HTRA1関連脳小血管病

Cerebral small vessel disease (CSVD) is a major cause of lacunar stroke, vascular cognitive impairment, and gait disturbance, yet the development of disease-modifying therapies is limited by the lack of robust, non-invasive biomarkers of microvascular pathology. Arterial spin labeling (ASL) MRI enables quantitative, non-invasive, contrast-free measurement of cerebral blood flow (CBF) and is well suited for longitudinal studies. In routine clinical and research practice, single-delay three-dimensional pseudo-continuous ASL (pCASL) with an appropriately long post-labeling delay is the workhorse implementation and has already been applied in several CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and hereditary CSVD cohorts, while more advanced approaches such as multi-delay ASL and diffusion-prepared pCASL can additionally probe arterial transit time (ATT) and blood-brain barrier (BBB) water exchange. CADASIL, caused by pathogenic NOTCH3 variants, is a prototypical monogenic CSVD with relatively low etiologic heterogeneity, providing a powerful clinical model in which to study microvascular dysfunction and trial-ready imaging markers. In this review, we synthesize data on ASL in CADASIL, including relationships between CBF, cognition, and lesion burden, evidence from acute encephalopathic episodes, and emerging work on ATT and BBB water exchange. We further compare perfusion profiles across monogenic (HTRA1-related CSVD, Fabry disease) and sporadic CSVD, and discuss how ASL-derived measures-CBF, ATT, and BBB water exchange rate-can be incorporated as imaging endpoints in CADASIL therapeutic trials. In particular, standardized single-delay three-dimensional pCASL provides a practical, scalable method to quantify regional CBF as a primary perfusion endpoint.

We report herein a 57-year-old man who presented with recurrent cerebral infarctions in one year. His father had multiple stroke episodes starting in his late 50s. Brain MRI FLAIR showed diffuse hyperintensities in the deep white matter, suggesting cerebral small vessel disease (CSVD). Notably, susceptibility-weighted imaging (SWI) revealed dot-like lesions along the surface of the midbrain ("Chocolate Chip Sign"). These findings suggested high temperature requirement A serine peptidase 1 (HTRA1)-related CSVD. The mutational analysis of the HTRA1 gene disclosed a heterozygous missense variant (NM_002775.4:c.754G>A, p.Ala252Thr). "Chocolate Chip Sign" on SWI could be useful in diagnosing heterozygous HTRA1-related CSVD.

Heterozygous HTRA1 gene variants are associated with hereditary cerebral small vessel disease (CSVD). HTRA1 also plays an important role in bone metabolism; however, its association with abnormal bone formation remains unclear. A 51-year-old man with minimal vascular risk factors was hospitalized for acute ischemic stroke, and magnetic resonance imaging demonstrated scattered deep cerebral white matter lesions. Anthropometric measurements revealed short stature and limb length. A genetic analysis revealed a heterozygous missense variant (c.889G>A, p. V297M) in HTRA1. The patient was diagnosed with heterozygous HTRA1-related CSVD. Our case suggests that this HTRA1 variant may contribute to shorter limbs and height.

RATIONALE: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy is a rare genetic condition classified as a cerebral small vessel disease (CSVD). Traditionally, this disorder has been linked to either homozygous or compound heterozygous mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene. Nevertheless, contemporary research has uncovered that heterozygous mutations in HTRA1 can also manifest in patients displaying patterns of autosomal dominant inheritance. In order to explore the association between the types of HTRA1 gene mutations and the genetic pattern of CSVD, in this case report, we identified a case of autosomal dominant hereditary CSVD due to a new heterozygous mutation of the HTRA1 gene in an Asian female. PATIENT CONCERNS: The patient experienced a later onset of cognitive disorder and gait disturbances, and notably, there was an absence of alopecia and spondylosis, which are commonly observed extra-neurological features associated with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. Neuroimaging conducted through magnetic resonance imaging revealed extensive white matter lesions and microbleeds localized within the brainstem and both cerebral hemispheres. Utilizing next-generation sequencing techniques, a novel heterozygous missense mutation in the HTRA1 gene (c.524 T>A:p.V175E) was identified. DIAGNOSES: The patient was diagnosed as HTRA1-related autosomal dominant CSVD. INTERVENTIONS: The patient was treated with donepezil and quetiapine because of the memory impairments and visual hallucination in the early stage of the disease course. After the diagnosis of CSVD and the clinical manifestations of depressive tendencies, we treated her with Cilostazol and Sertraline additionally. OUTCOMES: The patient symptoms were relieved temporarily. As the disease progresses, the patient experienced 2 episodes of epilepsy and 1 cerebral infarction event. LESSONS: This case suggests that individuals with the heterozygous HTRA1 mutation at V175E may also present clinical characteristics consistent with hereditary CSVD, expanding the recognized spectrum of HTRA1 mutations related to autosomal dominant small vessel disease.

BACKGROUND AND PURPOSE: Heterozygous HTRA1-related cerebral small vessel disease (hHTRA1-CSVD) presents diagnostic challenges due to its clinical and imaging similarities with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and sporadic cerebral small vessel disease (CSVD). Recently, the "chocolate chip sign" around the midbrain has been proposed as a potential imaging marker for hHTRA1-CSVD. However, the diagnostic value of similar findings around the pons remains unclear. This study aims to assess the diagnostic performance of the "pons chocolate chip sign" in distinguishing hHTRA1-CSVD from CADASIL and sporadic CSVD. MATERIALS AND METHODS: This cross-sectional study included seven patients with hHTRA1-CSVD, twenty-seven patients with CADASIL and twelve patients with sporadic CSVD. All participants underwent 7.0T magnetic resonance imaging (MRI). The "pons chocolate chip sign" was defined as round or ovoid hypointense dots (≥ 2 mm in diameter) surrounding the pons on T2*-weighted gradient echo images. The number of chocolate chips was independently assessed by two blinded neurologists. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis, with genetic diagnosis as the gold standard. RESULTS: The "pons chocolate chip sign" was found in 5/7 patients with hHTRA1-CSVD, compared to 2/27 in CADASIL and 0/12 in sporadic CSVD. ROC analysis revealed that it exhibited good discriminatory capability for hHTRA1-CSVD (area under the curve [AUC] = 0.84, 95% confidence interval [CI]: 0.63-1.00, P = 0.004). At an optimal cutoff of chocolate chips ≥ 1, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and Youden index were 71.42%, 94.87%, 71.42%, 94.87%, and 0.66, respectively. When the cutoff was increased to ≥ 3 chocolate chips, the specificity improved further, reaching 100%. CONCLUSIONS: The "pons chocolate chip sign" demonstrates high specificity for hHTRA1-CSVD and good discriminatory performance in differentiating hHTRA1-CSVD from CADASIL and sporadic CSVD.