Novel In-Frame Deletion in HTRA1 Gene, Responsible for Stroke at a Young Age and Dementia—A Case Study

Biallelic mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene are known to cause an extremely rare cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which belongs to the group of hereditary cerebral small vessel diseases and is mainly observed in the Japanese population. Even though this pathology is inherited in an autosomal recessive manner, recent studies have described symptomatic carriers with heterozygous HTRA1 mutations who have milder symptoms than patients with biallelic HTRA1 mutations. We present the case of a Lithuanian male patient who had a stroke at the age of 36, experienced several transient ischemic attacks, and developed an early onset, progressing dementia. These clinical symptoms were associated with extensive leukoencephalopathy, lacunar infarcts, and microbleeds based on brain magnetic resonance imaging (MRI). A novel heterozygous in-frame HTRA1 gene deletion (NM_002775.5:c.533_535del; NP_002766.1:p.(Lys178del)) was identified by next generation sequencing. The variant was consistent with the patient’s phenotype, which could not be explained by alternative causes, appeared highly deleterious after in silico analysis, and was not reported in the medical literature or population databases to date.

Segmentation of Cerebral Small Vessel Diseases-White Matter Hyperintensities Based on a Deep Learning System

Objective: Reliable quantification of white matter hyperintensities (WHMs) resulting from cerebral small vessel diseases (CSVD) is essential for understanding their clinical impact. We aim to develop and clinically validate a deep learning system for automatic segmentation of CSVD-WMH from fluid-attenuated inversion recovery (FLAIR) imaging using large multicenter data.Method: A FLAIR imaging dataset of 1,156 patients diagnosed with CSVD associated WMH (median age, 54 years; 653 males) obtained between September 2018 and September 2019 from Beijing Tiantan Hospital was retrospectively analyzed in this study. Locations of CSVD-WMH on the FLAIR scans were manually marked by two experienced neurologists. Using the manually labeled data of 996 patients (development set), a U-shaped novel 2D convolutional neural network (CNN) architecture was trained for automatic segmentation of CSVD-WMH. The segmentation performance of the network was evaluated with per pixel and lesion level dice scores using an independent internal test set (n = 160) and a multi-center external test set (n = 90, three medical centers). The clinical suitability of the segmentation results, classified as acceptable, acceptable with minor revision, acceptable with major revision, and not acceptable, was analyzed by three independent neuroradiologists. The inter-neuroradiologists agreement rate was assessed by the Kendall-W test.Results: On the internal and external test sets, the proposed CNN architecture achieved per pixel and lesion level dice scores of 0.72 (external test set), and they were significantly better than the state-of-the-art deep learning architectures proposed for WMH segmentation. In the clinical evaluation, neuroradiologists observed the segmentation results for 95% of the patients were acceptable or acceptable with a minor revision.Conclusions: A deep learning system can be used for automated, objective, and clinically meaningful segmentation of CSVD-WMH with high accuracy.

Hereditary Cerebral Small Vessel Diseases and Stroke: A Guide for Diagnosis and Management

Cerebral small vessel diseases represent a frequent cause of stroke and cognitive or motor disability in adults. A small proportion of cerebral small vessel diseases is attributable to monogenic conditions. Since the characterization in the late 1990s of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, several other monogenic conditions leading to adult-onset ischemic or hemorrhagic stroke have been described. In this practical guide, we summarize the key features that should elicit the differential diagnosis of a hereditary cerebral small vessel diseases in adult stroke patients, describe the main clinical and imaging characteristics of the major hereditary cerebral small vessel diseases that can manifest as stroke, and provide general recommendations for the clinical management of affected patients and their relatives.

A novel COL4A1 variant associated with recurrent epistaxis and glioblastoma

COL4A1-related disorders are characterized by a higher incidence of cerebral hemorrhage than other hereditary cerebral small vessel diseases. Accumulating data have shown broad phenotypic variations, and extracerebral hemorrhages have been linked to these disorders. Moreover, the coexistence of neural tumors has been described. Here, we report a Japanese family with a novel COL4A1 variant, including a patient with recurrent epistaxis and glioblastoma.

Brain MRI in Monogenic Cerebral Small Vessel Diseases: A Practical Handbook

: Monogenic cerebral small vessel diseases are a topic of growing interest, as several genes responsible have been recently described and new sequencing techniques such as Next generation sequencing are available. Brain imaging is a key exam in these diseases. First, since it is often the first exam performed, an MRI is key in selecting patients for genetic testing and for interpreting Next generation sequencing reports. In addition, neuroimaging can be helpful in describing the underlying pathological mechanisms involved in cerebral small vessel disease. With this review, we aim to provide Neurologists and Stroke physicians with an up-to date overview of the current neuroimaging knowledge on monogenic small vessel diseases.

Increased Premature Cerebral Small Vessel Diseases in Dialysis Patients: A Retrospective Cross-Sectional Study

<b><i>Background:</i></b> Growing data indicate a higher prevalence of cerebrovascular diseases in patients with ESRD. Cerebral small-vessel disease (CSVD) is an important risk factor of stroke and dementia. A comprehensive assessment of CSVD in a dialysis population is needed. <b><i>Methods:</i></b> In this retrospective cross-sectional study, we enrolled 179 dialysis patients and 351 controls matched by sex and age with normal serum creatinine. The presence and locations of 3 main features of CSVD in dialysis patients, including lacunes, cerebral microbleeds (CMBs), and white matter hyperintensities (WMHs), were evaluated with brain magnetic resonance imaging and compared with controls. Univariate and multivariate analyses were performed to identify risk factors. <b><i>Results:</i></b> Compared with controls, the prevalence of CSVD was significantly increased in dialysis patients (odds ratio [OR] 2.66, 95% confidence interval [CI] 1.26–5.62). Among them, risks of CMBs and WMHs were increased in dialysis (OR 4.01, 95% CI 1.78–9.42; 3.91, 95% CI 1.67–9.15), except for lacunes. The age of subjects with CSVD detected was significantly younger in the dialysis group (<i>p</i> = 0.002). Unlike controls, basal ganglia were most affected by lacunes and CMBs in dialysis patients. In dialysis patients, multivariate analysis further revealed that aging, smoking, and hyperlipidemia were significantly associated with CSVD, while dialysis modality was not significant. <b><i>Conclusion:</i></b> We demonstrated a higher prevalence and early-onset tendency of CSVD in dialysis patients, especially for CMBs and WMHs. Dialysis patients showed different patterns and associated factors for CSVD.

PIP2 corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.1 activity

Cerebral small vessel diseases (SVDs) are a central link between stroke and dementia—two comorbidities without specific treatments. Despite the emerging consensus that SVDs are initiated in the endothelium, the early mechanisms remain largely unknown. Deficits in on-demand delivery of blood to active brain regions (functional hyperemia) are early manifestations of the underlying pathogenesis. The capillary endothelial cell strong inward-rectifier K+ channel Kir2.1, which senses neuronal activity and initiates a propagating electrical signal that dilates upstream arterioles, is a cornerstone of functional hyperemia. Here, using a genetic SVD mouse model, we show that impaired functional hyperemia is caused by diminished Kir2.1 channel activity. We link Kir2.1 deactivation to depletion of phosphatidylinositol 4,5-bisphosphate (PIP2), a membrane phospholipid essential for Kir2.1 activity. Systemic injection of soluble PIP2 rapidly restored functional hyperemia in SVD mice, suggesting a possible strategy for rescuing functional hyperemia in brain disorders in which blood flow is disturbed.

Amyloid Positivity in Alzheimer/Subcortical-Vascular Spectrum

Objective:We investigated the frequency of Aβ positivity in the nine groups classified according to a combination of three different cognition states and three distinct levels of white matter hyperintensities (WMH) (minimal, moderate, and severe). We also aimed to determine which factors were associated with Aβ after controlling for WMH, and vice versa.Methods:A total of 1047 individuals with subjective cognitive decline (SCD, n=294), mild cognitive impairment (MCI, n=237), or dementia (n=516) who underwent Aβ positron emission tomography scans were recruited from the memory clinic at Samsung Medical Center in Seoul, Korea. We investigated the following: 1) Aβ positivity in the 9 groups, 2) the relationship between Aβ positivity and the WMH severity, and 3) clinical and genetic factors independently associated with Aβ or WMH.Results:Aβ positivity increased as the severity of cognitive impairment increased [SCD (15.7%), MCI (43.5%), and dementia (76.2%)], whereas it decreased as the severity of WMH increased [minimal (54.5%), moderate (53.9%), and severe (41.0%)] or the number of lacunes [0 (59.0%), 1-3 (42.0%), and >3 (23.4%)] increased. Aβ positivity was associated with higher education, absence of diabetes mellitus, and presence of APOE e4 after controlling for cognitive and WMH status.Conclusion:Our analysis of Aβ positivity involving a large sample classified according to the stratified cognitive states and WMH severity indicates that Alzheimer’s and cerebral small vessel diseases lie on a continuum. Our results offer clinicians insightful information about the association between Aβ, WMH, and cognition.