Vascular pathology and pathogenesis of cognitive impairment and dementia in older adults

Agrawal, Shweta; Schneider, Julie A.

doi:10.1016/j.cccb.2022.100148

Cited by 13 publications

(14 citation statements)

References 204 publications

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“…Large neuropathology studies have demonstrated that AD pathology commonly coexists with vascular pathology in individuals both with and without dementia 15 . More than half of the participants with AD had increased CSF levels of MMP‐10, considered a vascular marker, in our study.…”

Section: Discussionsupporting

confidence: 46%

Cerebrospinal fluid biomarker profiling of diverse pathophysiological domains in Alzheimer's disease

Trombetta,

Wu,

Kuo

et al. 2024

A&D Transl Res & Clin Interv

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INTRODUCTIONWhile Alzheimer's disease (AD) is defined by amyloid‐β plaques and tau tangles in the brain, it is evident that many other pathophysiological processes such as inflammation, neurovascular dysfunction, oxidative stress, and metabolic derangements also contribute to the disease process and that varying contributions of these pathways may reflect the heterogeneity of AD. Here, we used a previously validated panel of cerebrospinal fluid (CSF) biomarkers to explore the degree to which different pathophysiological domains are dysregulated in AD and how they relate to each other.METHODSTwenty‐five CSF biomarkers were analyzed in individuals with a clinical diagnosis of AD verified by positive CSF AD biomarkers (AD, n = 54) and cognitively unimpaired controls negative for CSF AD biomarkers (CU‐N, n = 26) using commercial single‐ and multi‐plex immunoassays.RESULTSWe noted that while AD was associated with increased levels of only three biomarkers (MMP‐10, FABP3, and 8OHdG) on a group level, half of all AD participants had increased levels of biomarkers belonging to at least two pathophysiological domains reflecting the diversity in AD. LASSO modeling showed that a panel of FABP3, 24OHC, MMP‐10, MMP‐2, and 8OHdG constituted the most relevant and minimally correlated set of variables differentiating AD from CU‐N. Interestingly, factor analysis showed that two markers of metabolism and oxidative stress (24OHC and 8OHdG) contributed independent information separate from MMP‐10 and FABP3 suggestive of two independent pathophysiological pathways in AD, one reflecting neurodegeneration and vascular pathology, and the other associated with metabolism and oxidative stress.DISCUSSIONBetter understanding of the heterogeneity among individuals with AD and the different contributions of pathophysiological processes besides amyloid‐β and tau will be crucial for optimizing personalized treatment strategies.Highlights A panel of 25 highly validated biomarker assays were measured in CSF. MMP10, FABP3, and 8OHdG were increased in AD in univariate analysis. Many individuals with AD had increased levels of more than one biomarker. Markers of metabolism and oxidative stress contributed to an AD multianalyte profile. Assessing multiple biomarker domains is important to understand disease heterogeneity.

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Section: Discussionsupporting

confidence: 46%

Cerebrospinal fluid biomarker profiling of diverse pathophysiological domains in Alzheimer's disease

Trombetta,

Wu,

Kuo

et al. 2024

A&D Transl Res & Clin Interv

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“…An additional 10% percent of the proteins showing differentially altered glycoproteoforms belong to the blood coagulation pathways. Cerebrovascular disease is the most common pathology underlying cognitive impairment in type 2 diabetes 32,33 . Blood coagulation pathways have been linked to initiation or aggravation of brain hypoperfusion and brain vascular in ammation 34 , and there is evidence from ADlike animal models, suggesting that the inhibition of coagulation in AD may serve as a new therapeutic target 34,35 .…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Global glycoproteomic analysis reveals specific glycation and glycosylation events associated with cognitive decline in older adults with type 2 diabetes

Tickotsky

Morgenstern

Cooper

et al. 2022

Preprint

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INTRODUCTION: Molecular mechanisms underlying the well-known association between Type 2 diabetes (T2D) and late-life cognitive impairment are unknown. Alterations in glyco post-translational modifications (PTM) of serum proteins reflect altered cellular physiology and are associated with T2D and impaired cognition. This novel large-scale mass spectrometry based glycoproteomics study aimed to identify therapeutic PTM targets that may link T2D with poor cognition. METHODS: We performed LC-MS/MS–based novel glycoproteomic profiling of sera samples from 23 cognitively normal older adults with T2D. At baseline all people had normal cognition, but during 36-months, 8 participants developed cognitive impairment while 15 maintained normal cognition RESULTS: We identified and quantified a total of 1,866 unique glycoproteoforms (i.e., peptides with a post-transcription sugar modification) that matched 201 annotated proteins. Group differences were observed for 72 glycoproteoforms at baseline. At the time of cognitive testing three years later, there were group differences for 137 glycoproteoforms. Group differences were observed for 14 glycoproteoforms both at baseline and at 3-year follow-up. DISCUSSION: Glycoproteoforms may contribute to cognitive impairment in T2D, may identify adults with T2D at risk for cognitive impairment and are high value therapeutic targets for new therapies to mitigate the negative cognitive effects of T2D in old age.

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“…Throughout the meeting, vascular contributions to cognitive impairment and dementia (VCID) seemed like prisoners on Alcatraz listening to the free citizens of neurodegeneration celebrate across the water. Yet only a minority of individuals living with dementia in their 80 s and 90 s, the largest and fastest growing cohort of those with the condition, have no cerebrovascular disease [15]. Furthermore, anti-amyloid studies typically impose upper age limits of 85 or 90 and have median participant ages in the low 70 s.…”

Section: What About Non-amyloid Pathways?mentioning

confidence: 99%

Alzheimer's disease: Have we opened the Golden Gate to disease-modifying therapy?

Isaacs

2024

Cerebral Circulation - Cognition and Behavior

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Vascular pathology and pathogenesis of cognitive impairment and dementia in older adults

Cited by 13 publications

References 204 publications

Cerebrospinal fluid biomarker profiling of diverse pathophysiological domains in Alzheimer's disease

Cerebrospinal fluid biomarker profiling of diverse pathophysiological domains in Alzheimer's disease

WITHDRAWN: Global glycoproteomic analysis reveals specific glycation and glycosylation events associated with cognitive decline in older adults with type 2 diabetes

Alzheimer's disease: Have we opened the Golden Gate to disease-modifying therapy?

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