White Matter Hyperintensities Accumulation Research Articles

Cardiorespiratory fitness attenuates age-associated aggregation of white matter hyperintensities in an at-risk cohort

BackgroundAge is the cardinal risk factor for Alzheimer’s disease (AD), and white matter hyperintensities (WMH), which are more prevalent with increasing age, may contribute to AD. Higher cardiorespiratory fitness (CRF) has been shown to be associated with cognitive health and decreased burden of AD-related brain alterations in older adults. Accordingly, the aim of this study was to determine whether CRF attenuates age-related accumulation of WMH in middle-aged adults at risk for AD.MethodsOne hundred and seven cognitively unimpaired, late-middle-aged adults from the Wisconsin Registry for Alzheimer’s Prevention underwent 3 T magnetic resonance imaging and performed graded maximal treadmill exercise testing from which we calculated the oxygen uptake efficiency slope (OUES) as our measure of CRF. Total WMH were quantified using the Lesion Segmentation Tool and scaled to intracranial volume. Linear regression adjusted for APOE4 carriage, family history, body mass index, systolic blood pressure, and sex was used to examine relationships between age, WMH, and CRF.ResultsAs expected, there was a significant association between age and WMH (p < .001). Importantly, there was a significant interaction between age and OUES on WMH (p = .015). Simple main effects analyses revealed that the effect of age on WMH remained significant in the Low OUES group (p < .001) but not in the High OUES group (p = .540), indicating that higher CRF attenuates the deleterious age association with WMH.ConclusionsHigher CRF tempers the adverse effect of age on WMH. This suggests a potential pathway through which increased aerobic fitness facilitates healthy brain aging, especially among individuals at risk for AD.

Effect of Long-Term Vascular Care on Progression of Cerebrovascular Lesions: Magnetic Resonance Imaging Substudy of the PreDIVA Trial (Prevention of Dementia by Intensive Vascular Care).

This study aimed to evaluate the effect of a nurse-led multidomain cardiovascular intervention on white matter hyperintensity (WMH) progression and incident lacunar infarcts in community-dwelling elderly with hypertension. The preDIVA trial (Prevention of Dementia by Intensive Vascular Care) was an open-label, cluster-randomized controlled trial in community-dwelling individuals aged 70 to 78 years. General practices were assigned by computer-generated randomization to 6-year nurse-led, multidomain intensive vascular care or standard care. Of 3526 preDIVA participants, 195 nondemented participants with a systolic blood pressure ≥140 mm Hg were consecutively recruited to undergo magnetic resonance imaging at 2 to 3 and 5 to 6 years after baseline. WMH volumes were measured automatically, lacunar infarcts assessed visually, blinded to treatment allocation. One hundred and twenty-six participants were available for longitudinal analysis (64 intervention and 62 control). Annual WMH volume increase in milliliter was similar for intervention (mean=0.73, SD=0.84) and control (mean=0.70, SD=0.59) participants (adjusted mean difference, -0.08 mL; 95% confidence interval, -0.30 to 0.15; P=0.50). Analyses suggested greater intervention effects with increasing baseline WMH volumes (P for interaction=0.03). New lacunar infarcts developed in 6 (9%) intervention and 2 (3%) control participants (odds ratio, 2.2; 95% confidence interval, 0.4-12.1; P=0.36). Nurse-led vascular care in hypertensive community-dwelling older persons did not diminish WMH accumulation over 3 years. However, our results do suggest this type of intervention could be effective in persons with high WMH volumes. There was no effect on lacunar infarcts incidence but numbers were low. URL: http://www.isrctn.com/ISRCTN29711771. Unique identifier: ISRCTN29711771.

APOE ε4 status is associated with white matter hyperintensities volume accumulation rate independent of AD diagnosis

To assess the relationship between carriage of APOE ε4 allele and evolution of white matter hyperintensities (WMHs) volume, we longitudinally studied 339 subjects from the Alzheimer's Disease Neuroimaging Initiative cohort with diagnoses ranging from normal controls to probable Alzheimer's disease (AD). A purpose-built longitudinal automatic method was used to segment WMH using constraints derived from an atlas-based model selection applied to a time-averaged image. Linear mixed models were used to evaluate the differences in rate of change across diagnosis and genetic groups. After adjustment for covariates (age, sex, and total intracranial volume), homozygous APOE ε4ε4 subjects had a significantly higher rate of WMH accumulation (22.5% per year 95% CI [14.4, 31.2] for a standardized population having typical values of covariates) compared with the heterozygous (ε4ε3) subjects (10.0% per year [6.7, 13.4]) and homozygous ε3ε3 (6.6% per year [4.1, 9.3]) subjects. Rates of accumulation increased with diagnostic severity; controls accumulated 5.8% per year 95% CI: [2.2, 9.6] for the standardized population, early mild cognitive impairment 6.6% per year [3.9, 9.4], late mild cognitive impairment 12.5% per year [8.2, 17.0] and AD subjects 14.7% per year [6.0, 24.0]. Following adjustment for APOE status, these differences became nonstatistically significant suggesting that APOE ε4 genotype is the major driver of accumulation of WMH volume rather than diagnosis of AD.

White Matter Hyperintensity Load Modulates Brain Morphometry and Brain Connectivity in Healthy Adults: A Neuroplastic Mechanism?

White matter hyperintensities (WMHs) are acquired lesions that accumulate and disrupt neuron-to-neuron connectivity. We tested the associations between WMH load and (1) regional grey matter volumes and (2) functional connectivity of resting-state networks, in a sample of 51 healthy adults. Specifically, we focused on the positive associations (more damage, more volume/connectivity) to investigate a potential route of adaptive plasticity. WMHs were quantified with an automated procedure. Voxel-based morphometry was carried out to model grey matter. An independent component analysis was run to extract the anterior and posterior default-mode network, the salience network, the left and right frontoparietal networks, and the visual network. Each model was corrected for age, global levels of atrophy, and indices of brain and cognitive reserve. Positive associations were found with morphometry and functional connectivity of the anterior default-mode network and salience network. Within the anterior default-mode network, an association was found in the left mediotemporal-limbic complex. Within the salience network, an association was found in the right parietal cortex. The findings support the suggestion that, even in the absence of overt disease, the brain actuates a compensatory (neuroplastic) response to the accumulation of WMH, leading to increases in regional grey matter and modified functional connectivity.

White matter hyperintensities and imaging patterns of brain ageing in the general population.

White matter hyperintensities are associated with increased risk of dementia and cognitive decline. The current study investigates the relationship between white matter hyperintensities burden and patterns of brain atrophy associated with brain ageing and Alzheimer's disease in a large populatison-based sample (n = 2367) encompassing a wide age range (20-90 years), from the Study of Health in Pomerania. We quantified white matter hyperintensities using automated segmentation and summarized atrophy patterns using machine learning methods resulting in two indices: the SPARE-BA index (capturing age-related brain atrophy), and the SPARE-AD index (previously developed to capture patterns of atrophy found in patients with Alzheimer's disease). A characteristic pattern of age-related accumulation of white matter hyperintensities in both periventricular and deep white matter areas was found. Individuals with high white matter hyperintensities burden showed significantly (P < 0.0001) lower SPARE-BA and higher SPARE-AD values compared to those with low white matter hyperintensities burden, indicating that the former had more patterns of atrophy in brain regions typically affected by ageing and Alzheimer's disease dementia. To investigate a possibly causal role of white matter hyperintensities, structural equation modelling was used to quantify the effect of Framingham cardiovascular disease risk score and white matter hyperintensities burden on SPARE-BA, revealing a statistically significant (P < 0.0001) causal relationship between them. Structural equation modelling showed that the age effect on SPARE-BA was mediated by white matter hyperintensities and cardiovascular risk score each explaining 10.4% and 21.6% of the variance, respectively. The direct age effect explained 70.2% of the SPARE-BA variance. Only white matter hyperintensities significantly mediated the age effect on SPARE-AD explaining 32.8% of the variance. The direct age effect explained 66.0% of the SPARE-AD variance. Multivariable regression showed significant relationship between white matter hyperintensities volume and hypertension (P = 0.001), diabetes mellitus (P = 0.023), smoking (P = 0.002) and education level (P = 0.003). The only significant association with cognitive tests was with the immediate recall of the California verbal and learning memory test. No significant association was present with the APOE genotype. These results support the hypothesis that white matter hyperintensities contribute to patterns of brain atrophy found in beyond-normal brain ageing in the general population. White matter hyperintensities also contribute to brain atrophy patterns in regions related to Alzheimer's disease dementia, in agreement with their known additive role to the likelihood of dementia. Preventive strategies reducing the odds to develop cardiovascular disease and white matter hyperintensities could decrease the incidence or delay the onset of dementia.

White Matter Hyperintensity Accumulation During Treatment of Late-Life Depression.

White matter hyperintensities (WMHs) have been shown to be associated with the development of late-life depression (LLD) and eventual treatment outcomes. This study sought to investigate longitudinal WMH changes in patients with LLD during a 12-week antidepressant treatment course. Forty-seven depressed elderly patients were included in this analysis. All depressed subjects started pharmacological treatment for depression shortly after a baseline magnetic resonance imaging (MRI) scan. At 12 weeks, patients underwent a follow-up MRI scan, and were categorized as either treatment remitters (n=23) or non-remitters (n=24). Among all patients, there was as a significant increase in WMHs over 12 weeks (t(46)=2.36, P=0.02). When patients were stratified by remission status, non-remitters demonstrated a significant increase in WMHs (t(23)=2.17, P=0.04), but this was not observed in remitters (t(22)=1.09, P=0.29). Other markers of brain integrity were also investigated including whole brain gray matter volume, hippocampal volume, and fractional anisotropy. No significant differences were observed in any of these markers during treatment, including when patients were stratified based on remission status. These results add to existing literature showing the association between WMH accumulation and LLD treatment outcomes. Moreover, this is the first study to demonstrate similar findings over a short interval (ie 12 weeks), which corresponds to the typical length of an antidepressant trial. These findings serve to highlight the acute interplay of cerebrovascular ischemic disease and LLD.

A systematic review of the evidence that brain structure is related to muscle structure and their relationship to brain and muscle function in humans over the lifecourse.

BackgroundAn association between cognition and physical function has been shown to exist but the roles of muscle and brain structure in this relationship are not fully understood. A greater understanding of these relationships may lead to identification of the underlying mechanisms in this important area of research. This systematic review examines the evidence for whether: a) brain structure is related to muscle structure; b) brain structure is related to muscle function; and c) brain function is related to muscle structure in healthy children and adults.MethodsMedline, Embase, CINAHL and PsycINFO were searched on March 6th 2014. A grey literature search was performed using Google and Google Scholar. Hand searching through citations and references of relevant articles was also undertaken.Results53 articles were included in the review; mean age of the subjects ranged from 8.8 to 85.5 years old. There is evidence of a positive association between both whole brain volume and white matter (WM) volume and muscle size. Total grey matter (GM) volume was not associated with muscle size but some areas of regional GM volume were associated with muscle size (right temporal pole and bilateral ventromedial prefrontal cortex). No evidence was found of a relationship between grip strength and whole brain volume however there was some evidence of a positive association with WM volume. Conversely, there is evidence that gait speed is positively associated with whole brain volume; this relationship may be driven by total WM volume or regional GM volumes, specifically the hippocampus. Markers of brain ageing, that is brain atrophy and greater accumulation of white matter hyperintensities (WMH), were associated with grip strength and gait speed. The location of WMH is important for gait speed; periventricular hyperintensities and brainstem WMH are associated with gait speed but subcortical WMH play less of a role. Cognitive function does not appear to be associated with muscle size.ConclusionThere is evidence that brain structure is associated with muscle structure and function. Future studies need to follow these interactions longitudinally to understand potential causal relationships.

Regional white matter hyperintensities: aging, Alzheimer's disease risk, and cognitive function

White matter hyperintensities (WMH) of presumed vascular origin, as seen on T2-weighted fluid attenuated inversion recovery magnetic resonance imaging, are known to increase with age and are elevated in Alzheimer's disease (AD). The cognitive implications of these common markers are not well understood. Previous research has primarily focused on global measures of WMH burden and broad localizations that contain multiple white matter tracts. The aims of this study were to determine the pattern of WMH accumulation with age, risk for AD, and the relationship with cognitive function utilizing a voxel-wise analysis capable of identifying specific white matter regions. A total of 349 participants underwent T1-weighted and high-resolution T2-weighted fluid attenuated inversion recovery magnetic resonance imaging and neuropsychological testing. Increasing age and lower cognitive speed and flexibility (a component of executive function), were both significantly associated with regional WMH throughout the brain. When age was controlled, lower cognitive speed and flexibility was independently associated with WMH in the superior corona radiata. Apolipoprotein E ε4 and parental family history of AD were not associated with higher burden of WMH. The results contribute to a larger body of literature suggesting that white matter measures are linked with processing speed, and illustrate the utility of voxel-wise analysis in understanding the effect of lesion location on cognitive function.

Neuropathologic basis of white matter hyperintensity accumulation with advanced age

To determine which vascular pathology measure most strongly correlates with white matter hyperintensity (WMH) accumulation over time, and whether Alzheimer disease (AD) neuropathology correlates with WMH accumulation. Sixty-six older persons longitudinally followed as part of an aging study were included for having an autopsy and >1 MRI scan, with last MRI scan within 36 months of death. Mixed-effects models were used to examine the associations between longitudinal WMH accumulation and the following neuropathologic measures: myelin pallor, arteriolosclerosis, microvascular disease, microinfarcts, lacunar infarcts, large-vessel infarcts, atherosclerosis, neurofibrillary tangle rating, and neuritic plaque score. Each measure was included one at a time in the model, adjusted for duration of follow-up and age at death. A final model included measures showing an association with p < 0.1. Mean age at death was 94.5 years (5.5 SD). In the final mixed-effects models, arteriolosclerosis, myelin pallor, and Braak score remained significantly associated with increased WMH accumulation over time. In post hoc analysis, we found that those with Braak score 5 or 6 were more likely to also have high atherosclerosis present compared with those with Braak score 1 or 2 (p = 0.003). Accumulating white matter changes in advanced age are likely driven by small-vessel ischemic disease. Additionally, these results suggest a link between AD pathology and white matter integrity disruption. This may be due to wallerian degeneration secondary to neurodegenerative changes. Alternatively, a shared mechanism, for example ischemia, may lead to both vascular brain injury and neurodegenerative changes of AD. The observed correlation between atherosclerosis and AD pathology supports the latter.

LC‐MS/MS identification of the one‐carbon cycle metabolites in human plasma

The one-carbon cycle is composed of four major biologically important molecules: methionine (L-Met), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and homocysteine (Hcy). In addition to these key metabolites, there are multiple enzymes, vitamins, and cofactors that play essential roles in the cascade of the biochemical reactions that convert one metabolite into another in the cycle. Simultaneous quantitative measurement of four major metabolites can be used to detect possible aberrations in this vital cycle. Abnormalities in the one-carbon cycle might lead to hyper- or hypomethylation, homocystinemia, liver dysfunction, and accumulation of white-matter hyperintensities in the human brain. Previously published methods describe evaluation of several components of the one-carbon cycle, but none to our knowledge demonstrated simultaneous measurement of all four key molecules (L-Met, SAM, SAH, and Hcy). We describe a novel analytical method suitable for simultaneous identification and quantification of L-Met, SAM, SAH, and Hcy with LC-MS/MS. Moreover, we tested this method to identify these metabolites in human plasma collected from patients with multiple sclerosis and healthy individuals. In a pilot feasibility study, our results indicate that patients with multiple sclerosis showed abnormalities in the one-carbon cycle.

Omega 3 Fatty Acids and White Matter Mediated Cognitive Decline in Older Adults

ObjectiveOmega 3 PUFAs may work on vascular pathology mediated cognitive decline, including brain white matter lesions and executive skills. We examined whether PUFAs are associated with cognitive domains (executive function and processing speeds) historically sensitive to the accumulation of white matter hyperintensities (WMH).MethodsThis cohort study of 86 non‐demented subjects used the Trail Making Test Part B to represent executive function and the Digit Symbol test for processing speed. Plasma eicosapentaenoic acid (EPA, 20:5n‐3) and docosahexaenoic acid (DHA, 22:6n‐3) were analyzed using GC and combined to form a PUFA index. WMH burden was measured as the total volume of WMH on MRI. Cognitive change was examined using mixed effects models.ResultsAt baseline, the mean age and MMSE were 86 and 28, respectively. Sixty‐two percent were female, 11% had at least one APOE4 risk allele and mean follow up was 4 years. The PUFA index was associated with a 1‐year delay in executive decline attributable to age after multivariate adjustment (p = 0.01). The significance of this index to executive decline was lost after adding WMH volume to the model (p = 0.89), while WMH remained a strong predictor of executive decline (p = 0.02).InterpretationHigher intake of PUFA may slow the decline in executive function by reducing WMH lesions in people at risk for dementia.

O4‐02‐05: Neuropathologic basis of white matter hyperintensity accumulation

O4‐02‐05: Neuropathologic basis of white matter hyperintensity accumulation

Metabolic syndrome and localization of white matter hyperintensities in the elderly population.

Metabolic syndrome (MetS) is defined as a clustering of metabolic disorders: abdominal obesity, dyslipidemia, hypertension, and hyperglycemia. Although specific components of MetS have been associated with white matter hyperintensities (WMH), less is known about the association between MetS as a whole and WMH, especially in normal aging. We aimed to: (1) investigate this association in a cohort of healthy elderly individuals, and (2) examine the relationship between MetS and the regional distribution of WMH, to further understanding of the relationship between MetS and structural brain changes. Analyses were carried out on 308 participants (48.1% men, age: 71.0 ± 3.9 years) from the French longitudinal ESPRIT (Enquête de Santé Psychologique--Risques, Incidence et Traitement) study, who were free of cerebrovascular disease cognitive and functional impairment. Logistic regression models were used to examine the cross-sectional association between MetS (defined using the National Cholesterol Education Program-Adult Treatment Panel III criteria) and (1) WMH volumes, and (2) WMH volumes according to their localization in insulofrontal and temporoparietal regions. After adjusting for potential confounders, participants with MetS had a twofold increased chance of presenting with high levels of WMH volume compared with those without (odds ratio [OR] = 2.74, 95% confidence interval [CI]: 1.25-6.03). MetS was specifically associated with an increase of temporoparietal WMH volumes, but no association was found between MetS and WMH localized in the insulofrontal region. Our findings suggest that effective management of MetS may reduce WMH accumulation in brain areas already vulnerable to the aging process.

Acceleration of White Matter Hyperintensity Burden Preceding Onset of Mild Cognitive Impairment (S24.006)

Objective: Determine the timing of white matter hyperintensity (WMH) burden acceleration in relation to mild cognitive impairment (MCI) onset. Background Cerebral white matter change, observed as hyperintensities on T2 MRI, are very common in cognitively intact elderly. Those with greater baseline and rates of WMH accumulation are at increased risk of MCI, a likely precursor of progressive dementia. The timing of acceleration of WMH increase relative to clinical transition to MCI has not been established. Design/Methods: 189 cognitively intact older volunteers from the Oregon Brain Aging Study underwent yearly evaluations, including brain MRI, and cognitive testing. MCI was defined as being the first of two consecutive Clinical Dementia Rating scores of 0.5 or higher. The time before MCI, when the change in WMH burden accelerates, was assessed using a mixed-effects model with a change point for subjects who developed MCI during follow up. Results: During a follow up duration of up to 22.2 years, 135 subjects developed MCI. Acceleration in %WMH volume increase occurred 10.6 years before MCI onset. On average, the annual rate of change in %WMH increased an additional 3.3% after the change point. Acceleration in %ventricular CSF volume increase and total brain volume decrease occurred 3.7 and 5.0 years before the onset of MCI, respectively. Out of 63 volunteers who converted to MCI and had autopsy, only 28.5% had Alzheimer9s disease (AD) as the sole etiology of their dementia, while almost just as many had both AD and significant ischemic cerebrovascular disease present. Conclusions: Acceleration in WMH burden, a common indicator of cerebrovascular disease in the elderly, is a pathological change that emerges early in the pre-symptomatic phase leading to MCI. Monitoring longitudinal WMH change may thus be useful in determining those at risk for cognitive impairment and for planning strategies for introducing disease specific modifying therapies prior to dementia onset. Supported by: NIH (P30 AG08017, M01 RR000334, R01 AG024059), Department of Veterans Affairs, Storms Family Fund at the Oregon Community Foundation, T&J Meyer Foundation. Disclosure: Dr. Silbert has nothing to disclose. Dr. Dodge has nothing to disclose. Dr. Perkins has nothing to disclose. Dr. Lahna has nothing to disclose. Dr. Kaye has received personal compensation for activities with Eli Lilly & Company as a participant on a data safety and monitoring board. Dr. Kaye has received research support from Elan Corporation, Danone Medical, Bristol-Myers Squibb Company, Satoris, and Intel.

White Matter Abnormalities and Cognition in a Community Sample

White matter hyperintensities (WMH) can compromise cognition in older adults, but differences in sampling, WMH measurements, and cognitive assessments contribute to discrepant findings across studies. We examined linear and nonlinear effects of WMH volumes on cognition in 253 reasonably healthy adults. After adjusting for demographic characteristics and total brain volumes, WMH burden was not associated with cognition in those aged 20-59. In participants aged 60 and older, models accounted for > or =58% of the variance in performance on tests of working memory, processing speed, fluency, and fluid intelligence, and WMH volumes accounted for variance beyond that explained by age and other demographic characteristics. Larger increases in WMH burden over 5 years also were associated with steeper cognitive declines over the same interval. Results point to both age-related and age-independent effects of WMH on cognition in later life and suggest that the accumulation of WMH might partially explain normal age-related declines in cognition.