Relationship between White Matter Hyperintensity Volume Analyzed from Fluid-Attenuated Inversion Recovery Using a Fully Automated Analysis Software and Cognitive Impairment

To assess the effect of weightlessness and the respective roles of CSF and vascular fluid on changes in white matter hyperintensity (WMH) burden in astronauts. We analyzed prespaceflight and postspaceflight brain MRI scans from 17 astronauts, 10 who flew a long-duration mission on the International Space Station (ISS) and 7 who flew a short-duration mission on the Space Shuttle. Automated analysis methods were used to determine preflight to postflight changes in periventricular and deep WMH, CSF, and brain tissue volumes in fluid-attenuated inversion recovery and high-resolution 3-dimensional T1-weighted imaging. Differences between cohorts and associations between individual measures were assessed. The short-term reversibility of the identified preflight to postflight changes was tested in a subcohort of 5 long-duration astronauts who had a second postflight MRI scan 1 month after the first postflight scan. Significant preflight to postflight changes were measured only in the long-duration cohort and included only the periventricular WMH and ventricular CSF volumes. Changes in deep WMH and brain tissue volumes were not significant in either cohort. The increase in periventricular WMH volume was significantly associated with an increase in ventricular CSF volume (ρ = 0.63, p = 0.008). A partial reversal of these increases was observed in the long-duration subcohort with a 1-month follow-up scan. Long-duration exposure to microgravity is associated with an increase in periventricular WMH in astronauts. This increase was linked to an increase in ventricular CSF volume documented in ISS astronauts. There was no associated change in or abnormal levels of WMH volumes in deep white matter as reported in U-2 high-altitude pilots.

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.

Background: Aged heart failure (HF) patients without dementia have a risk of cognitive impairment (CI) that attenuates the effect of treatment for HF. White Matter Hyperintensity (WMH) and gray matter atrophy in parahippocampal gyrus (PHG) are a potential risk of CI. However, it is not clear whether location and volume of local WMH is associated with atrophy in PHG and predicts prognosis of HF patients. Hypothesis: In HF patients without dementia, local WMH volume is associated with brain atrophy of PHG and predicts prognosis. Methods: We enrolled sixty-one HF patients (age 76±11 years, NYHA class II, EF47±17 %) in the study. We excluded patients with dementia using mini-mental state examination. We took 3D-T1 weighted images and Fluid Attenuated Inversion Recovery (FLAIR) images of whole brain using 1.5T magnetic resonance imaging (MRI). We performed image analysis using 2mm voxel-based morphometry with Statistical Parametric Mapping to evaluate the local WMH volume in the frontal, temporal, parietal, and occipital lobes, as well as the corpus callosum (CC), and to assess the severity of PHG atrophy. We quantified the severity of PHG atrophy using Z-scores. We constructed receiver operating characteristic (ROC) curves to determine the cut-off point of the each local WMH volume for estimating cardiac death and admission due to HF. We constructed Kaplan-Meier Curves adjusted with age, sex, presence of atrial fibrillation, diabetes, dyslipidemia, and blood pressure using inverse probability weighting method. Results: Local WMH volume of CC demonstrated the highest prognostic accuracy (area under the ROC curve 0.73). We divided patients into High-WMH group (n=36, volume of WMH in CC 0.65±37 mL) and Low-WMH group (n=25, volume of WMH in CC 0.14±0.07 mL) according to the cut-off value (0.24 mL) of local WMH volume in CC. As shown in representative cases in Figure1, the Z-score value in PHG (pink circle) was higher in High-WMH group (1.43±0.77) compared to Low-WMH group (0.93±0.63, P=0.01). Adjusted Kaplan-Meier curves showed poor prognosis of High-WMH group (Figure 2). Conclusions: In HF patients without dementia, local WMH in corpus callosum is a potential risk of CI and predicts poor prognosis.

Structural brain abnormalities are associated with late-life major depression, with numerous studies reporting increased white matter hyperintensities (WMH) and reduced cortical/subcortical grey matter volumes. There is strong evidence linking vascular disease to WMH, but limited evidence on its association with subcortical volumes. To investigate the relationship of orthostatic blood pressure changes to WMH and subcortical grey matter volumes in late-life depression. Thirty-eight people with depression and a similarly aged comparison group (n = 30) underwent fluid attenuated inversion recovery (FLAIR) and T(1)-weighted magnetic resonance imaging as well as systematic orthostatic blood pressure assessments. Volumetric estimates of WMH and subcortical grey matter were obtained for each participant and the relationship to blood pressure drop on active stand was examined. An association between orthostatic systolic blood pressure drop and WMH volumes in temporal and parietal regions was found in the depression group (age-corrected partial correlation r' = 0.31-0.35, P<0.05). Subcortical volumes were not related to blood pressure changes or WMH volumes in either group. We found evidence for an association between the degree of orthostatic systolic blood pressure drop and WMH volume in the depression group. Since blood pressure drops lead to WMH in animals our findings suggest systolic blood pressure drops may be a factor contributing to these lesions in late-life depression.

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.

PurposeQuantitative assessment of white matter hyperintensities (WMH) on structural Magnetic Resonance Imaging (MRI) is challenging. It is important to harmonise results from different software tools considering not only the volume but also the signal intensity. Here we propose and evaluate a metric of white matter (WM) damage that addresses this need.MethodsWe obtained WMH and normal-appearing white matter (NAWM) volumes from brain structural MRI from community dwelling older individuals and stroke patients enrolled in three different studies, using two automatic methods followed by manual editing by two to four observers blind to each other. We calculated the average intensity values on brain structural fluid-attenuation inversion recovery (FLAIR) MRI for the NAWM and WMH. The white matter damage metric is calculated as the proportion of WMH in brain tissue weighted by the relative image contrast of the WMH-to-NAWM. The new metric was evaluated using tissue microstructure parameters and visual ratings of small vessel disease burden and WMH: Fazekas score for WMH burden and Prins scale for WMH change.ResultsThe correlation between the WM damage metric and the visual rating scores (Spearman ρ > =0.74, p < 0.0001) was slightly stronger than between the latter and WMH volumes (Spearman ρ > =0.72, p < 0.0001). The repeatability of the WM damage metric was better than WM volume (average median difference between measurements 3.26% (IQR 2.76%) and 5.88% (IQR 5.32%) respectively). The follow-up WM damage was highly related to total Prins score even when adjusted for baseline WM damage (ANCOVA, p < 0.0001), which was not always the case for WMH volume, as total Prins was highly associated with the change in the intense WMH volume (p = 0.0079, increase of 4.42 ml per unit change in total Prins, 95%CI [1.17 7.67]), but not with the change in less-intense, subtle WMH, which determined the volumetric change.ConclusionThe new metric is practical and simple to calculate. It is robust to variations in image processing methods and scanning protocols, and sensitive to subtle and severe white matter damage.

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.

In cognitively normal (CN) elderly individuals, white matter hyperintensities (WMH) are commonly viewed as a marker of cerebral small vessel disease (SVD). SVD is due to exposure to systemic vascular injury processes associated with highly prevalent vascular risk factors (VRFs) such as hypertension, high cholesterol, and diabetes. However, cerebral amyloid accumulation is also prevalent in this population and is associated with WMH accrual. Therefore, we examined the independent associations of amyloid burden and VRFs with WMH burden in CN elderly individuals with low to moderate vascular risk. Participants (n = 150) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) received fluid attenuated inversion recovery (FLAIR) MRI at study entry. Total WMH volume was calculated from FLAIR images co-registered with structural MRI. Amyloid burden was determined by cerebrospinal fluid Aβ1-42 levels. Clinical histories of VRFs, as well as current measurements of vascular status, were recorded during a baseline clinical evaluation. We tested ridge regression models for independent associations and interactions of elevated blood pressure (BP) and amyloid to total WMH volume. We found that greater amyloid burden and a clinical history of hypertension were independently associated with greater WMH volume. In addition, elevated BP modified the association between amyloid and WMH, such that those with either current or past evidence of elevated BP had greater WMH volumes at a given burden of amyloid. These findings are consistent with the hypothesis that cerebral amyloid accumulation and VRFs are independently associated with clinically latent white matter damage represented by WMHs. The potential contribution of amyloid to WMHs should be further explored, even among elderly individuals without cognitive impairment and with limited VRF exposure.

BackgroundControversy exists regarding the etiological role of cerebral small vessel disease (CSVD) in Alzheimer's disease (AD). We thus evaluated the association between brain Aβ/tau burden and white matter hyperintensity (WMH) volume among subjects with varying severity levels of cognitive impairment.MethodA total of 84 stroke‐free subjects (healthy controls [HC]=10; subjective cognitive decline [SCD]=32; mild cognitive impairment [MCI]=26; dementia =16) were included. All patients underwent structural MRI, 11C‐ PIB, and 18F‐T807 PET to measure CSVD makers, Aβ deposition (A+) and pathologic tau (T+), respectively. WMH volume was quantified by automatic segmentation using AccuBrain® IV 1.1 (BrainNow Medical Technology Company Ltd.).ResultNo significant association was found between A+T+ and WMH volume in the overall population (β =‐0.03 ;95% CI, ‐0.04‐0.11; p=0.10). There was also no significant association found within different cognitive diagnostic group except in those with dementia, where we found that increasing global 11C‐ PIB SUVR correlated with lower WMH volume (B=‐1.76 ;95% CI, ‐2.92‐ ‐0.59; p=0.007). No significant association between 18F‐T807 SUVR and WMH volume was observedConclusionWe found no association between brain Aβ/tau burden and WMH volume except an inverse association was noted between Aβ and WMH in dementia patients. PiB retention might be restrained by WMH in those patients with higher CSVD burden.

Purpose : To determine the usefulness of fluid attenuated inversion recovery(FLAIR) imaging for the in detec-tion of high signal intensity of hippocampus or amygdala in mesial temporal sclerosis (MTS), compared with that of turbo spin-echo T2-weighted imaging. Materials and Methods : Two neuroradiologists independently analyzed randomly mixed MR images of 20 le-sions of 17 patients in whom MTS had been diagnosed, and ten normal controls. All subjects underwent both who performed both FLAIR and turbo spin-echo T2-weighted imaging, in a blind fashion. In order to deter-mine hippocampal morphology, oblique coronal images perpendicular to the long axis of the hippocampus were obtained. The detection rate of high signal intensity in hippocampus or amygdala, the radiologists ’preferred imaging sequence, and intersubject consistency of detection were evaluated. Signal intensity in hip-pocampus or amygdala was considered high if substantially higher than signal intensity in the cortex of adja-cent temporo-parietal lobe. Results : In all normal controls, FLAIR and spin-echo T2-weighted images showed normal signal intensity in hippocampus or amygdala. In MTS, the mean detection rate of high signal intensity in hippocampus or amyg-dala, as seen on FLAIR images was 93%, compared with 43% on spin-echo T2-weighted images. In all cases in which signal intensity on FLAIR images was normal, signal intensity on spin-echo T2-weighted images was al-so normal. The radiologists preferred the contrast properties of FLAIR to those of spin-echo T2-weighted images. Conclusion : In the diagnosis of MTS using MRI, FLAIR images are more useful for the detection of high signal intensity of hippocampus or amygdala than are spin-echo T2-weighted images. In the diagnosis of MTS, FLAIR imaging is therefore a suitable alternative to spin-echo T2-weighted imaging.

Estimating white matter hyperintensities volume in individuals with stroke using T1-weighted images

BackgroundHigher blood pressure (BP) is associated with greater white matter hyperintensity (WMH) volume, but research is limited in recently menopausal and postmenopausal women. Postmenopausal women have a greater burden of WMH than men and premenopausal women, but whether hormone therapy (HT) modifies the association between systolic and diastolic BP (SBP, DBP) and WMH is unknown. We investigated the association of SBP and DBP in recently postmenopausal women who participated in an HT trial with WMH volumes measured 14 years later and explored whether HT modified the results.MethodWomen with good cardiovascular (CV) health, who were previously enrolled in a randomized placebo‐controlled HT trial, the Kronos Early Estrogen Prevention Study (KEEPS), participated in the current observational KEEPS continuation (n = 212; median age = 67; range 58‐72). SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59) and continuation. Antihypertensive users were excluded (baseline, n = 34; continuation, n = 61). Approximately 10 years after the end of KEEPS HT versus placebo 4‐year interventions, automated WMH volumes were measured from 3D‐FLAIR MRI. Associations of KEEPS baseline and continuation SBP and DBP with log WMH volume at KEEPS continuation were tested using linear regression analyses adjusting for covariates in model 1 (age, total intracranial volume, study site) and model 2 (model 1 plus cardiovascular risk factors (CVRF)).ResultHigher KEEPS baseline SBP and DBP were associated with greater WMH volume measured 14 years later, and after adjusting for CVRF (p≤0.01). Similarly, in KEEPS continuation, higher SBP and DBP were associated with greater WMH volume measured concurrently and after adjusting for CVRF (p&lt;0.001). We did not find statistically significant evidence that HT versus placebo modified these associations. Topographically, higher SBP and DBP were associated with greater periventricular WMH in the frontal and parietal lobes after adjusting for age (Figure).ConclusionHigher SBP and DBP in recently menopausal women with good CV health were associated with greater WMH volumes more than a decade later after adjusting for CVRF, independent of randomization to HT. Our results show the importance of blood pressure control in recently menopausal women, that may reduce the white matter injury later in life.

White matter hyperintensities (WMH), identified on T2-weighted magnetic resonance images of the human brain as areas of enhanced brightness, are a major risk factor of stroke, dementia, and death. There are no large-scale studies testing associations between WMH and circulating metabolites. We studied up to 9290 individuals (50.7% female, average age 61 years) from 15 populations of 8 community-based cohorts. WMH volume was quantified from T2-weighted or fluid-attenuated inversion recovery images or as hypointensities on T1-weighted images. Circulating metabolomic measures were assessed with mass spectrometry and nuclear magnetic resonance spectroscopy. Associations between WMH and metabolomic measures were tested by fitting linear regression models in the pooled sample and in sex-stratified and statin treatment-stratified subsamples. Our basic models were adjusted for age, sex, age×sex, and technical covariates, and our fully adjusted models were also adjusted for statin treatment, hypertension, type 2 diabetes, smoking, body mass index, and estimated glomerular filtration rate. Population-specific results were meta-analyzed using the fixed-effect inverse variance-weighted method. Associations with false discovery rate (FDR)-adjusted P values (PFDR)<0.05 were considered significant. In the meta-analysis of results from the basic models, we identified 30 metabolomic measures associated with WMH (PFDR<0.05), 7 of which remained significant in the fully adjusted models. The most significant association was with higher level of hydroxyphenylpyruvate in men (PFDR.full.adj=1.40×10-7) and in both the pooled sample (PFDR.full.adj=1.66×10-4) and statin-untreated (PFDR.full.adj=1.65×10-6) subsample. In men, hydroxyphenylpyruvate explained 3% to 14% of variance in WMH. In men and the pooled sample, WMH were also associated with lower levels of lysophosphatidylcholines and hydroxysphingomyelins and a larger diameter of low-density lipoprotein particles, likely arising from higher triglyceride to total lipids and lower cholesteryl ester to total lipids ratios within these particles. In women, the only significant association was with higher level of glucuronate (PFDR=0.047). Circulating metabolomic measures, including multiple lipid measures (eg, lysophosphatidylcholines, hydroxysphingomyelins, low-density lipoprotein size and composition) and nonlipid metabolites (eg, hydroxyphenylpyruvate, glucuronate), associate with WMH in a general population of middle-aged and older adults. Some metabolomic measures show marked sex specificities and explain a sizable proportion of WMH variance.