Low White Matter Hyperintensities Research Articles

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.

Insulin-Like Growth Factor, Inflammation, and MRI Markers of Alzheimer's Disease in Predominantly Middle-Aged Adults.

Insulin-like growth factor 1 (IGF-1) signaling has been implicated in Alzheimer's disease pathogenesis, and further evidence suggests inflammation can be a moderator of this association. However, most research to date has been conducted on older adults. To investigate the association of serum IGF-1 and IGF binding protein 3 (IGFBP-3) concentrations with MRI markers of Alzheimer's disease in predominantly middle-aged adults, and further assess moderation by chronic inflammation. We included participants from the Framingham Heart Study (n = 1,852, mean age 46±8, 46% men) and the Study of Health in Pomerania (n = 674, mean age 50±13, 42% men) with available serum IGF-1, IFGBP-3, as well as brain MRI. IGF-1 and IFGBP-3 were related to MRI outcomes (i.e., total brain, cortical gray matter, white matter, white matter hyperintensities (WMH), and hippocampal volumes) using multivariable regression models adjusting for potential confounders. Subgroup analyses by C-reactive protein (CRP) concentrations were also performed. Cohort-specific summary statistics were meta-analyzed using random-effects models and corrected for multiple comparisons. Meta-analysis results revealed that higher IGF-1 concentrations were associated with lower WMH (estimate [β] [95% CI], -0.05 [-0.09, -0.02], p = 0.006) and larger hippocampal volumes (0.07 [0.02, 0.12], p = 0.01), independent of vascular risk factors. These associations occurred predominantly in individuals with CRP concentrations < 75th percentile. We did not observe associations between IGFBP-3 and MRI outcomes. Our findings suggest that IGF-1-related signaling may be implicated in brain health as early as midlife.

Poststroke White Matter Hyperintensities and Physical Activity: A CANVAS Study Exploratory Analysis.

White matter hyperintensities (WMHs) are associated with poststroke cognitive decline and mortality. Physical activity (PA) may decrease WMH risk by reducing vascular risk factors and promoting cerebral perfusion. However, the association between poststroke PA and WMH progression remains unclear. We examined the association between PA and WMH volume 12 months after stroke, and between PA and change in WMH volume between 3 and 12 months after stroke. We included ischemic stroke survivors from the Cognition And Neocortical Volume After Stroke cohort with available brain magnetic resonance imaging and objective PA data. Total, periventricular, and deep WMH volumes (in milliliters) were estimated with manually edited, automated segmentations (Wisconsin White Matter Hyperintensities Segmentation toolbox). Moderate-to-vigorous intensity PA (MVPA) was estimated using the SenseWear® Armband. Participants with MVPA ≥30 min·d -1 were classified as "meeting PA guidelines." We used quantile regression to estimate the associations between PA (MVPA and meeting PA guidelines) with WMH volume at 12 months and change in WMH volume between 3 and 12 months after stroke. A total of 100 participants were included (median National Institutes of Health Stroke Scale 2; interquartile range, 1-4). MVPA was not associated with WMH volume. In univariable analysis, meeting PA guidelines was associated with lower total, periventricular, and deep WMH volumes by 3.0 mL (95% confidence interval (CI), 0.5-9.7 mL), 2.8 mL (95% CI, 0.5-7.1 mL), and 0.9 mL (95% CI, 0.1-3.0 mL), respectively. However, in multivariable analysis, meeting PA guidelines was not associated with WMH volume, and older age was associated with greater WMH volume at 12 months. PA was not associated with change in WMH volume. Meeting PA guidelines was associated with lower WMH volume at 12 months in univariable analysis, but not in multivariable analysis. Age consistently predicted greater WMH volume.

Impact of thresholding on the consistency and sensitivity of diffusion MRI-based brain networks in patients with cerebral small vessel disease.

IntroductionThresholding of low‐weight connections of diffusion MRI‐based brain networks has been proposed to remove false‐positive connections. It has been previously established that this yields more reproducible scan–rescan network architecture in healthy subjects. In patients with brain disease, network measures are applied to assess inter‐individual variation and changes over time. Our aim was to investigate whether thresholding also achieves improved consistency in network architecture in patients, while maintaining sensitivity to disease effects for these applications.MethodsWe applied fixed‐density and absolute thresholding on brain networks in patients with cerebral small vessel disease (SVD, n = 86; ≈24 months follow‐up), as a clinically relevant exemplar condition. In parallel, we applied the same methods in healthy young subjects (n = 44; scan–rescan interval ≈4 months) as a frame of reference. Consistency of network architecture was assessed with dice similarity of edges and intraclass correlation coefficient (ICC) of edge‐weights and hub‐scores. Sensitivity to disease effects in patients was assessed by evaluating interindividual variation, changes over time, and differences between those with high and low white matter hyperintensity burden, using correlation analyses and mixed ANOVA.ResultsCompared to unthresholded networks, both thresholding methods generated more consistent architecture over time in patients (unthresholded: dice = .70; ICC: .70–.78; thresholded: dice = .77; ICC: .73–.83). However, absolute thresholding created fragmented nodes. Similar observations were made in the reference group. Regarding sensitivity to disease effects in patients, fixed‐density thresholds that were optimal in terms of consistency (densities: .10–.30) preserved interindividual variation in global efficiency and node strength as well as the sensitivity to detect effects of time and group. Absolute thresholding produced larger fluctuations of interindividual variation.ConclusionsOur results indicate that thresholding of low‐weight connections, particularly when using fixed‐density thresholding, results in more consistent network architecture in patients with longer rescan intervals, while preserving sensitivity to disease effects.

Frontal White Matter Hyperintensities Effect on Default Mode Network Connectivity in Acute Mild Traumatic Brain Injury.

The functional connectivity of the brain depends not only on the structural integrity of the cortex but also on the white matter pathways between cortical areas. White matter hyperintensities (WMH), caused by chronic hypoperfusion in the white matter, play a role in the outcome of traumatic brain injury (TBI) and other neurodegenerative disorders. Herein, we investigate how the location and volume of WMH affect the default-mode network (DMN) connectivity in acute mild TBI (mTBI) patients. Forty-six patients with acute mTBI and 46 matched healthy controls were enrolled in the study. All participants underwent T2-weighted fluid-attenuated inversion recovery magnetic resonance imaging (MRI), resting-state functional MRI (fMRI),and neuropsychological assessments. The volume and location of WMH were recorded. The relationships between the WMH volume and clinical assessments were evaluated using Spearman’s correlation. Patients with higher frontal lobe WMH volume had more severe post-concussion symptoms and poorer information processing speed. Moreover, these patients had significantly lower functional connectivity in the right middle temporal gyrus, left middle frontal gyrus, right superior frontal gyrus, and left anterior cingulate cortex, compared with patients with low frontal lobe WMH volume. Compared to the controls, the patients with high frontal WMH volume exhibited significantly lower functional connectivity in the right inferior temporal gyrus, left anterior cingulate cortex, and right superior frontal gyrus. These findings suggest that frontal lobe WMH volume may modulate the functional connectivity within the DMN. Therefore, the WMH volume in specific regions of the brain, particularly the frontal and parietal lobes, may accelerate the process of aging and cognitive impairment may be a useful biomarker for the diagnosis and prognosis of acute mTBI.

Neuropsychiatric symptoms as a sign of small vessel disease progression in cognitive impairment.

Neuropsychiatric symptoms associate cross-sectionally with cerebral small vessel disease but it is not clear whether these symptoms could act as early clinical markers of small vessel disease progression. We investigated whether longitudinal change in Neuropsychiatric Inventory (NPI) scores associated with white matter hyperintensity (WMH) progression in a memory clinic population. We included participants from the prospective Sunnybrook Dementia Study with Alzheimer's disease and vascular subtypes of mild cognitive impairment and dementia with two MRI and ≥ 1 NPI. We conducted linear mixed-effects analyses, adjusting for age, atrophy, vascular risk factors, cognition, function, and interscan interval. At baseline (n=124), greater atrophy, age, vascular risk factors and total NPI score were associated with higher baseline WMH volume, while longitudinally, all but vascular risk factors were associated. Change in total NPI score was associated with change in WMH volume, χ2=7.18, p=0.007, whereby a one-point change in NPI score from baseline to follow-up was associated with a 0.0017 change in normalized WMH volume [expressed as cube root of (WMH volume cm³ as % intracranial volume)], after adjusting for age, atrophy, vascular risk factors and interscan interval. In memory clinic patients, WMH progression over 1-2 years associated with worsening neuropsychiatric symptoms, while WMH volume remained unchanged in those with stable NPI scores in this population with low background WMH burden.

Causal structure discovery identifies risk factors and early brain markers related to evolution of white matter hyperintensities

Our goal was to understand the complex relationship between age, sex, midlife risk factors, and early white matter changes measured by diffusion tensor imaging (DTI) and their role in the evolution of longitudinal white matter hyperintensities (WMH). We identified 1564 participants (1396 cognitively unimpaired, 151 mild cognitive impairment and 17 dementia participants) with age ranges of 30–90 years from the population-based sample of Mayo Clinic Study of Aging. We used computational causal structure discovery and regression analyses to evaluate the predictors of WMH and DTI, and to ascertain the mediating effect of DTI on WMH. We further derived causal graphs to understand the complex interrelationships between midlife protective factors, vascular risk factors, diffusion changes, and WMH. Older age, female sex, and hypertension were associated with higher baseline and progression of WMH as well as DTI measures (P ≤ 0.003). The effects of hypertension and sex on WMH were partially mediated by microstructural changes measured on DTI. Higher midlife physical activity was predictive of lower WMH through a direct impact on better white matter tract integrity as well as an indirect effect through reducing the risk of hypertension by lowering BMI. This study identified key risks factors, early brain changes, and pathways that may lead to the evolution of WMH.

Cortico-striatal functional connectivity and cerebral small vessel disease: Contribution to mild Parkinsonian signs.

Mild Parkinsonian signs (MPS) are common in older adults. We hypothesized that MPS are associated with lower functional connectivity (FC) in dopamine-dependent cortico-striatal networks, and these associations vary with white matter hyperintensity (WMH), a risk factor for MPS. We examined resting-state functional MRI in 266 participants (mean age 83; 57% female; 41% African American) with data on MPS (Unified Parkinson's Disease Rating Scale), demographics, cognition, muscle-skeletal, and cardiometabolic health. FC between cortex and striatum was examined separately for sensorimotor, executive, and limbic functional subregions. Logistic regression tested the association of FC in each network with MPS, adjusted for covariates. Interactions of FC by WMH were tested; and analyses were repeated stratified by WMH above/below the median. Compared to those without MPS, those with MPS had lower cortico-striatal FC in the left executive network (adjusted odds ratio [95% confidence interval], p-value: 0.188 [0.043, 0.824], .027). The interaction with WMH was p = .064; left executive FC was inversely associated with MPS for high WMH (0.077 [0.010, 0.599], .014) but not low WMH participants (1.245 [0.128, 12.132], .850). MPS appear related to lower executive network FC, robust to adjustment for other risk factors, and stronger for those with higher burden of WMH. Future longitudinal studies should examine the interplay between cerebral small vessel disease and connectivity influencing MPS.

What do data‐driven Alzheimer’s disease subtypes tell us about white matter pathology and clinical progression?

AbstractBackgroundThe progression of Alzheimer’s Disease (AD) is heterogeneous with different brain regions manifesting pathology at different times during the disease. Differential sequences of grey matter (GM) volume changes, defining imaging‐based subtypes, may represent alternative disease origins, pathways or severity. Additionally, volumes of white matter hyperintensities (WMH), which increase with age, are associated with AD. In this study we used a machine learning method to estimate three types of AD trajectories and assessed their WMH load and longitudinal prognosis.MethodSubtype and Stage Inference (SuStaIn; Young et al., https://doi.org/10.1038/s41467‐018‐05892‐0) was used to estimate data‐driven disease progresion subtypes from cross‐sectional GM volumes in 795 subjects (from ADNI1/GO/2 with baseline 3T MRI scans processed with FreeSurfer 5.1 passing data quality control). Following additional quality control WMH volumes for 575 of these ADNI subjects were calculated using a Bayesian Model Selection method BaMoS (Sudre et al., https://doi.org/10.1109/TMI.2015.2419072) from three diagnostic groups: Healthy Controls (HC; n=181), Mild Cognitive Impairment (MCI; n=310) and Alzheimer’s Disease (AD; n=85). The association between SuStaIn subtypes and WMH and diagnostic conversion rates were evaluated using multiple pairwise comparisons and survival analysis, respectively.ResultSuStaIn identified three subtypes with distinct atrophy patterns: typical (atrophy begins in hippocampus and amygdala), cortical (atrophy starts in the temporal lobe, followed by cingulate and insula) and subcortical (atrophy begins in pallidum, putamen and caudate) (Figure 1). Participants with the subcortical subtype exhibited a significantly slower rate of clinical progression to MCI or AD (Figure 2, Table 1). Furthemore, subjects with the subcortical subtype showed lower median WMH (Figure 3a), a pattern observed across the diagnostic groups (Figure 3b).ConclusionParticipants classified as the subcortical subtype were least likely to have white matter structural changes associated with neurodegeneration and displayed the slowest rate of clinical conversion. While late hippocampal involvement in the subcortical subtype may explain less severe clinical symptoms and slower disease progression, the reason for lower WMH associated with this subtype trajectory is unknown. Further studies are needed to investigate the link between WMH and AD atrophy subtypes.

Cognitive resilience to tau and amyloid burden in a memory clinic population

AbstractBackgroundCognitive resilience (CR) is defined as the capacity to sustain a better‐than‐expected cognitive performance based on pathological burden. There is high variability in the individuals’ CR, and it has been demonstrated that individuals with high resilience develop symptoms later than those with low CR. The aim of this study it to investigate the association between demographic and clinical features and individual CR.Method144 subjects from the Geneva memory center cohort (N=37 cognitively unimpaired, N=84 mild cognitive impairment, N=23 dementia) that underwent amyloid PET, tau PET and an extensive neuropsychological battery were included. A linear regression model between amyloid and tau global standardized uptake value ratio (SUVr) vs Mini‐Mental State Examination (MMSE) was performed, and the residuals of the model were used as a measure of individual CR. A multivariate linear regression was used to assess the association between CR and age, sex, education, and white matter hyperintensities.ResultMean age was 72.2 (sd = 7.8), 72 were female (50%), and mean years of education was 13.9 (4.1). Greater CR was associated with better education (β = 0.26, p = 0.001), older age (β = 0.25, p = 0.002) and low white matter hyperintensities (β = ‐0.17, p = 0.037). No associations were observed between CR and gender (gender, β = 0.06, p = 0.455).ConclusionWe confirmed in our population that education is strongly associated with CR. Future development of this study will be to investigate brain resilience (BR), defined as the relationship between atrophy and amyloid and tau, and the longitudinal cognitive trajectory of the individuals with high BR and/or CR compared to those with low BR and/or CR. the definite article More (Definitions, Synonyms, Translation)

Sex and cerebral small vessel disease‐specific longitudinal trajectories of amyloid, tau, and neurodegeneration

AbstractBackgroundThe AT(N) model of Alzheimer’s disease (AD) posits a temporal evolution of β‐amyloid (Aβ) accumulation followed by tau then neurodegeneration. We investigated whether longitudinal relationships of these pathologies varied by sex and cerebral small vessel disease burden (cSVD), hypothesizing stronger associations in women and those with high baseline cSVD.MethodParticipants included 37 non‐demented older adults (mean 74 y/o at inclusion; 59% female; 89% white; 29% APOE4+). Tau was measured once at time 0 using 18F‐AV‐1451 in an AD composite region of interest. Global amyloid and cerebral metabolism in lateral temporal lobe (neurodegeneration) were measured at repeated annual visits (8 years before tau‐PET to 2 years after), using 11C‐PiB and 18F‐fluorodeoxyglucose (FDG)‐PET. cSVD at study inclusion was characterized by high or low white matter hyperintensity (WMH) volume on MRI. We calculated individual slopes of Aβ and cerebral metabolism up to the tau‐PET visit (time ‐8 to 0) using linear mixed effects models. Using age‐adjusted linear regression models, we examined associations of Aβ slope, tau, and cerebral metabolism slope or metabolism at the final visit (time≥0). We tested effect modification by sex and WMH using interaction terms and stratified analyses when interaction p&lt;0.10.ResultAssociations of Aβ slope with tau varied by sex (p‐interaction=0.007) but not WMH. Greater increase in Aβ slope was associated with greater tau in women (β=3.5, p=0.004), but not men (β= ‐1.2, p=0.34). Tau did not predict cerebral metabolism at the final FDG visit (β=0.10, p=0.67), but increasing Aβ slope predicted hypometabolism at the final FDG visit (β= ‐2.1, p=0.01). Neither of these relationships varied by sex or WMH. Associations of cerebral metabolism slope with tau varied by sex (p‐interaction=0.08), but not WMH. Decreasing cerebral metabolism slope was associated with greater tau in women (β= ‐16.3, p=0.05), but not men (β=4.7, p=0.59). Further adjustment for APOE4 (N=31) did not appreciably alter results.ConclusionIn non‐demented older adults, we found that associations of Aβ and cerebral hypometabolism with later increased tau were stronger in women than men; cSVD did not modify these associations. Tau did not predict later cerebral metabolism, while Aβ did.

Association between cerebral small‐vessel disease and Alzheimer’s disease pathologies

AbstractBackgroundControversy 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.

Metabolic syndrome impact on cognitive composites domain scores and on white matter hyperintensities in subjective cognitive decline: The FACEHBI Cohort

AbstractBackgroundTo explore the impact of Metabolic Syndrome (MetS) and its components on Cognitive Composites (CCs) domain scores and on White Matter Hyperintensities (WMHs) in individuals experiencing Subjective Cognitive Decline (SCD).MethodTwo hundred participants from the FACEHBI cohort underwent structural Magnetic Resonance Imaging (MRI), 18F‐Florbetaben Positron Emission Tomography (FBB‐PET), and a comprehensive neuropsychological assessment. MetS was defined using the Joint Interim Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention criteria (elevated fasting glucose, elevated blood pressure, reduced HDL‐C, elevated triglycerides and elevated waist circumference). WMHs were addressed through the Fazekas scale, the Age‐related white matter changes (ARWMC) scale, and the FreeSurfer pipeline. Ten CCs domain scores were created using principal components analysis (PCA): (1) executive function fluency, (2) executive function processing speed, (3) executive function attention, (4) verbal memory, (5) visual memory, (6) face–name associative memory, (7) face–occupation associative memory, (8) language, (9) visuoperception, and (10) praxis. Age, sex, education, and Apolipoprotein E (APOE) were used as adjusting variables. Several analyses were performed to explore a sex effect.ResultForty‐seven individuals matched the MetS criteria. This syndrome behaves differently based on sex. Only women with MetS showed better performance in language (p = .002; OR = 2.12) than those without MetS. The only differentiating component between both groups (presence/absence MetS) was that women in the MetS subgroup presented greater abdominal obesity (Mann‐Whitney p = .001). From Mets group, antihypertensive drug treatment was significantly associated with better praxis scores (p = .012; OR = 1.84) and HDL‐C drug treatment with better language scores but worse episodic memory performance (p = .028; OR = 1.60; and p = .007; OR = .57, respectively). Drug treatment for elevated glucose was associated with low WMH load in the ARWMC scale (β= ‐.144; p = .045).ConclusionThis study demonstrated a protective effect of MetS in cognitive performance among SCD women with greater abdominal obesity and a lack of association between MetS and WMH load, although further investigation is needed to explore the long term impact of its entity.

Cerebral small vessel disease, cardiovascular risk factors, and future walking speed in old age: a population-based cohort study

BackgroundThe purpose of this study was to examine the associations between combined and individual cerebral small vessel disease (cSVD) markers on future walking speed over 9 years; and to explore whether these associations varied by the presence of cardiovascular risk factors (CRFs).MethodsThis population-based cohort study included 331 adults, aged ≥60 years, without limitation in walking speed (≥0.8 m/s). At baseline, cSVD markers, including white matter hyperintensities (WMH), lacunes, and perivascular spaces (PVS), were assessed on magnetic resonance imaging. The modifiable CRFs (physical inactivity, heavy alcohol consumption, smoking, hypertension, high total cholesterol, diabetes, and overweight/obese) were combined into a score. The association between baseline cSVD markers and the decline in walking speed was examined using linear mixed-effects models, whereas Cox proportional hazards models were used to estimate the association with walking speed limitation (defined as < 0.8 m/s) over the follow-up.ResultsOver the follow-up period, 76 (23.0%) persons developed walking speed limitation. Participants in the highest tertile of the combined cSVD marker score had a hazard ratio (HR) of 3.78 (95% confidence interval [CI] 1.70-8.45) for walking speed limitation compared with people in the lowest score tertile, even after adjusting for socio-demographics, CRFs, cognitive function, and chronic conditions. When investigating the cSVD markers individually, having the highest burden of WMH was associated with a significantly faster decline in walking speed (β coefficient − 0.020; 95% CI -0.035-0.004) and a greater HR of walking speed limitation (HR 2.78; 95% CI 1.31-5.89) compared with having the lowest WMH burden. Similar results were obtained for the highest tertile of PVS (HR 2.13; 95% CI 1.04-4.36). Lacunes were associated with walking speed limitation, but only in men. Having ≥4 CRFs and high WMH volume simultaneously, showed a greater risk of walking speed limitation compared with having ≥4 CRFs and low WMH burden. CRFs did not modify the associations between lacunes or PVS and walking speed.ConclusionsCombined cSVD markers strongly predict walking speed limitation in healthy older adults, independent of cognitive function, with WMH and PVS being the strongest contributors. Improving cardiovascular health may help to mitigate the negative effects of WMH on future walking speed.

The interactive effect of MCI subtype and white‐matter hyperintensity load on the expression of large‐scale neurofunctional networks

AbstractBackgroundMild Cognitive Impairment (MCI) is a condition with a large degree of clinical heterogeneity. A major classification is that between 'amnestic' and 'non‐amnestic' patients. It is known that large‐scale neural networks differ between these two subtypes. White‐matter‐hyperintensities (WMH) load may contribute to affecting the efficiency of these networks. It is unknown, however, whether WMH burden influences the expression of major brain networks in a similar way in both amnestic and non‐amnestic MCI. We thus hypothesised that an interactive effect on brain networks would exist between MCI subtype and WMH load.MethodOne‐hundred‐and‐twenty‐three MCI patients were included in this study, retrospectively selected from our internal Ageing Database and the Treviso Dementia Registry initiative. They all completed an MRI protocol inclusive of resting‐state fMRI and neuroanatomical acquisitions. FLAIR scans were processed with the ‘Lesion Segmentation Tool’ to quantify global WMH volume (i.e., lower vs. higher). Resting‐state scans were preprocessed and denoised with the CONN toolbox and an independent component analysis was run to extract five major large‐scale networks: default‐mode, salience, left‐right frontoparietal and visual. Subtype‐by‐WHM load ANOVAs were run to test for significant interactions for each of the five inferential models, controlling for major confounding factors.ResultSignificant interactions were found in two models only. Within the salience network having a lower WMH load was associated with stronger connectivity in the right insula significantly more among amnestic patients. Within the left frontoparietal network, having a lower WMH load was associated with stronger connectivity in the right frontoinsular cortex significantly more among amnestic patients, and in the left mediotemporal lobe significantly more among non‐amnestic patients.ConclusionThe interplay of two important clinical variables such as MCI subtype and WMH load has a significant effect on the expression of two large‐scale brain networks that sustain stimuli selection and integration and executive control. This pattern is expressed in alignment with clinical symptoms of subtypes. WMH load contributes to down‐regulating the efficiency of large‐scale brain networks in a way that is dependent on MCI subtype and aligned with vulnerability of each subtype. This is an important element of prognostic utility.

White-Matter Hyperintensity Load and Differences in Resting-State Network Connectivity Based on Mild Cognitive Impairment Subtype.

“Mild cognitive impairment” (MCI) is a diagnosis characterised by deficits in episodic memory (aMCI) or in other non-memory domains (naMCI). Although the definition of subtypes is helpful in clinical classification, it provides little insight on the variability of neurofunctional mechanisms (i.e., resting-state brain networks) at the basis of symptoms. In particular, it is unknown whether the presence of a high load of white-matter hyperintensities (WMHs) has a comparable effect on these functional networks in aMCI and naMCI patients. This question was addressed in a cohort of 123 MCI patients who had completed an MRI protocol inclusive of T1-weighted, fluid-attenuated inversion recovery (FLAIR) and resting-state fMRI sequences. T1-weighted and FLAIR images were processed with the Lesion Segmentation Toolbox to quantify whole-brain WMH volumes. The CONN toolbox was used to preprocess all fMRI images and to run an independent component analysis for the identification of four large-scale haemodynamic networks of cognitive relevance (i.e., default-mode, salience, left frontoparietal, and right frontoparietal networks) and one control network (i.e., visual network). Patients were classified based on MCI subtype (i.e., aMCI vs. naMCI) and WMH burden (i.e., low vs. high). Maps of large-scale networks were then modelled as a function of the MCI subtype-by-WMH burden interaction. Beyond the main effects of MCI subtype and WMH burden, a significant interaction was found in the salience and left frontoparietal networks. Having a low WMH burden was significantly more associated with stronger salience-network connectivity in aMCI (than in naMCI) in the right insula, and with stronger left frontoparietal-network connectivity in the right frontoinsular cortex. Vice versa, having a low WMH burden was significantly more associated with left-frontoparietal network connectivity in naMCI (than in aMCI) in the left mediotemporal lobe. The association between WMH burden and strength of connectivity of resting-state functional networks differs between aMCI and naMCI patients. Although exploratory in nature, these findings indicate that clinical profiles reflect mechanistic interactions that may play a central role in the definition of diagnostic and prognostic statuses.

The association between white matter hyperintensity volume and gait performance under single and dual task conditions in older people with dementia: A cross-sectional study

Background: Understanding the relationship between white matter hyperintensities (WMHs) and gait may assist in understanding the central control of gait and determining treatment modalities. These relationships are yet to be realized in older people with dementia. Objective: To examine the association between WMH volume and gait under single-task and dual task (DT) conditions in people with dementia. Methods: Twenty-eight community-dwelling older people with dementia (median age=83 years; [IQR=77–86]; 36% female) had timed gait speed assessed at usual pace. Gait (speed, stride length, cadence) was assessed using the GAITRite® mat under three conditions (n = 18/28): a) single-task, b) functional DT: carrying a glass of water and c) cognitive DT: counting backwards from 30. WMH volumes were quantified using a fully automated segmentation toolbox. Results: Total, temporal and parietal WMH volumes were negatively correlated with timed and functional DT gait speed, and with stride length under single-task, functional DT and cognitive DT conditions. Frontal WMH volumes were negatively correlated with timed gait speed and stride length under single-task and functional DT conditions. Participants with higher total WMH burden had significantly slower timed and functional DT gait speed and reduced stride length under single-task, functional DT and cognitive DT conditions compared to participants with lower WMH burden. Conclusions: WMH volume was associated with slower gait speed and reduced stride length, but not cadence, under single-task and DT conditions in people with dementia. Further research is needed to confirm these findings and determine whether vascular risk management can improve gait in older people with dementia.

HbA1c and brain health across the entire glycaemic spectrum.

AimTo understand the relationship between HbA1c and brain health across the entire glycaemic spectrum.Materials and MethodsWe used data from the UK Biobank cohort consisting of 500,000 individuals aged 40–69 years. HbA1c and diabetes diagnosis were used to define baseline glycaemic categories. Our outcomes included incident all‐cause dementia, vascular dementia (VD), Alzheimer's dementia (AD), hippocampal volume (HV), white matter hyperintensity (WMH) volume, cognitive function and decline. The reference group was normoglycaemic individuals (HbA1c ≥35 & <42 mmol/mol). Our maximum analytical sample contained 449,973 individuals with complete data.ResultsPrediabetes and known diabetes increased incident VD (HR 1.54; 95% CI = 1.04, 2.28 and HR 2.97; 95% CI = 2.26, 3.90, respectively). Known diabetes increased all‐cause and AD risk (HR 1.91; 95% CI = 1.66, 2.21 and HR 1.84; 95% CI = 1.44, 2.36, respectively). Prediabetes and known diabetes elevated the risks of cognitive decline (OR 1.42; 1.48, 2.96 and OR 1.39; 1.04, 1.75, respectively). Prediabetes, undiagnosed and known diabetes conferred higher WMH volumes (3%, 22% and 7%, respectively) and lower HV (36, 80 and 82 mm3, respectively), whereas low‐normal HbA1c had 1% lower WMH volume and 12 mm3 greater HV.ConclusionBoth prediabetes and known diabetes are harmful in terms of VD, cognitive decline and AD risks, as well as lower HV. Associations appeared to be somewhat driven by antihypertensive medication, which implies that certain cardiovascular drugs may ameliorate some of the excess risk. Low‐normal HbA1c levels, however, are associated with more favourable brain health outcomes and warrant more in‐depth investigation.

Brain Resilience: The Effect of White Matter Disease on Brain Networks in Cognitively Normal Older Adults

Brain pathologies are increasingly understood to confer mobility risk, but the malleability of functional brain networks may be a mechanism for mobility reserve. In particular, white matter hyperintensities (WMH) are strongly associated with mobility and alter functional network connectivity. To assess the potential role of brain networks as a mechanism of mobility reserve, 116 participants with MRI from the Brain Networks and Mobility Function (B-NET) were categorized into 4 groups based on median splits of SPPB scores and WMH burden: Expected Healthy (EH: low WMH, SPPB>10, N=45), Expected Impaired (EI: high WMH, SPPB10, N=24), Unexpected Impaired (EI: low WMH, SPPB<10, N=10) and Unexpected Unhealthy (UH: low WMH, SPPB<10, N=37). Functional brain networks were calculated using graph theory methods and white matter hyperintensities were quantified with the Lesion Segmentation Toolbox (LST) in SPM12. Somatomotor cortex community structure (SMC-CS) was similar between UH and EH with both having higher consistency than EI and UI. However, UH displayed a unique increase in second-order connections between the motor cortex and the anterior cingulate. It is possible that this increase in connections is a signal of higher reserve or resilience in UH participants and may indicate a mechanism of compensation in regards to mobility function and advanced WMH burden. These data suggest functional brain networks may be a mechanism for mobility resilience in older adults at mobility risk due to WMH burden.

Parental Longevity Is Associated With Brain Volumes in Selected Areas

A few studies report that parental longevity is associated with faster gait speed, less memory decline, a lower risk of Alzheimer’s disease, and lower white matter hyperintensities. Data on structural neuroimaging correlates of parental longevity and its spatial distribution are limited. This study aims to examine relationships of parental longevity with regional brain volumes. We identified 10,513 participants from UK Biobank (mean age=58±6, ranged40-70, 50%women) with data on parental longevity and information on MRI regional brain volumes that have been related to executive function (dorsolateral prefrontal cortex), memory (hippocampus, parahippocampal gyrus, inferior temporal lobe, middle temporal lobe) and motor function (precentral gyrus, putamen, caudate, corpus callosum). Participants were categorized based on whether at least one parent lived to age 85 or older or neither parent survived to age 85. Associations of parental longevity with each brain volume measure were examined using linear regression, adjusted for age, sex, education, ApoE e4 status, total gray matter atrophy, white matter hyperintensities, hypertension, and glucose. Compared to participants whose both parents died before 85, those with at least one parent surviving to 85 had greater brain volumes in hippocampus, parahippocampal gyrus, inferior temporal lobe, middle temporal lobe, and precentral gyrus in fully adjusted models (Bonferroni corrected p<0.01). There were no significant associations with volumes in dorsolateral prefrontal cortex, putamen or caudate. Parental longevity is associated with preserved brain structure localized in memory- and motor-related cortical regions. These findings support previous reports that parental longevity is associated with better memory and gait with aging.