Arterial Stiffness and β-Amyloid Progression in Nondemented Elderly Adults

Hughes, Timothy M.; Kuller, Lewis H.; Barinas‐Mitchell, Emma; McDade, Eric; Klunk, William E.; Cohen, Ann D.; Mathis, Chester A.; DeKosky, Steven T.; Price, Julie C.; López, Oscar L.

doi:10.1001/jamaneurol.2014.186

Cited by 164 publications

(148 citation statements)

References 35 publications

Supporting

Mentioning

139

Contrasting

Unclassified

Order By: Relevance

“…In a study of elderly individuals without dementia, higher arterial stiffness and blood pressure were associated with higher β-amyloid deposition and more severe subclinical SVD [45]. 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.…”

Section: Perspectivesmentioning

confidence: 99%

Aortic Stiffness, Cerebrovascular Dysfunction, and Memory

Cooper

Mitchell

2016

Pulse

View full text Add to dashboard Cite

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.

show abstract

Section: Perspectivesmentioning

confidence: 99%

Aortic Stiffness, Cerebrovascular Dysfunction, and Memory

Cooper

Mitchell

2016

Pulse

View full text Add to dashboard Cite

show abstract

“…Several other effects of hypertension may also play a role. These could include impaired perivascular drainage as a consequence of collagenous thickening and reduced pulsatility of arteries and arterioles [48][49][50]; reduced receptor-mediated transport of Aβ across the endothelium into the bloodstream; degeneration of pericytes [51], leading to reduced clearance of soluble Aβ40 and Aβ42 from the interstitial fluid [52];…”

Section: Groups (Supplementarymentioning

confidence: 99%

Effects of Hypertension and Anti-Hypertensive Treatment on Amyloid-β (Aβ) Plaque Load and Aβ-Synthesizing and Aβ-Degrading Enzymes in Frontal Cortex

Ashby

Miners

Kehoe

et al. 2016

JAD

View full text Add to dashboard Cite

Epidemiological data associate hypertension with a predisposition to Alzheimer's disease (AD) and a number of post-mortem and in vivo studies also demonstrate that hypertension increases amyloid-beta (Aβ) pathology. In contrast anti-hypertensive medications reportedly improve cognition and decrease the risk of AD, while certain classes of anti-hypertensive drugs are associated with decreased AD-related pathology. We investigated the effects of hypertension and anti-hypertensive treatment on Aβ plaque load in post-mortem frontal cortex in AD. Aβ load was significantly increased in hypertensive (N = 20) relative to normotensive cases (N = 62) and was also significantly higher in treated (N = 9) than untreated hypertensives (N = 11). We then looked into mechanisms by which hypertension and treatment might increase Aβ load, focusing on Aβ-synthesising enzymes, β-and γ-secretase, and Aβ-degrading enzymes, angiotensin-converting enzyme (ACE), insulin-2 degrading enzyme (IDE) and neprilysin. ACE and IDE protein levels were significantly lower in hypertensive (N = 21) than normotensive cases (N = 64), perhaps translating to decreased Aβ catabolism in hypertensives. ACE level was significantly higher in treated (N = 9) than untreated hypertensives (N = 12), possibly reflecting feedback upregulation of the reninangiotensin system. Prospective studies in larger cohorts stratified according to antihypertensive drug class are needed to confirm these initial findings and to elucidate the interactions between hypertension, anti-hypertensive treatments and Aβ metabolism.Keywords: Alzheimer's disease, amyloid β protein, anti-hypertensive, hypertension, β-secretase, BACE, γ-secretase, angiotensin-converting enzyme, insulin-degrading enzyme Abbreviations: Aβ = amyloid-beta; AβPP = amyloid-beta precursor protein; ACE = angiotensin-converting enzyme; ACEI = angiotensin-converting enzyme inhibitor; AD = Alzheimer's disease; AngII = angiotensin II; ARB = angiotensin receptor blocker; BBB = blood brain barrier; CCB = calcium channel blocker; IDE = insulin-degrading enzyme; NEP = neprilysin; NFT = neurofibrillary tangle

show abstract

“…There is also strong evidence from observational and experimental studies that CAA and arteriolosclerotic small vessel disease (SVD) impede the clearance of interstitial solutes (including Aβ) from the brain 20, 21, 22, 59, 60. Hughes et al 23 found that arterial stiffness in elderly nondemented people correlated with the amount of cerebral Aβ, as demonstrated by Aβ‐positron emission tomography. Kester et al 27 showed that the level of Aβ42 in the CSF in nondemented elderly people was lower in those with ischaemic WM abnormalities on magnetic resonance imaging (reduction in Aβ42 in the CSF being associated with increased AD pathology).…”

Section: Introductionmentioning

confidence: 99%

Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease

2015

View full text Add to dashboard Cite

The earliest decline in cerebral perfusion in Alzheimer's disease (AD) is in the medial parietal cortex (precuneus). We have analyzed precuneus in post‐mortem tissue from 70 AD and 37 control brains to explore the pathophysiology of the hypoperfusion: the contribution of arteriolosclerotic small vessel disease (SVD) and cerebral amyloid angiopathy (CAA), and of the vasoconstrictors endothelin‐1 (EDN1) and angiotensin II (Ang II), and the association with Aβ. The myelin‐associated glycoprotein:proteolipid protein‐1 ratio (MAG:PLP1) was used as an indicator of oxygenation of the precuneus prior to death. MAG:PLP1 was reduced ∼50% in early AD (Braak stage III–IV). Although MAG:PLP1 remained low in advanced AD (stage V–VI), the reduction was less pronounced, possibly reflecting falling oxygen demand. Reduction in cortical MAG:PLP1 correlated with elevation in vascular endothelial growth factor (VEGF), another marker of hypoperfusion. Cortical MAG:PLP1 declined nonsignificantly with increasing SVD and CAA, but significantly with the concentration of EDN1, which was elevated approximately 75% in AD. In contrast, with reduction in cortical MAG:PLP1, Ang II level and angiotensin‐converting enzyme (ACE) activity declined, showing a normal physiological response to hypoperfusion. MAG:PLP1 was reduced in the parietal white matter (WM) in AD but here the decline correlated positively (ie, physiologically) with WM EDN1. However, the decline of MAG:PLP1 in the WM was associated with increasing cortical EDN1 and perhaps reflected vasoconstriction of perforating arterioles, which traverse the cortex to perfuse the WM. EDN1 in the cortex correlated highly significantly with both soluble and insoluble Aβ42, shown previously to upregulate neuronal endothelin‐converting enzyme‐2 (ECE2), but not with Aβ40. Our findings demonstrate reduced oxygenation of the precuneus in early AD and suggest that elevated EDN1, resulting from Aβ42‐mediated upregulation of ECE2, is a contributor.

show abstract

Arterial Stiffness and β-Amyloid Progression in Nondemented Elderly Adults

Cited by 164 publications

References 35 publications

Aortic Stiffness, Cerebrovascular Dysfunction, and Memory

Aortic Stiffness, Cerebrovascular Dysfunction, and Memory

Effects of Hypertension and Anti-Hypertensive Treatment on Amyloid-β (Aβ) Plaque Load and Aβ-Synthesizing and Aβ-Degrading Enzymes in Frontal Cortex

Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease

Contact Info

Product

Resources

About