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

ABSTRACT: 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.

SUBMITTER: Habes M

PROVIDER: S-EPMC5006227 | biostudies-other | 2016 Apr

REPOSITORIES: biostudies-other

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

Habes Mohamad M Erus Guray G Toledo Jon B JB Zhang Tianhao T Bryan Nick N Launer Lenore J LJ Rosseel Yves Y Janowitz Deborah D Doshi Jimit J Van der Auwera Sandra S von Sarnowski Bettina B Hegenscheid Katrin K Hosten Norbert N Homuth Georg G Völzke Henry H Schminke Ulf U Hoffmann Wolfgang W Grabe Hans J HJ Davatzikos Christos C

Brain : a journal of neurology 20160224 Pt 4

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 atrop ...[more]

PMID: 26912649

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Project description:BackgroundWhite matter hyperintensities are an important marker of cerebral small vessel disease. This disease burden is commonly described as hyperintense areas in the cerebral white matter, as seen on T2-weighted fluid attenuated inversion recovery magnetic resonance imaging data. Studies have demonstrated associations with various cognitive impairments, neurological diseases, and neuropathologies, as well as clinical and risk factors, such as age, sex, and hypertension. Due to their heterogeneous appearance in location and size, studies have started to investigate spatial distributions and patterns, beyond summarizing this cerebrovascular disease burden in a single metric-its volume. Here, we review the evidence of association of white matter hyperintensity spatial patterns with its risk factors and clinical diagnoses.Design/methodsWe performed a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement. We used the standards for reporting vascular changes on neuroimaging criteria to construct a search string for literature search on PubMed. Studies written in English from the earliest records available until January 31st, 2023, were eligible for inclusion if they reported on spatial patterns of white matter hyperintensities of presumed vascular origin.ResultsA total of 380 studies were identified by the initial literature search, of which 41 studies satisfied the inclusion criteria. These studies included cohorts based on mild cognitive impairment (15/41), Alzheimer's disease (14/41), Dementia (5/41), Parkinson's disease (3/41), and subjective cognitive decline (2/41). Additionally, 6 of 41 studies investigated cognitively normal, older cohorts, two of which were population-based, or other clinical findings such as acute ischemic stroke or reduced cardiac output. Cohorts ranged from 32 to 882 patients/participants [median cohort size 191.5 and 51.6% female (range: 17.9-81.3%)]. The studies included in this review have identified spatial heterogeneity of WMHs with various impairments, diseases, and pathologies as well as with sex and (cerebro)vascular risk factors.ConclusionThe results show that studying white matter hyperintensities on a more granular level might give a deeper understanding of the underlying neuropathology and their effects. This motivates further studies examining the spatial patterns of white matter hyperintensities.

Project description:White matter hyperintensities negatively impact white matter structure and relate to cognitive decline in aging. Diffusion tensor imaging detects changes to white matter microstructure, both within the white matter hyperintensity and extending into surrounding (perilesional) normal-appearing white matter. However, diffusion tensor imaging markers are not specific to tissue components, complicating the interpretation of previous microstructural findings. Myelin water imaging is a novel imaging technique that provides specific markers of myelin content (myelin water fraction) and interstitial fluid (geometric mean T2). Here we combined diffusion tensor imaging and myelin water imaging to examine tissue characteristics in white matter hyperintensities and perilesional white matter in 80 individuals (47 older adults and 33 individuals with chronic stroke). To measure perilesional normal-appearing white matter, white matter hyperintensity masks were dilated in 2 mm segments up to 10 mm in distance from the white matter hyperintensity. Fractional anisotropy, mean diffusivity, myelin water fraction, and geometric mean T2 were extracted from white matter hyperintensities and perilesional white matter. We observed a spatial gradient of higher mean diffusivity and geometric mean T2, and lower fractional anisotropy, in the white matter hyperintensity and perilesional white matter. In the chronic stroke group, myelin water fraction was reduced in the white matter hyperintensity but did not show a spatial gradient in perilesional white matter. Across the entire sample, white matter metrics within the white matter hyperintensity related to whole-brain white matter hyperintensity volume; with increasing white matter hyperintensity volume there was increased mean diffusivity and geometric mean T2, and decreased myelin water fraction in the white matter hyperintensity. Normal-appearing white matter adjacent to white matter hyperintensities exhibits characteristics of a transitional stage between healthy white matter and white matter hyperintensities. This effect was observed in markers sensitive to interstitial fluid, but not in myelin water fraction, the specific marker of myelin concentration. Within the white matter hyperintensity, interstitial fluid was higher and myelin concentration was lower in individuals with more severe cerebrovascular disease. Our data suggests white matter hyperintensities have penumbra-like effects in perilesional white matter that specifically reflect increased interstitial fluid, with no changes to myelin concentration. In contrast, within the white matter hyperintensity there are varying levels of demyelination, which vary based on the severity of cerebrovascular disease. Diffusion tensor imaging and myelin imaging may be useful clinical markers to predict white matter hyperintensity formation, and to stage neuronal damage within white matter hyperintensities.

Project description:White matter hyperintensities as seen on brain T2-weighted magnetic resonance imaging are associated with varying degrees of cognitive dysfunction in stroke, cerebral small vessel disease and dementia. The pathophysiological mechanisms within the white matter accounting for cognitive dysfunction remain unclear. With the hypothesis that gliovascular interactions are impaired in subjects with high burdens of white matter hyperintensities, we performed clinicopathological studies in post-stroke survivors, who had exhibited greater frontal white matter hyperintensities volumes that predicted shorter time to dementia onset. Histopathological methods were used to identify substrates in the white matter that would distinguish post-stroke demented from post-stroke non-demented subjects. We focused on the reactive cell marker glial fibrillary acidic protein (GFAP) to study the incidence and location of clasmatodendrosis, a morphological attribute of irreversibly injured astrocytes. In contrast to normal appearing GFAP+ astrocytes, clasmatodendrocytes were swollen and had vacuolated cell bodies. Other markers such as aldehyde dehydrogenase 1 family, member L1 (ALDH1L1) showed cytoplasmic disintegration of the astrocytes. Total GFAP+ cells in both the frontal and temporal white matter were not greater in post-stroke demented versus post-stroke non-demented subjects. However, the percentage of clasmatodendrocytes was increased by >2-fold in subjects with post-stroke demented compared to post-stroke non-demented subjects (P = 0.026) and by 11-fold in older controls versus young controls (P < 0.023) in the frontal white matter. High ratios of clasmotodendrocytes to total astrocytes in the frontal white matter were consistent with lower Mini-Mental State Examination and the revised Cambridge Cognition Examination scores in post-stroke demented subjects. Double immunofluorescent staining showed aberrant co-localization of aquaporin 4 (AQP4) in retracted GFAP+ astrocytes with disrupted end-feet juxtaposed to microvessels. To explore whether this was associated with the disrupted gliovascular interactions or blood-brain barrier damage, we assessed the co-localization of GFAP and AQP4 immunoreactivities in post-mortem brains from adult baboons with cerebral hypoperfusive injury, induced by occlusion of three major vessels supplying blood to the brain. Analysis of the frontal white matter in perfused brains from the animals surviving 1-28 days after occlusion revealed that the highest intensity of fibrinogen immunoreactivity was at 14 days. At this survival time point, we also noted strikingly similar redistribution of AQP4 and GFAP+ astrocytes transformed into clasmatodendrocytes. Our findings suggest novel associations between irreversible astrocyte injury and disruption of gliovascular interactions at the blood-brain barrier in the frontal white matter and cognitive impairment in elderly post-stroke survivors. We propose that clasmatodendrosis is another pathological substrate, linked to white matter hyperintensities and frontal white matter changes, which may contribute to post-stroke or small vessel disease dementia.

Dataset Information

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

Publications

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

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