracy rate. The energy density and functional connection (FC) strength of the theta band in frontal region of the CSVD group were significantly lower than those of the control group, and the theta oscillation in the retrieval phase was significantly higher than that in the coding phase. However, there was no significant change in FC strengths among three phases. Both in the two groups, the FC was significantly positively correlated with accuracy and negatively correlated with reaction time (RT). Conclusion Our results indicated that CSVD patients have significant working memory impairment, and the lack of theta oscillation in the frontal region and the abnormal functional connection of the brain network may be one of its potential neurophysiological mechanisms.

Imaging Markers of Vascular Brain Health: Quantification, Clinical Implications, and Future Directions

Cerebrovascular disease (CVD) manifests through a broad spectrum of mechanisms that negatively impact brain and cognitive health. Oftentimes, CVD changes (excluding acute stroke) are insufficiently considered in aging and dementia studies which can lead to an incomplete picture of the etiologies contributing to the burden of cognitive impairment. Our goal with this focused review is 3-fold. First, we provide a research update on the current magnetic resonance imaging methods that can measure CVD lesions as well as early CVD-related brain injury specifically related to small vessel disease. Second, we discuss the clinical implications and relevance of these CVD imaging markers for cognitive decline, incident dementia, and disease progression in Alzheimer disease, and Alzheimer-related dementias. Finally, we present our perspective on the outlook and challenges that remain in the field. With the increased research interest in this area, we believe that reliable CVD imaging biomarkers for aging and dementia studies are on the horizon.

Neuropathology of Vascular Brain Health: Insights From Ex Vivo Magnetic Resonance Imaging–Histopathology Studies in Cerebral Small Vessel Disease

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.