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Elevated plasma homocysteine levels in patients with amyotrophic lateral sclerosis

From the Operative Unit of Neurology, "Lorenzo Bonomo" Hospital, Andria, Italy (S.Z., L.S.); Department of Neurological Sciences, University of Bari, Italy (I.L.S., P.L., V.S., R.T.); and Department of Epidemiology, Harvard School of Public Health; Division of Aging, Harvard Medical School, Boston, MA (G.L.).

Address correspondence and reprint requests to Dr. Giancarlo Logroscino, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115 glogrosc{at}hsph.harvard.edu

Background: Both in vitro and in vivo studies indicate that homocysteine (Hcy) may be directly involved in the damage of motor neurons and in several pathways implicated in amyotrophic lateral sclerosis (ALS) pathogenesis.

Objective: To determine whether plasma Hcy levels were higher in ALS patients than healthy controls and to examine the relationship between Hcy levels and clinical ALS phenotypes.

Methods: In a cross-sectional study, we compared Hcy, B₁₂, and folate levels in 62 patients with ALS and 88 age- and sex-matched controls recruited as outpatients in a tertiary clinical center.

Results: Patients with ALS had higher median plasma Hcy levels (11.2 [range 5.8 to 46] vs 9.7 [range 4.5 to 15.9] µmol/L; p = 0.0004) and lower folate levels (4.4 [range 1.7 to 22.1] vs 5.8 [range 2.3 to 21.1] ng/mL; p = 0.0003), compared with controls. Multivariate logistic regression revealed a strong direct association between plasma Hcy levels and presence of ALS (odds ratios adjusted for age, sex, and B-vitamin levels comparing the top tertile [Hcy levels 11.6 µmol/L] with the bottom tertile [Hcy levels < 9.2 µmol/L]: 6.4; 95% CI 2.2 to 19.1; p for trend = 0.0008). We also found a trend for higher Hcy levels in patients with shorter interval from symptom onset to diagnosis (ODI; <14 months), compared with patients with longer ODI (>14 months; median Hcy levels 11.8 [range 5.8 to 46] vs 10.1 [range 7.2 to 17.6] µmol/L; p = 0.09). In a multivariate model, Hcy levels strongly correlated with shorter interval onset diagnosis (r² = 0.18; p = 0.01).

Conclusions: Plasma homocysteine (Hcy) levels were significantly increased in patients with amyotrophic lateral sclerosis (ALS) compared with healthy controls. ALS cases with shorter time to diagnosis presented higher Hcy levels, suggesting that higher Hcy may be linked to faster progression of the disease.

Abbreviations: ALS = amyotrophic lateral sclerosis; EEC-R = El Escorial Revised Criteria; FRS = functional rating scale; Hcy = homocysteine; MRC = Medical Research Council; ODI = onset–diagnosis interval; OR = odds ratio.

Disclosure: The authors report no conflicts of interest.

Received February 28, 2007. Accepted in final form July 3, 2007