Fei Han

Aims: To better comprehend relationships between the analysis along the perivascular space (ALPS) index and glymphatic dysfunction, we assessed the spatiotemporal patterns of structural brain injury related to the ALPS index in a longitudinal study. Methods: We performed voxel/vertex‐wise analysis to explore the relationship between lower ALPS index and brain parenchymal injury. We also performed brain network connectivity analysis to investigate the relationship between white matter disruption and cortical atrophy. Results: The lower baseline ALPS index showed an association with drastic progression of disruption of white matter microstructural integrity, primarily located in the subcortical regions where association fibers are distributed. Brain network connectivity analysis revealed an association of the lower ALPS index with a disconnected sub‐network in the midline and right frontal lobe, where association fibers are widely distributed. The lower ALPS index also displayed a correlation with cortical atrophy in the projection areas of both association and projection fibers in cross‐sectional analysis. However, this correlation was nonsignificant in longitudinal analysis. Conclusion: The ALPS index could be considered a composite marker of perivascular dynamics and white matter microstructural integrity, shedding light on the spatial pattern of disruption of white matter integrity in community‐dwelling populations.

Background: Acute intermittent porphyria (AIP) is the most common and severe form of acute hepatic porphyria, caused by heterozygous mutations in the HMBS gene. Due to its non-specific clinical manifestations and low clinical awareness among clinicians, AIP is frequently misdiagnosed, leading to significant diagnostic delays and potentially fatal complications. Case presentation: We report a 20-year-old female patient who presented with a 9-month history of recurrent abdominal pain, paralytic ileus, unexplained liver injury, and hyponatremia, followed by progressive limb weakness. She was initially misdiagnosed with Guillain–Barré syndrome (GBS) and received intravenous immunoglobulin and systemic glucocorticoids. However, her condition deteriorated, and she developed life-threatening respiratory muscle paralysis requiring invasive mechanical ventilation. The diagnosis of AIP was confirmed by positive urinary porphobilinogen (PBG) testing and identification of the heterozygous HMBS c.517C>T pathogenic variant. The patient was treated with high-dose carbohydrate loading therapy and comprehensive supportive care, resulting in gradual clinical improvement. Discussion and Conclusions: This case exemplifies the substantial diagnostic challenges associated with AIP, especially when it manifests with peripheral neuropathy that closely mimics GBS. The triad of absent albuminocytologic dissociation in cerebrospinal fluid, preceding visceral symptoms, and inadequate response to standard first-line GBS therapy should immediately raise clinical suspicion for AIP. Enhanced clinical awareness of this rare disorder and timely implementation of urinary PBG screening are of paramount importance to prevent irreversible neurological complications and optimize long-term patient outcomes.

BACKGROUND: Stenosis and dolichoectasia of cranial arteries likely reflect distinct mechanisms. Their contributions to lacunar stroke and cerebral small-vessel disease (cSVD) remain contentious. We investigated the associations of large-artery stenosis (LAS) and arterial widening with stroke subtype, cSVD markers, incident infarcts, and clinical outcomes. METHODS: We prospectively recruited patients with lacunar or mild nonlacunar stroke, with demographic, stroke-related, cognitive, functional, and magnetic resonance imaging (index and incident infarcts, cSVD markers) assessments at baseline and 1 year. LAS was defined as ≥50% intracranial or cervical artery stenosis; basilar artery dolichoectasia was defined by basilar artery diameter, bifurcation height, and lateral displacement; and intracranial carotid and middle cerebral artery diameters were also measured. Associations were estimated from multivariable logistic, linear, and proportional odds regression models adjusted for age, sex, and vascular risk factors. We further conducted a systematic literature review to synthesize evidence on relationships between large-artery pathology and cSVD. RESULTS: Among 229 patients (mean age, 65.9±11.1 years; 131 [57.2%] lacunar stroke), LAS and basilar artery dolichoectasia were present in 20.5% and 15.7%, respectively. After adjustment, LAS (odds ratio, 0.49 [95% CI, 0.23–0.99]) and the presence of any embolic source were associated with lower odds of lacunar versus non-lacunar stroke, and not with cSVD markers or incident infarcts. In contrast, basilar artery dolichoectasia was strongly associated with lacunar stroke (odds ratio, 4.67 [95% CI, 1.87–13.14]), higher cSVD scores (ordinal analysis; odds ratio, 2.57 [95% CI, 1.28–5.25]), incident infarcts (75% subcortical; odds ratio, 2.29 [95% CI, 1.01–5.14]), and greater progression of white matter hyperintensities over 1 year (β, 0.15 [95% CI, 0.01–0.29] per log ₁₀ -transformed volume). Similar associations were observed for wider intracranial arteries. The systematic review supported these findings. CONCLUSIONS: cSVD, including lacunar stroke, was unrelated to LAS but strongly associated with dolichoectasia and wider arteries. These findings support a nonatheromatous, intrinsic microvascular pathology, particularly segmental arteriolar disorganization, as the principal mechanism of lacunar stroke and cSVD. Mechanism-specific diagnostic and therapeutic strategies are warranted.

Introduction: Cerebral small vessel disease (CSVD) is a common cause of functional decline in the elderly, yet its diagnosis often relies on neuroimaging, which may be inaccessible in routine practice. Given that gait impairment is a core feature of CSVD, we aimed to develop and validate a clinically applicable diagnostic model by integrating quantitative spatiotemporal gait parameters with conventional clinical features. Methods: This case–control study included 417 healthy controls from a community-based cohort and 117 hospital-based CSVD patients. Conventional clinical characteristics and quantitative spatiotemporal gait parameters were collected from all participants. A two-stage modeling approach was used, in which least absolute shrinkage and selection operator (LASSO) regression was first applied for predictor screening, followed by multivariable logistic regression for constructing the final diagnostic model. Model performance was assessed by discrimination (area under the curve [AUC]), calibration, and clinical utility (decision curve analysis [DCA]). Results: Six key variables were included in the final diagnostic model: sex, hypertension, body mass index (BMI), stride length, step frequency, and step width. The model exhibited excellent discrimination, achieving an AUC of 0.914 (95% CI: 0.886–0.943), along with strong calibration. DCA further confirmed its clinical utility, showing a greater net benefit across a wide range of threshold probabilities compared to default screening strategies. Conclusion: The diagnostic model developed in this study effectively identifies individuals at high risk of CSVD by leveraging quantitative spatiotemporal gait parameters alongside conventional clinical features.

Background: The mechanisms underlying covert versus symptomatic acute infarcts in cerebral small vessel disease are unclear. Methods: Based on the multicenter Cerebral Small Vessel Disease Disability and Outcome Cohort Study, we consecutively enrolled patients presenting with an acute lacunar stroke within 30 days or patients without acute stroke symptoms but with moderate to severe white matter hyperintensities. Between August 2016 and June 2019, 1710 patients (mean age 61.87±11.28 years, 37.25% female) were recruited across 30 hospitals in China. We compared the clinical and imaging characteristics between individuals with incidental diffusion‐weighted imaging (DWI)‐positive lesions and those with recent small subcortical infarcts (RSSI). Results: The prevalence of incidental DWI‐positive lesions and RSSI was 2.28% and 31.64%. Patients with incidental DWI‐positive lesions were older, had lower blood pressure and lipid levels, and more prior lacunar stroke. Incidental DWI‐positive lesions were typically smaller and round/ovoid, more often involved the subcortical white matter and cerebral cortex. RSSI more frequently affected perforating artery territories, 39.9% of RSSI cases were consistent with branch atheromatous disease. Incidental DWI‐positive lesions patients had a higher risk of 90‐day recurrent stroke (hazard ratio [HR], 8.28 [95% CI, 1.96–34.90], log‐rank P <0.001). They also had lower Mini‐Mental State Examination scores after adjustment for age and sex. Conclusions: Atherosclerosis and branch atheromatous disease appear to be predominant causes of RSSI among Chinese patients with cerebral small vessel disease. Incidental DWI‐positive lesions likely reflecting intrinsic small vessel injury constitute a cerebral small vessel disease marker and carry prognostic value for stroke recurrence and cognitive decline.

Background: Stenosis and dolichoectasia of cranial arteries likely reflect distinct mechanisms. Their contributions to lacunar stroke and cerebral small vessel disease (cSVD) remain contentious. We investigated associations of large artery stenosis (LAS) and arterial widening with stroke subtype, cSVD markers, incident infarcts, and clinical outcomes. Methods: We prospectively recruited patients with lacunar or mild non-lacunar stroke, with demographic, stroke-related, cognitive, functional, and MRI (index and incident infarcts, cSVD markers) assessments at baseline and one year. LAS was defined as ≥50% intracranial or cervical artery stenosis; basilar artery dolichoectasia (BADE) by basilar artery diameter, bifurcation height, and lateral displacement; and intracranial carotid and middle cerebral artery diameters were also measured. Associations were estimated using multivariable regression adjusted for age, sex, and vascular risk factors. We further conducted a systematic literature review to synthesize evidence on relationships between large artery pathology and cSVD. Results: Among 229 patients (mean age 65.9±11.1 years; 131 [57.2%] lacunar stroke), LAS and BADE were present in 20.5% and 15.7%, respectively. After adjustment, LAS (odds ratio [OR], 0.49; 95%CI, 0.23-0.99) and the presence of any embolic source were associated with lower odds of lacunar versus non-lacunar stroke, and not with cSVD markers or incident infarcts. In contrast, BADE was strongly associated with lacunar stroke (OR, 4.67; 95%CI, 1.87-13.14), higher cSVD scores (ordinal analysis; OR, 2.57; 95%CI, 1.28-5.25), incident infarcts (75% subcortical; OR, 2.29; 95%CI, 1.01-5.14), and greater progression of white matter hyperintensities over one year (β, 0.15; 95%CI, 0.01-0.29; per log ₁₀ -transformed volume). Similar associations were observed for wider intracranial arteries. The systematic review supported these findings. Conclusions: cSVD, including lacunar stroke, was unrelated to LAS, but strongly associated with dolichoectasia and wider arteries. These findings support a non-atheromatous, intrinsic microvascular pathology, particularly segmental arteriolar disorganization, as the principal mechanism of lacunar stroke and cSVD. Mechanism-specific diagnostic and therapeutic strategies are warranted. Clinical Perspective: What Is New?: ● Large artery stenosis was unlikely to represent a causal mechanism for lacunar stroke and showed no association with cerebral small vessel disease (cSVD) imaging markers. ● Dolichoectasia and intracranial arterial widening emerged as vascular phenotypes strongly associated with cSVD, including its progression and lacunar stroke subtype. What Are the Clinical Implications?: ● Distinct large artery phenotypes have divergent etiopathological implications for cSVD. Our findings support a non-atheromatous, intrinsic microvascular pathology as the principal mechanism of lacunar stroke and cSVD. ● Mechanism-based therapeutic strategies for lacunar stroke and cSVD, moving beyond conventional approaches focused on atherosclerosis or cardioembolism, are warranted.

Background: Lacunes of presumed vascular origin are a key imaging marker of cerebral small-vessel disease (cSVD), predicting stroke and dementia risk. Their incidence and determinants have not been systematically quantified across different populations, and implications for clinical research remain unclear. Aims: This study aims to estimate the annualized incidence of new lacunes across diverse populations, identify study-level factors contributing to heterogeneity, summarize patient-level risk factors for incident lacunes, and provide empirical data to inform sample size estimation for studies using incident lacunes as an imaging outcome. Summary of review: Thirty-one studies comprising 12,646 participants and 56,073 person-years were included. The pooled overall incidence was 3.27 per 100 person-years (95% CI, 2.12–4.42), ranging from 1.50 to 8.03 across populations. Rates were highest in cSVD patients (8.03; 95% CI, 3.8–12.27), intermediate in stroke and memory-clinic patients, and lower in community-based, hypertensive, and non-specific artery disease cohorts. Meta-regression showed that baseline lacune prevalence was positively associated with incidence (β = 0.057; 95% CI, 0.006–0.108; P = 0.031). At the individual level, male sex, baseline lacunes, hypertension, and diabetes were associated with higher risk. In cSVD populations, detecting a 30% relative risk reduction required 563, 867, and 1782 participants per arm for 3-, 2-, and 1-year follow-up, respectively. Conclusion: Incident lacune rates vary substantially across populations and are strongly influenced by baseline lacune burden and vascular risk factors. These findings provide context for population selection and sample size considerations in studies using incident lacunes as an imaging outcome.

Background: Cognitive decline and incident dementia in ageing populations have been linked to brain parenchymal injury and the ALPS index (ALPS-I). Objective: This investigation aimed to elucidate whether the baseline ALPS-I could predict incident dementia and cognitive decline in this population. Methods: In total, 973 dementia-free participants from the Shunyi Study (mean age, 57 years; 37% male) received MRI between 2013 and 2016 to quantify the ALPS-I. The longitudinal relationships between the ALPS-I and cognitive deterioration in various cognitive areas were evaluated via linear mixed models. Cox proportional hazard models were utilized to explore the link between the index and incident dementia. Mediation assessments were carried out to identify the potential mediating effects of brain parenchymal injury on the link between the ALPS-I and cognition. Results: The baseline ALPS-I predicted longitudinal changes in global cognition (Montreal Cognitive Assessment), language (verbal fluency test), visuospatial perception (block design subtest of Wechsler intelligence scale), and executive function (Trail Making Test). A lower score was markedly associated with a higher incident dementia risk. Mediation analysis revealed that fractional anisotropy mediated the associations between the ALPS-I and executive function (mediation effect: 21.9%) and visuospatial perception (mediation effect: 68.8%). The white matter hyperintensity fraction was found to mediate the link between the ALPS-I and global cognition (mediation effect: 55.0%). Conclusions: This longitudinal evidence supports a link between the ALPS-I and cognitive degeneration. Furthermore, the link is mediated by subcortical parenchymal injury.

Background and purpose: Neuroimaging phenotypes remain poorly characterized in patients with deficiency of adenosine deaminase 2 (DADA2). We aimed to characterize cerebral microangiopathy patterns and establish diagnostic imaging biomarkers for DADA2. Methods: We retrospectively analyzed consecutively enrolled DADA2 patients with neurological involvement from two ongoing prospective cohorts. The demographic, clinical, and neuroimaging data were evaluated, focusing on neuroimaging lesion patterns and cerebral small vessel disease (CSVD) imaging markers. Results: Thirteen patients were included, with 69.2% males. The median age at neurological onset was 17 (7–26) years. A striking disparity emerged between acute ischemic burden and chronic small vessel injury markers. During a follow-up of 51 (0.5–193) months,138 ischemic lesions were observed in all patients, primarily involving the pons (38 lesions), thalamus (21 lesions), internal capsule (20 lesions), and basal ganglia (18 lesions). Conversely, only one cerebral microbleed (CMB) was detected in all patients. Mild white matter hyperintensities (WMH) were observed in 9 patients. Infratentorial atrophy was prevailing and present in 69.2% (n = 9) patients. Additionally, hemorrhagic stroke was less frequent (n = 6, 46.2%) than infarction. Conclusion: DADA2 exhibited a profoundly high risk of stroke recurrence, with substantial lesions being clinically asymptomatic, underscoring the importance of routine neuroimaging evaluation for DADA2 patients. This disease presents a unique CSVD phenotype characterized by brainstem-deep gray nucleus ischemic predominance and infratentorial atrophy yet paradoxically low burdens of CMBs and WMH compared to other CSVD. This distinctive imaging triad not only facilitates early recognition and timely intervention, but also suggests a pathophysiological divergence from other CSVD.

Background and aims: Covert MRI markers of cerebral small vessel disease (CSVD) can coexist with large artery atherosclerosis. We aimed to explore whether the spatial distributions of these markers were diverse in people with or without intracranial artery stenosis (ICAS). Methods: This cross-sectional analysis included 1206 stroke-free participants (aged 55.69±9.27, 62.94% female) with brain MRI and MR angiography from community-based Shunyi cohort. We analysed the relationships between ICAS and CSVD markers. We also compared the probability maps of lacunes, cerebral microbleeds (CMB), white matter hyperintensities (WMH) and cortex morphology at a voxel/vertex-wise level in groups with and without ICAS. Results: ICAS increased the risk of lacunes by 2.99-fold (95% CI 1.99 to 4.50, p<0.001), lacunes ≥3 by 5.32 times (95% CI 2.76 to 10.28, p<0.001), correlated with WMH volume (β=0.332, SE=0.059, p<0.001), WMH Fazekas scores ≥5 (OR 4.50, 95% CI 2.44 to 8.29, p<0.001) and brain parenchymal fraction (β=−0.012, SE=0.002, p<0.001), but not with CMB. ICAS is associated with lacunes in the corresponding blood supply area. Lacunes that coexist with ICAS were prone in basal ganglia, while the lacunes without ICAS appeared in centrum semiovale more often. WMH with ICAS was prone to present in deep white matter involving the bilateral pyramidal tracts and superior thalamic radiation. People with ICAS were susceptible to worse cortical atrophy of right superior frontal and left rostral anterior cingulate. No obvious distributional differences were found for CMB between the two groups. Conclusions: Since ICAS may be involved in the upstream pathogenesis of lacunes, white matter lesions and cortical atrophy, the impact of ICAS should not be ignored when evaluating MRI markers of CSVD.