Th. Müller

Elevated plasma levels of homocysteine in Parkinson's disease.

Significantly elevated plasma levels of homocysteine, but not cysteine and cysteinylglycine, were found in treated parkinsonian patients compared to controls. Elevated levels of homocysteine may be either caused by an unknown endogenous metabolic disturbance or by antiparkinsonian treatment, because no association to severity or duration of disease was found. Based on the results of this study one may speculate that homocysteine may be an independent risk factor for vascular disease in Parkinson’s disease.

Diagnostic staging of Parkinson's disease: conceptual aspects

Summary.Insidious onset of mild, unspecific, sensitive, vegetative, psychopathological, cognitive and perceptive disturbances, i.e. visual and olfactory dysfunction, with a resulting change of personal behaviour, i.e. reduced stress tolerance, precede the initially intermittendly occurring motor symptoms in patients with Parkinson’s disease (PD). Novel neuropathological findings suggest an expansion pattern of the neurodegenerative process beyond the nigral dopaminergic neurons with the initial event located outside the brain. We related these clinical observations of premotor symptoms of PD to this novel neuropathological concept of emerging neurodegeneration, which starts in the enteric system and then rises via spinal cord and brainstem to nigral and subsequent cortical neurons. We describe an initial premotor phase, which starts in non dopaminergic areas, and subdivide it according to the onset of gastrointestinal and brainstem associated and sensory deficits. Then motor symptoms occur and increase in the further course of PD similar to the Hoehn and Yahr stages. Our proposed diagnostic concept aims to an earlier diagnosis of PD. In addition, attention should be given to diseases of the gastrointestinal tract and psychosomatic disorders, all of which, if not or ineffectively treated, may contribute to an enhanced vulnerability for PD. The concept takes into account, that an as far unknown pathogen, e.g. viral infection or nutritional component, that meets a genetically predisposed person with a long lasting disturbed enteric nervous system, may be at risk for PD. Earlier premotor diagnosis of PD will enable more convincing future results on the therapeutic efficacy of neuroprotective compounds.

3-OMD and homocysteine plasma levels in parkinsonian patients

Summary. One main metabolizing pathway of levodopa is O-methylation to 3-O-methyldopa (3-OMD) by catechol-O-methyltransferase (COMT). Since COMT requires Mg2+ and S-adenosylmethionine as methyl donor for this transmethylating process, COMT converts S-adenosylmethionine to S-adenosylhomocysteine and subsequent homocysteine. Objective of this study was to demonstrate relations between plasma levodopa, 3-OMD and total homocysteine in treated parkinsonian subjects. We measured homocysteine, levodopa and 3-OMD by HPLC. We compared plasma homocysteine in two groups of treated parkinsonian subjects subdivided according to their 3-OMD level. Homocysteine was significantly (p = 0.002) elevated in the group with higher 3-OMD concentrations and positively (r = 0.52, p = 0.0006) correlated to 3-OMD. Homocysteine induces vascular disease. Previous studies showed an increase of ischaemic heart- and cerebrovascular disease in treated parkinsonian patients.

DISTORTED COLOR DISCRIMINATION IN DE NOVO' PARKINSONIAN PATIENTS

Article abstract—We performed the Farnsworth-Munsell 100–hue test in 16 “de novo” patients with Parkinsons disease and 16 age-matched controls to determine their color discrimination ability. “he mean total error score in patients was significantly elevated as compared with controls (64.6 in patients versus 16.0 in controls). We conclude that the impairment of color discrimination may be an early sign in Parkinsons disease.

Elevated levels of harman and norharman in cerebrospinal fluid of parkinsonian patients.

SummaryDeath of dopaminergic neurons in Parkinsons disease (PD) may partially be caused by synthesis and accumulation of endogenous and exogenous toxins. Because of structural similarity to MPTP, β-carbolines, like norharman and harman, have been proposed as putative neurotoxins. In vivo they may easily be formed by cyclization of indoleamines with e.g. aldehydes. For further elucidation of the role of β-carbolines in neurodegenerative disorders harman and norharman levels in cerebrospinal fluid (CSF) were measured in 14 patients with PD and compared to an age- and sex-matched control group (n=14). CSF levels of norharman and harman in PD were significantly higher compared to controls. These results may suggest a possible role of harman and norharman or its N-methylated carbolinium ions in the pathophysiological processes initiating PD. However the origin of increased levels of these β-carbolines remains unclear. On the one hand one may speculate, that unknown metabolic processes induce the increased synthesis of harman and norharman in PD. On the other hand a possible impact of exogenous sources may also be possible.

Hyperhomocysteinaemia in Parkinson’s disease

Sirs: A significant increased hazard ratio for both ischaemic heart and cerebrovascular disease was found in a cohort of 220 parkinsonian patients [2]. Mild hyperhomocysteinaemia has been suggested as a risk factor for atherosclerosis and vascular disease [9]. A significant elevation of plasma homocysteine in parkinsonian patients was found in comparison with controls [1]. However, a major drawback of that study was the insufficient clinical information given on total levodopa dosage, severity of disease and age of subjects. The aim of our study reported here was to evaluate a possible relationship between hyperhomocysteinaemia and Parkinson’s disease (PD). We determined plasma levels of homocysteine in 22 parkinsonian patients treated with levodopa/decarboxylase inhibitor and in ageand sex-matched controls. Characteristics of the patients and controls and homocysteine levels are given in Table 1. Excluded as controls were subjects with neurodegenerative diseases, current smokers and individuals with a known history of alcohol abuse or metabolic disturbances such as hypercholesterolaemia, diabetes mellitus, hypertension or hypovitaminosis. Matching was done within an age range of 4 years. Blood samples were drawn in the morning between 8 and 9 a.m. after 10 h of fasting, from a peripheral vein drop-wise in plastic vacuum tubes containing EDTA for estimating plasma levels of homocysteine. Within 10 min the samples were centrifuged for 15 min, 300 × gav at 10 °C. The resulting supernatant (plasma) was decanted and stored at –80 °C. The time period between freezing and evaluation of the plasma samples was no longer than 3 months. Levels of homocysteine were measured by an automated high-performance liquid chromatography (HPLC) method with reverse phase separation and fluorescent detection, by NaBH4/monobromobimane (mBrB) reduction followed by mBrB derivation [8]. We compared homocysteine levels for all patients and controls and stratified by age and gender using Student’s t test. Additionally, we evaluated the association between disease severity and homocysteine levels among cases using Spearman’s rank correlation coefficient and linear regression. Finally, a multivariate linear regression model was built and residuals analysed for normal distribution. Patients had a median Hoehn and Yahr Score (HYS) of 3.25 and a Unified Parkinson’s Disease Rating Scale (UPDRS) score of 48. Twentyone patients received conventional pharmacotherapy including levodopa/benserazide or carbidopa preparations and various other antiparkinsonian drugs (amantadine: n =1, bromocriptine: n = 9, budipine: n = 4; pergolide: n = 5, selegiline n = 11 mg). In univariate linear regression, significant positive associations between plasma levels of homocysteine and age were found in patients [β-coefficient: 0.41; 95% confidence interval (CI) 0.11–0.71] and (borderline) in controls (β = 0.20; 95% CI 0.002–0.39). Mean total homocysteine was significantly elevated (mean difference 3.7 μmol/l; 95% CI 0.5–6.9) in parkinsonian patients compared with controls. Stratified analysis (t test) revealed that this difference was mainly caused by a significant and large difference in male subjects aged 64 years and older (mean difference 11.04 μmol/l; 95% CI 5.97–16.11). Differences in younger ages and in gender did not reach statistical significance. The two measures of PD severity in patients were found to be significantly associated with age (Spearman’s rank correlation: UPDRS r = 0.68, P = 0.001; HYS r = 0.61, P = 0.01) and homocysteine (Spearman’s rank correlation: UPDRS r = 0.43, P = 0.04; HYS r = 0.48, P = 0.02), but not with levodopa dosage in descriptive analysis. Finally, a significant relation between homocysteine and total daily levodopa dose was observed in univariate linear regression (β: 0.014; 95% CI 0.004–0.024). Multivariate regression revealed that only two factors were independent predictors of plasma homocysteine levels. The final multivariate linear regression model included age (β: 0.31; 95% CI 0.03–0.60) and daily levodopa dose (β: 0.01; 95% CI 0.001–0.020) explaining together about 40% of the variance in homocysteine levels (adj. r2 = 0.39). LETTER TO THE EDITORS J Neurol (1998) 245 :811–812

The motor performance test series in Parkinson's disease is influenced by depression

SummaryThe Motor Performance Test Series (MPTS) is widely used for treatment control in Parkinsons disease (PD). To elucidate the possible influence of depression on the fine motor skills in PD, 54 patients with idiopathic PD were investigated with the MPTS. 27 patients with major intensity of depression were compared to 27 age and motor disability matched patients with minor symptoms of depression, evaluated by the Zung depression scale. As determined by the subtest aiming, a significant lower ability for precise, quick complex arm-hand movements in depressed Parkinsonian patients was found. This result may be explained partly by motivation deficits in depressed patients with PD. On the other hand impairment of special motor loops including frontal lobe projections to specific thalamic subnuclei or to the caudate nucleus may cause disturbances of the subtest aiming in depressed Parkinsonian patients. On the basis of these findings impaired aiming may be explained by diminished ability for complex, semivoluntary movements in depressive Parkinsonian patients. The influence of psychiatric comorbidity on MPTS subtest aiming has to be considered in further therapy studies using evaluation of motor deficits by MPTS.

Depression in Parkinson's disease: biogenic amines in CSF of “de novo” patients

SummaryIntroduction. Etiology of depression in Parkinsons disease (PD) is associated with serotonergic dysfunction. Previous studies, supporting this hypothesis, were performed on patients treated with antiparkinsonian drugs. To eliminate the influence of parkinsonian drug therapy and to elucidate significance of different biochemical pathways in PD associated with depression we determined levels of biogenic amines in cerebrospinal fluid (CSF) of 26 untreated “de novo” Parkinsonian patients.Material and methods. Patients were scored with the Hamilton depression scale (HD) and subdivided into groups with HD score ≥ 18 and HD score <18. Diagnosis of depression was made according to DSM III R. Both groups were matched for age and motor disability.Results. In both groups no significant differences appeared between CSF levels of dopamine, noradrenaline, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 3-methoxy-4-hydroxyphenylglycol and 5-hydroxyindole acetic acid, determined by high-performance liquid chromatography.Discussion. In contrast to previous studies on treated Parkinsonian patients no sign of altered serotonin metabolism especially in context with severity of depression in early stages of PD was found. Due to our results, we suggest, that biochemical markers of depression in CSF of PD may be influenced by antiparkinsonian therapy and that depression in PD may respond to serotonin reuptake inhibitors mainly in later stages of PD.

Chromatic and achromatic visual evoked potentials in Parkinson's disease

Chromatic and achromatic visual evoked potentials (VEP) were evaluated in 39 patients with idiopathic Parkinsons disease (PD) (age 64.0 +/- 8.6 years) and 43 healthy controls (age 62.8 +/- 8.7 years). The following pattern-reversal checkerboard stimuli were performed: (1) achromatic with luminance contrast 86% (achr.hk.) (2) achromatic with luminance contrast 20% (achr.lk.); (3) chromatic isoluminant blue-yellow (by.); (4) chromatic isoluminant red-green (rg.). The mean latencies N70, P100, and N135 of chromatic and achromatic VEP were significantly delayed in patients with PD as compared to controls. The highest rate (41.0%) of pathological findings could be demonstrated by achromatic stimulation (luminance contrast 86%). Isolated abnormalities of chromatic VEP (in combination with normal achromatic VEP) were found in 5 (12.8%) patients. The delay of VEP-latencies was significantly correlated with the severity of motor symptoms in PD patients. We conclude that VEP are valuable tools to demonstrate a dysfunction of the visual system in PD. Although chromatic VEP are less sensitive than achromatic VEP, the combination of both will increase the diagnostic yield. Therefore, there seems to exist a variety of individual characters of visual impairment in PD.

[123I]β-CIT SPECT Visualizes Dopamine Transporter Loss in de novo Parkinsonian Patients

Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the basal ganglia, which may be visualized by single photon emission computed tomography (SPECT) in combination with the cocaine analog methyl-3-β-(4-β[123I]iodophenyl)tropane-2β-carboxylate ([123I]β-CIT). The aim of our study was to correlate findings of SPECT with clinical data of 34 previously untreated, idiopathic parkinsonian patients [age: 59.58±10.03 (mean±SD) years; Hoehn and Yahr Scale (HYS) mean range: 1.97±0.83, ranges I–III; Unified PD Rating Scale 3.0 (UPDRS, 30.64±18.68) and 15 healthy controls (age 47.93±10.47 years). SPECT scans were performed with a single-head γ-camera 24 h after intravenous injection of [123I]β-CIT. Comparison of the striatum/cerebellum (S/C) ratio of [123I]β-CIT uptake of controls and parkinsonian subjects, subdivided according to their HYS range, was significant. No influence of age or sex was observed. Significant correlations were found between scores of the HYS, UPDRS parts I–III, part II, part III, and the S/C ratio of [123I]β-CIT uptake. Moreover, SPECT with the radiotracer [123I]β-CIT revealed side-to-side differences in parkinsonian patients and significant associations to contralateral clinical extrapyramidal symptomatology. Our data show that SPECT with [123I]β-CIT is a valuable tool for estimating disease severity in PD.