Longitudinal Cognitive Changes in Cerebral Small Vessel Disease: The Effect of White Matter Hyperintensity Regression and Progression.

BackgroundWhite matter hyperintensity (WMH) is prevalent in elderly populations. Ischemia is characterized by a decline in cerebral blood flow (CBF) and may play a key role in the pathogenesis of WMH. However, the association between CBF reduction and WMH progression remains controversial. This study aimed to investigate the association between CBF and the progression of WMH at a 2-year follow-up of community-based, asymptomatic adults in a longitudinal cohort study across the lifespan.MethodsAsymptomatic adults who participated in a community-based study were recruited and underwent brain structural and perfusion magnetic resonance imaging (MRI) at baseline and at a 2-year follow-up visit. The CBF was measured on pseudo-continuous arterial spin-labeling (pCASL) MRI. The WMH was evaluated on T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) images. Tissue segmentation was conducted on T1-weighted (T1W) images to derive binary masks of gray matter and normal-appearing white matter. Linear mixed effect models were conducted to analyze the cross-sectional and longitudinal associations between CBF and WMH.ResultsA total of 229 adults (mean age 57.3±12.6 years; 94 males) were enrolled at baseline, among whom 84 participants (mean age 54.1±11.9 years; 41 males) completed a follow-up visit with a mean time interval of 2.77±0.44 years. At baseline, there was a decreasing trend in gray matter (GM) CBF with an increase of WMH burden (P=0.063), but this association was attenuated after adjusting for age (P=0.362). In the longitudinal analysis, baseline WMH volume was significantly associated with the reduction of perfusion in GM [coefficient =−1.96, 95% confidence interval (CI): −3.25 to −0.67; P=0.004] and normal appearing white matter (coefficient =−0.99, 95% CI: −1.66 to −0.31; P=0.005) during follow-up. On the contrary, neither baseline CBF in GM (P=0.888) nor normal appearing white matter (P=0.850) was associated with WMH progression. In addition, CBF changes within WMH were significantly associated with both baseline (coefficient =−0.014, 95% CI: −0.025 to −0.003; P=0.017) and progression (coefficient =−1.01, 95% CI: −1.81 to −0.20; P=0.015) of WMH volume.ConclusionsA WMH burden was not found to be directly associated with cortex perfusion at baseline due to the effects of age on both CBF and WMH. However, baseline WMH volume could predict the reduction of perfusion.

Cerebral Small Vessel Disease (SVD); lacunes, Cerebral Microbleeds (CMBs), and White Matter Hyperintensities (WMH) have a vital role in cognitive impairment and dementia. SVD in lobar location is related to cerebral amyloid angiopathy, whereas SVD in a deep location with hypertensive arteriopathy. It remains unclear how different locations of SVD affect long-term cognitive decline. The present study aimed to analyse the association between different locations and severity of SVD with global and domain-specific cognitive decline over the follow-up interval of 3 years. We studied 428 participants who had performed MRI scans at baseline and at least 3 neuropsychological assessments. Locations of lacunes and CMBs were categorized into strictly lobar, strictly deep and mixed-location, WMH volume into anterior and posterior. The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Harmonization Neuropsychological Battery was used to assess cognitive function. To analyse the association between baseline location and severity of SVD with cognitive decline, linear regression models with generalized estimated equations were constructed to calculate the mean difference, 95% confidence interval and two-way interaction factor between time and SVD. Increased numbers of baseline CMBs were associated with a decline in global cognition as well as a decline in executive function and memory domains. Location-specific analysis showed similar results with strictly lobar CMBs. There was no association with strictly deep and mixed-location CMBs with cognitive decline. Baseline WMH volume was associated with a decline in global cognition, executive function and memory. Similar results were obtained with anterior and posterior WMH volumes. Lacunes and their locations were not associated with cognitive decline. Strictly lobar CMBs, as well as WMH volume in anterior and posterior regions, were associated with cognitive decline. Future research focuses are warranted to evaluate interventions that may prevent cognitive decline related to SVD.

<i>Stroke</i> : Highlights of Selected Articles

Introduction: White matter hyperintensities (WMH) are linked to cognitive decline and stroke. We hypothesized that Black race would be associated with greater WMH progression in the ACCORDION MIND trial. Methods: The primary outcome is WMH progression in mL, evaluated by fitting linear regression to WMH volume on the month 80 MRI and including the WMH volume on the baseline MRI. The primary predictor is patient race, with the exclusion of patients defined as “other” race. We also derived predicted probabilities of our outcome for systolic blood pressure (SBP) levels. Results: We included 276 patients who completed the baseline and month 80 MRI, of which 207 were white, 48 Black, and 21 Hispanic. During follow-up, the mean number of SBP, LDL, and A1c measurements per patient was 21, 8, and 15. The mean (SD) WMH progression was 3.3 (5.4) mL for blacks, 2.5 (3.2) mL for Hispanics, and 2.4 (3.3) mL for whites. In the multivariate regression model (Table 1), Black, compared to white, patients had significantly more WMH progression (β Coefficient 1.26, 95% CI 0.45-2.06, p=0.002). Hispanic, compared to white, patients did not have significantly different WMH progression (p=0.392), nor was there a difference when comparing Hispanic to Black patients (p=0.162). The predicted WMH progression was significantly higher for Black compared to white patients across a mean SBP of 117 to 139 mm Hg (Figure 1). Conclusions: Black diabetic patients in ACCORDION MIND have a higher risk of WMH progression than white patients across a normal range of systolic blood pressure.

BackgroundThere is increasing evidence for an association between white matter hyperintensities (WMH) and brain beta‐amyloid deposition. WMH are not exclusive correlates of a single etiology, and the spatial topography can associate with different pathologic markers of vascular or neurodegenerative disease. How WMH are longitudinally associated with brain beta‐amyloid burden requires further investigation, particularly with respect to co‐existent vascular risk factors and differences across brain regions.MethodWe retrospectively measured WMH on MRI and vascular risk factors in a combined neuroimaging data set comprised of the ADNI, AIBL and OASIS3 studies, which included harmonized centiloid estimates of beta‐amyloid burden from PET imaging. WMH were measured using the TrUE‐Net algorithm. Vascular risk factors were extracted from provided clinical data and used to calculate individual revised Framingham Stroke Risk Profile (FSRP) scores. Five established data‐driven WM regions (juxtacortical, deep frontal, periventricular, parietal, posterior) were used for regional relationships with WMH volume and growth. Linear mixed effects modelling was used to determine the relationship between the growth rate of normalized regional WMH volumes and baseline beta‐amyloid burden, controlling for age, sex, APOE4 status, and vascular risk factors.Result1245 participants [48.7% female, mean age 71.7 y (SD 7.6 y)] had at least 3 brain MRIs suitable for WMH volume measurement. Linear mixed models demonstrate robust independent cross‐sectional relationships between WMH and baseline beta‐amyloid burden (p <0.001), age (p <0.001) and FSRP (p <0.001). Growth rates of WMH increased with baseline beta‐amyloid burden (p <0.05) and decreased with vascular risk (p <0.001), above and beyond age, sex, and APOE4 status. Regional analyses revealed both baseline beta‐amyloid burden and FSRP associated with the juxtacortical deep frontal and periventricular regions, but the parietal region was unique to beta‐amyloid (p <0.05). Longitudinally, the association for beta‐amyloid burden (p <0.005) persisted in only the parietal WMH and no normalized regional values associated longitudinally with FSRP.ConclusionOur study suggests that in Alzheimer disease research cohorts, WMH progression is associated with beta‐amyloid burden, particularly in parietal white matter. Vascular risk associated WMH were influential for WMH volume but did not associate with WMH progression in a regionally specific manner.

White matter hyperintensities (WMH) are a common cause of subcortical vascular cognitive impairment (SVCI). The silent yet progressive nature of WMH in cognitive decline underscores the need for reliable biomarkers for early detection and monitoring of its progression. This study aims to investigate the association between functional near-infrared spectroscopy (fNIRS) signals during mental and physical activities and WMH volume. Additionally, it explores the relationship between fNIRS signals and WMH progression. We recruited 27 patients with mild cognitive impairment (MCI) presenting WMH clinical characteristics. Data from fNIRS and MRI scans were collected during their first visit. Ten of them underwent fNIRS and MRI scans in a second visit two years later. WMH volume analysis used volBrain lesionBrain 1.0 (https://www.volbrain.net). ROC curve analysis was applied to the normalized WMH volume to determine a cut-off value for distinguishing between the subcortical vascular MCI (svMCI) and amnestic MCI (aMCI) groups. We compared fNIRS data during cognitive tests and physical activities between svMCI and aMCI groups at the first visit and in the two-year follow-up. While cognitive profiles were similar between groups, svMCI patients showed significantly reduced fNIRS signals, particularly in the left orbitofrontal cortex (OFC) during verbal fluency tasks (P = 0.005), with further reductions in the left dorsolateral prefrontal cortex (P = 0.049), left OFC (P = 0.012), and right OFC (P = 0.02) over two years. Baseline WMH volume correlated negatively with fNIRS signals during the Stroop test (r = -0.837, P = 0.005). Changes in WMH volume over two years correlated positively with changes in fNIRS signals in the right ventrolateral prefrontal cortex during memory tasks (r = 0.886, P = 0.033) and left OFC during balance tasks (r = 0.786, P = 0.028). Our results suggest that fNIRS signals have the potential to serve as biomarkers for WMH progression.

To the Editor: The recent article by DeCarli et al1 addresses a somewhat neglected aspect of white matter hyperintensities (WMH), the significance of their anatomical location. The authors argue that the commonly accepted categorization into deep (DWMH) and periventricular (PVWMH) WMH is arbitrary, because the 2 are very highly correlated, and a spatial analysis does not reveal distinct populations. We think that this conclusion is premature, because the categorization depends on a number of factors. The first limitation of their analysis is that they examined individuals in their 70s who presented to a specialty clinic, suggesting that the white matter lesions in their sample were at an advanced stage. If an analogy is drawn from cerebral atrophy in dementia, regional differences in atrophy that are present in the different subtypes of dementia become less prominent in the later stages. In our study of WMH in middle age (60 to 64 years), the correlation of DWMH and PVWMH was much lower ( r =0.621; …

BackgroundPatients with Alzheimer’s disease (AD) often exhibit neuropsychiatric symptoms (NPS), particularly delusions. Previous studies have shown an association between white matter hyperintensities (WMH) and specific NPS. This study aims to explore the relationship between WMH volume and delusions in AD patients by comparing the WMH volumes of delusional and non-delusional subgroups.Methods80 AD patients were divided into a delusion group (n = 36) and a non-delusion group (n = 44) based on the Neuropsychiatric Inventory (NPI). The brain cortical volume and WMH volume were quantitatively calculated for all 80 patients, including total WMH volume, periventricular WMH (PVWMH) volume, deep WMH volume, as well as bilateral frontal lobe, temporal lobe, parietal lobe, and occipital lobe WMH volumes. Firstly, we compared the differences in WMH volumes between the delusion group and non-delusion group. Then, within the delusion group, we further categorized patients based on severity scores of their delusional symptoms into mild (1 point), moderate (2 points), or severe groups (3 points). We compared the WMH volumes among these three groups to investigate the role of WMH volume in delusional symptoms.ResultsThere was a significant difference in left occipital lobe WMH volume between the delusion group and non-delusion group(P < 0.05). Within the delusion group itself, there were significant differences in overall WMH volume as well as PVWMH volume among patients with mild or severe levels of delusions(P < 0.05).ConclusionLeft occipital lobe WMH volume may be associated with the occurrence of delusional AD patients, and the total volume of whole-brain WMH and PVWMH volume may affect the degree of severity of delusional symptoms.

BackgroundWMH in MRI are common among the elderly. WMH are associated with increased cognitive impairment and risk of Alzheimer`s disease (AD). Although WMH contribute to AD pathology, their clinical implications are not fully understood. This study aimed to assess whether WMH predict AD and investigate the association between WMH (including subclassified WMH volume) and cognitive function in AD.MethodThis study enrolled 171 patients with AD. All participants underwent clinical evaluations including brain MRI study and neuropsychological tests using the CERAD‐K neuropsychological assessment battery. In addition, Charlson comorbidity index, the Korean version of the Geriatric Depression Scale short from were administered. WMH volume was calculated using automated quantification method with SPM and MATLAB image processing software. WMH were classified according to the distance from the ventricular surface. WMH located in juxtaventricular areas, within 3 mm from the ventricular surface, were classified as juxtaventricular with matter hyperintensities (JVWMH). WMH located within 3–13 mm or farther than 13 mm from the ventricular surface were classified as periventricular white matter hyperintensities (PVWMH) or deep white matter hyperintensities (DWMH), respectively. WMH volume data were right‐skewed. Consequently, WMH volume data were logarithmic transformed.ResultThe AD group had a higher mean WMH volume(20.7 ± 18.2 ml). Multivariate linear regression analysis showed that total WMH volume in AD was associated with poor performance in categorical verbal fluency test (p = 0.008) and word list memory test (p = 0.023). JVWMH volume in AD was associated with poor performance on categorical verbal fluency test (p = 0.013) and digit span test forward (p = 0.037). PVWMH volume in AD was associated with poor performance on categorical verbal fluency test (p = 0.011) and word list memory test (p = 0.021), whereas DWMH volume showed no association with cognitive dysfunction in AD.ConclusionTotal WMH, JVWMH and PVWMH were associated specifically with executive function, immediate memory, and working memory, independently of hippocampal atrophy in AD. WMH were associated with AD risk and cognitive dysfunction differentially according to the distance from the ventricular surface.

BackgroundBrain glymphatic system is thought to play a critical role in the pathogenesis of Alzheimer’s disease (AD).ObjectiveTo investigate the relationships between glymphatic function and AD-signature region volumes, plasma biomarkers and disease progression in cognitively unimpaired older adults.MethodsTwo datasets comprising a total of 229 cognitively unimpaired older adults were enrolled. Brain glymphatic function was assessed using diffusion tensor imaging along the perivascular space (DTI-ALPS). The associations between the DTI-ALPS index and volumes in AD-signature regions, including the basal forebrain, entorhinal cortex and hippocampus, were evaluated, along with white matter hyperintensity (WMH) volumes. In dataset 1 with plasma biomarkers, the mediation effects of DTI-ALPS index on plasma biomarkers and cognition were examined. In dataset 2 with follow-up data, the baseline DTI-ALPS index was correlated with the annual percent change in volumes of AD-signature regions and WMH.ResultsThe DTI-ALPS index showed positive correlations with volumes in the basal forebrain, entorhinal cortex and hippocampus, and negative correlations with WMH volumes in both datasets. The DTI-ALPS index negatively associated with plasma phosphorylated tau (ptau) and mediated the relationship between ptau and cognition. The baseline DTI-ALPS index was negatively associated with WMH progression at follow-up.ConclusionWorse glymphatic system function indicates decreased AD-signature region volumes, severe WMH lesions, elevated plasma ptau, and accelerated WMH progression before the occurrence of objective cognitive impairment. Therapeutic methods targeting the glymphatic system may prevent cognitive decline through the clearance of AD pathological proteins and the deceleration of WMH lesions.

BackgroundGrowing evidence suggests that not only cerebrovascular disease but also Alzheimer’s disease (AD) pathological process itself cause cerebral white matter degeneration, resulting in white matter hyperintensities (WMHs). Some preclinical evidence also indicates that white matter degeneration may precede or affect the development of AD pathology. This study aimed to clarify the direction of influence between in vivo AD pathologies, particularly beta-amyloid (Aβ) and tau deposition, and WMHs through longitudinal approach.MethodsTotal 282 older adults including cognitively normal and cognitively impaired individuals were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B PET for measuring Aβ deposition, [18F] AV-1451 PET for measuring tau deposition, and MRI scans with fluid-attenuated inversion recovery image for measuring WMH volume. The relationships between Aβ or tau deposition and WMH volume were examined using multiple linear regression analysis. In this analysis, baseline Aβ or tau were used as independent variables, and change of WMH volume over 2 years was used as dependent variable to examine the effect of AD pathology on increase of WMH volume. Additionally, we set baseline WMH volume as independent variable and longitudinal change of Aβ or tau deposition for 2 years as dependent variables to investigate whether WMH volume could precede AD pathologies.ResultsBaseline Aβ deposition, but not tau deposition, had significant positive association with longitudinal change of WMH volume over 2 years. Baseline WMH volume was not related with any of longitudinal change of Aβ or tau deposition for 2 years. We also found a significant interaction effect between baseline Aβ deposition and sex on longitudinal change of WMH volume. Subsequent subgroup analyses showed that high baseline Aβ deposition was associated with increase of WMH volume over 2 years in female, but not in male.ConclusionsOur findings suggest that Aβ deposition accelerates cerebral WMHs, particularly in female, whereas white matter degeneration appears not influence on longitudinal Aβ increase. The results also did not support any direction of influence between tau deposition and WMHs.

This work aimed to determine the potential link between white matter hyperintensity (WMH) burden and serum amyloid A (SAA) level in patients with acute ischemic stroke. Consecutive patients with acute large artery atherosclerosis (LAA) stroke between April 2021 and May 2022 were included. WMH volumes (periventricular, deep, and total) were measured using the Fazekas score and a semiautomated volumetric analysis on fluid-attenuated inversion recovery-magnetic resonance imaging. The burdens of WMH were scored to assess the dose-dependent association between SAA and WMH volume. Multivariate regression and a two-piecewise linear regression model were used to evaluate whether SAA levels are an independent predictor of WMH, and to discover the threshold effect or saturation effect of SAA levels with respect to WMH volume. The mean age of patients was 63.2 ± 11.5years, with 65.9% men. The median SAA level was 3.93mg/L and the total WMH volume of 6.86cm3. In the multivariable analysis, SAA remained an independent predictor of total WMH volume [β = 0.82, 95% confidence interval (CI) = 0.49-1.07, p < 0.001], periventricular WMH volume (adjusted β = 0.76, 95% CI = 0.46-1.07, p < 0.001), and deep WMH volume (adjusted β = 0.26, 95% CI = 0.06-0.45, p = 0.011) after controlling for confounders. Furthermore, SAA levels were associated with periventricular Fazekas score, deep Fazekas score, and Fazekas grades. Threshold effect and saturation effect analyses demonstrated a nonlinear relationship between SAA levels and periventricular white matter hyperintensity (PVWMH) volumes, with SAA levels (2.12-19.89mg/L) having significant dose-dependent relationships with periventricular WMH volumes (adjusted β = 1.98, 95% CI = 1.12-2.84, p < 0.001). SAA level ranging from 2.12 to 19.89mg/L is dose-dependently associated with periventricular WMH development. These findings point the way forward for future research into the pathophysiology of WMH.

Associations between accelerometer-derived sedentary behavior and physical activity with white matter hyperintensities in middle-aged to older adults.

BackgroundThe brain and retina may share pathophysiological mechanisms in various central nervous system disorders, suggesting the potential associations between retinal layer thickness and cerebral white matter hyperintensities (WMH).MethodA total of 149 participants without dementia aged over 65 years (mean age: 75.4, SD: 5.4, range: 65‐91; male: 90 [60.4%]) from the randomly sampled community‐dwelling prospective cohort were included in the analysis. Using spectral‐domain optical coherence tomography, we assessed the thickness of 6 retinal layers in the macular region, the peripapillary retinal nerve fiber layers, and the subfoveal choroid. We classified WMH into 3 groups using the distance from the ventricle surface: juxtaventricular (JVWMH, &lt; 4mm), periventricular (PVWMH, &gt;4mm, &lt;14mm), and deep WMH (DWMH &gt; = 14mm). The associations between retinal layer thickness and WMH volume were examined using linear regression models adjusting age, sex, comorbid hypertension, and diabetes.ResultThe thicknesses of superior outer, inferior outer ganglion cell layers (GCL) and superior outer, inferior outer, total outer inner plexiform layers (IPL) were negatively associated with the total WMH, PVWMH, and DWMH volumes. Reduced thicknesses of total outer GCL and temporal outer inner nuclear layer (INL) were associated with higher total WMH and PVWMH volumes. Center GCL thickness was positively associated with JVWMH volume, and nasal outer GCL thickness was negatively associated with DWMH volume.ConclusionOuter GCL and IPL thicknesses may be associated with WMH volume in older adults. This study may also suggest differential associations based on etiology between retinal layer subfields and WMH subgroups.

We aimed to determine associations between multiple vascular risk factors (VRF) at ∼73 years and progression of white matter hyperintensities (WMH) from ∼73 years to ∼76 years. We calculated correlations and generalized estimating equation models of a comprehensive range of VRF at 73 years and change in WMH volume from 73 years to 76 years. Higher systolic (rho = 0.126, p = 0.009) and diastolic (rho = 0.120, p = 0.013) blood pressure at 73 years were significant predictors for greater WMH volume at 76 years in a simple correlation model. However, neither measured blood pressure nor self-reported hypertension at 73 years was significant predictors of WMH volume change in a fully adjusted model which accounted for initial WMH volume at 73 years. Lower high-density lipoprotein cholesterol (beta = −0.15 % intracranial, −1.80 mL; p < 0.05) and current smoking (beta = 0.43 % intracranial, 5.49 mL; p < 0.05) were the only significant VRF predictors of WMH volume change from 73 years to 76 years. A focus on smoking cessation and lipid lowering, not just antihypertensives, may lead to a reduction in WMH growth in the eighth decade of life.