Research Advancements on the Correlation Between Spontaneous Intracerebral Hemorrhage of Different Etiologies and Imaging Markers of Cerebral Small Vessel Disease.

Objective: The purpose of this review is to identify the correlation between ICH and CSVD imaging markers under SMASH-U classification by searching and analyzing a large number of literatures in recent years, laying a theoretical foundation for future clinical research. At the same time, by collecting clinical data to evaluate patient prognosis, analyzing whether there are differences or supplements between clinical trial conclusions and previous theories, and ultimately guiding clinical diagnosis and treatment through the analysis of imaging biomarkers. Methods: In this review, by searching CNKI, Web of Science, PubMed, FMRS and other databases, the use of "spontaneous intracerebral hemorrhage", "hypertensive hemorrhagic cerebral small vessel disease", "cerebral small vessel disease imaging", "Based cerebral small vessel diseases", "SMASH the -u classification" and their Chinese equivalents for the main search term. We focused on reading and analyzing hundreds of relevant literatures in the last decade from August 2011 to April 2020, and also included some earlier literatures with conceptual data sources. After screening and ranking the degree of relevance to this study, sixty of them were cited for analysis and elaboration. Results: In patients with ICH, the number of cerebral microbleeds in lobes, basal ganglia, and the deep brain is positively correlated with ICH volume and independently correlated with neurological functional outcomes; white matter hyperintensity severity is positively correlated with ICH recurrence risk; multiple lacunar infarction independently predict the risk of ICH; severe brain atrophy is an independent risk factor for a poor prognosis in the long term in patients diagnosed with ICH; and the number of enlarged perivascular spaces is correlated with ICH recurrence. However, small subcortical infarct and ICH are the subject of few studies. Higher CSVD scores are independently associated with functional outcomes at 90 days in patients diagnosed with ICH.

CADASIL: A NOTCH3-associated cerebral small vessel disease.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease (CSVD), pathologically characterized by a non-atherosclerotic and non-amyloid diffuse angiopathy primarily involving small to medium-sized penetrating arteries and leptomeningeal arteries. In 1996, mutation in the notch receptor 3 gene (NOTCH3) was identified as the cause of CADASIL. However, since that time other genetic CSVDs have been described, including the HtrA serine peptidase 1 gene-associated CSVD and the cathepsin A gene-associated CSVD, that clinically mimic the original phenotype. Though NOTCH3-associated CSVD is now a well-recognized hereditary disorder and the number of studies investigating this disease is increasing, the role of NOTCH3 in the pathogenesis of CADASIL remains elusive. AIM OF REVIEW: This review aims to provide insights into the pathogenesis and the diagnosis of hereditary CSVDs, as well as personalized therapy, predictive approach, and targeted prevention. In this review, we summarize the current progress in CADASIL, including the clinical, neuroimaging, pathological, genetic, diagnostic, and therapeutic aspects, as well as differential diagnosis, in which the role of NOTCH3 mutations is highlighted. KEY SCIENTIFIC CONCEPTS OF REVIEW: In this review, CADASIL is revisited as a NOTCH3-associated CSVD along with other hereditary CSVDs.

Main features of COL4A1-COL4A2 related cerebral microangiopathies.

COL4A1 and COL4A2 genes encode the alpha1 and the alpha2 chains of type IV collagen, a key component of basement membranes. Mutations located in the coding sequence of COL4A1/COL4A2 genes are responsible for an autosomal dominant (AD) cerebral angiopathy that manifest in either adults, children or fetuses. The most typical among such mutations are missense glycine mutations in the triple helix. They increase the susceptibility to brain hemorrhage but can also promote the occurrence of multiple other types of systemic manifestations that can involve the eyes, kidneys or muscles. This condition is characterized by a very incomplete penetrance, and a wide phenotypic variability even among members of the same family. Recently, mutations in the COL4A1 3'UTR non-coding region that upregulate COL4A1 expression, and COL4A1/COL4A2 duplications, have been shown to cause AD forms of ischemic cerebral small vessel disease in adults. Herein, we summarize the genetic and pathophysiological aspects of these conditions, detail their clinical and imaging characteristics and discuss some principles in their clinical management.

Serial magnetic resonance imaging changes of pseudotumor lesions in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: a case report.

BACKGROUND: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an adult-onset rare monogenic microvasculopathy. Its typical neuroimaging features are punctate white matter lesions or pseudotumor alterations. RVCL-S is often under-recognized and misdiagnosed because of its rarity and similar imaging manifestations to multiple sclerosis or brain malignant mass. CASE PRESENTATION: Here we report a case of a 36-year-old Chinese man who developed multiple tumefactive brain lesions spanning over two years leading to motor aphasia, cognitive decline, and limb weakness. He also presented with slight vision loss, and fundus fluorescein angiography indicated retinal vasculopathy. He underwent brain biopsies twice and showed no evidence of malignancy. Given the family history that his father died of a brain mass of unclear etiology, RVCL-S was suspected, and genetic analysis confirmed the diagnosis with a heterozygous insertion mutation in the three-prime repair exonuclease 1 gene. He was given courses of corticosteroids and cyclophosphamide but received little response. CONCLUSIONS: The present case is one of the few published reports of RVCL-S with two-year detailed imaging data. Serial magnetic resonance images showed the progression pattern of the lesions. Our experience emphasizes that a better understanding of RVCL-S and considering it as a differential diagnosis in patients with tumefactive brain lesions may help avoid unnecessary invasive examinations and make an earlier diagnosis.

High clinical heterogeneity in a Chinese pedigree of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S).

BACKGROUND: Being a newly defined disease, RVCL-S is underrecognized by clinicians globally. It is an autosomal dominantly inherited small vessel disease caused by the heterozygous C-terminal frameshift mutation in TREX1 gene. RVCL-S is featured by cerebral dysfunction, retinopathy, and vasculopathy in multiple internal organs. Misdiagnosis may cause devastating consequences in patients, such as iatrogenic PML caused by misuse of immunosuppressants. Thus, increasing awareness of this disease is in urgent need. RESULTS: We uncovered a large Chinese origin RVCL-S pedigree bearing the TREX1 mutation. A comprehensive characterization combining clinical, genetic, and neuropathological analysis was performed. The Intrafamilial comparison showed highly heterogeneous clinical phenotypes. Mutation carriers in our pedigree presented with retinopathy (8/13), seizures (2/13), increased intracranial pressure (1/13), mild cognitive impairment (3/13), stroke-like episode (3/13), mesenteric ischemia (1/13), nephropathy (9/13), ascites (3/13), hypertension (9/13), hyperlipidemia (3/8), hypoalbuminemia (3/8), normocytic anemia (3/8), subclinical hypothyroidism (1/8), hyperfibrinogenemia (1/8), hyperparathyroidism (2/8), and abnormal inflammatory markers (4/8). The constellation of symptoms is highly varied, making RVCL-S a challenging diagnosis. Comparison with reported RVCL-S pedigrees further revealed that the mesenteric ischemia is a novel clinical finding and the MRS pattern of brain lesions is emulating neoplasm and tumefactive demyelination. CONCLUSION: Our reports characterize a highly heterogeneous RVCL-S pedigree, highlight the probability of misdiagnosis in clinical practice, and broaden the clinical spectrum of RVCL-S.

A novel heterozygous HTRA1 mutation is associated with autosomal dominant hereditary cerebral small vessel disease.

BACKGROUND: We investigated whether a heterozygous mutation that we newly identified in HTRA1 (high-temperature requirement serine protease A1 gene) in a pedigree with autosomal dominant hereditary cerebral small vessel disease (SVD) reduces the function of HTRA1 and affects the transforming growth factor-ß1 (TGF-ß1)/Smad signaling. METHODS: Whole-exome sequence from the proband and her two sisters was examined using whole-exome enrichment and sequencing. Expression of HTRA1 and TGF-ß1/Smad and HTRA1 activity were assayed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blotting analyses after transfecting wild-type and mutant HTRA1 genes into HEK293 cells. RESULTS: A new heterozygous mutation (c.614C>G:p.Ser205Cys) in HTRA1 was identified in the sequence encoding the trypsin-like serine protease domain. The mutation was predicted to be deleterious by in silico tools. Moreover, in vitro activity and protein analyses revealed a loss-of-function effect of the mutation: the proteolytic activity of mutant HTRA1 was decreased, and, notably, this was accompanied by an increase in TGF-ß1/Smad protein levels. CONCLUSIONS: The heterozygous mutation HTRA1 S205C causing diminished protease activity is associated with-and could represent a cause of-autosomal dominant hereditary cerebral SVD. Our results also indicate a relationship between HTRA1 and TGF-ß1/Smad signaling.

Hereditary cerebral small vessel disease and stroke.

Cerebral small vessel disease is considered hereditary in about 5% of patients and is characterized by lacunar infarcts and white matter hyperintensities on MRI. Several monogenic hereditary diseases causing cerebral small vessel disease and stroke have been identified. The purpose of this systematic review is to provide a guide for determining when to consider molecular genetic testing in patients presenting with small vessel disease and stroke. CADASIL, CARASIL, collagen type IV mutations (including PADMAL), retinal vasculopathy with cerebral leukodystrophy, Fabry disease, hereditary cerebral hemorrhage with amyloidosis, and forkhead box C1 mutations are described in terms of genetics, pathology, clinical manifestation, imaging, and diagnosis. These monogenic disorders are often characterized by early-age stroke, but also by migraine, mood disturbances, vascular dementia and often gait disturbances. Some also present with extra-cerebral manifestations such as microangiopathy of the eyes and kidneys. Many present with clinically recognizable syndromes. Investigations include a thorough family medical history, medical history, neurological examination, neuroimaging, often supplemented by specific examinations e.g of the of vision, retinal changes, as well as kidney and heart function. However molecular genetic analysis is the final gold standard of diagnosis. There are increasing numbers of reports on new monogenic syndromes causing cerebral small vessel disease. Genetic counseling is important. Enzyme replacement therapy is possible in Fabry disease, but treatment options remain overall very limited.