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Age and Ageing Advance Access originally published online on March 15, 2007
Age and Ageing 2007 36(3):339-343; doi:10.1093/ageing/afm006
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Copyright © The Author 2007. Published by Oxford University Press on behalf of the British Geriatrics Society.

Homocysteine and post-stroke cognitive decline*

Sir—Normal fasting total plasma homocysteine (tHcy) concentrations range from 5 to 15 µmol l–1 [1, 2]. Hyperhomocysteinaemia has been classified as moderate, intermediate or severe if levels are 15–30, >30–100 or >100 µmol l–1, respectively [3]. Whereas severe hyperhomocysteinaemia is uncommon, moderate levels can exist in healthy controls [4]. Hyperhomocysteinaemia has been associated with risk of stroke, myocardial infarction (MI) [5], Alzheimer's disease (AD) [6] and vascular dementia [7]. Studies of cognitive decline and tHcy in healthy controls, however, conflict [8, 9]. Vascular disease patients may have higher tHcy than AD patients [10], thus, hyperhomocysteinaemia in demented subjects [7] could be due to concomitant vascular disease, rather than a cause of dementia. This, however, is controversial since elevated tHcy has existed in pathologically confirmed AD cases both with and without vascular disease as well as in vascular dementia [11].

How hyperhomocysteinaemia promotes dementia is unknown, although mechanisms are proposed [12, 13] which may explain co-occurrence with vascular disease, stroke and AD.

Sixty per cent of non-demented stroke subjects had tHcy >15 µmol l–1 and higher levels were related to attentional and executive function deficits [4]. This leads us to hypothesise that stroke patients with hyperhomocysteinaemia should be pre-disposed to dementia. Our objective was to investigate whether tHcy at 3 months post-stroke predicted cognitive outcome in elderly, well recovered, non-demented subjects. We examined whether tHcy associated with incidence of dementia/general cognitive decline or changes in attention, language expression and executive function over 2 years.

Methods

Approval was granted by local research ethics committees. Three hundred and fifty-four patients gave written informed consent (with assent from next-of-kin where available) to clinical and neuropsychological investigations. tHcy was measured using standard techniques [14] in 170 subjects giving additional consent for blood sampling at 3 months post-stroke.

Hospital notes were reviewed for pre-stroke hypertension, atrial fibrillation (AF), MI, hypercholestraemia and diabetes. Clinical and CT scan evidence-based diagnoses of stroke, Oxford Community Stroke Project (OCSP) classification [15] and smoking and alcohol habits were recorded. One hundred and fifty-four subjects (90.6%) had ischaemic infarctions, 2 (1.2%) haemorrhagic infarctions, 2 (1.2%) intracerebral haemorrhages and 4 (2.4%) exhibited transient ischaemic attacks. Of those with ischaemic infarctions, 8 (5.2%) had total anterior circulation infarcts (TACI), 65 (42.2%) had partial anterior circulation infarcts (PACI), 56 (36.4%) exhibited lacunar infarcts (LACI) and 24 (15.6%) showed posterior circulation infarcts (POCI).

The CAMCOG [16] and Cognitive Drug Research computerised battery [17] were performed at 3, 15 and 27 months post-stroke. Incident dementia was diagnosed using DSMIV criteria. ‘Decliners’ were defined as those who attained the primary outcome (dementia or a CAMCOG score below 80) at 27 months. Secondary outcomes were changes in (i) total CAMCOG score, (ii) executive function and language expression sub-scores from the CAMCOG and (iii) power of attention (PoA) [18]. Potential confounders were age, gender, AF, hypertension, MI, hypercholestraemia, diabetes, the methylene tetrahydrofolate reductase (MTHFR) T allele, the APOE4 allele; a history of smoking or excessive alcohol consumption; and vitamin B12, RCF and creatinine levels. Statistical evaluation is described in Appendix 1 on the journal website (http://www.ageing.oxfordjournals.org).

This project was funded by the Medical Research Council with additional staffing support from the Alzheimer's Research Trust. The sponsors played no role in the design, execution, analysis, interpretation of data or writing of the study.

Results

Although the 170 participants with tHcy measures were similar to those for whom tHcy was not measured in age and gender, they differed in mean baseline CAMCOG scores (87 versus 84 respectively: P = 0.002, logistic regression).

Characteristics of participants are summarised in Appendix 2 on the website (http://www.ageing.oxfordjournals.org). Eighty-seven of the 170 participants (51.2%) had hyperhomocysteinaemia (>15 µmol l–1); 99% of these between 15 and 30 µmol l–1. There was a higher prevalence of MI in the upper homocysteine quartile (P from Chi-squared comparing tHcy quartiles = 0.020). Lower levels of vitamin B12 and RCF and higher levels of creatinine associated with higher levels of homocysteine (P from one-way ANOVA comparing quartiles = 0.011, <0.001 and <0.001 respectively). Since 11 participants were awaiting re-assessment at 27 months, 21 withdrew and 12 died, the cohort was left with 126 for the primary outcome analysis. These 126 patients were similar to the 44 not re-assessed in relation to age, gender, homocysteine level (P-values from logistic regression = 0.361, 0.413, 0.655, respectively), and in terms of evidence-based diagnoses of stroke (P-value from Chi–squared = 0.508). There was, however, a difference in baseline CAMCOG score between those assessed and not assessed at 27 months (logistic regression P–values = 0.048: mean CAMCOG = 87 and 85 respectively).

Table 1 shows cognitive changes across homocysteine quartiles. One hundred subjects did not attain decliner status at 27 months. Sixteen of the 26 decliners had dementia. There was no significant difference between decliners and non-decliners in terms of stroke type; decliners had ischaemic infarctions: 8% TACI, 48% PACI, 36% LACI, 8% POCI. Neither homocysteine level nor any confounders were significantly associated with cognitive decline or changes in secondary cognitive outcomes over 27 months (Table 2).


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  		Table 1. Changes in cognitive performance between 3 and 27 months post-stroke

 

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  		Table 2. Logistic and linear regression results examining the association of homocysteine (i) as a continuous variable and (ii) as a categorical variable, with the (a) primary and (b) secondary outcome measures

 
Discussion

Our cohort comprised Caucasian, well-recovered elderly patients. In contrast to a younger multi-ethnic cohort in south London [19] that may explain differences in the outcomes with respect to infarction sub-types; we noted fewer TACI and more PACI (in the London cohort TACI was around 22%). These differences make it difficult to generalise between our cohort and unselected population groups. Our mean tHcy (16.0 µmol l–1) and frequencies of hyperhomocysteinaemia were, however, similar to those previously described [4, 7].

We found no associations between tHcy and cognitive change, therefore, 3-month post-stroke tHcy measurement may not predict cognitive decline. The Sydney Stroke Study (N = 131), however, reported correlations between tHcy and cognitive impairments between 3 and 6 months [4]. These contrasting results could be due to different homocysteine sampling times, assessment intervals and ages of participants. It is plausible that early homocysteine measurement is predictive of cognitive decline in the acute phase and up to 6 months. However, once this period has passed, it may no longer be the case. It is unclear how homocysteine levels change following stroke. In one study, acute phase homocysteine levels of 8 to 9 µmol l–1 were similar to those of controls although they had risen by the convalescent phase to around 10.0 µmol l–1 [20]. In contrast, research on participants in the VISP Trial examined the acute phase in more detail and demonstrated a mean level of 11.3 µmol l–1 at day 1, increasing significantly to 13.3 µmol l–1 at days 10–14 [21]. One limitation to these studies, including our own, is that the pre-stroke tHcy was not measured and thus it is difficult to assess whether the stroke itself and/or the post-stroke recovery response reflect long-term tHcy elevations. Further studies will need to address this.

Our trend for increased prevalence of MI with increasing homocysteine concentrations agrees with others [5]. The trend for lower levels of vitamin B12 and RCF with higher tHcy is consistent with their roles in homocysteine metabolism.

Our lack of association between homocysteine and cognitive decline could be explained by methodology. Our sample size, although comparable to the Sydney Stroke study (with Odds Ratio of 3.27) [4], may still be inadequate for detecting longitudinal decline. There was additional sampling bias because those patients for whom we obtained tHcy were less impaired than those for whom we did not; more impaired patients are less inclined to undergo additional investigations. Losses to follow up increased the potential for residual confounding further as did the exclusion of aphasic or severely disabled subjects or those developing dementia within 3 months of stroke. Homocysteine was measured once only. Whilst this is accepted practice, it is reasonable to propose repeated measurements to compare dynamic changes in homocysteine [20, 21] with cognitive changes. Length of exposure to elevated homocysteine may be important in determining cognitive effect [22]; how well single measures reflect this is unknown. Finally, our relatively homogeneous homocysteine levels may not have provided enough variability to detect associations within 27 months; longer follow up may be appropriate.

There is still debate about the feasibility of improving outcome for cardiovascular patients by modulating tHcy. Although the VISP study did not demonstrate overall efficacy for folate and vitamin B administration following stroke, a retrospective sub-analysis suggested that higher B12 doses may be more appropriate [23]. The NORVIT study [24] similarly, did not reduce risk of recurrent cardiovascular disease following MI. Another trial whilst demonstrating a homocysteine lowering effect of folate and B vitamin therapy did not demonstrate concurrent improvement in cognitive function in healthy elderly subjects over 2 years [25]. Our question about whether there is an association between elevated homocysteine levels and post-stroke cognitive impairment/dementia is, nevertheless, important. Clearly if there is no proven causal relationship between tHcy and cognitive impairment, tHcy lowering strategies will not serve to reduce dementia incidence and other mechanisms will need to be investigated. However, if there is a causal relationship, further modification of current folate/vitamin B treatment regimens may be necessary.

In summary, single post-stroke homocysteine measurements did not predict dementia or cognitive decline at 27 months post-stroke in well-recovered elderly subjects.

Key points

  • Fifty-one per cent of elderly non-demented stroke patients have hyperhomocysteinaemia at 3 months post-stroke.
  • Seventy-nine per cent of elderly stroke patients scored above 80 points on the CAMCOG at 27 months post-stroke.

Conflicts of Interest Declaration

There are no conflicts of interest.

Acknowledgements

We would like to thank Cognitive Drug Research Ltd and Professor David Smith and Carole Johnston of OPTIMA, University Department of Pharmacology, Oxford, for technical advice and assistance.

Notes

*This was presented as a poster at the Autumn Meeting of the British Geriatrics Society: Harrogate International Centre, Harrogate, Yorkshire. 5–7 Oct 2005.

Elise N. Rowan1,*, Heather O. Dickinson3, Sally Stephens1, Clive Ballard2, Raj Kalaria1 and Rose Anne Kenny1

1 Institute for Ageing and Health, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK
2 Wolfson Centre for Age Related Disorders, Kings College, London, UK
3 Centre for Health Services Research, University of Newcastle upon Tyne, UK

* To whom correspondence should be addressed Tel: 0191 256 33 83; Fax: 0191 256 33 89 Email: e.n.rowan{at}ncl.ac.uk

References

  1. Ueland PM, Refsum H, Stabler SP, Malinow MR, Andersson A, Allen RH. Total homocysteine in plasma or serum: methods and clinical applications. Clin Chem (1993) 39:1764–79.[Abstract]
  2. Jacobsen DW, Gatautis VJ, Green R, Robinson K, Savon SR, Secic M. Rapid HPLC determination of total homocysteine and other thiols in serum and plasma: sex differences and correlation with cobalamin and folate concentrations in healthy subjects. Clin Chem (1994) 40:873–81.[Abstract/Free Full Text]
  3. Kang SS, Wong PW, Malinow MR. Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr (1992) 12:279–98.[CrossRef][Web of Science][Medline]
  4. Sachdev P. Homocysteine, cerebrovascular disease and brain atrophy. J. Neurol. Sci. (2004) 226:25–9.[CrossRef][Web of Science][Medline]
  5. Bots ML, Launer LJ, Lindemans J, Hoes AW, Hofman A, Witteman JC. Homocysteine and short-term risk of myocardial infarction and stroke in the elderly: The Rotterdam Study. Archives of Internal Medicine (1999) 159:38–44.[Abstract/Free Full Text]
  6. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. New England Journal of Medicine (2002) 346:476–83.[Abstract/Free Full Text]
  7. McIlroy SP, Dynan KB, Lawson JT, Patterson CC, Passmore P. Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype and risk for stroke, vascular dementia and Alzheimer disease in Northern Ireland. Stroke (2002) 33:2351–6.[Abstract/Free Full Text]
  8. Luchsinger JA, Tang M-X, Shea MD, Miller J, Green MD, Mayeux R. Plasma homocysteine levels and risk of Alzheimer disease. Neurology (2004) 62:1972–6.[Abstract/Free Full Text]
  9. Ravaglia G, Forti F, Maioli F, Martelli M, Servadei L, Brunetti N. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr (2005) 82:636–43.[Abstract/Free Full Text]
  10. Miller JW, Green R, Mungas DM, Reed BR, Jagust WJ. Homocysteine, vitamin B6 and vascular disease in AD patients. Neurology (2002) 58:1471–5.[Abstract/Free Full Text]
  11. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, Vitamin B12, and serum total Homocysteine levels in confirmed Alzheimer disease. Arch Neurol (1998) 55:1449–55.[Abstract/Free Full Text]
  12. Kruman II, Kumaravel TS, Lohani A, Pedersen WA, Cutler RG, Kruman Y. Folic acid deficiency and homocysteine impair DNA repair in hippocamplal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease. Journal of Neuroscience (2002) 22:1752–62.[Abstract/Free Full Text]
  13. Hassan A, Hunt BJ, O'Sullivan M, Bell R, D'Souza R, Jeffery S. Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction. Brain (2004) 127:212–9.[Abstract/Free Full Text]
  14. Nexo E, Engbaek F, Ueland PM, Westby C, O'Gorman P, Johnson C. Evaluation of novel assays in clinical chemistry: quantification of plasma total homocysteine. Clin Chem (2000) 46:1150–6.[Abstract/Free Full Text]
  15. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and natural history of clinically identifiable sub types of cerebral infarction. Lancet (1991) 337:1521–6.[CrossRef][Web of Science][Medline]
  16. Roth M, Tym E, Mountjoy CQ, Huppert FA, Hendrie H, Verma S. CAMDEX. A standardised instrument for the diagnosis of mental disorder in the elderly with special reference to the early detection of dementia. British Journal of Psychiatry (1986) 149:698–709.[Abstract/Free Full Text]
  17. Simpson PM, Surmon DJ, Wesnes KA, Wilcock GK. The cognitive drug research computerised assessment system for demented patients: a validation study. Int J Geriatr Psychiatry (1991) 6:95–102.[CrossRef][Web of Science]
  18. Wesnes KA, Ward T, McGinty A, Petrini O. The memory enhancing effects of ginkgo biloba/Panax ginseng combination in healthy middle aged volunteers. Psychopharmacology (2000) 152:353–61.[CrossRef][Medline]
  19. Hajat C, Dundas R, Stewart JA, Lawrence E, Rudd AG, Howard R. Cerebrovascular risk Factors and stroke Subtypes: Differences between Ethnic Groups. Stroke (2001) 32:37–42.[Abstract/Free Full Text]
  20. Meiklejohn DJ, Vickers MA, Dojkhuisen R, Greaves M. Plasma homocysteine concentrations in the acute and convalescent periods of atherothrombotic stroke. Stroke (2001) 32:57–62.[Abstract/Free Full Text]
  21. Howard VJ, Sides EG, Newman GC, Cohen SN, Howard G, Malinow MR. Changes in plasma homocyst(e)ine in the acute phase after stroke. Stroke (2002) 33:473–8.[Abstract/Free Full Text]
  22. Wright CB, Lee H-S, Paik MC, Stabler SP, Allen RH, Sacco RL. Total homocysteine and cognition in a tri-ethnic cohort. The Northern Manhattan Study. Neurology (2004) 63:254–60.[Abstract/Free Full Text]
  23. Spence DJ, Bang H, Chambless LE, Stampfer MJ. Vitamin intervention for Stroke Prevention Trial. An Efficacy Analysis. Stroke (2005) 36:2404–9.[Abstract/Free Full Text]
  24. Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T. Homocysteine lowering and cardiovascular events after acute myocardial infarction. The New England Journal of Medicine (2006) 354:1578–88.[Abstract/Free Full Text]
  25. McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM. A controlled trial of homocysteine lowering and cognitive performance. The New England Journal of Medicine (2006) 354:2764–72.[Abstract/Free Full Text]

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