White matter hyperintensities predict amyloid increase in Alzheimer's disease

Grimmer, Timo; Faust, Maximilian; Auer, Florian; Alexopoulos, Panagiotis; Förstl, Hans; Henriksen, Gjermund; Perneczky, Robert; Sorg, Christian; Yousefi, Behrooz H.; Drzezga, Alexander; Kurz, Alexander

doi:10.1016/j.neurobiolaging.2012.01.016

Cited by 120 publications

(104 citation statements)

References 32 publications

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“…15 Some studies found that WMLs were better predictors of dementia than hippocampal volume, 16 and others showed that WMLs were associated with increased Ab deposition in subjects with AD. 33 Cross-sectional studies have shown WMLs were associated with markers of neurodegeneration, but not with Ab deposition, 12,34 while other studies reported an association between severity of WMLs and low CSF Ab-42 levels only in APOE e4 carriers. 35 We found that WMLs are predictors of incident AD, but (as with PiB retention and neurodegeneration) there were individuals without WMLs who progressed to dementia, and others with severe WMLs who remained CN.…”

Section: Resultsmentioning

confidence: 99%

Amyloid, neurodegeneration, and small vessel disease as predictors of dementia in the oldest-old

et al. 2014

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Objective: To examine the association between brain structural changes and b-amyloid deposition, and incident dementia in 183 elderly subjects without dementia (mean age 85.5 years) 2 years later.Methods: Subjects had a brain structural MRI scan and a PET scan with 11 C-labeled Pittsburgh compound B (PiB) in 2009, and were evaluated clinically in 2011.Results: At baseline evaluation, of the 183 participants (146 cognitively normal [CN]); 37 mild cognitive impairment [MCI]), 139 (76%) were PiB1, had small hippocampal volume (,25th percentile), or had high white matter lesion (WML) volume (.75th percentile). Two years later, 111 (61%) were classified as CN, 51 (28%) as MCI, and 21 (11%) as dementia. At baseline, 51% of the CN participants and 67.5% of the MCI cases were PiB1. Thirty percent of the CN and 51% of the MCI cases had small hippocampi, and 24% of the CN and 40.5% of the MCI cases had abnormal WMLs. Of the 21 participants who progressed to dementia, 20 (95%) had at least one imaging abnormality. Only 3 (14%) were only PiB1, 1 (5%) had only small hippocampi, 1 (5%) had only WMLs, 1 (5%) was biomarker negative, and the other 16 had various pairs of imaging abnormalities. Continuous variables of PiB retention, left and right hippocampal volume, and WML volume were independent predictors of dementia in a logistic regression analysis controlling for age, sex, education level, and Mini-Mental State Examination scores. Conclusions:The prevalence of b-amyloid deposition, neurodegeneration (i.e., hippocampal atrophy), and small vessel disease (WMLs) is high in CN older individuals and in MCI. A combination of 2 or 3 of these factors is a powerful predictor of short-term incidence of dementia. Studies of cognition and neurodegeneration in the oldest-old are important because these individuals are at the highest risk of developing dementia, especially Alzheimer disease (AD). 1 Furthermore, the neurodegenerative process that causes AD begins years before the clinical expression of the syndrome.2-4 The proportion of subjects without dementia who have amyloid deposition detected in vivo is approximately 20% to 30%, 4 with rates up to 65% in those aged 80 years or older. 4,5 Amyloid deposition detected with Pittsburgh compound B (PiB) is associated with the development of AD from mild cognitive impairment (MCI), 6,7 and to MCI or AD from normal cognition. 8 Similarly, low hippocampal volume, as a marker of neurodegeneration, is associated with progression to AD in cognitively normal (CN) subjects and in those with MCI.9 It has been hypothesized that AD pathology starts with amyloid deposition, followed by neuronal loss closer

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Section: Resultsmentioning

confidence: 99%

Amyloid, neurodegeneration, and small vessel disease as predictors of dementia in the oldest-old

et al. 2014

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“…[27][28][29]31,32 However, there were also studies showing positive relationships between WMC and amyloid. 33,34 For instance, in sporadic AD patients, WMC at baseline was significantly related to the progression of amyloid deposition in 28 months, 33 suggesting that WMC might accelerate the aggregation of amyloid protein produced in situ. However, the positive association between WMC and amyloid burden seemed to be predominant in the posterior brain regions, which are not the typical topography of AD but CAA.…”

Section: Wmc and Amyloid Plaquesmentioning

confidence: 99%

“…22 Amyloid PET can detect comorbid amyloid deposition in patients with high vascular burden. 23 We reviewed the potential interactions between CVD and amyloid plaques and their relationships with cognitive impairment, with reference to in-vivo clinical studies using amyloid PET imaging [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] and autopsy studies measuring amyloid plaques.…”

mentioning

confidence: 99%

Cerebrovascular Disease, Amyloid Plaques, and Dementia

Liu

Wong

Law

et al. 2015

Stroke

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Absence of vascular dementia in an autopsy series from a dementia clinic. J Am Geriatr Soc. 1998;46:597-604. 6. Seno H, Ishino H, Inagaki T, Iijima M, Kaku K, Inata T. A neuropathological study of dementia in nursing homes over a 17-year period, in Shimane Prefecture, Japan. Gerontology. 1999;45:44-48. 7 However, an unresolved issue remains on the temporal relationship between the development of vascular and amyloid pathologies as other potential factors, such as the overproduction of Aβ caused by genetic mutations in APP and presenilin genes might also take part in the abnormal amyloid accumulation. Atherosclerosis and Amyloid PlaquesAtherosclerosis in large cerebral arteries can compromise cerebral blood flow and cause cerebral hypoperfusion. Patients with AD had a higher proportion and more pronounced atherosclerosis in the circle of Willis than those patients with non-AD dementias (except VaD) as shown in autopsy studies. 41,[55][56][57][58] Moreover, there was a high concordance between the ratings of atherosclerosis with amyloid plaques and CAA ratings. 41Through [18F] AV-45 PET examination, amyloid deposition in patients with dementia having unilateral carotid artery stenosis was increased. More importantly, the distribution of the amyloid disposition was found to be lateralized to the side of stenosis.26 Together, these clinical and pathological findings suggest that there is a shared cause between atherosclerosis and amyloid deposition. Infarcts and Amyloid PlaquesMost amyloid PET studies did not find significant relationships between infarcts and amyloid deposition. 27,28 In fact, a study showed that in patients with subcortical vascular cognitive impairment, the number of lacunes was negatively related with the PiB retention ratio. 29 In patients with recent ischemic stroke, although a relatively increased PiB retention was found in peri-infarct region comparing to the contralateral mirror region, this increased regional PiB retention did not translate into a higher global PiB retention. 30 In experimental stroke models in transgenic mouse with amyloid deposition (APPswe/PS1dE9), increase in new amyloid plaques around the infarcted area was only transient, in which the accumulation most probably reflected an impaired amyloid clearance pathway caused by infarcted tissue. 59 Moreover, the possibility that the observed increase in local PiB retention being a result of leakage of free PiB because of the blood-brain barrier damage could not be excluded. 30 Overall, thus far, there is no solid evidence of a significant interaction between cerebral infarcts and global amyloid burden. Sources of Funding

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“…76,77 Besides, WMH burden at baseline has been associated with subsequent brain amyloid deposition in a longitudinal study. 78 More subtle WM changes, such as those identified on diffusion MRI, have been associated with cognitive dysfunction in AD 79 and brain amyloid load. 80 However, there has also been reports of WMH being associated with cognitive decline but not with brain amyloid deposition or longitudinal change in AD-specific biomarkers, such as CSF Ab 42 .…”

Section: Cardiovascular Risk Factors and Cognitive Declinementioning

confidence: 99%

“…158 In one recent longitudinal study, baseline severity of white matter lesions correlated with increased PiB retention after a mean follow-up interval of 28 months. 78 The authors suggested that the association between WMH --a sign of CVD --and progression of amyloid load might be mediated by impaired amyloid clearance due to vascular damage.…”

Section: Unraveling the Relationship Between Ad And Cardiovascular Rimentioning

confidence: 99%

The link between cardiovascular risk, Alzheimer's disease, and mild cognitive impairment: support from recent functional neuroimaging studies

Ferreira

Tamashiro-Duran

Squarzoni

et al. 2014

Rev. Bras. Psiquiatr.

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Objective: To review functional neuroimaging studies about the relationship between cardiovascular risk factors (CVRFs), Alzheimer's disease (AD), and mild cognitive impairment (MCI). Methods: We performed a comprehensive literature search to identify articles in the neuroimaging field addressing CVRF in AD and MCI. We included studies that used positron emission tomography (PET), single photon emission computerized tomography (SPECT), or functional magnetic resonance imaging (fMRI). Results: CVRFs have been considered risk factors for cognitive decline, MCI, and AD. Patterns of AD-like changes in brain function have been found in association with several CVRFs (both regarding individual risk factors and also composite CVRF measures). In vivo assessment of AD-related pathology with amyloid imaging techniques provided further evidence linking CVRFs and AD, but there is still limited information resulting from this new technology. Conclusion: There is a large body of evidence from functional neuroimaging studies supporting the hypothesis that CVRFs may play a causal role in the pathophysiology of AD. A major limitation of most studies is their cross-sectional design; future longitudinal studies using multiple imaging modalities are expected to better document changes in CVRF-related brain function patterns and provide a clearer picture of the complex relationship between aging, CVRFs, and AD.

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White matter hyperintensities predict amyloid increase in Alzheimer's disease

Cited by 120 publications

References 32 publications

Amyloid, neurodegeneration, and small vessel disease as predictors of dementia in the oldest-old

Amyloid, neurodegeneration, and small vessel disease as predictors of dementia in the oldest-old

Cerebrovascular Disease, Amyloid Plaques, and Dementia

The link between cardiovascular risk, Alzheimer's disease, and mild cognitive impairment: support from recent functional neuroimaging studies

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