Impact of leukoaraiosis on the infarct growth rate and clinical outcome in acute large vessel occlusion stroke after endovascular thrombectomy.

INTRODUCTION: As a marker of chronic cerebral small vessel disease, leukoaraiosis (LA) was reported to impact the recruitment of collaterals in acute ischemic stroke (AIS). We intended to explore the impact of LA on the infarct growth rate (IGR) and clinical outcome by impaired collateral development in AIS patients with large vessel occlusion (LVO) who underwent endovascular thrombectomy (EVT). PATIENTS AND METHODS: Two hundred thirty-six AIS patients who underwent EVT were retrospectively reviewed. The severity of LA was graded using the Fazekas scale with non-contrast CT. IGR was calculated by the acute core volume on CT perfusion divided by the time from stroke onset to imaging. The collateral status after LVO was assessed using the ASITN/SIR collateral scale. The clinical outcomes after EVT were evaluated using a modified Rankin Scale (mRS). The Alberta stroke program early CT score (ASPECTS), the National Institutes of Health Stroke Scale (NIHSS) score at admission, and the modified treatment in cerebral infarction (mTICI) score after EVT were also included. Correlations between those factors were analyzed. RESULTS: Patients with severe LA had significantly larger core volume on CTP (p = 0.022) and lower collateral grade (p < 0.001). Faster IGR was significantly associated with higher LA severity (adjusted odds ratio [aOR]: 1.53; 95% CI: 1.02-2.33; p = 0.046), higher NIHSS (aOR: 1.04; 95% CI: 1.00-1.09; p = 0.032) and impaired collaterals (aOR: 2.26; 95% CI: 1.27-4.03; p = 0.005). In mediation analysis, collaterals explained 33% of the effect of LA on fast IGR. There was correlation between the severity of LA and mRS (p = 0.007). DISCUSSION AND CONCLUSION: The increasing severity of LA is associated with impaired collateral status and fast infarct growth. These findings suggest that LA may become a predictive imaging biomarker for the likelihood of progression of tissue injury and clinical outcome after EVT in acute large vessel occlusion stroke.

Urinary microalbumin/creatinine ratio is a predictor of the occurrence and severity of leukoaraiosis.

OBJECTIVE: To investigate the correlation between the urinary microalbumin/creatinine ratio (UACR) and the occurrence and severity of leukoaraiosis. METHODS: A total of 323 patients were retrospectively recruited. Demographic, clinical, and laboratory data were collected at the time of admission, and the UACR was calculated based on the levels of urinary microalbumin and creatinine. All patients showed improvement in cranial magnetic resonance imaging (MRI) examination. The subjects were divided into leukoaraiosis and non-leukoaraiosis groups according to the results of the cranial MRI examination. According to the Fazekas standard score, the patients in the leukoaraiosis group were divided into the mild leukoaraiosis group: Fazekas (1-2 points), moderate leukoaraiosis group: Fazekas (3-4points); and severe leukoaraiosis group: Fazekas (5-6 points). RESULTS: A regression analysis was performed to adjust for confounding factors. (1) Compared with the non-leukoaraiosis group, UACR level was higher in the leukoaraiosis group at admission, and the difference between the groups was statistically significant (p < 0.05). (2) In the multivariate logistic regression analysis, UACR was correlated with the occurrence of leukoaraiosis, which may be an independent risk factor. (3) The UACR levels increased gradually in the mild, moderate and severe leukoaraiosis groups, and the difference was statistically significant (p< 0.05). (4) In the ordered multi-category logistic regression analysis, UACR was correlated with the severity of leukoaraiosis, which may be an independent risk factor. CONCLUSION: UACR is associated with the occurrence and severity of leukoaraiosis, and may be an independent risk factor.

Correlation study and clinical value analysis between cerebral microbleeds and white matter hyperintensity with high-field susceptibility-weighted imaging.

This study aimed to investigate the relationship between white matter hyperintensity (WMH) and cerebral microbleeds (CMBs) using susceptibility-weighted imaging (SWI) with high resolution. Additionally, it sought to analyze the clinical significance of SWI with high resolution and its potential to guide intravenous thrombolysis in stroke patients. In this retrospective analysis, we examined 96 patients with hypertension after acute stroke in our hospital using SWI. Demographic and medical data of these 96 patients were collected. Spearman correlation analysis was performed to investigate the relationship between CMBs and the grading of WMH. A significant positive correlation was observed between CMBs and the grade of WMH (R = 0.593, P < .05). The data also revealed a superior ROC area under the curve for the modified Fazekas grading of WMH, which was 0.814 (P < .05). There is a positive correlation between CMBs and the grading of leukoaraiosis in patients with acute stroke and hypertension. The higher the degree of WMH, the more severe the microvascular lesions, increasing the likelihood of intracranial hemorrhage. SWI can provide valuable guidance for administering intravenous thrombolysis in patients with acute stroke.

Disconnection of Network Hubs Underlying the Executive Function Deficit in Patients with Ischemic Leukoaraiosis.

BACKGROUND: Cognitive impairment is the most common clinical manifestation of ischemic leukoaraiosis (ILA), but the underlying neurobiological pathways have not been well elucidated. Recently, it was thought that ILA is a "disconnection syndrome". Disorganized brain connectome were considered the key neuropathology underlying cognitive deficits in ILA patients. OBJECTIVE: We aimed to detect the disruption of network hubs in ILA patients using a new analytical method called voxel-based eigenvector centrality (EC) mapping. METHODS: Subjects with moderate to severe white matters hyperintensities (Fazekas score ≥3) and healthy controls (HCs) (Fazekas score = 0) were included in the study. The resting-state functional magnetic resonance imaging and the EC mapping approach were performed to explore the alteration of whole-brain network connectivity in ILA patients. RESULTS: Relative to the HCs, the ILA patients exhibited poorer cognitive performance in episodic memory, information processing speed, and executive function (all ps < 0.0125). Additionally, compared with HCs, the ILA patients had lower functional connectivity (i.e., EC values) in the medial parts of default-mode network (i.e., bilateral posterior cingulate gyrus and ventral medial prefrontal cortex [vMPFC]). Intriguingly, the functional connectivity strength at the right vMPFC was positively correlated with executive function deficit in the ILA patients. CONCLUSION: The findings suggested disorganization of the hierarchy of the default-mode regions within the whole-brain network in patients with ILA and advanced our understanding of the neurobiological mechanism underlying executive function deficit in ILA.

Effect of leukoaraiosis on collateral circulation in acute ischemic stroke treated with endovascular therapy: a meta-analysis.

BACKGROUND AND OBJECTIVE: The recruitment of collateral circulation correlates with a balance of the microvasculature. Uncertainty remains to be made about the association of leukoaraiosis with leptomeningeal collaterals. To explore the effect of leukoaraiosis on leptomeningeal collaterals in patients treated with endovascular therapy. METHODS: Observational studies exploring the correlation between leukoaraiosis and leptomeningeal collaterals in large vessel occlusion treated with endovascular therapy were searched from PubMed, EMBASE, and Cochrane Libraries databases. Two independent reviewers retrieved eligible literature, extracted purpose-related data, and utilized the Newcastle-Ottawa Scale to evaluate the risk of bias. A Mantel-Haenszel method was used to calculate the odds ratio (OR). Meta-regression and subgroup analyses were conducted to clarify heterogeneity. RESULTS: Data from 10 studies with 1606 patients were extracted for pooled analysis. Compared to non-severe leukoaraiosis, patients with severe leukoaraiosis showed significant relevance to poor leptomeningeal collaterals (OR, 2.13; 95% confidence interval [1.27-3.57]; P = 0.004). Meta-regression indicated that sample size (coefficient = -0.007299, P = 0.035) and the number of female patients (coefficient = -0.0174709, P = 0.020) were sources of heterogeneity. Furthermore, all of the countries (USA versus France versus China, Q = 3.67, P = 0.159), various assessment scales of leukoaraiosis (the Fazekas scale versus Non-Fazekas scales, Q = 0.77, P = 0.379), and different imaging methods of leukoaraiosis (computed tomography versus magnetic resonance imaging, Q = 2.12, P = 0.146) and leptomeningeal collaterals (computed tomography angiography versus digital subtraction angiography, Q = 1.21, P = 0.271) showed no contribution to the effect size. CONCLUSION: Severe leukoaraiosis is associated with poor leptomeningeal collaterals in patients treated with endovascular therapy. Further studies may focus on whether the finding applies to different stroke subtypes.

Leukoaraiosis severity is related to increased risk of early neurological deterioration in acute ischemic stroke: a retrospective observational study.

OBJECTIVES: The relationship between leukoaraiosis and early neurological deterioration in acute cerebral infarction patients remains controversial. We tried to determine whether an association existed between leukoaraiosis and early neurological deterioration in patients with acute ischemic stroke. MATERIALS AND METHODS: We retrospectively enrolled acute cerebral infarction patients admitted to our our department within 4.5-72.0 h of symptom onset between January 2016 and March 2022. On the basis of the van Swieten scale, leukoaraiosis was evaluated as supratentorial white matter hypoattenuation on admission head CT and graded as 0 (absent), 1 (mild), 2 (moderate) and 3-4 (severe). Early neurological deterioration was defined as an increase in the National Institute of Health Stroke Scale score by > = 2 points in the total score, or > = 1 point in motor power within the first seven days after admission. RESULTS: Among 736 patients, 522 (70.9%) patients had leukoaraiosis, and of these, 332 (63.6%) had mild leukoaraiosis, 41 (7.9%) had moderate leukoaraiosis, and 149 (28.5%) had severe leukoaraiosis. 118 (16.0%) patients experienced early neurological deterioration: 20 of the 214 (9.5%) patients without leukoaraiosis and 98 of the 522 (18.8%) patients with leukoaraiosis. In multiple regression analysis, we found van Swieten scale predicted early neurological deterioration independently (OR = 1.570; 95% CI: 1.226-2.012). CONCLUSIONS: Leukoaraiosis is common in acute cerebral infarction patients and leukoaraiosis severity is related to increased risk of early neurological deterioration in the patients.

How often does white matter hyperintensity volume regress in cerebral small vessel disease?

BACKGROUND AND OBJECTIVES: It has been suggested that white matter hyperintensity lesions (WMHs), which typically progress over time, can also regress, and that this might be associated with favorable cognitive performance. We determined the prevalence of WMH regression in patients with cerebral small vessel disease (SVD) and examined which demographic, clinical, and radiological markers were associated with this regression. METHODS: We used semi-automated lesion marking methods to quantify WMH volume at multiple timepoints in three cohorts with symptomatic SVD; two with moderate-to-severe symptomatic SVD (the SCANS observational cohort and the control arm of the PRESERVE interventional trial) and one with mild-to-moderate SVD (the RUN DMC observational cohort). Mixed-effects ordered logistic regression models were used to test which factors predicted participants to show WMH regression. RESULTS: No participants (0/98) in SCANS, 6/42 (14.3%) participants in PRESERVE, and 6/276 (2.2%) in RUN DMC showed WMH regression. On multivariate analysis, only lower WMH volume (OR: 0.36, 95% CI: 0.23-0.56) and better white matter microstructural integrity assessed by fractional anisotropy using diffusion tensor imaging (OR: 1.55, 95% CI: 1.07-2.24) predicted participant classification as regressor versus stable or progressor. DISCUSSION: Only a small proportion of participants demonstrated WMH regression across the three cohorts, when a blinded standardized assessment method was used. Subjects who showed regression had less severe imaging markers of disease at baseline. Our results show that lesion regression is uncommon in SVD and unlikely to be a major factor affecting the use of WMH quantification as an outcome for clinical trials.

Cortical atrophy and leukoaraiosis, imaging markers of cerebrovascular small vessel disease, are associated with driving behavior changes among cognitively normal older adults.

BACKGROUND: Cerebral small vessel disease (CSVD) as measured by cortical atrophy and white matter hyperintensities [leukoaraiosis], captured via magnetic resonance imaging (MRI) are increasing in prevalence due to the growth of the aging population and an increase in cardiovascular risk factors in the population. CSVD impacts cognitive function and mobility, but it is unclear if it affects complex, functional activities like driving. METHODS: In a cohort of 163 cognitively normal, community-dwelling older adults (age ≥ 65), we compared naturalistic driving behavior with mild/moderate leukoaraiosis, cortical atrophy, or their combined rating in a clinical composite termed, aging-related changes to those without any, over a two-and-a-half-year period. RESULTS: Older drivers with mild or moderate cortical atrophy and aging-related changes (composite) experienced a greater decrease in the number of monthly trips which was due to a decrease in the number of trips made within a one-to-five-mile diameter from their residence. Older drivers with CSVD experience a larger reduction in daily driving behaviors than drivers without CSVD, which may serve as an early neurobehavioral marker for functional decline. CONCLUSIONS: As CSVD markers, leukoaraiosis and cortical atrophy are standard MRI metrics that are widely available and can be used for screening individuals at higher risk for driving safety risk and decline in community mobility.

Impact of leukoaraiosis in patients with acute ischemic stroke treated with thrombectomy: a post hoc analysis of the DIRECT-MT trial.

BACKGROUND: The influence of leukoaraiosis in patients with acute ischemic stroke (AIS) given intra-arterial treatment (IAT) with or without preceding intravenous thrombolysis (IVT) remains unknown. OBJECTIVE: To assess the clinical and radiological outcomes of IAT in patients with or without leukoaraiosis. METHODS: Patients of the direct mechanical thrombectomy trial (DIRECT-MT) whose leukoaraiosis grade could be assessed were included. DIRECT-MT was a randomized clinical trial performed in China to assess the effect of direct IAT compared with intravenous thrombolysis plus IAT. We employed the Age-Related White Matter Changes Scale for grading leukoaraiosis (ARWMC, 0 indicates no leukoaraiosis, 1-2 indicates mild-to-moderate leukoaraiosis, and 3 indicates severe leukoaraiosis) based on brain CT. The primary outcome was the score on the modified Rankin Scale (mRS) assessed at 90 days. RESULTS: There were 656 patients in the trial, 649 patients who were included, with 432 patients without leukoaraiosis, and 217 (33.4%) patients with leukoaraiosis divided into mild-to-moderate (n=139) and severe groups (n=78). Leukoaraiosis was a predictor of a worse mRS score (adjusted OR (aOR)=0.7 (95% CI 0.5 to 0.8)) and higher mortality (aOR=1.4 (1.1 to 1.9)), but it was not associated with symptomatic intracranial hemorrhage (sICH) (aOR=0.9 (0.5 to 1.5)). IVT preceding IAT did not increase sICH risk for patients with no (aOR=1.4 (0.6 to 3.4)), mild-to-moderate (aOR=1.5 (0.3 to 7.8)), or severe (aOR=1.5 (0.1 to 21.3)) leukoaraiosis. CONCLUSION: Patients with leukoaraiosis with AIS due to large vessel occlusion are at increased risk of a poor functional outcome after IAT but demonstrate similar sICH rates, and IVT preceding IAT does not increase the risk of sICH in Chinese patients with leukoaraiosis.

Measures of intracranial compartments in acute intracerebral haemorrhage: data from the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke-2 Trial (RIGHT-2).

BACKGROUND AND PURPOSE: Intracerebral haemorrhage volume (ICHV) is prognostically important but does not account for intracranial volume (ICV) and cerebral parenchymal volume (CPV). We assessed measures of intracranial compartments in acute ICH using computerised tomography scans and whether ICHV/ICV and ICHV/CPV predict functional outcomes. We also assessed if cistern effacement, midline shift, old infarcts, leukoaraiosis and brain atrophy were associated with outcomes. METHODS: Data from 133 participants from the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke-2 Trial trial were analysed. Measures included ICHV (using ABC/2) and ICV (XYZ/2) (by independent observers); ICHV, ICV and CPV (semiautomated segmentation, SAS); atrophy (intercaudate distance, ICD, Sylvian fissure ratio, SFR); midline shift; leukoaraiosis and cistern effacement (visual assessment). The effects of these measures on death at day 4 and poor functional outcome at day 90 (modified Rankin scale, mRS of >3) was assessed. RESULTS: ICV was significantly different between XYZ and SAS: mean (SD) of 1357 (219) vs 1420 (196), mean difference (MD) 62 mL (p<0.001). There was no significant difference in ICHV between ABC/2 and SAS. There was very good agreement for ICV measured by SAS, CPV, ICD, SFR, leukoaraiosis and cistern score (all interclass correlations, n=10: interobserver 0.72-0.99, intraobserver 0.73-1.00). ICHV/ICV and ICHV/CPV were significantly associated with mRS at day 90, death at day 4 and acute neurological deterioration (all p<0.05), similar to ICHV. Midline shift and cistern effacement at baseline were associated with poor functional outcome but old infarcts, leukoaraiosis and brain atrophy were not. CONCLUSIONS: Intracranial compartment measures and visual estimates are reproducible. ICHV adjusted for ICH and CPV could be useful to prognosticate in acute stroke. The presence of midline shift and cistern effacement may predict outcome but the mechanisms need validation in larger studies.

The Impact of Periventricular Leukoaraiosis in Post-stroke Oropharyngeal Dysphagia: A Swallowing Biomechanics and MRI-Based Study.

Oropharyngeal dysphagia is a highly prevalent post-stroke complication commonly associated with topographically specific gray-matter damage. In contrast, the role of damage to the extensive white matter brain network (leukoaraiosis) in post-stroke oropharyngeal dysphagia has not yet been clarified. We aim to assess the role of leukoaraiosis in post-stroke oropharyngeal dysphagia. We designed a cross-sectional study and retrospectively collected from our database patients with dysphagia affected by a recent stroke and on whom both a brain 1.5 T-MRI and a videofluoroscopy had been performed. Leukoaraiosis was assessed in brainstem and in cerebral regions (periventricular or deep) with Fazekas scale. Penetration-Aspiration-Scale and time to laryngeal vestibule closure and to upper esophageal sphincter opening were analyzed. Study population (n = 121; 57% men, 75.5 ± 9.4y) presented mostly supratentorial ischemic PACI-type strokes. Of the patients, 86% had unsafe swallows (PAS = 3.97 ± 2.04); 94.2% had cerebral leukoaraiosis (Fazekas = 3.36 ± 1.7) and 42.1% had brainstem-leukoaraiosis, hypertension being the main risk factor. We found both significant positive associations between degree of periventricular-leukoaraiosis and total-leukoaraiosis and presence of risk of aspirations (p = 0.016 and p = 0.023, respectively); and a correlation between periventricular-leukoaraiosis and PAS scale severity (r = 0.179, p = 0.049). No correlations/associations were found between stroke volume and dysphagia in this study. Our study supports a role for leukoaraiosis in the pathophysiology of dysphagia. Stroke is associated with chronic short-connection/circuit injury and damage to periventricular white matter long connections is a relevant neuro-pathophysiological mechanism contributing to impaired safety of swallow in post-stroke oropharyngeal dysphagia patients.

Parietal and occipital leukoaraiosis due to cerebral ischaemic lesions decrease the driving safety performance of healthy older adults.

Leukoaraiosis, a common ischaemic lesion diagnosed using magnetic resonance imaging (MRI), can influence driving safety performance (DSP). Most older drivers with leukoaraiosis are unaware of their affliction. Japan is a super-aged country, where preventing accidents caused by older drivers is an urgent national issue. We investigated the subcortical and periventricular leukoaraiosis regions that were most involved in DSP decline. The driving skills of 101 drivers (49 men, 52 women; mean age, 77.88 ± 3.77 years) without dementia were assessed by official driving instructors, using actual vehicles on a closed-circuit course. Parietal and occipital (but not frontal or temporal) leukoaraiosis volumes were significantly correlated with decreased DSP scores regardless of age, especially when turning right at intersections, which needs more attention than turning left because left-side driving is legally enforced in Japan. Occipital leukoaraiosis was also involved via a decline in dynamic visual cognitive function. MRI-based assessment of leukoaraiosis volume and localisation may enable the identification of older drivers prone to DSP deterioration. Risk factors for leukoaraiosis include smoking and lifestyle-related diseases such as hypertension. Thus, brain healthcare in patients with MRI-diagnosed leukoaraiosis may be particularly useful for the risk management of traffic accidents caused by the elderly in Japan.

Spatial Relation Between White Matter Hyperintensities and Incident Lacunes of Presumed Vascular Origin: A 14-Year Follow-Up Study.

BACKGROUND: The underlying mechanisms of incident lacunes regarding their spatial distribution remain largely unknown. We investigated the spatial distribution pattern and MRI predictors of incident lacunes in relation to white matter hyperintensity (WMH) over 14 years follow-up in sporadic small vessel disease. METHODS: Five hundred three participants from the ongoing prospective single-center Radboud University Nijmegen Diffusion Tensor and Magnetic resonance Cohort (RUN DMC) were recruited with baseline assessment in 2006 and follow ups in 2011, 2015, and 2020. Three hundred eighty-two participants who underwent at least 2 available brain MRI scans were included. Incident lacunes were systematically identified, and the spatial relationship between incident lacunes located in subcortical white matter and WMH were determined using a visual rating scale. Adjusted multiple logistic regression and linear mixed-effect regression models were used to assess the association between baseline small vessel disease markers, WMH progression, and incident lacunes. Participants with atrial fibrillation were excluded in multivariable analysis. RESULTS: Eighty incident lacunes were identified in 43 patients (mean age 66.5±8.2 years, 37.2% women) during a mean follow-up time of 11.2±3.3 years (incidence rate 10.0/1000 person-year). Sixty percent of incident lacunes were in the white matter, of which 48.9% showed no contact with preexisting WMH. Baseline WMH volume (odds ratio=2.5 [95% CI, 1.6-4.2]) predicted incident lacunes after adjustment for age, sex, and vascular risk factors. WMH progression was associated with incident lacunes independent of age, sex, baseline WMH volume, and vascular risk factors (odds ratio, 3.2 [95% CI, 1.5-6.9]). Baseline WMH volume and progression rate were higher in participants with incident lacunes in contact with preexisting WMH. No difference in vascular risk factors was observed regarding location or relation with preexisting WMH. CONCLUSIONS: The 2 different distribution patterns of lacunes regarding their relation to WMH may suggest distinct underlying mechanisms, one of which may be more closely linked to a similar pathophysiology as that of WMH. The longitudinal relation between WMH and lacunes further supports plausible shared mechanisms between the 2 key markers.

The contribution of white matter pathology, hypoperfusion, lesion load, and stroke recurrence to language deficits following acute subcortical left hemisphere stroke.

Aphasia, the loss of language ability following damage to the brain, is among the most disabling and common consequences of stroke. Subcortical stroke, occurring in the basal ganglia, thalamus, and/or deep white matter can result in aphasia, often characterized by word fluency, motor speech output, or sentence generation impairments. The link between greater lesion volume and acute aphasia is well documented, but the independent contributions of lesion location, cortical hypoperfusion, prior stroke, and white matter degeneration (leukoaraiosis) remain unclear, particularly in subcortical aphasia. Thus, we aimed to disentangle the contributions of each factor on language impairments in left hemisphere acute subcortical stroke survivors. Eighty patients with acute ischemic left hemisphere subcortical stroke (less than 10 days post-onset) participated. We manually traced acute lesions on diffusion-weighted scans and prior lesions on T2-weighted scans. Leukoaraiosis was rated on T2-weighted scans using the Fazekas et al. (1987) scale. Fluid-attenuated inversion recovery (FLAIR) scans were evaluated for hyperintense vessels in each vascular territory, providing an indirect measure of hypoperfusion in lieu of perfusion-weighted imaging. We found that language performance was negatively correlated with acute/total lesion volumes and greater damage to substructures of the deep white matter and basal ganglia. We conducted a LASSO regression that included all variables for which we found significant univariate relationships to language performance, plus nuisance regressors. Only total lesion volume was a significant predictor of global language impairment severity. Further examination of three participants with severe language impairments suggests that their deficits result from impairment in domain-general, rather than linguistic, processes. Given the variability in language deficits and imaging markers associated with such deficits, it seems likely that subcortical aphasia is a heterogeneous clinical syndrome with distinct causes across individuals.

Longitudinal Changes of White Matter Hyperintensities in Sporadic Small Vessel Disease: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: White matter hyperintensities (WMHs) are frequent imaging features of small vessel disease (SVD) and related to poor clinical outcomes. WMH progression over time is well described, but regression was also noted recently, although the frequency and associated factors are unknown. This systematic review and meta-analysis aims to assess longitudinal intraindividual WMH volume changes in sporadic SVD. METHODS: We searched EMBASE and MEDLINE for articles up to 28 January 2022 on WMH volume changes using MRI on ≥2 time points in adults with sporadic SVD. We classified populations (healthy/community-dwelling, stroke, cognitive, other vascular risk factors, and depression) based on study characteristics. We performed random-effects meta-analyses with Knapp-Hartung adjustment to determine mean WMH volume change (change in milliliters, percentage of intracranial volume [%ICV], or milliliters per year), 95% CI, and prediction intervals (PIs, limits of increase and decrease) using unadjusted data. Risk of bias assessment tool for nonrandomized studies was used to assess risk of bias. We followed Preferred Reporting in Systematic Review and Meta-Analysis guidelines. RESULTS: Forty-one articles, 12,284 participants, met the inclusion criteria. Thirteen articles had low risk of bias across all domains. Mean WMH volume increased over time by 1.74 mL (95% CI 1.23-2.26; PI -1.24 to 4.73 mL; 27 articles, N = 7,411, mean time interval 2.7 years, SD = 1.65); 0.25 %ICV (95% CI 0.14-0.36; PI -0.06 to 0.56; 6 articles, N = 1,071, mean time interval 3.5 years, SD = 1.54); or 0.58 mL/y (95% CI 0.35-0.81; PI -0.26 to 1.41; 8 articles, N = 3,802). In addition, 13 articles specifically mentioned and/or provided data on WMH regression, which occurred in asymptomatic, stroke, and cognitive disorders related to SVD. DISCUSSION: Net mean WMH volume increases over time mask wide-ranging change (e.g., mean increase of 1.75 mL ranging from 1.25 mL decrease to 4.75 mL increase), with regression documented explicitly in up to one-third of participants. More knowledge on underlying mechanisms, associated factors, and clinical correlates is needed, as WMH regression could be an important intervention target.

PR interval duration is associated with the presence of white matter hyperintensities: Insights from the epidemiologic LIFE-Adult Study.

BACKGROUND: PR interval prolongation is a preliminary stage of atrial cardiomyopathy which is considered as an intermediate phenotype for atrial fibrillation (AF). AF is a known risk factor for cerebrovascular adverse outcomes including stroke. Cerebral ischemia is one cause of white matter hyperintensities (WMHs), and cognitive dysfunction. AIM: To analyze the relationship between PR interval and WMHs. MATERIALS AND METHODS: We performed a cross-sectional analysis with individuals from the LIFE-Adult-Study (a population-based cohort study of randomly selected individuals from Leipzig, Germany) with available brain MRI and ECG. The Fazekas stages were used to quantify WMHs (0 = none; 1 = punctate foci; 2 = beginning confluence; 3 = large confluent areas). Stages 2-3 were defined as advanced WMHs. The PR interval was measured from resting 12-lead ECG. PR duration >200ms was defined as PR interval prolongation. We used a binary logistic regression for statistical analysis. We examined the relationship between MRI and ECG measures and adjusted them for clinical risk factors. RESULTS: We included 2464 individuals (age 59±15 years, 47% women) into analyses. The median PR interval was 160ms (interquartile range 143-179), and 319 (13%) individuals with advanced WMHs, were significantly older, had more cardiovascular comorbidities and risk factors compared to individuals without WMHs (all p<0.005). On univariable analysis, PR interval duration (OR 1.01, 95%CI 1.01-1.02, p≤0.001) and PR interval ≥160 ms (OR 2.1, 95%CI 1.6-2.7, p≤0.001) were associated with advanced WMHs. In multivariable analysis, while PR interval duration was not associated with WMHs in the whole cohort, individuals with PR ≥160ms had higher risk for WMHs. CONCLUSION: PR interval duration is associated with advanced WMHs beside advanced age, hypertension, and history of stroke. Further research is needed to determine whether changes in PR interval indices are clinically relevant for changes in WMHs.

Pattern and Severity of Leukoaraiosis and Microvascular Resistance- Inputs from a TCD Study from South Asia.

Background and Purpose: Leukoaraiosis is thought to be related to long-standing microvascular ischemia. The pathogenic mechanisms and hemodynamic changes could be different for periventricular and deep white matter leukoaraiosis. In this cross-sectional study, we examined whether the Pulsatility Index (PI) in Transcranial Doppler ultrasonography (TCD), which can give indirect information regarding downstream microvascular resistance and compliance, is different for leukoaraiosis in periventricular and deep locations. Correlation between presence of leukoaraiosis and PI was also studied since it was not studied in South-Asian patients before. Methods: Consecutive patients with suspected lacunar stroke or white-matter disease, undergoing MR brain imaging were included. Vascular imaging was done with CT or MR Angiography to rule out significant (>50%) stenosis. Fazeka's grading was done for severity of leukoaraiosis and mean PI in the middle cerebral artery (MCA) was obtained with trans-temporal TCD. Results: Ninety patients (Mean age 61 ± 10.9 years, 29% females) were available for final analysis. Age, hypertension, diabetes mellitus, CAD, and presence of leukoaraiosis were strongly associated with elevated mean PI in univariate analysis. In multivariate analysis, presence of leukoaraiosis was significantly associated with higher mean PI after adjusting for other variables. Mean PI strongly correlated with both periventricular (Spearman's correlation coefficient 0.56, P = 0.01) and deep white matter (Spearman's correlation coefficient 0.63, P = 0.01) leukoaraiosis. Conclusions: Our study confirms the correlation of Pulsatility Index with leukoaraiosis in South-Asian patients. Interestingly, changes in microvascular resistance appeared to be similar for both periventricular and deep white matter leukoaraiosis in spite of potential differences in etiopathogenesis.

APOE4 and Confluent White Matter Hyperintensities Have a Synergistic Effect on Episodic Memory Impairment in Prodromal Dementia.

BACKGROUND: White matter hyperintensities (WMH) are a known risk factor for cognitive decline. While the ɛ4 allele of apolipoprotein E gene (APOE4) is another risk factor for cognitive decline, it remains unclear how APOE4 affects the relationship between WMH and cognitive decline, specifically in the prodromal stage of dementia. OBJECTIVE: To determine how APOE4 moderates the relationship between WMH and cognition in prodromal dementia. METHODS: Two-hundred-sixteen participants with prodromal dementia underwent magnetic resonance imaging (MRI), neuropsychological testing (global and domain wise), cardiovascular risk factor assessments, and APOE genotyping. Visual ratings for WMH as well as total and lobar WMH volumes were quantified. Moderation analysis was performed to determine the influence of APOE4 on the relationship between WMH and performance on global and domain-specific cognitive measures. The role of confluent and non-confluent WMH on cognition was additionally studied using logistic regression. RESULTS: APOE4 carriers (n = 49) had poorer memory and higher global WMH (10.01 mL versus 6.23 mL, p = 0.04), temporal WMH (1.17 mL versus 0.58 mL, p = 0.01), and occipital WMH (0.38mL versus 0.22 mL, p = 0.02) compared to APOE4 non-carriers (n = 167). Moderation analysis revealed that APOE4 positivity strengthened the relationship between higher global as well as lobar WMH burden and poorer episodic memory. Furthermore, APOE4 carriers with confluent WMH were 4.81 times more likely to have impaired episodic memory compared to non-confluent WMH and non-APOE carriers. CONCLUSION: The impact of WMH on memory may be strongest among APOE4 carriers. Clinicians targeting WMH would need to consider the APOE4 allele and WMH severity status to strategize cognitive interventions.

High-Density Lipoprotein Is Associated with Leukoaraiosis Severity in Patients with Acute Ischemic Stroke.

Many patients with acute ischemic stroke (AIS) are found to accompany with leukoaraiosis (LA) in brain imaging. The risk factors of LA in patients with AIS were examined in this study. Patients with AIS were recruited and underwent head magnetic resonance imaging. According to Fazekas scores, patients were divided into LA group and non-LA group. We compared demographic and laboratory characteristics in two groups. Multivariate logistic regression analysis demonstrated that high-density lipoprotein (HDL), age, stroke history, admission SBP, and homocysteine were independent risk factors for LA in patients with AIS (P < 0.05). Multinomial logistic regression analysis demonstrated that HDL was an independent risk factor for moderate LA (OR 4.151, 95% CI 1.898-9.078, P < 0.001) and severe LA (OR 3.151, 95% CI 1.350-7.358, P = 0.008). In order to further explore the correlation between HDL level and the severity of LA, HDL was categorized in quartiles and multinomial logistic regression analysis was presented. Regression analysis showed that HDL ≥ 1.34 mmol/L was correlated with moderate and severe LA after adjusting for corresponding confounding factors in different models. After 1-year follow-up, patients were divided into regular statin therapy group and irregular statin therapy group. There was no significant difference in HDL level between two groups; however, the proportion of patients with increased Fazekas scores in regular statin therapy group was significantly less than that in the irregular statin therapy group (P < 0.05). In conclusion, HDL was an independent risk factor for LA and associated with the severity of LA in patients with AIS; regular statin therapy may be negatively related with the progress of LA. These results provide more evidences for controlling risk factors and severity of LA in patient with AIS.

Impact of different white matter hyperintensities patterns on cognition: A cross-sectional and longitudinal study.

OBJECTIVES: White matter hyperintensities (WMH) are highly prevalent in older adults and considered to be a contributor to cognition impairment. However, the strategic WMH lesion distribution related to cognitive impairment is still debated. The aim of this study was to characterize the spatial patterns of WMH associated with cognitive impairment and explore its risk factors. METHODS: We retrospectively analyzed patients who underwent T2 fluid attenuated inversion recovery (FLAIR) and mini-mental state examination (MMSE) in two centers. WHM was classified into four patterns based on T2 FLAIR as follows: (1) multiple subcortical spots (multi-spots); (2) peri-basal ganglia (peri-BG); (3) anterior subcortical patches (anterior SC patches); and (4) posterior subcortical patches (posterior SC patches). We cross-sectionally and longitudinally estimated associations between different WMH patterns and all-cause dementia and cognitive decline. Multivariable logistic regression analysis was followed to identify risk factors of WMH patterns related to cognitive impairment. RESULTS: A total of 442 patients with WMH were enrolled, with average age of 71.6 ± 11.3 years, and MMSE score of 24.1 ± 5.4. Among them, 281 (63.6%), 66 (14.9%), 163 (36.9%) and 197 (44.6%) patients presented multi-spots, peri-BG, anterior SC patches and posterior SC patches, respectively. Patients with anterior SC patches were more likely to have all-cause dementia in cross-sectional study (OR 2.002; 95% CI 1.098-3.649; p = 0.024), and have cognitive decline in longitudinal analysis (OR 3.029; 95% CI 1.270-7.223; p = 0.012). Four patterns of WMH referred to different cognitive domains, and anterior SC patches had the most significant and extensive impact on cognition after Bonferroni multiple comparison correction (all p < 0.0125). In addition, older age (OR 1.054; 95% CI 1.027-1.082; p < 0.001), hypertension (OR 1.956; 95% CI 1.145-3.341; p = 0.014), higher percentage of neutrophils (OR 1.046; 95% CI 1.014-1.080; p = 0.005) and lower concentration of hemoglobin (OR 0.983; 95% CI 0.967-1.000; p = 0.044) were risk factors for the presence of anterior SC patches. CONCLUSIONS: Different patterns of subcortical leukoaraiosis visually identified on MRI might have different impacts on cognitive impairment. Further studies should be undertaken to validate this simple visual classification of WMH in different population.