Progressive White Matter Changes in Mitochondrial Disease: A Quantitative MRI Study.

Cerebral white matter hyperintensities are an important contributor to ageing brain pathology. Progression in white matter hyperintensity volume is associated with cognitive decline and gait impairment. Understanding the factors associated with white matter hyperintensity progression provides insight into pathogenesis and may identify novel treatment targets to improve cognitive health. We postulated that the immune system interaction with cerebral vessels and tissue may be associated with disease progression, and thus evaluated the relationship of blood leucocyte gene expression to progression of cerebral white matter hyperintensities. A brain MRI was obtained at baseline in 166 patients assessed for a cognitive complaint, and then repeated at regular intervals over a median of 5.9 years (interquartile range 3.5-8.2 years). White matter hyperintensity volumes were measured by semi-automated segmentation and percentage change in white matter hyperintensity per year calculated. A venous blood sample obtained at baseline was used to measure whole-genome expression by RNA sequencing. The relationship between change in white matter hyperintensity volumes over time and baseline leucocyte gene expression was analysed. The mean age was 77.8 (SD 7.5) years and 60.2% of participants were female. The median white matter hyperintensity volume was 13.4 ml (SD 17.4 ml). The mean change in white matter hyperintensity volume was 12% per year. Patients were divided in quartiles by percentage change in white matter hyperintensity volume, which was: -3.5% per year in quartile 1, 7.4% per year in quartile 2, 11.7% in quartile 3 and 33.6% per year in quartile 4. There were 148 genes associated with changing white matter hyperintensity volumes over time (P < 0.05 r > |0.2|). Genes and pathways identified have roles in endothelial dysfunction, extracellular matrix remodelling, altered remyelination, inflammation and response to ischaemia. ADAM8, CFD, EPHB4, FPR2, Wnt-B-catenin, focal adhesion kinase and SIGLEC1 were among the identified genes. The progression of white matter hyperintensity volumes over time is associated with genes involved in endothelial dysfunction, extracellular matrix remodelling, altered remyelination, inflammation and response to ischaemia. Further studies are needed to evaluate the role of peripheral inflammation in relation to rate of white matter hyperintensity progression and the contribution to cognitive decline.

Accelerated progression of white matter hyperintensities and subsequent risk of mortality: a 12-year follow-up study

Introduction: Retrospective and epidemiological studies have shown that white matter hyperintensity (WMH) is associated with vascular dementia, but WMH progression on serial MRIs has not been examined in a prospective study of diabetic patients, who have a higher risk of the adverse outcomes associated with WMH including dementia. Methods: This is a secondary analysis of the Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes Follow-on Study (ACCORDION). The primary outcome was 4 cognitive tests measured at a baseline visit and month 80 follow-up visit, including Rey’s Auditory Verbal Learning Test (RAVLT), Mini Mental Status Examination (MMSE), Stroop test, and Digit Symbol Coding (DSC). The primary predictor was WMH progression, represented as the WMH volume on the month 80 MRI with the baseline WMH volume included in the model. We predicted change in the cognitive scores by modelling their association with WMH progression. Results: We included 262 patients, with a mean (SD) baseline age of 62.7 (5.3) years and 56.1% male. The mean (SD) WMH volume on the baseline and month 80 MRIs was 1.9 (3.0) and 4.3 (6.0) mL, respectively. The change in WMH was significantly associated with the change in RAVLT score in the linear regression model (β Coef -0.132, p=0.029). (Table). The mean (SD) RAVLT at baseline and month 80 was 8.0 (2.4) and 8.5 (2.8). Conclusions: WMH progression in diabetic patients is associated with worse performance on memory testing over an 80 month period. Though preliminary and not able to account for location of WMH, our results are consistent with the hypothesis that WMH progression is harmful to cognition in diabetics. The SPRINT MIND trial recently reported that intensive blood pressure control attenuates WMH progression and development of mild cognitive impairment, but excluded patients with diabetes. Against this backdrop, our data suggest that diabetics should be included in future trials to reduce WMH progression.

BackgroundWhile sclerosis of the corticospinal and corticobulbar white matter tracts is a key pathological feature of Amyotrophic Lateral Sclerosis (ALS) and previous work in the context of other neurodegenerative diseases has established the link between white matter hyperintensities (WMHs) as magnetic resonance imaging (MRI) markers of white matter damage and disease progression, WMHs remain unexplored in ALS. The present work investigates the relationship between presence and progression of WMHs and disease severity and survival in ALS patients.MethodWe included longitudinal MRI and clinical data of 232 ALS patients and 207 matched controls from the Canadian ALS Neuroimaging Consortium (CALSNIC) (Kalra et al. 2019). T1‐weighted and FLAIR MRIs were used to perform WMH segmentation using BISON pipeline (Figure 1) (Dadar et al. 2021). Patients with survival data (N = 110) were categorized as “short” (N = 45) or “long” (N = 65) survivors based on their time‐to‐outcome from the baseline MRI with a 24‐month cut‐off threshold. Linear mixed effect modeling was employed to investigate the differences in WMH burden and longitudinal progression between the ALS patients as well as survival groups and matched controls, and to assess the relationship between WMH progression and disease severity as measured by ALSFRS‐R. Age and sex were considered as covariates and participant IDs as random effects.ResultCompared to healthy controls, ALS patients had significantly greater longitudinal WMH progression (911.5 mm3/year, p < 0.0001) (Figure 2A). Furthermore, patients in the short survival group experienced greater WMH progression than those in the long survival group (1006 mm3/year, p < 0.0001) (Figure 2B). Finally, for every 500 mm3 increase in WMH volume, the ALSFRS‐R scores decreased by a full point (p < 0.001) (Figure 3A). While both survival groups experienced increased disease severity with increased WMH volume (p < 0.001), their rates of change did not significantly differ (Figure 3B).ConclusionThis study has shown, for the first time, that ALS patients present with greater WMH progression, and that WMH progression is linked to disease severity and survival in patients, highlighting the utility of WMH as a biomarker of disease progression and prognosis in ALS.

White matter hyperintensities (WMHs) relate to cognitive and physical impairment. Although WMHs typically progress over time, regression has also been observed. Our aim was to explore baseline clinical phenotypes associated with subsequent WMH volume change in the UK Biobank (UKB). We included participants with total volume of WMHs at first and follow-up brain MRI. We assessed 107 preselected clinical phenotypes measured at baseline and preprocessed using the Phenome Scan Analysis Tool (PHESANT). We derived a measure of WMH change as the residual from a linear regression of follow-up WMH volumes on baseline WMH volumes to account for baseline WMH burden. We ran (1) linear regressions for continuous WMH change as the outcome and (2) multinomial logistic regressions comparing progression, regression, and stable groups after categorizing WMH volume change using an established percentile-based approach. Models were unadjusted, partially adjusted (age, sex, total brain tissue volume, follow-up time), or fully adjusted (further adding blood pressure; BP). We corrected p values using false discovery rate (FDR) correction. We included 4,329 participants (median age 52; interquartile range 12), 54.6% female, with a median follow-up of 2.3 years (range 1-7 years). Across follow-up, total brain volume decreased (mean decrease 16,058 mm3) and WMH volume increased (median increase 293 mm3; both p < 0.001). WMHs progressed in 53.9% of participants, regressed in 26.01%, and remained stable in 20%. In fully adjusted linear models, higher diastolic BP was the only baseline phenotype associated with greater WMH progression (0.10 SD higher WMH change per 1 SD higher inverse-rank normal transformed diastolic BP; 95% CI 0.05-0.15, FDR p < 0.05). In multinomial models, hip pain lasting more than 3 months (odds ratio [OR] 0.25, 95% CI 0.11-0.58) and faster walking pace (OR 0.79, 95% CI 0.66-0.95) were inversely associated with WMH progression, whereas hip pain was also inversely associated with WMH regression vs stability (OR 0.31, 95% CI 0.12-0.79; all FDR p < 0.05). We established vascular risk factors associated with subsequent WMH volume change in the studied cohort. Distinct clinical and demographic profiles characterized WMH progression, regression, and stable groups. Results suggest that vascular factors relate to WMH change but are sensitive to covariate control. Further studies should establish factors differentially and causally related to WMH progression, regression, and stability.

White matter hyperintensities (WMHs) of presumed vascular origin are common neuroimaging markers of brain aging. While WMHs typically progress over time, WMHs regression is increasingly being reported. However, its clinical relevance remains unclear, particularly in community-based populations. We investigated associations of WMHs regression and progression, including total WMH, periventricular (PWMHs), and deep WMHs (DWMHs), with longitudinal cognitive decline and structural brain atrophy. We analyzed longitudinal data from 2496 UK Biobank participants (median [IQR] age 61 [56–67] years, 52.8% female) without dementia or conditions confounding WMH measures. Brain MRI and cognitive assessments were conducted at baseline and follow-up (2–3 years apart). Absolute WMH volume change was categorized into tertiles representing regression (Tertile 1), stability (Tertile 2), and progression (Tertile 3). Cognitive outcomes included processing speed (reaction time) and fluid intelligence; brain structural outcomes included volumes (% intracranial volume) of total brain, gray matter, white matter, and hippocampi. Associations were examined using multivariable-adjusted linear mixed-effects models, with moderation analyses for age and sex. At baseline, WMH regression and progression groups showed larger WMH volumes than the stable group (p < 0.001). Over the follow-up, total WMH regression (β = 0.029 [95% CI 0.003 to 0.054], p = 0.027) and PWMH regression (β = 0.029 [0.003 to 0.054], p = 0.027) were associated with slower decline in processing speed, but not significantly associated with decline in fluid intelligence or brain structures (all p > 0.05). In contrast, PWMH progression was associated with faster declines in total brain (β=−0.078 [− 0.143 to − 0.012], p = 0.020) and white matter volumes (β=−0.048 [− 0.092 to − 0.005], p = 0.030). Progression in total WMH (β=−0.0016 [− 0.002 to − 0.001], p < 0.001), PWMH (β=−0.0019 [− 0.003 to − 0.001], p < 0.001), and DWMH (β=−0.0008 [− 0.001 to − 0.0002], p = 0.011) was linked to accelerated hippocampal atrophy, with the effects of total WMH and PWMH progression significant only in participants < 65 years (p-interaction < 0.05). Compared with stable WMH, WMH regression was associated with improved processing speed and comparable brain structure, whereas WMH progression was associated with accelerated brain atrophy, particularly hippocampal atrophy. These associations were predominantly driven by periventricular lesions. These findings highlight the dynamic nature and potential reversibility of microvascular injury, supporting WMH regression as a promising intervention target for preserving cognition and brain integrity.

Introduction: White matter hyperintensity (WMH) is associated with a higher risk of stroke, dementia, and depression. Prior research has suggested that renal impairment and diabetes may predispose to the development of WMH. Here, we evaluated the association between WMH volume (WMHv), macroalbuminuria, and glycemic control in a cohort of diabetic patients. Methods: This is a secondary analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) dataset. The primary outcome is WMH progression in mL, evaluated by fitting linear regression to WMHv on the month 40 MRI and including the WMHv on the baseline MRI in the model. The primary predictors were incident macroalbuminuria, defined as new onset urinary albumin &gt;300mg/day, and the ACCORD glucose randomization arm. Results: We included 502 patients. The mean (SD) WMHv at baseline was 2.1 (3.9) mL and at month 40 was 3.6 (5.7) mL. Twenty-three patients (4.6%) developed macroalbuminuria during the study period, who had a higher mean WMH progression (2.9 vs. 1.4 mL, p=0.012). In a linear regression model adjusted for mean systolic blood pressure during follow-up, macroalbuminuria was a significant predictor of WMH progression (Beta 1.20, 95% CI 0.17-2.22, p=0.022). In the same model, the interaction term between glucose randomization arm and macroalbuminuria was highly significant (Beta 3.38, 95% CI 1.20-5.57, p=0.003). The predicted follow-up WMHv for the interaction term are in Figure 1, showing that macroalbuminuria with intensive glycated hemoglobin reduction (goal A1c&lt;6%) was associated with the most WMH progression. Conclusion: In diabetic patients, the development of macroalbuminuria was associated with WMH progression over 40 months, although only in patients assigned to intensive glycemic control. This finding is consistent with the adverse events seen in ACCORD with intensive glycemic control.

Both white matter hyperintensities (WMHs) and lacunar infarctions (LIs) are magnetic resonance imaging (MRI) markers of cerebral small vessel disease (SVD). However, the association between WMH and LI remains unclear. In this study, we asked whether WMH progression is related to LI occurrence using retrospective data. Overall, 8475 WMH patients with at least two MRI images were screened, and 187 patients were included in the final study; 76 patients had WMH with LI (WL), and 111 patients had WMH without LI (WOL). The 187 patients were divided into three groups according to WMH progression: Group 1 (no progression), Group 2 (0-53.64% WMH progression) and Group 3 (≥53.64% WMH progression). We found that both WMH volumes and Fazekas scores were higher in WL patients compared with those in WOL patients according to the 1st and 2nd MRI images (P<0.001), whereas WMH progression was not significantly different between these two groups (P>0.05). Importantly, we found that the occurrence rates for LI were increased in Groups 2 and 3 compared with those in Group 1. Multiple logistic regression analysis demonstrated that the risk of LI occurrence was significantly increased in Group 2 versus that in Group 1 (odds ratio, 3.36; 95% CI, 1.48 to 7.67; P=0.004) after adjusting for the baseline patient characteristics and the interval between the two MRI scans. Additionally, with a stratification time of less than 24 months, the risk of LI occurrence was higher in Group 2 versus that in Group 1, after adjusting for baseline confounding factors (odds ratio, 3.68; 95% CI, 1.51 to 8.99; P=0.004). In conclusion, we found that WMH progression was significantly associated with LI occurrence, particularly within the first two years, and that this progression could serve as an independent indicator of LI development.

To evaluate the relationship of white matter hyperintensities (WMH) with decline in lower extremity function (LEF) over approximately 3 years in dementia-free older adults with memory complaints. We obtained brain MRI data from 458 community-dwelling adults, aged 70 years or over, at baseline, and from 358 adults over an average follow-up of 963 days. We evaluated LEF using the Short Physical Performance Battery (SPPB). We related baseline WMH volumes and progression to SPPB scores over time, using mixed-effect linear regressions. For the secondary analyses, we categorized baseline WMH volume into quartiles, and dichotomized the WMH progression to compare fast and slow progression. Baseline WMH volume (β = -0.017, 95% confidence interval [CI] -0.025 to -0.009), as well as WMH progression (β = -0.002, 95% CI -0.003 to -0.001), significantly associated with a decline in SPPB performance in adjusted analyses. Compared with the lowest quartile of baseline WMH volume, the highest quartile associated with a decline in SPPB performance (β = -0.301, 95% CI -0.558 to -0.044). Fast progression also associated with a decline in SPPB performance. We found clinically meaningful differences in the SPPB, with higher scores in participants with slow progression of WMH, at both 24 and 36 months. Baseline level and WMH progression associated with longitudinal decline in SPPB performance among older adults. We detected clinically meaningful differences in SPPB performance on comparing fast with slow progression of WMH, suggesting that speed of WMH progression is an important determinant of LEF during aging.

White matter hyperintensity (WMH) has been recognised as a surrogate marker of small vessel disease and is associated with cognitive impairment. We investigated the dynamic change in WMH in patients with severe WMH at baseline, and the effects of longitudinal change of WMH volume on cognitive decline and cortical thinning. Eighty-seven patients with subcortical vascular mild cognitive impairment were prospectively recruited from a single referral centre. All of the patients were followed up with annual neuropsychological tests and 3T brain magnetic resonance imaging. The WMH volume was quantified using an automated method and the cortical thickness was measured using surface-based methods. Participants were classified into WMH progression and WMH regression groups based on the delta WMH volume between the baseline and the last follow-up. To investigate the effects of longitudinal change in WMH volume on cognitive decline and cortical thinning, a linear mixed effects model was used. Seventy patients showed WMH progression and 17 showed WMH regression over a three-year period. The WMH progression group showed more rapid cortical thinning in widespread regions compared with the WMH regression group. However, the rate of cognitive decline in language, visuospatial function, memory and executive function, and general cognitive function was not different between the two groups. The results of this study indicated that WMH volume changes are dynamic and WMH progression is associated with more rapid cortical thinning.

Previous studies suggested an association between increased intracranial arterial pulsatility and the severity of microangiopathic white matter hyperintensities (WMH). However, possible confounders such as age and hypertension were seldomly considered and longitudinal data are lacking. We here aimed to explore whether increased middle cerebral artery pulsatility is associated with baseline severity and progression of cerebral small vessel disease-related WMH in elderly individuals. The study population consisted of elderly participants from the community-based ASPS (Austrian Stroke Prevention Study). Baseline and follow-up assessment comprised transcranial Doppler sonography, brain magnetic resonance imaging, and clinical/laboratory examination of vascular risk factors. Pulsatility index on transcranial Doppler sonography was averaged from baseline indices of both middle cerebral arteries and was correlated with baseline WMH severity and WMH progression over a median follow-up period of 5 years in uni- and multivariable analyses. WMH severity was graded according to the Fazekas scale, and WMH load was quantified by semiautomated volumetric assessment. The study cohort comprised 491 participants (mean age: 60.7±6.9 years; female: 48.5%). Pulsatility index was increased in participants with more severe WMH at baseline (P<0.001) but was not associated with WMH progression during follow-up (rs: 0.097, P=0.099). In multivariable analyses, only arterial hypertension remained significantly associated with baseline severity (P=0.04) and progression (P=0.008) of WMH, although transcranial Doppler sonography pulsatility index was not predictive (P>0.1, respectively). This community-based cohort study of elderly individuals does not support the pulsatility index of the middle cerebral artery on transcranial Doppler sonography as an independent marker of microangiopathic WMH severity and progression over time.

The objective of this study was to test if blood-brain barrier (BBB) disruption, detected using dynamic susceptibility contrast (DSC) imaging, would predict progression of white matter hyperintensities (WMHs) over the subsequent year in patients with chronic cerebrovascular disease. The study included patients with a history of stroke and at least early confluence of WMH. Magnetic resonance imaging (MRI) scans performed at baseline (> 3 months from stroke) and again 1 year later were segmented to calculate the WMH volume expressed as a fraction of the total brain volume. Change in WMH volume between the 2 timepoints and progression of WMH were the outcome measures. BBB disruption was measured using DSC imaging on the baseline MRI. WMH masks were dilated by 3 mm to create a mask of the adjacent normal appearing white matter (penumbra). BBB disruption was averaged within the WMH and the penumbra. Fifty patients were included; median age was 69 years, and 46% were women. The mean WMH fraction was 1.25% at baseline and 1.36% at 1 year. The mean baseline BBB disruption was 0.20% in the WMH and 0.22% in the penumbra. More severe BBB disruption was associated with greater WMH progression when measured in the WMH (ß = 0.95, confidence interval [CI] = 0.39-1.51, r2 = 0.19, p = 0.001) and in the penumbra (ß = 0.81, CI = 0.10-1.53, r2 = 0.10, p = 0.027). The best predictor of progression was BBB disruption in the penumbra with an odds ratio (OR) of 2 (OR = 2, CI = 1.01-3.96, p = 0.046) for each 0.1% increase in BBB disruption. More severe BBB disruption was predictive of greater WMH progression in patients with chronic cerebrovascular disease. ANN NEUROL 2026;99:437-448.

BackgroundSome individuals seem less susceptible to the effect of high white matter hyperintensity (WMH) load on cognition reflecting differences in individual cognitive reserve (CR). Little is known about young‐ or middle‐aged participants. The aim of the present study was to examine (1) the effect of WMH on global cognition in three different age groups and (2) if education (as proxy for CR) moderates this association.MethodWe included 707 healthy participants (18‐85 years) without evidence of cardiovascular/neurological disease (young‐aged: 18‐44 years (Ø33.5±6.7): n = 108; middle‐aged: 45‐65 years (Ø57.9±5.5): n = 341; old‐aged: &gt;65 years (Ø72.0±4.1): n = 258) from the population‐based 1000BRAINS study. An extensive cognitive assessment was conducted. The sum of all cognitive domain z‐scores defined the global score. Education was classified according to the International Standard Classification of Education as total years of formal education, combining school and vocational training. Magnetic resonance imaging (MRI) was carried out on a 3‐Tesla‐MR‐scanner (Tim‐TRIO, Siemens Medical Systems, Erlangen, Germany). WMH volume was determined using the Brain‐Intensity‐Abnormality‐Classification‐Algorithm. The associations of global cognition as outcome with WMH volume (in cm3) as predictor were analyzed using linear models (PROCESS v4.1 macro for SPPS) stratified by age group resulting in regression coefficient b with 95% confidence intervals (CI; adjusted for age, sex, depression, diabetes mellitus). To examine moderation effects of education, all models contained an interaction term (WMH x education).ResultHigher WMH volume was associated with lower global cognition in middle‐aged participants (b:‐0.27 (‐0.52 to ‐0.03, all reported results are fully adjusted). This effect was moderated by education (interaction term: b:‐0.07 (‐0.014 to ‐0.01)). In the young‐aged group, the association between WMH load and cognition was ‐1.27 (‐3.30 to 0.77). No association was found in the old‐aged group (b: ‐0.03 (‐0.20 to 0.14)).ConclusionHigher WMH load was associated with lower cognitive performance only in middle‐aged participants and was moderated to a small degree by education. Overall, the influence of WMH on global cognition in our cohort of healthy participants seems limited. Future analyses will focus on specific cognitive domains that might be more vulnerable to higher WMH load and will examine participants with certain cardiovascular risk profile.

Background: Real-time regional cerebral oxygen saturation (rScO 2 ) measurement using near-infrared spectroscopy (NIRS) may aid in the identification of intracerebral ischemia in critically ill patients. Ischemia to the cerebral white matter results in injury detectable by brain MRI as white matter hyperintensities (WMH). We hypothesized that rScO 2 as assessed by NIRS correlates with the degree of WMH progression in patients admitted to a neurocritical care unit (NCCU). Materials and Methods: Retrospective study of eight comatose patients (Glasgow Coma Scale ≤8) in the NCCU who were continuously monitored for three days after their coma onset with NIRS to assess rScO 2, and who had a brain MRI upon admission and before their hospital discharge. Semi-automated volumetry based on intensity thresholding was used to quantify the WMH volume on FLAIR sequences. The degree of WMH progression was calculated by subtracting the WMH volume of the admission MRI from discharge MRI. Spearman rank correlation was used to determine the strength of association between the rScO 2 (averaged over the monitoring period) and the degree of WMH progression. Results: The median averaged rScO 2 was 61 (IQR (48-73) and the lowest 45. Overall, rScO 2 inversely correlated with WMH progression (rho -.738, p= 0.037); i.e., a lower rScO 2 was associated with greater WMH progression (Figure 1). Patients with greater WMH progression had a worse modified Rankin Scale on discharge (rho .769, p= 0.026). Interpretation: Our study provides proof of principle that rScO 2 as assessed by non-invasive NIRS monitoring may aid detection of cerebral white matter injury.

Introduction: While retrospective studies have shown that poor control of vascular risk factors is associated with progression of white matter hyperintensity (WMH), it has not been studied prospectively. Hypothesis: We hypothesize that higher systolic blood pressure (SBP) mean, LDL cholesterol, and Hgb A1c will be correlated with WMH progression in diabetics. Methods: This is a secondary analysis of the Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes Follow-on Study (ACCORDION). The primary outcome was WMH progression, evaluated by fitting linear regression models to the WMH volume on the month 80 MRI and adjusting for the WMH volume on the baseline MRI. The primary predictors were the mean values of SBP, LDL, and A1c from baseline to month 80. We defined a good vascular risk factor profile as mean SBP &lt;120 mm Hg and mean LDL &lt;120 mg/dL. Results: We included 292 patients, with a mean (SD) age of 62.6 (5.3) years and 55.8% male. The mean number of SBP, LDL, and A1c measurements per patient was 17, 5, and 12. We identified 86 (29.4%) patients with good vascular risk factor profile. In the linear regression models, mean SBP and LDL were associated with WMH progression and in a second fully adjusted model they both remained associated with WMH progression (Table). Those with a good vascular risk factor profile had less WMH progression (β Coefficient -0.80, 95% CI -1.42, -0.18, p=0.012). Conclusions: Our data reinforce prior research showing that higher SBP and LDL is associated with progression of WMH in diabetics, likely secondary to chronic microvascular ischemia, and suggest that control of these factors may have protective effects. This study has unique strengths, including prospective serial measurement of the exposures, validated algorithmic measurement methodology for WMH, and rigorous adjudication of study data. Clinical trials are needed to investigate the effect of vascular risk factor reduction on WMH progression.