Regional White Matter Hyperintensity Volume, Not Hippocampal Atrophy, Predicts Incident Alzheimer Disease in the Community

Brickman, Adam M.; Provenzano, Frank A.; Muraskin, Jordan; Manly, Jennifer J.; Blum, Sonja; Apa, Zoltan L.; Stern, Yaakov; Brown, Truman R.; Luchsinger, José A.; Mayeux, Richard

doi:10.1001/archneurol.2012.1527

Cited by 212 publications

(211 citation statements)

References 35 publications

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“…25 In addition, parietal WMH volume has been shown to predict incident dementia independent of hippocampal volume. 26 Our findings suggest that PVWMH are a risk marker for cognitive deterioration both by amyloid-related and independent mechanisms. Previous studies exploring the association between pathologic and in vivo biomarkers of Ab load and WMH have shown conflicting results.…”

mentioning

confidence: 58%

Periventricular hyperintensities are associated with elevated cerebral amyloid

Marnane¹,

Aljawadi²,

Mortazavi³

et al. 2016

Neurology

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Objective: To investigate the association between periventricular white mater hyperintensities (PVWMH) and biomarkers of elevated cerebral b-amyloid (Ab) in the Alzheimer's Disease Neuroimaging Initiative, a large prospective multicenter observational study. Methods:The burden of frontal, parietal, and occipital PVWMH on 3T fluid-attenuated inversion recovery MRI was evaluated in 698 cognitively normal participants and participants with mild cognitive impairment (MCI) using a novel semiquantitative visual rating scale. Results were correlated with CSF-Ab, florbetapir-PET, and fluorodeoxyglucose (FDG)-PET.Results: Increased burden of parietal, occipital, and frontal PVWMH was associated with elevated cerebral amyloid evidenced by high florbetapir-PET signal (p , 0.01) and low CSF-Ab (p , 0.01).In logistic regression models, including PVWMH, age, sex, APOE status, vascular risk factors, pulse pressure, vascular secondary prevention medications, education, ethnicity, and race, parietal, occipital, and frontal PVWMH burden was independently associated with high florbetapir-PET uptake (p , 0.05). In a similar logistic regression model, parietal and occipital (p , 0.05) but not frontal (p 5 0.05) PVWMH were independently associated with CSF-Ab. Weaker associations were found between parieto-occipital PVWMH and elevated CSF-tau (p , 0.05) and occipital PVWMH and elevated CSF-phospho-tau (p , 0.05). PVWMH were associated with cerebral hypometabolism on FDG-PET independent of CSF-Ab levels (p , 0.05). Absolute and consistency of agreement intraclass correlation coefficients were, respectively, 0.83 and 0.83 for frontal, 0.78 and 0.8 for parietal, and 0.45 and 0.75 for occipital PVWMH measurements.Conclusions: Increased PVWMH were associated with elevated cerebral amyloid independent of potential confounders such as age, APOE genotype, and vascular risk factors. The mechanisms underlying the association between PVWMH and cerebral amyloid remain to be clarified. Pathologic and imaging studies have shown that in Alzheimer disease (AD), cerebral small vessel disease (SVD) is coexistent in up to 80% and hastens cognitive deterioration.1 Whether this reflects parallel neuronal injury or synergistic worsening of AD pathogenic mechanisms remains unclear. 2There has been recent interest in the putative role of SVD in disruption of physiologic interstitial fluid bulk flow and paravascular mechanisms of b-amyloid (Ab) clearance.3 If SVD is an

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mentioning

confidence: 58%

Periventricular hyperintensities are associated with elevated cerebral amyloid

Marnane¹,

Aljawadi²,

Mortazavi³

et al. 2016

Neurology

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“…32 WMLs, as markers of small vessel disease, are independent predictors of dementia. 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.…”

Section: Resultsmentioning

confidence: 99%

“…13 Furthermore, white matter lesions (WMLs), as markers of small vessel disease, are also risk factors for MCI 14 and incident dementia. 15 WMLs, but not smaller hippocampal volume, may predict incident AD, 16 and cross-sectional studies found that neurodegeneration is associated with WMLs 12,17 but not amyloid deposition. 12 Thus, the sequence of pathologic events in the transition from normal cognition to dementia is complex; some individuals may progress to AD with asynchronous patterns of amyloidosis and neurodegeneration, with or without small vessel disease.…”

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confidence: 98%

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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“…White matter hyperintensities (WMH), alterations in brain white matter identified via magnetic resonance imaging (MRI), are common in old age and associated with cognitive impairment and dementia 1, 2, 3, 4, 5, 6, 7. However, the relation of WMH with the risk of developing mild cognitive impairment (MCI), often the precursor to Alzheimer's disease, remains unclear.…”

Section: Introductionmentioning

confidence: 99%

White matter hyperintensities, incident mild cognitive impairment, and cognitive decline in old age

Boyle

Fleischman

et al. 2016

Ann Clin Transl Neurol

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ObjectiveExamine the association of white matter hyperintensities (WMH) with risk of incident mild cognitive impairment (MCI) and rate of decline in multiple cognitive systems in community‐based older persons.MethodsParticipants (n = 354) were older persons initially free of cognitive impairment from two ongoing longitudinal epidemiologic studies of aging. All underwent brain magnetic resonance imaging (MRI) for quantification of WMH and gray matter volumes and detailed annual clinical evaluations including 17 cognitive tests. Proportional hazards models were used to examine the relationship between WMH and incident MCI, and mixed‐effects models were used to examine the relationship between WMH and decline in global cognition and five specific cognitive systems.ResultsDuring up to about 6 years of follow‐up (mean = 4.1), 106 (30% of 354) persons developed MCI. In a proportional hazards model adjusted for age, gender, and education, WMH volume was associated with a substantially increased risk of MCI (P < 0.001). Thus, a person with a high WMH volume (90th percentile) was about 2.7 times more likely to develop MCI compared to a person with a low volume (10th percentile). WMH volume also was associated with an increased rate of decline in global cognition (P < 0.001), perceptual speed, working memory, episodic memory, and semantic memory. Associations persisted after adjustment for total gray matter volume, vascular risk factors, and vascular diseases.Interpretation WMH contribute to the development of MCI and are associated with progressive decline in multiple cognitive systems in old age.

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Regional White Matter Hyperintensity Volume, Not Hippocampal Atrophy, Predicts Incident Alzheimer Disease in the Community

Cited by 212 publications

References 35 publications

Periventricular hyperintensities are associated with elevated cerebral amyloid

Periventricular hyperintensities are associated with elevated cerebral amyloid

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

White matter hyperintensities, incident mild cognitive impairment, and cognitive decline in old age

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