Shourav, Md Manjurul Islam

Introduction: Migraine with aura may be the earliest symptom in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Female patients have a higher incidence of migraine with an increased associated disability. In this study, we systematically evaluate the clinical features and management of migraine in female patients with CADASIL in a multi-center health system. Methods: Clinical data was extracted from the electronic medical records of female patients diagnosed with CADASIL and managed at Mayo Clinic Enterprise. Diagnosis was confirmed by a pathogenic NOTCH3 mutation or granular osmiophilic material on skin biopsy. Results: Forty-three female patients with CADASIL were identified. Twenty-two patients (51.2%) had a diagnosis of migraine with aura and eight patients (18.6%) had a diagnosis of migraine without aura. The most common type of aura was visual (81.8%). Nineteen patients (63.3%) required at least one acute medicine and/or one preventive medicine. Acute therapy helped in 18 cases (94.7%) and preventive therapy helped in 13 cases (68.4%). Six patients (20%) tried at least three forms of acute therapy, and eleven patients (36.7%) tried at least three forms of preventive therapy. The presence of visual aura was associated with higher likelihood of need for acute therapy (OR = 3.0, 95% CI = 1.6 - 5.8, P = 0.015). However, the presence of any type of aura was associated with lower likelihood of need for or resistance to preventive therapy (OR = 0.08, 95% CI = 0.01 - 0.57, P = 0.005). Also, headache onset after age of 45 years was associated with higher likelihood of need for or resistance to preventive therapy (OR = 38.0, 95% CI = 2.7 - 528.0, P <0.001). The most common acute therapy was nonsteroidal anti-inflammatory drugs (NSAIDs) (14, 73.7%). Classes of preventive therapy involved anticonvulsants (15, 78.9%), antidepressants (11, 57.9%), Botox injections (7, 36.8%), beta blockers (6, 31.6%), calcium channel blockers (3, 15.8%), and calcitonin gene-related peptide (CGRP) inhibitors (3, 15.8%). Conclusion: Half of female patients with CADASIL had a diagnosis of migraine with aura. Around two thirds of them tried at least one form of acute therapy, most commonly NSAIDs, or preventive therapy, most commonly anticonvulsants. Resistance to preventive therapy was seen in more than 30% of the cases, highlighting the need for advances in migraine management in CADASIL.

Introduction: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral small vessel disease, yet there is currently no biomarker for early detection. This study aims to identify retinal biomarkers of NOTCH3 carriers using optical coherence tomography (OCT) from the UK Biobank. Methods: We conducted a cross-sectional, matched case-control study of individuals with or without CADASIL from the UK Biobank between 2006 and 2010. All participants had retinal OCT scan and cognitive assessment. Cases were identified based on pathogenic NOTCH3 mutations and 1:1 matched with healthy controls based on age, sex, hypertension, diabetes mellitus, and smoking status. Baseline characteristics and cognitive test scores were compared using chi-square or Mann-Whitney-U test appropriately. Macular thickness (central, inner, and outer subfields) (Figure) and retinal nerve fiber layer (RNFL) thickness were compared using Wilcoxon signed-rank test. Results: Our analysis included 134 participants (67 CADASIL cases, 67 controls) with a mean age of 54±8 years. There were no differences in visual acuity between the two groups. CADASIL performed worse in prospective memory (0.043), verbal and numerical reasoning (p=0.178), visual memory (p=0.227), and processing speed (p=0.101) than matched controls. Participants with CADASIL had significantly thinner macular inner subfield at the superior (p=0.006), temporal (p=0.008), and nasal (p=0.034) quadrants, and significantly thinner RNFL (p=0.008) compared to controls (Table). Conclusion: Individuals with CADASIL have reduced thickness in the inner macular subfield and RFNL relative to matched controls. These retinal group differences were not associated with differences in visual acuity and may reflect early pericyte dysfunction and microvascular ischemia. Longitudinal studies are needed to assess the temporal relationship between these retinal changes and disease progression.

Background: Intracranial atherosclerosis (ICAS) is a common stroke cause, with a recurrent stroke risk of up to 18% per year despite treatment advances. Although lipid-lowering therapies reduce cardiovascular events, their effect on stroke risk in ICAS remains unclear. Objective: To perform a systematic review and meta-analysis assessing the efficacy of lipid-lowering therapies in improving stroke outcomes among patients with ICAS. Methods: A systematic search of PubMed, Embase, Web of Science, Cochrane, and other databases was conducted from inception to November 2023. Eligible studies compared lipid-lowering therapies (Statins and PCSK9i) to standard care or placebo in patients with ICAS. The primary outcome was the incidence of stroke. Pooled relative risks (RR) with 95% confidence intervals (CI) were calculated using a random-effects model, and forest plots were constructed. Chi-square and I 2 statistics were used to assess heterogeneity. Results: Seven observational studies and two randomized controlled trials involving 1,902 ICAS patients were included. Of these, 801 received lipid-lowering therapy, and 1,101 received standard care or placebo. The weighted mean follow-up was 17.6 months (IQR 9.75-25.5). The weighted mean age was 63.7 years (range 55-68) for the lipid-lowering group and 64.0 years (range 50-66) for controls. Females comprised 42% of both groups. Hypertension was present in 74% of the intervention group and 71% of controls. A history of stroke was reported in 32% of the intervention group and 29% of controls. The weighted mean baseline LDL level was 105 mg/dL in the intervention group and 107 mg/dL in controls. The weighted mean change in LDL pre- and post-treatment in the intervention group was -47.18 mg/dL, compared to -12.39 mg/dL in controls. The incidence of ischemic stroke was 5.0% (40/801) in the lipid-lowering group versus 13.0% (143/1,101) in controls (RR 0.40; 95% CI 0.24-0.64; P<0.001, Figure 1a). Subgroup analysis of studies comparing statin versus no statin treatment showed an RR of 0.40 (95% CI 0.30-0.92; P<0.05, Figure 1b). Another subgroup analysis comparing PCSK9 inhibitors and statins versus statins only found an RR of 0.44; 95% CI 0.20-0.96; P<0.05, Figure 1c). Conclusions: Lipid-lowering therapies significantly reduce the risk of ischemic stroke in patients with intracranial atherosclerosis. The addition of PCSK9 inhibitors to statins appears to provide added stroke risk reduction.

Background: Carotid stenosis has been associated with stroke and cognitive impairment. It remains unclear if hypometablism, a marker for neurodegeneration, may be in the mechanistic pathway in the association between carotid stenosis and cognitive decline. This study aims to investigate whether patients with carotid stenosis exhibit reduced cerebral glucose metabolism, using 18-FDG PET imaging as a sensitive measure of brain’s glucose metabolism. Methods: We have identified 138 patients from one health care system who underwent 18-FDG PET imaging and had extracranial carotid imaging (doppler ultrasound/CT angiography/MR angiography) within 1 year of PET scan. Severity of carotid stenosis was defined using NASCET criteria as <50% (mild), 50-69% (moderate), >70% (high-grade). Cerebral glucose metabolism was quantified by measuring standardized uptake value ratio (SUVR) after normalizing to pons in 12 different regions of interest (ROI). Hypometabolism was defined using the cutoff of SUVR <1.41. SUVR and hypometabolism measures were compared across severity of carotid stenosis. Results: Of 138 patients identified, 54 were excluded due to indeterminant ipsilateral hemisphere status. Mild, moderate and severe stenosis was present in 86.9%, 4.8%, 8.3%, respectively. The analysis revealed a numerically reduced cerebral glucose metabolism in patients with moderate to severe carotid stenosis compared to control subjects (Table 1). The most pronounced decrease in FDG uptake was observed in regions supplied by the affected carotid artery, particularly the ipsilateral cortical areas. There was a numerically increased risk of hypometabolism with increasing carotid stenosis: Adjusted odds of hypometabolism ipsilateral to the carotid stenosis were 2.90, 5.56 across patients with moderate and high-grade carotid stenosis in sensorimotor cortex (trend-P=0.095). These findings were consistent across different regions supplied by the stenotic carotid artery but attenuated in territories supplied by unaffected posterior arteries (Table 2). Conclusions: FDG-PET imaging demonstrates reduced glucose metabolism in patients with carotid stenosis, suggesting that cerebral hypoperfusion may contribute to the metabolic disturbances observed in these patients. These results underscore the importance of early detection and management of carotid stenosis to mitigate potential cerebral metabolic deficits and the associated risk of dementia and ischemic stroke.

Importance Typical cysteine-altering NOTCH3 ( NOTCH3 cys ) variants are highly prevalent (approximately 1 in 300 individuals) and are associated with a broad spectrum of small vessel disease (SVD), ranging from early-onset stroke and dementia (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) to nonpenetrance. A staging system that captures the full NOTCH3 -SVD severity spectrum is needed and currently lacking. Objective To design a simple disease severity staging system that captures the broad clinicoradiological NOTCH3 -SVD severity spectrum. Design, Setting, and Participants A cohort study was performed in which the NOTCH3 -SVD severity staging system was developed using a discovery cohort (2019-2020) and validated in independent international CADASIL cohorts (1999-2023) and the UK Biobank. Clinical and imaging data were collected from participants originating from 23 international CADASIL cohorts and from the UK Biobank. Eligibility criteria were presence of a NOTCH3 cys variant, availability of brain magnetic resonance imaging, and modified Rankin Scale score. The discovery cohort consisted of 195 NOTCH3 cys -positive cases from families with CADASIL; the validation set included 1713 NOTCH3 cys -positive cases from 15 countries. The UK Biobank cohort consisted of 101 NOTCH3 cys -positive individuals. Data from 2-year (2019-2023) and 18-year (1999-2017) follow-up studies were also analyzed. Data analysis was performed from July 2023 to August 2024. Main Outcomes and Measures Percentage of cases following the sequence of events of the NOTCH3 -SVD stages, and the association between the stages and ischemic stroke, intracerebral hemorrhage, global cognition, processing speed, brain volume, brain microstructural damage, and serum neurofilament light chain (NfL) level. Results The NOTCH3 -SVD staging system encompasses 9 disease stages or substages, ranging from stage 0 (premanifest stage) to stage 4B (end stage). Of all 1908 cases, which included 195 in the discovery cohort (mean [SD] age, 52.4 [12.2] years) and 1713 in the validation cohorts (mean [SD] age, 53.1 [13.0] years), 1789 (94%) followed the sequence of events defined by the NOTCH3 -SVD staging system. The NOTCH3 -SVD stages were associated with neuroimaging outcomes in the NOTCH3 cys -positive cases in the CADASIL cohorts and in the UK Biobank and with cognitive outcomes and serum NfL level in cases from the CADASIL cohorts. The NOTCH3 -SVD staging system captured disease progression and was associated with 18-year survival. Conclusions and Relevance The NOTCH3 -SVD staging system captures the full disease spectrum, from asymptomatic individuals with a NOTCH3 cys variant to patients with end-stage disease. The NOTCH3 -SVD staging system is a simple but effective tool for uniform disease staging in the clinic and in research.