Citations

Introduction: Cerebral Amyloid Angiopathy (CAA) is caused by the progressive deposition of β-amyloid in the walls of small to medium-sized cerebral vessels. Although seizures represent a debilitating manifestation of CAA, little is known about their prevalence or associated factors. We aim to fill this gap by determining the prevalence of seizures in CAA and identify factors associated with an increased risk of seizures. Methods: We identified consecutive patients with CAA, evaluated within the Mayo Clinic health system between January 2010 and December 2023 using the ICD-10 code. Data on demographics and comorbidities were compared between those with and without seizures using the chi-square test for categorical variables and independent samples t-test for continuous variables. Odds ratios (OR) were estimated after adjusting for age, sex, and race in multivariable logistic regression. Results: We included 1,914 patients with CAA with a mean age of 75.4 ± 8.6 years, of whom 52.3% were female and 87.5% were white. Seizures were observed in 347 patients (18.1%). Individuals with seizures were significantly younger (mean age 67.7 ± 9.1 vs. 77.2 ± 7.5 years, p < 0.001). Multivariable modeling identified alcohol abuse (OR 1.92, 95% CI 1.03-3.56, p=0.04), diabetes mellitus (OR 2.14, 95% CI 1.13-4.06, p=0.02), hypertension (OR 1.79, 95% CI 1.33 - 2.41, p= <0.001), liver disease (OR 1.75, 95% CI 1.14-2.69, p=0.01), and ischemic stroke (OR 1.33, 95% CI 1.01-1.74, p=0.04) as independently associated with an increased risk of seizures. Conclusion: We found that seizures affect nearly one in five patients with CAA. Also, comorbidities such as alcohol abuse, diabetes mellitus, hypertension, liver disease, and ischemic stroke were found to be significantly associated with an increased risk of seizures. Longitudinal studies are warranted to confirm these risk factors, some of which may be modifiable.

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.

Introduction: Extracranial carotid artery pathology accounts for 15-20% of ischemic strokes. Advancements in magnetic resonance angiography (MRA) with vessel wall imaging (VWI) have enabled the identification of vulnerable plaques, aiding in risk stratification for neurovascular events. This pilot study aimed to identify proteins in plaques with and without vulnerable features on MRA with VWI. Hypothesis: There is a differential proteomic profile of vulnerable and non-vulnerable, thus, these can serve as potential biomarkers for disease progression, stroke prevention, and therapeutic targets. Methods: Consecutive patients undergoing carotid endarterectomy (CEA) were included in the study cohort with pre-operative MRA with VWI. A retrospective chart review was conducted to extract pertinent clinical data including cardiovascular risk factors and medications. The proteomic analysis involved Tandem Mass Tag (TMTpro) labeling of peptides, basic pH HPLC fractionation, and NanoLC-tandem mass spectrometry. Results: A total of sixteen plaques were retrieved from fifteen patients. There were 73.3% male patients. The most common comorbidities were hyperlipidemia (93.3%) and hypertension (80%). 31.2% of patients had symptomatic disease. Eleven plaques were vulnerable in preoperative MRI with VWI. From those, intraplaque hemorrhage was the most common feature (81.1%) . Proteomic analysis revealed 23 relevant proteins significantly elevated in vulnerable plaques, including Proteinase 3 (PRTN3), Phospholipid Transfer Protein (PLTP), and S100 Calcium-Binding Protein A12 (S100A12), with increased abundance exceeding two-fold changes or above (P<0.001). Conversely, three proteins exhibited reduced abundance in vulnerable plaques including Dynamin-3 (DNM3), Transmembrane Protein 181 (TMEM181), and Adducin-3 (ADD3) (P<0.05). All results are summarized in Figure 1A-C and Table I and II. Conclusion: This study contributes to the understanding of protein biomarkers associated with carotid plaque vulnerability, offering insights into disease progression, stroke prevention, and identification of potential therapeutic targets (Figure 1D) . Furthermore, these patients could benefit from early surgical intervention if these biomarkers were to be detected. We present a comprehensive study of multiple proteins with significant bioavailability in explanted plaque specimens that can serve as a foundation for identifying blood biomarkers for future validation studies.

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.