Vitamin B12 Status and Rate of Brain Volume Loss In Community-Dwelling Elderly

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Brain Volume, Vitamin B12 and the Elderly

http://www.vitasearch.com/CP/experts/AVoldiatzoglouAT10-12-08.pdf

Vogiatzoglou, MSc.

Department of Physiology

Anatomy and Genetics, University of Oxford, Le Gros Building

South Parks Rd., Oxford OX1 3QX, UK

00441865272196

anna.vogiatzoglou@...

“Vitamin B12 Status and Rate of Brain Volume Loss In Community-Dwelling

Elderly, "

Neurology, 2008;71(11):826-32. 46641 (10/2008)

Kirk Hamilton: Can you please share with us your educational background

and current position?

Vogiatzoglou: I am a registered dietician with an MSc. in clinical

nutrition and I am currently a research

assistant in the University of Oslo while in the last year of my Ph.D.

at the University of Oxford.

1KH: What got you interested in studying the role of vitamin B12 and

brain volume loss?

AV: My interest lies in the study of vitamin B12 and its relation to

cognitive function. Vitamin B12 has

recently received increasing attention in the medical community because

increasing data suggest that low B12

status may increase the risk of cognitive impairment and dementia.

KH: What is the biochemistry of vitamin B12 that might actually affect

the volume of the brain? What is the

mechanism?

AV: Shrinkage of the brain has been linked to cognitive function and

decline. Low levels of plasma B12,

within what is usually considered to be the normal range, can affect

brain volume possibly by disturbing the

integrity of brain myelin, through inflammation or disturbance of

metabolic pathways. Vitamin B12 is important

for the maintenance of a healthy nervous system. Nerves are surrounded

by an insulating fatty sheath comprised

of a complex protein called myelin. B12 plays a vital role in the

metabolism of fatty acids essential for the

maintenance of myelin. Prolonged B12 deficiency can lead to nerve

degeneration and irreversible neurological

damage. Low concentrations of B12 may also influence brain function

through metabolic pathways such as

methylation reactions in the brain. However, further work is required to

establish whether these associations are

causal.

KH: Can you explain what holotranscobalamin is and why it is an accurate

measure of vitamin B12 status?

What are the levels of vitamin B12 deficiency, insufficiency, and

sufficiency with regards to

holotranscobolamin? And serum vitamin B12 levels?

AV: Cobalamin (vitamin B12) is absorbed and distributed by three

proteins; intrinsic factor, transcobalamin

and haptocorrin. Intrinsic factor is needed for B12 uptake in the

intestine and plasma transcobalamin is

responsible for transport of the vitamin to all cells of the body. The

portion of cobalamin bound to

transcobalamin is called holotranscobalamin. Holotranscobalamin

represents the biologically active fraction of

B12 available for tissue uptake and therefore has been proposed as a

potential indicator of B12 status and a

more useful marker than plasma B12. Levels of holotranscobalamin <35

pmol/L are considered low while

levels of plasma B12 <150 pmol/L are considered deficient.

KH: Why did you measure methylmalonic acid as a functional test of

vitamin B12 insufficiency?

AV: We measured methylmalonic acid (MMA) as it is a sensitive and early

indicator of B12 deficiency at the

tissue level. MMA is a compound that is usually produced in very small

amounts during amino acid (protein)

metabolism. Normally, B12 acts as a cofactor in the conversion of

methylmalonyl CoA to succinyl CoA. If there

is not enough B12 to act as a cofactor, then methylmalonyl CoA

concentrations begin to rise and the body

converts the methylmalonyl CoA to MMA instead. This causes MMA levels to

rise in both the blood and the

urine when B12 levels are low. Increased concentrations of MMA are often

detectible before the occurrence of

the hematologic changes (for example, anemia and large red blood cells)

seen with B12 deficiency. Some

patients with MMA elevations may not have any symptoms at all while

others may have neuropathy (numbness

and tingling in the hands and feet) or mental or behavioural changes

(confusion, irritability, depression),

symptoms that are often seen with classic B12 deficiency.

KH: Can you tell us about your study and the basic results?

AV: This is a study of 107 healthy volunteers living in Oxfordshire, UK

aged 61 to 87. They were recruited

following advertisements and were carefully screened to exclude any with

cognitive impairment at the start. All

volunteers underwent brain scans (CT, MRI and SPECT), memory testing and

physical exams once a year for

up to 5 years. Blood samples were collected each year to measure B12

levels and many other substances, such

as folate, homocysteine, methylmalonic acid, holotranscobalamin, etc.

The aim of the study was to identify

factors that predict cognitive decline and which are associated with

changes in brain scans, such as loss of tissue

volume. The MRI scans were of the whole volume of the brain and serial

scans were subtracted from each other

using software developed in Oxford by Prof. Steve . This enables

small changes (less than 1% per year) to

be measured accurately. The study found that elderly people who had

higher vitamin B12 levels in the blood

are less likely to experience brain shrinkage compared with those who

had lower levels, but still within

the normal range. Our study suggests, but does not prove, that by

modifying our vitamin B12 status we might

be able to protect our brain and so possibly prevent cognitive decline.

KH: What are the risk factors to vitamin B12 insufficiency in the elderly?

AV: Vitamin B12 deficiency is a major public health problem,

particularly among the elderly, as it is

estimated to affect 10%–15% of people >60 years. The most common causes

of vitamin B12 deficiency are

malabsorption and low dietary intake. Both causes become more common

with age.

Malabsorption of B12 can result from many causes. The most common causes

are an autoimmune condition

known as pernicious anemia and food-bound vitamin B12 malabsorption.

Conservative estimates indicate that

2%–3% of the population has or will develop pernicious anaemia (type A

chronic atrophic gastritis), caused by

failure of gastric intrinsic factor production (a protein needed for B12

uptake in the intestine). The prevalence

of B12 deficiency due to food-bound B12 malabsorption may be as high as

30% among the elderly. This

condition is usually caused by a chronic inflammation of the lining of

the stomach (atrophic gastritis), which

ultimately results in gastric atrophy. In this condition, food-bound B12

is not released, and can therefore not be

bound to intrinsic factor.

Other causes of malabsorption are:

 The chronic use of a number of drugs such as antiepileptic agents

(carbamazepine, phenytoin, primidone),

proton pump inhibitors (omeprazole), histamine (H2) receptor antagonists

(cimetidine, ranitidine),

antidiabetic drug metformin, antibiotics (chloramphenicol, neomycin)

 Diseases such as pancreatic insufficiency, hyperthyroidism, diabetes

mellitus, renal insufficiency, Zollinger

–Ellison syndrome, intestinal diseases, especially of the ileum (celiac

disease, Crohn’s disease, ileitis)

 Defective transport of vitamin B12 due to genetic polymorphisms.

 Also smoking and regular alcohol intake

Dietary deficiency can be caused due to a strict vegetarian (vegan) diet

or due to a poor diet usual in the elderly.

Moreover, increased needs (pregnancy and breastfeeding, anaemia,

haemodialysis) can lead to B12 deficiency.

KH: What would you recommend as far as vitamin B12 supplementation in

the elderly? What would the daily

dose be? Should the elderly be supplemented at all?

AV: Vitamin B12 supplementation has been found to improve B12 status,

correct anemia due to B12

deficiency and prevent birth defects in infants. However, studies have

provided mixed results on the

improvement of cognitive function, mainly because the trials were not

well designed. In this study we did not

look at whether taking vitamin B12 supplements would slow the rate of

shrinkage of the brain. Three years ago

we started a trial to look at this question, in which we are giving

elderly people with memory problems B

vitamins (folate, B6 and B12) and scanning their brains at the start and

after two years. See: http://controlledtrials.

com/ISRCTN94410159 . The results of this trial will be known in 2009.

So, we think it is too early to

advise people to take B12 supplements to prevent their brains from

shrinking. What we can say, is that our

results suggest that rather than maintaining one’s B12 at a level that

is ‘just above’ the cut-off for deficiency it

might be prudent to aim to keep it higher up the normal range. This can

be achieved by dietary means by eating

plenty of the foods that are a good source of B12, such as milk

(low-fat, preferably), fish, meat and, in the USA,

fortified breakfast cereals. A varied diet should provide enough vitamin

B12 to prevent deficiency in most

individuals 50 years of age and younger. However, the Institute of

Medicine of the National Academies

recommends that individuals over the age of 50 should get most of their

vitamin B12 from vitamin

supplements or fortified food because of the high incidence of impaired

absorption from foods that come

from animals in this age group.

KH: When should people be screened for vitamin B12 sufficiency? Should

we use holotranscobolamin or

serum vitamin B12 levels? If so what are the optimal levels we are

aiming for?

AV: Vitamin B12 or cobalamin deficiency is considered a frequent

disorder, especially among elderly

patients, but is often unrecognized because the initial clinical

manifestations are subtle and non-specific or are

attributed to the normal aging process. Because of the potential

seriousness and irreversibility of the symptoms

(particularly neurological), detection and treatment of early stages of

cobalamin deficiency is important.

Elderly >60 years should check regularly their serum B12 and consult

their physician.

The diagnosis of B12 deficiency has traditionally been based on low

serum vitamin B12 levels, usually less than

200 pg/mL (148 pmol/L), along with clinical evidence of disease.

However, studies indicate that older patients

tend to present neuropsychiatric disease in the absence of hematologic

findings. Measurements of metabolites

such as MMA and homocysteine have been shown to be more sensitive in the

diagnosis of B12 deficiency than

measurement of serum B12 levels alone.

A simple, reliable, accurate and generally accepted screening tool for

measuring vitamin B12 status is not

available. There are several markers of B12 status but each one of them

separately has low diagnostic accuracy.

The ones most commonly used are:

 Decreased concentrations of plasma B12 which is the standard clinical

screening test.

 Increased concentrations of homocysteine and MMA that are generally

considered more sensitive

metabolic markers of B12 status.

 Decreased concentrations of plasma holotranscobalamin, which has been

suggested as a more sensitive

marker of B12 status because holotranscobalamin is the biologically

active fraction of total B12 that can be

delivered into all cells.

Low B12 status can be detected more accurately by measuring all of these

markers together. In our study we use

all of these markers of B12 status, which is one of the strengths of the

study. However, it is not easy to use all

these markers in every day practice. Measurement of serum B12 is firstly

ordered and if low-normal levels are

detected a follow-up of homocysteine and MMA is usually ordered.

Measurement of holotranscobalamin is

currently not widely available to use for routine clinical practice as

it is expensive and has not yet been

sufficiently evaluated.

KH: Since plasma vitamin B12 is so easy to measure can you please share

what levels of plasma vitamin B12

within the normal range may be more optimal? > 500 pmol/L than the

classic deficiency levels of < 200 pg/ml

(148 pmol/L)?

AV: As mentioned above, the diagnosis of B12 deficiency has

traditionally been based on low B12 levels,

usually less than 200 pg/ml (148 pmol/L). For adults, the lower limit of

B12 is approximately 170–250 pg/ml

(120–180 pmol/liter). This number is based on the level associated with

the most severe manifestation of

deficiency, pernicious anemia. The normal blood level of B12 ranges

between 200 and 600 pg/ml (148-443

pmol/l). However, normal and deficiency values for serum or plasma

vitamin B12 may vary from lab to lab and

from country to country. A number of studies have suggested a higher cut

off point than the 148 pmol/L

typically used for B12 deficiency. The findings of our study also

suggest that B12 levels >300 pmol/L would

be optimal and protect against anemia and neurological symptoms.

KH: Do you have any further comments on this very interesting subject?

AV: More research is needed into the relationship between nutrition and

the brain, in particular

dementia. This is a poorly funded area in comparison with molecular

biology and yet it has the potential

to save millions of people world-wide from developing brain diseases.

--

ne Holden, MS, RD

" Ask the Parkinson Dietitian " http://www.parkinson.org/

" Eat well, stay well with Parkinson's disease "

" Parkinson's disease: Guidelines for Medical Nutrition Therapy "

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