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1 Department of Medicine, Division of Geriatrics, Queen's University, Kingston, Ontario, Canada.
2 Behavioural Neurology Program and Rotman Research Institute, Baycrest Centre for Geriatric Care, Department of Medicine (Division of Neurology), Mt. Sinai Hospital, University Health Network, University of Toronto, Ontario, Canada.
Address correspondence to Angeles Garcia, MD, PhD, Department of Medicine (Geriatrics), Queen's University, St. Mary's of the Lake Hospital, 340 Union Street, P.O. Box 3600, Kingston, Ontario, Canada K7L 5A2. E-mail: garciaa{at}pccchealth.org
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Abstract |
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Methods. This prospective cohort study was conducted in healthy community-dwelling older adults without cerebrovascular disease at baseline and followed them for 2.3 years. Cobalamin, red blood cell folate, total serum homocysteine (tHcy), and creatinine levels were measured and recorded. Cognitive measures included the Mini Mental State Examination, California Verbal Learning Test, Mattis Dementia Rating Scale, and Stroop Neuropsychological Inventory.
Results. At baseline, participants with elevated tHcy levels had lower Stroop scores (72.7 vs 85.35, p <.05) than did participants with normal tHcy levels. The tHcy levels correlated significantly with Stroop scores at baseline and follow-up. At follow-up, tHcy levels had increased in 104 participants (group I) and decreased in 76 participants (group II). Compared to mean baseline values, the mean tHcy in both groups had changed significantly at follow-up (p <.05 and p <.001, respectively). Participants in group I had significantly lower Stroop scores in multivariate analyses at follow-up than at baseline. The scores of participants in group II at follow-up were not significantly different than their scores at baseline. The rate of change of tHcy levels and the rate of change of the Stroop scores were significantly correlated (r = –0.264, p <.001) after multivariate analysis. Stroop scores decreased by 22% at follow-up in participants whose tHcy levels increased by 40% from baseline to follow-up.
Conclusion. Elevated tHcy levels and increases in tHcy during a short period of time are associated with decreased Stroop scores in otherwise cognitively normal elderly volunteers.
Elevated tHcy levels have also been found to be an independent risk factor for the development of Alzheimer's disease. In a recent 8-year follow-up study in a population sample of the Framingham Study cohort, Seshadri and colleagues (8) found that elevated tHcy was an independent risk factor for the development of Alzheimer's disease 8 years after baseline, and that the risk increased with higher levels of tHcy at baseline. Similarly, an association between elevated tHcy and dementia has been described in various populations (9–13). In a recent review article, Lökk (14) referred to tHcy as the most sensitive marker of cobalamin/folic acid metabolic function and the factor that correlates most strongly with parameters of cognition.
It is unclear at this point which are the early cognitive changes associated with elevated tHcy, what are the effects of increases of tHcy levels over time on cognitive function of otherwise healthy older adults, or whether reduction of tHcy levels is followed by changes in cognitive function. To address these questions, we conducted a prospective study in a large cohort of cognitively normal adults at baseline.
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METHODS |
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Laboratory Investigations
Serum cobalamin, red blood cell (RBC) folate, and creatinine levels were determined by standard procedures. The tHcy determinations were made by Metabolite Labs (Denver, CO) using capillary gas chromatography–mass spectrometry and high-performance liquid chromatography (15). Serum samples were obtained within 30 minutes of blood collection and maintained at –70°. Normal values are cobalamin, 165 to 740 pmol/L; RBC folate, 200 to 1300 nmol/l; and tHcy, 5.1 to 13.9 nmol/l.
Data were collected systematically, both at baseline and at follow-up, on participant demographic factors, medical history, medications, and diet. Hypertension was defined in accordance with the World Health Organization criteria as a systolic blood pressure of 160 mmHg or more, a diastolic blood pressure of 95 mmHg or more, or the use of antihypertensive medication. Diabetes mellitus was defined according to the criteria of the American Diabetes Association or by the participant's use of diabetes mellitus medications.
Psychometric Measures
Cognitive tests administered included the Stroop Neuropsychological Screening Test (16), the Mattis Dementia Rating Scale (DRS) (17), and the California Verbal Learning Test (CVLT) (18). The Stroop is a test of executive function measuring attention and concentration in the face of interference and cognitive flexibility. In this test, the participant is asked to read a list of color names, each printed in a noncorresponding ink color. Then the participant is asked to name the colors of the ink, not the written word, from a second, different list. Executive functions are defined as high-level cognitive functions involved in the control and direction of lower-level functions (19). The Mattis DRS is a screening test for dementia and includes subsets for attention, initiation and perseveration, construction, conceptualization, and memory. The CVLT is a verbal learning test that assesses verbal memory (recall, recognition, cuing effects, types of errors, and learning characteristics) and the effect of interference on recall and recognition. The CVLT compiles 27 outcome variables into 5 main categories (recall measures, learning characteristics, recall errors, recognition measures, and contrast measures). An MMSE was also administered in the follow-up visit and the scores were compared with those recorded at baseline.
Statistical Analyses
Differences between cognitive scores at baseline and follow-up were measured using the paired Student's t test. An unpaired t test was used to compare the differences between participants with elevated and participants with normal tHcy levels, and differences at baseline between participants who were followed and those who were not. Pearson's coefficients were used to assess the relation between cognitive scores and tHcy at baseline and follow-up.
For the follow-up analysis, we separated the participants into two groups: those who had a significant increase in tHcy levels from baseline to follow-up (group I), and those who had a significant decrease in tHcy levels (group II). We calculated the rate of change for Stroop scores and tHcy levels between the baseline and follow-up measurements for each participant as the value at follow-up minus the value at baseline divided by the value at baseline. In group I (those who experienced a tHcy increase), we separated the participants into five percentiles according to the percentage of change of tHcy level (<10%, 10.1%–20%, 20.1%–30%, 30.1%–40%, and >40%). We compared the mean changes of the Stroop score in these five subgroups using analysis of variance and post hoc tests.
We performed linear regression analyses to identify independent predictors of the rate of change in Stroop scores. We included in the regression model as independent variables age, education, sex, cobalamin level, RBC folate level, tHcy level, and diagnoses of diabetes mellitus and hypertension. All tests were two sided and a probability value less than.05 was considered to be statistically significant. We used SPSS software (version 11; Chicago, IL) for all analyses.
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RESULTS |
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Univariate analyses showed a significant correlation between tHcy levels and Stroop scores at baseline (r = –.146. p <.05) and at follow-up (r = –.126, p <.05) but no significant correlation between tHcy levels and the other cognitive scores (MMSE, DRS, CVLT) at baseline or at follow-up.
When we compared the psychometric test scores at baseline with scores obtained at follow-up among all the participants, we found significant decreases in the Stroop (p =.001) and CVLT scores (p <.001) (data not shown). The mean rate of change for the Stroop score from baseline to follow-up was –3.5%, and the mean rate of change for total recall trials 1 to 5 of the CVLT was –3.3%. The rate of change of the Stroop score was significantly correlated with the rate of change of tHcy levels (r = –0.223, p =.003), but we found no correlation between the rate of change of tHcy and the rate of change of the CVLT scores.
From baseline to follow-up, 104 participants had a significant increase in their tHcy levels (group I) (8.87 vs 10.4, p <.05), and 76 participants had a significant decrease of tHcy levels (group II) (12.0 vs 9.3, p <.001). Table 1 shows the characteristics of the two groups. We found no differences between the 2 groups in relation to age, years of education, and time interval between baseline and follow-up testing. However, cobalamin, creatinine, and RBC folate levels and the prevalence of hypertension all differed between the two groups. Comparison of baseline scores of participants in groups I and II showed that the CVLT and DRS total scores were similar between the two groups, but the mean Stroop score was higher in group I than in group II (86.7 vs 81.0, p <.05).
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As shown in Table 3, tHcy levels increased by more than 40% from baseline to follow-up in 8.7% participants (all were <14 nmol/l and, therefore, within normal limits for our laboratory), and Stroop scores decreased by 22%. The rate of change in Stroop scores was not significant among participants whose tHcy levels increased by less than 40%.
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DISCUSSION |
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Stroop scores decreased among participants whose tHcy levels increased from baseline to follow-up even though their tHcy levels at follow-up were still within the upper range of normal. This might suggest that the metabolically significant factor is the relative increase in tHcy levels, regardless of the established normal range.
Reductions in tHcy levels from baseline to follow-up (group II) were not associated with changes in the Stroop scores. This could be a result of the fact that the tHcy levels of participants in group II at follow-up were still within the upper bracket of normal, and further reductions in tHcy to levels within the lower normal range might be required. Alternatively, the effects of tHcy on brain structures might be irreversible and, therefore, only stabilization of scores might be expected.
We found no association between increases in tHcy levels and global cognitive function, measured by DRS or MMSE scores, at the 2.3 years of follow-up in our population, whereas Seshadri and colleagues (8) found a significant decrease in the MMSE scores in participants with elevated tHcy at a follow-up of 8 years (8), and den Heijer and colleagues (20) found an association between tHcy and cortical and hippocampal atrophy. In univariate analyses, we also found that verbal memory function measured by CVLT scores was significantly lower in participants whose tHcy levels had increased at follow-up, compared with participants whose tHcy levels had decreased; however, this relation was not significant after adjustment for confounding variables. McCaddon and colleagues (1) have described a significant memory decline (primarily visuospatial) in persons with elevated tHcy at a follow-up interval of 5 years. We postulate that detection of significant decreases in executive function scores resulting from incremental increases in tHcy levels might appear earlier than declines in verbal memory or global cognitive measures. Alternatively, the association we found in our population between increases in tHcy and decreases in Stroop scores might explain, in part, the proposed decrease in the stability of executive function seen in elderly persons (21) regardless of possible future cognitive changes.
Among the multiple studies that addressed the issue of prediction of future cognitive impairment by use of various cognitive tests in nondemented populations, few have investigated executive function. Chen and colleagues (22) found that executive dysfunction (measured by the Trail Making Test, Part B) could be a subtle manifestation of incipient Alzheimer's disease, along with memory dysfunction. The Stroop test is a measure of attention and concentration in the face of interference, a test of executive function such as use of strategy and response flexibility (focused attention). Continued follow-up of our population might clarify whether the observed decrease in Stroop scores represents a preclinical phase of further cognitive impairment or whether it is solely associated with what might be classified as "normal brain aging" without evolving into a pathologic state.
As shown in Table 1, both cobalamin and RBC folate levels increased from baseline to follow-up in all participants. We cannot explain why some persons experience increases in tHcy while others do not, but this observation might present practical questions with regard to treatment aimed at decreasing the levels of tHcy.
Recently, the relation between Alzheimer's disease and tHcy has been attributed to the vascular effects of elevated tHcy (23). McCaddon and coworkers (24) postulated that cerebral oxidative stress increases the oxidation of an intermediate form of cobalamin generated in the methionine synthase pathway, impairing homocysteine metabolism.
Conclusion
Our results suggest that a significant relationship between increases in tHcy levels over time and decline in performance in a test of executive function exists independently of other factors in otherwise healthy elderly persons. We also observed a trend in verbal memory decline at a relatively short follow-up period. Furthermore, the results seem to indicate that levels of tHcy in the upper limit of the normal range might already be related to worsening of cognitive function, and that decreases in tHcy concentrations to the lower part of the normal range might be needed to avoid worsening of cognitive function.
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Acknowledgments |
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Dr. Freedman was supported by the Saul A. Silverman Family Foundation, Toronto, Canada, as part of a Canada International Scientific Exchange Program project.
The authors thank all the volunteers for their contribution to the study, Donna Kearney for secretarial support, and Andrew Day for statistical advice.
Received March 4, 2003
Accepted June 16, 2003
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