Blood-based Biomarkers of Microvascular Pathology in Alzheimer's disease
Résumé
Sporadic Alzheimer's disease (AD) is a genetically complex and chronically progressive neurodegenerative disorder with molecular mechanisms and neuropathologies centering around the amyloidogenic pathway, hyperphosphorylation and aggregation of tau protein, and neurofibrillary degeneration. While cerebrovascular changes have not been traditionally considered to be a central part of AD pathology, a growing body of evidence demonstrates that they may, in fact, be a characteristic feature of the AD brain as well. In particular, microvascular abnormalities within the brain have been associated with pathological AD hallmarks and may precede neurodegeneration. In-vivo assessment of microvascular pathology provides a promising approach to develop useful biological markers for early detection and pathological characterization of AD. This review focuses on established blood-based biological marker candidates of microvascular pathology in AD. These candidates include plasma concentration of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) that are increased in AD. Measures of endothelial vasodilatory function including endotheline (ET-1), adrenomedulline (ADM), and atrial natriuretic peptide (ANP), as well as sphingolipids are also significantly altered in mild AD or during the predementia stage of mild cognitive impairment (MCI), suggesting sensitivity of these biomarkers for early detection and diagnosis. In conclusion, the emerging clinical diagnostic evidence for the value of blood-based microvascular biomarkers in AD is promising, hoewever, still requires validation in phase II and III diagnostic trials. Moreover, it is still unclear whether the described protein dysballances are early or downstream pathological events and how the detected systemic microvascular alterations relate to cerebrovascular and neuronal pathologies in the AD brain.
Mots clés
neurodegeneration
cerebrovascular
microvascular
vasodilation
vasoconstriction
early detection
diagnosis
blood
cerebrospinal fluid
CSF
vascular cell adhesion molecule-1
VCAM-1
intercellular adhesion molecule-1
ICAM-1
selectin
endotheline
ET-1
adrenomedulline
ADM
atrial natriuretic peptide
ANP
sphingolipids
ceramides
Alzheimer's disease
AD
dementia
mild cognitive impairment
MCI
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