Factors related with hyperhomocysteinemia (HHcy) and the impact of HHcy in Parkinson’s disease (PD) are not well understood. We investigated the factors associated with increased levels of homocysteine (Hcy) and the relationship between HHcy and motor symptoms, cognitive status, and vascular risk in patients with Parkinson’s disease. Among 60 patients (29 males, 48.3%) with PD, the stage of the disease, the severity of clinical symptoms, and the patients’ cognitive status were measured using a modified Hoehn and Yahr Staging Scale (mHY), Unified Parkinson’s Disease Rating Scale (UPDRS) II and III, and Mini-Mental State Examination (MMSE), respectively. Patients were also noted for having dyskinesia and hallucinations. Serum vitamin B12, folic acid, and plasma Hcy levels were measured. Furthermore, the presence of vascular risk factors was recorded. Finally, we investigated carotid artery intima-media thickening and stenosis using colour Doppler ultrasonography as well as the presence of ischemic lesions using brain imaging techniques. Plasma Hcy levels were higher with advanced age and in males. In addition, there was an inverse relationship between Hcy and vitamin B12 levels. There was no correlation between HHcy and the stage of the disease, severity of motor symptoms, cognitive status as assessed by the MMSE, vascular risk factors, carotid artery atherosclerotic findings, and ischemic brain lesions. Plasma Hcy levels may rise due to several factors in PD. However, the resulting HHcy has no significant effect on the clinical picture in terms of motor features, cognitive status, and vascular diseases.
Hyperhomocysteinemia (HHcy) is an established risk factor for cardiovascular, cerebrovascular, and peripheral vascular diseases [
Experimental studies have demonstrated that Hcy can be neurotoxic and excitotoxic to the substantia nigra. Furthermore, Hcy may be associated with dyskinesias, which is an indicator of possible neurodegeneration due to the disruption of the balance of striatal activity [
The prevalence of neuropsychiatric symptoms, such as depression and dementia, is increased in PD [
Therefore, we examined the relationship between plasma Hcy levels and the severity of PD-related motor features and cognitive status. We also determined the risk of vascular disease in PD patients by using vascular risk factors, previous vascular diseases, atherosclerotic findings detected by carotid artery colour Doppler ultrasonography, and ischemic changes in brain imaging studies.
This prospective study included 60 patients (29 males, 48.3%) randomly selected from patients diagnosed with idiopathic PD according to the UK Brain Bank criteria [
For all patients, the duration of the disease, on-going treatments, and dosage and duration of levodopa therapy were recorded. In addition, patients were also examined for the presence of vascular risk factors, such as hypertension, diabetes mellitus, and hyperlipidemia and for vascular diseases, such as coronary artery disease and stroke.
The stage of PD and the severity of disease findings were determined by the “modified Hoehn and Yahr (mHY) Staging Scale” and “Unified Parkinson’s Disease Rating Scale” (UPDRS) II and III, respectively [
The assessment of global cognitive status was conducted with the standardised “Mini-Mental State Examination” (MMSE). We also noted the presence of visual hallucinations.
Blood samples were collected from peripheral veins into vacuum tubes containing EDTA in the early morning after 12 hours of fasting and 12-hour drug-free periods. Plasma Hcy levels were measured by high-performance liquid chromatography with fluorescence detection (HPLC-FLD). Serum vitamin B12 and folic acid levels were measured by an immunoassay.
The carotid arteries of patients and control subjects were investigated using carotid colour Doppler ultrasonography with a 6 to 11 MHz linear probe performed by the same physician in the Radiology Department who was blinded from the clinical history of 50 subjects. The common carotid arteries and extracranial internal carotid arteries were investigated on the axial and longitudinal planes using the B mode and colour Doppler methods, starting at the origin and including the bifurcation point; intimal thickening, plaques, and stenosis were noted. The frequency levels, gain adjustments, and grey scale and Doppler parameters were manually adjusted to optimise visualisation of stenosis [
Among 45 patients, ischemic lesions at the lacunar and specific arterial irrigation areas were recorded by brain computed tomography (CT) and magnetic resonance imaging (MRI) examinations.
The study was carried out according to the Helsinki Declaration and was approved by the Institutional Ethics Committee.
All statistical data analyses were performed with SPSS Statistics (version 19, IBM, Chicago, IL, USA). Prior to the analysis, the normality of the distribution of Hcy levels was examined and the distribution of the 60 values was found to be consistent with the normal distribution (Kolmogorov-Smirnov: 0.066,
The mean age of 60 patients (29 males, 48.3%) with idiopathic PD was
Demographic and clinical characteristics and values of vitamin B12 and folic acid in PD patients
PD ( | |
---|---|
Age (years) | 68.4 ± 8.95 |
Duration of disease (years) | 7.0 ± 5.75 |
Age of PD onset (years) | 61.4 ± 10.92 |
mHY stage | 2.2 ± 0.99 |
UPDRS-II score | 12.1 ± 6.86 |
UPDRS-III score | 17.4 ± 8.37 |
UPDRS tremor subscore | 2.3 ± 1.56 |
UPDRS rigidity subscore | 1.4 ± 0.90 |
UPDRS bradykinesia subscore | 7.1 ± 3.29 |
UPDRS gait/postural instability subscore | 3.4 ± 2.99 |
MMSE score | 24.2 ± 4.21 |
Vitamin B12 (pg/ml) | 344.4 ± 206.54 |
Folic acid (ng/ml) | 9.3 ± 3.74 |
PD: Parkinson’s disease; mHY: modified Hoehn and Yahr Staging Scale; UPDRS: Unified Parkinson’s Disease Rating Scale; MMSE: Mini-Mental State Examination.
In male and female patients, the mean plasma Hcy levels were
Correlation between plasma homocysteine levels and demographic and clinical characteristics and serum B12 and folic acid values.
Homocysteine levels | ||
---|---|---|
|
| |
Age (years) | 0.27 |
|
Duration of disease (years) | 0.23 | 0.07 |
Age of PD onset (years) | 0.14 | 0.30 |
mHY stage |
|
0.44 |
UPDRS-II score | 0.09 | 0.48 |
UPDRS-III score | 0.01 | 0.91 |
UPDRS tremor subscore | 0.11 | 0.42 |
UPDRS rigidity subscore | 0.18 | 0.16 |
UPDRS bradykinesia subscore | −0.01 | 0.92 |
UPDRS gait/postural instability subscore | 0.02 | 0.90 |
MMSE score | 0.03 | 0.85 |
Vitamin B12 (pg/ml) |
|
|
Folic acid (ng/ml) | 0.06 | 0.68 |
PD: Parkinson’s disease; mHY: modified Hoehn and Yahr Staging Scale; UPDRS: Unified Parkinson’s Disease Rating Scale; MMSE: Mini-Mental State Examination.
There was also no significant correlation between plasma Hcy levels and the presence of dyskinesia. Likewise, although the patients with hallucinations had slightly higher plasma Hcy levels, this difference was not statistically significant.
We found no significant correlation between plasma Hcy levels and diabetes mellitus, hypertension, hyperlipidemia, or coronary artery disease. Two patients had a history of strokes; their plasma Hcy levels were 15.5 and 20.4
The mean plasma Hcy levels of the patients with intima-media thickening (IMT), atherosclerotic plaques, and stenosis of greater than 50% as detected by colour Doppler ultrasonography of the carotid artery were found to be slightly higher than those of patients without these symptoms, but the difference was not statistically significant. Similarly, we found no significant relationship between plasma Hcy levels and multiple ischemic lesions detected by brain imaging studies (Table
Plasma homocysteine levels and their relationships with hallucinations, dyskinesia, vascular risk factors, carotid colour Doppler US, brain MRI findings, and anti-parkinsonian medication in patients with Parkinson’s disease.
|
Homocysteine levels ( |
| ||
---|---|---|---|---|
Hallucinations | Absent | 46 | 13.34 ± 4.62 | 0.13 |
Present | 14 | 15.53 ± 4.99 | ||
|
||||
Dyskinesia | Absent | 44 | 14.14 ± 5.00 | 0.44 |
Present | 16 | 13.05 ± 4.05 | ||
|
||||
Hypertension | Absent | 33 | 14.15 ± 4.38 | 0.60 |
Present | 27 | 13.49 ± 5.25 | ||
|
||||
Diabetes mellitus | Absent | 51 | 14.15 ± 4.83 | 0.24 |
Present | 9 | 12.12 ± 4.18 | ||
|
||||
Hyperlipidemia | Absent | 39 | 13.35 ± 4.48 | 0.27 |
Present | 21 | 14.77 ± 5.23 | ||
|
||||
Coronary heart disease | Absent | 47 | 13.6 ± 5.02 | 0.44 |
Present | 13 | 14.77 ± 3.67 | ||
|
||||
Previous stroke | Absent | 58 | 13.71 ± 4.76 | 0.22 |
Present | 2 | 17.95 ±3.47 | ||
|
||||
Carotid colour Doppler US | Normal | 14 | 12.96 ± 4.18 | 0.42 |
Atherosclerotic findings |
36 | 14.24 ± 5.27 | ||
|
||||
Brain MRI | Normal | 22 | 13.08 ± 4.88 | 0.85 |
Ischemic lesions |
23 | 13.37 ± 5.03 | ||
|
||||
Anti-parkinsonian medication | LD ± DA | 31 | 15.06 ± 4.78 | 0.07 |
LD ± DA ± COMTI | 18 | 12.89 ± 5.08 | ||
DA | 11 | 11.25 ± 3.26 |
US: ultrasonography; MRI: magnetic resonance imaging; LD: levodopa; DA: dopamine agonists; COMTI: catechol O-methyl transferase inhibitors.
When the correlation between ongoing treatments and plasma Hcy levels was examined, the patients on only dopamine agonist therapy and on LD therapy without COMT inhibitors were found to have the lowest and highest plasma Hcy levels, respectively. However, the difference between plasma Hcy levels and treatment groups was not statistically significant.
Although the dose and duration of LD therapy in patients with plasma Hcy levels >14
Comparison of daily levodopa dose and duration of levodopa medication between patients with plasma homocysteine levels ≤14 and >14
Homocysteine levels ( |
|
||
---|---|---|---|
Homocysteine |
Homocysteine | ||
Levodopa dose (mg/daily) | 370.50 ± 138.20 | 430.65 ± 232.26 | 0.26 |
Duration of levodopa medication (years) | 5.54 ± 5.68 | 7.65 ± 5.32 | 0.16 |
In PD, motor symptoms occur as a result of dopaminergic cell loss and therefore LD replacement therapy is the most effective treatment option. Patients treated with LD have been reported to have higher plasma Hcy levels [
Plasma Hcy levels may also be affected by the patient’s methylene tetrahydrofolate reductase (MTHFR) enzyme genotype and vitamin B status, except in cases of LD therapy [
In elderly individuals, Hcy is an independent risk factor for vascular diseases, cognitive deterioration, and dementia [
Some studies have suggested a correlation between HHcy, advanced age, and male gender, but this correlation has not been demonstrated in other studies [
In our study, as reported in the literature, we did not find a significant correlation between plasma Hcy levels and the duration of PD [
Following the
In one study, the plasma Hcy levels of patients with dyskinesia were found to be higher, but no correlation was found between plasma Hcy levels and the duration of dyskinesia. Hence, it was suggested that plasma HHcy may play a role in the development of dyskinesias due to the toxic effects of Hcy on dopaminergic and nondopaminergic neurons [
Hcy is thought to affect dopamine turnover and cause dyskinesia by disrupting the balance of striatal activity. However, some studies have not demonstrated an association between plasma Hcy levels and an increased risk of dyskinesia [
HHcy is a major risk factor for vascular diseases and has been associated with stroke, myocardial infarction, and dementia in elderly individuals without PD [
Previous studies evaluated IMT in patients with PD who were treated with long-term LD therapy and identified hypertrophic changes. Furthermore, these studies found a correlation between the duration of LD therapy and the degree of the intima-media hypertrophy [
In the literature, there are studies indicating no correlation between LD-related HHcy and IMT of the carotid artery or even showing a lower IMT in PD patients than in controls [
In our study, we compared the plasma Hcy levels of patients with and without vascular changes, including carotid artery IMT, atherosclerotic plaques, and stenosis, but we did not find any significant correlations.
The prevalence of coronary artery disease has been reported to be increased in patients with high levels of Hcy on LD therapy [
Ischemic brain lesions may affect the clinical condition in PD. Nonetheless, clinically evident cerebrovascular disease is rarely seen in PD patients [
The decrease in blood pressure in PD has been thought to provide protection against stroke [
Patients with PD have a 4–6 times greater risk of developing dementia compared with the age-matched population [
Dementia is a common nonmotor feature in PD. Moreover, the relationship between increased levels of Hcy and dementia in PD has not been fully clarified, although a significant proportion of PD patients develop cognitive impairment [
In a rodent study, Lee et al. showed a decrease in dopamine levels and behavioural changes following intraventricular injection of Hcy [
Zoccolella et al. found higher Hcy levels in PD patients than in controls and in PD patients with dementia than in patients without dementia and suggested a significant association between high Hcy levels and dementia [
In many studies, plasma Hcy levels were correlated with cognitive function, dementia, and markers of neurodegeneration in PD patients [
The difference between the results of the studies arises from the retrospective nature of some studies, the small number of patients, and the diversity of neuropsychiatric batteries.
Degenerative brain changes associated with disease are the primary cause of cognitive and motor deterioration in PD. However, comorbid hypoperfusion can contribute to the emergence and severity of this cognitive and motor deterioration [
In conclusion, plasma Hcy levels may be elevated for a variety of reasons in PD, and HHcy is a well-known risk factor for vascular disease and dementia in the elderly. Because of the higher prevalence of vascular diseases and increased risk of cognitive impairment throughout the course of PD, PD patients often have coincidental vascular diseases or dementia. In addition, LD therapy is not the only cause of HHcy. Hence, given the results of our study, we conclude that HHcy has no significant effect on clinical status in PD in terms of motor deterioration, vascular disease, and dementia.
The authors declare that there are no conflicts of interest regarding the publication of this paper.