Biomarkers of cognitive decline and dementia

Abstract

Cognitive impairment in the elderly encompasses many forms, ranging from subtle impairments in otherwise cognitively healthy individuals through mild cognitive impairment and dementia. Brain structural and functional changes underlie the observed cognitive impairment.

Complementary to the clinical observation, biomarkers have been proposed as in vivo indicators of the underlying pathophysiology and neurobiological changes in a sufficiently reliable manner that they could be used to detect, track, and predict the disease course over time.

In this thesis we used a combination of epidemiological and clinic-based approaches to investigate the mechanisms underlying vascular cognitive impairment (VCI) and Alzheimer’s disease (AD) and to identify possible biomarkers that could help early diagnosis of such conditions. To do so, a set of circulating and cerebrospinal fluid (CSF) biomarkers were studied in healthy and cognitively impaired subjects. Then, these measures were related to grey matter (GM) volumes, white matter (WM) integrity and cognition.

The first two studies are part of the population-based Barcelona-ASIA neuropsychology study. Study I aimed to compare the cognitive patterns of risk markers for cerebrovascular disease (CVD) with the cognitive profile in relation to novel and traditional vascular risk factors (VRF) in a community-dwelling sample. Biomarkers of inflammation, endothelial dysfunction and vascular thrombosis were selected. Results showed that VRF and circulating markers of inflammation and endothelial dysfunction predicted performance in several cognitive domains. Cognitive patterns of inflammatory markers overlapped those related to VRF. Markers of endothelial dysfunction predicted lower performance in verbal memory.

Study II was designed to further explore the structural changes mediating the relationships between risk markers of CVD and cognition. For that purpose the same set of markers of risk for CVD were related to GM atrophy and WM integrity and cognition. The main finding was an association of inflammation and vascular thrombosis with WM integrity loss in cortico-subcortical pathways and association fibres of frontal and temporal lobes. As expected, none of the biomarkers was related to GM volume changes. Vascular thrombosis also predicted lower performance in processing speed.

The third study is a memory clinic-based investigation that was conducted aiming to test the potential use of CSF biomarkers cut-offs as components for the diagnostic work-up in AD. We assessed GM and cognitive patterns in cognitively impaired subjects using CSF Aβ1-42, t-tau and p-tau181 cut-offs as grouping criteria. Results indicated that patients with abnormal CSF levels of t-tau and p-tau (but not Aβ1-42) showed impairment and signs of regional GM atrophy in brain regions characteristic for AD, compared to those with normal levels. More specifically, GM volume differences were found in temporal, inferior parietal, lateral occipital and widespread prefrontal regions.

Studies I and II show that risk markers of inflammation and vascular thrombosis are related to a VCI profile for both cognitive patterns and structural brain changes. A microvascular damage of WM projections in fronto-subcortical pathways, but not GM atrophy, could mediate the association between these pathogenic processes and cognitive performance. Markers of endothelial dysfunction are related to a different cognitive pattern which is characteristic of both vascular and neurodegenerative mechanisms. Study III provides evidence that patients with abnormal CSF levels of t-tau and p-tau (but not Aβ1-42) show cognitive an AD profile according to GM density patterns and cognitive impairment.

Taken together, these results suggest that, complementary to the clinical observation, plasma and CSF markers and structural imaging are well placed to improve early diagnosis of both VCI and AD.

El terme deteriorament cognitiu (DC) es refereix al contínuum de canvis cognitius associats a l’envelliment sa i patològic. El diagnòstic precoç de les persones amb DC és clau, ja que els tractaments són més eficaços quan s’inicien als inicis de la malaltia.

Els biomarcadors s’han proposat com a eines pel diagnòstic precoç del DC i la demència. Es consideren indicadors in vivo de la patologia i s’han plantejat com a possibles eines pel diagnòstic, pronòstic i seguiment del DC i la patologia subjacent.

L’objectiu general de la present tesi era explorar els mecanismes patofisiològics subjacents al deteriorament cognitiu vascular (DCV) i la (MA). Per aquest motiu, vàrem mesurar diversos biomarcadors sanguinis i de LCR en persones sanes i en persones amb diagnòstic de deteriorament cognitiu i vàrem relacionar-los amb canvis de l’estructura cerebral i de la cognició. L’objectiu final era identificar possibles biomarcadors pel diagnòstic precoç d’aquestes malalties.

Els estudis I i II s’emmarquen dins del projecte Barcelona-ASIA Neuropsicologia i tenien com a objectiu estudiar la relació entre biomarcadors en plasma de malaltia vascular cerebral (MVC) i canvis estructurals i cognitius. Els resultats obtinguts mostren que els biomarcadors d’inflamació i trombosi vascular es relacionen amb un perfil de deteriorament cognitiu vascular tant a nivell cognitiu com estructural. La lesió microvascular dels tractes de SB còrtico-subcorticals mediaria l’associació entre aquests mecanismes i la cognició. Els marcadors de disfunció endotelial es relacionen amb un perfil cognitiu diferent, que és característic tant de processos vasculars com neurodegeneratius. L’estudi III té com a objectiu valorar el possible ús dels biomarcadors de líquid cefaloraquidi pel diagnòstic de la MA. En concret, vàrem estudiar els perfils estructurals i cognitius en persones amb deteriorament cognitiu emprant punts de tall de líquid cefaloraquidi com a criteri d’agrupació. Els resultats mostren que pacients amb DC i amb nivells patològics de t-tau i p-tau al LCR (però no d’Aβ1-42) presenten un perfil cognitiu i estructural de MA.

En conclusió, els resultats obtinguts en la present tesi suggereixen que, complementaris a l’observació clínica, els biomarcadors de LCR i plasma, així com els indicadors de morfologia cerebral podrien ser d’ús pel diagnòstic precoç del DCL i la demència.