Zi-Yue Liu

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: 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: 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: Existing stroke prediction models tend to overestimate contemporary stroke risk and inadequately incorporate neuroimaging parameters. This study aimed to develop a novel and accurate stroke prediction model for a community‐based population by integrating comprehensive neuroimaging data. Methods: A prospective cohort study was conducted involving 1586 eligible participants from northern rural China. Baseline clinical and neuroimaging data were collected, with annual follow‐ups to assess incident stroke. Least absolute shrinkage and selection operator regression was used to identify key predictors, which were subsequently incorporated into a Cox proportional hazards model to develop the final predictive model. Internal validation was performed via 500 times bootstrap resampling. Model performance was evaluated using time‐dependent receiver operating characteristic curves, Brier scores, calibration plots, and decision curve analysis. Results: During a mean follow‐up of 8.0 years, 54 incident strokes occurred among 1173 participants (4.6%). The final model incorporating least absolute shrinkage and selection operator–selected predictors (current smoking, diabetes, high cerebral small‐vessel disease burden, and severe intracranial artery stenosis) showed strong discrimination, with area under the curve values of 0.88 (95% CI, 0.83–0.92) for 5‐year and 0.84 (95% CI, 0.79–0.90) for 7‐year prediction. Bootstrap validation confirmed model robustness (area under the curve values, 0.87 and 0.83, respectively). The model was well calibrated (Brier scores, 0.03 at 5 years and 0.04 at 7 years), and decision curve analysis indicated favorable net clinical benefit. A clinically applicable nomogram was developed for individualized risk assessment. Conclusions: The newly developed predictive model, combining clinical and neuroimaging features, provides accurate prediction of 5‐year and 7‐year stroke risk. Targeted management of diabetes, smoking, silent cerebral small‐vessel disease, and intracranial artery stenosis is essential for primary stroke prevention in community populations.

Objectives There is limited understanding of the differences between cerebral amyloid angiopathy (CAA) with and without intracerebral hemorrhage (ICH). This article aimed to describe the characteristics of CAA and identify the risk factors of CAA-ICH in a multicenter cohort. Methods Patients consecutively enrolled in the national multicenter prospective Cerebral Small Vessel Disease Cohort Study who met the Boston diagnostic criteria for CAA or CAA-related inflammation were included in this study. The demographic characteristics and clinical data were collected. The clinical and radiographic differences between CAA with and without ICH were compared to identify the risk factors for CAA-ICH. Results A total of 219 CAA patients were included, with an average age of 67.12 ± 9.93. Of all patients, 26.0% were CAA with ICH. Univariate analysis showed that CAA-ICH is associated with carrying more APOE ε2 allele, less lobar cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), lower Fazekas scale, a tendency of gait disorder, and acute onset (P < 0.05). The generalized linear mixed model yielded statistically significant associations between CAA with ICH and carrying the APOE ε2 allele, cSS, the lower number of lobar CMBs, and the lower Fazekas scale (P < 0.05). Conclusion It is meaningful to classify CAA with and without ICH, as there may be different mechanisms between the two. CAA with ICH has a susceptibility to carrying APOE ε2, cSS, and a relatively small number of CMBs. Fewer CMBs do not mean lower susceptibility to ICH in CAA. Larger prospective cohort studies are necessary to further clarify these conclusions.

Background: This study aims to investigate the temporal and spatial patterns of structural brain injury related to deep medullary veins (DMVs) damage. Methods and Results: This is a longitudinal analysis of the population‐based Shunyi cohort study. Baseline DMVs numbers were identified on susceptibility‐weighted imaging. We assessed vertex‐wise cortex maps and diffusion maps at both baseline and follow‐up using FSL software and the longitudinal FreeSurfer analysis suite. We performed statistical analysis of global measurements and voxel/vertex‐wise analysis to explore the relationship between DMVs number and brain structural measurements. A total of 977 participants were included in the baseline, of whom 544 completed the follow‐up magnetic resonance imaging (age 54.97±7.83 years, 32% men, mean interval 5.56±0.47 years). A lower number of DMVs was associated with a faster disruption of white matter microstructural integrity, presented by increased mean diffusivity and radial diffusion (β=0.0001 and SE=0.0001 for both, P =0.04 and 0.03, respectively), in extensive deep white matter (threshold‐free cluster enhancement P P <0.05, adjusted for age, sex, and total intracranial volume). Conclusions: Our findings posed the dynamic pattern of brain parenchymal lesions related to DMVs injury, shedding light on the interactions and chronological roles of various pathological mechanisms.

Background and objectives: Previous studies reported that carriers of rare NOTCH3 variants comprised over 10% of the general population and are susceptible to a heavy overall burden of cerebral small vessel disease, while the injury patterns remain uncovered. This study aimed to investigate the imaging features in relation to rare NOTCH3 variants and the interaction between cortical atrophy and white matter lesions from a longitudinal view, with respect to spatial and dynamic patterns. Methods: As part of a community-based cohort, we included participants with complete Whole-Exome Sequencing and brain MRI in the baseline analysis. All participants were invited for a five-year follow-up MRI, and those who did not complete the follow-up were excluded from the longitudinal analysis. NOTCH3 variants with minor allele frequency NOTCH3 variants), among whom 661 had a follow-up brain MRI (13.76% carried rare NOTCH3 variants). Rare NOTCH3 variant carriers had a heavier white matter hyperintensity burden (1.65 vs 0.85 ml, p=0.025) and had more extensive WMH distributed in the periventricular areas. We also found that rare NOTCH3 variant carriers were susceptible to worse cortical atrophy (β=-0.004, SE=0.002, p=0.057, adjusted for age and sex). Cortical atrophy of multiple regions in the frontal and parietal lobes was related to white matter hyperintensity progression. Discussion: Individuals with rare NOTCH3 variants have a distinct pattern of brain parenchymal damage related to CSVD. Our findings uncover the important genetic predisposition in age-related cerebral small vessel disease in the general population.

Background: This study investigated the correlation between the expression of DARS2 and metabolic parameters of ¹⁸F-FDG PET/CT, and explored the potential mechanisms of DARS2 affecting the proliferation and glycolysis of lung adenocarcinoma (LUAD) cells. Methods: This study used genomics and proteomics to analyze the difference in DARS2 expression between LUAD samples and control samples. An analysis of 62 patients with LUAD who underwent ¹⁸F-FDG PET/CT examinations before surgery was conducted retrospectively. The correlation between DARS2 expression and PET/CT metabolic parameters, including SUVmax, SUVmean, MTV, and TLG, was examined by Spearman correlation analysis. In addition, the molecular mechanism of interfering with DARS2 expression in inhibiting LUAD cell proliferation and glycolysis was analyzed through in vitro cell experiments. Results: DARS2 expression was significantly higher in LUAD samples than in control samples (p < 0.001). DARS2 has high specificity (98.4%) and sensitivity (95.2%) in the diagnosis of LUAD. DARS2 expression was positively correlated with SUVmax, SUVmean, and TLG (p < 0.001). At the same time, the sensitivity and specificity of SUVmax in predicting DARS2 overexpression in LUAD were 88.9% and 65.9%, respectively. In vitro cell experiments have shown that interfering with DARS2 expression can inhibit the proliferation and migration of LUAD cells, promote cell apoptosis, and inhibit the glycolytic activity of tumor cells by inhibiting the expression of glycolytic related genes SLC2A1, GPI, ALDOA, and PGAM1. Conclusions: Overexpression of DARS2 is associated with metabolic parameters on ¹⁸F-FDG PET/CT, which can improve LUAD diagnosis accuracy. DARS2 may be a useful biomarker to diagnose, prognosis, and target treatment of LUAD patients.