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Background Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease. Although additional missense variants were described, their pathogenic role yet remains inconclusive. Methods and results We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. Conclusions Our study apart from identifying the p. Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

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.

Variants in the Omi/HtrA2 gene have been nominated as a cause of Parkinson's disease. This sequencing study of Omi/HtrA2 in 95 probands with apparent autosomal dominant inheritance of Parkinson's disease did not identify any pathogenic mutations. In addition, there was no association between common variations in the Omi/HtrA2 gene and susceptibility to Parkinson's disease in any of our four patient-control series (n = 2373). Taken together our results do not support a role for Omi/HtrA2 variants in the pathogenesis of Parkinson's disease.

Objective: To assess the importance of MAPT variant p.A152T in the risk of synucleinopathies. Methods: In this case-control study, we screened a large global series of patients and controls, and assessed associations between p.A152T and disease risk. We included 3,229 patients with clinical Parkinson disease (PD), 442 with clinical dementia with Lewy bodies (DLB), 181 with multiple system atrophy (MSA), 832 with pathologically confirmed Lewy body disease (LBD), and 2,456 healthy controls. Results: The minor allele frequencies (MAF) in clinical PD cases (0.28%) and in controls (0.2%) were not found to be significantly different (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.63-2.98, p 0.42). However, a significant association was observed with clinical DLB (MAF 0.68%, OR 5.76, 95% CI 1.62-20.51, p 0.007) and LBD (MAF 0.42%, OR 3.55, 95% CI 1.04-12.17, p 0.04). Additionally, p.A152T was more common in patients with MSA compared to controls (MAF 0.55%, OR 4.68, 95% CI 0.85-25.72, p 0.08) but this was not statistically significant and therefore should be interpreted with caution. Conclusions: Overall, our findings suggest that MAPT p.A152T is a rare low penetrance variant likely associated with DLB that may be influenced by coexisting LBD and AD pathology. Given the rare nature of the variant, further studies with greater sample size are warranted and will help to fully explain the role of p.A152T in the pathogenesis of the synucleinopathies. © 2015 American Academy of Neurology.

Recent immunohistochemical studies point to the dorsal motor nucleus of the vagus nerve as the point of departure of initial changes which are related to the gradual pathological developments in the dopaminergic system. In the light of current investigations, it is likely that biochemical changes within the peripheral nervous system may influence the physiology of the dopaminergic system, suggesting a putative role for it in the development of neurodegenerative disorders. By using Fourier transform infrared microspectroscopy, coupled with statistical analysis, we examined the effect of chronic, unilateral electrical vagus nerve stimulation on changes in lipid composition and in protein secondary structure within dopamine-related brain structures in rats. It was found that the chronic vagal nerve stimulation strongly affects the chain length of fatty acids within the ventral tegmental area, nucleus accumbens, substantia nigra, striatum, dorsal motor nucleus of vagus and the motor cortex. In particular, the level of lipid unsaturation was found significantly increasing in the ventral tegmental area, substantia nigra and motor cortex as a result of vagal nerve stimulation. When it comes to changes in protein secondary structure, we could see that the mesolimbic, mesocortical and nigrostriatal dopaminergic pathways are particularly affected by vagus nerve stimulation. This is due to the co-occurrence of statistically significant changes in the content of non-ordered structure components, alpha helices, beta sheets, and the total area of Amide I. Macromolecular changes caused by peripheral vagus nerve stimulation may highlight a potential connection between the gastrointestinal system and the central nervous system in rat during the development of neurodegenerative disorders.

BackgroundRecently, 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. MethodsIn 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). ResultsOur 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. ConclusionOur 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.

BACKGROUND: Pain is a common non-motor symptom of Parkinson's disease. We investigated the analgesic efficacy of prolonged-release oxycodone-naloxone (OXN PR) in patients with Parkinson's disease and chronic, severe pain.METHODS: We did this phase 2 study in 47 secondary care centres in the Czech Republic, Germany, Hungary, Poland, Romania, Spain, and the UK. We enrolled patients with Hoehn and Yahr Stage II-IV Parkinson's disease, at least one type of severe pain, and an average 24-h pain score of at least 6 (assessed on an 11-point rating scale from 0=no pain to 10=pain as bad as you can imagine). Participants were randomly assigned (1:1) with a validated automated system (block size four) to either oral OXN PR or placebo for 16 weeks (starting dose oxycodone 5 mg, naloxone 2·5 mg, twice daily). Patients and investigators were masked to treatment assignment. The primary endpoint was average 24-h pain score at 16 weeks in the full analysis population. This study is registered with EudraCT (2011-002901-31) and ClinicalTrials.gov (NCT01439100).FINDINGS: We enrolled 202 patients; 93 were assigned to OXN PR and 109 to placebo; the full analysis population consisted of 88 patients versus 106 patients. Least squares mean average 24-h pain score at 16 weeks in the full analysis population was 5·0 (95% CI 4·5 to 5·5) in the OXN PR group versus 5·6 (5·1 to 6·0) in the placebo group (difference -0·6, 95% CI -1·3 to 0·0; p=0·058). Similar proportions of patients in each group had adverse events (60/92 [65%] vs 76/109 [70%]), treatment-related adverse events (52/92 [57%] vs 62/109 [57%]), and serious adverse events (5/92 [5%] vs 7/109 [6%]). Treatment-related nausea was more common in the OXN PR group than in the placebo group (16/92 [17%] vs 10/109 [9%]), as was treatment-related constipation (16/92 [17%] vs 6/109 [6%]).INTERPRETATION: The primary endpoint, based on the full analysis population at week 16, was not significant. Nonetheless, the results of this study highlight the potential efficacy of OXN PR for patients with Parkinson's disease-related pain and might warrant further research on OXN PR in this setting.FUNDING: Mundipharma Research.

Objective: To assess the role of CHCHD2 variants in patients with Parkinson disease (PD) and Lewy body disease (LBD) in Caucasian populations. Methods: All exons of the CHCHD2 gene were sequenced in a US Caucasian patient-control series (878 PD, 610 LBD, and 717 controls). Subsequently, exons 1 and 2 were sequenced in an Irish series (355 PD and 365 controls) and a Polish series (394 PD and 350 controls). Immunohistochemistry and immunofluorescence studies were performed on pathologic LBD cases with rare CHCHD2 variants. Results: We identified 9 rare exonic variants of unknown significance. These variants were more frequent in the combined group of PD and LBD patients compared to controls (0.6% vs 0.1%, p = 0.013). In addition, the presence of any rare variant was more common in patients with LBD (2.5% vs 1.0%, p = 0.050) compared to controls. Eight of these 9 variants were located within the gene9s mitochondrial targeting sequence. Conclusions: Although the role of variants of the CHCHD2 gene in PD and LBD remains to be further elucidated, the rare variants in the mitochondrial targeting sequence may be a risk factor for Lewy body disorders, which may link CHCHD2 to other genetic forms of parkinsonism with mitochondrial dysfunction.

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 [123I]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 presence of late-onset neurological symptoms in male carriers of premutation expansions of the fragile X mental retardation 1 (FMR1) gene has been described recently. One of the clinical symptoms in this fragile X-associated tremor/ataxia syndrome (FXTAS) is parkinsonism. To test the possible association between expanded FMR1 alleles and Parkinson's disease (PD), we determined the size of the FMR1 CGG repeat in 414 male cases of clinically diagnosed parkinsonism, the majority of whom had PD. None of our patients had expanded FMR1 repeats within the premutation range (55-200 CGG repeats). Five patients (1.2%) carry intermediate-size alleles (41-54 CGG repeats). Expansions within the FMR1 gene are not associated with PD in our study.

Synchrotron microbeam X-ray fluorescence (μ-SXRF) was applied for topographic and quantitative analysis of selected elements in human brain and spinal cord. The main goal of the study is a better understanding of the role of elements, mainly metals, in processes leading to degeneration and atrophy of nerve cells in cases of two neurodegenerative disorders, i.e. Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). The samples were taken during the autopsy from patients deceased with PD, ALS, and from a patient who died due to non-neurological conditions. In measurements, a 5 x 2 μm 2 X-ray beam was applied for scanning the thin tissue slices. Two-dimensional maps of elemental distribution were compared with histopathological sections. The results obtained showed that the spatial distribution of selected elements precisely corresponds to the microscopic views of scanned area of tissue. Moreover, differences in accumulation of selected elements in nerve cell bodies and areas representing white matter between patients affected by PD, ALS and the control case were noticed. The present investigation showed that the μ-SXRF technique is suitable for elemental analysis at the single cell level in applications in neurological research.

Genome-wide association studies (GWAS) in Parkinson’s disease (PD) have identified over 20 genomic regions associated with disease risk. Many of these loci include several candidate genes making it difficult to pinpoint the causal gene. The locus on chromosome 2q24.3 encompasses three genes: B3GALT1, STK39, and CERS6. In order to identify if the causal variants are simple missense changes, we sequenced all 31 exons of these three genes in 187 patients with PD. We identified 13 exonic variants including four non-synonymous and three insertion/deletion variants (indels). These non-synonymous variants and rs2102808, the GWAS tag SNP, were genotyped in three independent series consisting of a total of 1976 patients and 1596 controls. Our results show that the seven identified 2q24.3 coding variants are not independently responsible for the GWAS association signal at the locus; however, there is a haplotype, which contains both rs2102808 and a STK39 exon 1 6bp indel variant, that is significantly associated with PD risk (Odds Ratio [OR] = 1.35, 95% CI: 1.11–1.64, P = 0.003). This haplotype is more associated than each of the two variants independently (OR = 1.23, P = 0.005 and 1.10, P = 0.10, respectively). Our findings suggest that the risk variant is likely located in a non-coding region. Additional sequencing of the locus including promoter and regulatory regions will be needed to pinpoint the association at this locus that leads to an increased risk to PD.

Subthalamic nucleus (STN) deep brain stimulation (DBS) is well established for the treatment of the motor symptoms of Parkinson's disease (PD). However, the effect of STN DBS on autonomic symptoms has not been well studied. We examined 19 patients undergoing STN DBS for PD. The patients were administered a questionnaire to evaluate the pre-operative and post-operative autonomic function. All patients reported a significant post DBS improvement of one or more symptoms of the autonomic dysfunction (urinary and gastrointestinal function). In particular, we have shown the most significant improvement in the urinary function after STN DBS. Further larger studies are required with respect to the effect of STN DBS on the autonomic function.

The best validated susceptibility variants for Parkinson's disease are located in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotypedefining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p ≥ 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.

We recently showed that mutation of the VPS35 gene can cause late-onset Parkinson’s disease. In the present study we sequenced 702 affected subjects from the Mayo Clinic Parkinson’s disease patient-control series for the VPS29 and VPS26A/B genes. We identified only two rare non-synonymous variants in the VPS26A p.K93E and VPS29 p.N72H. The results show that mutations in the genes composing the retromer cargo recognition subunit are not a common cause of Parkinson’s disease.

Objectives: The objective of this study is to clarify the role of (G 4 C 2 ) n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson9s Disease (GEO-PD) cohort. Methods: C9orf72 (G 4 C 2 ) n repeats were assessed in a GEO-PD cohort of 7,494 patients diagnosed with PD and 5,886 neurologically healthy control individuals ascertained in Europe, Asia, North America, and Australia. Results: A pathogenic (G 4 C 2 ) n>60 expansion was detected in only 4 patients with PD (4/7,232; 0.055%), all with a positive family history of neurodegenerative dementia, amyotrophic lateral sclerosis, or atypical parkinsonism, while no carriers were detected with typical sporadic or familial PD. Meta-analysis revealed a small increase in risk of PD with an increasing number of (G 4 C 2 ) n repeats; however, we could not detect a robust association between the C9orf72 (G 4 C 2 ) n repeat and PD, and the population attributable risk was low. Conclusions: Together, these findings indicate that expansions in C9orf72 do not have a major role in the pathogenesis of PD. Testing for C9orf72 repeat expansions should only be considered in patients with PD who have overt symptoms of frontotemporal lobar degeneration/amyotrophic lateral sclerosis or apparent family history of neurodegenerative dementia or motor neuron disease.

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.

Background A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer’s disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer’s disease-related risk variant in TREM2 (rs75932628, p.R47H) with other related neurodegenerative disorders. Results The study included 609 patients with frontotemporal dementia, 765 with amyotrophic lateral sclerosis, 1493 with Parkinson’s disease, 772 with progressive supranuclear palsy, 448 with ischemic stroke and 1957 controls subjects free of neurodegenerative disease. A significant association was observed for the TREM2 p.R47H substitution in susceptibility to frontotemporal dementia (OR = 5.06; p-value = 0.001) and Parkinson’s disease (OR = 2.67; p-value = 0.026), while no evidence of association with risk of amyotrophic lateral sclerosis, progressive supranuclear palsy or ischemic stroke was observed. Conclusions Our results suggest that the TREM2 p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson’s disease in addition to Alzheimer’s disease. These findings suggest a more general role for TREM2 dysfunction in neurodegeneration, which could be related to its role in the immune response.

Objective Mutations in the α-synuclein-encoding gene SNCA are considered as a rare cause of Parkinson's disease (PD). Our objective was to examine the frequency of the SNCA point mutations among PD patients of Polish origin. Methods Detection of the known SNCA point mutations A30P (c.88G>C), E46K (c.136G>A) and A53T (c.157A>T) was performed either using the Sequenom MassArray iPLEX platform or by direct sequencing of the SNCA exons 2 and 3. As the two novel substitutions A18T (c.52G>A) and A29S (c.85G>T) were identified, their frequency in a control population of Polish origin was assessed and in silico analysis performed to investigate the potential impact on protein structure and function. Results We did not observe the previously reported point mutations in the SNCA gene in our 629 PD patients; however, two novel potentially pathogenic substitutions A18T and A29S were identified. Each variant was observed in a single patient presenting with a typical late-onset sporadic PD phenotype. Although neither variant was observed in control subjects and in silico protein analysis predicts a damaging effect for A18T and pA29S substitutions, the lack of family history brings into question the true pathogenicity of these rare variants. Conclusions Larger population based studies are needed to determine the pathogenicity of the A18T and A29S substitutions. Our findings highlight the possible role of rare variants contributing to disease risk and may support further screening of the SNCA gene in sporadic PD patients from different populations.

Synchrotron radiation based x-ray fluorescence (SRXRF) was applied to the quantitative evaluation of elemental changes in substantia nigra pars compacta (SNc) in Parkinson's disease (PD) in the framework of a study on the role of chemical elements in the pathophysiology of PD. The analysis was carried out for dopaminergic nerve cells and extraneuronal spaces. The mass fractions of P, S, Cl, K, Ca, Fe, Cu, Zn, Br and Rb were determined. The application of standard samples developed especially for the determination of elemental mass fractions in thin tissue sections using the SRXRF technique is presented. Two-dimensional maps of elemental distribution show that the location of nerve cells in SNc sections is precisely visualized by the high levels of most elements. It was found that statistically significant differences between control and PD neurons are observed for S (p = 0.04), Cl (p = 0.02), Ca (p = 0.08), Fe (p = 0.04) and Zn (p = 0.04). The mass fractions of P (p = 0.08), S (p = 0.07), Cl (p = 0.04), Zn (p = 0.08) and Rb (p = 0.08) in areas outside the nerve cell bodies differed significantly between PD and control groups. A clear cluster separation between the PD nerve cells and neurons representing the control group was noticed. It was found that Cl, Fe, Ca and Zn are the most significant elements in the general discrimination between PD nerve cells and the control. The comparison between the extraneuronal spaces showed that Cl, Fe and Cu differentiate the PD and control group the most. The evident contribution of chemical elements to the pathophysiology of PD was shown.

Background Recent clinical studies have shown that the dorsal motor nucleus of the vagus nerve is one of the brain areas that are the earliest affected by α-synuclein and Lewy body pathology in Parkinson's disease. This observation raises the question: how the vagus nerve dysfunction affects the dopamine system in the brain? Methods The rats underwent surgical implantation of the microchip (MC) in the abdominal region of the vagus. In this study, we examined the effect of chronic, unilateral electrical stimulation of the left nerve vagus, of two different types: low-frequency (MCL) and physiological stimulation (MCPh) on the dopamine and serotonin metabolism determined by high-pressure chromatography with electrochemical detection in rat brain structures. Results MCL electrical stimulation of the left nerve vagus in contrast to MCPh stimulation, produced a significant inhibition of dopamine system in rat brain structures. Ex vivo biochemical experiments clearly suggest that MCL opposite to MCPh impaired the function of dopamine system similarly to vagotomy. Conclusion We suggest a close relationship between the peripheral vagus nerve impairment and the inhibition of dopamine system in the brain structures. This is the first report of such relationship which may suggest that mental changes (pro-depressive) could occur in the first stage of Parkinson's disease far ahead of motor impairment.

Background Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease. Although additional missense variants were described, their pathogenic role yet remains inconclusive. Methods and results We performed the largest multicenter study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. Conclusions Our study apart from identifying the p. Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

The identification of genetic causes for Mendelian disorders has been based on the collection of multi-incident families, linkage analysis, and sequencing of genes in candidate intervals. This study describes the application of next-generation sequencing technologies to a Swiss kindred presenting with autosomal-dominant, late-onset Parkinson disease (PD). The family has tremor-predominant dopa-responsive parkinsonism with a mean onset of 50.6 ± 7.3 years. Exome analysis suggests that an aspartic-acid-to-asparagine mutation within vacuolar protein sorting 35 (VPS35 c.1858G>A; p.Asp620Asn) is the genetic determinant of disease. VPS35 is a central component of the retromer cargo-recognition complex, is critical for endosome-trans-golgi trafficking and membrane-protein recycling, and is evolutionarily highly conserved. VPS35 c.1858G>A was found in all affected members of the Swiss kindred and in three more families and one patient with sporadic PD, but it was not observed in 3,309 controls. Further sequencing of familial affected probands revealed only one other missense variant, VPS35 c.946C>T; (p.Pro316Ser), in a pedigree with one unaffected and two affected carriers, and thus the pathogenicity of this mutation remains uncertain. Retromer-mediated sorting and transport is best characterized for acid hydrolase receptors. However, the complex has many types of cargo and is involved in a diverse array of biologic pathways from developmental Wnt signaling to lysosome biogenesis. Our study implicates disruption of VPS35 and retromer-mediated trans-membrane protein sorting, rescue, and recycling in the neurodegenerative process leading to PD.

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. 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). 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. 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.

Deep brain stimulation (DBS) for alleviation of motor symptoms in advanced Parkinson's disease (PD) is well established. However, autonomic effects of DBS are less clear.To review published data on autonomic dysfunctions in DBS-treated patients with PD.Medline bibliographic search was performed with the selected relevant keywords, through June 10th, 2010. Thirty three original papers meeting the criteria were identified.Effect of DBS on autonomic dysfunctions observed in PD differs depending on the underlying etiology. DBS of the subthalamic nucleus has no direct effects on cardiovascular functions. Relative improvement results from reduced levodopa intake. Majority of gastrointestinal and urinary tract disorders improve with neurostimulation. However, prolonged body weight gain is observed. Furthermore, urinary tract functions normalize, and in male patients with Parkinson's disease sexual satisfaction increases. Sweating disorders are markedly reduced. On the contrary, chronic stimulation in the area of STN may induce autonomic adverse effects including sialorrhea and urinary retention. In exceptional cases withdrawal of medication before planned DBS surgery may result in life-threatening parkinsonism-hyperpyrexia syndrome. Thus discontinuation of levodopa should be an inpatient procedure.Selection of patients who undergo DBS should weigh potential benefits and risks resulting from multidirectional effects of neurostimulation on autonomic nervous system.

A role for the immune system in the pathogenesis of Parkinson's Disease (PD) has previously been suggested. A recent genome-wide association (GWA) study identified an association between one single nucleotide polymorphism (SNP) in the human leucocyte antigen (HLA) region (HLA-DRA rs3129882) and PD in a population of American patients with European ancestry. In that study, the minor rs3129882 allele (G) was associated with an increased risk of PD under an additive model. Due to the increased likelihood of obtaining false positive results in GWA studies compared to studies conducted based on a hypothesis-driven approach, repeated validation of findings from GWA studies are necessary. Herein, we evaluated the association between rs3129882 and PD in three different Caucasian patient-control series (combined 1313 patients and 1305 controls) from the US, Ireland, and Poland. We observed no association (OR: 0.96, P = 0.50) between rs3129882 and PD when analyzing our data under an additive or dominant model. In contrast, when examined under a recessive model, the GG genotype was observed to be protective in the Irish (OR: 0.55, P = 0.008), Polish (OR: 0.67, P = 0.040) and combined (OR: 0.75, P = 0.006) patient-control series. In view of these diverging results, the exact role of genetic variation at the HLA region and susceptibility to PD remains to be resolved.

Parkinson disease (PD) is the most common neurodegenerative movement disorder with age-related prevalence. Approximately 1% of the population is affected at 65 years, which increases to 4%–5% in 85-year-olds.1 To date, several loci containing pathogenic or risk variants have been identified; the most recent, PARK16 , was nominated through 2 genome-wide association studies (GWAS) using samples of Japanese and European ancestry.2,3 This new locus, located in 1q32, was originally identified in the Asian study with p values ranging from 10 −7 to 10 −12 . PARK16 did not reach significance level in the European GWAS or its replication ( p value >10 −4 ); however, combining samples from stage I and II indicated an association. The most significant SNP in the European study (rs823128) showed a 1% difference in minor allele frequency (MAF) between patients with PD (4%) and control subjects (3%), resulting in an odds ratio (OR) of 0.66 ( p value = 7.3 × 10 −8 ) (of note, the allele frequencies seem to have been mistakenly switched in the combined analysis).3 In contrast, the MAF of rs823128 appears to be more common in the Japanese population, with a lower frequency in patients with PD (10%) …

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.We genotyped rs1805874 in four independent Caucasian patient-control series (1543 PD patients, 1771 controls).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).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.

To assess for the presence of gastric dysmotility in familial and sporadic Parkinson disease (PD).10 subjects with familial Parkinson disease (fPD), 35 subjects with sporadic Parkinson disease (sPD), and 15 controls, all from academic tertiary care movement disorders centers, were studied. fPD was defined as the presence of at least 2 affected individuals within 2-3 consecutive generations in a family. Molecular genetic analysis has not revealed, thus far, any known genomic abnormality in these families. Gastric emptying was assessed by dynamic abdominal scintigraphy over 92 min following ingestion of a solid meal containing 99mTc-labeled colloid of 40 MBq activity. The main outcome measures were gastric emptying half-time and radiotracer activity over the gastric area at 46 and at 92 min.Gastric emptying time was delayed in 60% of subjects with PD. In comparison to mean t(1/2) of 38 +/- 7 min in controls, mean t(1/2) was 58 +/- 25 min in fPD (p = 0.02) and 46 +/- 25 min in sPD (p = 0.10). Both fPD and sPD groups included subjects with delayed gastric emptying at an early stage of disease.Patients with fPD showed significantly delayed gastric emptying in comparison to normal age-matched individuals. Further studies of gastrointestinal dysfunction in PD, particularly fPD, are warranted.