Aggregate effects of vascular risk factors on cerebrovascular changes in autopsy‐confirmed Alzheimer's disease

Bangen, Katherine J.; Nation, Daniel A.; Delano‐Wood, Lisa; Weissberger, Gali H.; Hansen, Lawrence A.; Galasko, Douglas; Salmon, David P.; Bondi, Mark W.

doi:10.1016/j.jalz.2013.12.025

Cited by 96 publications

(85 citation statements)

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“…Our findings that multimorbidity is not associated with biomarkers of amyloid deposition are in agreement with previous studies suggesting that Table 3 Association between multimorbidity and abnormal imaging biomarkers in cognitively normal individuals: Mayo Clinic 32 In a clinicopathologic imaging study, 37 subcortical vascular pathology and atherosclerosis contributed to lower cortical GM volume after AD pathology was considered, further suggesting the importance of vascular pathology to neurodegenerative processes. Diabetes mellitus and hypertension have also been associated with brain pathology such as ischemic lesions or atrophy in imaging studies.…”

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confidence: 90%

“…Although the exact mechanism for the association of multimorbidity with neuroimaging measures of neurodegeneration cannot be delineated in the current study, we hypothesize that known mechanisms governing the association of chronic diseases, specifically, vascular conditions such as diabetes 30 postmortem 32 biomarkers could be involved in these pathologic processes. In the present study, the most common dyads (i.e., hypertension and hyperlipidemia, hypertension and arthritis, hyperlipidemia and arthritis, hypertension and diabetes mellitus, cancer and hypertension, hyperlipidemia and diabetes mellitus) that were associated with hypometabolism and decreased cortical thickness in AD signature regions all included vascular conditions.…”

mentioning

confidence: 87%

“…This is consistent with dyads previously found to be associated with risk of incident MCI in the MCSA cohort. 3 A second hypothesis is that the aggregate effect of multiple co-occurring chronic conditions on brain pathology may differ from the simple summation of their individual effects-as suggested for example by investigators 32 for the co-presence of multiple vascular risk factors and their aggregate effect on brain pathology. As such, the insight provided by the association of multiple co-occurring conditions (i.e., multimorbidity) with antemortem brain pathology is informative and relevant for early detection and intervention for those at increased risk of brain pathology.…”

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confidence: 99%

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Multimorbidity and neuroimaging biomarkers among cognitively normal persons

et al. 2016

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Objective: To assess the cross-sectional association between multimorbidity and imaging biomarkers of brain pathology in the population-based Mayo Clinic Study of Aging (MCSA). Methods:The study consisted of 1,449 MCSA participants who were cognitively normal at the time of MRI. A subset of the participants also had 11 C-Pittsburgh compound B (n 5 689) and 18 fluorodeoxyglucose (n 5 688) PET scans available. Information on multimorbidity (defined as $2 chronic conditions) in the 5 years prior to the first imaging study was captured from the medical record using ICD-9 codes for chronic conditions and the Rochester Epidemiology Project medical records linkage system. The cross-sectional association of multimorbidity and imaging biomarkers was examined using logistic and linear regression models.Results: Among 1,449 cognitively normal participants (mean age 79 years; 50.9% men), 85.4% had multimorbidity ($2 chronic conditions). Multimorbidity and severe multimorbidity ($4 chronic conditions) were associated with abnormal Alzheimer disease (AD) signature meta-region of interest (meta-ROI) 18 Conclusions: Multimorbidity was associated with brain pathology through mechanisms independent of amyloid deposition and such neuronal injury and pathology was present before any symptomatic evidence of cognitive impairment. Longitudinal follow-up will provide insights into potential causal associations of multimorbidity with changes in brain pathology. Multimorbidity has a prevalence of 20%-30% in the general population, 1 and increases with age from 55% to 98% among persons older than 60 years.1 Multimorbidity is becoming the norm among adults in primary care settings, 2 mandating the need to investigate not only the causes, but also the association with future health outcomes. Multimorbidity is associated with an increased risk for hospitalizations and increased length of stay, worsening quality of life and physical functioning, polypharmacy, mild cognitive impairment, 3 and depression, resulting in significant economic costs for the health care system.2 Several of the common chronic conditions that contribute to multimorbidity are established risk factors for mild cognitive impairment (MCI) or dementia (e.g., vascular diseases, cerebrovascular disease, depression, or chronic obstructive pulmonary disease).3-8 We hypothesized, therefore, that multimorbidity may also be associated with abnormal brain imaging findings that are characteristically present in persons with Alzheimer disease (AD) dementia, but this association has not been studied. Thus, the objective of this study was to determine the cross-sectional associations between multimorbidity From the Departments of Health Sciences Research

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confidence: 87%

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Multimorbidity and neuroimaging biomarkers among cognitively normal persons

et al. 2016

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“…Subsequently, Hughes et al [46] showed that elevated arterial stiffness was related to progressive β-amyloid deposition in the brain of nondemented elderly adults over 2 years. In addition, Bangen et al [47] revealed that the most common forms of cerebrovascular remodeling among patients with AD were atherosclerosis at the circle of Willis and arteriosclerosis. These data emphasize that remodeling of the aorta, elevated central hemodynamic load, and the subsequent damage and dysfunction of intracranial vessels convey a cumulative effect on brain structure and function that contribute to dementias, including AD, with advancing age.…”

Section: Perspectivesmentioning

confidence: 99%

Aortic Stiffness, Cerebrovascular Dysfunction, and Memory

Cooper

Mitchell

2016

Pulse

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Background: Aortic stiffness is associated with cardiovascular and cerebrovascular events and cognitive decline. This mini-review focuses on relations of aortic stiffness with microvascular dysfunction and discusses the contribution of abnormal pulsatile hemodynamics to cerebrovascular damage and cognitive decline. We also provide a rationale for considering aortic stiffness as a putative and important contributor to memory impairment in older individuals. Summary: Aging is associated with stiffening of the aorta but not the muscular arteries, which reduces wave reflection and increases the transmission of pulsatility into the periphery. Aortic stiffening thereby impairs a protective mechanism that shields the peripheral microcirculation from excessive pulsatility within downstream target organs. Beyond midlife, aortic stiffness increases rapidly and exposes the cerebral microcirculation to abnormal pulsatile mechanical forces that are associated with microvascular damage and remodeling in the brain. Aortic stiffening and high-flow pulsatility are associated with alterations in the microvasculature of the brain; however, a mechanistic link between aortic stiffness and memory has not been established. We showed that in a community-based sample of older individuals, cerebrovascular resistance and white matter hyperintensities - markers of cerebrovascular remodeling and damage - mediated the relation between higher aortic stiffness and lower performance on memory function tests. These data suggest that microvascular and white matter damage associated with excessive aortic stiffness contribute to impaired memory function with advancing age. Key Messages: Increasing evidence suggests that vascular etiologies - including aortic stiffness and microvascular damage - contribute to memory impairment and the pathogenesis of dementia, including Alzheimer's disease. Interventions that reduce aortic stiffness may delay memory decline among older individuals.

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“…Besides that, by using a linear regression statistical approach, we could establish associations without determining normal/abnormal cutoff values in neuroimaging variables, showing that the association of comorbidities with neurodegeneration may be part of a continuum [20,21]. Interactions among vascular risk factors, frequently observed as comorbidities in older adults, are probably implicated in this pathophysiology [22,23]. Multimorbidity has been recognized as an entity by itself, exceeding the simple coexistence of multiple chronic conditions [24].…”

Section: Discussionmentioning

confidence: 97%

Multimorbidity Is Associated with Preclinical Alzheimer’s Disease Neuroimaging Biomarkers

Mendes

Montcel

Lévy

et al. 2018

Dement Geriatr Cogn Disord

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Background: Identifying comorbidities that influence preclinical Alzheimer’s disease (AD) can give some insight into the AD early stages trajectories to allow new treatment venues and to guide public health systems to prevent subsequent dementia. Objective: To examine the association of multimorbidity with AD neuroimaging markers in cognitively normal older adults. Methods: This study had a cross-sectional design. Data regarding 14 comorbidities were obtained for all 318 adults aged 70–85 years, recruited from the community to an ongoing prospective monocentric cohort. They underwent standardized neuropsychological and neuroimaging assessment with automated methods that measured hippocampal volumes, white matter hyperintensity volumes, fluorodeoxyglucose positron emission tomography (FDG-PET) standardized uptake values (SUV) in AD signature regions, and amyloid positron emission tomography (amyloid-PET) SUV ratios. Linear regression was used to assess the association of multimorbidity with AD neuroimaging biomarkers. Results: Multimorbidity is signif icantly associated with lower hippocampal volumes (–0.03 ± 0.01; p = 0.012; R² = 0.017) and lower FDG-PET SUV (–0.027 ± 0.009; p = 0.005; R² = 0.022), with no association with amyloid deposition (0.001 ± 0.007; p = 0.884; R² = 0.0001). Taken individually, obesity and excessive alcohol use are associated with lower FDG-PET values, whereas obstructive sleep apnea and mood disorders are related to lower amyloid-PET SUV ratios. Conclusion: Multimorbidity is associated with preclinical AD imaging markers of neurodegeneration, but not with amyloid.

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Aggregate effects of vascular risk factors on cerebrovascular changes in autopsy‐confirmed Alzheimer's disease

Cited by 96 publications

References 50 publications

Multimorbidity and neuroimaging biomarkers among cognitively normal persons

Multimorbidity and neuroimaging biomarkers among cognitively normal persons

Aortic Stiffness, Cerebrovascular Dysfunction, and Memory

Multimorbidity Is Associated with Preclinical Alzheimer’s Disease Neuroimaging Biomarkers

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