Common Impact of Chronic Kidney Disease and Brain Microhemorrhages on Cerebral Aβ Pathology in SHRSP

Abstract

While chronic kidney disease seems to be an independent risk factor for cognitive decline, its impact on cerebral amyloid-β (Aβ) depositions, one hallmark of Alzheimer's Disease (AD) pathology, has not been investigated. Utilizing 80 male nontransgenic spontaneously hypertensive stroke prone rats (SHRSP) at various ages (12 to 44 weeks), tubulointerstitial renal damage, prevalence of cerebral microhemorrhages and Aβ accumulations were quantified. Using age-adjusted general linear models we investigated the main and interaction effects of renal damage and cerebral microhemorrhages on cerebral Aβ load. In addition, using post mortem human brain tissue of 16 stroke patients we examined the co-localization of perivascular Aβ deposits and small vessel wall damage. Statistical models revealed an age-independent main effect of tubulointerstitial kidney damage on brain Aβ accumulations, which was reinforced by the consecutive presence of cerebral microhemorrhages. Moreover, cerebral microhemorrhages independently predicted brain Aβ burden in SHRSP. In up to 69% of all human cases perivascular Aβ deposits were detected in the direct vicinity of small vessel wall damage. Our results support the associations between vascular pathology and Aβ deposition, and demonstrate a relationship between chronic kidney disease and cerebral Aβ pathology. Hence, our data suggest that prevention of chronic renal damage may reduce cerebral Aβ pathology.

Invited Review: The spectrum of age‐related small vessel diseases: potential overlap and interactions of amyloid and nonamyloid vasculopathies

“…By now, there is quite common acceptance that DPA is initiated by endothelial damage and BBB breakdown , which so far is in general not considered when investigating human autopsy tissue. In DPA animal models, BBB integrity loss is commonly found in the same cortical areas affected by CAA . Furthermore, its association with cortical atrophy and cortical microinfarcts (see above) supports the idea that DPA is a mixed cortical‐subcortical instead of a pure subcortical condition.…”

Corticosteroid Treatment Guided by Peripheral Blood Mononuclear Cell Counts in Cerebral Amyloid Angiopathy-related Inflammation: A Case Report

“…Amyloid-related pathology and hypertensive cerebral small vessel disease have synergistic effects on the progression of lobar microbleeds [15]. There is also evidence from animal studies for an age-independent effect of tubulointerstitial kidney damage on brain Aβ accumulation, which can be reinforced by the co-presence of cerebral microhemorrhages [16].…”

Behavioral Changes During Development of Chronic Kidney Disease in Rats

“…It has been shown that CKD leads to cardiovascular disease (4), stroke (5) and decreased locomotor activity (6). Individual's quality of life can be further decreased by sexual dysfunction (7), neurological and mental disorders including anxiety and depression (7)(8)(9)(10)(11), as well as cognitive impairment (12)(13)(14)(15)(16)(17) or epileptic seizures (18), all of which lead to increased socio-economic burden of affected people (19). Although, the exact pathophysiological mechanisms underlying the neurological complications of CKD remain unclear, there are several factors that might play a role, e.g., uremic encephalopathy (20), oxidative stress (21)(22)(23) and inflammation (21,22).…”