Periventricular hyperintensities are associated with elevated cerebral amyloid

Marnane, Michael; Aljawadi, Osama; Mortazavi, Shervin; K, Pogorzelec; Wang, Bing Wei; Feldman, Howard; Hsiung, Ging-Yuek Robin

doi:10.1212/wnl.0000000000002352

Cited by 74 publications

(59 citation statements)

References 35 publications

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“…With regards to candidate gene analysis the most remarkable finding was a negative association between methylation at cg25748868 in TREM2 and WMH (standardized regression coefficient = -11,3, p = 3.9-E03); however, this did not survive Bonferroni correction for multiple testing (a <1.1E-03) and neither did any of the other tested comparisons (full data not shown). WMH load has been consistently associated with AD; TREM2 hypomethylation and overexpression have been previously observed when comparing blood samples of AD and controls, while increased TREM2 methylation and hydroxymethylation have been observed in AD brain [34][35][36][37][38]. Overall it is likely that previously identified associations between cell composition and Parkinson's disease as well as methylation and expression changes in ABCA7, TREM2 and SNCA with AD and SNCA methylation with dementia with Lewy bodies are specific for those conditions and thus not present in our dataset [27,34,[39][40][41].…”

Section: Resultsmentioning

confidence: 78%

Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

et al. 2018

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Aim:The present study investigated the link between peripheral DNA methylation (DNAm), cognitive impairment and brain aging. Methods: We tested the association between blood genome-wide DNAm profiles using the Illumina 450K arrays, cognitive dysfunction and brain MRI measures in selected participants of the Whitehall II imaging sub-study. Results: Eight differentially methylated regions were associated with cognitive impairment. Accelerated aging based on the Hannum epigenetic clock was associated with mean diffusivity and global fractional anisotropy. We also identified modules of co-methylated loci associated with white matter hyperintensities. These co-methylation modules were enriched among pathways relevant to β-amyloid processing and glutamatergic signaling. Conclusion: Our data support the notion that blood DNAm changes may have utility as a biomarker for cognitive dysfunction and brain aging. DNA methylation (DNAm) changes have been linked with the pathophysiology of brain aging, Alzheimer's disease (AD) and other types of dementia [1,2]. Considering the relative stability of DNAm and the fact that it is directly modulated by both underlying genetic sequence and environmental exposures it appears as a promising peripheral biomarker for brain-related changes [3]. Peripheral changes in mRNA and proteins that are downstream of DNAm regulation further support this concept [4,5]. Studies have shown differences in blood DNAm when comparing AD subjects with controls [6], but interestingly when looking at specific genes there is little overlap between brain and blood DNAm changes in AD [7,8]. However, a good peripheral biomarker does not have to mirror disease-associated changes in the brain; it could also simply represent a peripheral response to central pathology. At present, there is limited data available on the potential utility of peripheral DNAm as a marker for cognitive decline before the onset of dementia. One study of patients with Type 2 diabetes mellitus who later developed presymptomatic dementia highlighted leukocyte DNAm changes that were comparable to changes identified in blood in AD patients and could thus potentially represent early markers of dementia [9]. Recently DNAm epigenetic clocks have been developed, which provide a measure of epigenetic age, based on DNAm levels at 353 CpG sites [10] and 71 CpG sites [11], respectively. A number of studies have utilized the epigenetic age in blood, based on the DNAm epigenetic clock, to show correlations with cognitive function, white matter hyperintensities (WMH), Parkinson's disease, Down syndrome and all-cause mortality [12][13][14][15][16].

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Section: Resultsmentioning

confidence: 78%

Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

et al. 2018

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“…Ante-mortem WMH have been previously linked with more severe CAA neuropathology [77], and in vivo studies have shown MRI WMH are associated with CAA [18,78]. A previous study that induced hyperhomocysteinemia (a risk factor for stroke) in APP/PS1 transgenic mice found that congophilic amyloid deposition was reduced in the parenchyma, but increased in the vasculature, i.e., CAA [79].…”

Section: Discussionmentioning

confidence: 99%

A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer’s Disease Neuropathology

Alosco

Sugarman

Besser

et al. 2018

JAD

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Background: White matter hyperintensities (WMH) on magnetic resonance imaging have been postulated to be a core feature of Alzheimer’s disease. Clinicopathological studies are needed to elucidate and confirm this possibility. Objective: This study examined: 1) the association between ante-mortem WMH and autopsy-confirmed Alzheimer’s disease neuropathology (ADNP), 2) the relationship between WMH and dementia in participants with ADNP, and 3) the relationships among cerebrovascular disease, WMH and ADNP. Methods: The sample included 82 participants from the National Alzheimer’s Coordinating Center’s Data Sets who had quantitated volume of WMH from ante-mortem FLAIR MRI and available neuropathological data. The Clinical Dementia Rating (CDR) scale (from MRI visit) operationalized dementia status. ADNP+ was defined by moderate to frequent neuritic plaques and Braak stage III-VI at autopsy. Cerebrovascular disease neuropathology included infarcts or lacunes, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy. Results: 60/82 participants were ADNP+. Greater volume of WMH predicted increased odds for ADNP (p=0.037). In ADNP+ participants, greater WMH corresponded with increased odds for dementia (CDR≥1; p=0.038). WMH predicted cerebral amyloid angiopathy, microinfarcts, infarcts and lacunes (p’s<0.04). ADNP+ participants were more likely to have moderate-severe arteriolosclerosis and cerebral amyloid angiopathy compared to ADNP− participants (p’s<0.04). Conclusions: This study found a direct association between total volume of WMH and increased odds for having ADNP. In patients with Alzheimer’s disease, FLAIR MRI WMH may be able to provide key insight into disease severity and progression. The association between WMH and ADNP may be explained by underlying cerebrovascular disease.

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“…Thus, our findings along with previous findings provide evidence that vascular pathologies may be contributing factors to AD development, acting either independently from more classically known AD pathologies or due to a common upstream process. While some studies have found WMSA to be associated with classic AD pathologies such as cerebral amyloid [51], others have found WMSA and cerebral amyloid to be independent predictors of AD [14] and that vascular risk factors are associated with WMSA independent of CSF amyloid levels [52]. The findings of increased regional WMSA volume independent of global volume suggests that there is something unique about AD that results in this regional WMSA accumulation, and that WMSA do not simply represent a comorbid vascular condition that is found to be heightened in individuals with AD.…”

Section: Discussionmentioning

confidence: 99%

Differential Regional Distribution of Juxtacortical White Matter Signal Abnormalities in Aging and Alzheimer’s Disease

Lindemer

Greve

Fischl

et al. 2017

JAD

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Background White matter signal abnormalities (WMSA) (also known as ‘hyperintensities’) on MRI are commonly seen in normal aging and increases have been noted in Alzheimer’s disease (AD), but whether there is a spatial specificity to these increases is unknown. Objective To discern whether or not there is a spatial pattern of WMSA in the brains of individuals with AD that differs from those who exhibit cognitively healthy aging. Method Structural MRI data from the Alzheimer’s Disease Neuroimaging Initiative public database were used to quantify WMSA in 35 regions of interest (ROIs). Regional measures were compared between cognitively healthy older controls (OC; n = 107) and individuals with a clinical diagnosis of AD (n = 127). Regional WMSA volume was also assessed in individuals with mild cognitive impairment (MCI; n = 74) who were 6, 12, and 24 months away from AD conversion. Results WMSA volume was significantly greater in AD compared to OC in 24 out of 35 ROIs after controlling for age, and nine were significantly higher after normalizing for total WMSA. Regions with greater WMSA volume in AD included rostral frontal, inferior temporal, and inferior parietal WM. In MCI, frontal and temporal regions demonstrated significantly greater WMSA volume with decreasing time-to-AD-conversion. Discussion Individuals with AD have greater regional volume of WMSA compared to OC regardless of age or total WMSA volume. Accumulation of regional WMSA is linked to time to AD conversion in individuals with MCI. These findings indicate WMSA is an important pathological component of AD development.

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Periventricular hyperintensities are associated with elevated cerebral amyloid

Cited by 74 publications

References 35 publications

Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer’s Disease Neuropathology

Differential Regional Distribution of Juxtacortical White Matter Signal Abnormalities in Aging and Alzheimer’s Disease

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