Unraveling Cognitive Decline - Integrating Biomarkers of Neurodegeneration, Vascular Pathology, and Neuroinflammation

BackgroundUnderstanding the interplay between different pathologies is essential for correlating specific pathologies with cognitive symptoms and predicting the clinical effects of emerging therapies later on. This thesis investigates interactions among biomarkers of small vessel disease (SVD), neuroinflammation, and Alzheimer’s disease (AD), their relation to infection in the brain parenchyma, and their combined effects on cognition. These findings aim to clarify the mechanisms underlying cognitive decline.MethodsFour cohorts were analyzed, encompassing different pathologies associated with cognitive decline, including data from the University of Pennsylvania, the Swedish BioFINDER study, and a cohort of infectious encephalitis patients from Southern Sweden. These retrospective case-control studies examined vascular, inflammatory, and infectious factors in relation to AD pathology. ResultsPaper I: Automatic segmentation of medial temporal lobe (MTL) subregions, which can identify atrophy patterns in the MTL closely related to cognitive decline, is feasible in a clinical setting of prodromal AD. However, issues of image quality due to motion artifacts remain to be addressed.Paper II: Enlarged perivascular spaces were associated with other SVD markers but not with cognitive decline or early AD pathogenesis, supporting distinct pathological mechanisms for AD and vascular pathology. Paper III: White matter lesions were linked to neuroinflammatory biomarkers, especially placental growth factor (PlGF), independent of Aβ status or cognitive impairment, highlighting PlGF as a potential marker for cerebral vascular pathology.Paper IV: Patients with infectious encephalitis exhibited episodic and semantic memory impairment six years post-infection, similar to mild cognitive impairment patients. Cognitive decline correlated with unilateral MTL atrophy but not with AD typical biomarkers.Conclusion This thesis highlights the multifaceted contributions of neurodegenerative, vascular, inflammatory, and infectious factors to cognitive decline, as well as their interplay. Findings advance the understanding of dementia pathogenesis and could be of value in further differentiating vascular and AD typical pathophysiological features.