Brainstem phenotype of cathepsin A-related arteriopathy with strokes and leukoencephalopathy.
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ABSTRACT:
SUBMITTER: Hwang YT
PROVIDER: S-EPMC5499977 | biostudies-literature | 2017 Aug
REPOSITORIES: biostudies-literature
Publications
Brainstem phenotype of cathepsin A-related arteriopathy with strokes and leukoencephalopathy.
Hwang Yun Tae YT Lakshmanan Rahul R Davagnanam Indran I Thompson Andrew G B AGB Lynch David S DS Houlden Henry H Bajaj Nin N Eriksson Sofia H SH Bamiou Doris-Eva DE Warren Jason D JD
Neurology. Genetics 20170706 4
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Project description:Cerebral small vessel disease (CSVD) causes dementia and gait disturbance due to arteriopathy. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary form of CSVD caused by loss of high-temperature requirement A1 (HTRA1) serine protease activity. In CARASIL, arteriopathy causes intimal thickening, smooth muscle cell (SMC) degeneration, elastic lamina splitting, and vasodilation. The molecular mechanisms were proposed to involve the accumulation of matrisome proteins as substrates or abnormalities in transforming growth factor β (TGF-β) signaling. Here, we show that HTRA1-/- mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation. In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex. In the thickened intima, matrisome proteins, including the hub protein fibronectin (FN) and latent TGF-β binding protein 4 (LTBP-4), which are substrates of HTRA1, accumulated. Candesartan treatment alleviated matrisome protein accumulation and normalized the vascular distensibility and cerebral blood flow. Furthermore, candesartan reduced the mRNA expression of Fn1, Ltbp-4, and Adamtsl2, which are involved in forming the extracellular matrix network. Our results indicate that these accumulated matrisome proteins may be potential therapeutic targets for arteriopathy in CARASIL.
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Project description:BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease (CSVD). Intracerebral hemorrhage (ICH) is reported to be increasing in CADASIL patients from areas where the p.R544C mutation is prevalent (e.g., Jeju and Chinese Taiwan) but is rare in Caucasians. We attempted to determine potentially genetic, clinical, and/or neuroimaging risk factors for ICH in Chinese CADASIL patients.MethodsThis retrospective observational study included 190 patients with CADASIL and 179 patients with sporadic CSVD. NOTCH3 genotypes as well as clinical and neuroimaging manifestations were compared between ICH and non-ICH patients, and both logistic regression and a subgroup analysis were used to adjust for confounding factors.ResultsOf 190 CADASIL patients in the present study, 43 patients (22.6%) had ICH lesions. A total of 62 ICH lesions were recorded. Thalamic ICH lesions were the most common (40.3%), followed by basal ganglia (32.3%) and temporal lobe (8.1%). In subgroup analysis, the ICH group had a higher prevalence of CMB than the non-ICH group, including in the basal ganglia region (58.3% vs. 23.3%, p = 0.037) and thalamus (75.0% vs. 38.3%, p = 0.020). The p.R544C mutation (aOR 6.390; 95% CI, 1.308-31.225; p = 0.022) and total SVD score (aOR 1.731; 95% CI, 1.003-2.990; p = 0.049) were independently associated with ICH.ConclusionsICH is a common clinical manifestation of CADASIL patients in southeast coastal China. Hypertension, total SVD score, and the p.R544C mutation are associated with CADASIL ICH.Trial registrationClinicalTrials.gov identifier: (NCT04318119).
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Project description:BackgroundImpaired cerebrovasoreactivity is thought to play an important role in the pathophysiology of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to clarify the association between cerebrovascular reactivity and stroke in patients with CADASIL.MethodsWe retrospectively recruited 14 patients with CADASIL, eight of whom had symptomatic stroke. They underwent quantitative single-photon emission computed tomography using an autoradiographic method at rest and after acetazolamide (ACZ) administration. Regional cerebral blood flow (rCBF) in the cerebral cortex, lenticular nucleus, thalamus, and cerebellum was measured. We compared the rCBF parameters between patients with and without stroke.ResultsThe baseline characteristics and magnetic resonance imaging findings were similar between the two groups, except for a higher frequency of pyramidal tract sign (75% vs. 0%) and a larger number of old lacunes (15.4 ± 8.8 vs. 2.2 ± 1.8) in the patients with stroke. Of the rCBF parameters measured, significantly lower flow (mL/100 g/min) was observed in ACZ-rCBF in the thalamus (35.6 ± 9.4 vs. 51.1 ± 7.6, p = 0.01) and ΔrCBF in the thalamus (10.6 ± 3.7 vs. 21.0 ± 7.9, p = 0.02) in the patients with stroke.ConclusionCerebrovasoreactivity in the thalamus was significantly associated with stroke in patients with CADASIL.
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