Vitamin D deficit is associated with accelerated brain aging in the general population
Psychiatry Research: Neuroimaging Volume 327, December 2022, 111558 https://doi.org/10.1016/j.pscychresns.2022.111558
JanTerock ab† SarahBonk a †StefanFrenzel a Katharina Wittfeld ac LindaGarvert a Norbert Hosten d Matthias Naucke Henry Völzke f SandraVan der Auwera ac†Hans JoergenGrabe ac†
Vitamin D deficiency has been associated with reduced neurocognitive functioning and the neurodegenerative processes. However, existing evidence on brain structural correlates of vitamin D deficiency is controversial. We sought to investigate associations of vitamin D levels with imaging patterns of brain aging. In addition, we investigated whether low vitamin D levels were associated with gray matter volumes, whole brain volumes and hippocampus volumes. Structural MRI data and vitamin D levels were obtained in 1,865 subjects from the general population. Linear regressions were applied to investigate the association of vitamin D levels and vitamin D deficiency with imaging derived brain age, total brain, gray matter and hippocampal volumes. Different sets of covariates were included. Vitamin D deficiency was significantly associated with increased brain age. Also, linear vitamin D levels were significantly associated with total brain and gray matter volumes, while no significant association with hippocampal volume was found. Further interaction analyses showed that this association was only significant for male subjects. Our results support previous findings suggesting that vitamin D-deficient individuals have an accelerated brain aging. In addition, associations between vitamin D levels and total brain/ gray matter volumes suggest neuroprotective effects of vitamin D on the brain.
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Introduction
Vitamin D is a steroid hormone which is involved in various metabolic processes, particularly in the regulation of calcium and phosphate balance (Holick 2006). Apart from these classical effects, associations of vitamin D levels with accelerated aging (Annweiler et al., 2010; Gómez-Oliva et al., 2020a) and mortality (Heath et al., 2019) have been shown. More specifically, converging evidence points to a role of vitamin D deficiency in the pathophysiology of various neuropsychiatric disorders (Parker et al., 2017; Terock et al., 2020a, b; Bonk et al., 2020) and particularly of neurodegenerative processes (Gezen-Ak and Dursun 2019; Janjusevic et al., 2022). For example, lower vitamin D levels were repeatedly found to be associated with worse memory performance, executive dysfunction and overall impaired cognitive functioning in older adults (Kuźma et al., 2016; Annweiler et al., 2018; Sultan et al., 2020). Moreover, there is evidence from human and animal studies suggesting that low vitamin D levels increase the risk of developing mild cognitive impairment (Ouma et al., 2018) and Alzheimer's dementia (Littlejohns et al., 2014; Bivona et al., 2021; Navale et al., 2022). In contrast, Karakis et al. (2016) reported that vitamin D status was related to various subclinical parameters of advanced brain aging, but not risk for dementia in participants from the Framingham heart study (Karakis et al., 2016). Markers associated with advanced brain age included poorer neuropsychological functioning as well as smaller hippocampal volumes.
However, it should be acknowledged that while many cross-sectional studies found associations between low vitamin D and
- cognitive impairment,
- risk for dementia or
- neurostructural decline,
longitudinal studies yielded more mixed results:
For example, in their study on older, community-dwelling adults, Laughlin et al. found that even moderately low vitamin D levels were associated with poor cognitive functioning, while low vitamin D did not predict 12-year cognitive decline, indicating that reverse causality may at least partly account for the observed associations (Laughlin et al., 2017). In their systematic review and meta-analysis, Goodwill et al. (2017) conclude that cross-sectional studies show significant associations between low vitamin D and poorer cognition, while interventional studies still need to show a clear effect of vitamin D supplementation on cognition (Goodwill and Szoeke 2017). Moreover, some studies even showed negative associations between vitamin D status and cognitive function: For example, in Lam et al. reported that serum vitamin D-concentrations were negatively associated with measures of verbal learning and memory in a small cross-sectional study (Lam et al., 2016). In a study on very old participants aged 85 and older, very low, but also very high levels of vitamin D were associated with cognitive impairment (Granic et al., 2015).
Converging evidence suggests that vitamin D and its active form have direct influence on brain structure, neuronal integrity as well as memory capacity in humans and animals: For example, Al-Amin et al. applied structural as well as diffusion MRI datasets of elderly patients found that vitamin D deficiency is associated with reduced hippocampal volumes and connection deficits with the right hippocampus as the center of the disrupted network in patients showing mild cognitive impairment (Al-Amin et al., 2019). Miller et al. reported, that lower vitamin D levels were associated with accelerated cognitive decline (Miller et al., 2015). However, data on the relationship between vitamin D and brain aging are not fully consistent: a recent study on a large dementia-free Dutch sample showed that vitamin D deficiency was associated with smaller brain tissue and white matter volumes as well as hippocampus volume, but not with gray matter volume or white matter integrity (Croll et al., 2021).
In humans, various studies investigated the relationship between vitamin D metabolism and brain structural alterations and particularly brain age, indicating a key role of vitamin D in brain aging processes: In their systematic review and meta-analysis, Annweiler et al. (2014) provided an overview of vitamin D depletion/ repletion and their link with brain morphometric changes (Annweiler et al., 2014). In a recent large-scale examination of prospective data from the UK Biobank, Navale et al. (2022) reported that vitamin D-levels were associated in a non-linear fashion with lower volumes of total brain, gray matter and white matter in subjects with high as well as low vitamin D-levels (Navale et al., 2022). Ali et al. found a positive association between vitamin D levels and the left calcarine sulcus in older adults (Ali et al., 2020). Moreover, previous studies found associations between vitamin D status and brain volumetric changes in subjects with schizophrenia (Berg et al., 2018) and bipolar disorder(Gurholt et al., 2018). Foucault et al. reported that vitamin D levels were positively associated with cingulate cortex thickness in 80 elderly participants from the general population (Foucault et al., 2019). In a cross-sectional study on 217 community-dwelling older adults, higher vitamin D levels were associated with larger gray matter volume, but not total brain volume or white matter volume (Brouwer-Brolsma et al., 2015). Different studies also demonstrated associations between vitamin D levels and white matter abnormalities in non-clinical elderly adults (Shih et al., 2020; Croll et al., 2021). In a recent study, Khairy and Attia investigated the interplay between vitamin D and different factors including brain-derived neurotrophic factor (BDNF), oxidative stress and cholinergic function in rats (Khairy and Attia 2021). The authors reported that vitamin D supplementation significantly mitigated reductions in BDNF and acetylcholinesterase, concluding that vitamin D counteracts age-related brain dysfunction.
In summary, results from previous studies suggest that low vitamin D levels and vitamin D deficiency are involved in the pathophysiology of various neuropsychological deficits and accelerated brain aging and impaired memory functioning. In this study, we sought to investigate whether low vitamin D levels were associated with altered volumes of the gray matter as well as of the whole brain in a large population-based sample. In addition, we investigated putative associations of vitamin D levels with imaging patterns of brain aging. Finally, considering the key role of the hippocampus for learning and memory performance, we aimed at investigating the relation of vitamin D levels and hippocampal gray matter volume.
Section snippets
Sample and sample recruitment
We included 1865 study participants from the Study of Health in Pomerania-Trend baseline (SHIP-TREND-0), a general population-based cohort study, who were randomly recruited from the adult population in West Pomerania, Germany (Grabe et al., 2005; John et al., 2001; Völzke et al., 2011). A two-stage stratified cluster sample of adults aged 20 to 82 years (baseline) was drawn at random from local population registration files in which every resident has to be included by law. Among the net
Results
The sample data is characterized in Table 1. The gender ratio is almost equal with a slightly higher percentage of women (51.2%) than men (48.8%). Ages ranged between 21.9 and 81.5 years with a mean age of 51.7 years. The calculated brain age has a wider range from 18 years to 99.5 years. Vitamin D has a mean of 24.3 ng/ml and ranges from 6.2 to 63.7 ng/ml.
Discussion
Using data from a large general-population sample, we found that vitamin D deficiency was associated with neuroimaging patterns of advanced brain aging, which supports and extends previous results suggesting a link between vitamin D deficits and brain structural alterations (Foucault et al., 2019; Ali et al., 2020) in elderly individuals. Moreover, our results revealed that vitamin D levels were positively associated with total brain and gray matter volumes as well as hippocampal volume. In the . . .
Contributors
JT, SB and SV developed the content alignment of manuscript. SB calculated the analyses with support of SF. JT and SB wrote the manuscript with support of LG and SV. NH provided support regarding the evaluation and processing of the neuroimaging. MN helped collecting, evaluating and analyzing of laboratory results. HG raised the funding, implemented and supervised the SHIP studies. All authors have read and approved the final version of the manuscript.SF performed data curation and supported
S.B. and S.V. were supported by the Federal Ministry of Education and Research (BMBF, gr. No. 01KU2004) under the frame of ERA PerMed (TRAJECTOME project, ERAPERMED2019-108). L.G. was supported by the German Research Foundation (DFG, grant no. 403694598)
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VitaminDWiki - Cognitive category contains
Very brief summary of Cognitive decline
Treatment : Vitamin D intervention slows or stops progression
Prevention : Many observational studies - perhaps Vitamin D prevents
Omega-3 both prevents and treats cognition
Wonder the benefits if both Vitamin D AND Omega-3 were to be used
Dementia page - 50 items
see also Overview Alzheimer's-Cognition and Vitamin D
Overview Parkinson's and Vitamin D
Cardiovascular (
Click here for details
Poor cognition 26 percent more likely if low Vitamin D (29 studies) – meta-analysis July 2017
Every schizophrenia measure was improved when vitamin D levels were normalized – June 2021
Cognitive Impairment and Dementia often associated with low Vitamin D – April 2020
IQ levels around the world are falling (perhaps lower Vitamin D, Iodine, or Omega-3)
Search VitaminDWiki for "WHITE MATTER" 325 items as of March 2023
Types of evidence that Vitamin D helps brain problems - 2014
See also VitaminDWiki
- Brain and Vitamin D - many studies
- Vitamin D supplementation resulted in thicker Brain Cortex – RCT June 2021
Wonder low D shrinks the brain, or if low D did not allow the brain to grow originally
The brain is developing during most of the fetus time
Details at Ensure a healthy pregnancy and baby - take Vitamin D before conception
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