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Healthy Aging

Vitamin B12 Improves Homocysteine Levels, But Not Cognitive Outcomes (2)

By Kristen Schepker, Assistant Editor

B vitamins are widely promoted for the treatment and prevention of many forms of dementia. But new research raises questions about the efficacy of B vitamins for slowing cognitive decline.

A Dutch multicenter study published last December in Neurology investigated the effects of folic acid and vitamin B12 B12 Crystalson cognitive performance in elderly people with elevated homocysteine (Hcy) levels (van der Zwaluw, et al. Neurol. 2014; 83(23): 2158-2166).

The double-blind, randomized, placebo-controlled trial included 2,919 participants aged 65 years and older with Hcy levels between 12 and 50 µmol/L. Over the course of two years, each participant received either a daily tablet containing 400 µg folic acid and 500 µg vitamin B12 (B-vitamin group) or a placebo. All tablets also contained 15 µg vitamin D3.

The cognitive function analysis was actually a sub-project of the B-PROOF trial (B vitamins for Prevention of Osteoporotic Fractures).

The Using the Mini-Mental State Examination (MMSE), researchers assessed participants’ global cognitive function at baseline and again after two years. They looked at various aspects of cognitive function, including episodic memory, attention, working memory, information processing speed, and executive function.

Following a two year supplementation period, there were no clinically significant differences in cognitive function between the B-vitamin and placebo groups, leading the authors to conclude that folic acid and vitamin B12 supplementation does not confer any benefit on cognitive performance among elderly people.

Supplementation did slow the rate of decline in global cognition, but the difference was slight, and, the authors say, could have been due to chance.

Unexpected Observations

The absence of cognitive improvements was despite the fact that supplementation did reduce Hcy levels significantly. Hcy concentrations were decreased significantly by 5.0 µmol/L in the B-vitamin group (95% confidence interval −5.3 to −4.7), and 1.3 µmol/L in the placebo group (−1.6 to −0.9).

The lack of apparent cognitive benefit was unexpected, and the observations seem to run counter to the view that chronic systemic inflammation--indicated by Hcy elevations--is a major driver of cognitive decline in older age. They also raise questions about whether B-vitamins should be recommended for treatment and prevention of dementia

A substantial body of past research suggested that that B-vitamin status can affect age-related cognitive performance and decline (Morris, M. Adv Nutr. 2012; 3(6): 801–812), and this makes sense given the diverse roles B-vitamins play in cell metabolism.

In particular, vitamin B12 -- or cyancobalamin (Cbl) -- plays a vital part in red blood cell development and healthy nervous system functioning. Vitamin B12 deficiency can manifest in a variety of symptoms, including anemia, changes in mood and cognition, motor weakness, poor muscle control, and nonspecific gastrointestinal symptoms.


Previous research has indicated that elevated Hcy is a risk factor for Alzheimer’s disease (Jager, et al. Int J Ger Psy. 2012; 27: 592-600). Low folate and elevated Hcy levels have been associated with poor cognitive function and increased risk for dementia (Raman, et al. J Nut. 2007;137(7): 1789-1794).


Additionally, folates, and vitamin B12 support healthy brain metabolism and are implicated in the prevention of various conditions, including central nervous system development disorders, mood disorders, and dementias, including Alzheimer’s disease and vascular dementia (Reynolds, E. Lancet Neurol. 2006; 5(11): 949–960).


It was certainly logical, then, to think that vitamin B supplementation might improve cognition in at-risk elderly people, especially if the regimen could produce a meaningful decrease in Hcy, though small trials looking at this question have produced inconsistent results.


The recent Dutch study is by far the largest to date on this important subject.


Form & Function


HumanBrainIn a piece published in the European Journal of Clinical Nutrition shortly after the van der Zwaluw paper made the news, Thakkar and Billa underscore the fact that, like many physiological phenomena, the interactions between the B vitamins and the human nervous system are more complex than we might like them to be.


They note that there are two active co-enzyme forms of vitamin B12 -- methylcobalamin (MeCbl) and adenosylcobalamin (AdCbl) -- which are formed as a result of two distinct metabolic cascades. Both forms of the vitamin are essential and fulfill distinct functions, contributing to confusion among researchers and healthcare providers around exactly which form to use in the context of patient care (Thakkar & Billa. Eur J Clin Nut. 2015; 69, 1-2).

MeCbl, along with folate, primarily supports blood cell and brain development during childhood. Found in the cytosol, MeCbl “predominates in blood and in other body fluids.” AdCbl, on the other hand, is “the major form in cellular tissues stored in the mitochondria.” AdCbl deficiency disrupts carbohydrate, fat, and amino-acid metabolism and affects neuronal myelin synthesis.

Today, as Thakkar and Billa explain, MeCbl is largely used and promoted as the preferred treatment for vitamin B12 deficiency. As an active form of the vitamin, some have argued, it may be more effective than cyanocobalamin. That may not be the case.

They suggest that rather than choosing one form over the other, clinicians ought to treat B12 deficiency with either a combination of both MeCbl and AdCbl, or to use cyanocobalamin on its own, in order to support the vitamin’s neurological and haematopoietic pathways.

Another important fact to consider in assessing the clinical significance of the van der Zwaluw study is that the study was not designed specifically to look at cognitive function, nor were the subjects stratified according to baseline B vitamin levels. The findings may not be generalizable to older people with frank B-vitamin deficiencies or to younger individuals.

As research into the influence of vitamin B12 status on cognitive performance continues, the distinctions between its many forms and functions may become clearer. B vitamins may not, in and of themselves, be a quick fix for the problem of age-associated cognitive decline, but given what we know about the role of these vitamins in neuronal, digestive, and cardiovascular function it makes good clinical sense to screen patients for B12 deficiency through all stages of life.


Carotenoids May Prevent Macular Degeneration & Dementia

By Erik Goldman | Editor in Chief

kale-smDaily supplementation with plant-derived carotenoids can reduce the risk of age-associated macular degeneration, and may also have a role in prevention of Alzheimer's disease, according to James Stringham, PhD, of the Nutritional Neuroscience Laboratory at the University of Georgia, Atlanta.

Overmedication: An Underrated Problem Among Seniors

By Bettina Krasner | Contributing Writer - Vol. 15, No. 2. Summer, 2014

It's no secret that medication management is a major health concern for seniors.

Is Neuro-Regeneration a Reality?

By Erik Goldman | Editor in Chief - Vol. 15, No. 2. Summer, 2014

For generations, the prevailing medical wisdom has been that neurodegeneration is irreversible, and that adults simply cannot re-grow lost or damaged neurons.

Autologous Serum Therapy Offers New Option for Osteoarthritis

By Bianca Garilli, ND, Contributing Writer - Vol. 14, No. 3. Fall, 2013

A new injection-based modality that uses the body’s own cytokines to reduce joint inflammation was recently introduced in the US, and it has great promise for relieving joint pain, back pain, tendonitis and other symptoms of osteoarthritis (OA).

Beyond Balance: T'ai Chi Dramatically Improves Seniors' Overall Health

By Kathy Capobianco, Contributing Writer

The practice of T'ai Chi is one of the safest and most beneficial forms of exercise for elderly people. It builds muscle strength and bone density, reduces CVD risk, improves sleep, and prevents neurocognitive problems. Plus, it's fun!

Are Grains Destroying Our Brains?

By Erik Goldman - Vol. 14, No. 3. Fall, 2013
In his forthcoming book, Grain Brain, functional neurologist David Perlmutter contends that America's grain-heavy diet is a prime driver of dementia. That means dementia's preventable, but it requires eliminating grain foods.

Vitamin D Deficiency Widespread Among Elders with Hip Fractures

By John Otrompke | Contributing Writer - Vol. 15, No. 2. Summer, 2013
CHICAGO-- Living in a southern, sunny climate is no safeguard against hip fractures, according to a new study by researchers at Kaiser Permanente showing that Vitamin D insufficiency is rampant among people hospitalized for hip fractures.

Bad to the Bone: Smoking Compromises Outcomes of Orthopedic Surgery

By John Otrompke | Contributing Writer - Vol. 15, No. 3. Fall, 2013
CHICAGO-- Among its many evils, smoking is detrimental to bone and connective tissue. Several studies presented at this year’s annual meeting of the American Academy of Orthopedic Surgeons show that smoking raises the odds of poor outcomes in common orthopedic procedures.

In short, smokers are much less likely to benefit from orthopedic surgeries like hip replacements and fracture repairs, and more likely to have complications.

Hip replacement patients who smoked experienced a higher rate of surgical revision, according to one study presented at AAOS. In a second paper, researchers found that smokers undergoing orthopedic treatment for pain experienced no benefit. A third study concluded that smokers had a higher rate of non-union and longer healing times after surgery.

“Nicotine-mediated vasoconstriction is considered to be the primary etiology of these effects, and we can postulate that decreased blood flow to the operative site results in decreased oxygenation of tissue, which can subsequently lead to soft-tissue and wound-healing complications,” said Bhaveen H. Kapadia, MD, orthopedic research fellow in the Center for Joint Preservation and Replacement at Sinai Hospital, Baltimore. Dr. Kapadia presented the hip replacement study.


Dr. Kapadia and colleagues reviewed record for all hip replacements performed at Sinai between 2007 and 2009, and found that 110 of the patients were former or current tobacco users, with a mean age of 55. These patients were compared to a control group of non-smokers.  

They found that 8% of the smoking patients required a surgical revision within 46 months of the original procedures, compared to 1% of those who did not smoke. In five of the smoking patients, surgical revisions were required because of infection, while four revisions were done to address pain and component loosening. Of those patients who continued to smoke, six out of 65, or 9.2%, had revisions; in former smokers the number was two out of 45, or 4.4%.

Caleb J. Behrend, MD, a resident in training at the University of Rochester, New York presented data from large study of 6,779 patients who received treatment for painful spinal disorders. Nearly 9% of the patients over age 55, and 23.9% of those under 55 were smokers at the time they sought treatment.

The patients were asked to subjectively assess their pain during treatment. Researchers found that non-smokers had less pain than patients who smoked, regardless of age. In addition, non-smokers and patients who quit smoking during treatment experienced clinically meaningful reduction in pain, but those who continued smoking during treatment had no such improvements.

Those patients in the Rochester study who quit experienced an average reduction of pain by 1.5 points on a ten-point scale, which was statistically and clinically significant.  

“There’s kind of a myth that smoking makes smokers feel better,” said Dr. Behrend. “They may think so, but it certainly isn’t helping them if you actually look at the data. The clinical science shows very profound association between smoking and other chronic pain problems, such as leg and central back pain.”

Fracture Complications

Smoking had a negative effect on rates of bone union following fracture repair procedures, as well as recovery time following surgery, according to a metanalysis presented at the AAOS meeting.

The adjusted odds of non-union was 2.3 times higher in smoking patients than in non-smokers, and mean healing time for all fracture types was 30.2 weeks in smokers, compared to 24.1 weeks in non-smokers. However, this metanalysis did not show a significantly higher rate of infection among smokers.

The report was based on data from 18 studies between 1993 and 2011, representing 6,480 patients, 1,457 of whom were smokers at the time of surgery.

“The main direction for future research is to look at the effects of smoking cessation programs which can be instituted at the time of fractures,” said Mara L. Schenker, MD, an orthopedic surgery resident at the University of Pennsylvania in Philadelphia, who presented the metanalysis.

“This context is not like elective surgery where we can say to the patients in advance that they need to quit smoking. In this case, the patients come in and they’re injured, so we want to look at the effects of implementing a smoking cessation program at the time of surgery,” explained Dr. Schenker.

In general, orthopedic surgeons have recognized the detrimental effects of smoking on the musculoskeletal system, and many of them strongly recommend that whenever possible, patients should participate in smoking cessation programs prior to orthopedic surgery.

How Hyperglycemia Drives Cognitive Dysfunction

By Erik Goldman

Hyperglycemia and insulin resistance cause actual structural changes to key brain regions involved in cognition, greatly increasing the risk of cognitive dysfunction.



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