Type 2 diabetes mellitus accelerates brain aging and cognitive decline: complementary findings from UK Biobank and meta-analyses.
- State University of New York, United States
- Massachusetts General Hospital, United States
Abstract
Background: Type 2 diabetes mellitus is known to be associated with neurobiological and cognitive deficits; however, their extent, overlap with aging effects, and the effectiveness of existing treatments in the context of the brain are currently unknown.
Methods: We characterized neurocognitive effects independently associated with T2DM and age in a large cohort of human subjects from the UK Biobank with cross-sectional neuroimaging and cognitive data. We then proceeded to evaluate the extent of overlap between the effects related to T2DM and age by applying correlation measures to the separately characterized neurocognitive changes. Our findings were complemented by meta-analyses of published reports with cognitive or neuroimaging measures for T2DM and healthy controls (HC). We also evaluated in a cohort of T2DM diagnosed individuals using UK Biobank how disease chronicity and metformin treatment interact with the identified neurocognitive effects.
Results: The UK Biobank dataset included cognitive and neuroimaging data (N=20,314) including 1,012 T2DM and 19,302 HC, aged between 50 and 80 years. Duration of T2DM ranged from 0-31 years (mean 8.5±6.1 years); 498 were treated with metformin alone, while 352 were unmedicated. Our meta-analysis evaluated 34 cognitive studies (N=22,231) and 60 neuroimaging studies: 30 of T2DM (N=866) and 30 of aging (N=1,088). As compared to age, sex, education, and hypertension-matched HC, T2DM was associated with marked cognitive deficits, particularly in executive functioning and processing speed. Likewise, we found that the diagnosis of T2DM was significantly associated with gray matter atrophy, primarily within the ventral striatum, cerebellum, and putamen, with reorganization of brain activity (decreased in the caudate and premotor cortex and increased in the subgenual area, orbitofrontal cortex, brainstem and posterior cingulate cortex). The structural and functional changes associated with T2DM show marked overlap with the effects correlating with age but appear earlier, with disease duration linked to more severe neurodegeneration. Metformin treatment status was not associated with improved neurocognitive outcomes.
Conclusions: The neurocognitive impact of T2DM suggests marked acceleration of normal brain aging. T2DM gray matter atrophy occurred approximately 26% ± 14% faster than seen with normal aging; disease duration was associated with increased neurodegeneration. Mechanistically, our results suggest a neurometabolic component to brain aging. Clinically, neuroimaging-based biomarkers may provide a valuable adjunctive measure of T2DM progression and treatment efficacy based on neurological effects.
Funding: The research described in this paper was funded by the W. M. Keck Foundation (to LRMP), the White House Brain Research Through Advancing Innovative Technologies (BRAIN) Initiative (NSFNCS-FR 1926781 to LRMP), and the Baszucki Brain Research Fund (to LRMP). None of the funding sources played any role in the design of the experiments, data collection, analysis, interpretation of the results, the decision to publish, or any aspect relevant to the study. DJW reports serving on data monitoring committees for Novo Nordisk. None of the authors received funding or in-kind support from pharmaceutical and/or other companies to write this manuscript.
Data availability
All analyses reported in this manuscript were on either publicly available data (UK Biobank) or meta-analyses of listed published articles. Source code for all analyses conducted for this manuscript is uploaded as Source Code (Github Repo).
Article and author information
Author details
Lilianne Rivka Mujica-Parodi
Funding
W. M. Keck Foundation
- Lilianne Rivka Mujica-Parodi
National Science Foundation (NSFNCS-FR 1926781)
- Lilianne Rivka Mujica-Parodi
Baszucki Brain Research Fund
- Lilianne Rivka Mujica-Parodi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Antal et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 11,423
- views
-
- 2,169
- downloads
-
- 96
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Type 2 diabetes mellitus accelerates brain aging and cognitive decline: complementary findings from UK Biobank and meta-analyses.
eLife 11:e73138.
https://doi.org/10.7554/eLife.73138
Further reading
-
- Epidemiology and Global Health
Artificially sweetened beverages containing noncaloric monosaccharides were suggested as healthier alternatives to sugar-sweetened beverages. Nevertheless, the potential detrimental effects of these noncaloric monosaccharides on blood vessel function remain inadequately understood. We have established a zebrafish model that exhibits significant excessive angiogenesis induced by high glucose, resembling the hyperangiogenic characteristics observed in proliferative diabetic retinopathy (PDR). Utilizing this model, we observed that glucose and noncaloric monosaccharides could induce excessive formation of blood vessels, especially intersegmental vessels (ISVs). The excessively branched vessels were observed to be formed by ectopic activation of quiescent endothelial cells (ECs) into tip cells. Single-cell transcriptomic sequencing analysis of the ECs in the embryos exposed to high glucose revealed an augmented ratio of capillary ECs, proliferating ECs, and a series of upregulated proangiogenic genes. Further analysis and experiments validated that reduced foxo1a mediated the excessive angiogenesis induced by monosaccharides via upregulating the expression of marcksl1a. This study has provided new evidence showing the negative effects of noncaloric monosaccharides on the vascular system and the underlying mechanisms.
-
- Epidemiology and Global Health
- Microbiology and Infectious Disease
Influenza viruses continually evolve new antigenic variants, through mutations in epitopes of their major surface proteins, hemagglutinin (HA) and neuraminidase (NA). Antigenic drift potentiates the reinfection of previously infected individuals, but the contribution of this process to variability in annual epidemics is not well understood. Here, we link influenza A(H3N2) virus evolution to regional epidemic dynamics in the United States during 1997—2019. We integrate phenotypic measures of HA antigenic drift and sequence-based measures of HA and NA fitness to infer antigenic and genetic distances between viruses circulating in successive seasons. We estimate the magnitude, severity, timing, transmission rate, age-specific patterns, and subtype dominance of each regional outbreak and find that genetic distance based on broad sets of epitope sites is the strongest evolutionary predictor of A(H3N2) virus epidemiology. Increased HA and NA epitope distance between seasons correlates with larger, more intense epidemics, higher transmission, greater A(H3N2) subtype dominance, and a greater proportion of cases in adults relative to children, consistent with increased population susceptibility. Based on random forest models, A(H1N1) incidence impacts A(H3N2) epidemics to a greater extent than viral evolution, suggesting that subtype interference is a major driver of influenza A virus infection ynamics, presumably via heterosubtypic cross-immunity.
