Search

Background: Dopamine replacement therapy by its precursor, L-3.4-dihydroxyphenylalanine (L-DOPA), has been the treatment of choice for Parkinson's disease. However, the possible contributory effect of L-DOPA therapy on the progression of Parkinson's disease mediated by the L-DOPA-induced toxic metabolites remains elusive., Scope of Review: Prolong use of L-DOPA leads to behavioral impediments and instigate the generation of several toxic metabolites. One such metabolite is homocysteine, the level of which increases in the plasma of Parkinson's disease patients undergoing L-DOPA therapy, as well as in brain of animal models of the disease. In concoction with parkinsonian neurotoxins, Hcy exaggerates dopaminergic neurodegeneration, while its intranigral infusion has been demonstrated to decrease the dopamine level as well as causes dopaminergic neurodegeneration. Therefore, it can be propounded that elevated level of Hcy (hyperhomocysteinemia) is one of the underlying causes of L-DOPA-induced side-effects and aggravates the progressive nature of Parkinson's disease, which has been focused here. We have provided a conjectural discussion on the involvement of Hcy in L-DOPA-induced dyskinesia in Parkinson's disease., Conclusion: Hyperhomocysteinemia as a result of prolonged L-DOPA therapy is the emerging cause of L-DOPA-induced behavioral abnormalities and progressive nature of Parkinson's disease., General Significance: This review highlights that hyperhomocysteinemia could be a putative contributor of the side-effects of chronic L-DOPA therapy because of its neurotoxic potency., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: This study aims to investigate hyperhomocysteinemia (HHcy) resulted from treatment in patients with Parkinson's disease (PD) and to evaluate the therapeutic outcome of HHcy., Patients and Methods: Ninety-three newly diagnosed PD patients were divided into Madopar group (treated with Madopar) and non-Madopar group (not treated with Madopar). Plasma Hcy levels were measured. Five months later, 67 patients presenting with HHcy were randomly divided into treatment group (n = 34) (receiving methylcobalamin 500 µg, tid, and folic acid 50 mg, tid, orally) and control group (n = 33).  Madopar dosage was maintained in both groups. MRI examination was performed to detect cerebral ischemia and patients were evaluated by Webster's rating scale. Plasma Hcy levels were measured at 3-month follow-up. Webster's scores and MRI were performed at 6-month follow-up., Results: At the initial visit, Hcy levels of patients of Madopar group were significantly higher than those of non-Madopar group  (18.52 ± 6.48 µmol/L) vs. (15.78 ± 3.42), p < 0.05]. At 5-month follow-up, patients of the non-Madopar group presented significantly increased Hcy levels (18.97 ± 7.42 µmol/L) compare with pre-treatment Hcy levels (p < 0.05), whereas Hcy levels were slightly increased in patients of Madopar group (20.61 ± 7.87 µmol/L, p > 0.05). In the treatment group, serum Hcy levels were significantly decreased after 3-month treatment with methylcobalamin and folic acid (p < 0.01). However, serum Hcy levels were not significantly changed in patients of the control group. In addition, in the treatment group, no patient presented ischemic stroke with clinical symptoms and four patients were confirmed with new cerebral ischemic and lacunar lesions by MRI examination. However, in the control group, two ischemic strokes with clinical symptoms and 11 new cerebral ischemic and lacunar lesions were detected. Significant differences were observed between two groups (p < 0.05). Furthermore, post-treatment modified Webster scores were significantly decreased than pre-treatment scores for both groups. However, no significant differences were found between groups (p > 0.05)., Conclusions: Oral administration of Levodopa in the treatment of PD can cause HHcy, which can result in increased occurrence of ischemic stroke. Supplementation of methylcobalamin and folic acid can effectively reduce Hcy level and thereby prevent the occurrence of ischemic stroke.

Unlabelled: The present study was designed to evaluate antioxidant effects of betaine in the brain following administration of levodopa and benserazide, which are routinely used in the treatment of Parkinson's disease. Sprague-Dawley male rats were divided into levodopa (LD), Betaine (Bet.), levodopa plus betaine (LD/Bet.), levodopa plus benserazide (LD/Ben.), levodopa plus betaine-benserazide (LD/Bet.-Ben.) and control groups. The experimental groups received LD 300 mg/kg, Bet. 1.5 % w/w of the total diet, Ben. 75 mg/kg and distilled water to controls for 10 consecutive days, orally. The concentration of plasma total homocysteine significantly increased in LD/Ben.-treated rats when compared to the other groups. Brain glutathione peroxidase (GPx) activity and glutathione content both elevated with betaine treatment in LD/Bet. and LD/Bet.-Ben groups. Superoxide dismutase activity was also higher in controls and betaine-treated rats in comparison with LD and LD/Ben. groups. Likewise, catalase activity significantly increased in control and betaine groups when compared to LD- and LD/Ben.-treated rats. In contrast, brain lipid peroxidation significantly increased in response to LD and LD/Ben., Treatments: Regarding metabolism of LD in peripheral tissues, serumic dopamine concentration significantly increased in LD-treated rats in comparison with LD/Ben. group. The present results show beneficial antioxidant and methyl donor properties of betaine versus oxidative stress and hyperhomocysteinemia induced by levodopa and benserazide in an animal model.

The objectives of this study were to evaluate the risk of neuropathy in patients with Parkinson's disease (PD) and to evaluate the role of levodopa exposure as a potential risk factor. A multicenter study of 330 patients with PD and 137 healthy controls with a comparable age distribution was performed. With respect to levodopa exposure, 144 patients had long exposure (≥ 3 years) to levodopa (LELD), 103 patients had short exposure (<3 years) to levodopa (SELD), and 83 patients had no exposure to levodopa (NOLD). Nerve function was evaluated using the reduced total neuropathy score. Right sural sensory antidromic and peroneal motor nerve conduction studies were performed by neurophysiologists who were blinded to the existence of neuropathy clinical features or PD treatment. Overall, 19.40% of patients in the LELD group, 6.80% in the SELD group, 4.82% in the NOLD group, and 8.76% in the control group were diagnosed with neuropathy (axonal, predominantly sensory). Multivariate logistic analysis indicated that the risk of neuropathy was not influenced by disease duration, severity, or sex. The risk of neuropathy increased by approximately 8% for each year of age (P < 0.001; odds ratio [OR], 1.08; 95% confidence interval [CI], 1.037-1.128). The risk of neuropathy was 2.38 higher in the LELD group than in the control group (P = 0.022; OR, 2.38; 95% CI, 1.130-5.014). In a comparison between patients with and without neuropathy (Student's t test), the levodopa dose was higher (P < 0.0001), serum vitamin B12 levels were lower (P = 0.0102), and homocysteine levels were higher (P < 0.001) in the patients with neuropathy. Our results demonstrate that the duration of exposure to levodopa, along with age, is the main risk factor for the development of neuropathy. Screening for homocysteine and vitamin B12 levels and clinical-neurophysiological monitoring for neuropathy may be advisable in patients with PD who are receiving treatment with levodopa., (© 2013 International Parkinson and Movement Disorder Society.)

Homocysteine (Hcy) has recently become the focus of interest in the research on Parkinson's disease (PD) and other neurodegenarative disorders. Chronic treatment with levodopa (LD), considered the standard treatment for PD, leads to an increase in homocysteine concentration in serum and cerebro-spinal fluid. Independently from this effect, homocysteine is also regarded as a marker of neurodegenerative disorders. Main interest was focused on hyperhomocysteinemia (hHcy) as the potential risk factor for atheromatosis. Subsequently, its role in neuropsychiatric diseases, e.g. depression, mild cognitive impairment and dementia was investigated. The potential pathogenic role of Hcy in peripheral neuropathy in patients with PD that are treated with LD is an interesting hypothesis but the literature is scarce. Confirmation of this association may lead to introduction of preventive therapies, e.g. administration of vitamin B and inhibitors of catechol-O-methyl transferase (COMT) that may decrease the Hcy blood concentrations.

Levodopa/carbidopa (LD/CD) application elevates total plasma homocysteine (thcys). We determined thcys-, LD- and 3-O-methyldopa (3-OMD) concentrations in 28 patients with Parkinson's disease (PD) on a LD/CD duodenal gel treatment. We found a distinct thcys increase (29.52 ± 28.98 μmol/l [median ± SD]) above the 15 μmol/l threshold and a significant (R = 0.7) correlation between LD and 3-OMD. thcys ascent was observed in relation with the onset of atherosclerosis, non-motor symptoms and polyneuropathy in PD patients in the long term.

Background: Patients with Parkinson's disease (PD) and chronically treated with L-DOPA exhibit, in a percentage of 10-30%, supra-physiological levels of plasma total homocysteinemia (tHcy). In this study, we have investigated, in a group of hyper-homocysteinemic PD patients, the time of hyper-tHcy recurrence after discontinuation of 1-month folate supplementation given to normalize plasma tHcy levels., Methods: Plasma tHcy, cobalamin and folate were assayed before and after 1-month folate supplementation (5 mg/day), and after 2 and 4 months after folate discontinuation in 29 PD patients (16M/13F, mean age 69.4 +/- 6.9 years) stabilized on a mean L-DOPA dose of 509.4 +/- 312.1 mg/day., Results: After folate supplementation, plasma tHcy levels fell within the normal range in all patients. At the 2-month control after folate discontinuation, plasma tHcy remained within physiological values in 25 out of 29 patients. Conversely, 4 months after folate discontinuation, all patients exhibited hyper-tHcy., Conclusions: One-month intake of 5 mg/day folate normalizes plasma tHcy levels in all hyper-homocysteinemic PD patients. Following folate discontinuation, hyper-tHcy recurs in all patients within 4 months. Knowledge of this time interval is useful to optimize pulses of folate therapy in hyper-homocysteinemic patients with PD.

Parkinson's disease (PD) patients have been reported to have lower bone mineral density (BMD) and higher fracture risk than individuals without PD. We assessed the association between hyperhomocysteinemia due to levodopa intake and BMD in PD patients. We measured serum homocysteine (Hcy) concentrations and BMD in the proximal femur and lumbar spine of PD patients aged 55 years or older (n = 95) and three age-/gender-matched control subjects (n = 285). The prevalence of osteoporosis was higher in both men (2.5-fold) and women (1.7-fold) with PD than in controls, and adjusted odds ratios for osteoporosis were 3.57 (95% confidence interval [CI], 1.25-10.20) for men and 2.54 for women (95% CI, 1.31-4.93) with PD. Serum Hcy concentrations were significantly higher in PD patients (median = 13.0 micromol/l) than controls (median = 11.5 micromol/l) (P = 0.005). Serum Hcy concentrations were independently associated with BMD values at all proximal femur sites in all subjects (P = 0.005 to 0.012). In PD patients, higher serum Hcy concentrations were independently associated with higher fracture risk (P = 0.029). PD patients taking higher doses of levodopa had significantly higher serum Hcy concentrations (P = 0.013), and greater levodopa intake was associated with lower BMD values in some areas (P = 0.008 to 0.029). In conclusion, these findings indicate that hyperhomocysteinemia due to levodopa intake may be one additional risk factor for osteoporosis and fracture in PD patients. Reducing Hcy may be a therapeutic modality for treating osteoporosis in PD patients taking levodopa.

Dementia is a frequent non-motor feature of Parkinson's disease (PD). Elevated plasma homocysteine (Hcy) levels have been associated with both cognitive impairment and dementia. Increased Hcy levels have been observed in levodopa-treated patients with PD. The objective of our study was to evaluate the association between plasma Hcy levels and dementia in PD. We performed a multicenter cross-sectional study on patients with PD with (PDD) and without (PDnD) dementia and age- and sex-matched healthy controls. We compared Hcy levels in patients with PDD and PDnD and healthy controls, and we performed logistic regression analysis to search for an association between the presence of dementia and increased Hcy levels in PD. Patients with PD (121), PDD (42), and PDnD (79), and age- and sex-matched controls (154) were enrolled. Hcy levels were higher in patients with PD compared to controls (17.5 micromol/L +/- 10.2 vs. 11 +/- 4.1; P < 0.00001). Among patients with PD, Hcy levels were higher in the PDD group compared to the PDnD group (20.7 micromol/L +/- 12.1 vs. 15.8 +/- 8.5; P = 0.002). In a multivariate logistic regression model, higher Hcy levels [Odds ratios comparing the top (>18.9 micromol/L) with the bottom tertile (<12.4 micromol/L): 3.68; 95% CI: 1.14-11.83] were significantly associated with dementia. These data support the association between elevated Hcy levels and the presence of dementia in PD., ((c) 2009 Movement Disorder Society.)

Background: This study investigated whether brief exposure to nitrous oxide (N(2)O) exacerbates levodopa-induced hyperhomocysteinemia, and if co-treatment with folate or entacapone could reduce total plasma homocysteine (tHcy) levels., Methods: MALE WISTAR RATS (N=9 PER GROUP) WERE RANDOMLY TREATED WITH VEHICLE/N(2)O (GROUP 1), levodopa/nitrogen (group 2), levodopa/N(2)O (group 3), levodopa/N(2)O+folate (group 4), or levodopa/N(2)O+entacapone (group 5). tHcy was measured at 12 min, 4, 8, and 12 h after anesthesia., Results and Conclusion: The combination of N(2)O-exposure and levodopa treatment significantly increased tHcy in rats. This hyperhomocysteinemia could be prevented by entacapone but not folate co-administration.

In recent years, L-Dopa treatment has been indicated as an acquired cause of hyperhomocysteinemia (HHcy). The mechanism underlying L-Dopa-related HHcy is the O-methylation of the drug catalyzed by the enzyme catechol-O-methyltransferase (COMT). Folate and cobalamin status also influences the effects of L-Dopa on plasma homocysteine (Hcy) levels. Although clinical correlations of HHcy in Parkinson's disease still remain uncertain, management of elevated plasma Hcy levels has been advocated, due to multiple cytotoxic effects of Hcy on neurons. This review summarizes data available in the literature concerning the two main therapeutic approaches to L-Dopa-related HHcy (use of COMT inhibitors or B vitamins diet supplementation).

Elevated homocysteine is associated with increased risk of heart disease, stroke, and dementia. Therapy of Parkinson disease (PD) with levodopa elevates homocysteine. The authors conducted a 6-week, multicenter, randomized, double-blind, placebo-controlled trial to test whether folate 1 mg/vitamin B(12) 500 microg or entacapone reduced serum homocysteine in 35 levodopa-treated PD patients. Levodopa initiation caused a small elevation in homocysteine. Vitamin therapy, but not entacapone, resulted in a decrease in homocysteine compared to placebo.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article is being retracted at the request of the Editor in Chief because of the stated concerns listed below. The article was accepted for publication by a previous editor and editorial board nearly 15 years ago, at a time when submissions and documentation were in paper form, prior to the transition of The American Journal of Medicine to a digital submission and review process. The records, including the original manuscript and peer reviewers' comments, are no longer extant and consequently we are unable to review the comments of the peer reviewers and the editors involved at that time. Nevertheless, the allegations of Grey et al. (as detailed in their Letter of Concern, published in the March 2018 issue of AJM, Volume 131, Issue 3, pages e107–e108; DOI: 10.1016/j.amjmed.2017.10.009) seem valid. A response by the Editor-in-Chief was also published in that issue. Therefore, given the documentation of Grey et al, the journal has concluded that this article should be considered as likely fraudulent and should not be quoted in the scientific literature in support of its conclusions. The article is severely compromised by wide-ranging and serious concerns about governance, ethics, authorship, implausible study conduct, implausible workload, discrepant participant numbers and treatment groups, impossible data, implausible data, implausible outcome data and discrepant methodology. The concerns are detailed in the afore-referenced letter of concern and can be summarized as follows: • It is stated that the study was approved by the Human Investigation Committee of the Futase Social Insurance Hospital, yet Futase Hospital did not have an ethics committee until 2010. • Given the size of the hospital and volume of clinics undertaken, it is highly unlikely that the stated number of participants could have been recruited within 3 months, or followed up as reported. • There are inconsistencies in the reported data. In Table 1 the mean ages of participants by quartiles of plasma homocysteine are 69.0, 70.6, 71.9, and 72.6 years. The corresponding mean years since menopause are 13.7, 14.6, 15.2, and 16.2 years, meaning that the average age of menopause is 55–57 years, implausibly older than the expected value of 50 years. The plasma homocysteine data in quartile 1 are incorrect. Among 50 women with a range of 6.1-9.0 μmol/L, the reported mean (standard deviation), 7.1 (2.5) μmol/L, is not possible. • In Table 3 the rate of hip fractures in the cohort (72 per 1000 patient-years) is implausibly high, being at least 3 to 4 times that reported in large observational studies of PD. The 51 incident hip fractures in 50 women in quartile 4 represents an astonishing hip fracture incidence of 227 per 1000 patient-years, yet only 6 women (3%) in this quartile were lost to follow-up (Table 1), and none was apparently treated with medications known to reduce fracture risk. The reported incident rates for hip fracture are incorrect. We have attempted to contact the authors regarding these concerns and have received no response. We are therefore retracting this article since the evidence presented indicates that there has been scientific misconduct. Joseph S. Alpert, MD Professor of Medicine, University of Arizona College of Medicine, Tucson, Arizona; Editor in Chief, The American Journal of Medicine

Levodopa treatment has been shown to increase plasma homocysteine levels in Parkinson's disease (PD) patients and this may lead to an increased risk for coronary arterial diseases. Levodopa is metabolised via O-methylation by catechol-O-methyltransferase (COMT) using S-adenosyl-L-methionine (SAM) as the methyl donor, this leading to the subsequent formation of homocysteine. In this study, the effects of the COMT inhibitor, entacapone, on levodopa-induced hyperhomocysteinaemia were studied in rats. Using a single dose acute treatment paradigm, entacapone (10 or 30 mg/kg) prevented the levodopa (30 or 100 mg/kg) induced rise in plasma homocysteine levels in a dose-dependent manner. Five-day sub-chronic treatment with levodopa (3 x 100 mg/kg per day) resulted in a marked rise in plasma homocysteine levels when measured 2 hours post-treatment on Day 5. These levels fell but remained greater than baseline at 8 hours post-treatment on Day 5. Consistent with findings in the acute treatment test paradigm, the co-administration of entacapone (30 mg/kg) significantly (p<0.001) reduced levodopa-induced hyperhomocysteinaemia for up to 2 hours post-treatment on Day 5 of the sub-chronic study. These results suggest that entacapone may reduce levodopa-induced hyperhomocysteinaemia in PD patients.

Levodopa remains the mainstay treatment for Parkinson's disease (PD). Chronic treatment is associated with motor complications (MC) that marred the clinical benefit of levodopa. These problems and experimental data in cell cultures indicating a neurotoxic effect of levodopa have led to the idea of delaying the introduction of levodopa treatment for as long as possible. We here review recent data regarding the mechanism of action of levodopa and its application in clinical practice on the light of the marketing of the combination levodopa-carbidopa- entacapone. Accumulated evidence indicates that MC are mainly the consequence of disease severity governing the degree of dopaminergic depletion and the "pulsatile" dopaminergic stimulation provided by levodopa short plasma half-life. There is no in vivo or clinical evidence of a relevant neurotoxic effect of levodopa. In fact, the recent ELLDOPA study may suggest a neuroprotective effect. Entacapone reduces homocysteine plasma levels which could provide a mechanism to reduce cell death in PD. Currently, the combination levodopa-carbidopa-entacapone is particularly indicated for the treatment of "wearing off" fluctuations. Experimental evidence suggests that early treatment with levodopa-carbidopa-entacapone may substantially ameliorate the incidence of MC. Such a clinical study in "de novo" patients is underway. At present, the combination levodopa-carbidopa-entacapone is indicated when levodopa is judged necessary.

Levodopa, typically ingested chronically at high daily doses, is predictably methylated by means of a series of reactions using B vitamins, which convert methionine to homocysteine. Elevated total plasma homocysteine (tHcy), a risk factor for dementia, has been found in PD patients using levodopa. We prospectively measured the effects on plasma tHcy and B vitamins of levodopa initiation, and measured the effects of dose changes and of treatment with dopamine agonists and entacapone. We collected paired plasma samples, at baseline and again after several months treatment, from patients initiating levodopa (n = 30), from patients whose levodopa dose was doubled (n = 15), halved or stopped (n = 14), from patients starting or stopping entacapone (n = 15) and from patients initiating or doubling dopamine agonist monotherapy (n = 16). Vitamin B12, folate, and tHcy concentrations were measured. Baseline tHcy concentration of 8.7 (2.8) micromol/L increased to 10.1 (3.1) micromol/L (P = 0.004) an average of 94 (range 36 to 200) days after initiation of 604 (240 to 1050) mg/day of L-dopa. Average concentration of vitamin B12 fell from 380 to 291 pmol/ L (P = 0.01). Patients who doubled their daily levodopa dose experienced tHcy elevations from 9.5 to 11.1 micromol/L (P = 0.05). Levodopa reduction, agonist treatment, and entacapone treatment did not have significant effects. Levodopa elevates tHcy and lowers vitamin B12 concentration to modest degrees. The clinical implications, if any, have not yet been determined., (2004 Movement Disorder Society.)

Epidemiologic evidence has linked elevation of serum homocysteine to an increased risk of coronary artery disease, stroke, and dementia. An increase in homocysteine levels in Parkinson disease (PD) recently has been discovered. Although B vitamin status and genetic factors are important modifying influences determining the degree of this elevation, the main cause appears to be therapy with L-dopa. It has been suggested that breakdown of L-dopa by catechol-O-methyltransferase results in increased homocysteine formation. Therefore, there are reasons to suggest that management of PD may render patients at increased risk of stroke, heart disease, dementia, and even accelerated nigral degeneration. At present, no controlled prospective studies have evaluated this phenomenon, although they are ongoing.

Background: The antiparkinsonian drug L-dopa causes increased cellular synthesis of homocysteine and consequent hyperhomocysteinemia in rats. This effect of L-dopa on plasma homocysteine is accentuated under conditions of impaired homocysteine metabolism such as folate deficiency., Objective: To investigate the effect of L-dopa administration and B-vitamin status on plasma homocysteine concentrations in humans with PD., Methods: Plasma homocysteine, folate, vitamin B(12), and pyridoxal-5'-phosphate (PLP) concentrations were determined in 40 individuals diagnosed with idiopathic PD who were being treated as outpatients at the Boston University Medical Center Neurology Clinic. Twenty of the patients were on L-dopa therapy (treatment group) and 20 were L-dopa-naive (control group)., Results: The mean plasma homocysteine concentration was higher in the treatment group than in the controls (p = 0.018). Plasma homocysteine was correlated with plasma folate, vitamin B(12), and PLP concentrations in the treatment group (p

Background: Hyperhomocysteinemia is a risk factor for vascular disease and potentially for dementia and depression. The most common cause of elevated homocysteine levels is deficiency of folate or vitamin B(12). However, patients with Parkinson disease (PD) may have elevated homocysteine levels resulting from methylation of levodopa and dopamine by catechol O-methyltransferase, an enzyme that uses S-adenosylmethionine as a methyl donor and yields S-adenosylhomocysteine. Since S-adenosylhomocysteine is rapidly converted to homocysteine, levodopa therapy may put patients at increased risk for vascular disease by raising homocysteine levels., Objectives: To determine whether elevations in plasma homocysteine levels caused by levodopa use are associated with increased prevalence of coronary artery disease (CAD), and to determine what role folate and vitamin B(12) have in levodopa-induced hyperhomocysteinemia., Design/methods: Subjects included 235 patients with PD followed up in a movement disorders clinic. Of these, 201 had been treated with levodopa, and 34 had not. Blood samples were collected for the measurement of homocysteine, folate, cobalamin, and methylmalonic acid levels. A history of CAD (prior myocardial infarctions, coronary artery bypass grafting, or coronary angioplasty procedures) was prospectively elicited. We analyzed parametric data by means of 1-way analysis of variance or the t test, and categorical data by means of the Fisher exact test or chi(2) test., Results: Mean +/- SD plasma homocysteine levels were significantly higher in patients treated with levodopa (16.1 +/- 6.2 micro mol/L), compared with levodopa-naïve patients (12.2 +/- 4.2 micro mol/L; P<.001). We found no difference in the plasma concentration of folate, cobalamin, or methylmalonic acid between the 2 groups. Patients whose homocysteine levels were in the higher quartile (>or=17.7 micro mol/L) had increased prevalence of CAD (relative risk, 1.75; 95% confidence interval, 1.08-2.70;P=.04)., Conclusions: Levodopa therapy, rather than PD, is a cause of hyperhomocysteinemia in patients with PD. Deficiency of folate or vitamin B(12) levels does not explain the elevated homocysteine levels in these patients. To our knowledge, this is the first report that levodopa-related hyperhomocysteinemia is associated with increased risk for CAD. These findings have implications for the treatment of PD in patients at risk for vascular disease, and potentially for those at risk for dementia and depression.