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Plasma proteomic characterization of motoric cognitive risk and mild cognitive impairment
Gabriela T Gomez1, Sanish Sathyan2, Jingsha Chen3
1Department of Internal Medicine, Mass General Brigham, Boston, Massachusetts, USA.
Introduction:
Motoric cognitive risk (MCR) is a pre-dementia syndrome characterized by mobility and cognitive dysfunction. This study conducted a proteome-wide study of MCR and compared the proteomic signatures of MCR to that of mild cognitive impairment (MCI).
Methods:
Participants were classified as MCR using a memory questionnaire and 4-meter walk. We measured 4877 plasma proteins collected during late-life and midlife. Multivariable logistic regression related each protein to late-life MCR/MCI. MCR-associated proteins were replicated internally at midlife and in an external cohort.
Results:
Proteome-wide analysis (n = 4076) identified 25 MCR-associated proteins. Eight of these proteins remained associated with late-life MCR when measured during midlife. Two proteins (SVEP1 and TAGLN) were externally replicated. Compared to MCI, MCR had a distinct and much stronger proteomic signature enriched for cardiometabolic and immune pathways.
Discussion:
Our findings highlight the divergent biology underlying two pre-dementia syndromes. Metabolic and immune dysfunction may be a primary driver of MCR.
Highlights:
MCR is defined by concurrent cognitive and gait dysfunction. MCR protein biomarkers have key roles in cardiometabolic and vascular function. MCR biomarkers are also associated with cerebrovascular disease and dementia. MCR and MCI demonstrate overlapping but divergent proteomic signatures.
Insights
Motoric cognitive risk (MCR), a pre-dementia syndrome, shows distinct protein biomarkers linked to metabolic and immune pathways. These findings differentiate MCR from mild cognitive impairment (MCI), suggesting unique biological drivers.
Area of Science:
- Neuroscience
- Proteomics
- Gerontology
Background:
- Motoric cognitive risk (MCR) is a pre-dementia syndrome defined by concurrent mobility and cognitive impairments.
- Understanding the underlying biological mechanisms of MCR is crucial for early diagnosis and intervention.
Purpose of the Study:
- To conduct a proteome-wide study identifying plasma protein signatures associated with MCR.
- To compare the proteomic profile of MCR with that of mild cognitive impairment (MCI).
Main Methods:
- Participants were classified as MCR using cognitive and gait assessments.
- Plasma samples from late-life and midlife were analyzed for 4877 proteins.
- Proteins associated with MCR were validated using internal and external cohorts.
Main Results:
- Proteome-wide analysis identified 25 MCR-associated proteins, with 8 showing midlife association.
- Two proteins, SVEP1 and TAGLN, were externally replicated as MCR biomarkers.
- MCR exhibited a distinct proteomic signature, significantly different from MCI, enriched in cardiometabolic and immune pathways.
Conclusions:
- MCR and MCI present divergent proteomic signatures, highlighting distinct biological underpinnings.
- Metabolic and immune dysfunctions appear to be primary drivers of MCR.
- MCR protein biomarkers are implicated in cardiometabolic function, vascular health, and cerebrovascular disease.
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