DNAJC13 p.Asn855Ser mutation screening in Parkinson's disease and pathologically confirmed Lewy body disease patients.

BACKGROUND: Recently, a novel mutation in exon 24 of DNAJC13 gene (p.Asn855Ser, rs387907571) has been reported to cause autosomal dominant Parkinson's disease (PD) in a multi-incident Mennonite family. METHODS: In the present study the mutation containing exon of the DNAJC13 gene has been sequenced in a Caucasian series consisting of 1938 patients with clinical PD and 838 with pathologically diagnosed Lewy body disease (LBD). RESULTS: Our sequence analysis did not identify any coding variants in exon 24 of DNAJC13. Two previously described variants in intron 23 (rs200204728 and rs2369796) were observed. CONCLUSION: Our results indicate that the region surrounding the DNAJC13 p.Asn855Ser substitution is highly conserved and mutations in this exon are not a common cause of PD or LBD among Caucasian populations.

Death-associated protein kinase 1 variation and Parkinson's disease.

BACKGROUND AND PURPOSE: Mutations of the LRRK2 gene are now recognized as major risk factors for Parkinson's disease. The Lrrk2 protein is a member of the ROCO family, which also includes Lrrk1 and Dapk1. Functional genetic variants of the DAPK1 gene (rs4877365 and rs4878104) have been previously associated with Alzheimer's disease. METHODS: Herein, we assessed the role of DAPK1 variants (rs4877365 and rs4878104) in risk of Parkinson's disease with Sequenom iPLEX genotyping, employing one Taiwanese series (391 patients with Parkinson's disease, 344 controls) and five separate Caucasian series' (combined sample size 1962 Parkinson's disease patients, 1900 controls). RESULTS: We observed no evidence of association for rs4877365 and rs4878104 and risk of Parkinson's disease in any of the individual series or in the combined Caucasian series under either an additive or recessive model. CONCLUSION: These specific DAPK1 intronic variants do not increase the risk of Parkinson's disease. However, further functional studies are required to elucidate the potential therapeutic implications with the dimerization of the Dapk1 and Lrrk2 proteins.

Calbindin-1 association and Parkinson's disease.

BACKGROUND AND PURPOSE: Calcium levels have been proposed to play an important role in the selective vulnerability of nigrostriatal dopaminergic neurons in Parkinson's disease (PD). Recently, an association was reported between the calcium buffer, calbindin (rs1805874) and risk of PD in a Japanese patient-control series. METHODS: We genotyped rs1805874 in four independent Caucasian patient-control series (1543 PD patients, 1771 controls). RESULTS: There was no evidence of an association between rs1805874 and disease risk in individual populations or in the combined series (odds ratio: 1.04, 95% CI: 0.82-1.31, P = 0.74). DISCUSSION: Our study shows there is no association between rs1805874 and risk for PD in four Caucasian populations. This suggests the effect of calbindin on PD risk displays population specificity.

GRN 3'UTR+78 C>T is not associated with risk for Parkinson's disease.

BACKGROUND AND PURPOSE: A single nucleotide polymorphism in the 3'-untranslated region of the progranulin gene (GRN; 3'UTR+78C>T; rs5848) was reported to alter the risk for frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). rs5848 is located within a micro-RNA binding site and affects the expression of GRN. METHODS: As FTLD-U patients often present with parkinsonism, we investigated the association of GRN rs5848 and risk of Parkinson's disease in two Caucasian patient-control series (n = 1413) from the US and Poland. RESULTS: No association was observed between rs5848 and susceptibility to Parkinson's disease (individual series and combined analysis). CONCLUSIONS: This finding shows that GRN rs5848 does not affect the risk of Parkinson's disease in the US and Polish populations.

Peripheral mechanisms of intestinal dysmotility in rats with salsolinol induced experimental Parkinson's disease.

Gastrointestinal dysmotility in Parkinson's disease (PD) has been attributed in part to peripheral neurotoxine action. Our purpose was the evaluation of the salsolinol effect on intramuscular interstitial cells of Cajal (ICC), duodenal myoelectrical activity (DMA) and vagal afferent activity (VAA) in rats with experimental PD. Twenty rats were divided into 2 equal groups. Experimental PD was produced in one group by 3 weeks of the intraperitoneal salsolinol injections (50 mg/kg/day), whereas the 2-nd group served as control. DMA and VAA were recorded in both groups during fasting and stepwise--gastric distension (GD) of 10 ml. Subsequently fragments of duodenum were removed and intramuscular ICC were assessed as c-Kit antigen percentage in the duodenal muscular zone. Analyses of the fasting DMA and VAA recordings didn't reveal differences between the compared groups. During GD increase of DMA dominant frequency (p=0.04) and VAA frequency (p<0.01) was observed in the controls whereas in the salsolinol group both parameters remained unchanged. Image analysis of duodenum revealed decreased c-Kit expression in the salsolinol-injected animals (p=0.05). The results of our study may suggest the direct effect of salsolinol on both ICC and neuronal pathways of gastro-duodenal reflexes.

Increase in salsolinol level in the cerebrospinal fluid of parkinsonian patients is related to dementia: advantage of a new high-performance liquid chromatography methodology.

The study was carried out on the lumbar cerebrospinal fluid (CSF) samples taken from nonparkinsonian, early parkinsonian, and advanced parkinsonian patients. Some patients showed dementia, and some were treated with L-dopa. In the samples, salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) was assayed with a newly developed sensitive high-performance liquid chromatography (HPLC) method; 3-O-methyldopa (3-O-MD) and homovanillic acid (HVA) were also assayed by HPLC. CSF salsolinol concentrations were significantly enhanced in patients with signs of dementia, regardless of the degree of parkinsonism, and were not affected by L-dopa treatment; HVA and, particularly, 3-O-MD levels were elevated in patients receiving L-dopa. The strong association of CSF salsolinol level with dementia, but not with L-dopa treatment suggests that salsolinol does not originate from L-dopa metabolism, and that its elevation is an indicator of neurodegenerative processes resulting in damage to brain areas mediating cognitive functions. We found no correlation between the advancement of parkinsonism and the concentrations of 3-O-MD and HVA.

Neurochemical changes induced by acute and chronic administration of 1,2,3,4-tetrahydroisoquinoline and salsolinol in dopaminergic structures of rat brain.

The finding that endogenous tetrahydroisoquinolines may be involved in the etiology of Parkinson's disease suggests that their administration may cause changes resembling those observed in parkinsonian brain. We tested, using a high-performance liquid chromatography method, how single and chronic administration of 1,2, 3,4-tetrahydroisoquinoline and salsolinol affects dopamine and serotonin metabolism in the neurons of extrapyramidal and mesolimbic dopaminergic systems. We report that chronic administration of tetrahydroisoquinoline and salsolinol causes a decrease in a dopamine metabolism: the effect of tetrahydroisoquinoline was limited to the striatum, while salsolinol caused also a dramatic decline of dopamine level in the substantia nigra. The effect of both compounds on serotonin metabolism was small or absent. The tetrahydroisoquinolines produced no changes in the nucleus accumbens. The results indicate that tetrahydroisoquinoline and salsolinol specifically affect the nigrostriatal dopamine system, but only when administered chronically, and thus are compatible with the view that endogenous tetrahydroisoquinolines may participate in pathogenesis of Parkinson's disease.

The effect of transcutaneous nerve stimulation (TENS) on gastric electrical activity.

UNLABELLED: TENS became widely accepted method of treatment pain syndromes in clinical practice. Lately has been shown that its affects also gastrointestinal tract by releasing NANC neurotransmitter VIP. The aim of this study was to evaluate the effects of TENS on gastric myoelectric activities measured by electrogastrography (EGG). Eighteen healthy men (mean age 23 +/- 1.7) were included in the study. Healthy volunteers were divided on 3 groups each 6 persons: with normogastria occurring at 94.5 +/- 7% of recording time--group A, with predominant bradygastria (36.6 +/- 14%)--group B and with tachygastria (33 +/- 14%)--group C. In fasted condition EGG (Synectics, Sweden) was recorded with skin electrodes. TENS 15 min was performed with use of Sinus 5 stimulator (6 Hz, 0.1 ms duration, intensities 10-20 mA, Zimmer, Germany). Stimulating electrodes were placed on non-dominant hand. RESULTS: None of the subjects during TENS reported any side effects or symptoms, during the all studies. In group A in the fasting recordings, after TENS, an decrease of the normal values in the range 2-4 cpm down to 78.5 +/- 21% of recording time (p = 0.03) occurred. The dominant frequency in the bradygastric region increased up to 17.7 +/- 7% of the total recording. In group B TENS decreased bradygastria level from 36.6 +/- 14% to 20.6 +/- 15% (p = 0.02). TENS did not significantly affect tachygastria in group C. Amplitude of the EGG signal after TENS in group B and C increased by 40 and 150% respectively (p < 0.05). Significant decrease of the amplitude was observed in group A (13%). We conclude that TENS by activating centrally mediated somato-visceral reflexes affects gastric electrical activity. Our results suggest that TENS may be useful in treatment of the gastric dysrhythmia.

Acute hemorrhagic encephalitis (Hurst disease) associated with neuroaxonal dystrophy.

Two cases that fulfil the clinical and neuropathological criteria of acute hemorrhagic encephalitis are described. Histological examination revealed additionally focal changes in the white matter characteristic for neuroaxonal dystrophy. The differences in the clinical course and morphological picture observed in both cases are discussed.

Sarcomatosis of leptomeninges, brain and spinal cord coexisting with von Recklinghausen's neurofibromatosis. A case report and review of the literature.

A case of 56-year-old male with sarcomatosis of leptomeninges as well as of the brain and spinal cord coexisting with Recklinghausen's neurofibromatosis is presented. Neurological and neurophysiological symptoms of the disease resembled those of amyotrophic lateral sclerosis (ALS). Patient died 7 months after onset of the initial symptoms. The post-mortem examination revealed neoplastic infiltration of the leptomeninges of brain and spinal cord. Histologically sarcomatosis of the leptomeninges was diagnosed and immunohistochemical analysis of the neoplastic infiltrates can indicate fibrohistiocytic origin of the neoplasm, suggesting also a probable contribution of perineurial cells in the pathogenesis of the tumor. On the grounds of the performed immunohistochemical study together with a review of the literature, the differential diagnosis of malignant mesenchymal tumors of the CNS is discussed with a special regard to their histogenesis.

Gastric electromechanical dysfunction in Parkinson's disease.

This study was designed to evaluate gastric myoelectrical and mechanical activities in idiopathic Parkinson's disease (IPD) patients. Twenty patients with IPD (14 male and 6 female, mean age 42 +/- 9 years) were studied. Patients were divided into two groups: group A--early stage of disease (no. = 6) and group B--advanced IPD (no. = 14). Electrogastrography (EGG) was performed in fasting and postprandial conditions (Synectics system). The cross-sectional area of the gastric antrum was measured by sonography (Hitachi EUB-240). The antral area in fasting conditions was 2.1 +/- 0.4 and 4.2 +/- 1.2 cm2 and gastric emptying was 75 +/- 5 and 125 +/- 12 min in groups A and B respectively. EGG showed dysrhythmias (range 1-6 cycles per minute) in about 75% of both groups of IPD patients without increase in signal amplitude after a meal. Our results suggest that gastric motility is particularly impaired in patients with advanced IPD. It may be caused by the primary degenerative process in the autonomic nervous system of the gut.

[Salsolinol, 3-O-methyl-dopa and homovanillic acid in the cerebrospinal fluid of Parkinson patients]. / Salsolinol oraz 3-0-metyldopa i kwas homowanilinowy w plynie mózgowo-rdzeniowym u osób z choroba parkinsona.

Salsolinol is one of the dopamine-derived tetrahydroisoquinolines, supposed to be a potent dopaminergic neurotoxin, similar to MPTP. Its systemic administration induced parkinsonism in monkeys. The aim of the study was to compare the concentration of salsolinol and the metabolite of L-dopa, 3-O-MD, and the metabolite of dopamine, HVA, in the cerebrospinal fluid of patients with different degrees of parkinsonism, treated or nontreated with l-dopa. Lumbar CSF was obtained from 26 patients with Parkinson's disease (15 early and 11 advanced parkinsonism) and from six healthy controls. The presence of salsolinol, HVA and 3-O-MD was assayed with a sensitive HPLC method employing C18 (Hypersil BDS) column. The analysis of the results demonstrated that the concentration of salsolinol was related to the degree of parkinsonism but not affected by l-dopa treatment. In contrast, HVA and 3-O-MD were significantly elevated in patients receiving l-dopa but did not correlate with the severity of parkinsonism. The results suggest that salsolinol in the cerebrospinal fluid does not originate from exogenous l-dopa and its elevation in cerebrospinal fluid may be an indicator of the advancement of parkinsonism.

[Autonomic nervous system dysfunction in Parkinson's disease evaluated by the heart rhythm variability test]. / Zaburzenia ukladu autonomicznego w chorobie Parkinsona oceniane testem zmiennosci rytmu serca.

It is well recognized that autonomic dysfunction are common in Parkinson's disease (PD). Fourteen patients with early PD and 8 patients with advanced PD aged from 38-71 were investigated. Heart rate variability at rest differ significantly between patients with advanced PD and age-matched controls. Cardiovascular autonomic dysfunction in PD mainly affects parasympathetic but also sympathetic system, and occurs only in advanced cases. Heart rate variability is a useful non-invasive test to assess autonomic dysfunction in PD.

[The effect of chronic alcohol use on heart rate variability]. / Wplyw przewleklego spozycia alkoholu na zmiennosc rytmu zatokowego serca.

A long lasting alcohol intake causes, amongst numerous systemic damages, also the autonomic nervous system (ANS) dysfunction, which causes the autonomic heart rate regulation disorders. The aim of the study was to evaluate the autonomic regulation of the circulation in chronic alcoholism. Seventeen alcoholics, 24-55 years of age (mean 43 +/- 5.2 years) were examined. They have been abstainers for 2-6 years. The cardiac ANS function was evaluated using the HRV measurement. The HRV was registered using V6 EKG lead. The recording was performed through the 15 min of resting conditions and 5 min of the deep breathing test. A group containing healthy volunteers, matched for age and gender, for the comparison of the HRV results was recruited. In the examined group, during the resting conditions, the significant RR period changes weren't observed (999.7 +/- 139.2 vs. 967 +/- 144.9; p > 0.05). The nonsignificant lower values of the spectral analysis parameters of HRV: LF (954.1 +/- 1162.6 vs. 1456.4 +/- 1327.1; p > 0.05) and HF (676.4 +/- 414.2 vs. 1557 +/- 1854.4; p > 0.05) and LF/HF ratio (1.5 +/- 1.14 vs. 1.38 +/- 1.28; p > 0.05) were also noticed. In response to the DB test, the mean value of the RR period wasn't significantly changed (921.4 +/- 152.3 vs. 930.6 +/- 137.8; p > 0.05). In DB test the significant decrease of LF (3465.8 +/- 2750.1 vs. 11558.6 +/- 7902.5; p < 0.001) and HF (406.1 +/- 366.8 vs. 1665 +/- 1757.1; p < 0.01) was observed. No significant change of LF/HF mean ratio (11.6 +/- 6.97 vs. 14.7 +/- 11.6; p > 0.05) was noticed. The results of our study indicate on the maintenance of the HRV disorders in chronic alcoholics, during the abstinence.

Characterization of DCTN1 genetic variability in neurodegeneration.

OBJECTIVE: Recently, mutations in DCTN1 were found to cause Perry syndrome, a parkinsonian disorder with TDP-43-positive pathology. Previously, mutations in DCTN1 were identified in a family with lower motor neuron disease, in amyotrophic lateral sclerosis (ALS), and in a family with ALS/frontotemporal dementia (FTD), suggesting a central role for DCTN1 in neurodegeneration. METHODS: In this study we sequenced all DCTN1 exons and exon-intron boundaries in 286 samples diagnosed with Parkinson disease (PD), frontotemporal lobar degeneration (FTLD), or ALS. RESULTS: This analysis revealed 36 novel variants (9 missense, 5 silent, and 22 noncoding). Segregation analysis in families and association studies in PD, FTLD, and ALS case-control series did not identify any variants segregating with disease or associated with increased disease risk. CONCLUSIONS: This study suggests that pathogenic mutations in DCTN1 are rare and do not play a common role in the development of Parkinson disease, frontotemporal lobar degeneration, or amyotrophic lateral sclerosis.

Clinical and genetic evaluation of 8 Polish families with levodopa-responsive parkinsonism.

We studied 8 large Polish families with parkinsonism, 6 of which were newly identified. Thirty-six family members had well-documented levodopa-responsive parkinsonism. The phenotype of affected individuals was indistinguishable from that of persons with idiopathic Parkinson disease (PD). The pattern of inheritance in 5 families was consistent with autosomal dominant transmission; in 3 families the mode of inheritance was uncertain. Single photon emission computed tomography (SPECT) studies with the dopamine transporter radioligand [(123)I]FP-CIT were performed in 1 family. The SPECT study showed striatal presynaptic dopaminergic degeneration consistent with sporadic PD in 1 affected family member and no signs of nigrostriatal dopaminergic dysfunction in 5 at-risk individuals. Sequence analysis in all 8 families excluded known genes associated with familial parkinsonism. Genome-wide 2-point linkage studies in the largest 2 families did not identify significant linkage (z > 3.0), although positive scores were obtained for 5q23 (D5S1462 and D5S2501), a locus previously implicated in disease susceptibility.

The antibodies against Bordetella pertussis in sera of patients with Parkinson's disease and other non-neurological diseases.

OBJECTIVES: It has been reported that the prevalance of parkinsonism might be associated with exposure to whooping cough. METHODS: Examination of levels of antibodies against Bordetella pertussis in serum using enzyme-linked immunosorbent assay (ELISA) tests [presence of IgG antibodies against filamentous hemagglutinin and pertussis toxin (PT)] were performed in 81 persons (including 45 patients with controls) (age-matched groups). RESULTS: Positive results were found in patients with Parkinson's disease (PD), patients with other non-inflammatory diseases, and controls (about 40-45% in each group). A detailed examination of separate responses (IgG and IgA antibodies against PT, and a whole cell immune response) and of the serum level of immunoglobulins IgG, IgA and IgM was also performed. CONCLUSION: Our results demonstrate numerous cases of whooping cough serum antibodies among the adult population (also among PD patients). The results of our research, i.e. a common occurrence of Bordetella pertussis infection do not provide evidence of relationship between PD and the above-mentioned infection.