The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 56:M775-M779 (2001)
© 2001 The Gerontological Society of America
Cobalamin Supplementation Improves Cognitive and Cerebral Function in Older, Cobalamin-Deficient Persons
Dieneke Z. van Asselta,
Jaco W. Pasmanb,
Henk J. van Lierc,
Dick M. Vingerhoetsb,
Petra J. Poelse,
Yolande Kuina,
Henk J. Blomd and
Willibrord H. Hoefnagelsa
a Departments of Geriatric Medicine, Laboratories of
b Departments of Clinical Neurophysiology, Laboratories of
c Departments of Medical Statistics, Laboratories of
d Pediatrics and Neurology, University Medical Centre Nijmegen, The Netherlands
e Neurology, University Medical Centre Nijmegen, The Netherlands
Dieneke Z. van Asselt, Department of Geriatric Medicine, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands E-mail: D.vanAsselt{at}czzoger.azn.nl.
Decision Editor: John E. Morley, MB, BCh
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Abstract
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Background. Mild cobalamin (Cbl) deficiency is frequently found in older persons and is associated with cognitive and cerebral abnormalities. The effects of Cbl supplementation on these abnormalities are largely unknown.
Methods. In a single-blind, placebo-controlled intervention study, 16 healthy community-dwelling elderly subjects with low plasma Cbl concentration and no cognitive impairments were studied. Subjects underwent 1 month of treatment with placebo, followed by 5 months of treatment with intramuscular injections of hydroxycobalamin. Before and after measurements of plasma cobalamin, total homocysteine (tHcy), methylmalonic acid (MMA), quantitative electroencephalograph (qEEG), and psychometric tests were taken.
Results. After Cbl supplementation, plasma Cbl concentrations increased, and plasma MMA and tHcy concentrations decreased. The performance on the Verbal Word Learning Test, Verbal Fluency and Similarities improved. qEEG showed more fast activity and less slow activity. Lower plasma tHcy concentrations were related to increased fast activity on qEEG on the one hand and improved performance on the Verbal Word Learning Test and Similarities on the other. Increased fast or decreased slow activity on qEEG was associated with improved performance on the Verbal Word Learning Test, Similarities and Verbal Fluency.
Conclusions. Electrographic signs of improved cerebral function and improved cognitive function were found after Cbl supplementation in older subjects with low plasma Cbl concentrations who were free of significant cognitive impairment. These improvements were related to a reduction of plasma tHcy concentration.
MILD or subtle cobalamin (Cbl, vitamin B12) deficiency (1) is very common in the elderly, with prevalences ranging from 12% to 25% (2)(3)(4). This condition is characterized by low to low-normal plasma Cbl concentrations, elevated plasma methylmalonic acid (MMA), and/or total homocysteine (tHcy) concentrations and the absence of overt hematological or neurological abnormalities. Associations between the Cbl status and cognitive performance in both healthy older subjects (5)(6)(7)(8) and cognitively impaired older patients (9) have been reported previously. Abnormal EEG with the presence of slow frequencies has been described in patients with classical pernicious anemia (10)(11)(12) and in demented, mildly Cbl-deficient elderly patients (13). Whereas Cbl supplementation corrects the metabolic abnormalities (i.e., elevated plasma MMA and tHcy concentrations) (14)(15), the effects of Cbl supplementation on cognitive and cerebral dysfunction have not been adequately studied. To investigate the effects of Cbl supplementation on cognition and cerebral function, we performed a single-blind intervention study with a placebo period and determined the effects on plasma Cbl, MMA, tHcy, quantitative EEG (qEEG), and neuropsychological tests in community-dwelling older subjects with low plasma cobalamin concentrations.
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Methods
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Subjects
Community-dwelling, healthy older subjects were invited through advertisements in local newspapers to have their plasma Cbl concentration measured. Of the 189 persons who responded, 28 (15%) had low (
150 pmol/l) plasma Cbl concentrations; 16 of the 28 respondents agreed to participate in our intervention study. Two subjects dropped out: one found the protocol burdensome, and one was diagnosed with a lung tumor and died shortly afterward. In their place, two community-dwelling outpatients from the geriatric department with low plasma Cbl concentrations, also detected by screening, agreed to participate. One suffered from depression, and the other had personality changes. None of the participating subjects had anemia, low concentrations of folate in serum or erythrocytes, myelopathy, history of Cbl deficiency, ongoing Cbl or folate supplementation, severe diseases, or severe cognitive or sensory problems.
Protocol
Subjects were seen at baseline, after 4 weeks of placebo (weekly intramuscular water injections), and after 5 months of intramuscular hydroxocobalamin injections (weekly 1000 µg for 4 weeks and monthly 1000 µg for 4 months). Subjects were told, without clarifying the protocol to them, that they would receive placebo and cobalamin at different times during the investigation. Injections were administered by the principal investigator (DvA) with a syringe covered with nontransparent tape. Identical procedures were carried out at baseline, after placebo, and after hydroxocobalamin and consisted of medical history, neurological examination, venepuncture, neuropsychological tests, and qEEG recording. The health status was measured qualitatively and quantitatively at baseline.
Laboratory Techniques
Two trained psychological assistants who were blind for the trial setup and unaware of the results carried out the neuropsychological tests. The assessment battery included the Mini-Mental State Examination (MMSE), the Geriatric Depression Scale (GDS), Trail Making Test, Similarities, Rivermead Behavioral Face Recognition Test, Verbal Fluency, Verbal Word Learning Test (with immediate and delayed recall), and Forward and Backward Digit Span (WAIS-R). Except for the MMSE and GDS, three different test versions were used. EEG was recorded with a 21-channel digital EEG system (Brain Electrical Signal Topography, Korneuburg, Austria) using the international 10-20 system. The EEG was recorded while the subject was alert with the eyes closed on a couch in a semi-darkened room. The sample frequency was 204.8 Hz per channel with a filter setting of 0.15 to 70 Hz (-3 dB). For qEEG analysis, six 10-second segments without artifacts or signs of drowsiness were selected. Fourteen common-reference (F[rontal]3, F7, C[entral]3, T[emporal]3, T5, P[arietal]3, O[ccipital]1, and F4, F8, C4, T4, T6, P4, O2) derivations were constructed and 12 bipolar (F3-C3, F7-T3, C3-P3, T3-T5, T5-O1, P3-O1 and F4-C4, F8-T4, C4-P4, T4-T6, T6-O2, P4-O2) derivations were constructed. For each derivation, the relative power was calculated for the following frequency bands: delta (
, 1–4 Hz), theta (
, 4–8 Hz), alpha (
, 8–12 Hz), beta1 (ß1, 12.5–25.0 Hz), and beta2 (ß2, 25.0–40.0 Hz). Power is the extent to which a certain frequency occurs in a specific frequency band, and relative power is the percentage of the sum of the power in all five frequency bands. Delta and theta represent slow cerebral activity, alpha represents normal background cerebral activity, and beta represents fast cerebral activity.
Plasma Cbl concentration was measured by competitive radioisotope binding techniques (Solid Phase Boil Dualcount; Diagnostic Products, Los Angeles, CA). Plasma MMA concentration was determined by stable isotope dilution capillary gas chromatography-mass spectrometry (16). In the preparation procedure of the samples, solvent extraction with ethylacetate was used instead of solid-phase extraction. Plasma tHcy concentration was measured by an automated high-performance liquid chromatography method with reverse-phase separation and fluorescent detection (17). Plasma MMA and tHcy levels >0.32 µmol/l and >19.9 µmol/l, respectively (95th percentile in healthy older controls), were considered elevated (18). The committee for Experimental Research with Humans of the University Hospital Nijmegen approved the protocol. Written informed consent was obtained from all participants.
Statistics
Results are presented as medians with minimum and maximum values. The effect of Cbl supplementation on outcome measures was assessed by the following expression: (outcome measure after Cbl supplementation - outcome measure after placebo) - (outcome measure after placebo - outcome measure at baseline). If the distribution of the variable after application of this formula was normal, the one-sample t test was used. If the distribution of the variable was not normal, the Wilcoxon Signed Rank Test was used. The Spearman correlation coefficient was used to describe the correlation between continuous variables. A p value of .05 was considered significant. SAS Software (SAS Institute, Cary, NC) was used for statistical analysis. Multiple testing (176 statistical tests and 1284 correlation coefficients) was performed because the aim of the analysis was to identify potentially important changes; however, it was unknown where these changes could be expected.
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Results
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Subjects
Sixteen community-dwelling older subjects (median age 71 years [range 64–89], seven men and nine women) with low plasma Cbl concentrations (150 pmol/l) were examined. Five subjects considered their health very good, six considered their health good, and five considered their health fair. Ten subjects reported the following chronic diseases: ischemic heart disease (n = 2), hypertension (n = 2), respiratory problems (n = 2), diabetes (n = 1), and arthritis (n = 4). Twelve subjects used prescribed medications (the median number of medications was 3; range 1–8). All subjects were independent for activities of daily living. One subject had a MMSE score of 23. At the end of the trial, subjects were asked about the effect of Cbl supplementation on their overall health: eight subjects felt that their health had improved, seven felt that it had remained the same, and one subject felt that it had deteriorated.
Biochemical Changes
Baseline biochemical characteristics are presented in Table 1 . Before Cbl supplementation, elevated plasma MMA was present in nine subjects, and elevated plasma tHcy was present in five subjects. After Cbl supplementation, all subjects had normal plasma MMA, and plasma tHcy was still elevated in two subjects. Plasma Cbl concentrations increased, and plasma MMA and tHcy concentrations decreased (Table 1 ). Plasma MMA and tHcy also decreased in the subjects with pre-treatment concentrations in the normal range: median decrease in plasma MMA (n = 7) 0.07 mmol/l (-0.14–0.0) (p = .004); median decrease plasma tHcy (n = 11) 3.80 mmol/l (-8.60–0.0) (p < .0001). After placebo, the changes in the biochemical parameters were nonsignificant (Table 1 ).
Electroneurophysiologic Changes
After Cbl supplementation, qEE G showed more fast cerebral activity (increased relative power in beta1 and beta2 frequency band) and less slow cerebral activity (decreased relative power in theta and delta frequency band) (Table 2 ). After placebo, opposite changes in qEEG were observed (i.e., less fast cerebral activity with more slow cerebral activity as compared with baseline) (data not shown).
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Table 2. Changes in Relative Powers in the Five Frequency Bands After Hydroxocobalamin Supplementation Corrected for Placebo-effect in 16 Older Subjects With Low Plasma Cobalamin (Cbl) Concentrations
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Cognitive Changes
After placebo, performances on the Similarities and Verbal Fluency had worsened. After Cbl supplementation, performance on delayed recall of the Verbal Word Learning Test had improved (Table 3 ). Cbl supplementation (after correction for placebo) caused better performance on the Verbal Word Learning Test (delayed recall), Verbal Fluency and Similarities. Performance on MMSE, GDS, the Trail Making Test, Face Recognition Test, and Digit Span remained unchanged. The decrease in plasma tHcy after Cbl supplementation was associated with an increase in the Similarities score (r = -.58, p = .02). Lower tHcy concentrations were associated with better performances on immediate (r = -.55, p = .03) and delayed (r = -.58, p = .02) recall of the Verbal Word Learning Test. No associations could be demonstrated between Cbl or MMA and cognitive performance. The decrease in plasma tHcy after Cbl supplementation was associated with an increase in fast cerebral activity in the temporal region (r = -.53, p = .04 and r = -.50, p = .05). Lower tHcy concentrations were associated with more fast cerebral activity in the frontal, central, and temporal regions (correlation coefficients [n = 17] ranged from -0.50 to -0.68). The decrease in plasma MMA after Cbl supplementation was associated with an increase in fast cerebral activity in the temporal region (r = -.52, p = .04) and with a decrease in slow cerebral activity in the central (r = .54, p = .03) and frontal (r = .52, p = .04) region. Lower MMA concentrations were associated with more normal background cerebral activity (correlation coefficients [n = 20] ranged from -0.50 to -0.69) and less slow cerebral activity (correlation coefficients [n = 12] ranged from 0.49–0.70) in the frontal, central, and temporal regions. The increase in fast cerebral activity in the fronto-temporal regions after Cbl supplementation was associated with improved performance on delayed recall of the Verbal Word Learning Test (correlation coefficients [n = 3] ranged from 0.51–0.61) and Similarities (r = .54, p = .03). The decrease in slow cerebral activity in the fronto-temporal region was also associated with improved performance on Similarities (r = -.57, p = .02). More fast cerebral activity in the frontal, central, and temporal regions was associated with better performance on immediate and delayed recall of the Verbal Word Learning Test and Word Fluency (correlation coefficients [n = 32] ranged from 0.49–0.66). Less slow cerebral activity in the fronto-temporal region was associated with improved performance on Verbal Fluency (r = -.54, p = .03).
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Discussion
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This is the first intervention study with placebo period measuring the effects of Cbl supplementation on cognitive performance and cerebral function in community-dwelling older subjects with low plasma cobalamin concentrations but with no significant cognitive dysfunction. The effect of Cbl supplementation on cognition was that subjects performed better on the Verbal Word Learning Test, Verbal Fluency and Similarities. The change for the Verbal Word Learning test is especially convincing. Improvement after Cbl supplementation on the verbal fluency test has also been described in a retrospective study on patients from a memory disorders clinic (19). It cannot be excluded that the improvement represents a practice effect. We tried to overcome this problem by using three different versions. In contrast, performance on Verbal Fluency and Similarities worsened after placebo. Several explanations come to mind. First, the changes after placebo are within the variation of the test. Second, it could be that the poorer cognitive performance was due to progression of the deficiency in some subjects during the 1-month placebo period. Indeed, the qEEG also worsened after placebo, showing more slow and less fast activity. Improved cognitive performance after Cbl supplementation was accompanied by electrographically improved cerebral function. In Cbl deficiency, abnormal EEGs show increased activity of the slow waves (i.e., theta and delta activity) and slowed alpha frequencies (10)(11)(12)(13). Our findings are in concert with these descriptions (i.e., disappearing of increased slow rhythms in favor of fast rhythms with Cbl treatment). To calculate the effect of Cbl supplementation on cerebral function, as opposed to describe, we performed a quantitative analysis of the EEG data. In the literature we found no information on quantitative EEG or the relative power in Cbl-deficient patients. For a frame of reference we compared our qEEG findings with those in Alzheimer patients and normal aging. In mild Alzheimer's disease there are increases in slow theta activity and decreases in fast beta activity, whereas with greater severity of dementia, there are also decreases in alpha activity and increases in slow delta activity (20)(21). In normal aging, slow delta activity increases, and fast beta activity decreases (22). Thus, the changes in electrographical cerebral function after Cbl supplementation in older subjects with low Cbl concentrations are opposite to the changes in Alzheimer's disease and normal aging. Two hypotheses for cognitive impairment in Cbl deficiency have been postulated: hypomethylation and cerebrovascular disease (23). A reduced availability of methyl groups within the central nervous system can cause demyelination of the brain (24). Cobalamin is required for the methylation of homocysteine to methionine, which is activated into S-adenosyl-methionine that subsequently donates its methyl group to numerous methyl acceptors such as myelin, neurotransmitters, and membrane phospholipids, each of which is crucial to the function and integrity of the nervous system. Consequently, hypomethylation of these substances could lead to cognitive dysfunction. Second, Cbl deficiency causes hyperhomocysteinemia, which is associated with increased cardiovascular risk, including stroke (25). Therefore, it has been suggested that hyperhomocysteinemia-related cognitive dysfunction may be mediated by cerebrovascular changes. It is, however, difficult to conceive that stroke-related neuronal damage is reversible by lowering the plasma homocysteine concentration as observed in the present study. A more plausible explanation would be that by lowering the plasma tHcy concentration the endothelium-dependent, nitric-oxide–dependent vasodilatation is improved (26). An epidemiological study found plasma homocysteine to be a predictor of spatial copying performance; however, this association was not explained by the clinical diagnosis of vascular disease (7). The associations we found between plasma tHcy and cognitive performance on the one hand and electrographical cerebral function on the other support the involvement of homocysteine in Cbl-related cognitive changes. The present study may have some caveats. First, a placebo-controlled trial would have been a stronger experimental design. However, whereas there is a need for this information, it would seem unethical to withhold treatment from older persons with low Cbl levels. We attempted to overcome the absence of a control group by introducing a placebo period and by analyzing the effect on the outcome measures for the whole group (i.e., each subject was his own control). A crossover design was not possible because Cbl has a long and unpredictable washout period. Second, the possibility that some of our findings are due to chance cannot be excluded. However, the number of significant differences (n = 37) or significant correlations (n = 100) exceed that expected by chance (n = 9 and n = 64 for differences and correlations, respectively) and the internal consistency of relations and the fact that significant changes in tHcy concen-trations, qEEG, and cognitive tests were interrelated argues against an entirely spurious set of outcomes. A larger, placebo-controlled trial is required to establish whether detection and treatment in the subclinical state is of advantage to older persons. The present study has identified qEEG and some cognitive tests as valuable outcome measures for such an investigation.
In sum, electrographical signs of improved cerebral function and improved cognitive function were found after Cbl supplementation in older subjects with low plasma Cbl concentrations who were free of significant cognitive impairment. These improvements were related to a reduction of plasma tHcy concentration.
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Acknowledgments
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This study was supported by a grant from The Netherlands Program for Research and Aging (NESTOR), funded by the Ministry of Health, Welfare and Sports and the Ministry of Education, Culture and Sciences.
We gratefully thank the laboratory technicians of the Department of Clinical Neurophysiology, especially Rita Westdorp, Henny Janssen, Miriam Heykens, José Bor, and Joann van Duuren, Jan Moleman for his assistance with the qEEG analysis, the staff and personnel of the Laboratory of Endocrinology and Reproduction for performing the Cbl and folate assays, and the psychological assistants Lisette Grimberg and Hanneke Nijsten for administering the cognitive tests, Wim van den Broek for his help in the preparation and performance of the cobalamin absorption tests, and Richard Zuiderent, Jan de Jong, and Addy de Graaf-Hess for performing the MMA and tHcy assays.
Received December 5, 2000
Accepted January 16, 2001
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Abstract
Methods
