Cerebral Autosomal Dominant Arteriopathy Research Articles

The Roles of NOTCH3 p.R544C and Thrombophilia Genes in Vietnamese Patients With Ischemic Stroke: Study Involving a Hierarchical Cluster Analysis

Background The etiology of ischemic stroke is multifactorial. Several gene mutations have been identified as leading causes of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary disease that causes stroke and other neurological symptoms. Objective We aimed to identify the variants of NOTCH3 and thrombophilia genes, and their complex interactions with other factors. Methods We conducted a hierarchical cluster analysis (HCA) on the data of 100 patients diagnosed with ischemic stroke. The variants of NOTCH3 and thrombophilia genes were identified by polymerase chain reaction with confronting 2-pair primers and real-time polymerase chain reaction. The overall preclinical characteristics, cumulative cutpoint values, and factors associated with these somatic mutations were analyzed in unidimensional and multidimensional scaling models. Results We identified the following optimal cutpoints: creatinine, 83.67 (SD 9.19) µmol/L; age, 54 (SD 5) years; prothrombin (PT) time, 13.25 (SD 0.17) seconds; and international normalized ratio (INR), 1.02 (SD 0.03). Using the Nagelkerke method, cutpoint 50% values of the Glasgow Coma Scale score; modified Rankin scale score; and National Institutes of Health Stroke Scale scores at admission, after 24 hours, and at discharge were 12.77, 2.86 (SD 1.21), 9.83 (SD 2.85), 7.29 (SD 2.04), and 6.85 (SD 2.90), respectively. Conclusions The variants of MTHFR (C677T and A1298C) and NOTCH3 p.R544C may influence the stroke severity under specific conditions of PT, creatinine, INR, and BMI, with risk ratios of 4.8 (95% CI 1.53-15.04) and 3.13 (95% CI 1.60-6.11), respectively (Pfisher<.05). It is interesting that although there are many genes linked to increased atrial fibrillation risk, not all of them are associated with ischemic stroke risk. With the detection of stroke risk loci, more information can be gained on their impacts and interconnections, especially in young patients.

The imaging findings of migraine with visual aura in a CADASIL patient.

Head MRI images of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)patients during migraine attacks are rare.

Blood vessel organoids generated by base editing and harboring single nucleotide variation in Notch3 effectively recapitulate CADASIL-related pathogenesis.

Human blood vessel organoids (hBVOs) offer a promising platform for investigating vascular diseases and identifying therapeutic targets. In this study, we focused on in vitro modeling and therapeutic target finding of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of hereditary stroke disorder caused by mutations in the NOTCH3 gene. Despite the identification of these mutations, the underlying pathological mechanism is elusive, and effective therapeutic approaches are lacking. CADASIL primarily affects the blood vessels in the brain, leading to ischemic strokes, migraines, and dementia. By employing CRISPR/Cas9 base-editing technology, we generated human induced pluripotent stem cells (hiPSCs) carrying Notch3 mutations. These mutant hiPSCs were differentiated into hBVOs. The NOTCH3 mutated hBVOs exhibited CADASIL-like pathology, characterized by a reduced vessel diameter and degeneration of mural cells. Furthermore, we observed an accumulation of Notch3 extracellular domain (Notch3ECD), increased apoptosis, and cytoskeletal alterations in the NOTCH3 mutant hBVOs. Notably, treatment with ROCK inhibitors partially restored the disconnection between endothelial cells and mural cells in the mutant hBVOs. These findings shed light on the pathogenesis of CADASIL and highlight the potential of hBVOs for studying and developing therapeutic interventions for this debilitating human vascular disorder.

Pro-Hemorrhagic Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Associated with NOTCH3 p.R75P Mutation with Low Vascular NOTCH3 Aggregation Property.

Intracerebral hemorrhage (ICH) and cerebral microbleeds (CMB) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy are more common in East Asian populations than in people of white European ancestry. We hypothesized that the ethnic difference is explained by the East Asian-specific NOTCH3 p.R75P mutation. This retrospective observational study included 118 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in Japanese and Korean cohorts. We investigated whether the p.R75P mutation is associated with symptomatic ICH and multiple CMB (>5) using quasi-Poisson regression models. We predicted the NOTCH3 extracellular domain protein structures in silico and graded NOTCH3 extracellular domain immunostaining in skin vessels of some patients, with subsequent comparisons between p.R75P and other conventional mutations. Among 63 Japanese patients (median age 55 years; 56% men), 15 had a p.R75P mutation, significantly associated with symptomatic ICH (adjusted relative risk 9.56, 95% CI 2.45-37.31), multiple CMB (3.00, 1.34-6.71), and absence of temporopolar lesions (4.91, 2.29-10.52) after adjustment for age, sex, hypertension, and antithrombotics. In the Korean cohort (n = 55; median age 55 years; 51% men), the p.R75P mutation (n = 13) was also associated with symptomatic ICH (8.11, 1.83-35.89), multiple CMB (1.90, 1.01-3.56), and absence of temporopolar lesions (2.32, 1.08-4.97). Structural analysis revealed solvent-exposed free cysteine thiols in conventional mutations, directly causing aggregation, whereas a stereochemically incompatible proline residue structure in p.R75P lowers correct disulfide bond formation probability, indirectly causing aggregation. Pathologically, the p.R75P mutation resulted in less vascular NOTCH3 extracellular domain accumulation than the other conventional mutations. NOTCH3 p.R75P mutation is associated with hemorrhagic presentations, milder temporopolar lesions, and distinct mutant protein structure properties. ANN NEUROL 2024.

Enlarged perivascular spaces are associated with white matter injury, cognition and inflammation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Enlarged perivascular spaces have been previously reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, but their significance and pathophysiology remains unclear. We investigated associations of white matter enlarged perivascular spaces with classical imaging measures, cognitive measures and plasma proteins to better understand what enlarged perivascular spaces represent in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and whether radiographic measures of enlarged perivascular spaces would be of value in future therapeutic discovery studies for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Twenty-four individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and 24 age- and sex-matched controls were included. Disease status was determined based on the presence of NOTCH3 mutation. Brain imaging measures of white matter hyperintensity, brain parenchymal fraction, white matter enlarged perivascular space volumes, clinical and cognitive measures as well as plasma proteomics were used in models. White matter enlarged perivascular space volumes were calculated via a novel, semiautomated pipeline, and levels of 7363 proteins were quantified in plasma using the SomaScan assay. The relationship of enlarged perivascular spaces with global burden of white matter hyperintensity, brain atrophy, functional status, neurocognitive measures and plasma proteins was modelled with linear regression models. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and control groups did not exhibit differences in mean enlarged perivascular space volumes. However, increased enlarged perivascular space volumes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy were associated with increased white matter hyperintensity volume (β = 0.57, P = 0.05), Clinical Dementia Rating Sum-of-Boxes score (β = 0.49, P = 0.04) and marginally with decreased brain parenchymal fraction (β = -0.03, P = 0.10). In interaction term models, the interaction term between cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease status and enlarged perivascular space volume was associated with increased white matter hyperintensity volume (β = 0.57, P = 0.02), Clinical Dementia Rating Sum-of-Boxes score (β = 0.52, P = 0.02), Mini-Mental State Examination score (β = -1.49, P = 0.03) and marginally with decreased brain parenchymal fraction (β = -0.03, P = 0.07). Proteins positively associated with enlarged perivascular space volumes were found to be related to leukocyte migration and inflammation, while negatively associated proteins were related to lipid metabolism. Two central hub proteins were identified in protein networks associated with enlarged perivascular space volumes: CXC motif chemokine ligand 8/interleukin-8 and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. The levels of CXC motif chemokine ligand 8/interleukin-8 were also associated with increased white matter hyperintensity volume (β = 42.86, P = 0.03), and levels of C-C motif chemokine ligand 2/monocyte chemoattractant protein 1 were further associated with decreased brain parenchymal fraction (β = -0.0007, P < 0.01) and Mini-Mental State Examination score (β = -0.02, P < 0.01) and increased Trail Making Test B completion time (β = 0.76, P < 0.01). No proteins were associated with all three studied imaging measures of pathology (brain parenchymal fraction, enlarged perivascular spaces, white matter hyperintensity). Based on associations uncovered between enlarged perivascular space volumes and cognitive functions, imaging and plasma proteins, we conclude that white matter enlarged perivascular space volumes may capture pathologies contributing to chronic brain dysfunction and degeneration in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

First report of a p.Cys484Tyr Notch3 mutation in a CADASIL patient with acute bilateral multiple subcortical infarcts—case report and brief review

BackgroundCADASIL(Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)is an inherited small vessel disease caused by mutations in NOTCH3 gene. Although NOTCH3 has numerous hotspots of gene mutations, mutations in exons 9 are rare. The p.C484T gene mutation type associated with it has not been reported in any relevant cases yet. Furthermore, CADASIL patients rarely present with acute bilateral multiple subcortical infarcts.Case presentationWe report the case of a Chinese female patient with CADASIL who experienced “an acute bilateral subcortical infarction” because of“hemodynamic changes and hypercoagulability”. In genetic testing, we discovered a new Cys484Tyr mutation in exon 9, which has also been found in the patient’s two daughters.ConclusionsIt is important to note that this discovery not only expands the mutation spectrum of Notch3 mutations in CADASIL patients, but also examines the mechanism behind acute bilateral subcortical infarction in CADASIL patients via case reviews and literature reviews, in order to provide some clinical recommendations for early intervention, diagnosis, and treatment in similar cases in the future.

Decreased retinal vascular density is associated with cognitive impairment in CADASIL: an optical coherence tomography angiography study.

This study aimed to assess alterations in retinal vascular density in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients using optical coherence tomography angiography (OCTA) and investigate their association with MRI and cognitive features. Twenty-five patients with CADASIL and forty healthy controls were evaluated by Cirrus HD-OCT 5000 with AngioPlex OCTA to determine changes in macular retinal vasculature. Retinal vasculature parameters between two groups were compared. The MRI lesion burden and neuropsychological scales were also examined in patients. The association between OCTA parameters and MRI/cognitive features was evaluated using partial Spearman rank correlation. The vessel density and perfusion density of whole image in macular region (vessel density: t =  - 2.834, p = 0.005; perfusion density: t =  - 2.691, p = 0.007) were significantly decreased in patients with CADASIL. Moreover, vessel density of whole image in macular region was negatively associated with Fazekas scores (ρ =  - 0.457; p = 0.025) and the number of lacunar infractions (ρ =  - 0.425, p = 0.038) after adjustment for age. Decreased macular vessel density and perfusion density of whole image were also associated with MoCA scores (vessel density: ρ = 0.542, p = 0.006; perfusion density: ρ = 0.478, p = 0.018) and other domain-specific neuropsychological tests (p < 0.05) after adjustment for age. Decreased retinal vascular density was associated with increased MRI lesion burden and cognitive impairment in patients with CADASIL. Our findings suggest that the degree of retinal vascular involvement, as demonstrated by OCTA, may be consistent with the severity of MRI lesions and the degree of cognitive impairment in patients.

Progress to Clarify How NOTCH3 Mutations Lead to CADASIL, a Hereditary Cerebral Small Vessel Disease.

Notch signaling is conserved in C. elegans, Drosophila, and mammals. Among the four NOTCH genes in humans, NOTCH1, NOTCH2, and NOTCH3 are known to cause monogenic hereditary disorders. Most NOTCH-related disorders are congenital and caused by a gain or loss of Notch signaling activity. In contrast, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 is adult-onset and considered to be caused by accumulation of the mutant NOTCH3 extracellular domain (N3ECD) and, possibly, by an impairment in Notch signaling. Pathophysiological processes following mutant N3ECD accumulation have been intensively investigated; however, the process leading to N3ECD accumulation and its association with canonical NOTCH3 signaling remain unknown. We reviewed the progress in clarifying the pathophysiological process involving mutant NOTCH3.

Distinctive feeding vessel architecture and sparse collateralization may underlie the characteristic early temporal pole and external capsule white matter compromise in CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic cause of stroke. Mutations in the NOTCH3 gene cause vasculopathic changes predominantly involving medium and small brain arteries leading to progressively impaired cerebrovascular autoregulation, hypoperfusion, and ischemia. Magnetic resonance neuroimaging of CADASIL patients shows progressive white matter hyperintensity and accumulation of deep infarcts. Though these findings resemble in many respects changes seen in hypertensive cerebral small vessel disease, CADASIL is distinguished by early and extensive involvement of two regions: the white matter of the anterior temporal poles and the external capsules. Despite the longstanding reliance on presence of these findings to render a diagnosis of CADASIL, to our knowledge no pathophysiologic explanation has hitherto been advanced for the early and extensive temporal pole and external capsule. This paper advances the hypothesis that two distinctive features of the vascularization of temporal polar and external capsule white matter underly their early injury in CADASIL. First, the intermediate lumen diameters (0.75–1.00 mm) and the obtuse takeoff angles of the temporopolar artery (supplying temporal pole white matter) and the lateral lenticulostriate arteries (supplying the external capsule) cause intensified radial and sheer wall stress and vessel injury. Second, the sparse collateral supply to these regions potentiates the ischemic insult from compromise of directly supplying vessels.

A multicenter, single-arm, phase II clinical trial of adrenomedullin in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of hereditary cerebral small vessel disease (SVD), currently lacks disease-modifying treatments. Adrenomedullin (AM), a vasoactive peptide with angiogenic, vasodilatory, anti-inflammatory, and anti-oxidative properties, shows potential effects on the neuro-glial-vascular unit. ObjectiveThe AdrenoMedullin for CADASIL (AMCAD) study aims to assess the efficacy and safety of AM in patients with CADASIL. Sample sizeOverall, 60 patients will be recruited. MethodsThe AMCAD is a multicenter, investigator-initiated, single-arm phase II trial. Patients with a confirmed CADASIL diagnosis, based on NOTCH3 genetic testing, will receive an 8-h AM treatment (15 ng/kg/min) for 14 days following a baseline assessment (from day 1 to day 14). Follow-up evaluations will be performed on days 15, 28, 90, and 180. Study outcomesThe primary endpoint is the cerebral blood flow change rate in the frontal cortex, evaluated using arterial spin labeling magnetic resonance imaging, from baseline to day 28. Summary statistics, 95% confidence intervals, and a one-sample t-test will be used for analysis. ConclusionThe AMCAD study aims to represent the therapeutic potential of AM in patients with CADASIL, addressing an unmet medical need in this challenging condition. Clinical Trial RegistrationjRCT 2,051,210,117 (https://jrct.niph.go.jp/en-latest-detail/jRCT2051210117).

A Patient with Severe Headache and Uncontrolled Blood Pressure in the Emergency Department: A Case Report

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare angiopathy inherited in an autosomal dominant manner. Because it manifests as nonspecific symptoms such as migraine with aura, ischemic stroke and transient ischemic attack, cognitive impairment, and dementia, the diagnosis may begin with a physician’s suspicion. Here, we describe a 69-year-old female patient with severe headaches and uncontrolled blood pressure at our emergency department and been diagnosed with CADASIL.

Comparison of models for stroke-free survival prediction in patients with CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, which is caused by mutations of the NOTCH3 gene, has a large heterogeneous progression, presenting with declines of various clinical scores and occurrences of various clinical event. To help assess disease progression, this work focused on predicting the composite endpoint of stroke-free survival time by comparing the performance of Cox proportional hazards regression to that of machine learning models using one of four feature selection approaches applied to demographic, clinical and magnetic resonance imaging observational data collected from a study cohort of 482 patients. The quality of the modeling process and the predictive performance were evaluated in a nested cross-validation procedure using the time-dependent Brier Score and AUC at 5 years from baseline, the former measuring the overall performance including calibration and the latter highlighting the discrimination ability, with both metrics taking into account the presence of right-censoring. The best model for each metric was the componentwise gradient boosting model with a mean Brier score of 0.165 and the random survival forest model with a mean AUC of 0.773, both combined with the LASSO feature selection method.

Case Report: Cerebral Autosomal Dominant Arteriopathy with Sub-Cortical Infarcts and Leukoencephalopathy (CADASIL) with Ataxia

Mood disorders, cognitive decline, headaches, and stroke are among the key symptoms of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, or CADASIL [1]. Rarely, ataxia has been noted as a presenting ailment in this case [2]. A man 48 years of age showed signs of developing ataxia. Magnetic resonance imaging (MRI) of the brain showed focal tiny infarct in lest internal capsule, subacute intraparenchymal hemorrhage involving lest temporal lobe, few old lacunal infarct in bilateral ganglio capsular region, right thalamus and bilateral fronto-parietal periventricular white matter. A mutation in the NOTCH3 gene was verified through genetic testing. It found a variant c.268C&gt;T (p.Arg90Cys). We also address the potential etiology of cerebellar ataxia linked to CADASIL and other factors that could lead to a different differential diagnosis. CADASIL is an uncommon cause of progressive ataxia.

Treatment with Cerebrolysin Prolongs Lifespan in a Mouse Model of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare familial neurological disorder caused by mutations in the NOTCH3 gene and characterized by migraine attacks, depressive episodes, lacunar strokes, dementia, and premature death. Since there is no therapy for CADASIL the authors investigate whether themulti-modal neuropeptide drug Cerebrolysin may improve outcome in a murine CADASIL model. Twelve-month-old NOTCH3R169C mutant mice (n=176) are treated for nine weeks with Cerebrolysin or Vehicle and histopathological and functional outcomes are evaluated within the subsequent ten months. Cerebrolysin treatment improves spatial memory and overall health, reduces epigenetic aging, and prolongs lifespan, however, CADASIL-specific white matter vacuolization is not affected. On the molecular level Cerebrolysin treatment increases expression of Calcitonin Gene-Related Peptide (CGRP) and Silent Information Regulator Two (Sir2)-like protein 6 (SIRT6), decreasesexpression of Insulin-like Growth Factor 1 (IGF-1), and normalizes the expression of neurovascular laminin. In summary, Cerebrolysin fosterslongevity and healthy aging without specifically affecting CADASIL pathology. Hence, Cerebrolysin may serve a therapeutic option for CADASIL and other disorders characterized by accelerated aging.

Accelerated cerebral amyloid angiopathy and vascular alterations in a mixed mouse model of Alzheimer’s disease and cerebral small vessel disease

AbstractBackgroundWhile aging is the primary risk factor for Alzheimer’s disease (AD), emerging evidence suggests that vascular dysfunction, present in cerebral small vessel diseases (CSVD) such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is also a major contributor for disease progression. Indeed, several studies have provided clinical evidence for a close synergistic relationship between AD and CSVD in cases where both diseases coexist. CSVD can elicit amyloid pathology, while Alzheimer’s‐associated cerebral amyloid angiopathy (CAA) and Ab plaque deposition may lead to concomitant vascular damage. Mutations in genes such as APP, PSEN1, and PSEN2 are not limited to AD, as APP mutations can also cause CAA, while PSEN1 and PSEN2 are involved in Notch3 signaling, a process known to be dysregulated in CADASIL. Here, we aimed to investigate the additive or synergistic effects of amyloid pathology and CADASIL‐related vascular damage on disease progression.MethodTo explore alterations in amyloid and vascular pathology when AD and CADASIL‐related CSVD coexist, we used PET/CT and histology to analyze over time the amyloid deposition in the form of plaques and CAA in a relevant mouse model of AD (5xFAD) carrying the Notch3 C456R mutation that causes CADASIL. Methoxy‐X04, Thioflavin‐S, or 6E10 were used to visualize amyloid accumulation in fixed brain tissues. The progression of microvascular dysfunction and neuroinflammation were assessed by immunofluorescence staining, Western blotting, RNA sequencing, and real‐time PCR.ResultAdult 5xFAD‐Notch3C456R mice showed accelerated parenchymal and vascular amyloid deposition compared to 5xFAD mice. Progressive gliosis and microvascular damage were concomitant to parenchymal and vascular amyloid accumulation. These changes were associated with blood‐brain barrier disruption and reduction in pericyte coverage of cerebral capillaries.ConclusionWe found accelerated amyloid plaque deposition, CAA, gliosis, and vascular damage in a mixed murine model of AD and CADASIL, suggesting that CSVD‐associated vascular changes directly contribute to AD pathology. This model offers novel opportunities to investigate the intricate interplay between CSVD and AD. This research was funded by NIH/NINDS grant RF1NS117486.

Early biomarkers of vascular brain dysfunction

AbstractCerebral small vessel disease (cSVD) is a major cause of brain degeneration and dementia for which we have no therapies. My lab applies new molecular omics technology to human biospecimen for an initial unbiased approach to discovery of clinically‐relevant dysregulated molecular pathways in humans living with disease. A major obstacle is lack of in vivo gold standards. As such, we have focused our efforts on an autosomal dominant form of disease–CADASIL (Cerebral Autosomal Dominant Arteriopathy Subcortical Infarcts and Leukoencephalopathy) caused by mutations in NOTCH3. Given its autosomal dominant nature, CADASIL provides a unique opportunity to build an all‐in‐human modeling pipeline for discovery of biomarkers and therapeutics for VCID. We take a systems biology approach, using brain tissue, plasma and patient‐derived stem cells to model disease and uncover biomarkers as well as therapeutic targets. We then perform cross‐disease comparisons with other cSVD subtypes, such as hypertensive cSVD and Cerebral Amyloid Angiopathy to identify shared pathologies. Finally, we investigate the relevance of uncovered molecular pathways to brain dysfunction and degeneration in prevalent neurodegenerative disease syndromes such as AD, FTD, and PD.

Contribution of the APOE Genotype to Cognitive Impairment in Individuals With NOTCH3 Cysteine-Altering Variants.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most prevalent monogenic cerebral small-vessel disease. Phenotype variability in CADASIL suggests the possible role of genetic modifiers. We aimed to investigate the contributions of the APOE genotype and Neurogenic locus notch homolog protein 3 (NOTCH3) variant position to cognitive impairment associated with CADASIL. Patients with the cysteine-altering NOTCH3 variant were enrolled in a cross-sectional study, including the Mini-Mental State Examination (MMSE), brain magnetic resonance imaging, and APOE genotyping. Cognitive impairment was defined as an MMSE score <24. The associations between the MMSE score and genetic factors were assessed using linear regression models. Bayesian adjustment for confounding was used to identify clinical confounders. A total of 246 individuals were enrolled, among whom 210 (85%) harbored the p.R544C variant, 96 (39%) had cognitive impairment, and 150 (61%) had a history of stroke. The APOE ɛ2 allele was associated with a lower MMSE score (adjusted B, -4.090 [95% CI, -6.708 to -1.473]; P=0.023), whereas the NOTCH3 p.R544C variant was associated with a higher MMSE score (adjusted B, 2.854 [95% CI, 0.603-5.105]; P=0.0132) after adjustment for age, education, and history of ischemic stroke. Mediation analysis suggests that the associations between the APOE ɛ2 allele and MMSE score and between the NOTCH3 p.R544C variant and MMSE score are mediated by mesial temporal atrophy and white matter hyperintensity, respectively. APOE genotype may modify cognitive impairment in CADASIL, whereby individuals carrying the APOE ɛ2 allele may present a more severe cognitive impairment.

Abstract 017: Rapid Progression Of Microhemorrhage In A Patient With An Atypical CADASIL Variant

Introduction CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a rare inherited disorder in which thickening occurs in the walls of small and medium‐sized blood vessels, which results in decreased cerebral blood delivery. CADASIL is most often established as a diagnosis with identification of a heterozygous pathogenic variant of the NOTCH3 gene by way of molecular genetic testing. In this abstract we identify an atypical presentation of CADASIL with a heterozygous pathologic variant of the HTRA1 gene. This case is unusual in its late onset, as the disease typically presents in the third to fourth decade of life. Additionally, the prevalence of microbleeds in CADASIL typically correlates with patient age. Methods Electronic charts of a patient with recurrent strokes and positive genetic testing were reviewed. Results A 63‐year‐old right‐handed African American male with hypertension, hyperlipidemia, diabetes mellitus, and a history of cerebrovascular disease and cervical myelopathy initially presenting in 2020 lower extremity weakness and progressive apraxia of speech. He had a documented history of transient‐ischemic attack and was noted to have undergone progressive cognitive decline. His presentation raised concern for etiology such as vasculitis or multiple sclerosis and prompted a genetic workup, which was obtained on outpatient follow‐up. The patient presented several more times emergently with similar symptoms that included the reoccurrence and progression of his spastic lower extremity weakness as well as the development of a pseudo‐bulbar affect. Initial MRI brain demonstrated areas of DWI hyperintensity scattered throughout the bilateral hemispheres without ADC correlation. Post‐contrast T2 sequencing demonstrated hyperintensities in the callosal splenium and left centrum semiovale. Genetic testing consisting of Hereditary Cerebral Small Vessel Disease and Hereditary Spastic Paraplegia panels through Invitae were obtained. The first panel evaluates 10 genes for variants which are associated with hereditary forms of cerebral small vessel disease, encompassing those conditions in which small arteries, arterioles, venules, and capillaries of the brain are compromised. The Hereditary Cerebral Small Vessel Disease genetic panel resulted in the positive identification of a likely‐pathogenic variant of the HTRA1 gene, which is associated with CADASIL 2. The Hereditary Spastic Paraplegia genetic panel was unremarkable, as were CSF studies obtained for evaluation of a demyelinating or inflammatory cause. Repeat MRI obtained twice more over the patient’s repeated presentations and demonstrated a large interval increase in areas of low‐signal gradient echo over the course of approximately three months, which represented an evolution in the number of microhemorrhages beyond what would be expected in such a short period of time. Conclusion Scientific literature describes the prevalence of microhemorrhages in CADASIL to be somewhere between 38‐75%. However, there have been few studies which detail such a rapid progression of microhemorrhages in this patient population as well as such a late progression of the disease. Our case demonstrates a unique presentation of CADASIL and provides a remarkable example of rapid, late‐in‐life disease presentation. Further research is needed to elucidate and characterize disease leading to early diagnosis and management.

Modifiable vascular risk factors for outcomes in patients with CADASIL: A literature review and meta-analysis of cross-sectional analyzes

ObjectiveTo investigate the association between outcomes of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and common modifiable vascular risk factors. MethodsStudies published between 1993 and February 2023 from PubMed, Embase, Cochrane, CNKI, and WanFang, along with their references, were systematically examined. Cross-sectional analyzes in patients with CADASIL with information on modifiable cerebrovascular risk factors and outcomes were included. Meta-analysis was conducted if at least three studies were available for each risk factor and outcome. ResultsWe included nine studies and 1687 samples in the analysis. The results of the meta-analysis showed that hypertension was positively associated with stroke in patients with CADASIL (OR = 2.69; 95 % CI: 2.02–3.57). Other vascular risk factors, including diabetes mellitus, dyslipidemia, hyperhomocysteinemia, smoking, alcohol drinking, and obesity, did not show stable correlations between the three outcomes (stroke, dementia, and disability). ConclusionsHypertension was significantly associated with stroke in patients with CADASIL. The role of other vascular risk factors in CADASIL and its outcomes: stroke, dementia, and disability, remains ambiguous.

Detecting a Novel NOTCH3 Variant in Patients with Suspected CADASIL: A Single Center Study

Introduction: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of familial cerebral small vessel disease in adults and is caused by NOTCH3 variants. Clinical manifestations of CADASIL include recurrent ischemic strokes, dementia, migraine or migraineous headaches, epileptic seizures, and psychiatric disorders. The clinical-radiological phenotype of the disease is also highly variable. In this study, we investigated the variability of clinical, radiological, and genetic data in patients analyzed for NOTCH3 variant in our clinic. Methods: We performed clinical and neuropsychological examination, cerebral magnetic resonance imaging (MRI) and Doppler sonography of cerebral arteries in all patients. Next-generation sequencing test was used for detect variants in NOTCH3 gene from all CADASIL patients. Results: By using the next-generation sequencing method, heterozygous c.380C>T pathogenic variant was detected in the 4th exon of the NOTCH3 gene in 3 patients. This is a previously unreported novel variant and resulted in the replacement of the amino acid Proline at 127th position with Leucine. Discussion and Conclusion: The discovery of this novel pathogenic variant region may contribute to the expansion of the clinical and genetic spectrum of diseases associated with NOTCH3, leading to further research and treatment options for this disease in the future.