Cerebrospinal Fluid Biomarkers of Neurovascular Dysfunction in Mild Dementia and Alzheimer'S Disease

Abstract

Alzheimer's disease (AD) is the most common form of age-related dementias. In addition to genetics, environment, and lifestyle, growing evidence supports vascular contributions to dementias including dementia because of AD. Alzheimer's disease affects multiple cell types within the neurovascular unit (NVU), including brain vascular cells (endothelial cells, pericytes, and vascular smooth muscle cells), glial cells (astrocytes and microglia), and neurons. Thus, identifying and integrating biomarkers of the NVU cell-specific responses and injury with established AD biomarkers, amyloid-β (Aβ) and tau, has a potential to contribute to better understanding of the disease process in dementias including AD. Here, we discuss the existing literature on cerebrospinal fluid biomarkers of the NVU cell-specific responses during early stages of dementia and AD. We suggest that the clinical usefulness of established AD biomarkers, Aβ and tau, could be further improved by developing an algorithm that will incorporate biomarkers of the NVU cell-specific responses and injury. Such biomarker algorithm could aid in early detection and intervention as well as identify novel treatment targets to delay disease onset, slow progression, and/or prevent AD.

Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

“…According to the two-hit vascular hypothesis of AD , damage to blood vessels is the initial insult, causing BBB dysfunction and diminished brain perfusion that, in turn, lead to neuronal injury and Aβ accumulation in the brain 5,6,47,50 . Cerebrovascular disruption is influenced by lifestyle and might act independently and/or synergistically with Aβ to promote AD pathology, which is accelerated by genetic risk factors, such as carriage of the ε4 allele of apolipoprotein E ( APOE*ε4 ), vascular risk factors (such as hypertension, diabetes and dyslipidemia) and environmental risk factors (such as pollution) 47,50 .…”

“…Cerebrovascular disruption is influenced by lifestyle and might act independently and/or synergistically with Aβ to promote AD pathology, which is accelerated by genetic risk factors, such as carriage of the ε4 allele of apolipoprotein E ( APOE*ε4 ), vascular risk factors (such as hypertension, diabetes and dyslipidemia) and environmental risk factors (such as pollution) 47,50 .…”

“…Other CSF biomarkers of aberrant angiogenesis, endothelial dysfunction, mural cell injury, inflammatory cytokines and chemokines in AD and other neurodegenerative disorders have been reviewed in detail elsewhere 50,206,207 , and are not examined here.…”

Pericytes of the neurovascular unit: key functions and signaling pathways

“…Several dominantly inherited rare vasculotropic APP mutations within Aβ 21 to 23 residues (e.g., Dutch, Flemish, Iowa, Arctic) primarily affect the cerebrovascular system leading to BBB breakdown, CAA, and hemorrhages with recurrent strokes, as recently reviewed 87 . Although APP mutations lead to degeneration of mural cells, whether deficient PDGF-BB/PDGFRβ signaling might contribute to loss of pericytes, rupture of blood vessels, and/or BBB disruption is currently unknown.…”

Paving the Way Toward Complex Blood-Brain Barrier Models Using Pluripotent Stem Cells

“…However, it is affected and undergoes breakdown during normal aging [3], as well as in several brain disorders, including stroke [4] and epilepsy [5]. It is also perturbed in many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) [6], Parkinson's disease (PD) [7], Huntington's disease (HD) [8], vascular dementia [9], and Alzheimer's disease (AD) [10][11][12][13].…”