Presence Of Lacunes Research Articles

Baseline and Longitudinal MRI Markers Associated With 16-Year Mortality in Patients With Cerebral Small Vessel Disease.

Information on whether small vessel disease (SVD) reduces life expectancy is limited. Moreover, the excess mortality risk attributed specifically to SVD compared with controls from the general population has not been evaluated. This study aimed to investigate the baseline and progression of MRI markers of SVD associated with mortality in a 16-year follow-up cohort study and to determine the excess long-term mortality risk of patients with SVD. Participants with SVD from the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort (RUN DMC) study (with MRI assessments in 2006, 2011, 2015, and 2020) were followed until their death or December 1, 2021. Adjusted Cox regression analyses and linear mixed-effect regression models were used to investigate the association between MRI markers of SVD and mortality. The excess mortality risk of SVD was calculated by comparing mortality data of the RUN DMC study with the general population matched by sex, age, and calendar year. 200 of 503 (39.9%) participants died during a follow-up period of 15.9 years. Cause of death was available for 182 (91%) participants. Baseline white matter hyperintensity volume (HR 1.3 per 1-SD increase [95% CI 1.1-1.5], p = 0.010), presence of lacunes (1.5 [95% CI 1.1-2.0], p = 0.008), mean diffusivity (HR 1.1 per 1-SD increase [95% CI 1.1-1.2], p = 0.001), and total brain volume (HR 1.5 per 1-SD decrease [95% CI 1.3-1.9], p < 0.001) were associated with all-cause mortality after adjusting for age, sex, and vascular risk factors. Total brain volume decrease over time was associated with all-cause mortality after adjusting for age, sex, and vascular risk factors (HR 1.3 per 1-SD decrease [95% CI 1.1-1.7], p = 0.035), and gray matter volume decrease remained significant after additionally adjusting for its baseline volume (1.3 per 1-SD decrease [1.1-1.6], p = 0.019). Participants with a Fazekas score of 3, presence of lacunes, or lower microstructural integrity had an excess long-term mortality risk (21.8, 15.7, 10.1 per 1,000 person-years, respectively) compared with the general population. Excess long-term mortality risk only exists in patients with severe SVD (Fazekas score of 3, presence of lacunes, or lower microstructural integrity). This could help in assisting clinicians to predict the clinical outcomes of patients with SVD by severity.

Motor Function Is Associated with Cerebral Small Vessel Disease and Can Predict Mortality and Poor Functional Outcome

Introduction: The primary objective of this study was to elucidate the predictive role of subtle motor impairment evaluated using the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III on mortality and functional outcome. The secondary objective was to evaluate the association of motor impairment with small vessel disease (SVD) severity. Methods: We derived data from a Japanese cohort of patients with evidence of SVD who were enrolled from 2015 to 2019, and followed until 2023. The present study included 586 participants who agreed for UPDRS Part III evaluation. The severity of white matter hyperintensities (WMHs) and the presence of lacunes were evaluated. Cox proportional hazard models and multiple logistic regression analysis were used to examine the association between UPDRS Part III score and all-cause death and functional outcome defined by the modified Rankin Scale (mRS) score at the last visit, respectively. Results: The median age was 71 years, and the median UPDRS Part III score was 2. The UPDRS Part III score was associated with the severity of WMH (r = 0.225, p < 0.001) and the number (0, 1, ≥2) of lacunes (p < 0.001). During a mean follow-up period of 4.8 years, 29 patients died. The Cox proportional hazard analysis revealed that high UPDRS Part III scores (≥5) were associated with a higher risk of all-cause death compared to low (score 0) and middle (score 1–4) scores (adjusted hazard ratio 3.04; 95% confidence interval, 1.50–7.34, p = 0.005). In multivariate logistic analysis, high UPDRS Part III scores were associated with poor functional outcome (mRS of ≥3) compared with low and middle scores after adjusting for confounding factors (adjusted odds ratio 1.86; 95% confidence interval 1.02–3.41, p = 0.043). Conclusions: Subtle motor impairment was associated with the severity of WMH and number of lacunes and could predict mortality and poor functional outcome independently of vascular risk factors and severity of WMH and lacunes.

Cingulate sulcus sign: a descriptive analysis in a cerebral small vessel disease population.

The cingulate sulcus sign (CSS) has been observed in patients with idiopathic normal pressure hydrocephalus (iNPH), suggesting potential disruptions in cerebrospinal fluid circulation and compromised glymphatic system. Although there are similarities in the underlying mechanisms between cerebral small vessel disease (CSVD) and iNPH, the relationship between CSS and CSVD remains unclear. This study aimed to investigate the prevalence and potential mechanisms of CSS in patients with CSVD. Data from patients diagnosed with CSVD at Shengjing Hospital of China Medical University between January 2020 and October 2022 were retrospectively collected, including general information, global cognitive function [assessed by measuring Mini-Mental State Examination (MMSE)], and four CSVD magnetic resonance imaging (MRI) markers [(white matter hyperintensity (WMH), cerebral microbleeds (CMBs), lacunes, and enlarged perivascular spaces (EPVS)], CSS and the Evan's index (EI). A total of 308 patients were included, and CSS was detected in 80 patients (26%). Univariate analysis revealed that MMSE scores in the CSS group were significantly lower compared to the non-CSS group (p < 0.001). Multivariable analysis showed an independent correlation between CSS and the presence of lacunes (odds ratio [OR] 0.358, 95% confidence interval [CI] 0.193-0.663, p = 0.001), presence of lobar dominant CMBs (OR 2.683, 95%CI 1.385-5.195, p = 0.003), periventricular WMH Fazekas score (OR 1.693, 95% CI 1.133-2.529, p = 0.01), and EI (OR 1.276, 95% CI 1.146-1.420, p < 0.001). This preliminary study showed that CSS can be observed in some patients with CSVD. The presence of CSS may represent different mechanisms of CSVD pathogenesis and reflect differences in the degree of cerebrospinal fluid (CSF)/interstitial fluid (ISF) stasis.

Automated diffusion-weighted image analysis along the perivascular space index reveals glymphatic dysfunction in association with brain parenchymal lesions.

Brain glymphatic dysfunction is critical in neurodegenerative processes. While animal studies have provided substantial insights, understandings in humans remains limited. Recent attention has focused on the non-invasive evaluation of brain glymphatic function. However, its association with brain parenchymal lesions in large-scale population remains under-investigated. In this cross-sectional analysis of 1030 participants (57.14 ± 9.34 years, 37.18% males) from the Shunyi cohort, we developed an automated pipeline to calculate diffusion-weighted image analysis along the perivascular space (ALPS), with a lower ALPS value indicating worse glymphatic function. The automated ALPS showed high consistency with the manual calculation of this index (ICC = 0.81, 95% CI: 0.662-0.898). We found that those with older age and male sex had lower automated ALPS values (β = -0.051, SE = 0.004, p < .001, per 10 years, and β = -0.036, SE = 0.008, p < .001, respectively). White matter hyperintensity (β = -2.458, SE = 0.175, p < .001) and presence of lacunes (OR = 0.004, 95% CI < 0.002-0.016, p < .001) were significantly correlated with decreased ALPS. The brain parenchymal and hippocampal fractions were significantly associated with decreased ALPS (β = 0.067, SE = 0.007, p < .001 and β = 0.040, SE = 0.014, p = .006, respectively) independent of white matter hyperintensity. Our research implies that the automated ALPS index is potentially a valuable imaging marker for the glymphatic system, deepening our understanding of glymphatic dysfunction.

Retinal sub-layer thicknesses, presence of lacunes, and their interaction with cognitive performance in recent single subcortical infarction.

Retinal sub-layer thicknesses, presence of lacunes, and their interaction with cognitive performance in recent single subcortical infarction.

#2183 Does thrombotic microangiopathy drive the occurrence and pattern of cerebrovascular disease in malignant hypertension?

Abstract Background and Aims Malignant hypertension (MHT) is characterized by diffuse microvascular damage caused by severe hypertension, often presenting with multiple organ involvement. Cerebrovascular injury, occurring in both acute and chronic forms, stands as a hallmark of the disease, being identified in up to half of patients. Thrombotic microangiopathy (TMA), defined as the association of mechanical hemolytic anemia with thrombocytopenia, also emerges as a frequent complication in MHT patients. However, the potential contribution of TMA to cerebrovascular disease remains unexplored. The secondary objective of this study was to provide a comprehensive description of the patterns of cerebrovascular injury occurring in MHT, with a focus on acute ischemic strokes (AIS). Method We retrospectively assessed the brain MRI of patients admitted to the kidney intensive care unit at Tenon hospital for malignant hypertension during the 2017-2023 period. Brain MRIs were performed on a systematic basis regardless of neurological symptoms and were independently reviewed by two trained specialists in a blinded fashion. Patterns of acute cerebrovascular disease, defined as AIS, intracerebral hematoma (ICH) or posterior reversible encephalopathy syndrome (PRES), were systematically assessed. Number of AIS lesions, their size and localization were recorded. Underlying chronic cerebral small vessel disease (CSVD) was defined as presence of lacunes, white matter hyperintensities, cerebral microbleeds or perivascular spaces. Severity of the chronic cerebrovascular disease was measured using a validated CSVD score. Results A total of 60 patients were admitted for malignant hypertension, with a mean age of 42.9 years. 40 patients (66.7%) presented with severe acute kidney injury. Cerebrovascular disease, either acute or chronic, was found in 42 patients (70.0%). Underlying chronic CSVD was present in 33 patients (55.0%). Acute patterns of injury occurred in 27 patients (45.0%). AIS was the most frequent (33.3%), followed by PRES (21.7%). Only one patient presented with ICH. Among patients with AIS, 14 (70%) presented with multiple simultaneous lesions. Of note, most patients with AIS exhibited diffuse encephalopathy syndrome (60.0%) rather than focal deficit (40.0%). Systemic TMA was present at admission in 34 patients (56.7%). In an exploratory data analysis, presence of AIS on brain MRI was associated with the presence of underlying CVSD (p = 0.013), but not with the presence of TMA at admission (p = 0.79). No association was found between TMA and PRES (p = 0.22). Conclusion Our study confirmed the high incidence of cerebrovascular disease during MHT. Most notably, 1 in 3 patients presented with AIS. TMA did not appear to increase the incidence nor to influence the pattern of brain injury.

The analysis of association between single features of small vessel disease and stroke outcome shows the independent impact of the number of microbleeds and presence of lacunes

The impact of small vessel disease (SVD) on stroke outcome was investigated either separately for its single features in isolation or for SVD sum score measuring a qualitative (binary) assessment of SVD-lesions. We aimed to investigate which SVD feature independently impacts the most on stroke outcome and to compare the continuous versus binary SVD assessment that reflects pronouncement and presence correspondingly. Patients with a first-ever anterior circulation ischemic stroke were retrospectively investigated. We performed an ordered logistic regression analysis to predict stroke outcome (mRS 3 months, 0–6) using age, stroke severity, and pre-stroke disability as baseline input variables and adding SVD-features (lacunes, microbleeds, enlarged perivascular spaces, white matter hyperintensities) assessed either continuously (model 1) or binary (model 2). The data of 873 patients (age 67.9 ± 15.4, NIHSS 24 h 4.1 ± 4.8) was analyzed. In model 1 with continuous SVD-features, the number of microbleeds was the only independent predictor of stroke outcome in addition to clinical parameters (OR 1.21; 95% CI 1.07–1.37). In model 2 with the binary SVD assessment, only the presence of lacunes independently improved the prediction of stroke outcome (OR 1.48, 1.1–1.99). In a post hoc analysis, both the continuous number of microbleeds and the presence of lacunes were independent significant predictors. Thus, the number of microbleeds evaluated continuously and the presence of lacunes are associated with stroke outcome independent from age, stroke severity, pre-stroke disability and other SVD-features. Whereas the presence of lacunes is adequately represented in SVD sum score, the microbleeds assessment might require another cutoff and/or gradual scoring, when prediction of stroke outcome is needed.

An Investigation of Cerebral Vascular Functional Properties in Middle-to-Old Age Community People With High Vascular Risk Profiles.

Vascular degeneration is an important cause of brain damage in aging. Assessing the functional properties of the cerebral vascular system may aid early diagnosis and prevention. To investigate the relationships between potential vascular functional markers and vascular risks, brain parenchymal damage, and cognition. Retrospective. Two hundred two general community subjects (42-80 years, males/females: 127/75). 3 T, spin echo T1W/T2W/FLAIR, resting-state functional MRI with an echo-planar sequence (rsfMRI), pseudo-continuous arterial spin labeling (pCASL) with a three-dimensional gradient-spin echo sequence. Cerebral blood flow (CBF) in gray matter calculated using pCASL, blood transit times calculated using rsfMRI, and the SD of internal carotid arteries signal (ICAstd) calculated using rsfMRI; visual assessment for lacunes; quantification of white matter hyperintensity volume; permutation test for quality control; collection of demographic and clinical data, Montreal Cognitive Assessment, Mini-Mental State Examination. Kolmogorov-Smirnov test; Spearman rank correlation analysis; Multivariable linear regression analysis controlling for covariates; The level of statistical significance was set at P < 0.05. Age was negatively associated with ICAstd (β = -0.180). Diabetes was associated with longer blood transit time from large arteries to capillary bed (β = 0.185, adjusted for age, sex, and intracranial volume). Larger ICAstd was associated with less presence of lacunes (odds ratio: 0.418, adjusted for age and sex). Higher gray matter CBF (β = 0.154) and larger ICAstd (β = 0.136) were associated with better MoCA scores (adjusted for age, sex, and education). Prolonged blood transit time, decreased ICAstd, and diminished CBF were associated with vascular dysfunction and cognitive impairment. They may serve as vascular functional markers in future studies. 3 TECHNICAL EFFICACY: Stage 3.

Cerebrovascular and cardiovascular autonomic regulation in sickle cell patients with white matter lesions.

White matter lesions (WMLs) are frequent in sickle cell disease (SCD), with a prevalence described to be as high as 53% by age 30. Cerebrovascular regulation and cardiovascular autonomic regulation, more specifically the sympatho-vagal balance, can be altered in SCD. In this study the association between WMLs, cerebrovascular regulation and sympatho-vagal balance was assessed in SCD patients. Sickle cell disease patients with no history of stroke were prospectively evaluated for cerebrovascular reactivity using the breath-holding test (BHT), the sympatho-vagal balance (ratio low frequency/high frequency [HF]) using heart rate variability parameters and cerebral autoregulation in the time domain using correlation index Mx, and arterial cerebral compliance based on continuous assessment of cerebral blood flow velocities using transcranial Doppler ultrasound and arterial blood pressure with photo-plethysmography. WMLs were assessed with magnetic resonance imaging using Fazekas score grading and the presence of lacunes. Forty-one patients (F/M 25/16) were included. Median age was 37.5 years (19-65). Twenty-nine (70.7%) patients had SS genotype. Eleven patients had WMLs (26.8%). Patients with WMLs were significantly older (p < 0.001), had a lower HF (p < 0.005) and an impaired cerebral arterial compliance (p < 0.014). The receiver operating curve for the regression model including age and HF showed a higher area under the curve compared to age alone (0.946 vs. 0.876). BHT and Mx did not significantly differ between the two groups. Lower parasympathetic activity and impaired cerebral arterial compliance were associated with WMLs in adults with SCD. This could potentially yield to a better understanding of pathophysiological parameters leading to premature cerebrovascular ageing in SCD.

White Matter Hyperintensity Volume and Poststroke Cognition: An Individual Patient Data Pooled Analysis of 9 Ischemic Stroke Cohort Studies.

White matter hyperintensities (WMH) are associated with cognitive dysfunction after ischemic stroke. Yet, uncertainty remains about affected domains, the role of other preexisting brain injury, and infarct types in the relation between WMH burden and poststroke cognition. We aimed to disentangle these factors in a large sample of patients with ischemic stroke from different cohorts. We pooled and harmonized individual patient data (n=1568) from 9 cohorts, through the Meta VCI Map consortium (www.metavcimap.org). Included cohorts comprised patients with available magnetic resonance imaging and multidomain cognitive assessment <15 months poststroke. In this individual patient data meta-analysis, linear mixed models were used to determine the association between WMH volume and domain-specific cognitive functioning (Z scores; attention and executive functioning, processing speed, language and verbal memory) for the total sample and stratified by infarct type. Preexisting brain injury was accounted for in the multivariable models and all analyses were corrected for the study site as a random effect. In the total sample (67 years [SD, 11.5], 40% female), we found a dose-dependent inverse relationship between WMH volume and poststroke cognitive functioning across all 4 cognitive domains (coefficients ranging from -0.09 [SE, 0.04, P=0.01] for verbal memory to -0.19 [SE, 0.03, P<0.001] for attention and executive functioning). This relation was independent of acute infarct volume and the presence of lacunes and old infarcts. In stratified analyses, the relation between WMH volume and domain-specific functioning was also largely independent of infarct type. In patients with ischemic stroke, increasing WMH volume is independently associated with worse cognitive functioning across all major domains, regardless of old ischemic lesions and infarct type.

Plasma neurofilament light chain in relation to 10-year change in cognition and neuroimaging markers: a population-based study

Neurofilament light chain (NfL) is a promising biomarker for risk stratification and disease monitoring of dementia, but its utility in the preclinical disease stage remains uncertain. We determined the association of plasma NfL with (change in) neuroimaging markers and cognition in the population-based Rotterdam Study, using linear and logistic regression and mixed-effects models. Plasma NfL levels were measured using the Simoa NF-light™ assay in 4705 dementia-free participants (mean age 71.9 years, 57% women), who underwent cognitive assessment and brain MRI with repeated assessments over a 10-year follow-up period. Higher plasma NfL was associated with worse cognitive performance at baseline (g-factor: β = − 0.12 (− 0.15; − 0.09), p < 0.001), and accelerated cognitive decline during follow-up on the Stroop color naming task (β = 0.04 (0.02; 0.06), p < 0.001), with a smaller trend for decline in global cognition (g-factor β = − 0.02 (− 0.04; 0.00), p = 0.044). In the subset of 975 participants with brain MRI, higher NfL was associated with poorer baseline white matter integrity (e.g., global mean diffusivity: β = 0.12 (0.06; 0.19), p < 0.001), with similar trends for volume of white matter hyperintensities (β = 0.09 (0.02; 0.16), p = 0.011) and presence of lacunes (OR = 1.55 (1.13; 2.14), p = 0.007). Plasma NfL was not associated with volumes or thickness of the total gray matter, hippocampus, or Alzheimer signature regions. In conclusion, higher plasma NfL levels are associated with cognitive decline and larger burden of primarily white matter pathology in the general population.

Basal Ganglia and Brainstem Located Cerebral Microbleeds Contributed to Gait Impairment in Patients with Cerebral Small Vessel Disease.

The mechanism of gait disorder in patients with cerebral small vessel disease (CSVD) remains unclear. Limited studies have compared the effect of cerebral microbleeds (CMBs) and lacunes on gait disturbance in CSVD patients in different anatomical locations. To investigate the relationship of quantitative gait parameters with varied anatomically located MRI imaging markers in patients with CSVD. Quantitative gait tests were performed on 127 symptomatic CSVD patients all with diffuse distributed white matter hyperintensities (WMHs). CMBs and lacunes in regard to anatomical locations and burdens were measured. The correlation between CSVD imaging markers and gait parameters was evaluated using general linear model analysis. Presence of CMBs was significantly associated with stride length (β= -0.098, p = 0.0272) and right step length (β= -0.054, p = 0.0206). Presence of CMBs in basal ganglia (BG) was significantly associated with stride length and step length. Presence of CMBs in brainstem was significantly associated with gait parameters including stride length, step length, step height, and step width. Presence of lacunes in brainstem was significantly associated with gait speed (β= -0.197, p = 0.0365). However, presence of lacunes in the other areas was not associated with worse gait performances. BG and brain stem located CMBs contributed to gait impairment in symptomatic CSVD patients.

Correlation of blood pressure levels at different time periods throughout the day with total CSVD burden and MRI imaging markers.

Hypertension is an important risk factor for atherosclerotic cerebral small vessel disease (CSVD). Higher blood pressure is associated with a higher CSVD burden and the presence of relevant magnetic resonance imaging (MRI) markers. However, the effect of blood pressure level on CSVD burden and imaging markers including white matter hyperintensity (WHM), lacune, enlarged perivascular spaces (EPVS), and cerebral microbleed (CMB) remains unknown. The purpose of this study was to investigate the correlation between blood pressure level and CSVD burden at different time periods throughout the day. In total, 144 in-patients with CSVD (66.4 ± 9.8 years, 50% male) were enrolled and underwent brain MRI, and 24-h ambulatory blood pressure was assessed. Patients were categorized into five groups according to their MRI-evaluated total CSVD burden scores (0-4). Spearman's correlation analysis was performed to examine the correlation between blood pressure levels at different time periods and the total CSVD score or the markers of periventricular WMH, deep WMH, lacune, EPVS, and CMB. Of the 144 patients, 83.3% (120/144) harbored one or more CSVD markers of interest. The systolic blood pressure (SBP) of 24-h, daytime, nighttime, and morning differed significantly among the five groups. The SBP levels increased significantly with the total CSVD scores during 24 h (P = 0.018), daytime (P = 0.018), and nighttime (P = 0.035). Spearman's correlation analysis demonstrated that the SBP of 24 h, daytime, nighttime, and morning and the diastolic blood pressure (DBP) of 24 h and morning positively and significantly correlated with the total CSVD score (P < 0.05). A logistic regression analysis indicated that both morning SBP and DBP were independent risk factors for total CSVD burden (OR = 1.13, 95% CI: 1.02-1.23, P = 0.015; OR = 1.19, 95% CI: 1.06-1.33, P = 0.005). Spearman's correlation analysis indicated a significant positive correlation between morning SBP and higher deep WMH Fazekas score (r = 0.296, P < 0.001), EPVS grade in the basal ganglia (r = 0.247, P = 0.003), and the presence of lacune (r = 0.173, P = 0.038) and CMB (r = 0.326, P < 0.001). Morning DBP only correlated positively with the presence of CMB (r = 0.292, P < 0.001). Higher SBP signficantly correlated with total CSVD burden in patients with atherosclerotic CSVD. Early morning blood pressure level is an important indicator to reflect the severity of CSVD patients.

The effects of carotid artery stiffness on cerebral small vessel disease and cognition

AbstractBackgroundCarotid artery stiffness is associated with cognitive impairment and dementia, however, the underlying mechanism remains unknown. We examined the association of carotid artery stiffness with cerebral small vessel disease (CSVD) markers, cognitive impairment, dementia with its subtypes, as well as cognitive performance.MethodIn this case‐control study, 272 subjects from a memory clinic underwent physical and medical evaluation along with carotid ultrasonography, 3T brain magnetic resonance imaging and detailed neuropsychological assessment. Carotid ultrasonography was conducted to assess arterial compliance (AC), pressure‐strain elastic modulus (Ep), β‐index, augmentation index (AI), and pulse wave velocity‐β (PWV‐β). Brain MRIs were graded for white matter hyperintensities (WMH), lacunes, and cerebral microbleeds (CMBs). Participants were classified as no cognitive impairment, cognitive impairment no dementia, as well as dementia and its subtypes; Alzheimer’s disease (AD) and vascular dementia (VaD). Cognition was assessed using NINDS–Canadian Stroke Network harmonization neuropsychological battery.ResultIncreased carotid β‐index (β = 0.73, P&lt;0.001), Ep (β = 0.86, P&lt;0.001), and PWV‐β (β = 0.83, P&lt;0.001) were independently associated with WMH. Ep (OR = 1.42, 95%CI = 1.05–1.93), and PWV‐β (OR = 1.43, 95%CI = 1.05–1.94) were associated with presence of lacunes. Ep was associated with AD (OR = 1.59, 95%CI = 1.01‐2.73) and VaD (OR = 2.23, 95%CI = 1.04‐5.94). Additionally, PWV‐β was associated with VaD (OR = 2.24, 95%CI = 1.07–5.62). All carotid artery stiffness measurements, except AI, were associated with worse performance in global cognition, visuomotor speed and memory after adjusting for age, sex, education, hypertension, diabetes, hyperlipidaemia, cardiovascular disease, and smoking. These associations became attenuated but remained significant with global cognition after adjusting for CSVD markers (β‐index; β = ‐0.27, P = 0.04), Ep; β = ‐0.30, P = 0.03), and PWV‐β; β = ‐0.32, P = 0.02).ConclusionCarotid artery stiffening is associated with WMH, lacunes, and etiologic subtypes of dementia. Carotid artery stiffening is also associated with global cognition independent of CSVD. Elevated carotid artery stiffness may help identify patients at risk for developing CSVD and dementia.

Distinct imaging features of cerebral small vessel disease are related to rare NOTCH3 variants (S36.002)

<h3>Objective:</h3> To investigate the longitudinal imaging features of cerebral small vessel disease (SVD) in relation to rare <i>NOTCH3</i> variants, including spatial patterns, dynamic patterns, and the interaction between the cortical atrophy and white matter lesions. <h3>Background:</h3> Previous studies reported that rare <i>NOTCH3</i> variants were identified in over 10% of the general population and the carriers have a susceptibility to heavy SVD burden. The correlating imaging characteristics deserve in-depth investigation to uncover the important genetic predisposition in age-related SVD in the general population. <h3>Design/Methods:</h3> Rare <i>NOTCH3</i> variants were identified through Whole-Exome Sequencing. The White matter hyperintensities (WMH) volume and WMH probability maps were assessed through quantitative segmentation. Brain structural volumes and vertex-wise cortex maps were obtained from the longitudinal FreeSurfer analysis suite. Between-group differences were compared through data statistical analysis of global measurements, and voxel/vertex-wise analysis of WMH maps or cortex maps. <h3>Results:</h3> A total of 1054 patients were included in the baseline analysis (13.56% rare <i>NOTCH3</i> variant carriers), while 661 included in the longitudinal analysis (13.76% rare <i>NOTCH3</i> variant carriers). We found that rare <i>NOTCH3</i> variant carriers had heavier WMH burden (1.65 vs 0.85ml, P=0.025) and more presence of lacunes (23.78% vs 14.84, P=0.010). More importantly, rare <i>NOTCH3</i> variant carriers had a distinct WMH distribution and progression pattern in periventricular areas. These features appeared more prominent in the EGFr-involving subgroup. Also, we found that rare <i>NOTCH3</i> variant carriers showed susceptibility to worse cortical atrophy (β=−0.004, SE=0.002, adjusted for age and sex). Of most interest, the progressing of frontal brain atrophy is related to WMH progression, which indicated the role of rare <i>NOTCH3</i> variant in age-related SVD and a structural network disconnection phenomenon. <h3>Conclusions:</h3> Our findings posed a distinct MRI profile of age-related SVD in rare <i>NOTCH3</i> variant carriers and shed new light on the pathogenic mechanisms of rare <i>NOTCH3</i> SNPs. <b>Disclosure:</b> Zi-Yue Liu has nothing to disclose. Feifei Zhai has nothing to disclose. Jing-Yi Liu has nothing to disclose. Yi-Jun Zhou has nothing to disclose. Mei-jun Shu has nothing to disclose. Xiaohong Huang has nothing to disclose. Fei Han has nothing to disclose. Mingli Li has nothing to disclose. Lixin Zhou has nothing to disclose. Jun Ni has nothing to disclose. Ming Yao has nothing to disclose. Shuyang Zhang has nothing to disclose. Liying Cui has nothing to disclose. Zhengyu Jin has nothing to disclose. Yi-Cheng Zhu has nothing to disclose.

Cerebral Small Vessel Disease Progression Increases Risk of Incident Parkinsonism.

Cerebral small vessel disease (SVD) is associated with motor impairments and parkinsonian signs cross-sectionally, however, there are little longitudinal data on whether SVD increases risk of incident parkinsonism itself. We investigated the relation between baseline SVD severity as well as SVD progression, and incident parkinsonism over a follow-up of 14 years. This study included 503 participants with SVD, and without parkinsonism at baseline, from the RUN DMC prospective cohort study. Baseline inclusion was performed in 2006 and follow-up took place in 2011, 2015, and 2020, including magnetic resonance imaging (MRI) and motor assessments. Parkinsonism was diagnosed according to the UK Brain Bank criteria, and stratified into vascular parkinsonism (VaP) and idiopathic Parkinson's disease (IPD). Linear mixed-effect models were constructed to estimate individual rate changes of MRI-characteristics. Follow-up for incident parkinsonism was near-complete (99%). In total, 51 (10.2%) participants developed parkinsonism (33 VaP, 17 IPD, and 1 progressive supranuclear palsy). Patients with incident VaP had higher SVD burden compared with patients with IPD. Higher baseline white matter hyperintensities (hazard ratio [HR]=1.46 per 1-SD increase, 95% confidence interval [CI]=1.21-1.78), peak width of skeletonized mean diffusivity (HR=1.66 per 1-SD increase, 95% CI=1.34-2.05), and presence of lacunes (HR=1.84, 95% CI=0.99-3.42) were associated with increased risk of all-cause parkinsonism. Incident lacunes were associated with incident VaP (HR=4.64, 95% CI=1.32-16.32). Both baseline SVD severity and SVD progression are independently associated with long-term parkinsonism. Our findings indicate a causal role of SVD in parkinsonism. Future studies are needed to examine the underlying pathophysiology of this relation. ANN NEUROL 2023;93:1130-1141.

Abstract 163: Cerebral Amyloid Deposition Predicts Long-term Cognitive Decline In Intracerebral Hemorrhage Survivors

Background: To investigate the role of cerebral amyloid deposition for long-term cognitive outcomes in spontaneous intracerebral hemorrhage (ICH) survivors. Methods: Patients experiencing an ICH without over dementia were included (n = 68). Each patient received the brain MRI and Pittsburgh Compound B (PiB) PET at baseline, and the cognitive function was followed up using Mini-mental Status Examination (MMSE) and clinical dementia rating (CDR) with an overall median of 3.8 years. The association between follow-up cognitive outcomes and neuroimaging markers was explored using multivariable Cox regression models. Positive amyloid scan was defined as global PiB standardized uptake value ratio &gt; 1.2. Results: Patients with PiB(+) were older (72.1 ± 7.8 vs. 59.9 ± 11.7, p = 0.002) and were more frequently associated with probable CAA (54.5% vs. 8.8%, p=0.001) than patients with PiB(-). PiB(+) was associated with a higher risk of dementia conversion (32.9 vs. 4.0 per 100-person-years, HR=16.4 [3.5-75.5], p &lt;0.001) and cognitive decline (defined as MMSE decline≥ 2, 58.8 vs.9.9 per 100-person-years, HR=6.1 [2.0-18.8], p=0.002) compared to PiB(-). Higher lobar microbleed number and the presence of lacune were also associated with cognitive worsening (both p&lt;0.005). In the cox models, PiB(+) was an independent predictor of dementia conversion (HR=12.3 [2.9-52.6], p=0.001) or cognitive decline (HR=7.9 [2.4-26.0], p=0.001) after adjustment for age, sex, educational years, lobar microbleeds and lacune. In the subgroup of patients who were non-CAA (n=57), PiB(+) remained an independent predictor of cognitive worsening (both p&lt;0.005). Conclusions: We demonstrate the strong association between positive amyloid scan and long-term cognitive change in ICH survivors, suggesting cerebral amyloid deposition as an important driving factor for cognitive impairment in hemorrhagic small vessel disease.

Lacunes may worsen cognition but not motor function in Parkinson's disease.

As one of the imaging markers of cerebral small vessel disease, lacunes has received little attention. The objective of this study was to investigate the associations of lacunes, cognition and motor function in patients with Parkinson's disease (PD) and whether these associations are independent of other imaging markers. Patients were consecutively included from April 2019 to July 2022 in Beijing Rehabilitation Hospital. All patients underwent brain magnetic resonance imaging scans, clinical scale evaluations, and neuropsychological tests, as well as quantitative evaluation of postural control. To eliminate the possible factors contributing to cognition and motor dysfunction in patients with PD, in particular white matter hyperintensities and enlarged perivascular space in the basal ganglia, multivariate linear regression models were constructed to sort out the effect of lacunes. Ninety-four patients were included in this study, 56 without lacunes and 38 with lacunes. Patients with lacunes showed shorter disease duration, slower gait speed and spent more time on Trail-Making Test part A (TMT-A) than those without lacunes. The number of lacunes were positively correlated with the time to complete the TMT-A and negatively related to gait speed. Multivariate linear regression models showed that the presence of lacunes was associated with longer TMT-A time after adjusting for potential confounders. Lacunes were independently associated with worse visual scanning, attention, and processing speed in patients with PD. In addition, lacunes may accelerate the course of PD. Early treatment of vascular disease provides an alternate way to mitigate some motor and cognitive dysfunction in patients with PD.

The impact of cerebral small vessel disease burden and its imaging markers on gait, postural control, and cognition in Parkinson's disease.

This study aimed to investigate how cerebral small vessel disease (CSVD) burden and its imaging markers are related to alterations in different gait parameters in Parkinson's disease (PD) and whether they affect attention, information processing speed, and executive function when global mental status is relatively intact. Sixty-five PD patients were divided into the low CSVD burden group (n = 43) and the high CSVD burden group (n = 22). All patients underwent brain magnetic resonance imaging scans, clinical scale evaluations, and neuropsychological tests, as well as quantitative evaluation of gait and postural control. Multivariable linear regression models were conducted to investigate associations between CSVD burden and PD symptoms. Between-group analysis showed that the high CSVD group had worse attention, executive dysfunction, information processing speed, gait, balance, and postural control than the low CSVD group. Regression analysis revealed that greater CSVD burden was associated with poor attention, impaired executive function, and slow gait speed; white matter hyperintensity was associated with slow gait speed, decreased cadence, increased stride time, and increased stance phase time; the presence of lacune was associated only with poor attention and impaired executive function; enlarged perivascular space in the basal ganglia was associated with gait speed. CSVD burden may worsen gait, postural control, attention, and executive function in patients with PD, and different imaging markers play different roles. Early management of vascular risks and treatment of vascular diseases provide an alternate way to mitigate some motor and cognitive dysfunction in PD.

Intracranial Carotid Arteriosclerosis Mediates the Association Between Blood Pressure and Cerebral Small Vessel Disease.

Intracranial arteriosclerosis could explain the association between blood pressure (BP) and cerebral small vessel disease (CSVD). Therefore, we tested whether intracranial carotid artery calcification (ICAC) mediates the association between BP and CSVD and determined pathophysiological mechanisms based on ICAC subtypes. One thousand four hundred fifty-eight stroke-free participants from the Rotterdam Study (mean age, 68 years; 52% women) underwent nonenhanced computed tomography scans to quantify ICAC volume (mm3) between 2003 and 2015. ICAC was categorized into intimal and internal elastic lamina calcifications. CSVD included white matter hyperintensities volume, the presence of lacunes, and cerebral microbleeds visualized on magnetic resonance imaging. Office BP included systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Mediation analysis included a 2-way decomposition to determine the direct association between BP and CSVD and the indirect or mediated effect (negative or positive mediations expressed in %) of log-ICAC volume on such association. BP and log-ICAC were correlated and were also associated with CSVD. In all participants, total log-ICAC volume mediated the association of diastolic BP (-14.5%) and pulse pressure (16.5%) with log-white matter hyperintensities. Internal elastic lamina log-ICAC volume mediated -19.5% of the association between diastolic BP and log-white matter hyperintensities; intimal log-ICAC volume did not mediate associations. For lacunes, total and internal elastic lamina log-ICAC volume mediated the association of diastolic BP (-40% and -45.8%) and pulse pressure (26.9% and 18.2%). We did not observe mediations for cerebral microbleeds. Intracranial arteriosclerosis mediates the association between BP and CSVD. Internal elastic lamina calcification, considered a proxy of arterial stiffness, is the leading mechanism explaining the link between BP and CSVD.