EAL

NSUP: Vitamin B12 (2008)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

The purpose of this research was to provide further evidence of the presence and extent of vitamin-related effects on cognitive performance in old age. Of particular interest was to extend the generality of earlier findings in terms of the cognitive domains assessed, and especially to examine the relationship beween low levels of serum vitamin B₁₂ and folic acid (FA) and cognitive functioning in very old age.

Inclusion Criteria:

All residents of the Kungsholmen parish Stockhom, Sweden who were 75 years of age and above.

Exclusion Criteria:

Dementia (n=528)
Non-completion of cognitive tests (n=27)
Psychiatric diagnosis (n=20)
Undergoing treatment with antidepressants and/or neuroleptics without having received a psychiatric diagnosis (n=9)
Lack of sufficient visual or auditory capaabilitiesto manage the sensory demands of cognitive testing (n=9)
Non-screening for B₁₂ or FA status duing medical examination (n=34)
Supplementation with B₁₂ or FA (n=17)
Subject who were prescribed anticonvulsant drugs (n=1), antimetabolites (n=1) or trimetoprim (n=1)

Description of Study Protocol:

Recruitment

Between 1987 and 1989 all residents of the Kungsholmen parish in Stockholm, Sweden were asked to participate in a study concerning medical, psychological, and social problems associated with the aging process (N=2368).
1810 were screened in an initial examination.

Design

The four subsamples of non-demented persons age 75-96 years (normal B₁₂/normal FA [n=175]; low B₁₂/normal FA [n=67]; normal B₁₂/low FA [n=23], and low B₁₂/low FA [n=14]) were matched for age and education and compared to a control group.

Blinding used (if applicable)

Intervention (if applicable)

Statistical Analysis

Separate one-way analysis of variance (ANOVA) revealed no group differences with respect to age, education, or distribution of gender (Fs < 2.60).
ANOVA was performed on the Mini-Mental State Examination (MMSE) data.
A 2 x 2 MANOVA was conducted on the cognitive data, including the raw scores for dependent variables.
The clock setting and clock reading data were analyzed with separate 2 x 2 ANOVAs.
The Block Design data were analyzed with a 2 x 2 mixed ANOVA with repeated measures on the last factor.
A 2 x 2 ANOVA was conducted on each of the dependent variables.

Data Collection Summary:

Timing of Measurements

Blood samples were collected on the morning of the same day that cognitive testing took place.
- Blood analysis included analysis of ferritin, FA, and vitamin B₁₂status.
The radioimmunoassay method was used for the analysis of vitamin B₁₂and FA.
- The same lab performed all blood and serum testing.
Cognitive testing was comprised of psychometric and memory tests administered by trained psychologists at the Stockholm Gerontology Research Center or in the homes of subjects.
Tests administered included:
- Clock Test
- Clock Reading Test
- Block Design Test
- Trail Making Test
- Digit Span Forward and Backward
- Verbal Fluency

Dependent Variables

Spatial orientation (assesed by Clock Setting and Clock Reading Tests)
Visuospatial functioning (assessed by Block Design Test)
Perceptual-motor speed (assessed by the Trail Making Test (TMT) A and B)
Attention (assessed by the Trail Making Test (TMT) A and B)
Short-term memory (assessed by Digit Span Forward and Backward)
Verbal Fluency (assessed by category and letter fluency)
- All dependent variables testing was accomplished by examining performance on the Clock Setting and Clock Reading Tests, the modified Block Design Test, TMT-A, TMT-B, Digit Span Forward and Backward, and letter and category fluency tests.

Independent Variables

Folic Acid status
B₁₂status

Control Variables

Age
General Health Status
Medication Use
Alcohol Use
Visual capacity
Medical history
Depression classification

Description of Actual Data Sample:

Initial N: 1810 subjects

Attrition (final N): 230 subjects

Age:

All subjects were between 75-96 years of age

Ethnicity: N/A

Other relevant demographics:

No subjects suffered from alcohol abuse
Few smokers (n=30)
All subjects were living independently in their own homes or in sheltered housing.
The mean years of education were around 8 for each group (which is representativefor this age cohort in Stockholm, Sweden).

Anthropometrics

Location: Stockholm, Sweden

Summary of Results:

Clock Test, TMT, Digit Span performance across serum vitamin group and test condition
	N B₁₂/N Fola	L B₁₂/N Fola	N B₁₂ /L Fola	L B₁₂/ L Fola
Clock Setting
M	3.74	3.55	3.48	3.07
SD	1.05	1.27	1.27	1.14
Clock reading
M	4.71	4.58	4.48	4.64
SD	0.70	0.85	1.34	0.63
TMT A (accuracy)
M	11.93	11.91	12.00	12.00
SD	0.55	0.38	0.00	0.00
TMT B (accuracy)
M	10.00	9.66	8.40	8.27
SD	2.45	2.61	3.35	3.44
TMT A (time)
M	67.60	72.93	71.70	92.08
SD	47.70	62.59	36.45	49.35
TMT B (time)
M	146.18	155.86	203.68	206.80
SD	94.58	104.12	151.55	115.26
Digit Span Forward
M	5.52	5.45	5.30	5.14
SD	1.06	1.00	0.76	0.95
Digit Span Backward
M	4.34	4.13	3.87	3.50
SD	1.06	1.01	0.87	1.02

Author Conclusion:

There was an overall affect of FA status on cognitive performance whereas the overall effect of B₁₂ status, or the interaction term did not approach statistical significance.
Low vitamin levels affected tasks that involve fluid abilities such as abstract and complex processing of new information.
Low folate levels may have negative repercussions for the active use of short-term memory processes.
Low levels of both B₁₂ and FA influence verbal fluency, when the task has little inherent structure and, therefore, puts higher demands on self-initiated processing.

Funding Source:

Government:

Swedish Society for Medical Research, The Swedish Foundation for Health Care Sceinces adn Allergy Reserach, the Committee for Nursing Science, Stockholm Genontolgy Research Center

Industry:

University/Hospital:

Karolina Institute, University of Uppsala

Not-for-profit

Foundation associated with industry:

Reviewer Comments:

In some of the vitamin groups the number of subjects was relatively small, especially compared with other groups.
There may have been difficulty in detecting small differences in cognitive performance.
Some of the cognitive tests tap into a wide variety of cognitive functions and it is difficult to determine the exact locus of the effect.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	N/A

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	Yes
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	???
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	Yes
5.	Was blinding used to prevent introduction of bias?		???
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	N/A
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	???
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	???
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	???
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	???
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	N/A
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	Yes
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	N/A
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	N/A
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	N/A
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	Yes
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	N/A
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	N/A
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	No
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes