Background: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) can be misdiagnosed as multiple sclerosis (MS). This study aims to contrast demographic, clinical, neuroimaging, and genetic features of CADASIL patients with vs. without prior MS misdiagnosis. Methods: We conducted a retrospective cohort study to compare genetically or histopathologically confirmed CADASIL patients with and without a prior MS misdiagnosis across Mayo Clinic. Patients were classified into high-, medium-, low-, or unknown-risk by location of NOTCH3 mutation. Disease severity was assessed using NOTCH3 Small-Vessel Disease (N3SVD) scale. Between-group comparisons used independent t-test for age, chi-square or Fisher’s exact test for categorical variables, and Mann–Whitney U test for quantitative variables. Within the misdiagnosed subgroup, neuroimaging changes between MS to CADASIL diagnosis were assessed using Wilcoxon signed-rank test for quantitative data and Stuart–Maxwell test for categorical data. Significance was set at p<0.05 (two-sided). Results: Among 107 patients (mean age 57.5±13.4 yrs) with CADASIL, 12 (11.2%) had a prior MS misdiagnosis (Table 1). Compared to patients without misdiagnosis (n=95), those misdiagnosed were younger, more frequently Asian, more likely to undergo lumbar puncture (83.3% vs 26.3%, p <0.001), and less likely to have had stroke (33.3% vs 65.3%, p =0.031). There were no significant differences in deep white matter hyperintensity scores or lacune counts. However, the misdiagnosed group had a higher median modified Rankin Scale ( p =0.008) and a different distribution of N3SVD stages ( p =0.017), with a higher proportion in stage 3A (33.3% vs 5.3%). There was no significant difference in genetic risk categories (Figure), but 5 of 12 misdiagnosed cases clustered in the medium risk EGFR 13, 13.5, and 14 domains. Among the misdiagnosed, 41.7% received MS-specific treatment during a median of 10.2 months (range 0.4–138.1) before diagnostic correction (Table 2). Over this period, there were no significant changes in DWMH score, lacune count, mRS, or N3SVD stage (all p >0.05). Conclusions: About one in nine CADASIL patients had a prior MS diagnosis. Atypical presentations in younger individuals without a clear stroke history may prompt consideration of MS over CADASIL, leading to diagnostic delays and unnecessary treatments. EGFR domain risk category did not correlate with misdiagnosis.

Introduction: Studies suggest that stroke and hypoperfusion from heart failure (HF) may contribute to cognitive decline. However, the relationship between the HF subtypes and cognition remains poorly described in real-world populations. Hypothesis: We hypothesized that HF subtypes are differentially associated with cognitive impairment and that lower left ventricular ejection fraction (LVEF) correlates with poorer cognitive performance. Methods: We conducted a cross-sectional study of patients aged ≥18 years seen at a Heath System in 2022 who underwent both echocardiogram and cognitive assessment within one year. HF was classified into four groups based on 2022 American Heart Association HF guideline: No heart failure, HFpEF (HF with preserved LVEF), HFmrEF (HF with mid-range LVEF), and HFrEF (HF with reduced LVEF). Cognitive impairment was categorized using the Montreal Cognitive Assessment (MOCA) as normal (≥26), mild (18–25), moderate (10–17), and severe (<10). Multivariable linear regression assessed the correlation between EF and MoCA, and logistic regression evaluated the association between HF subtypes and severity of cognitive loss, adjusting for age, sex, race, hypertension, diabetes, dyslipidemia, chronic kidney disease, stroke. Results: A total of 1,695 patients were included in the study (mean age, 75.3±14 years; 48.3% female). 82.0% had HFpEF; 7.1%, HFmrEF; 7.9%, HFrEF, and 3.0% no HF. LVEF was positively associated with MoCA score (β=0.028, p=0.032). Patients with LVEF ≤40% had lower MoCA scores (17.7 ± 6.2 vs. 19.1 ± 5.9, p=0.008) and higher adjusted odds of moderate/severe cognitive impairment (aOR 2.49, 95%CI 1.20-5.15, p=0.014), compared to those with LVEF >40%. Adjusted odds of moderate to severe cognitive impairment were 1.14 for HFpEF, 0.99 for HFmrEF, and 2.81 for HFrEF compared to patients with no heart failure (trend-P=0.031, Table). Conclusions: Lower LVEF was independently associated with worse cognitive performance. Patients with HFrEF had a 2.5-fold higher risk of moderate to severe cognitive impairment. This association was not observed in patients with HFpEF or HFmrEF, suggesting differential cognitive effects across HF subtypes. Further studies are warranted to confirm these findings and evaluate the impact of interventions targeting EF and HF subtypes on cognitive outcomes.

Objectives: Cerebral hemodynamic impairment in patients with asymptomatic high-grade internal carotid artery (ICA) stenosis confers a risk of stroke and cognitive decline, but correlations between degree of stenosis and hemodynamic impairment are derived from small case series only. Using baseline data from 282 participants in the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis – Hemodynamics (CREST-H) study, we hypothesized that degree of stenosis, measured by peak systolic velocity (PSV) and end diastolic velocity (EDV) in the ipsilateral ICA, would correlate with time-to-peak (TTP) delay using MR (n=275) or CT (n=7) perfusion scans, adjusting for demographic and cardiovascular risk variables. Methods: Using a 7-10MHz Doppler probe, ICA PSV and EDV were assessed. Doppler results were adjudicated centrally. Dynamic contrast perfusion imaging was standardized across 61 CREST-H sites, using sequential T2*-weighted time-sequence scanning (e.g. TR=1500, TE=25ms, flip angle=60deg, phase=128, slice thickness=5mm for GE 3T magnet). CTP was acquired with standard clinical protocols. TTP delay was calculated in the ipsilateral versus contralateral MCA/ACA territories using OLEA software. Linear regression used TTP delay as the outcome variable and PSV and EDV as predictor variables, adjusting for covariates.The 282 with complete data for all variables were included in the analysis. Results: Among 392 CREST-H participants, 63% were men, 7% Black, 3% Hispanic, 33% with less than college education. Tables 1a/b show the regression results for PSV and EDV as main predictor variables. PSV and EDV on the index side significantly correlated with TTP delay (p=0.004, p=0.002 respectively). Neither PSV nor EDV on the non-index side correlated with TTP delay (p=0.49, p=0.82). Compared with moderate exercise, vigorous exercise correlated with lower TTP delay in both models (p=0.05. p=0.04). Compared with college graduates, those with HS education had longer TTP delays in both models (p=0.03. p=0.02). Conclusions: In this large cohort of patients with high-grade asymptomatic carotid stenosis, higher flow velocities correlated with greater TTP delays, suggesting an increasing hemodynamic impairment with greater degree of stenosis above 70%. Our findings have implications for management of asymptomatic carotid stenosis which are being tested in the CREST-H and CREST-2 studies. Exercise and education may independently impact cerebral hemodynamics.

Background Plaque lipidomics generates molecular profiles that reflect plaque lipid metabolism and may reveal signatures of plaque vulnerability. Among lipid classes, ceramides and triglycerides (TAG) have been implicated in atherosclerosis, but their profiles in carotid plaque vulnerability have not been systematically evaluated. Objective By using liquid chromatography-tandem mass spectrometry (LC-MS/MS), untargeted global lipidomics was carried out to compare lipid profiles between vulnerable and nonvulnerable lesions as defined by magnetic resonance angiography with vessel wall imaging (MRA-VWI). Methods We performed a prospective single-center case-control study of plaque lipidomics comparing carotid plaques with and without vulnerable features as defined by MRA-VWI. Excised plaques were snap-frozen for lipidomics. Lipids were annotated and quantified using LC-MS/MS. Statistical analysis was performed to identify lipids showing significant differences between vulnerable and nonvulnerable plaques. Results Between April 2023 and August 2024, 28 patients were enrolled. A total of 400 lipid species across 27 subclasses from phospholipids, sphingolipids, fatty acids, sterols, and glycerides were characterized. Several classes of lipids including ceramides, hexosylceramides, monosialodihexosylganglioside, and TAGs were significantly higher in vulnerable plaques compared with nonvulnerable plaques. Conclusions Our findings highlight a distinct profiling of lipids in vulnerable plaques, which are associated with inflammation and structural remodeling. These lipid alterations may reflect biological processes involved in plaque destabilization and support lipidomics as a promising tool for biomarker discovery and potential therapeutic target in carotid artery disease. Clinical Relevance Assessment of plaque vulnerability is emerging as a clinically actionable strategy for risk stratification in extracranial carotid artery disease and stroke prevention. This study links in vivo magnetic resonance angiography with vessel wall imaging–defined vulnerability to an ex vivo lipidic profile, showing enrichment of ceramides, glycosphingolipids, gangliosides, and triglycerides in vulnerable carotid plaques. If validated, these lipid signatures could enable objective biomarkers to complement vessel wall imaging for risk stratification, timing of revascularization, and mechanistic targets for therapies aimed at plaque stabilization. Furthermore, this integrates imaging with lipid biology to advance precision vascular care.

Clinical evaluation of carotid artery stenosis predominantly relies on categories of stenosis derived from duplex ultrasound (DUS) Doppler velocity measurements. Quantification of plaque area and tissue composition from DUS B-mode images may facilitate risk-stratification of patients at risk for future stroke. The assessments may also facilitate quantification of the effectiveness of vascular risk-factor modification in changing plaque area and individual plaque tissue constituents. We analyzed the reliability and repeatability of semi-automatic quantification of plaque area and tissue-composition from DUS B-mode images obtained at enrollment of CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) participants. CREST-2 is a multi-center randomized trial comparing the effectiveness of surgery or stenting vs medical management to prevent stroke or death in asymptomatic ≥70% carotid stenosis. Patients undergo standardized DUS testing at enrollment and annually thereafter. Images are analyzed centrally at the University of Maryland Vascular Imaging Core Facility. Longitudinal B-mode images of the carotid bifurcation obtained at baseline from 100 randomly selected patients were analyzed in this study. Images underwent digital image-brightness normalization, manual plaque outlining, and automatic pixel brightness assessment to quantify area and tissue-composition using a custom MATLAB-based program. For intra-observer comparisons, one observer repeated the measurements 4 weeks later to prevent recall-bias. For inter-observer comparisons, a second blinded observer repeated each measurement independently. Output parameters included grayscale median (GSM), plaque area (PA), and tissue composition (area of plaque hemorrhage [HA], lipid [LA], fibrous [FA], muscle [MA] and calcified [CA] tissues). Reliability and repeatability of measurements was assessed using Bland-Altman plots and correlation coefficients. A total of 200 measurements were analyzed for intra-observer, and 200 for inter-observer comparisons of each output parameter in 100 patients. The mean ± SD of plaque measurements were GSM (43.2 ± 22.1), area (61.5 ± 30.5 mm2), HA (6.2 ± 10.7 mm2), LA (9.1 ± 8.1 mm2), FA (9.3 ± 10.1 mm2), MA (16.4 ± 10.2 mm2), and CA (1.8 ± 3.5 mm2). Twenty-three percent of patients had a high-risk plaque (GSM ≤25) at baseline. Plaque area (Fig 1), GSM, and tissue composition measurements each demonstrated low intra- and inter-observer variability on Bland-Altman plots. Intra- and inter-class correlation coefficients for each measurement were high (Fig 2). Standardized analysis of B-mode images obtained in CREST-2 for measuring plaque area, GSM, and tissue composition is feasible, reliable, and repeatable. These measurements can play an important role in measuring plaque progression or regression, in assessing the impact of medical therapy on plaques, and in identifying high-risk plaque features in CREST-2.Fig 2Output parameters for image analysis. Intra-plaque hemorrhage (Red), lipid (Yellow), fibrous (Aqua Blue), muscular (Green), and calcification (Blue) components in carotid plaque. The embedded table shows intra- and Inter-class correlation coefficients for gray scale median (GSM), plaque area, and tissue composition measurements.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Objective: To test the hypothesis that severity of carotid stenosis is inversely correlated with cognitive measures. Background: Studies have suggested that ischemic stroke from carotid stenosis may lead to cognitive impairment. However, the relationship between the degree of carotid stenosis and cognition has not been established. Design/Methods: We performed a cross-sectional study across one health care system, assessing patients with carotid Duplex ultrasound and the Montreal Cognitive Assessment (MoCA) that were done within one year from 2018 to 2022. Carotid stenosis was defined using Doppler velocity parameters as <50% normal, 50–69% moderate, 70–99% high-grade, and occluded. Cognition was quantified using MoCA where cognitive impairment was defined as MoCA <18. Multivariable regression analyses were performed to evaluate the linear relationship between carotid stenosis parameters and MoCA, and the odds of cognitive impairment across severity of carotid stenosis. Interaction analyses by age and stroke were performed. Results: Of 1,172 patients included in the study, 73.0%, 16.8%, 8.4% and 1.8% had normal, moderate, high-grade, and occluded carotids. Mean age was 73±12 years, 41.5% were female, 17.1% had prior stroke. ICA/CCA ratio was inversely associated with MoCA scores (β-coefficient=−0.362, p=0.010). Mean MoCA decreased with increasing degree of carotid stenosis (normal=20.8, moderate=20.4, high-grade=19.4, occluded=18.7;trend-p=0.021). There was a dose-dependent relationship between degree of carotid stenosis and cognitive impairment: Adjusted odds of cognitive impairment were 1.31, 2.14, 2.73 across patients with moderate, high-grade and occluded carotids (trend-P=0.016). Interaction analyses showed that age modified the relationship between carotid stenosis and cognition (p=0.003) where the association was observed in patients age ≥65 years (aOR=3.04, p=0.001) but not in age<65 years (aOR=0.46, p=0.175). No interaction was observed with stroke. Conclusions: Our study showed an inverse relationship between degree of carotid stenosis and cognition, particularly in patients 65 years or older. Future trials may consider testing whether carotid revascularization may prevent further cognitive decline in selected populations. Disclosure: Dr. Lin has nothing to disclose. Mr. Mateti has nothing to disclose. Dr. Erben has nothing to disclose. Dr. Barrett has nothing to disclose. The institution of Dr. Taner has received research support from NIH. Dr. Brott has nothing to disclose. The institution of Dr. Meschia has received research support from NINDS. The institution of Dr. Meschia has received research support from NINDS.

Objective To identify novel genes involved in the etiology of intracranial aneurysms (IAs) or subarachnoid hemorrhages (SAHs) using whole-exome sequencing. Methods We performed whole-exome sequencing in 13 individuals from 3 families with an autosomal dominant IA/SAH inheritance pattern to look for candidate genes for disease. In addition, we sequenced PCNT exon 38 in a further 161 idiopathic patients with IA/SAH to find additional carriers of potential pathogenic variants. Results We identified 2 different variants in exon 38 from the PCNT gene shared between affected members from 2 different families with either IA or SAH (p.R2728C and p.V2811L). One hundred sixty-four samples with either SAH or IA were Sanger sequenced for the PCNT exon 38. Five additional missense mutations were identified. We also found a second p.V2811L carrier in a family with a history of neurovascular diseases. Conclusion The PCNT gene encodes a protein that is involved in the process of microtubule nucleation and organization in interphase and mitosis. Biallelic loss-of-function mutations in PCNT cause a form of primordial dwarfism (microcephalic osteodysplastic primordial dwarfism type II), and ≈50% of these patients will develop neurovascular abnormalities, including IAs and SAHs. In addition, a complete Pcnt knockout mouse model (Pcnt−/−) published previously showed general vascular abnormalities, including intracranial hemorrhage. The variants in our families lie in the highly conserved PCNT protein-protein interaction domain, making PCNT a highly plausible candidate gene in cerebrovascular disease.