White Matter Hyperintensities Change Research Articles

The Associations Between Serum Insulin-like Growth Factor-I, Brain White Matter Volumes, and Cognition in Mild Cognitive Impairment and Alzheimer's Disease.

Insulin-like growth factor-I (IGF-I) regulates myelin, but little is known whether IGF-I associates with white matter functions in subjective and objective mild cognitive impairment (SCI/MCI) or Alzheimer's disease (AD). To explore whether serum IGF-I is associated with magnetic resonance imaging - estimated brain white matter volumes or cognitive functions. In a prospective study of SCI/MCI (n = 106) and AD (n = 59), we evaluated the volumes of the total white matter, corpus callosum (CC), and white matter hyperintensities (WMHs) as well as Mini-Mental State Examination (MMSE), Trail Making Test A and B (TMT-A/B), and Stroop tests I-III at baseline, and after 2 years. IGF-I was comparable in SCI/MCI and AD (113 versus 118 ng/mL, p = 0.44). In SCI/MCI patients, the correlations between higher baseline IGF-I and greater baseline and 2-year volumes of the total white matter and total CC lost statistical significance after adjustment for intracranial volume and other covariates. However, after adjustment for covariates, higher baseline IGF-I correlated with better baseline scores of MMSE and Stroop test II in SCI/MCI and with better baseline results of TMT-B and Stroop test I in AD. IGF-I did not correlate with WMH volumes or changes in any of the variables. Both in SCI/MCI and AD, higher IGF-I was associated with better attention/executive functions at baseline after adjustment for covariates. Furthermore, the baseline associations between IGF-I and neuropsychological test results in AD may argue against significant IGF-I resistance in the AD brain.

Impact of long-term white matter hyperintensity changes on mobility and dexterity.

White matter hyperintensities (WMH), a common feature of cerebral small vessel disease, are related to worse clinical outcomes after stroke. We assessed the impact of white matter hyperintensity changes over 1 year after minor stroke on change in mobility and dexterity, including differences between the dominant and non-dominant hands and objective in-person assessment versus patient-reported experience. We recruited participants with lacunar or minor cortical ischaemic stroke, performed medical and cognitive assessments and brain MRI at presentation and at 1 year. At both time points, we used the timed-up and go test and the 9-hole peg test to assess mobility and dexterity. At 1 year, participants completed the Stroke Impact Scale. We ran two linear mixed models to assess change in timed-up and go and 9-hole peg test, adjusted for age, sex, stroke severity (National Institutes of Health Stroke Scale), dependency (modified Rankin Score), vascular risk factor score, white matter hyperintensity volume (as % intracranial volume) and additionally for 9-hole peg test: Montreal cognitive assessment, hand (dominant/non-dominant), National Adult Reading Test (premorbid IQ), index lesion side. We performed ordinal logistic regression, corrected for age and sex, to assess relations between timed-up and go and Stroke Impact Scale mobility, and 9-hole peg test and Stroke Impact Scale hand function. We included 229 participants, mean age 65.9 (standard deviation = 11.13); 66% male. 215/229 attended 1-year follow-up. Over 1 year, timed-up and go time increased with aging (standardized β [standardized 95% Confidence Interval]: 0.124[0.011, 0.238]), increasing National Institutes of Health Stroke Scale (0.106[0.032, 0.180]), increasing modified Rankin Score (0.152[0.073, 0.231]) and increasing white matter hyperintensity volume (0.176[0.061, 0.291]). Men were faster than women (-0.306[0.011, 0.238]). Over 1 year, slower 9-hole peg test was related to use of non-dominant hand (0.290[0.155, 0.424]), aging (0.102[0.012, 0.192]), male sex (0.182[0.008, 0.356]), increasing National Institutes of Health Stroke Scale (0.160 [0.094, 0.226]), increasing modified Rankin Score (0.100[0.032, 0.169]), decreasing Montreal cognitive assessment score (-0.090[-0.167, -0.014]) and increasing white matter hyperintensity volume (0.104[0.015, 0.193]). One year post-stroke, Stroke Impact Scale mobility worsened per second increase on timed-up and go, odds ratio 0.67 [95% confidence interval 0.60, 0.75]. Stroke Impact Scale hand function worsened per second increase on the 9-hole peg test for the dominant hand (odds ratio 0.79 [0.71, 0.86]) and for the non-dominant hand (odds ratio 0.88 [0.83, 0.93]). Decline in mobility and dexterity is associated with white matter hyperintensity volume increase, independently of stroke severity. Mobility and dexterity declined more gradually for stable and regressing white matter hyperintensity volume. Dominant and non-dominant hands might be affected differently. In-person measures of dexterity and mobility are associated with self-reported experience 1-year post-stroke.

Vascular dysfunction in sporadic bvFTD: white matter hyperintensity and peripheral vascular biomarkers

BackgroundVascular dysfunction was recently reported to be involved in the pathophysiological process of neurodegenerative diseases, but its role in sporadic behavioral variant frontotemporal dementia (bvFTD) remains unclear. The aim of this study was to systematically explore vascular dysfunction, including changes in white matter hyperintensities (WMHs) and peripheral vascular markers in bvFTD.MethodsThirty-two patients with bvFTD who with no vascular risk factors were enrolled in this cross-sectional study and assessed using positron emission tomography/magnetic resonance (PET/MRI) imaging, peripheral plasma vascular/inflammation markers, and neuropsychological examinations. Group differences were tested using Student’s t-tests and Mann–Whitney U tests. A partial correlation analysis was implemented to explore the association between peripheral vascular markers, neuroimaging, and clinical measures.ResultsWMH was mainly distributed in anterior brain regions. All peripheral vascular factors including matrix metalloproteinases-1 (MMP-1), MMP-3, osteopontin, and pentraxin-3 were increased in the bvFTD group. WMH was associated with the peripheral vascular factor pentraxin-3. The plasma level of MMP-1 was negatively correlated with the gray matter metabolism of the frontal, temporal, insula, and basal ganglia brain regions. The WMHs in the frontal and limbic lobes were associated with plasma inflammation markers, disease severity, executive function, and behavior abnormality. Peripheral vascular markers were associated with the plasma inflammation markers.ConclusionsWMHs and abnormalities in peripheral vascular markers were found in patients with bvFTD. These were found to be associated with the disease-specific pattern of neurodegeneration, indicating that vascular dysfunction may be involved in the pathogenesis of bvFTD. This warrants further confirmation by postmortem autopsy. Targeting the vascular pathway might be a promising approach for potential therapy.

Magnetic Resonance Imaging Tissue Signatures Associated With White Matter Changes Due to Sporadic Cerebral Small Vessel Disease Indicate That White Matter Hyperintensities Can Regress.

White matter hyperintensities (WMHs) might regress and progress contemporaneously, but we know little about underlying mechanisms. We examined WMH change and underlying quantitative magnetic resonance imaging tissue measures over 1 year in patients with minor ischemic stroke with sporadic cerebral small vessel disease. We defined areas of stable normal-appearing white matter, stable WMHs, progressing and regressing WMHs based on baseline and 1-year brain magnetic resonance imaging. In these areas we assessed tissue characteristics with quantitative T1, fractional anisotropy (FA), mean diffusivity (MD), and neurite orientation dispersion and density imaging (baseline only). We compared tissue signatures cross-sectionally between areas, and longitudinally within each area. WMH change masks were available for N=197. Participants' mean age was 65.61 years (SD, 11.10), 59% had a lacunar infarct, and 68% were men. FA and MD were available for N=195, quantitative T1 for N=182, and neurite orientation dispersion and density imaging for N=174. Cross-sectionally, all 4 tissue classes differed for FA, MD, T1, and Neurite Density Index. Longitudinally, in regressing WMHs, FA increased with little change in MD and T1 (difference estimate, 0.011 [95% CI, 0.006-0.017]; -0.002 [95% CI, -0.008 to 0.003] and -0.003 [95% CI, -0.009 to 0.004]); in progressing and stable WMHs, FA decreased (-0.022 [95% CI, -0.027 to -0.017] and -0.009 [95% CI, -0.011 to -0.006]), whereas MD and T1 increased (progressing WMHs, 0.057 [95% CI, 0.050-0.063], 0.058 [95% CI, 0.050 -0.066]; stable WMHs, 0.054 [95% CI, 0.045-0.063], 0.049 [95% CI, 0.039-0.058]); and in stable normal-appearing white matter, MD increased (0.004 [95% CI, 0.003-0.005]), whereas FA and T1 slightly decreased and increased (-0.002 [95% CI, -0.004 to -0.000] and 0.005 [95% CI, 0.001-0.009]). Quantitative magnetic resonance imaging shows that WMHs that regress have less abnormal microstructure at baseline than stable WMHs and follow trajectories indicating tissue improvement compared with stable and progressing WMHs.

Higher HbA1c Is Associated With Greater 2-Year Progression of White Matter Hyperintensities.

White matter hyperintensity (WMH) lesions on brain MRI images are surrogate markers of cerebral small vessel disease (CSVD). Longitudinal studies examining the association between diabetes and WMH progression have yielded mixed results. Thus, in this study we investigated the association between HbA1c, a biomarker for the presence and severity of hyperglycemia, and longitudinal WMH change after adjusting for known risk factors for WMH progression. We recruited 64 participants from South Korean memory clinics to undergo brain MRI at the baseline and a two-year follow-up. We found: First, higher HbA1c was associated with greater global WMH volume (WMHV) changes after adjusting for known risk factors (B = 7.7E-04, p = 0.025); Second, the association between baseline WMHV and WMHV progression was only significant at diabetic levels of HbA1c (p < 0.05, when HbA1c > 6.51%), and non-APOE ε4 carriers showed a stronger association between HbA1c and WMHV progression (B = -2.59E-03, p = 0.004); Third, associations of WMHV progression with HbA1c were particularly apparent for deep WMHV change (B = 7.17E-04, p < 0.01) compared to periventricular WMHV change, and for frontal (B = 5.00E-04, p < 0.001) and parietal (B = 1.534-04, p < 0.05) WMHV change compared to occipital and temporal WMHV change. In conclusion, higher HbA1c levels were associated with greater two-year WMHV progression, especially in non-APOE ε4 participants or those with diabetic levels of HbA1c. These findings demonstrate that diabetes may potentially exacerbate cerebrovascular and white matter disease.

Associations between adiposity and white matter hyperintensities: Cross-sectional and longitudinal analyses of 34,653 participants.

White matter hyperintensities (WMH) increase the risk of stroke and cognitive impairment. This study aims to determine the cross-sectional and longitudinal associations between adiposity and WMH. Participants were enrolled from the UK Biobank cohort. Associations of concurrent, past, and changes in overall and central adiposity with WMH were investigated by linear and nonlinear regression models. The association of longitudinal adiposity and WMH volume changes was determined by a linear mixed model. Mediation analysis investigated the potential mediating effect of blood pressure. In 34,653 participants with available adiposity measures and imaging data, the concurrent obese group had a 25.3% (β [95% CI] = 0.253 [0.222-0.284]) higher WMH volume than the ideal weight group. Increment in all adiposity measures was associated with a higher WMH volume. Among them, waist circumference demonstrated the strongest effect (β [95% CI] = 0.113 [0.101-0.125]). Past adiposity also demonstrated similar effects. Among the subset of 2664 participants with available WMH follow-up data, adiposity measures were predictive of WMH change. Regarding changes of adiposity, compared with ideal weight stable group, those who turned from ideal weight to overweight/obese had a 8.1% higher WMH volume (β [95% CI] = 0.081 [0.039-0.123]), while participants who turned from overweight/obese to ideal weight demonstrated no significant WMH volume change. Blood pressure partly meditates the associations between adiposity and WMH. Both concurrent and past adiposity were associated with a higher WMH volume. The detrimental effects of adiposity on WMH occurred throughout midlife and in the elderly and may still exist after changes in obesity status.

Predicting progression of white matter hyperintensity using coronary artery calcium score based on coronary CT angiography-feasibility and accuracy.

Coronary artery disease (CAD) usually coexists with subclinical cerebrovascular diseases given the systematic nature of atherosclerosis. In this study, our objective was to predict the progression of white matter hyperintensity (WMH) and find its risk factors in CAD patients using the coronary artery calcium (CAC) score. We also investigated the relationship between the CAC score and the WMH volume in different brain regions. We evaluated 137 CAD patients with WMH who underwent coronary computed tomography angiography (CCTA) and two magnetic resonance imaging (MRI) scans from March 2018 to February 2023. Patients were categorized into progressive (n = 66) and nonprogressive groups (n = 71) by the change in WMH volume from the first to the second MRI. We collected demographic, clinical, and imaging data for analysis. Independent risk factors for WMH progression were identified using logistic regression. Three models predicting WMH progression were developed and assessed. Finally, patients were divided into groups based on their total CAC score (0 to <100, 100 to 400, and > 400) to compare their WMH changes in nine brain regions. Alcohol abuse, maximum pericoronary fat attenuation index (pFAI), CT-fractional flow reserve (CT-FFR), and CAC risk grade independently predicted WMH progression (p < 0.05). The logistic regression model with all four variables performed best (training: AUC = 0.878, 95% CI: 0.790, 0.938; validation: AUC = 0.845, 95% CI: 0.734, 0.953). An increased CAC risk grade came with significantly higher WMH volume in the total brain, corpus callosum, and frontal, parietal and occipital lobes (p < 0.05). This study demonstrated the application of the CCTA-derived CAC score to predict WMH progression in elderly people (≥60 years) with CAD.

Multi-Site Cross-Site Inter-Rater and Test-Retest Reliability and Construct Validity of the MarkVCID White Matter Hyperintensity Growth and Regression Protocol.

White matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer's Disease. Conducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol. The NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were analyzed in relation to WMH changes to explore its construct validity. ICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p < 0.028) but was not associated with WMH regression. The present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.

Trial of the MIND Diet for Prevention of Cognitive Decline in Older Persons

BackgroundFindings from observational studies suggest that dietary patterns may offer protective benefits against cognitive decline, but data from clinical trials are limited. The Mediterranean–DASH Intervention for Neurodegenerative Delay, known as the MIND diet, is a hybrid of the Mediterranean diet and the DASH (Dietary Approaches to Stop Hypertension) diet, with modifications to include foods that have been putatively associated with a decreased risk of dementia.MethodsWe performed a two-site, randomized, controlled trial involving older adults without cognitive impairment but with a family history of dementia, a body-mass index (the weight in kilograms divided by the square of the height in meters) greater than 25, and a suboptimal diet, as determined by means of a 14-item questionnaire, to test the cognitive effects of the MIND diet with mild caloric restriction as compared with a control diet with mild caloric restriction. We assigned the participants in a 1:1 ratio to follow the intervention or the control diet for 3 years. All the participants received counseling regarding adherence to their assigned diet plus support to promote weight loss. The primary end point was the change from baseline in a global cognition score and four cognitive domain scores, all of which were derived from a 12-test battery. The raw scores from each test were converted to z scores, which were averaged across all tests to create the global cognition score and across component tests to create the four domain scores; higher scores indicate better cognitive performance. The secondary outcome was the change from baseline in magnetic resonance imaging (MRI)–derived measures of brain characteristics in a nonrandom sample of participants.ResultsA total of 1929 persons underwent screening, and 604 were enrolled; 301 were assigned to the MIND-diet group and 303 to the control-diet group. The trial was completed by 93.4% of the participants. From baseline to year 3, improvements in global cognition scores were observed in both groups, with increases of 0.205 standardized units in the MIND-diet group and 0.170 standardized units in the control-diet group (mean difference, 0.035 standardized units; 95% confidence interval, −0.022 to 0.092; P=0.23). Changes in white-matter hyperintensities, hippocampal volumes, and total gray- and white-matter volumes on MRI were similar in the two groups.ConclusionsAmong cognitively unimpaired participants with a family history of dementia, changes in cognition and brain MRI outcomes from baseline to year 3 did not differ significantly between those who followed the MIND diet and those who followed the control diet with mild caloric restriction. (Funded by the National Institute on Aging; ClinicalTrials.gov number, NCT02817074.)

Mediterranean diet and longitudinal change of white matter hyperintensity in cognitively intact young and older adults

AbstractBackgroundA healthy dietary pattern, Mediterranean diet (MeDi), has been reported to be associated with better brain and cognition. White matter hyperintensities (WMHs), seen in brain magnetic resonance imaging, are considered to be due to cerebral small vessel diseases and have been shown to predict faster cognitive decline in older adults. However, current evidence on the association between MeDi and WMH is inconsistent and longitudinal data are scarce. This study aims to examine whether better adherence to MeDi is associated with less accumulation of WMH over time.MethodThis longitudinal study was conducted among 183 cognitively intact adults aged 20‐80 years. MeDi was calculated from dietary data assessed by a self‐reported food frequency questionnaire, ranging from 0‐55, with a higher score indicating better adherence. WMH was assessed by 3T MRI, and log‐transformed prior to analyses. A one‐sample T‐test was used to examine if WMH burden increased from baseline to follow‐up over an average of five years. Multivariable linear regression was used to estimate the effect of MeDi on the change in WMH. Covariates included age, gender, race/ethnicity, education, IQ, follow‐up interval, caloric intake, baseline WMH, baseline total gray matter volume, and baseline mean cortical thickness. Moderation effects by age (young: &lt;43, middle‐aged: 43‐65, and older: ≥65 years), sex, and race/ethnicity (non‐Hispanic White and other, non‐Hispanic Black, and Hispanic) were examined, followed by stratification analyses.ResultAmong all participants, WMH increased from baseline to follow‐up (mean difference [follow‐up‐baseline][standard error(SE)] = 0.31[0.04], p&lt;0.001). A higher MeDi was associated with less increase of WMH (β[SE] = ‐0.014[0.006], p = 0.034), adjusting by all covariates. The association between MeDi and WMH change was moderated by age group (young group as the reference, p‐interaction[middle‐aged*MeDi] = 0.024, p‐interaction[older*MeDi] = 0.017), adjusting by follow‐up interval: the association was observed among the young group (β[SE] = ‐0.038[0.010], p&lt;0.001), but not among the middle‐aged ((β[SE] = ‐0.002[0.013, p = 0.872]) or the older group ((β[SE] = ‐0.002[0.009], p = 0.836). No significant moderation effects by sex or race/ethnicity were found, adjusting by age and follow‐up interval.ConclusionBetter adherence to MeDi was associated with reduced increase of WMH over time. Following a healthy diet, especially at an early age, may help maintain a healthy brain.

Association between hypertension and neurovascular inflammation in both normal-appearing white matter and white matter hyperintensities

The major vascular cause of dementia is cerebral small vessel disease (SVD), including white matter hyperintensities (WMH) amongst others. While the underlying pathology of SVD remains unclear, chronic hypertension and neuroinflammation are recognized as important risk factors for SVD and for the conversion of normal-appearing white matter (NAWM) to WMH. Unfortunately, most studies investigating the role of neuroinflammation in WMH relied on peripheral blood markers, e.g., markers for systemic or vascular inflammation, as a proxy for inflammation in the brain itself. However, it is unknown whether such markers accurately capture inflammatory changes within the cerebral white matter. Therefore, we aimed to comprehensively investigate the impact of hypertension on perivascular- and neuroinflammation in both WMH and NAWM. We conducted high field brain magnetic resonance imaging (MRI), followed by (immuno-)histopathological staining of neuroinflammatory markers on human post-mortem brains of elderly people with a history of hypertension (n = 17) and age-matched normotensive individuals (n = 5). MRI images were co-registered to (immuno-)histopathological data including stainings for microglia and astroglia to assess changes in MRI-based WMH at microscopic resolution. Perivascular inflammation was carefully assessed based on the severity of perivascular astrogliosis of the smallest vessels throughout white matter regions. Hypertension was associated with a larger inflammatory response in both WMH and NAWM. Notably, the presence of close-range perivascular inflammation was twice as common among those with hypertension than in controls both in WMH and NAWM, suggesting that neurovascular inflammation is critical in the etiology of WMH. Moreover, a higher degree of microglial activation was related to a higher burden of WMH. Our results indicate that neuro(vascular)inflammation at the level of the brain itself is involved in the etiology of WMH. Future therapeutic strategies focusing on multitarget interventions including antihypertensive treatment as well as neuroinflammation may ameliorate WMH progression.

Peripheral blood leukotriene B4 and E4 as biomarkers in Alzheimer’s disease

AbstractBackgroundWe showed recently that use of leukotriene receptor antagonists, typically used in asthma therapy, was associated with preserved executive function among people with Alzheimer’s disease (AD) dementia. The aim of this study was to determine if leukotriene B4 (LTB4) and E4 (LTE4) would be associated with longitudinal changes in cognitive performance and cerebrovascular disease markers in people with AD.MethodParticipants with clinical AD or mild cognitive impairment were identified from the Ontario Neurodegenerative Disease Research Initiative. LTB4 and LTE4 were extracted from fasting serum and quantified using ultra‐high performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS). Concentrations below the limit of detection were imputed using quantile regression imputation of left‐censored data. Cognition was assessed using composite scores for executive function (Trails Making Test B, Symbol Digit Modalities Test, Stroop switching task, and verbal fluency) and memory (Rey Auditory Verbal Learning Test and Brief Visuospatial Memory Test). White matter hyperintensities (WMH), lacunes, and perivascular spaces (PVS) were quantified using T2‐weighted structural magnetic resonance imaging (MRI). Longitudinal associations between baseline LTB4 or LTE4 and cognition and imaging markers at baseline and 1‐year‐follow‐up were assessed using mixed‐effects linear regression models, controlling for baseline demographic factors, medication use, and vascular comorbidities. Findings were corrected for multiple comparisons using a 5% false discovery rate.ResultAmong 158 participants (mean age = 69.22 years, 51% female, mean education = 14.61 years), higher baseline concentrations of LTB4 were not associated with performance in executive function or memory over time nor with changes in WMH, lacunes, or PVS over time. Higher baseline concentrations of LTE4 were associated with better performance in memory over time (β = 0.153 [95% CI = 0.026, 0.287]; however, this finding did not survive correction for multiple comparisons (adjusted p = 0.260; Table 1).ConclusionIn a group of patients with AD, higher LTB4 and LTE4 in serum were not associated with changes in cognitive performance nor markers of cerebrovascular disease. These findings suggest very little potential for serum leukotrienes as biomarkers for cognitive decline of cerebrovascular disease progression in AD.

Discrete white matter hyperintensity (WMH) growth quantification is superior to measurements of total longitudinal WMH volume change: implications for clinical trials in VCID

AbstractBackgroundSmall vessel ischemic disease (SVID) is a major risk factor for late‐life cognitive impairment and dementia (VCID). White matter hyperintensities (WMH) are a SVID biomarker that can be detected on MRI FLAIR imaging. Prior studies show dynamic change in WMH volumes that increase and decrease within subjects over time. We reported a method to quantify discrete WMH volume growth and regression in individuals over one‐year with instrumental validation performed within the MarkVCID consortium. The present study provides preliminary evidence for the clinical relevance of this methodology.Method3D MRI T1‐weighted and FLAIR images at baseline and 12‐month follow‐up visits for sixty‐one participants (mean age 74 ± 5.9 years, 31 women) were analyzed. The Stroop test was administered using the CANS‐MCI computerized battery. WMH growth and regression were quantified for all participants. A linear regression model was used to assess the association of dynamic WMH changes with Stroop performance.ResultWMH growth, but not regression or total WMH volume changes was associated with Stroop performance at the 12‐months (β = ‐0.24, P = 0.02) after controlling for sex, and age (graph).ConclusionThese data show that WMH growth, but not regression or total WMH volume change, was associated with a decline in performance on the Stroop test over12‐months. These findings highlight the importance of studying dynamic, within subject, WMH growth and regression rather than solely focusing on longitudinal change in total WMH volume measurements. Measurement of WMH growth may help reduce sample sizes, facilitate clinical trial conduct, and optimize the potential to identify interventions intended to mitigate SVID contributions to VCID.

Physical activity moderates the association between white matter hyperintensity burden and cognitive change.

ObjectiveGreater physical activity (PA) could delay cognitive decline, yet the underlying mechanisms remain unclear. White matter hyperintensity (WMH) burden is one of the key brain pathologies that have been shown to predict faster cognitive decline at a late age. One possible pathway is that PA may help maintain cognition by mitigating the detrimental effects of brain pathologies, like WMH, on cognitive change. This study aims to examine whether PA moderates the association between WMH burden and cognitive change.Materials and methodsThis population-based longitudinal study included 198 dementia-free adults aged 20–80 years. Leisure-time physical activity (LTPA) was assessed by a self-reported questionnaire. Occupational physical activity (OPA) was a factor score measuring the physical demands of each job. Total physical activity (TPA) was operationalized as the average of z-scores of LTPA and OPA. Outcome variables included 5-year changes in global cognition and in four reference abilities (fluid reasoning, processing speed, memory, and vocabulary). Multivariable linear regression models were used to estimate the moderation effect of PA on the association between white matter hyperintensities and cognitive change, adjusting for age, sex, education, and baseline cognition.ResultsOver approximately 5 years, global cognition (p < 0.001), reasoning (p < 0.001), speed (p < 0.001), and memory (p < 0.05) scores declined, and vocabulary (p < 0.001) increased. Higher WMH burden was correlated with more decline in global cognition (Spearman’s rho = –0.229, p = 0.001), reasoning (rho = –0.402, p < 0.001), and speed (rho = –0.319, p < 0.001), and less increase in vocabulary (rho = –0.316, p < 0.001). Greater TPA attenuated the association between WMH burden and changes in reasoning (βTPA^*WMH = 0.029, 95% CI = 0.006–0.052, p = 0.013), speed (βTPA^*WMH = 0.035, 95% CI = –0.004–0.065, p = 0.028), and vocabulary (βTPA^*WMH = 0.034, 95% CI = 0.004–0.065, p = 0.029). OPA seemed to be the factor that exerted a stronger moderation on the relationship between WMH burden and cognitive change.ConclusionPhysical activity may help maintain reasoning, speed, and vocabulary abilities in face of WMH burden. The cognitive reserve potential of PA warrants further examination.

Mediterranean Diet and White Matter Hyperintensity Change over Time in Cognitively Intact Adults.

Current evidence on the impact of Mediterranean diet (MeDi) on white matter hyperintensity (WMH) trajectory is scarce. This study aims to examine whether greater adherence to MeDi is associated with less accumulation of WMH. This population-based longitudinal study included 183 cognitively intact adults aged 20–80 years. The MeDi score was obtained from a self-reported food frequency questionnaire; WMH was assessed by 3T MRI. Multivariable linear regression was used to estimate the effect of MeDi on WMH change. Covariates included socio-demographic factors and brain markers. Moderation effects by age, gender, and race/ethnicity were examined, followed by stratification analyses. Among all participants, WMH increased from baseline to follow-up (mean difference [follow-up-baseline] [standard deviation] = 0.31 [0.48], p < 0.001). MeDi adherence was negatively associated with the increase in WMH (β = −0.014, 95% CI = −0.026–−0.001, p = 0.034), adjusting for all covariates. The association between MeDi and WMH change was moderated by age (young group = reference, p-interaction[middle-aged × MeDi] = 0.075, p-interaction[older × MeDi] = 0.037). The association between MeDi and WMH change was observed among the young group (β = −0.035, 95% CI = −0.058–−0.013, p = 0.003), but not among other age groups. Moderation effects by gender and race/ethnicity did not reach significance. Greater adherence to MeDi was associated with a lesser increase in WMH over time. Following a healthy diet, especially at younger age, may help to maintain a healthy brain.

Cortical Thickness and White Matter Hyperintensity Changes Are Associated With Sarcopenia in the Cognitively Normal Older Adults.

Objective We aimed to explore the impact of sarcopenia on the cortical thickness, white matter hyperintensity (WMH), and subcortical volumes in the cognitively normal older adults. Methods Sixty cognitively normal older adults with and without sarcopenia were enrolled in the study. They underwent T1 and FLAIR magnetic resonance imaging. Information on muscle mass, muscle strength and muscle function were measured using bioelectrical impedance analysis, handgrip strength and 5 time-chair stand test (CST) respectively. Structural magnetic resonance images were analyzed and processed using Freesurfer v6.0. Results Compared to the control group, the sarcopenia group demonstrated reduced cortical thickness in left superior frontal, precentral, right post central, inferior parietal, rostral middle frontal superior parietal and both lateral occipital and paracentral gyrus. Volumes of left hippocampus, and periventricular WMH were also reduced in the Sarcopenia group. In addition, we found a significant positive correlation between the left precuneus thickness and muscle mass. Periventricular WMH volumes were also positively correlated with the 5CST score. Conclusion Sarcopenia affects cortical and subcortical structures in the cognitively normal older adults. These structural changes might be associated with underlying neurobiological mechanisms of sarcopenia in the cognitively normal older adults.

White matter hyperintensities-related cortical changes and correlation with mild behavioral impairment

PurposeThe aim of this study was to analyze cortical thickness and gray matter volume (GMV) changes in white matter hyperintensities (WMH) which were associated brain regions and their association with mild behavioral impairment (MBI) by means of voxel- and surface-based morphology (VBM and SBM). MethodsA total of 60 patients underwent 3T MRI scan and MBI checklist (MBI-C) assessment and were divided into two groups: lower WMH (LWMH) and higher WMH (HWMH). After adjusting for confounding factors i.e. age, gender, education, and total intracranial volume, we found a GMV decrease in the left anterior insula (AIns), right middle frontal gyrus, right central operculum, right fusiform gyrus, left cerebellum exterior, and thalamus proper in the HWMH group based VBM, while in the HWMH group based SBM we found cortical thickness decrease in the left lingual, right posterior cingulate cortex (rPCC), right precentral, left superior frontal, right medial orbitofrontal gyrus, and left pars opercularis. ResultsThe HWMH group had higher MBI-C scores. The GMV in the left AIns and thalamus proper and the thickness of rPCC negatively correlated with the MBI-C scores. The mediation analysis suggested that WMH may partially mediate MBI-C scores by reducing the GMV and cortical thickness of the mentioned brain regions. ConclusionsIn WMH patients, the occurrence of MBI is associated with atrophy of gray matter and cortex. The occurrence of MBI may be partially mediated by WMH through gray matter and cortical atrophy. It provides a new insight into the relationship between WMH and dementia.

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

BackgroundPR 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.AimTo analyze the relationship between PR interval and WMHs.Materials and methodsWe 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.ResultsWe 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.ConclusionPR 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.

Stage-Dependent Cerebral Blood Flow and Leukoaraiosis Couplings in Subcortical Ischemic Vascular Disease and Alzheimer's Disease.

Background: Alzheimer’s disease (AD) and subcortical ischemic vascular disease (SIVD) have both been associated with white matter hyperintensities (WMHs) and altered cerebral blood flow (CBF) although the etiology of AD is still unclear.Objective: To test the hypothesis that CBF and WMHs have differential effects on cognition and that the relationship between CBF and WMHs changes with the subtypes and stages of dementia.Methods: Forty-two patients with SIVD, 50 patients with clinically-diagnosed AD, and 30 cognitively-normal subjects were included. Based on the Clinical Dementia Rating (CDR), the patients were dichotomized into early-stage (CDR = 0.5) and late-stage (CDR = 1 or 2) groups. CBF and WMH metrics were derived from magnetic resonance imaging and correlated with cognition.Results: Hierarchical linear regression revealed that CBF metrics had distinct contribution to global cognition, memory, and attention, whereas WMH metrics had distinct contribution to executive function (all p < 0.05). In SIVD, the WMHs in frontotemporal areas correlated with the CBF in bilateral thalami at the early stage; the correlation then became between the WMHs in basal ganglia and the CBF in frontotemporal areas at the late stage. A similar corticosubcortical coupling was observed in AD but involved fewer areas.Conclusion: A stage-dependent coupling between CBF and WMHs was identified in AD and SIVD, where the extent of cortical WMHs correlated with subcortical CBF for CDR = 0.5, whereas the extent of subcortical WMHs correlated with cortical CBF for CDR = 1–2.

Retinal microvascular changes in white matter hyperintensities investigated by swept source optical coherence tomography angiography

BackgroTo assess the microvascular changes in the macular region and the foveal avascular zone (FAZ) area in participants with white matter hyperintensities (WMHs) using swept source optical coherence tomography angiography (SS OCTA).MethodsThis cross-sectional study included a total of 23 WMH participants (45 eyes) and 20 age-matched healthy participants (40 eyes). SS OCTA (VG200; SVision Imaging, Ltd., Luoyang, China) was used to assess the retinal vessel density (VD) and the FAZ area. VD was measured in the superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) within a 6 × 6-mm scan centred on the macula using a 5-mm Macula circle. The FAZ area was automatically measured on the inner retina layer within a 3 × 3-mm scan in the macular region.ResultsThere was no significant difference in VD in the SVP between the two groups. However, VD in both the ICP and DCP was significantly decreased in WMH participants (P = 0.028, P = 0.016). The FAZ area was significantly enlarged in WMH participants (P = 0.030). The signal quality was significantly lower in WMH participants (P < 0.001).ConclusionsThis study suggested that WMH participants have retinal microvascular and foveal avascular zone area changes compared with healthy controls. Further longitudinal studies with larger sample sizes are warranted to identify the value of our findings in the early evaluation of WMHs.