Relationship between Vitamin C Deficiency and Cognitive Impairment in Older Hospitalised Patients: A Cross-Sectional Study

Round 1

Reviewer 1 Report

The cross-sectional study by Sharma and coworkers regards the relationship between vitamin C deficiency and cognitive impairment in older patients admitted to a Geriatric Evaluation and Maintenance Unit.

The study is very interesting and shows that people with low vitamin C plasma levels present cognitive impairment.

Some points need to be better addressed:

1. It should be interesting to assess, whenever possible, which areas of cognition are mainly involved at the MMSE test (orientation, attention, concentration, short term memory);
2. Regarding polypharmacy, please provide the kind of drugs used. Are there drugs with anticholinergic properties or potentially leading to cognitive impairment? (i.e., benzodiazepines, antipsychotics and so on);
3. It should be interesting as well to know whether or not cognitive impairment is more frequent in the oldest age group.

Please, provide number and date of registration of the Ethical approval.

Author Response

We thank reviewer for useful comments.

The cross-sectional study by Sharma and coworkers regards the relationship between vitamin C deficiency and cognitive impairment in older patients admitted to a Geriatric Evaluation and Maintenance Unit.

The study is very interesting and shows that people with low vitamin C plasma levels present cognitive impairment.

Some points need to be better addressed:

1. It should be interesting to assess, whenever possible, which areas of cognition are mainly involved at the MMSE test (orientation, attention, concentration, short term memory);

Response: We thank reviewer for their comments and suggestions. We agree with the reviewer’s comments that it would be interesting to assess the specific areas of cognition involved in the MMSE. Unfortunately, we did not specifically analyse these specific cognitive domains. However, we did use the clock drawing test (CDT) in addition to the MMSE, which does tap different neuropsychological areas for its completion such as the perceptual, executive, motor and visuospatial abilities.^{1 2} We have now added a statement in the limitations section of this manuscript.

“We used the total MMSE score to assess cognition, the impact of vitamin C deficiency on specific areas of cognition involved in the performance of the MMSE such as orientation, attention, concentration and short term memory was not determined.”

1. Regarding polypharmacy, please provide the kind of drugs used. Are there drugs with anticholinergic properties or potentially leading to cognitive impairment? (i.e., benzodiazepines, antipsychotics and so on);

Response: We have now determined drugs with anticholinergic activity which can potentially impact cognition as advised by the reviewer. These have been mentioned in methods section page 6 and in Table 1.

           “Medications with anticholinergic activity, which can impact cognition (such as use of antihistamines, antiparkinson, opiates, antimuscarinic, antipsychotic and antiepileptic drugs)[35] were also determined.”

1. It should be interesting as well to know whether or not cognitive impairment is more frequent in the oldest age group.

Response: The mean (SD) age of our population was 84.4 (6.4) years and 91 (56.6%) had cognitive impairment. In the oldest age group (≥85 years), the proportion of patients who had cognitive impairment was 68.1%. Vitamin C deficiency was more common in the oldest of old patients with cognitive impairment but not statistically significantly different compared to those with normal cognition (32.6% vs 13.0%, P=0.078)

Please, provide number and date of registration of the Ethical approval.

Response: We have now provided these details.

References

1. Colombo M, Vaccaro R, Vitali SF, et al. Clock drawing interpretation scale (CDIS) and neuro-psychological functions in older adults with mild and moderate cognitive impairments. Arch Gerontol Geriatr 2009;49 Suppl 1:39-48.doi:10.1016/j.archger.2009.09.011
2. Nagahama Y, Okina T, Suzuki N, et al. Neural correlates of impaired performance on the clock drawing test in Alzheimer's disease. Dement Geriatr Cogn Disord 2005;19:390-6.doi:10.1159/000084710

Reviewer 2 Report

This manuscript tests the relationship between Vitamin C deficiency and the presence of cognitive impairment in older adults currently hospitalized.

The results are well presented and the comparisons are logical and appropriate.

The biggest drawback of the study was noted by you already and it is that the MMSE is not the most sensitive tool for measuring cognitive impairment. However the Clock Drawing Test (CDT) is sensitive and you should provide a reference or two on its use, explaining why you used in in addition to the MMSE (as well as instead  other such tools). It is hoped that you,, if you continue to use the MMSE in future studies, will also use at least one other screening test in order to strengthen your conclusions.

You indicate that your study supports the literature that indicate a correlation between vitamin C status nd cognitive status. Please comment further on whether there is anything about your study (beyond the age range of the subjects) that supported this conclusion.

Recommended additional key words: clock drawing test, MMSE

Why is rehabilitation unit one of the key phrases? Perhaps exchange with hospital?

Discussion: Could you add a recommendation for possible treatment? Is there evidence that vitamin C supplementation can improve cognition? Is there a good reason for knowing the vitamin C status of persons with a diagnosis of dementia?

Author Response

This manuscript tests the relationship between Vitamin C deficiency and the presence of cognitive

impairment in older adults currently hospitalized.

The results are well presented and the comparisons are logical and appropriate.

The biggest drawback of the study was noted by you already and it is that the MMSE is not the most sensitive tool for measuring cognitive impairment. However the Clock Drawing Test (CDT) is sensitive and you should provide a reference or two on its use, explaining why you used in addition to the MMSE (as well as instead other such tools). It is hoped that you,, if you continue to use the MMSE in future studies, will also use at least one other screening test in order to strengthen your conclusions.

Response: We than reviewer for comments. We agree with the reviewer that MMSE is not the most sensitive tool for measuring cognitive impairment, while, the CDT is highly sensitive and specific in the detection of mild dementia and reasonably accurate in separating patients with mild cognitive impairment from healthy controls. The combination of the CDT with the MMSE enhances the psychometric properties of these scales and has been validated in differentiating patients suffering from dementia from those without dementia. We have now included this in the text and have also added supporting references. We plan to use additional tools if we continue to use MMSE for our future studies to strengthen our conclusions. We have now included this statement along with two new references in the Materials and methods section on page 3.

“We used the CDT in addition to the MMSE because studies indicate that the CDT is highly sensitive and specific in detection of mild dementia and is reasonably accurate in separating patients with mild cognitive impairment (MCI) from healthy patients, and the combination of the CDT with the MMSE enhances the psychometric properties of these scales and is valid for detection of dementia^{1 2}”

You indicate that your study supports the literature that indicate a correlation between vitamin Cstatus and cognitive status. Please comment further on whether there is anything about your study

(beyond the age range of the subjects) that supported this conclusion.

Response: We found that even after adjustment for a number of other factors apart from age, which can be associated with cognitive impairment such as higher number of comorbidities, education level, depression, socioeconomic status, polypharmacy, haemoglobin, creatinine, vitamin D and B12 levels, vitamin C deficiency was associated with cognitive impairment. We have now included this statement in the discussion section on page 10 with 6 new references.

“This association remained significant after adjustment for not only age but also various factors which can be associated with cognitive impairment such as higher number of comorbidities as determined by the Charlson index, education level, depression, socioeconomic status, polypharmacy, haemoglobin, creatinine, vitamin D and B12 levels.^3-8”

 Recommended additional key words: clock drawing test, MMSE

Response: We have now included these key words as suggested by the reviewer.

Why is rehabilitation unit one of the key phrases? Perhaps exchange with hospital?

Response: We have now changed this to older hospitalised patients as suggested by the reviewer.

Discussion: Could you add a recommendation for possible treatment? Is there evidence that vitamin C supplementation can improve cognition? Is there a good reason for knowing the vitamin C status of persons with a diagnosis of dementia?

Research: Although animal studies^{9 10} have indicated that higher supplementation of vitamin C reduces amyloid plaque burden in cortex and hippocampus. However, there is dearth of quality RCTs testing benefits of vitamin C supplementation among patients with cognitive impairment. We have included a statement with reference to a recent systematic review ¹¹, which found only one trial which used combined vitamin C and E supplementation among patients with cognitive impairment and found no conclusive evidence in support because of the low quality of the included study. We have now included this in the discussion section.

“Animal studies[58,59] have indicated that higher supplementation of vitamin C reduced amyloid plaque burden in 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 [60]which included randomised or quasi-randomised 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 in reducing risk of progression to dementia with supplementation due to very low-quality evidence. Due to this research gap, it will be difficult to determine whether routine determination of vitamin C status in patients with cognitive impairment is a useful and cost-effective strategy?”

References

1. Cacho J, Benito-León J, García-García R, et al. Does the combination of the MMSE and clock drawing test (mini-clock) improve the detection of mild Alzheimer's disease and mild cognitive impairment? J Alzheimers Dis 2010;22:889-96.doi:10.3233/jad-2010-101182
2. Heinik J, Solomesh I, Bleich A, et al. Are the clock-drawing test and the MMSE combined interchangeable with CAMCOG as a dementia evaluation instrument in a specialized outpatient setting? J Geriatr Psychiatry Neurol 2003;16:74-9.doi:10.1177/0891988703016002002
3. Lipnicki DM, Sachdev PS, Crawford J, et al. Risk factors for late-life cognitive decline and variation with age and sex in the Sydney Memory and Ageing Study. PLoS One 2013;8:e65841.doi:10.1371/journal.pone.0065841
4. Sattler C, Toro P, Schönknecht P, et al. Cognitive activity, education and socioeconomic status as preventive factors for mild cognitive impairment and Alzheimer's disease. Psychiatry Res 2012;196:90-5.doi:10.1016/j.psychres.2011.11.012
5. Peters R, Burch L, Warner J, et al. Haemoglobin, anaemia, dementia and cognitive decline in the elderly, a systematic review. BMC Geriatr 2008;8:18.doi:10.1186/1471-2318-8-18
6. Chaiben VBO, Silveira TBD, Guedes MH, et al. Cognition and renal function: findings from a Brazilian population. J Bras Nefrol 2019;41:200-07.doi:10.1590/2175-8239-jbn-2018-0067
7. Goodwill AM, Szoeke C. A Systematic Review and Meta-Analysis of The Effect of Low Vitamin D on Cognition. J Am Geriatr Soc 2017;65:2161-68.doi:10.1111/jgs.15012
8. Moretti R, Torre P, Antonello RM, et al. Vitamin B12 and folate depletion in cognition: a review. Neurol India 2004;52:310-8.doi:
9. Frontiñán-Rubio J, Sancho-Bielsa FJ, Peinado JR, et al. Sex-dependent co-occurrence of hypoxia and β-amyloid plaques in hippocampus and entorhinal cortex is reversed by long-term treatment with ubiquinol and ascorbic acid in the 3 × Tg-AD mouse model of Alzheimer's disease. Mol Cell Neurosci 2018;92:67-81.doi:10.1016/j.mcn.2018.06.005
10. Kook SY, Lee KM, Kim Y, et al. High-dose of vitamin C supplementation reduces amyloid plaque burden and ameliorates pathological changes in the brain of 5XFAD mice. Cell Death Dis 2014;5:e1083.doi:10.1038/cddis.2014.26
11. McCleery J, Abraham RP, Denton DA, et al. Vitamin and mineral supplementation for preventing dementia or delaying cognitive decline in people with mild cognitive impairment. Cochrane Database Syst Rev 2018;11:Cd011905.doi:10.1002/14651858.CD011905.pub2