Cognitive Impairment & Vitamin C levels
Relationship between Vitamin C Deficiency and Cognitive Impairment in Older Hospitalized Patients: A Cross-Sectional Study
Vitamin C is a powerful antioxidant and facilitates neurotransmission. This study explored the association between vitamin C deficiency and cognitive impairment in older hospitalized patients.
This prospective study recruited 160 patients ≥ 75 years admitted under a Geriatric Unit in Australia. Cognitive assessment was performed by use of the Mini-Mental-State-Examination (MMSE) and patients with MMSE scores <24 were classified as cognitively impaired. Fasting plasma vitamin C levels were determined using high-performance liquid chromatography. Patients were classified as vitamin C deficient if their levels were below 11 micromol/L. Logistic regression analysis was used to determine whether vitamin C deficiency was associated with cognitive impairment after adjustment for various covariates. The mean (SD) age was 84.4 (6.4) years and 60% were females. A total of 91 (56.9%) were found to have a cognitive impairment, while 42 (26.3%) were found to be vitamin C deficient. The mean (SD) MMSE scores were significantly lower among patients who were vitamin C deficient (24.9 (3.3) vs. 23.6 (3.4), p-value = 0.03). Logistic regression analysis suggested that vitamin C deficiency was 2.9-fold more likely to be associated with cognitive impairment after adjustment for covariates (aOR 2.93, 95% CI 1.05–8.19, p-value = 0.031).
Vitamin C deficiency is common and is associated with cognitive impairment in older hospitalized patients.
Vitamin C also referred to as ascorbic acid, is a powerful antioxidant that cannot be synthesized by humans and some other primates due to the lack of an enzyme called gluconolactone oxidase. Vitamin C plays an essential biological role by acting as a co-factor for a number of enzymes, which are required for proper functioning across a number of organs and tissue systems. In the gastrointestinal tract, vitamin C helps in the absorption of non-heme iron and is involved in the formation of bile acids via cholesterol hydroxylation. In addition, it plays a role in immune function and is involved in the synthesis of corticosteroids, aldosterone, adrenal hormones, and the formation of collagen. Severe vitamin C deficiency results in the development of scurvy, which can manifest as bleeding, fatigue, bony pains, skin manifestations such as perifollicular hemorrhages, petechiae, and ecchymosis.
Vitamin C plays a significant role in the functioning of the brain by regulating neurotransmitter synthesis and release. These functions include acting as a co-factor for dopamine beta-hydroxylase, which converts dopamine to noradrenaline. Vitamin C is involved in the modulation of glutamatergic, dopaminergic, cholinergic, and GABAergic neurotransmission and regulates the release of catecholamines and acetylcholine from synaptic vesicles. In addition, the antioxidant properties of vitamin C limit damage caused by ischemia-reperfusion mediated injury and protect against glutamate excitotoxicity.
Previous studies indicate that vitamin C deficiency may have a role in neurocognitive dysfunction and may be associated with cognitive impairment, depression, and confusion. Two cross-sectional studies have linked lower vitamin C status with greater cognitive impairment. However, an Australian study in otherwise healthy volunteers found no association between cognitive dysfunction and vitamin C deficiency. A systematic review by Travica et al., which included 50 studies, found no correlation between vitamin C levels and cognition, however, the majority of studies included in this review involved community-dwelling healthy participants with a higher baseline cognitive performance, which could have narrowed the chance of detecting cognitive effects of vitamin C. In addition, the studies included in this meta-analysis had limitations in terms of handling of blood samples and biochemical analyses because underestimation of vitamin C concentrations could occur if the sample was not protected from light and not transported on ice.
Furthermore, some of the studies to date have other methodological limitations namely: use of small sample size and a variable definition for classification of patients as vitamin C deficient, with one study classifying patients with vitamin C levels below 28 μmol/L as deficient while another study using even higher cut-off levels. Evidence suggests that clinical manifestations of scurvy usually develop once vitamin C levels drop below 11.4 μmol/L, thus it is possible that cognitive dysfunction may not be present at a higher vitamin C level and manifests only in patients who have a severe vitamin C deficiency. The present study investigated the relationship between cognitive status and vitamin C deficiency in older hospitalized patient’s units using lower vitamin C cut-off levels, which usually result in clinical manifestations of scurvy. The hypothesis for this research was that vitamin C deficiency is common in older hospitalized patients and that patients with severe vitamin C deficiency will have lower cognitive scores.
A total of 603 patients were admitted under the geriatric unit between May and December 2020, of whom, 176 patients were approached by convenient sampling for participation and 160 patients were recruited for this study. The characteristics of patients who were not approached for participation were not significantly different from those who were included in this study in terms of age, sex, Charlson index, living status, and length of hospital stay (LOS) (p > 0.05). The mean (SD) age was 84.4 (6.4) years range (73–105 years) and 96 (60%) were females. All patients were residing in their own homes and 78 (48.7%) were living with their partners. The mean Charlson index was 8.4 (2.6) and the majority of patients were on polypharmacy (130; 81.3%) and many were admitted with falls as the principal diagnosis (69, 43.1%). The mean (SD) MMSE score was 24.6 (3.4) (range 19–30). A total of 69 (43.1%) patients had normal cognition (MMSE score ≥ 24) and 91 (56.9%) were found to have cognitive impairment (MMSE score < 24). Patients with cognitive impairment were older, with a higher Charlson index and frailty score, and were less likely to have a university degree than cognitively intact patients (p < 0.05). However, there was no difference with regards to gender, nutrition status, marital status, and the number of medications between the cognitively normal and impaired groups (p > 0.05). The mean (SD) vitamin C levels were 26.8 (23.0) μmol/L, (range 3–148). The median (IQR) time from hospital admission to the collection of vitamin C samples was 4 (4, 4) days. A total of 118 (73.7%) patients were not vitamin C deficient (vitamin C levels ≥ 11 μmol/L), while 42 (26.3%) were classified as vitamin C deficient (levels <11 μmol/L).
The median (IQR) time for the collection of the vitamin C sample after hospital admission was not significantly different between patients who were not vitamin C deficient compared to those who had vitamin C deficiency (4 (4, 3) vs. 4 (4, 4) days, p-value = 0.095). Patients with vitamin C deficiency were more likely to be current smokers with a higher Charlson index and mean creatinine level than patients who were not vitamin C deficient. When compared to patients who were not vitamin C deficient, the mean (SD) MMSE scores were significantly lower among patients who were vitamin C deficient (24.9 (3.3) vs. 23.6 (3.4), p-value = 0.03). However, there was no difference in the proportion of patients who made errors on the CDT between the two groups.
Logistic regression analysis suggested that vitamin C deficiency was 2.9-fold more likely to be associated with cognitive impairment after adjustment for age, sex, Charlson index, MUST score, HARP score, depression, living status (whether alone), education level, socioeconomic status, fruit/vegetable intake, polypharmacy, hemoglobin, creatinine, vitamin D and vitamin B12 levels (aOR 2.93, 95% CI 1.05–8.19, p-value = 0.031). Sensitivity analysis confirmed that vitamin C deficiency was associated with cognitive impairment after adjustment for the above-mentioned covariates (Coefficient 1.03, Bootstrap SE 0.50, 95% CI 0.05–2.03, p-value 0.039). The margins plot suggested that lower MMSE scores increase the probability of being diagnosed with vitamin C deficiency.
A substantial proportion (26.3%) of older hospitalized patients were vitamin C deficient. Only a few clinical characteristics, namely a history of current smoking and higher Charlson index and creatinine levels predicted vitamin C deficiency. Vitamin C deficiency was associated with an increased risk of cognitive impairment as assessed by the MMSE scores but not when assessed by the CDT even after adjustment for a number of covariates.
The results of our study corroborate previous evidence that a high proportion of older hospitalized patients have a vitamin C deficiency. Interestingly, our study indicates that there are only a few clinical correlates, which can predict a low vitamin C of the home-dwelling but currently hospitalized elderly. Furthermore, according to this study, the symptoms, which were compatible with the diagnosis of scurvy, were not significantly different among patients with or without vitamin C deficiency. Scurvy is characterized by prominent skin manifestations, including perifollicular hyperkeratosis, cork-screw hairs, gingival bleeding, petechiae, and ecchymosis Bruising and bleeding, which characterize scurvy, can be seen in older hospitalized patients because of a number of reasons such as falls, senile purpura (which occurs because of increased skin fragility associated with aging) and the adverse effects of commonly administered medications such as antiplatelet agents, anti-coagulants and glucocorticoids. Moreover, perifollicular hyperkeratosis, which is regarded as a hallmark of scurvy, may be difficult to differentiate from leukocytoclastic vasculitis. It may, therefore, be difficult to diagnose vitamin C deficiency solely on clinical grounds in older hospitalized patients. Given the high prevalence of vitamin C deficiency in hospitalized patients, there is a need for heightened vigilance, and biochemical confirmation of vitamin C status is required in suspected cases.
This study indicates that vitamin C deficiency was associated with cognitive impairment as reflected by lower MMSE scores in vitamin C deficient patients when compared to those who were not vitamin C deficient. This association remained significant after adjustment for not only age but also various factors, which can be associated with cognitive impairment such as a higher number of comorbidities as determined by the Charlson index, education level, depression, socioeconomic status, polypharmacy, hemoglobin, creatinine, vitamin D and B12 levels. Our study results are in line with a study by Gale et al. from the UK, which involved 921 community-dwelling older people ≥ 65 years. Their study found that patients with moderate to severe vitamin C deficiency were 1.6-fold (OR 1.6, 95% CI 1.1–2.3) more likely to be diagnosed with cognitive impairment assessed by use of the Hodgkinson abbreviated mental test. Similarly, another recent study from New Zealand, which included a cohort of 404 people aged 49–51 years, found that the odds of mild cognitive impairment, as determined by Montreal Cognitive Assessment (MOCA), were twice as high for individuals whose vitamin C levels were below 23 μmol/L (OR 2.1, 95% CI 1.2–3.7, p = 0.01). However, our study results are contrary to an Australian study, which included healthy adults aged 24–96 years and assessed cognitive function by use of a battery of cognitive screening tools: the Modified Mini-Mental State Examination (3MS), the Revised Hopkins Verbal Learning Test (HVLT-R), the Symbol Digits Modalities Test (SDMIT) and the Swinburne University Computerised Cognitive Assessment Battery (SUCCAB). That study found that there was no difference with respect to the diagnosis of major cognitive impairment with 3MS test among patients with adequate or inadequate vitamin C status. However, patients who were in the adequate vitamin C group had significantly higher scores on measures of recognition, immediate and delayed recall assessed by the HVLT-R and on SDMT screening when compared to vitamin C inadequate group.
Finally, using the SUCCAB, that study found that, although the accuracy to reaction time was significantly higher in the adequate vitamin C group for certain tasks, there was no difference with respect to measures of episodic memory or general alertness and motor speed when compared to the vitamin C inadequate group. The discrepancy in the results of this study compared to our study, in terms of cognition, could be related to their inclusion of much younger patients and likely healthier patients with a wide age range from the community compared to older hospitalized patients in our study. In addition, that study used higher vitamin C cut-off levels (<28 μmol/L vs. <11 μmol/L) for diagnosing vitamin C deficiency compared to our study. It is possible that cognitive dysfunction is apparent only with severely low vitamin C status (i.e., vitamin C levels < 11 μmol/L) and may not manifest with less severe degrees of hypovitaminosis C (11–28 μmol/L). In support of this conjecture, a re-analysis of our own data using these authors’ looser definition of vitamin C deficiency showed no significant alteration of cognition in the deficient subjects (data not shown).
Subtle changes in cognition might be detectable with a less severe deficiency of vitamin C. Animal studies have indicated that higher supplementation of vitamin C reduced amyloid plaque burden in the cortex and hippocampus in mice with resultant amelioration of blood-brain barrier disruption and mitochondrial alteration. However, evidence in relation to the benefits of vitamin C supplementation on cognition is limited. A recent meta-analysis , which included randomized or quasi-randomized placebo-controlled trials of vitamin and mineral supplementation for preventing dementia or delaying cognitive decline among patients with mild cognitive impairment, found only one trial, which included combined vitamin E and C supplementation in 256 patients and found no conclusive data for supplementation, reducing the risk of progression to dementia due to very low-quality evidence. Due to this research gap, it will be difficult to determine whether the routine determination of vitamin C status in patients with cognitive impairment, let alone its supplementation, is a useful and cost-effective strategy.
Vitamin C deficiency is common, and there are few clinical correlates that can usefully lead to the identification of this condition in older hospitalized patients. Vitamin C deficiency is associated with cognitive impairment, and further studies are needed to confirm and characterize this association in greater detail.
Relationship between Vitamin C Deficiency and Cognitive Impairment in Older Hospitalised Patients: A Cross-Sectional Antioxidants 2022, 11(3), 463; https://doi.org/10.3390/antiox11030463