The effect of white matter hyperintensities on neurodegeneration in mild cognitive impairment

Tosto, Giuseppe; Zimmerman, Molly E.; Hamilton, Jamie; Carmichael, Owen; Brickman, Adam M.

doi:10.1016/j.jalz.2015.05.014

Cited by 89 publications

(82 citation statements)

References 54 publications

(54 reference statements)

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“…The present study showed that WMH increased odds for dementia (and ADNP) in participants with autopsy-confirmed ADNP above and beyond the contributions of APOE ε4 carrier status. These findings extend in vivo studies that associate WMH with accelerated cognitive decline and brain atrophy, and increased risk for AD dementia [23–28,31,32,68], but were without autopsy confirmation of underlying ADNP. Taken together, the present findings corroborate recent research studies that propose WMH to be a contributor to the pathogenesis of AD [30,35].…”

Section: Discussionsupporting

confidence: 78%

“…Previous studies that have examined the association between WMH and CSF total tau in AD dementia also provide evidence that WMH promote tau pathology and exacerbate the effects of tau on clinical status; additionally, the relationship between WMH and CSF total tau may be independent of beta-amyloid [32,69]. WMH are typically interpreted to be MRI markers of small vessel CBVD, which may explain their association with ADNP.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study proposed that the underlying pathologies of WMH are a core feature of AD, based on findings that participants with autosomal-dominant AD had increased burden of WMH long before clinical symptom onset and WMH predicted CSF beta-amyloid levels in mutation carriers only [30]. WMH have been shown to predict increased CSF total tau and progressive medial temporal lobe atrophy in AD [31,32], as well as PET cortical amyloid uptake in older adults [16,33] and individuals with AD dementia [34], even more so than traditional AD neuroimaging and cognitive biomarkers [33]. The spatial distribution of WMH in AD has also been shown to be distinct from that found in “normal aging” [35–39], suggesting that WMH may have some degree of specificity to AD.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Alosco

Sugarman

Besser

et al. 2018

JAD

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“…It has been suggested from this data that WMHs, by interacting with tau abnormalities, may exert direct pathological influence on the development and progression of dementia (Tosto et al, 2015). The pathology underlying WMHs is traditionally associated with cerebrovascular changes and compromised integrity of the blood brain barrier, which together result in a region of poor perfusion and thus enhanced MRI signals (Black et al, 2009; Young et al, 2008).…”

Section: Loss Of Myelination Is a Pathological Hallmark Of The Agimentioning

confidence: 78%

DNA damage in the oligodendrocyte lineage and its role in brain aging

Tse

Herrup

2017

Mechanisms of Ageing and Development

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Myelination is a recent evolutionary addition that significantly enhances the speed of transmission in the neural network. Even slight defects in myelin integrity impair performance and enhance the risk of neurological disorders. Indeed, myelin degeneration is an early and well-recognized neuropathology that is age associated, but appears before cognitive decline. Myelin is only formed by fully differentiated oligodendrocytes, but the entire oligodendrocyte lineage are clear targets of the altered chemistry of the aging brain. As in neurons, unrepaired DNA damage accumulates in the postmitotic oligodendrocyte genome during normal aging, and indeed may be one of the upstream causes of cellular aging - a fact well illustrated by myelin co-morbidity in premature aging syndromes arising from deficits in DNA repair enzymes. The clinical and experimental evidence from Alzheimer's disease, progeroid syndromes, ataxia-telangiectasia and other conditions strongly suggest that oligodendrocytes may in fact be uniquely vulnerable to oxidative DNA damage. If this damage remains unrepaired, as is increasingly true in the aging brain, myelin gene transcription and oligodendrocyte differentiation is impaired. Delineating the relationships between early myelin loss and DNA damage in brain aging will offer an additional dimension outside the neurocentric view of neurodegenerative disease.

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“…In addition, another study by Tosto et al 37 demonstrated that white matter hyperintensities promote tau accumulation and not vice versa, further proving that cerebrovascular changes precede LOAD-related neurodegenerative processes. The protective effect of hypertension on LOAD and its association with stroke, which in turn increases the risk for LOAD, depicts a complex scenario of multiple intercorrelated causal effects that cannot be reduced to a single variable-outcome association.…”

Section: Discussionmentioning

confidence: 95%

The Role of Cardiovascular Risk Factors and Stroke in Familial Alzheimer Disease

et al. 2016

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The effect of white matter hyperintensities on neurodegeneration in mild cognitive impairment

Cited by 89 publications

References 54 publications

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

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

DNA damage in the oligodendrocyte lineage and its role in brain aging

The Role of Cardiovascular Risk Factors and Stroke in Familial Alzheimer Disease

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