Purpose: Small dense low-density lipoprotein cholesterol (S-LDL-C) has been suggested as a particularly atherogenic factor for ischemic stroke (IS) in observational studies, but the causality regarding the etiological subtype remains unclear. This study aims to explore the causal effects of small dense low-density lipoprotein cholesterol (S-LDL-C), medium (M-LDL-C) and large (L-LDL-C) subfractions on the lifetime risk of ischemic stroke (IS) and main subtypes using two-sample Mendelian randomization (TSMR) design.Methods: We identified genetic instruments for S-LDL-C, M-LDL-C and L-LDL-C from a genome-wide association study of 115 082 UK Biobank participants. Summary-level data for genetic association of any ischemic stroke (AIS), large artery stroke (LAS), small vessel stroke (SVS) and cardioembolic stroke (CES) were obtained from MEGASTROKE consortium. Accounting for the pleiotropic effects of triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C), we conducted multivariable TSMR analysis.Results: In univariable TSMR, we found a causal association between genetically predicted S-LDL-C and LAS (IVW-FE: odds ratio (OR) = 1.481, 95% confidence interval (CI): 1.117–1.963, P = 0.006, q = 0.076) but not AIS, SVS or CES. No causal effects were observed for M-LDL-C or L-LDL-C in terms of AIS and IS subtype. In multivariable analysis, the causal association between S-LDL-C and LAS remained significant (IVE-MRE: OR = 1.329, 95% CI: 1.106–1.597, P = 0.002).Conclusions: Findings supported a causal association between S-LDL-C and LAS. Further studies are warranted to elucidate the underlying mechanism and clinical benefit of targeting S-LDL-C.

Background: Neuronal intranuclear inclusion disease (NIID) is a rare, progressive neurodegenerative disorder that can present with stroke-like episodes, posing a significant diagnostic challenge. This difficulty is compounded when it coincides with intracranial atherosclerotic stenosis, a common cause of recurrent stroke. Case presentation: We report the case of a 64-years-old woman without conventional vascular risk factors who presented with a recurrent acute focal neurological deficit–her sixth similar episode over 8 years, each previously diagnosed as cerebral infarction. Brain magnetic resonance imaging (MRI) revealed a new area of restricted diffusion in the right frontoparietal region and an ipsilateral middle cerebral artery (MCA) M2 segment stenosis (>50%). Crucially, a systematic review of the diffusion-weighted imaging (DWI) sequences identified the pathognomonic linear hyperintensity along the corticomedullary junction, known as the “ribbon sign,” which is highly suggestive of NIID. Despite a negative genetic test for the NOTCH2NLC GGC repeat expansion, the diagnosis was confirmed by a minimally invasive skin biopsy, which demonstrated characteristic non-membranous intranuclear inclusions on electron microscopy. Conclusion: We highlight the imperative to recognize this specific and pathognomonic neuroimaging pattern even in the presence of coincidental atherosclerosis. Furthermore, we detail the systematic diagnostic approach when genetic testing is unrevealing, emphasizing the pivotal role of targeted tissue biopsy in achieving a definitive diagnosis. This report underscores the key learning points in evaluating acute stroke mimics with atypical evolution.