Postmortem brain 7T MRI with minimally invasive pathological correlation in deceased COVID-19 subjects

Background Brain abnormalities are a concern in COVID-19, so we used minimally invasive autopsy (MIA) to investigate it, consisting of brain 7T MR and CT images and tissue sampling via transethmoidal route with at least three fragments: the first one for reverse transcription polymerase chain reaction (RT-PCR) analysis and the remaining fixed and stained with hematoxylin and eosin. Two mouse monoclonal anti-coronavirus (SARS-CoV-2) antibodies were employed in immunohistochemical (IHC) reactions. Results Seven deceased COVID-19 patients underwent MIA with brain MR and CT images, six of them with tissue sampling. Imaging findings included infarcts, punctate brain hemorrhagic foci, subarachnoid hemorrhage and signal abnormalities in the splenium, basal ganglia, white matter, hippocampi and posterior cortico-subcortical. Punctate brain hemorrhage was the most common finding (three out of seven cases). Brain histological analysis revealed reactive gliosis, congestion, cortical neuron eosinophilic degeneration and axonal disruption in all six cases. Other findings included edema (5 cases), discrete perivascular hemorrhages (5), cerebral small vessel disease (3), perivascular hemosiderin deposits (3), Alzheimer type II glia (3), abundant corpora amylacea (3), ischemic foci (1), periventricular encephalitis foci (1), periventricular vascular ectasia (1) and fibrin thrombi (1). SARS-CoV-2 RNA was detected with RT-PCR in 5 out of 5 and IHC in 6 out 6 patients (100%). Conclusions Despite limited sampling, MIA was an effective tool to evaluate underlying pathological brain changes in deceased COVID-19 patients. Imaging findings were varied, and pathological features corroborated signs of hypoxia, alterations related to systemic critically ill and SARS-CoV-2 brain invasion.

Early-onset vascular leukoencephalopathy caused by bi-allelic NOTCH3 variants

Objective Heterozygous NOTCH3 variants are known to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), with patients typically presenting in adulthood. We describe three patients presenting at an early age with a vascular leukoencephalopathy. Genome sequencing revealed bi-allelic variants in the NOTCH3 gene. Methods Clinical records and available MRI and CT scans of three patients from two unrelated families were retrospectively reviewed. Results The patients presented at 9-14 months of age with developmental delay, seizures, or both. The disease course was characterized by cognitive impairment and variably recurrent strokes, migraine attacks, and seizures. MRI findings pointed at a small vessel disease, with extensive cerebral white matter abnormalities, atrophy, lacunes in the basal ganglia, microbleeds and microcalcifications. The anterior temporal lobes were spared. Bi-allelic cysteine-sparing NOTCH3 variants in exons 1, 32 and 33 were found. Interpretation This study indicates that bi-allelic loss-of-function NOTCH3 variants may cause a vascular leukoencephalopathy, distinct from CADASIL.

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.

Spatiotemporal Dynamics of Cerebral Vascular Permeability in Type 2 Diabetes-Related Cerebral Microangiopathy

AimsDiabetes-related cerebral microangiopathy can manifest as cerebral small vessel disease (CSVD) and exhibit cognitive decline. To find the early change of function in advance, this study examined the spatiotemporal dynamics of cerebral vascular permeability (Ktrans) in the progression of type 2 diabetes mellitus (T2DM).MethodsKtrans was cross-sectionally measured in T2DM and non-diabetes groups with or without CSVD using dynamic contrast-enhanced MRI (DCE-MRI).ResultsIn all patients with T2DM, the Ktrans of white matter (WM) was increased, whereas the Ktrans of gray matter (GM) was increased only in T2DM with CSVD. The involvement of WM was earlier than GM and was before the CSVD features could be visualized on MRI. Among the commonly available four CSVD items of MRI, microbleeds were the most sensitive, indicating the increased permeability in all patients. Increased Ktrans in T2DM was more associated with moderate WM hyperintensity but less with the presence of lacunae or multiple perivascular spaces, in contrast to patients without diabetes. The differential correlation suggested distinct mechanisms underlying diabetes-related CSVD and other CSVDs.ConclusionsThis study highlights the early development of cerebral microangiopathy with increased BBB leakage in T2DM, before the CSVD features can be visualized on MRI. The results may increase the proactivity of clinicians in recognizing the subsequent neurological comorbidities.

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.