Showing posts with label vitamin B. Show all posts
Showing posts with label vitamin B. Show all posts
Wednesday, May 20, 2026
Wednesday, May 6, 2026
We Asked Doctors Which Supplements Actually Support Healthy Aging—These Are the 9 They Recommended
If your doctor hasn't already given you supplement protocols(amounts and timing)THEN YOU HAVE AN INCOMPETENT DOCTOR! No question about that.
We Asked Doctors Which Supplements Actually Support Healthy Aging—These Are the 9 They Recommended
Supplements are everywhere these days, promising to help improve nearly every facet of your health—some also say they can boost longevity or promote healthy aging.
Taking supplements can’t guarantee that you’ll live longer, and many products aren’t doctor-approved or backed by medical research.
But certain products stand out amongst the rest when it comes to helping you age well. Here are the nine supplements experts recommend.
Talk to your doctor before trying new supplements to see if they’re right for you. Some can negatively interact with certain prescription medications or worsen symptoms of underlying health conditions.
1. Omega-3 (Fish Oil)
Exploratory studies have found that omega-3, which is found in fish oil capsules, is associated with better memory.1 It may also be able to help slow biological aging when combined with vitamin D and exercise.
“Omega-3 fatty acids reduce chronic inflammation and support heart and brain health, [as well as] healthy aging,” John Rinker, MD, internal medicine physician at OSF HealthCare, told Health.
Fish oil capsules themselves have also been linked to lower rates of cardiovascular disease, Thomas Perls, MD, MPH, professor of medicine at the Boston University Chobanian & Avedisian School of Medicine and director of the New England Centenarian Study, told Health. However, research is mixed.2
Who should take it: Most people over 40 can take 1-2 grams of omega-3 fish oil capsules per day, Rinker said. Just be sure to avoid high doses if you’re taking a blood thinner, Kien Vuu, MD, author and performance and longevity medicine consultant, told Health.
2. Vitamin D3 + K2
Vitamin D3 and K2 are often combined into one supplement because they work together in a very specific way, and are “critical for immune balance, bone health, and vascular strength,” Vuu said.3
Also known as cholecalciferol, “vitamin D3 is necessary for calcium absorption for bone and muscle strength,” Chris Renna, DO, family medicine physician and founder of LifeSpan Medicine, told Health. It can also support immune function and create healthy skin, he said.4
Meanwhile, vitamin K2 is used to make proteins involved in blood clotting and bone metabolism. Plus, it may help prevent the buildup of minerals in your arteries.56
Who should take it: Supplements containing both vitamins D3 and K2 are specifically helpful for people over 50, Rinker said. But people should use caution if they’re taking Warfarin, or if they have existing calcium disorders or kidney dysfunction, he said.7
3. B Vitamins
There are eight types of B vitamins, and each one plays a crucial role in your health. They help with metabolism, DNA production, and immune system function, and can “protect neural pathways and enhance energy,” said Vuu.89
For older adults, deficiencies in vitamin B can contribute to health issues such as cardiovascular disease, stroke, cognitive disorders, mental health issues, and more.10
Researchers have suggested that vitamin B12, in particular, may be involved in aging at the cellular level, but evidence is still preliminary.11
Who should take it: If bloodwork shows that you have low vitamin B levels, your doctor might recommend you take a complex supplement once daily.
4. Magnesium
While most people take magnesium to improve sleep or reduce stress, experts said it could help with healthy aging, too.
Magnesium deficiency has been linked to increased chronic inflammation and other concerning cellular changes, which may raise people's risk of conditions such as heart disease, cancer, and Alzheimer’s disease.12
Plus, low levels of magnesium can also mess with your sleep, which is connected to longevity.13
Who should take it: “Magnesium typically helps most adults, especially those with a deficiency,” Rinker said. That can be diagnosed with a blood test.14 There are many different types and formulations of magnesium supplements, and a healthcare provider can help you choose which one might work best.15
5. CoQ10
Coenzyme Q10, or CoQ10, is an antioxidant that’s abundant in the body. It also helps with mitochondrial function, where it provides energy for cell growth.16 This is “vital to high-energy-demanding organs like our brain, heart, and skeletal muscle,” Renna explained.
As you age, your CoQ10 levels naturally decline. But research suggests taking CoQ10 supplements may help reduce inflammation, support heart health, and protect cells from damage called oxidative stress.1718
Who should take it: Some research suggests CoQ10 could lower “blood pressure and blood sugar, which may not be helpful to some people taking medicine prescribed to do those same things,” said Renna.1920
6. Fiber
According to Vuu, fiber supports your gut barrier’s integrity and calms chronic inflammation.21 It’s also been associated with a lower risk of all-cause mortality, as well as a lower risk of death from cardiovascular disease or cancer.22
Who should take it: The vast majority of Americans don’t get enough fiber each day.23 If you struggle to hit your goals, daily fiber supplements containing psyllium (Metamucil) or wheat dextrin (Benefiber) could help improve your gut and immune health as you age.24
7. Calcium
As you age, your bones get weaker. This increases the risk of conditions like osteoporosis, and in turn, bone fractures.25
Calcium supplements may help prevent this. The mineral has been linked to improved bone strength and bone density.2627
Who should take it: Most people don't get enough calcium, and a supplement can be helpful if you struggle to get enough in your diet.28 However, excess calcium can be dangerous—have a healthcare provider check your levels before starting a supplement, particularly if you have other health conditions.26
8. Creatine
Creatine is often thought of as a “bodybuilder supplement.” But according to Rinker, creatine can help people preserve muscle mass and reduce the risk of muscle wasting, or sarcopenia, as they get older. It could “also help with inflammation and joint health,” he added.29
Some evidence suggests that creatine supplementation for older adults can enhance memory, though more research is needed.30
Who should take it: Most creatine comes in powder form that’s mixed into beverages, and it can be taken anytime. The supplement is great for active people, but use it with caution if you have existing kidney issues.31
9. Curcumin (Turmeric)
Curcumin—the main active ingredient in turmeric—helps tamp down inflammation in the body, Darshan Shah, MD, surgeon, longevity medicine specialist, and founder of Next Health, told Health.
Because of this, it could be helpful for longevity purposes. One study suggested curcumin may have a positive effect against neurodegenerative diseases, cognitive decline, and sarcopenia.32 Another review found that taking curcumin extract may be able to relieve knee pain from osteoarthritis.33
Who should take it: Oral turmeric supplements are popular and could be beneficial for people with inflammatory conditions, Rinker said. "But it's advisable to exercise caution if you have gallstones or [gastrointestinal] sensitivity," he added.34
Thursday, July 17, 2025
The Role of Vitamins in Neurodegeneration: A Brief Review of Mechanisms, Clinical Evidence, and Therapeutic Perspectives
Pretty useless, nothing on how to test for this and NOTHING ON AMOUNTS!
The Role of Vitamins in Neurodegeneration: A Brief Review of Mechanisms, Clinical Evidence, and Therapeutic Perspectives
Affiliations
- PMID: 40659185
- DOI: 10.1111/psyg.70071
Abstract
This review evaluates the role of vitamins in neurodegeneration.
Low levels of B vitamins have been associated with cognitive decline. B vitamins may help inhibit amyloid plaque aggregation.
Vitamin D deficiency has been linked to an increased risk of cognitive impairment, correlating with Alzheimer's pathology.
Vitamin E may help delay Alzheimer's disease progression and support functional abilities.
In Parkinson's disease, vitamin D shows promise in reducing dopaminergic neuron loss and improving motor and cognitive outcomes.
Vitamin C reduces oxidative stress and preserves neuronal integrity.
Vitamin K has gained attention for its role in cognitive health, with studies suggesting that higher levels may be linked to improved cognitive performance.(Not to be taken while on warfarin(rat poison)) In conclusion, a better understanding of the translational potential of these vitamins may inform preventive and therapeutic strategies for neurodegenerative diseases. Clinicians should consider vitamin supplementation for aging-related conditions. Further studies are needed to confirm its therapeutic potential and clarify underlying mechanisms in neurodegeneration.
Keywords: Alzheimer's disease; cognitive impairment; neurodegeneration; neuroprotection; oxidative damage; vitamin supplementation.
© 2025 Japanese Psychogeriatric Society.
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Saturday, June 25, 2022
Problem in the Recent American Heart Association Guideline on Secondary Stroke Prevention: B Vitamins to Lower Homocysteine Do Prevent Stroke
Have your doctor prove their well reasoned conclusion from this disagreement.
Problem in the Recent American Heart Association Guideline on Secondary Stroke Prevention: B Vitamins to Lower Homocysteine Do Prevent Stroke
Originally published24 Jun 2022https://doi.org/10.1161/STROKEAHA.122.038640Stroke. 2022;0:10.1161/STROKEAHA.122.038640
Abstract
In this article, we discuss a problem in the most recent American Heart Association guideline on secondary stroke prevention that apparently arose from the rules of evidence imposed on the guideline panel. We are told by the cochair of the panel that American Heart Association rules about guidelines for secondary prevention prohibited consideration of primary prevention studies and secondary analyses of secondary prevention studies. However, evidence-based medicine should consider all the best external evidence available and also clinical judgement. The most important problem in the guideline was the recommendation that B vitamins to lower homocysteine do not prevent recurrent stroke. When considering all the best external evidence, it is clear that B vitamins do prevent stroke, but in the early secondary stroke prevention studies, the benefit of B vitamins in participants with good renal function was apparently offset by harm from cyanocobalamin among participants with renal failure (level B-R evidence). We review the evidence that B vitamins should be used to prevent stroke, both in primary and secondary stroke prevention (class 2a recommendation). We also review issues in folate metabolism that require further study, with regard to the form of folate to be used for stroke prevention. We recommend that the guideline be revised to say that B vitamins to lower homocysteine prevent stroke and that methylcobalamin or hydroxycobalamin should be used instead of cyanocobalamin.
Saturday, April 16, 2022
B-vitamin supplementation on mitigating post-stroke cognition and neuropsychiatric sequelae: A randomized controlled trial
So no benefit.
B-vitamin supplementation on mitigating post-stroke cognition and neuropsychiatric sequelae: A randomized controlled trial
Hong Kuang Tanhttps://orcid.org/0000-0002-4743-85151, Kaavya Narasimhaluhttps://orcid.org/0000-0001-6116-30202,*, Simon Kang Seng Tinghttps://orcid.org/0000-0003-4852-97902, Shahul Hameed2, Hui Meng Chang2, Deidre Anne De Silvahttps://orcid.org/0000-0002-7123-23812, Christopher Li Hsian Chen3, and Eng King Tan2
Background and Purpose:
Background and Purpose:
A third of stroke patients suffer from post-stroke cognitive decline, depressive symptoms, and anxiety symptoms. B-vitamin supplementation provides a possible safe and affordable treatment to mitigate post-stroke neuropsychiatric sequelae via reducing homocysteine levels. Our study aims to examine the effect of B-vitamin supplementation in the prevention of post-stroke cognitive decline, depressive symptoms, and anxiety symptoms. Our secondary aims were to investigate associations between baseline factors and the three outcomes.
Methods:
Patients were recruited as part of a Singaporean substudy of a randomized controlled trial that examined the effect of B-vitamin supplementation on recurrent cardiovascular events. Cognitive decline, depressive symptoms, and anxiety symptoms were assessed with neuropsychological assessments and Hospital Anxiety and Depression Scale 6 monthly. Cox regression analyses were performed to determine treatment efficacy. Logistic regression used to examine factors associated with cognitive decline, depressive symptoms, and anxiety symptoms.
Results:
A total of 707 were included in the analyses. Survival and hazards ratio analysis showed no treatment effect of B-vitamins on cognitive decline, depressive symptoms, and anxiety symptoms. Cognitive decline was only associated with age. Depressive symptoms were associated with large anterior cerebral infarcts and hyperlipidemia.
Conclusions:
Our study showed no benefit of supplementation with B-vitamins for post-stroke cognitive decline, depressive symptoms, or anxiety symptoms. Depressive symptoms were associated with larger anterior cerebral infarcts, which may be reflective of the disability associated with larger infarcts.
Keywords
Stroke, B-vitamin, cognition, depression, anxiety
1Duke-NUS Medical School, Singapore
2Department of Neurology, National Neuroscience Institute (Singapore General Hospital Campus), Singapore
3Department of Pharmacology, National University of Singapore, Singapore
Corresponding author(s):
Kaavya Narasimhalu, Department of Neurology, National Neuroscience Institute, SGH Campus, Outram Road, Singapore 169608. Email: nkaavya@gmail.com
*
Kaavya Narasimhalu is now affiliated to Duke-NUS Medical School, Singapore
Introduction
Background
Stroke is a leading cause of disability and 30% of stroke patients experience some form of cognitive decline within 3 years post-stroke1—which includes both dementia2 and cognitive impairment no dementia (CIND).3 In addition, stroke can also result in neuropsychiatric complications such as depression4 and anxiety.5 One contributory factor postulated for these post-stroke sequelae is hyperhomocystinemia6—which may reduce brain volume possibly through oxidative stress resulting in cognitive decline.7 Serum homocysteine levels can be lowered by B12, Folate, and B6 through methylation.8 Furthermore, an Australian substudy of the same international trial as our study found that B-vitamin supplementation associated with a lower hazard of major depression compared with placebo.9 Hence, using B-vitamins to lower post-stroke homocysteine serum concentrations was proposed as a treatment to mitigate these post-stroke cognitive decline, depression, and anxiety.10
Besides potential efficacy, there are other advantages of using B-vitamins as an alternative or augmentation to current conventional treatments. They can be safely added to current cardiovascular medications and are safer and have less adverse effects compared with prophylactically administering antidepressants to prevent post-stroke depression and anxiety. Furthermore, they may augment the efficacy of current standard antidepressant treatment as well.11 Therefore, studying the efficacy of B-vitamin supplementation on post-stroke cognitive and neuropsychiatric sequelae is important.
Although other studies examined the relationship between stroke and cognitive impairment, few studies looked specifically at the effects of B-vitamin on CIND, depressive, symptoms, and anxiety symptoms on patients who had either an ischemic stroke or a transient ischemic attack (TIA). Hence, our study (a substudy of a large scale multicentre randomized control trial designed to assess the impact of B-vitamin supplementation on recurrent vascular events in patients with a prior stroke—VITAmins To Prevent Stroke (VITATOPS))12 endeavors to examine the effects of B-vitamins on reducing the rates of post-stroke cognitive decline, depressive symptoms, and anxiety symptoms.
Aims and hypothesis
We aim to bridge this gap in the current literature by comparing the incidence rates of post-stroke cognitive impairment, depressive symptoms, and anxiety symptoms in those who received B-vitamin supplements post-stroke with those who did not. We hypothesize that patients who received B-vitamin supplementation would have reduced risk of acquiring post-stroke cognitive decline, depressive symptoms, and anxiety symptoms compared with those in the placebo group.
Methods
Patients
Patients were recruited as part of a larger multicentre, double blinded, placebo-controlled randomized trial VITATOPS12 that examined B-vitamins’ effects in reducing risk of major cardiovascular events in people who had a recent ischemic stroke or TIA link to CONSORT Statement (Appendix 1). In the Singapore study site, ischemic stroke and TIA patients who presented to Singapore General Hospital between July 2000 and May 2007 were approached for inclusion in this study within the first 7 months of their index event. Patients were excluded if they were on folate antagonists or B-vitamin supplements and were not willing to switch, had a short remaining life-expectancy, or were women of childbearing potential. However, patients on B-vitamin supplements and were willing to switch to the study medication were included.
In addition, those who fulfilled the diagnostic criteria for dementia at baseline were excluded.
Randomization
Patients were randomized by a telephone service or an interactive website using blocks stratified by hospital.
Protocol approvals, registrations, and patient consent
The study protocol was approved by Singapore General Hospital’s Institutional Review Board and Ethics Committee. Written consent was obtained from patients or legal guardians. The VITATOPS study was registered under clinical-trials.gov with the identification number NCT00097669.
Intervention
Patients enrolled in the study were required to take one composite tablet that contained 25 mg vitamin B6, 2 mg Folic acid, and 0.5 mg vitamin B12 or a placebo pill of similar color and texture daily. Adherence was checked by questioning, tablet count, and return of tablet container. Patients, clinicians, and caregivers were blinded. Patients were then followed up every 6 months up to a 5-year period after randomization.
Demographic and stroke-related measures
Baseline characteristics such as age, sex, ethnic background, smoking status, education level, medical history of diabetes, hypertension, dyslipidemia, stroke classification, ischemic heart disease, angina, myocardial infarction, previous stroke, and peripheral vascular diseases of patients were assessed. Baseline serum homocysteine, folate, and B12 levels were also recorded.
Neuropsychological assessment
Assessment of cognitive domains was performed with a battery of tests validated in Singapore13 at baseline and subsequently in 6 monthly intervals. Education-adjusted cutoffs of 1.5 standard deviations below established normal means14 were used on individual tests. Failure in at least half of the tests in a domain constituted failure in that domain. The assessment was administered in English, Malay, Mandarin, or Chinese dialects according to the subject’s habitual language. The cognitive domains measured included (a) Attention: Wechsler Memory Scale–Revised (WMS-R) Digit and Visual span,15 Auditory detection test;16 (b) Language function: Category Fluency (Animal and Food subtask)17 and Modified Boston naming test;18 (c) Verbal memory: Word List Recall (immediate, delayed recall, and delayed recognition),14 Story Recall (immediate and delayed recall); (d) Visual memory: Picture recall (immediate, delayed recall, and delayed recognition), WMS-R visual reproduction (immediate, delayed recall, and delayed recognition);15 (e) Visuoconstruction: Wechsler Memory Scale–Revised (WMS-R) subtest Visual Reproduction Copy task,15 Wechsler Adult Intelligence Scale–Revised (WAIS-R) Block Design subtest,15 and Clock Drawing;19 (f) Visuomotor speed: Symbol Digit Modality Test,20 Digit Cancelation,21 and Maze Task,22 and (g) Executive function: frontal assessment battery (FAB).23
Patients were characterized as having dementia as per Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria,24 cognitive impairment, no dementia (CIND),25 or no cognitive impairments (NCI). Patients with CIND had at least one objective domain impaired but did not meet criteria for dementia diagnosis. Cognitive decline was defined as a decline from NCI to CIND or dementia, or a decline from CIND to dementia. Patients were categorized as reporting depressive symptoms or anxiety symptoms if they scored 8 or more on the respective subscales on the Hospital Anxiety and Depression Scale (HADS).26
Statistical analysis
All demographic and clinical factors were summarized based on treatment status. Differences between treatment groups and other categorical and continuous variables were tested using chi—square test and independent t-test, respectively. Univariate and multivariate cox proportional hazard (CPH) regression were used for time to cognitive decline, depressive symptoms, and anxiety symptoms to compare treatment and placebo group over the duration post enrolment. Results from CPH were expressed as hazards ratio (HR) analysis with 95% confidence interval (95% CI). Kaplan–Meier curves were also presented for cognitive decline, depressive symptoms, and anxiety symptoms. Univariate and multivariate logistic regressions were subsequently used to examine relationships between the baseline characteristics and the development of cognitive decline, depressive symptoms, or anxiety symptoms in patients. Results from logistic regression were represented in terms of odds ratios (ORs) with 95% confidence intervals (CIs). A two-tailed alpha of 0.05 was deemed statistically significant. All analyses were done using the SPSS version 25.
Results
A total of 867 patients were recruited and randomized in VITATOPS in Singapore. One hundred thirty-two were excluded as they declined cognitive assessments. An additional 28 were excluded because they had dementia at baseline. In total, 707 patients were included in the analyses—349 patients in the placebo group and 358 patients in the treatment group (Figure 1). The mean time to recruitment was 7.5 days of the index stroke (median = 11 days, interquartile range = 3–24 days). There were no significant differences in the baseline characteristics between the placebo and treatment group (Table 1).
Figure 1. Consort figure. Number of patient included for analysis after excluding those who were not in VITATOPS-Cog and had dementia at baseline.
CPH used to compare differences between treatment and placebo group on the duration to cognitive decline (Total n = 594, Event n = 89, Censored n = 505, HR: 1.06, CI: 0.70–1.61, p = 0.79), depressive symptoms (Total n = 604, Event n = 74, Censored n = 530, HR: 1.45, CI: 0.89–2.35, p = 0.14), and anxiety symptoms (Total n = 604, Event n = 84, Censored n = 520, HR: 1.33, CI: 0.86–2.04, p = 0.20) found no differences between the groups. The Kaplan–Meier curves showed treatment group having lower incidence of anxiety symptoms compared with placebo group although the difference was not statistically significant (Figure 2).
Figure 2. Kaplan–Meier curves for duration to cognitive decline, severe depressive and anxiety symptoms. (a) Survival function for cognitive decline. (b) Survival function for depressive symptoms. (c) Survival function for anxiety symptoms.
Table 2 summarizes the logistic regression analysis results for outcome of cognitive decline. In univariate analysis, cognitive decline was associated with posterior circulation infarction (OR: 2.70, CI: 1.12–6.49, p = 0.03) and age (OR: 1.02, CI: 1.00–1.04, p = 0.03). In multivariate analysis, age (OR: 1.02, CI: 1.02–1.04, p = 0.03) was the only independent predictor of post-stroke cognitive decline.
Table 3 summarizes the logistic regression analysis results for the outcome of depressive symptoms. In univariate analysis, depressive symptoms were associated with LACI (OR: 2.37, CI: 0.91–7.70, p = 0.04), TACI (OR: 9.51, CI: 1.88–48.19, p = 0.01), hypertension (OR: 2.27, CI: 1.19–4.43, p = 0.01), and hyperlipidemia (OR: 0.58, CI: 0.35–0.95, p = 0.03). In multivariate analysis, TACI (OR: 10.60, CI: 2.02–55.76, p = 0.01), hypertension (OR: 2.42, CI: 1.24–4.72, p = 0.01), and lack of hyperlipidemia (OR: 0.54, CI: 0.23–0.90, p = 0.02) were independent predictors of depressive symptoms.
Table 4 summarizes the univariate analysis results for the outcome of anxiety symptoms. Univariate analysis showed no association between anxiety symptoms and baseline variables.
Discussion
In our study, B-vitamin supplementation was not associated with a reduction of post-stroke cognitive impairment, depressive symptoms, or anxiety symptoms. We found that the development of post-stroke cognitive impairment associated with older age, while the development of post-stroke depressive symptoms associated with large anterior hemispheric strokes, hypertension, and lack of hyperlipidemia.
B-vitamin supplementation’s inefficacy in mitigating cognitive decline in our study echoes results from other studies.27 This is likely because hyperhomocysteinemia is just one of many factors mediating post-stroke cognitive decline. Other risk factors for post-stroke cognitive decline include advanced age and type of stroke—although the latter association was not found in our study.28,29 This suggests that current standard of care, even when coupled with B-vitamin supplementation, is insufficient in mitigating post-stroke cognitive decline. Another possibility for the absent treatment effects could be the mean baseline homocysteine levels in both groups being in the normal range (<15μmol/L)—which are already protective against cognitive decline.30
Large anterior hemispheric strokes were associated with developing depressive symptoms in our study. We postulate that extensive neurostructural damage results in greater disability—which may precipitate depressive symptoms.31 This association was reflected in our findings and that of others.32,33 We postulate that the association between hypertension and depressive symptoms is due to increased incidence of small vessel disease34 among hypertensives. Our finding that hyperlipidemia protects against developing depressive symptoms is possibly due to statins’ potential protective effects against depression.35,36 Previous studies demonstrated that statins modulate inflammation—a postulated cause of depression in stroke patients.37 Since almost half of our participants in each group have hyperlipidemia, and were likely on statins, the therapeutic effect of B-vitamins on mitigating post-stroke depressive symptoms could have been masked. An earlier Australian substudy of VITATOPS found that B-vitamin supplementation reduces the hazard of major depression compared with placebo. Our findings likely differed from theirs’ due to different measurement tools being used (Mini-international Neuropsychiatric Interview (MINI) instead of HADS). Also, they split their sample into major and minor depression based on clinical assessment while our outcome measure was a screening tool (HADS). Furthermore, they had a longer duration of follow-up.
This study has several limitations. First, the outcome of depressive and anxiety symptoms was based on the HADS rather than clinical diagnosis—making it difficult to ascertain whether patients were truly clinically depressed or anxious which may dilute our associations. Second, while previous studies showed rates of 30–50% for post-stroke depressive and anxiety symptoms, our study’s rates (13–18%) likely resulted in a lack of statistical power. Third, the study design meant that patients could be on B-vitamin supplementation prior to randomization—diluting the effect of B-vitamin supplementation on our post-stroke outcomes.
In conclusion, our study did not find significant benefits of B-vitamin supplementation in mitigating post-stroke neuropsychiatric sequelae. Hence, further studies would need to address the limitations in this study and explore other factors affecting post-stroke cognitive decline, depressive symptoms, and anxiety symptoms.
Keywords
Stroke, B-vitamin, cognition, depression, anxiety
1Duke-NUS Medical School, Singapore
2Department of Neurology, National Neuroscience Institute (Singapore General Hospital Campus), Singapore
3Department of Pharmacology, National University of Singapore, Singapore
Corresponding author(s):
Kaavya Narasimhalu, Department of Neurology, National Neuroscience Institute, SGH Campus, Outram Road, Singapore 169608. Email: nkaavya@gmail.com
*
Kaavya Narasimhalu is now affiliated to Duke-NUS Medical School, Singapore
Introduction
Background
Stroke is a leading cause of disability and 30% of stroke patients experience some form of cognitive decline within 3 years post-stroke1—which includes both dementia2 and cognitive impairment no dementia (CIND).3 In addition, stroke can also result in neuropsychiatric complications such as depression4 and anxiety.5 One contributory factor postulated for these post-stroke sequelae is hyperhomocystinemia6—which may reduce brain volume possibly through oxidative stress resulting in cognitive decline.7 Serum homocysteine levels can be lowered by B12, Folate, and B6 through methylation.8 Furthermore, an Australian substudy of the same international trial as our study found that B-vitamin supplementation associated with a lower hazard of major depression compared with placebo.9 Hence, using B-vitamins to lower post-stroke homocysteine serum concentrations was proposed as a treatment to mitigate these post-stroke cognitive decline, depression, and anxiety.10
Besides potential efficacy, there are other advantages of using B-vitamins as an alternative or augmentation to current conventional treatments. They can be safely added to current cardiovascular medications and are safer and have less adverse effects compared with prophylactically administering antidepressants to prevent post-stroke depression and anxiety. Furthermore, they may augment the efficacy of current standard antidepressant treatment as well.11 Therefore, studying the efficacy of B-vitamin supplementation on post-stroke cognitive and neuropsychiatric sequelae is important.
Although other studies examined the relationship between stroke and cognitive impairment, few studies looked specifically at the effects of B-vitamin on CIND, depressive, symptoms, and anxiety symptoms on patients who had either an ischemic stroke or a transient ischemic attack (TIA). Hence, our study (a substudy of a large scale multicentre randomized control trial designed to assess the impact of B-vitamin supplementation on recurrent vascular events in patients with a prior stroke—VITAmins To Prevent Stroke (VITATOPS))12 endeavors to examine the effects of B-vitamins on reducing the rates of post-stroke cognitive decline, depressive symptoms, and anxiety symptoms.
Aims and hypothesis
We aim to bridge this gap in the current literature by comparing the incidence rates of post-stroke cognitive impairment, depressive symptoms, and anxiety symptoms in those who received B-vitamin supplements post-stroke with those who did not. We hypothesize that patients who received B-vitamin supplementation would have reduced risk of acquiring post-stroke cognitive decline, depressive symptoms, and anxiety symptoms compared with those in the placebo group.
Methods
Patients
Patients were recruited as part of a larger multicentre, double blinded, placebo-controlled randomized trial VITATOPS12 that examined B-vitamins’ effects in reducing risk of major cardiovascular events in people who had a recent ischemic stroke or TIA link to CONSORT Statement (Appendix 1). In the Singapore study site, ischemic stroke and TIA patients who presented to Singapore General Hospital between July 2000 and May 2007 were approached for inclusion in this study within the first 7 months of their index event. Patients were excluded if they were on folate antagonists or B-vitamin supplements and were not willing to switch, had a short remaining life-expectancy, or were women of childbearing potential. However, patients on B-vitamin supplements and were willing to switch to the study medication were included.
In addition, those who fulfilled the diagnostic criteria for dementia at baseline were excluded.
Randomization
Patients were randomized by a telephone service or an interactive website using blocks stratified by hospital.
Protocol approvals, registrations, and patient consent
The study protocol was approved by Singapore General Hospital’s Institutional Review Board and Ethics Committee. Written consent was obtained from patients or legal guardians. The VITATOPS study was registered under clinical-trials.gov with the identification number NCT00097669.
Intervention
Patients enrolled in the study were required to take one composite tablet that contained 25 mg vitamin B6, 2 mg Folic acid, and 0.5 mg vitamin B12 or a placebo pill of similar color and texture daily. Adherence was checked by questioning, tablet count, and return of tablet container. Patients, clinicians, and caregivers were blinded. Patients were then followed up every 6 months up to a 5-year period after randomization.
Demographic and stroke-related measures
Baseline characteristics such as age, sex, ethnic background, smoking status, education level, medical history of diabetes, hypertension, dyslipidemia, stroke classification, ischemic heart disease, angina, myocardial infarction, previous stroke, and peripheral vascular diseases of patients were assessed. Baseline serum homocysteine, folate, and B12 levels were also recorded.
Neuropsychological assessment
Assessment of cognitive domains was performed with a battery of tests validated in Singapore13 at baseline and subsequently in 6 monthly intervals. Education-adjusted cutoffs of 1.5 standard deviations below established normal means14 were used on individual tests. Failure in at least half of the tests in a domain constituted failure in that domain. The assessment was administered in English, Malay, Mandarin, or Chinese dialects according to the subject’s habitual language. The cognitive domains measured included (a) Attention: Wechsler Memory Scale–Revised (WMS-R) Digit and Visual span,15 Auditory detection test;16 (b) Language function: Category Fluency (Animal and Food subtask)17 and Modified Boston naming test;18 (c) Verbal memory: Word List Recall (immediate, delayed recall, and delayed recognition),14 Story Recall (immediate and delayed recall); (d) Visual memory: Picture recall (immediate, delayed recall, and delayed recognition), WMS-R visual reproduction (immediate, delayed recall, and delayed recognition);15 (e) Visuoconstruction: Wechsler Memory Scale–Revised (WMS-R) subtest Visual Reproduction Copy task,15 Wechsler Adult Intelligence Scale–Revised (WAIS-R) Block Design subtest,15 and Clock Drawing;19 (f) Visuomotor speed: Symbol Digit Modality Test,20 Digit Cancelation,21 and Maze Task,22 and (g) Executive function: frontal assessment battery (FAB).23
Patients were characterized as having dementia as per Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria,24 cognitive impairment, no dementia (CIND),25 or no cognitive impairments (NCI). Patients with CIND had at least one objective domain impaired but did not meet criteria for dementia diagnosis. Cognitive decline was defined as a decline from NCI to CIND or dementia, or a decline from CIND to dementia. Patients were categorized as reporting depressive symptoms or anxiety symptoms if they scored 8 or more on the respective subscales on the Hospital Anxiety and Depression Scale (HADS).26
Statistical analysis
All demographic and clinical factors were summarized based on treatment status. Differences between treatment groups and other categorical and continuous variables were tested using chi—square test and independent t-test, respectively. Univariate and multivariate cox proportional hazard (CPH) regression were used for time to cognitive decline, depressive symptoms, and anxiety symptoms to compare treatment and placebo group over the duration post enrolment. Results from CPH were expressed as hazards ratio (HR) analysis with 95% confidence interval (95% CI). Kaplan–Meier curves were also presented for cognitive decline, depressive symptoms, and anxiety symptoms. Univariate and multivariate logistic regressions were subsequently used to examine relationships between the baseline characteristics and the development of cognitive decline, depressive symptoms, or anxiety symptoms in patients. Results from logistic regression were represented in terms of odds ratios (ORs) with 95% confidence intervals (CIs). A two-tailed alpha of 0.05 was deemed statistically significant. All analyses were done using the SPSS version 25.
Results
A total of 867 patients were recruited and randomized in VITATOPS in Singapore. One hundred thirty-two were excluded as they declined cognitive assessments. An additional 28 were excluded because they had dementia at baseline. In total, 707 patients were included in the analyses—349 patients in the placebo group and 358 patients in the treatment group (Figure 1). The mean time to recruitment was 7.5 days of the index stroke (median = 11 days, interquartile range = 3–24 days). There were no significant differences in the baseline characteristics between the placebo and treatment group (Table 1).
Figure 1. Consort figure. Number of patient included for analysis after excluding those who were not in VITATOPS-Cog and had dementia at baseline.
CPH used to compare differences between treatment and placebo group on the duration to cognitive decline (Total n = 594, Event n = 89, Censored n = 505, HR: 1.06, CI: 0.70–1.61, p = 0.79), depressive symptoms (Total n = 604, Event n = 74, Censored n = 530, HR: 1.45, CI: 0.89–2.35, p = 0.14), and anxiety symptoms (Total n = 604, Event n = 84, Censored n = 520, HR: 1.33, CI: 0.86–2.04, p = 0.20) found no differences between the groups. The Kaplan–Meier curves showed treatment group having lower incidence of anxiety symptoms compared with placebo group although the difference was not statistically significant (Figure 2).
Figure 2. Kaplan–Meier curves for duration to cognitive decline, severe depressive and anxiety symptoms. (a) Survival function for cognitive decline. (b) Survival function for depressive symptoms. (c) Survival function for anxiety symptoms.
Table 2 summarizes the logistic regression analysis results for outcome of cognitive decline. In univariate analysis, cognitive decline was associated with posterior circulation infarction (OR: 2.70, CI: 1.12–6.49, p = 0.03) and age (OR: 1.02, CI: 1.00–1.04, p = 0.03). In multivariate analysis, age (OR: 1.02, CI: 1.02–1.04, p = 0.03) was the only independent predictor of post-stroke cognitive decline.
Table 3 summarizes the logistic regression analysis results for the outcome of depressive symptoms. In univariate analysis, depressive symptoms were associated with LACI (OR: 2.37, CI: 0.91–7.70, p = 0.04), TACI (OR: 9.51, CI: 1.88–48.19, p = 0.01), hypertension (OR: 2.27, CI: 1.19–4.43, p = 0.01), and hyperlipidemia (OR: 0.58, CI: 0.35–0.95, p = 0.03). In multivariate analysis, TACI (OR: 10.60, CI: 2.02–55.76, p = 0.01), hypertension (OR: 2.42, CI: 1.24–4.72, p = 0.01), and lack of hyperlipidemia (OR: 0.54, CI: 0.23–0.90, p = 0.02) were independent predictors of depressive symptoms.
Table 4 summarizes the univariate analysis results for the outcome of anxiety symptoms. Univariate analysis showed no association between anxiety symptoms and baseline variables.
Discussion
In our study, B-vitamin supplementation was not associated with a reduction of post-stroke cognitive impairment, depressive symptoms, or anxiety symptoms. We found that the development of post-stroke cognitive impairment associated with older age, while the development of post-stroke depressive symptoms associated with large anterior hemispheric strokes, hypertension, and lack of hyperlipidemia.
B-vitamin supplementation’s inefficacy in mitigating cognitive decline in our study echoes results from other studies.27 This is likely because hyperhomocysteinemia is just one of many factors mediating post-stroke cognitive decline. Other risk factors for post-stroke cognitive decline include advanced age and type of stroke—although the latter association was not found in our study.28,29 This suggests that current standard of care, even when coupled with B-vitamin supplementation, is insufficient in mitigating post-stroke cognitive decline. Another possibility for the absent treatment effects could be the mean baseline homocysteine levels in both groups being in the normal range (<15μmol/L)—which are already protective against cognitive decline.30
Large anterior hemispheric strokes were associated with developing depressive symptoms in our study. We postulate that extensive neurostructural damage results in greater disability—which may precipitate depressive symptoms.31 This association was reflected in our findings and that of others.32,33 We postulate that the association between hypertension and depressive symptoms is due to increased incidence of small vessel disease34 among hypertensives. Our finding that hyperlipidemia protects against developing depressive symptoms is possibly due to statins’ potential protective effects against depression.35,36 Previous studies demonstrated that statins modulate inflammation—a postulated cause of depression in stroke patients.37 Since almost half of our participants in each group have hyperlipidemia, and were likely on statins, the therapeutic effect of B-vitamins on mitigating post-stroke depressive symptoms could have been masked. An earlier Australian substudy of VITATOPS found that B-vitamin supplementation reduces the hazard of major depression compared with placebo. Our findings likely differed from theirs’ due to different measurement tools being used (Mini-international Neuropsychiatric Interview (MINI) instead of HADS). Also, they split their sample into major and minor depression based on clinical assessment while our outcome measure was a screening tool (HADS). Furthermore, they had a longer duration of follow-up.
This study has several limitations. First, the outcome of depressive and anxiety symptoms was based on the HADS rather than clinical diagnosis—making it difficult to ascertain whether patients were truly clinically depressed or anxious which may dilute our associations. Second, while previous studies showed rates of 30–50% for post-stroke depressive and anxiety symptoms, our study’s rates (13–18%) likely resulted in a lack of statistical power. Third, the study design meant that patients could be on B-vitamin supplementation prior to randomization—diluting the effect of B-vitamin supplementation on our post-stroke outcomes.
In conclusion, our study did not find significant benefits of B-vitamin supplementation in mitigating post-stroke neuropsychiatric sequelae. Hence, further studies would need to address the limitations in this study and explore other factors affecting post-stroke cognitive decline, depressive symptoms, and anxiety symptoms.
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