Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly

Vemuri, Prashanthi; Lesnick, Timothy G.; Przybelski, Scott A.; Knopman, David S.; Preboske, Greg M.; Kantarci, Kejal; Raman, Mekala R.; Machulda, Mary M.; Mielke, Michelle M.; Lowe, Val J.; Senjem, Matthew L.; Gunter, Jeffrey L.; Rocca, Walter A.; Roberts, Rosebud O.; Petersen, Ronald C.; Jack, Clifford R.

doi:10.1093/brain/awu393

Cited by 240 publications

(234 citation statements)

References 77 publications

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“…To argue that disproportionate vascular disease explains the current findings, vascular risk factors would need to have contributed to elevated brain amyloid, despite lack of evidence for this association. 25,26 If vascular and AD processes are simply additive, one would have predicted, in this study of individuals without dementia, less brain amyloid in blacks compared to whites (since more vascular disease is found in blacks, and, to have relatively normal cognition, high amounts of both amyloid and vascular disease would be unlikely). Thus, the vascular mechanism story does not fit the current observations.…”

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confidence: 80%

The ARIC-PET amyloid imaging study

et al. 2016

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Objective: To evaluate differences in amyloid deposition in a community-based cohort without dementia by age, sex, race, education, and APOE e4 allele status. Methods:Recruited from the longitudinal Atherosclerosis Risk in Communities study, 329 participants without dementia, ages 67-88 years, were imaged using florbetapir PET at 3 US community sites (Washington County, Maryland; Forsyth County, North Carolina; and Jackson, Mississippi). Standardized uptake value ratios (SUVRs) were calculated; global cortical SUVR .1.2 was evaluated as the primary outcome. Age, race, sex, education level, and number of APOE e4 alleles were evaluated in multivariable models including vascular risk factors, brain white matter hyperintensity and total intracranial volume, and cognitive status.Results: A total of 141 of the participants (43%) were black. In multivariable models, odds of elevated SUVR was increased in participants with increasing age (odds ratio [OR] 1.63, 95% confidence interval [CI] 1.01-2.65 per 10 years of age) and black race (OR 2.08, 95% CI 1.23-3.51) but did not differ by educational level. Each e4 allele was associated with increased odds of elevated SUVR (OR 2.65, 95% CI 1.61-4.39).Conclusions: In this community-based cohort without dementia, florbetapir uptake is associated with older age and APOE genotype. Black race was associated with higher SUVR, after adjusting for demographics, vascular risk factors, cognitive status, white matter hyperintensity volume, and APOE genotype, with effect sizes nearing those seen for APOE e4. Replication of these findings is needed in other cohorts, and reasons for and consequences of these observed differences by race warrant further study. The prevailing hypothesis behind the pathophysiology of Alzheimer disease (AD) focuses on the accumulation of brain amyloid in b-amyloid (Ab) plaques as a critical mechanism. Use of PET ligands that bind to Ab allows for the evaluation of Ab in persons with or without clinical symptoms. Although a recent meta-analysis reported positive amyloid scans in 10% of healthy 50-to 90-year-old participants, and in 27% of similarly aged adults with mild cognitive impairment (MCI), 1 few studies in persons of European extraction 2,3 have evaluated patterns of Ab deposition using PET, and none in black participants, to our knowledge. Using Ab imaging in a biracial cohort would allow further exploration of racial disparities in dementia etiology.Dementia is more prevalent in blacks than in whites, 4-6 although AD-type neuropathologic findings are found on autopsy with equal prevalence in both groups. 7,8 Thus, a larger component

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confidence: 80%

The ARIC-PET amyloid imaging study

et al. 2016

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“…Here we assumed that there is minimal to no mechanistic interaction between AD and cerebrovascular measures early in the disease process 10, 11

Next, we chose an MRI modality and specific regions that satisfied all 3 criteria mentioned above (regional independence, variability, and sensitivity) as a cerebrovascular health biomarker in the discovery dataset.

In an independent validation dataset, we finally evaluated the utility of the cerebrovascular health biomarker in providing independent information about cognition in addition to amyloidosis.

…”

Section: Methodsmentioning

confidence: 99%

“…Here we assumed that there is minimal to no mechanistic interaction between AD and cerebrovascular measures early in the disease process 10, 11…”

Section: Methodsmentioning

confidence: 99%

Development of a cerebrovascular magnetic resonance imaging biomarker for cognitive aging

Vemuri

Lesnick

Przybelski

et al. 2018

Annals of Neurology

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ObjectiveRecent availability of amyloid and tau positron emission tomography (PET) has provided us with a unique opportunity to measure the association of systemic vascular health with brain health after accounting for the impact of Alzheimer disease (AD) pathologies. We wanted to quantify early cerebrovascular health–related magnetic resonance imaging brain measures (structure, perfusion, microstructural integrity) and evaluate their utility as a biomarker for cerebrovascular health.MethodsWe used 2 independent samples (discovery, n = 390; validation, n = 1,035) of individuals, aged ≥ 60 years, along the cognitive continuum with imaging from the population‐based sample of Mayo Clinic Study of Aging. We ascertained vascular health by summing up recently existing cardiovascular and metabolic conditions (CMC) from health care records (hypertension, hyperlipidemia, cardiac arrhythmias, coronary artery disease, congestive heart failure, diabetes mellitus, and stroke). Using multiple regression models, we quantified associations between CMC and brain health after accounting for age, sex, education/occupation, and AD burden (from amyloid and tau PET).ResultsSystemic vascular health was associated with medial temporal lobe thinning, widespread cerebral hypoperfusion, and loss of microstructural integrity in several white matter tracts including the corpus callosum and fornix. Further investigations suggested that microstructural integrity of the genu of the corpus callosum was suitable for assessing prodromal cerebrovascular health, had similar distributions in the discovery and independent validation datasets, and predicted cognitive performance above and beyond amyloid deposition.InterpretationSystemic vascular health has significant impact on brain structure and function. Quantifying prodromal cerebrovascular health–related brain measures that are independent of AD pathology–related changes has great utility for cognitive aging. Ann Neurol 2018;84:713–724

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“…The degree to which WMH contribute to progressive cognitive decline among older persons initially free of cognitive impairment also is poorly understood. Cross‐sectional studies have shown that WMH are associated with subtle cognitive decrements, particularly in perceptual speed and executive functions,10, 11, 12 but little data are available on the relation of WMH with cognitive decline among persons initially free of cognitive impairment 7, 13, 14, 15, 16. A better understanding of the degree to which WMH increase the risk of MCI and contribute to progressive decline in multiple cognitive systems is needed to facilitate strategies to promote cognitive health in old age.…”

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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Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly

Cited by 240 publications

References 77 publications

The ARIC-PET amyloid imaging study

The ARIC-PET amyloid imaging study

Development of a cerebrovascular magnetic resonance imaging biomarker for cognitive aging

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

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