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Cerebral Microbleed Burdens in Specific Brain Regions Are Associated With Disease Severity of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

ABSTRACT: Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, caused by NOTCH3 mutations, is characterized by recurrent ischemic strokes and progressive cognitive decline. It remains unclear whether cerebral microbleeds (CMBs) can serve as a surrogate marker for disease progression in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. We aimed to investigate the CMB burdens in NOTCH3 mutation carriers at different disease stages and test their associations with cognitive performance. Methods and Results Forty-nine individuals carrying NOTCH3 cysteine-altering mutations received brain magnetic resonance imaging with T1-weighted and susceptibility-weighted images. Whole brain images were segmented into 14 regions using Statistical Parametric Mapping and FreeSurfer software, and semiautomatic methods were used to locate and quantify the number and volume of CMBs. In our study participants, the median of CMB counts was 13, with a wide individual variation (range, 0-286). CMBs were most frequently present in thalamus, followed by temporal lobe. In the whole brain, the CMB counts and CMB volume ratios (ie, CMB volume divided by the volume of corresponding brain region) gradually increased as the disease advanced. CMB counts in the thalamus and temporal and frontal lobes increased more rapidly than other brain regions as disease progressed. There were significant associations between Mini-Mental State Examination scores and CMB counts in the frontal lobe, temporal lobe, and pons. Conclusions CMBs may have an influential role in the clinical manifestations of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. CMB burdens and their distribution in different brain regions may be capable to serve as a disease marker for monitoring the disease severity of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

SUBMITTER: Chung CP

PROVIDER: S-EPMC7670534 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Cerebral Microbleed Burdens in Specific Brain Regions Are Associated With Disease Severity of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

Chung Chih-Ping CP Chen Jiun-Wei JW Chang Feng-Chi FC Li Wei-Chi WC Lee Yi-Chung YC Chen Li-Fen LF Liao Yi-Chu YC

Journal of the American Heart Association 20200617 13

Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, caused by <i>NOTCH3</i> mutations, is characterized by recurrent ischemic strokes and progressive cognitive decline. It remains unclear whether cerebral microbleeds (CMBs) can serve as a surrogate marker for disease progression in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. We aimed to investigate the CMB burdens in <i>NOTCH3</i> mutation carriers ...[more]

PMID: 32552418

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Project description:Arteries in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are susceptible to smooth muscle loss and fibrosis, but the molecular components underlying these dramatic vascular changes are not well characterized. The purpose of this study was to investigate the distribution of collagen isoforms in the cerebral vessels of North American CADASIL patients with classical NOTCH3 mutations. Expression of types I-VI collagen in brains obtained at autopsy from six CADASIL patients with cysteine-altering mutations in NOTCH3 was compared to control brain expression. We identified a consistent increase of types I, III, IV, and VI collagen in CADASIL brains. Strong accumulation of types I, III, IV and VI collagen was noted in all calibers of vessels, including small and medium-sized leptomeningeal arteries, small penetrating white matter arteries, and capillaries. Within leptomeningeal arteries, where we could define the three tunicae of each vessel, we found distinct collagen subtype distribution patterns in CADASIL. Types I and III collagen were largely found in either adventitial/medial or transmural locations. Type IV collagen was strictly intimal/medial. Type VI collagen was adventitial or adventitial/medial. Within the thickened penetrating arteries of CADASIL patients, all four collagens extended through most of the arterial wall. We observed increased staining of capillaries in CADASIL for types I, IV, and VI collagen. In conclusion, brain vascular collagen subtypes are increased in CADASIL in multiple layers of all sizes of arteries, with disease-specific changes most prominent in the tunica media and thickened small penetrating vessels. In diseased arteries, types I, III, and VI collagen spreads from an external location (adventitia) into the vascular media, while type IV collagen accumulates in an internal pattern (intima and media). These observations are consistent with a pathological role for collagen accumulation in the vascular media in CADASIL.

Dataset Information

Cerebral Microbleed Burdens in Specific Brain Regions Are Associated With Disease Severity of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

Publications

Cerebral Microbleed Burdens in Specific Brain Regions Are Associated With Disease Severity of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

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