Cerebrospinal Fluid C-Reactive Protein in Parkinson's Disease: Associations with Motor and Non-motor Symptoms.

Parkinson' disease (PD) is characterized by motor symptoms including bradykinesia, resting tremor, postural instability, and rigidity and non-motor symptoms such as cognitive impairment, sleep disorder, and depression. Neuroinflammation has been recently implicated in pathophysiology of both motor and non-motor symptoms of PD. One of the most notable inflammatory proteins is C-reactive protein (CRP), which is elevated in the conditions of systemic inflammation. Using BioFIND database, we scrutinized the possible association between cerebrospinal fluid (CSF) levels of CRP and severity of PD motor and non-motor symptoms. Eighty-four healthy controls (HCs) and 109 PD subjects were entered into this study. A significant correlation was observed between CSF CRP levels and Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS part III) score and Montreal Cognitive Assessment (MoCA) score in PD patients. We found significant correlations between MoCA score and CSF CRP levels in female patients and between CSF CRP and MDS-UPDRS part III score and MoCA score in male patients. In linear regression, CSF CRP could predict 6.9 and 10% of changes in MDS-UPDRS part III score in all PD patients male PD patients, respectively. In summary, we confirmed that CSF concentrations of CRP are in correlation with motor and non-motor severity in PD subjects. Our findings suggest that neuroinflammation plays an important role in the initiation and probably progression of PD motor and non-motor symptoms, which may give us a better insight into the underlying pathologic mechanisms in PD.

CSF biomarkers in different phenotypes of Parkinson disease.

CSF biomarker studies were performed in 6 patients each with tremor-dominant (TD) and non-tremor-dominant (NT) Parkinson disease (PD) patients, 27 Alzheimer disease (AD) and 17 age-matched controls. In both NT-PD and AD patients total tau levels and the cortex tau/Aß-42 were significantly increased compared to both TD-PD patients and controls (p < 0.01). These data in a small cohort confirm previous studies, corroborating the opinion that CSF levels of tau protein and the index total-tau/Aß-42 may be potential markers of the severity of neurodegeneration in PD.

Primary orthostatic tremor associated with a persistent cerebrospinal fluid monoclonal IgG band.

Primary orthostatic tremor is of unknown aetiology and is believed to be a distinct entity rather than a subtype of essential tremor. We describe the first patient with a typical phenotype of primary orthostatic tremor who has a persistent isolated monoclonal immunoglobulin G band in the cerebrospinal fluid.

Levels and proteolytic processing of chromogranin A and B and secretogranin II in cerebrospinal fluid in neurological diseases.

Human cerebrospinal fluid (CSF) contains chromogranin A and B and secretogranin II which represent peptides secreted from neuronal large dense core vesicles. Within these vesicles these precursor peptides are at least partly processed to smaller peptides. We analysed the CSF levels of chromogranins/secretogranin by radioimmunoassay using specific antisera. The degree of their processing was characterized by molecular sieve column chromatography followed by radioimmunoassay. As previously shown secretogranin II is fully processed to smaller peptides including the peptide secretoneurin, whereas processing of chromogranin A was more limited. For chromogranin B we found in this study a high degree of processing comparable to that of secretogranin II. An analysis of CSF from patients with multiple sclerosis, essential tremor, Alzheimer and Parkinson disease, did not reveal any differences in proteolytic processing of chromogranins/secretogranin when compared to control CSF. We conclude that in the four diseases investigated there is no change in the proteolytic processing of the chromogranins/secretogranin within the large dense core vesicles. The absolute levels of chromogranins/secretogranin varied in CSF collected in different hospitals, however their relative ratios were remarkable constant. We suggest to use this ratio as a parameter to standardise CSF levels of other peptides, e.g. neuropeptides. In Parkinson patients the chromogranin A/secretogranin II ratio was significantly increased whereas in Alzheimer patients and those with essential tremor and multiple sclerosis no change of the ratios was observed. Apparently there are only limited changes in the biosynthesis, processing, secretion and CSF clearance of these peptides in pathological conditions.

Change in the concentrations of amino acids in CSF and serum of patients with essential tremor.

The concentrations of amino acids in the cerebrospinal fluid (CSF) (n = 20) and serum (n = 20) taken from patients with essential tremor were measured by HPLC and compared with those of controls (n = 10). Reduced concentrations of some amino acids (asparagine, glutamine, glycine, threonine, isoleucine, leucine) were observed in serum taken from patients with tremor. Significant increases were detected in the concentrations of glutamate (p < 0.001) and aspartate (p < 0.01). The general tendency of the changes in CSF and serum was similar; although the highest differences were observed in amino acid concentrations in the serum of patients with essential tremor. Opposite shifts of some amino acids were detected, in the concentrations of aspartate, serine, tyrosine, leucine, and isoleucine, which may indicate the independence of the changes in the serum from those in the CSF. This study raises the possibility that a genetically determined metabolic disorder is involved in the etiology of essential tremor that appears peripherally and, partly, centrally. The slight increase in the concentration of glutamate together with the reduced levels of GABA, glycine, and serine in CSF may form the neurochemical basis of the central oscillation observed in essential tremor.

Theophylline concentrations in serum, saliva, and cerebrospinal fluid in patients with essential tremor.

Theophylline concentrations in saliva and serum were compared in 20 patients with essential tremor. There was a strong correlation between the concentrations in saliva and serum (r = 0.9, slope of 0.48). The ratio between unbound and bound theophylline as assessed by ultrafiltration was 0.30. This ratio was similar to that between theophylline concentrations in CSF and serum. The theophylline concentration in serum was not predictable from that obtained in saliva in individual cases. Moreover, the levels in saliva were about 20% higher than the unbound concentrations of theophylline in serum.

Total biopterin levels in the ventricular CSF of patients with Parkinson's disease: a comparison between akineto-rigid and tremor types.

Total L-erythro-biopterin (T-BP) levels in the ventricular cerebrospinal fluid (CSF) were measured in 43 patients with Parkinson's disease (PD) and 12 age-matched neurological controls. In 5 of the PD patients and 1 control, lumbar CSF T-BP values were also measured. The mean ventricular CSF T-BP level in the PD patients, 15.6 +/- 0.5 pmol/ml (mean +/- SE), was significantly lower than that in the controls (21.3 +/- 1.4 pmol/ml, P less than 0.0001). The mean T-BP concentration in the ventricular CSF was 1.9 times higher than that in the lumbar CSF (P less than 0.0005), indicating a rostrocaudal gradient for the T-BP value in the CSF. When the PD patients were classified according to their predominant clinical features into 24 akineto-rigid (A-R) type and 19 tremor (T) type, there was a significant negative correlation between the T-BP levels and duration of illness only for the A-R type patients (rho = -0.605, P less than 0.005). No such significant correlation was found in the T type patients. These results may indicate a difference of pathophysiological changes in the brain between the 2 types of PD.

Cyclic nucleotides in cerebrospinal fluid of drug-free Parkinson patients.

Concentrations of cyclic nucleotides--adenosine-3',5'-monophosphate (c-AMP) and guanosine-3',5'-monophosphate (c-GMP)--were measured in cerebrospinal fluid (CSF) of 17 drug-free Parkinson patients and 12 controls. No significant difference between the cyclic nucleotide contents (p greater than 0.05) in CSF of patients and controls was detected, nor was there a correlation between the content and the degree of neurological disability. Besides, no changes in the cyclic nucleotide contents were detected in the subgroups of patients according to the prominence of tremor or rigidity/akinesia as the main symptoms of the disease.

Ventricular cerebrospinal fluid concentrations of putative amino acid transmitters in Parkinson's disease and other disorders.

Concentrations of putative neuroactive substances glutamate, aspartate, gamma-aminobutyric acid, glycine, proline and ethanolamine were determined in ventricular cerebrospinal fluid collected in patients suffering from Parkinson's disease, pain syndromes or cerebellar tremor. Values are similar to those given in the literature for lumbar cerebrospinal fluid. A decrease in gamma-aminobutyric acid in Parkinson patients, as reported in lumbar cerebrospinal fluid, could not be observed. Further evidence for a rostro-caudal gradient for gamma-aminobutyric acid is supplied. New insights into pathophysiological mechanisms in any of the investigated syndromes may not be derived.

[Approaches to the study of dopamine metabolism in various extrapyramidal diseases]. / Podkhody k izucheniiu tserebral'nogo metabolizma dofamina pri nekotorykh ékstrapiramidnykh zabolevaniiakh.

The authors present the results of examining the content of 4-hydroxy-3-methoxy-phenylacetic or homovanillic acid (the principal end metabolite of dopamine) in the ventricular fluid of patients suffering from various extrapyramidal diseases. A considerable lowering of the homovanillic acid (HVA) concentration is demonstrated in patients with parkinsonism: this reflects the degeneration of the dopamine-containing pathways and the lowering of the dopamine synthesis in the basal ganglia in that disease. The treatment with L-DOPA leads to a considerable rise of the HVA level in the ventricular fluid, the fact, that points to an intensification of dopamine metabolism in the brain, when its precursor, i.e. L-DOPA is given to the patients. In patients with deforming muscular dystonia, statistically significant differences of the HVA concentration in the cerebrospinal fluid were noted. These differences correlated with the clinical manifestations of the disease. The concentration was found to be much higher in patients with local muscular rigidity, than in those in whose clinical picture the dystonic hyperkinesis was prevalent. It is concluded that in phenotypically different forms of the deforming muscular dystonia the character of the pathology of the central dopaminergic system is also different. Patients with Huntington's chorea showed a low level of the HVA in the intraventricular fluid. It is supposed that this is an evidence of either a fall of the dopamine total content in the brain because of the degeneration of the respective neurons, or of a deterioration of cerebral dopamine catabolism because of enzymatic insufficiency. The data obtained are of importance for understanding the pathogenesis, and for developing methods of treating extrapyramidal motor disturbances.

Cerebrospinal fluid monoamine metabolites and cyclic nucleotides in chronic schizophrenic patients with tardive dyskinesia or drug-induced tremor.

Lumbar CSF HVA, MHPG, 5HIAA, cAMP, and cGMP were measured in 12 chronic schizophrenics with tardive dyskinesia before and 3 weeks after sodium valproate (VPA) or cyproheptadine treatment. HVA levels significantly decreased and cAMP and cGMP levels significantly increased during the administration of VPA or cyproheptadine. There were no significant correlations between the degree of improvement in tardive dyskinesia and the changes of amine metabolities or cyclic nucleotides. None of the pretreatment values for CSF amine metabolites or cyclic nucleotides were different from those of 15 chronic schizophrenics without tardive dyskinesia as controls. Decrease of HVA and increase of cGMP during the treatment might indicate the normalization of dopaminergic-cholinergic imbalance in the brain. Furthermore, significantly low levels of 5HIAA were observed in the patients with drug-induced tremor. It is suggested that neuroleptic-induced tremor may be attributed to serotonergic dysfunction in the brain.

Isoelectric focusing and electrophoresis of the CSF proteins in tremor of different origins.

The CSF proteins have previously been very little investigated in the cerebellar syndrome of chronic alcoholism and in essential tremor. Such studies have been carried out more thoroughly by electrophoretic methods in Parkinson's disease but generally with normal results. In the present investigation the CSF proteins were examined by isoelectric focusing and quantitative paper electrophoresis in 10 patients with the cerebellar syndrome of chronic alcoholsm, 12 patients with Parkinson's disease and 16 subjects with essential tremor. Abnormal CSF proteins of very similar appearance were found on isoelectric focusing in the acidic pH interval 5.6-5.8 in 80% of the patients with the cerebellar syndrome of chronic alcoholism. In Parkinson's disease the most common aberration was evidence of nonspecific blood-CSF-barrier damage which occurred in half of the patients. In only 17% of these cases did other alterations appear, situated in the pH range alkaline to pH 5.8. Abnormal CSF proteins were found in 94% of the patients with essential tremor. The aberrant proteins appeared in both the acidic and alkaline pH regions, most frequently with anisoelectric point at pH 5.9, 7.2 and 9.3. There was a considerably higher frequency of CSF protein abnormalities in different pH ranges in patients with tremor of more pronounced degree as compared to those with only mild symptoms. The electrophoretic examinations failed to show any conclusive alterations. Barrier-damage patterns of mild or moderate degree or slightly increased levels of CSF beta1-globulin were occasionally found in all 3 diseases. The results indicate that isoelectric focusing of the CSF proteins may be of diagnostic value in the cerebellar syndrome of chronic alcoholism and in essential tremor but does not reveal any characteristic abnormalities in Parkinson's disease.

Amine metabolites in the cerebrospinal fluid of patients with disseminated sclerosis.

Mean homovanillic acid and 5-hydroxyindoleacetic acid concentrations were significantly low in the lumbar CSF of a group of patients with disseminated sclerosis (DS) who were severely disabled but not in the CSF of a less severely restricted group with DS. CSF concentrations were also low in a group of patients with superior cerebellar peduncular tremor due to DS and in a single patient with a similar tremor associated with a post-traumatic brain-stem lesion. The interpretation of abnormal CSF amine metabolite concentrations is discussed in the light of these findings.