Amyloid burden and white matter hyperintensities mediate age-related cognitive differences

Dupont, Pénélope Sévigny; Bocti, Christian; Joannette, Maude; Lavallée, Marie Maxime; Nikelski, Jim; Vallet, Guillaume T.; Chertkow, Howard; Joubert, Sven

doi:10.1016/j.neurobiolaging.2019.08.025

Cited by 15 publications

(10 citation statements)

References 74 publications

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“…One cross-sectional study found that the severity of white matter hyperintensities fully mediated performance on semantic tasks. 47 The authors concluded that these findings reflect a role for axonal integrity in lexical-semantic retrieval. We did not find group differences on tests of episodic memory.…”

Section: Discussionmentioning

confidence: 96%

“…That is, we found weak support for an impact of CBVD on naming and fluency performance. Given the classic presentation of these 2 syndromes, we would not expect this change with increased CBVD pathology but rather by increasing the impact of AD on cognition (although an executive component cannot be discounted 47,49 ). However, there was stronger support for an effect of CBVD on dementia severity, processing speed, and working memory, which is congruent with the additive effect that we would expect, given the classic presentation of CBVD.…”

Section: Discussionmentioning

confidence: 99%

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Trajectories of Cognitive Decline in Brain Donors With Autopsy-Confirmed Alzheimer Disease and Cerebrovascular Disease

et al. 2022

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Background and Objectives:Cerebrovascular disease (CBVD) is frequently co-morbid with autopsy-confirmed Alzheimer’s disease (AD), but it’s contribution to the clinical presentation of AD remains unclear. We leveraged the National Alzheimer’s Coordinating Center (NACC) uniform and neuropathology data sets to compare the cognitive and functional trajectories of AD+/CBVD+ and AD+/CBVD- brain donors.Methods:The sample included NACC brain donors with autopsy-confirmed AD (Braak stage ≥ 3, CERAD ≥ 2) and complete Uniform Data Set (UDS) evaluations between 2005 and 2019, and most recent UDS evaluation within two years of autopsy. CBVD was defined as moderate to severe arteriosclerosis or atherosclerosis. We employed propensity score weighting to isolate the effects of co-morbid AD and CBVD. This method improved the balance of covariates between AD+/CBVD+ and AD+/CBVD- groups. Longitudinal mixed-effects models were assessed with robust Bayesian estimation. UDS neuropsychological tests and the Clinical Dementia Rating Scale Sum of Boxes (CDR®-SB) were primary outcomes.Results:Of 2,423 brain donors, 1,476 were classified as AD+/CBVD+. Compared with AD+/CVBD- donors, the AD+/CBVD+ group had accelerated decline (i.e., group x time effects) on measures of processing speed (β = -0.93, 95%CI [-1.35, -0.51], Bayes factor [BF] = 130.75), working memory (β = 0.05, 95%CI [0.02, 0.07], BF = 3.59), verbal fluency (β = 0.10, 95%CI [0.04, 0.15], BF = 1.28), naming (β = 0.09, 95%CI [0.03, 0.16], BF = 0.69), and CDR®-SB (β = -0.08, 95%CI [-0.12, -0.05], BF = 18.11). Effects ranged from weak (BFs < 3.0) to strong (BFs < 150). We also found worse performance in the AD+/CBVD+ group across time on naming, β = -1.04, 95%CI [-1.83, -0.25], BF = 2.52, and verbal fluency, β = -0.73, 95%CI [-1.30, -0.15], BF = 1.34, and more impaired CDR®-SB scores, β = 0.45, 95%CI [0.01, 0.89], BF = 0.33.Discussion:In brain donors with autopsy confirmed AD, comorbid CBVD was associated with an accelerated functional and cognitive decline, particularly on neuropsychological tests of attention, psychomotor speed, and working memory. CBVD magnified effects of AD neuropathology on semantic-related neuropsychological tasks. Findings support a prominent additive and more subtle synergistic effect for co-morbid CBVD neuropathology in AD.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Trajectories of Cognitive Decline in Brain Donors With Autopsy-Confirmed Alzheimer Disease and Cerebrovascular Disease

et al. 2022

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“…The additive or interactive relationship between cerebrovascular lesions, such as WMH, and Alzheimer’s pathology, including Aβ, is still debated. There are arguments supporting additive and independent effects of those lesions [ 50 – 52 ] while other studies argue that WMH and Aβ have synergistic associations with cognition [ 25 , 26 , 53 ]. The present study is not designed to address this specific question.…”

Section: Discussionmentioning

confidence: 99%

“…Recent findings even showed linear increase in amyloid PET tracer binding from 20 to 60 years old [17]. The association between WMH and cortical Aβ is still debated [18][19][20][21] with some studies suggesting that WMH and cortical Aβ are independent and additive pathological processes leading to cognitive deficits while others propose that the lesions interact and have synergistic effects on cognition [19,[22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

White matter hyperintensities across the adult lifespan: relation to age, Aβ load, and cognition

Garnier‐Crussard¹,

Bougacha²,

Wirth³

et al. 2020

Alz Res Therapy

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Background White matter hyperintensities (WMH) are very frequent in older adults and associated with worse cognitive performance. Little is known about the links between WMH and vascular risk factors, cortical β-amyloid (Aβ) load, and cognition in cognitively unimpaired adults across the entire lifespan, especially in young and middle-aged adults. Methods One hundred and thirty-seven cognitively unimpaired adults from the community were enrolled (IMAP cohort). Participants underwent (i) a comprehensive neuropsychological assessment of episodic memory, processing speed, working memory, and executive functions; (ii) brain structural T1 and FLAIR MRI scans used for the automatic segmentation of total and regional (frontal, parietal, temporal, occipital, and corpus callosum) WMH; and (iii) a Florbetapir-PET scan to measure cortical Aβ. The relationships of total and regional WMH to age, vascular risk factors, cortical Aβ, and cognition were assessed within the whole sample, but also splitting the sample in two age groups (≤ or > 60 years old). Results WMH increased with age across the adult lifespan, i.e., even in young and middle-aged adults. Systolic blood pressure, diastolic blood pressure, and glycated hemoglobin were all associated with higher WMH before, but not after, adjusting for age and the other vascular risk factors. Higher frontal, temporal, and occipital WMH were associated with greater Aβ, but this association was no longer significant when adjusting for age and vascular risk factors. Higher total and frontal WMH were associated with worse performance in executive functions, with no interactive effect of the age group. In contrast, there was a significant interaction of the age group on the link between WMH and working memory, which was significant within the subgroup of young/middle-aged adults only. Adding cortical Aβ load in the models did not alter the results, and there was no interaction between WMH and Aβ on cognition. Conclusion WMH increased with age and were associated with worse executive functions across the adult lifespan and with worse working memory in young/middle-aged adults. Aβ load was weakly associated with WMH and did not change the relationship found between WMH and executive functions. This study argues for the clinical relevance of WMH across the adult lifespan, even in young and middle-aged adults with low WMH.

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“…Older adults without cognitive impairment also commonly have evidence of small vessel cerebrovascular disease (CVD) [2]. Whereas 39 the pathological hallmarks of AD are plaques and 40 tangles (primarily consisting of the accumulation of results, with some studies observing cross-sectional associations between WMH load and amyloid among cognitively normal participants [22] and other studies not finding such relationships [23][24][25][26].…”

Section: Introduction 34mentioning

confidence: 99%

Regional White Matter Hyperintensities and Alzheimer’s Disease Biomarkers Among Older Adults with Normal Cognition and Mild Cognitive Impairment

Newton

Tchounguen

Pettigrew

et al. 2023

JAD

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Background: Alzheimer’s disease (AD) frequently co-occurs with other brain pathologies. Recent studies suggest there may be a mechanistic link between AD and small vessel cerebrovascular disease (CVD), as opposed to simply the overlap of two disorders. Objective: We investigated the cross-sectional relationship between white matter hyperintensity (WMH) volumes (markers of CVD) and cerebrospinal fluid (CSF) biomarkers of AD. Methods: WMH volumes were assessed globally and regionally (i.e., frontal, parietal, temporal, occipital, and limbic). CSF AD biomarkers (i.e., Aβ 40, Aβ 42, Aβ 42/Aβ 40 ratio, phosphorylated tau-181 [p-tau181], and total tau [t-tau]) were measured among 152 non-demented individuals (134 cognitively unimpaired and 18 with mild cognitive impairment (MCI)). Results: Linear regression models showed that among all subjects, higher temporal WHM volumes were associated with AD biomarkers (higher levels of p-tau181, t-tau, and Aβ 40), particularly among APOE ɛ 4 carriers (independent of Aβ 42 levels). Higher vascular risk scores were associated with greater parietal and frontal WMH volumes (independent of CSF AD biomarker levels). Among subjects with MCI only, parietal WMH volumes were associated with a lower level of Aβ 42/Aβ 40. In addition, there was an association between higher global WMH volumes and higher CSF t-tau levels among younger participants versus older ones (∼<65 versus 65+ years), independent of Aβ 42/Aβ 40 and p-tau181. Conclusion: These findings suggest that although WMH are primarily related to systemic vascular risk and neurodegeneration (i.e., t-tau), AD-specific pathways may contribute to the formation of WMH in a regionally-specific manner, with neurofibrillary tangles (i.e., p-tau) playing a role in temporal WMHs and amyloid (i.e., Aβ 42/Aβ 40) in parietal WMHs.

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Amyloid burden and white matter hyperintensities mediate age-related cognitive differences

Cited by 15 publications

References 74 publications

Trajectories of Cognitive Decline in Brain Donors With Autopsy-Confirmed Alzheimer Disease and Cerebrovascular Disease

Trajectories of Cognitive Decline in Brain Donors With Autopsy-Confirmed Alzheimer Disease and Cerebrovascular Disease

White matter hyperintensities across the adult lifespan: relation to age, Aβ load, and cognition

Regional White Matter Hyperintensities and Alzheimer’s Disease Biomarkers Among Older Adults with Normal Cognition and Mild Cognitive Impairment

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