Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders

Zloković, Berislav V.

doi:10.1038/nrn3114

Cited by 2,432 publications

(2,514 citation statements)

References 210 publications

(280 reference statements)

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“…Second, as CBF decreases, adherens and tight junctions in the blood–brain barrier are disrupted, resulting in increased diffusion of lipid‐soluble proteins across capillary walls. Subsequently, blood‐derived neurotoxic proteins accumulate in the brain resulting in suppressed capillary blood flow and neurodegeneration 38, 39. Such changes can be exacerbated in older adults as blood–brain barrier breakdown has been reported in the hippocampus with normal aging 38.…”

Section: Discussionmentioning

confidence: 99%

Subclinical Compromise in Cardiac Strain Relates to Lower Cognitive Performances in Older Adults

Kresge

Khan

Wagener

et al. 2018

JAHA

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BackgroundGlobal longitudinal strain (GLS), reflecting total shortening of the myocardium during the cardiac cycle, has emerged as a more precise myocardial function measure than left ventricular ejection fraction (LVEF). Longitudinal strain may be selectively affected in subclinical heart disease, even in the presence of normal LVEF. This study examines subclinical cardiac dysfunction, assessed by GLS and LVEF, and cognition among older adults.Methods and ResultsVanderbilt Memory and Aging Project participants who were free of clinical dementia, stroke, and heart failure (n=318, 73±7 years, 58% male) completed neuropsychological assessment and cardiac magnetic resonance to quantify GLS and LVEF. Linear regression models related GLS and LVEF to neuropsychological performances, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive diagnosis, and APOE*ε4 status. Models were repeated with a cardiac×cognitive diagnosis interaction term. Compromised GLS (reflected by higher values) related to worse naming (β=−0.07, P=0.04), visuospatial immediate recall (β=−0.83, P=0.03), visuospatial delayed recall (β=−0.22, P=0.03), and verbal delayed recall (β=−0.11, P=0.007). LVEF did not relate to worse performance on any measure (P>0.18). No diagnostic interactions were observed.ConclusionsOur study results are among the first to suggest that compromised GLS relates to worse episodic memory and language performance among older adults who are free of clinical dementia, stroke, and heart failure. Subclinical cardiac dysfunction may correlate with cognitive health in late life, even when LVEF remains normal. The results add to growing evidence that GLS may be a more sensitive and preferred method for quantifying subclinical changes in cardiac function.

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Section: Discussionmentioning

confidence: 99%

Subclinical Compromise in Cardiac Strain Relates to Lower Cognitive Performances in Older Adults

Kresge

Khan

Wagener

et al. 2018

JAHA

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“…This meant that we could not directly relate our pathological findings to antemortem hypoperfusive and cognitive status. In addition, the lack of comparison of the SVD cases with controls without neurodegenerative pathologies was another limitation considering that PDGFRB positive pericytes may also degenerate in some neurodegenerative diseases 46, 55, 56, 59. The third limitation is that a histopathological study using postmortem human brains does not always uncover the entire cell process that occurs in the ageing human brain.…”

Section: Discussionmentioning

confidence: 99%

“…However, the exact mechanisms have yet to be fully elucidated. Recent studies have noted that attenuations of vasculature and white matter are also frequently observed in other neurodegenerative disorders, especially in Alzheimer's disease (AD) 46, 59. However, vascular risk factors are related to a lesser degree to a pure type of AD 10, 38 or mixed type (AD with vascular pathology) dementia 23 compared with vascular cognitive impairment.…”

Section: Introductionmentioning

confidence: 99%

Pericyte‐derived bone morphogenetic protein 4 underlies white matter damage after chronic hypoperfusion

et al. 2017

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Subcortical small vessel disease (SVD) is characterized by white matter damage resulting from arteriolosclerosis and chronic hypoperfusion. Transforming growth factor beta 1 (TGFB1) is dysregulated in the hereditary SVD, CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). However, very little is known about the role of the largest group in the TGFB superfamily – the bone morphogenetic proteins (BMPs) – in SVD pathogenesis. The aim of this study was to characterize signaling abnormalities of BMPs in sporadic SVD. We examined immunostaining of TGFB1 and BMPs (BMP2/BMP4/BMP6/BMP7/BMP9) in a total of 19 post‐mortem human brain samples as follows: 7 SVD patients (4 males, 76–90 years old); 6 Alzheimer's disease (AD) patients (2 males, 67–93 years old) and 6 age‐matched disease controls (3 males, 68–78 years old). We subsequently investigated the effects of oxygen–glucose deprivation and BMP4 addition on cultured cells. Furthermore, adult mice were subjected to chronic cerebral hypoperfusion using bilateral common carotid artery stenosis, followed by continuous intracerebroventricular infusion of the BMP antagonist, noggin. In the SVD cases, BMP4 was highly expressed in white matter pericytes. Oxygen–glucose deprivation induced BMP4 expression in cultured pericytes in vitro. Recombinant BMP4 increased the number of cultured endothelial cells and pericytes and converted oligodendrocyte precursor cells into astrocytes. Chronic cerebral hypoperfusion in vivo also upregulated BMP4 with concomitant white matter astrogliogenesis and reduced oligodendrocyte lineage cells, both of which were suppressed by intracerebroventricular noggin infusion. Our findings suggest ischemic white matter damage evolves in parallel with BMP4 upregulation in pericytes. BMP4 promotes angiogenesis, but induces astrogliogenesis at the expense of oligodendrocyte precursor cell proliferation and maturation, thereby aggravating white matter damage. This may explain white matter vulnerability to chronic hypoperfusion. The regulation of BMP4 signaling is a potential therapeutic strategy for treating SVD.

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“…However, limited understanding of the vascular tangent between the two diseases hampers the development of therapeutics and preventive strategies against AD. The blood–brain barrier (BBB) hinders the entry of most molecules into the brain and enables active transportation of penetrated molecules to the brain (Zlokovic, 2011). Dysfunction of the BBB has been demonstrated in the pathogenesis and progression of AD (Kalaria, 2010), even before dementia onset (Skoog et al, 1998) and also in the aging human hippocampus, which worsens with mci, a condition preceding AD (Montagne et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

High‐fat diet protects the blood–brain barrier in an Alzheimer's disease mouse model

et al. 2018

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Type 2 diabetes (T2D) is associated with increased risk of Alzheimer's disease (AD). There is evidence for impaired blood–brain barrier (BBB) in both diseases, but its role in the interplay between them is not clear. Here, we investigated the effects of high‐fat diet (HFD), a model for T2D, on the Tg2576 mouse model of AD, in regard to BBB function. We showed that HFD mice had higher weight, more insulin resistance, and higher serum HDL cholesterol levels, primarily in Tg2576 mice, which also had higher brain lipids content. In terms of behavior, Tg2576 HFD mice were less active and more anxious, but had better learning in the Morris Water Maze compared to Tg2576 on regular diet. HFD had no effect on the level of amyloid beta 1–42 in the cortex of Tg2576 mice, but increased the transcription level of insulin receptor in the hippocampus. Tg2576 mice on regular diet demonstrated more BBB disruption at 8 and 12 months accompanied by larger lateral ventricles volume in contrast to Tg2576 HFD mice, whose BBB leakage and ventricular volume were similar to wild‐type (WT) mice. Our results suggest that in AD, HFD may promote better cognitive function through improvements of BBB function and of brain atrophy but not of amyloid beta levels. Lipid metabolism in the CNS and peripheral tissues and brain insulin signaling may underlie this protection.

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Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders

Cited by 2,432 publications

References 210 publications

Subclinical Compromise in Cardiac Strain Relates to Lower Cognitive Performances in Older Adults

Subclinical Compromise in Cardiac Strain Relates to Lower Cognitive Performances in Older Adults

Pericyte‐derived bone morphogenetic protein 4 underlies white matter damage after chronic hypoperfusion

High‐fat diet protects the blood–brain barrier in an Alzheimer's disease mouse model

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