1. Introduction

WJET

World Journal of Engineering and Technology

2331-4222

Scientific Research Publishing

10.4236/wjet.2016.44054

WJET-71867

Articles

Chemistry&Materials Science Engineering

Homocysteine and Cognitive Impairment in Thai Elderly

Duangkamol

Viroonudomphol

¹Saowanee

Kajanachumpol

²Chaiwat

Prawettongsopon

Faculty of Science, Mahidol University, Bangkok, Thailand

Faculty of Nursing, Siam University, Bangkok, Thailand

Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

01112016

0404562571April 6, 2016Accepted: November 6, November 9, 2016

2014

This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

Background: The prevalence and incidence of dementia increase dramatically with age. Cognitive impairment is one major symptom of dementia. Older persons increase in our society, which means a big number of people with decreased cognitive function. So it is important to find out risk factors. The amino acid homocysteine may be a risk factor. Objective: The aim was to determine the independent association of homocysteine and cognitive performance in Thai elderly. Design: Concentrations of homocysteine were measured in fasting blood samples of 100 Thais aged 60 - 80 years. Global cognitive function was assessed by using with mini-Mental State Examination score (MMSE), and cognitive functions were assessed by a neuropsychological test battery. The relationship between homocysteine levels and neuropsychological test scores was assessed by multiple linear regression. Results: In the crude model, homocysteine was inversely associated with scores for learning slope test (B = ?0.048, p = 0.042) and verbal pair total test (B = ?0.124, p = 0.032). After adjusting for confounders, no association was found between homocysteine and cognitive impairment. Age (B = ?0.129, p = 0.007) was found to be a significant determinant of decreased learning slope score. Similarly, age (B = ?0.298, p = 0.009) and education (B = 0.267, p = 0.029) were found to be significant determinants of decreased verbal pair total score. Conclusions: In this study, it was found that no association between homocysteine and cognitive impairment in a population of institutionalized subjects. Age and education were more significantly associated with cognitive impairment scores than homocysteine.

Homocysteine Cognitive Impairment Thai

1. Introduction

The prevalence and incidence of dementia increase dramatically with age. It affects 8% of people age over 65 and more than 60,000 new cases each year in Canada. Alzheimer’s disease accounts more than 50% of dementia cases in Canada [1] . Since 2002, Thailand has been an ageing society with older persons constituting more than 10% of population. In Thailand, studies showed that the prevalence of dementia is 1.8% - 10.2% in the age group of 55 years and above [2] [3] . Health Systems Research Institute of Thailand surveyed 21,960 people aged over 60 years in 2008-2009. The findings showed that 12.4% of people aged over 60 years had dementia and 9.8% being male while 15.1% were female. According to the latest population census surveyed in 2010 by the Office of National Statistics, it reports that the ageing population accounted for 12% of the whole population, and it is expected that the number will increase to 17% by the year 2020. It is estimated that there are as huge number as at least 300,000 people who have been diagnosed as having dementia across the nation. Cognitive impairment is one major symptom of dementia. Older persons increase in our society, which means a big number of people with decreased cognitive function. Therefore, it is important to search for modifiable risk factors. The amino acid homocysteine may be such a risk factor [4] . Most longitudinal studies have found associations between cognitive function scores and homocysteine levels. As can be seen in Table A, studies involving healthy elderly people yielded conflicting results. Some have shown significant associations between homocysteine levels and cognitive function [5] - [11] , whereas others have not [12] [13] .

Studies investigate the relation between homocysteine and cognitive function scores, as shown in Table A [1] .

Therefore, it is important to search for modifiable risk factors. The amino acid homocysteine may be such a risk factor [4] .

Homocysteine is metabolized through 2 different pathways (Figure 1) [1] [14] . The effects of homocysteine in the brain are multiple but can be broadly divided into nurotoxic and vascular effects (Box 1) [1] [14] .

2. Subjects and Methods2.1. Subjects

The 100 subjects in this study were recruited from the Baan Bangkae Social Welfare Development Center for Older Persons, Bangkok and the vicinity. The study was approved by the Medical Ethics Committee of Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, and written informed consent was obtained from all participants. All resident who were aged 60 - 80 years were invited to participate. During a visit, trained interviewers administered a questionnaire covering, among other areas, sociodemographic background, medical history, and medication use. This was followed by 2 visits to the Baan Bangkae Social Welfare Development Center, where subjects underwent clinical examinations, including neuropsychologic testing.

Table A Studies investigating relation between homocysteine and cognitive function scores [<xref ref-type="bibr" rid="scirp.71867-ref1">1</xref>]

Study	Study population	Study design	Cognitive assessment	Results	Comment
Budge et al., 2002 [5]	158 community dwelling people age 60 - 91 yr	Cross section of prospective cohort	CMCOG, MMSE, GDS	Higher tHcy levels associated with lower memory scores per umol/L (OR 1.15, 95% CI 1.10 - 1.27)	OR adjusted for age, sex, serum cystatin C level and systolic blood pressure
Duthie et al., 2002 [6]	334 community dwelling people who had participated in Scottish Mental Survey of 1932 and 1947	Cross section	MMSE,NART, RPM, AVLT, WAIS	tHcy levels negatively associated with scores on RPM, WAIS in older cohort with higher tHcy levels (mean 10.9 umol/l, 95% CI 10.1 - 11.5)	Results adjusted for childhood intelligence quotient
Pins et al., 2002 [7]	1077 people aged 60 - 90 yr in Rotterdam Scan Study	Cross section of prospective cohort	Abbreviated Stroop tesatl Letter-Digit Substitution Task, Verbal fluency test, PPMST, Modified Rey’s test	Patients with tHcy > 14 umol/l had lower scores for global cognitive function (diference-0.20, 95%CI-0.30 - 0.11)	Results adjusted for age, sex, education level, depression, serum creatinine level
Miller et al., 2003 [8]	1789 community dwelling people aged > 60 yr in Sacramento Area Latino Study on Aging	Cross section of prospective cohort	3MSE, verbal and visual memory tests, object naming conceptualization and attention span tests	Inverse relation between tHcy levels and scores on 3MSE (p = 0.02), picture association (p = 0.05), verbal attention span (p = 0.04), and recognition tests (p = 0.001),	Multiple linear regression model included folate, cobalamin, age creatinine, sex, education and acculturation
Ravaglia et al., 2003 [9]	650 community dwelling people aged 65 - 91 yr (mean 73 yr) with normal cognitive function in Conselice Study	Population based study	MMSE	Inverse relation between odds of tHcy level > 15 umol/l and MMSE scores	Results adjusted for age, income, education level, serum creatinine level, serum vitamin B index, active lifestyle, coffee and meat consumption
Garcia et al., 2004 [10]	281 community dwelling people aged >65 yr	Cross section	Stroop, Mattis DRS, CVLT	Subjects with elevated tHcy levels (>13.9 umol/l) had lower stroop scores than those with normal tHcy levels in univariate analysis (p < 0.05)	Strongest association found between methylcitric acid and cognitive scores
Dufouil et al., 2003 [11]	1241 people aged >60 yr in Epidemiology of Vascular Aging Study	prospective cohort; 4-yr follow-up	MMSE, Trail Making Test Part B, Digit Symbol Substitution Test from the WAIS, Finger Tapping Test	Odds of cognitive decline 2.8 (95% CI 1.2 - 6.2) in patients with tHcy level > 15 umol/l	OR adjusted for age, sex, education level, baseline cognition, BMI, alcohol consumption, smoking, hypertension, hypercholesterolemia, Glycemix status, history of vascular disease, and folate and B₁₂ levels
Kalmijn et al., 1999 [12]	702 community dwelling people aged > 55 yr in Rotterdam Study	prospective cohort; mean follow-up 2.7 yr	MMSE	No association between tHcy and cognitive impairment (highest v. lowest tertile, OR 0.91, 95% CI 0.52 - 1.58)	OR adjusted for age, education level, and baseline MMSE score
Ravaglia et al., 2000 [13]	54 people aged > 65 yr in Conselice Study	Cross section of prospective cohort	MMSE, clock drawing test, prose memory test, Corsi block tapping task, Mental Deterioration Battery	No association between tHcy and cognitive test scores	Results adjusted for age, sex, education level, smoking status, alcohol or coffee consumption, and previous cardiovascular disease

Box 1. Effects of elevated homocysteine levels in the brain

Figure 1 Homocysteine is metabolized through 2 different pathways: the methionine synthase pathway and the cystathionine pathway. It has been proposed that impaired remethylation of homocysteine produces an increase of intracellular homocysteine that is toxic to neurons, and a decrease in S-adenosyl methionine. Impairment of this reaction would occur in states of cerebral oxidative stress, which would augment oxidation of an intermediate form of vitamin B<sub>12</sub> (cobalamin) produced in the methionine synthase reaction and compromise the conversion of the vitamin to its metabolically active form. By Canadian Medical Association, Angeles Garcia, and Katherine Zanibbi, CMAJ, 2004, 171, 897-9042.2. Laboratory Measurement

Venous blood sample after overnight fasting were drawn according to standard procedure. Plasma or serum was isolated and stored at −80˚C before analysis. Serum total homocysteine was measured at the clinical chemistry laboratory of the Ramathibodi Hospital, Mahidol University, Bangkok, using automated chemiluminescent enzyme immunoassay method (Diagnostic Products Corporation, Los Angeles, CA); the CV ranged from 4.1% to 10.2%.

Global cognitive function was assessed with the Thai language by using mini-Mental State Examination score (MMSE), and cognitive functions were assessed by a neuropsychological battery test for memory, executive function, attention, visual-spatial organization, information processing and motor speed.

Other measurements: The following variables were considered as possible confounders: age; sex; cigarette smoking (current, former, never); alcohol consumption, assessed with a semi quantitative food frequency questionnaire [15] ; level of education, group into 4 levels (complete primary education, lower vocational or general education, intermediate vocational or general education, and higher vocational training, college, or university) [16] ; and hypertension, which was defined in accordance with the WHO [17] as a systolic blood pressure of 160 mmHg or more, a diastolic blood pressure of 95 mmHg or more, or use of antihypertensive medication.

2.3. Statistical Analysis

Multiple linear regression analysis was used to examine the relations between homocysteine levels and neuropsychological test scores with control for potential confounding variables to evaluate whether the relations were altered by these other variables. All tests were two-sided, and a p value of less than 0.05 was considered to be statistically significant. All data analyses were done with SPSS version 17.0 (SPSS Inc., Chicago, IL).

3. Results

The characteristics of the study population are summarized in Table 1 and Table 2.

In Table 1, the mean ± SD age of participants was 72.8 ± 4.6 y. About one-half of the population had a history of hypertension (54.6%), 24.1% had diabetes mellitus and 15.1% had cardiovascular disease, respectively.

Table 2 for neuropsychological test found that the highest % abnormality test of C-W stimulustest, follow by digit symboltest, C stimulus, trial marking test D-KEFS condition 5, verbal pair total (VP total), retention, verbal paired associates 2(VP2), and block design (73.1, 38.3, 34.4, 26.6, 22.3, 15.6, 13.8 and 13.8), respectively.

Table 3 in the model 1, homocysteine was inversely associated with scores for learning slope test (B = −0.048, p = 0.042) and verbal pair total test (B = −0.124, p = 0.032). After adjusting for confounders, no association was found between homocysteine and cognitive impairment. Age (B = −0.129, p = 0.007) was found to be a significant determinant of decreased learning slope score (Table 4, model 2). Similarly, age (B = −0.298, p = 0.009) and education (B = 0.267, p = 0.029) were found to be significant determinants of decreased verbal pair total score (Table 5, model 3).

4. Discussion

High homocysteine levels have been associated with an increased risk of stroke and other cardiovascular events [18] , which, in turn have been related to decreased cognitive

Table 1 Demographic and laboratory characteristics of the study subjects

Variables	Value	% abnormal laboratory (only)
Age (y)	72.8 ± 4.6 (61 - 80)
Education (y)	6.3 (0 - 18)
Hypertension (%)	54.6
Diabetes mellitus (%)	24.1
Cardiovascular disease (%)	15.1
Homocysteine (µmol/L)	14.2	34.0
Vitamin B 12 (pg/mL)	612.1	4.26
Serum Folic (ng/ml)	11.6	0.0
RBC folate (ng/ml)	498.5	0.0
Cholesterol (mmol/L)	5.54	60.0
LDL (mmol/L)	3.49	50.0
HDL (mmol/L)	1.36	23.40
Creatinine (µmol/L)	70.8	4.3 (female) 12.0 (male)

Table 2 Cognitive performance of the study subjects

Test score	Median (95% CI )	% abnormal (<1.5 SD)
MMSE	27.0 (25.6 - 28.3)	0.0
VP1	0.0	0.0
Learning slope	2.09 (1.9 - 2.1)	3.2
VP2	1.5 (1.43 - 1.57)	13.8
VP total	5.0 (4.75 - 5.25)	22.3
Recognition	23.0 (21.85 - 24.15)	0.0
Retrieval	21.0 (19.95 - 22.05)	0.0
Retention	66.7 (63.36 - 70.03)	15.6
Digit forward	8.0 (7.6 - 8.4)	0.0
Digit backward	4.0 (3.8 - 4.2)	0.0
Block design	9.0 (8.5 - 9.5)	13.8
Trial Marking Test D-KEFS condition 5	52.6 (50.0 - 54.2)	26.6
Digit symbol	16.5 (15.6 - 17.4)	38.3
C stimulus	112.0 (106.4 - 117.6)	34.4
C-W stimulus	36.0 (34.2 - 37.8)	73.1

Table 3 Association between homocysteine and cognitive test score (model 1)

Cognitive test	Homocysteine (b)	p-value
MMSE	−0.010	0.752
VP1	−0.010	0.384
Learning slope	−0.048 (*)	0.042 (*)
VP2	−0.021	0.273
VP total	−0.124 (*)	0.032 (*)
Recognition	0.007	0.869
Retrieval	0.032	0.373
Retention	0.528	0.415
Digit forward	−0.007	0.798
Digit backward	0.004	0.870
Block design	−0.063	0.436
Trial Marking Test D-KEFS condition 5	0.584	0.081
Digit symbol	−0.255	0.196
C stimulus	−0.069	0.586
C-W stimulus	−0.498	0.087

Verbal pair total: VP total, *significant p < 0.05.

Table 4 Multiple linear regression between homocysteine, B12, folic, age, education, Cr and learning slope (model 2)

Cognitive test	B	p-value
Homocysteine	−0.015	0.520
Vitamin B 12	0.000	0.824
RBC folate	−1.126	0.971
Serum folic	0.005	0.876
Age	−0.129	0.007 (**)
Education	0.067	0.129

Table 5 Multiple linear regression between homocysteine, B12, folic, age, Cr and verbal pair total (model 3)

Cognitive test	B	p-value
Homocysteine	−0.080	0.252
Vitamin B 12	0.010	0.894
RBC folate	−0.006	0.716
Serum folic	0.013	0.786
Age	−0.298	0.009 (**)
Education	0.267	0.029 (*)

function and dementia [19] [20] [21] . Thus, we hypothesized that a high level of homocysteine was associated with cognitive function. However, in the present study, there was no significant association between high levels of homocysteine and cognitive impairment in a population of institutionalized subjects (Baan Bangkae). Several methodological

Considerations arise when we try to explain our negative findings. We used only one global measure of cognitive function, the MMSE. However, the MMSE is a valid and reliable test [22] . However, the MMSE was not developed to estimate change in cognitive impairment. In addition, with our definition of cognitive decline, we were able to find an association with known risk factors, such as age and education. Similar results from Seshadri et al. [23] which found that cognitive decline associated with age education, and stroke. Still, random misclassification may have diluted our results for cognitive decline [12] . Demographic variables, particularly age and education, were significantly associated with cognitive function scores than was homocysteine. The reasons may be the small number of sample size (100), normal level of homocysteine in blood samples (14 umol/l, 34.04% hyperhomocysteinemia) used cut-off point >15 umol/l compared with other study which had a higher homocysteine levels (cut-off point >13 umol/l) [1] [24] [25] [26] than our study 1, age of elderly Baan Bangkae, higher than other communities and had many diseases (HT, hyperlipidemia, DM, CVD) that effect homocysteine level and cognitive impairment.

5. Conclusion

In summary, although an association between homocysteine and cognitive impairment was biologically plausible, homocysteine did not seem to be a risk factor for cognitive impairment in this general population of the elderly. However, the possibility that homocysteine is truly not related to cognitive impairment cannot be discarded. Further researches such as a large number of participants and subjects in community are needed to find out for better quality of life in elderly population.

Acknowledgements

The authors gratefully acknowledge the coworkers at the research center of Ramathibodi Hospital, Mahidol University, Bangkok, Thailand and coworkers at Baan Bangkae Social Welfare Development Center for Older Persons, Bangkok and the vicinity. Finally, to the 100 subjects, whose were participated in this study.

Cite this paper

Viroonudomphol, D., Kajanachumpol, S. and Prawettongsopon, C. (2016) Homocysteine and Cognitive Impairment in Thai Elderly. World Journal of Engineering and Technology, 4, 562-571. http://dx.doi.org/10.4236/wjet.2016.44054

References1

Garcia, A. and Zanibbi K. (2004) Homocystrine and Cognitive Function in Elderly People. CMAJ, 171, 897-904. http://dx.doi.org/10.1503/cmaj.1031586

Lasuka, D. (2014) Dementia in Thailand Current Situation in Global Collaboration Center. Osaka University Booklet, 15, 43.

Senanarong

, Jamjumrus

, Harnphadungkit

, Vannasaeng S.

Udompunthurak

, S.

Prayoonwiwat

, N. and Poungvarin

,et al. (2001)Risk Factors for Dementia and Impaired Cognitive Status in Thai Elderly Journal of Medical Association of Thailand 84, 468-474.

Rosenberg, I.H. and Miller, J.W. (1992) Nutritional Factors in Physical and Cognitive Functions of Elderly People. The American Journal of Clinical Nutrition, 55, 1237S-1243S.

Budge, M.M., de jager C., Hogervorst, E. and Smith, A.D. (2002) Total Plasma Homocysteine, Age, Systolicblood Pressure, and Cognitive Performance in Older People. Journal of the American Geriatrics Society, 50, 2014-2018. http://dx.doi.org/10.1046/j.1532-5415.2002.50614.x

Duthie, S.J., Whalley, L.J., Collins, A.R., Leaper, S., Gerger, K. and Deary, I.J. (2003) Homocysteine, B Vitamin Status, and Cognitive Function in the Elderly [Published Erratum in The American Journal of Clinical Nutrition, 77, 523]. The American Journal of Clinical Nutrition, 75, 908-913.

Pins

N.D.

, den Heijer

, Hofman

, Koudstaal P.J.

Jolles

, J. and Clarke

,et al. (2002)Homocysteine and Cognitive Function in Elderly The Rotterdam Scan Study Neurology 59, 1375-1380.

Miller, J.W., Green, R., Ramos, M.I., Allen, L.H., Mungas, D.M. and Jagust, W.J. (2003) Homocysteine and Cognitive Function in the Sacramento Area Latino Study on Aging. The American Journal of Clinical Nutrition, 78, 441-447.

Ravaglia, G., Forti, P.L., Maioli, F., Muscari, A., Sacchetti, L. and Arnon, G. (2003) Homocysteine and Cognitive Function in Healthy Elderly Community Dwellers in Italy. The American Journal of Clinical Nutrition, 77, 668-673.

Garcia, A., Haron, Y., Evan, L., Smith, M., Freedman, M. and Roman, G. (2004) Metabolic markers of Cobalamin Deficiency and Cognitive Function in Normal Older Adults. Journal of the American Geriatrics Society, 52, 66-71. http://dx.doi.org/10.1111/j.1532-5415.2004.52012.x

Dufouil, C., Alperovitch, A., Ducros, V. and Tzourio, C. (2003) Homocysteine, White Matter Hyperintensities , and Cognition in Healthy Elderly People. Annals of Neurology, 53, 214-221. http://dx.doi.org/10.1002/ana.10440

Kalmijn, S., Laune,r L.J., Lindemans, J., Bots, M.L., Hojman, A. and Brereler, M.M. (1999) Total Homocysteine and Cognitive Decline in a Community-Based Sample of Elderly Subjects. The Rotterdam Study. American Journal of Epidemiology, 150, 283-289. http://dx.doi.org/10.1093/oxfordjournals.aje.a010000

Ravaglia, G., Forti, P., Maioli, F., Zanardi, V., Delmonte, E. and Grossi, G. (2000) Blood Homocysteine and Vitamin B Levels Are Not Associated with Cognitive Skills in Healthy Normally Aging Subjects. The Journal of Nutrition, Health and Aging, 4, 218-222. http://dx.doi.org/10.1503/cmaj.1031586

McCaddon, A., Regland, B., Hudson, P. and Davies, G. (2002) Functional Vitamin B(12) Deficiency and Alzheimer’s Disease. Neurology, 58, 1395-1399. http://dx.doi.org/10.1212/WNL.58.9.1395

Goldbohm

R.A.

, van den Brandt

P.A.

, Brants

H.A.

, van’t Veer

, Ai

, Sturman

F. and Hermus R.J.

,et al. (1994)Validation of a Dietary Questionnaire Used in a Large-Scale Prospective Cohort Study on Diet and Cancer European Journal of Clinical Nutrition 48, 253-265.

Unesco (1976) International Standard Classification of Education (ISCED). Unesco, Paris, France.

Final Report of the Working Group on Risk and High Blood Pressure (1985) An Epidemiological Approach to Describing Risk Associated with Blood Pressure Levels. Hypertension, 7, 641-651.

Boushey, C.J., Beresford, S.A., Omenn, G.S. and Motulsky, A.G. (1995) A Quantitative Assessment of Plasma Homocysteine as a Risk Factor of Vascular Disease. Probable Benefits of Increasing Folic Acid Intakes. JAMA, 274, 1049-1057. http://dx.doi.org/10.1001/jama.1995.03530130055028

Breteler, M.M.B., Claus, J.J., Grobbee, D.E. and Hofman, A. (1994) Cardiovascular Disease and Distribution of Cognitive Function in Elderly People: The Rotterdam Study. BMJ, 308, 1604-1608. http://dx.doi.org/10.1136/bmj.308.6944.1604

Hofman, A., Ott, A., Breteler M.M., Bots, M.L., Slooter, A.J., van Harskamp, F., van Dujin, C.N., van Broeckhoven, C. and Grobbee, D.E. (1997) Artherosclerosis, Apolipoprotein E, and the Prevalence of Dementia and Alzheimer’s Disease in the Rotterdam Study. The Lancet, 349, 151-154. http://dx.doi.org/10.1016/S0140-6736(96)09328-2

Tatemichi, T.K., Deamond, D.W., Stern, Y., Paik, M., Sano, M. and Bagiella, E. (1994) Cognitive Impairment after Stroke: Frequency, Patterns, and Relationship to Functional Abilities. Journal of Neurology, Neurosurgery, and Psychiatry, 57, 202-207. http://dx.doi.org/10.1136/jnnp.57.2.202

Tombaugh, T.N. and McIntyre, N.J. (1992) The Mini-Mental State Examination: A Comprehensive Review. Journal of the American Geriatrics Society, 40, 922-935. http://dx.doi.org/10.1111/j.1532-5415.1992.tb01992.x

Seshadri, S., Beiser, A., Selhub, J., Jacques, P.F., Rosenberg, I.H. and D’Agostino, R.B. (2002) Plasma Homocysteine as a Risk Factor for Dementia and Alzheimer’s Disease. The New England Journal of Medicine, 346, 476-483. http://dx.doi.org/10.1056/NEJMoa011613

Vogel, T., Dali-Youcef, N., Kaltenbach, G. and Andres, E. (2009) Homocysteine, Vitamine B12, Folate and Cognitive Functions: A Systemic and Critical Review of the Literature. International Journal of Clinical Practice, 63, 1061-1067. http://dx.doi.org/10.1111/j.1742-1241.2009.02026.x

Feng, L., Tze-Pin, Ng., Chuah, L., Niti, M. and Ee-Heok, K. (2006) Homocysteine, Folate, and Vitamin B-12 and Cognitive Performance in Older Chinese Adults: Findings from the Singapore Longitudinal Ageing Study. The American Journal of Clinical Nutrition, 84, 1506-1512.

Mooijaart, S.P., Gussekloo, J., Frolich, M., Jolles, J., Stott, D.J., Westendrop, R.G. and de Craen, A.J. (2005) Homocysteine, Vitamin B-12, and Folic Acid and the Risk of Cognitive Decline in Old Age: The Leiden 85-Plus Study. The American Journal of Clinical Nutrition, 82, 866-871.