Neurovascular dysfunction, inflammation and endothelial activation: Implications for the pathogenesis of Alzheimer's disease

Garrison Institute on Aging, and Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, Texas, USA.
Journal of Neuroinflammation (Impact Factor: 5.41). 03/2011; 8(1):26. DOI: 10.1186/1742-2094-8-26
Source: PubMed


Alzheimer's disease (AD) is an age-related disorder characterized by progressive cognitive decline and dementia. Alzheimer's disease is an increasingly prevalent disease with 5.3 million people in the United States currently affected. This number is a 10 percent increase from previous estimates and is projected to sharply increase to 8 million by 2030; it is the sixth-leading cause of death. In the United States the direct and indirect costs of Alzheimer's and other dementias to Medicare, Medicaid and businesses amount to more than $172 billion each year. Despite intense research efforts, effective disease-modifying therapies for this devastating disease remain elusive. At present, the few agents that are FDA-approved for the treatment of AD have demonstrated only modest effects in modifying clinical symptoms for relatively short periods and none has shown a clear effect on disease progression. New therapeutic approaches are desperately needed. Although the idea that vascular defects are present in AD and may be important in disease pathogenesis was suggested over 25 years ago, little work has focused on an active role for cerebrovascular mechanisms in the pathogenesis of AD. Nevertheless, increasing literature supports a vascular-neuronal axis in AD as shared risk factors for both AD and atherosclerotic cardiovascular disease implicate vascular mechanisms in the development and/or progression of AD. Also, chronic inflammation is closely associated with cardiovascular disease, as well as a broad spectrum of neurodegenerative diseases of aging including AD. In this review we summarize data regarding, cardiovascular risk factors and vascular abnormalities, neuro- and vascular-inflammation, and brain endothelial dysfunction in AD. We conclude that the endothelial interface, a highly synthetic bioreactor that produces a large number of soluble factors, is functionally altered in AD and contributes to a noxious CNS milieu by releasing inflammatory and neurotoxic species.

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Available from: Paula Grammas
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    • "AD pathology is characterized by changes in β-amyloid (Aβ) metabolism, abundance of soluble Aβ oligomers, parenchymal Aβ deposits and neurofibrillary tangles, synaptic dysfunction and neurodegeneration, and loss of cognitive function (Haass and Selkoe, 2007). The pathology is not restricted to the neuronal compartment as it also affects all cell types of the neurovascular unit including circulating leukocytes, endothelial cells, pericytes, perivascular antigenpresenting cells, astrocytes, and microglia (Iadecola, 2004;Grammas, 2011;Zlokovic, 2011). A particular attention has been paid to the vascular system where a number of studies have provided evidence for pronounced cerebrovascular dysfunction in AD. "
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    ABSTRACT: Alterations in density and morphology of the cerebral microvasculature have been reported to occur in Alzheimer's disease patients and animal models of the disease. In this study we compared magnetic resonance imaging (MRI) techniques for their utility to detect age-dependent changes of the cerebral vasculature in the arcAβ mouse model of cerebral amyloidosis. Dynamic susceptibility contrast (DSC)-MRI was performed by tracking the passage of a superparamagnetic iron oxide nanoparticle in the brain with dynamic gradient echo planar imaging (EPI). From this measurements relative cerebral blood volume [rCBV(DSC)] and relative cerebral blood flow (rCBF) were estimated. For the same animal maps of the relaxation shift index Q were computed from high resolution gradient echo and spin echo data that were acquired before and after superparamagnetic iron oxide (SPIO) nanoparticle injection. Q-values were used to derive estimates of microvessel density. The change in the relaxation rates ΔR2* obtained from pre- and post-contrast gradient echo data was used for the alternative determination of rCBV [rCBV(ΔR2*)]. Linear mixed effects modeling found no significant association between rCBV(DSC), rCBV(ΔR2*), rCBF, and Q with genotype in 13-month old mice [compared to age-matched non-transgenic littermates (NTLs)] for any of the evaluated brain regions. In 24-month old mice there was a significant association for rCBV(DSC) with genotype in the cerebral cortex, and for rCBV(ΔR2*) in the cerebral cortex and cerebellum. For rCBF there was a significant association in the cerebellum but not in other brain regions. Q-values in the olfactory bulb, cerebral cortex, striatum, hippocampus, and cerebellum in 24-month old mice were significantly associated with genotype. In those regions Q-values were reduced between 11 and 26% in arcAβ mice compared to age-matched NTLs. Vessel staining with CD31 immunohistochemistry confirmed a reduction of microvessel density in the old arcAβ mice. We further demonstrated a region-specific association between parenchymal and vascular deposition of β-amyloid and decreased vascular density, without a correlation with the amount of Aβ deposition. We found that Q mapping was more suitable than the hemodynamic read-outs to detect amyloid-related degeneration of the cerebral microvasculature.
    Full-text · Article · Jan 2016 · Frontiers in Aging Neuroscience
    • "e l s e v i e r . c o m / l o ca t e / n e u a g i n g and late-stage Alzheimer's disease, possibly reflecting the damage of cerebrovascular dysfunction to the ageing brain (Gallacher et al., 2010; Grammas, 2011; Zuliani et al., 2008). Acute-phase proteins such as C-reactive proteins (CRPs) and serum amyloid A (SAA) comprise another category of IMs that rise in concert with the systemic inflammatory response. "
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    ABSTRACT: Ageing is characterized by chronically elevated inflammatory markers (IMs). Peripheral IM levels have been found in negative correlations with brain structural measures including global and lobar volumes and the hippocampus. This study investigated the relationship between 10 peripheral IMs and voxel-based gray matter (GM) volumes in nondemented older adults (n = 463). Two proinflammatory cytokines (tumor necrosis factor-α [TNF-α] and interleukin-1β) and 2 vascular IMs (vascular cellular adhesion molecule-1 and plasminogen activator inhibitor-1) were negatively correlated with regional GM volumes. TNF-α and interleukin-1β were both significantly correlated with GM volumes in the left occipitotemporal area, left superior occipital gyrus, and left inferior parietal lobule; TNF-α was also significantly correlated with the bilateral medial prefrontal cortices and approached significance for the correlations with the bilateral hippocampi. Significant GM correlations with vascular cellular adhesion molecule-1 were located in the bilateral anterior cingulate cortices, and with plasminogen activator inhibitor-1 in the cerebellum and right hippocampus. The neuroanatomical correlation patterns of 2 proinflammatory cytokines and 2 vascular IMs might be reflective of the effects of neurodegenerative and vascular pathological processes in the ageing brain.
    No preview · Article · Nov 2015 · Neurobiology of aging
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    • "Vascular disease is a potentially modifiable cause of cognitive decline and dementia in older adults. Stroke, cardiovascular disease, peripheral vascular disease, hypertension, and diabetes have each been associated with cognitive deficits or dementia [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]. Although some of those diseases had markedly increased prevalence over time in AD patient admissions [e.g., type 2 diabetes (16% in 2002 to 23% in 2012), hypertension (45% in 2002 to 68% in 2012), peripheral vascular disease (4.7% to 7.6%)] and affected outcomes of hospitalization in adverse ways (e.g., congestive heart failure, pulmonary circulatory disorders), most were either unassociated with or inversely related to AD status among older patient admissions. "
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    ABSTRACT: In the inpatient setting, prevalence, predictors, and outcomes [mortality risk (MR), length of stay (LOS), and total charges (TC)] of Alzheimer's disease (AD) are largely unknown. We used data on older adults (60+ y) from the Nationwide Inpatient Sample (NIS) 2002-2012. AD prevalence was ∼3.12% in 2012 (total weighted discharges with AD±standard error: 474, 410±6,276). Co-morbidities prevailing more in AD inpatient admissions included depression (OR = 1.67, 95% CI: 1.63-1.71, p < 0.001), fluid/electrolyte disorders (OR = 1.25, 95% CI: 1.22-1.27, p < 0.001), weight loss (OR = 1.26, 95% CI: 1.22-1.30, p < 0.001), and psychosis (OR = 2.59, 95% CI: 2.47-2.71, p < 0.001), with mean total co-morbidities increasing over time. AD was linked to higherMRand longer LOS, but lower TC. TC rose in AD, while MR and LOS dropped markedly over time. In AD, co-morbidities predicting simultaneously higher MR, TC, and LOS (2012) included congestive heart failure, chronic pulmonary disease, coagulopathy, fluid/electrolyte disorders, metastatic cancer, paralysis, pulmonary circulatory disorders, and weight loss. In sum, co-morbidities and TC increased over time in AD, whileMRand LOS dropped. Fewco-morbidities predicted occurrence of AD or adverse outcomes in AD.
    Full-text · Article · Sep 2015 · Journal of Alzheimer's disease: JAD
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