Continuous subcutaneous (s.c.) apomorphine infusion is an effective therapy for Parkinson’s disease (PD), but a limitation is the formation of troublesome s.c. nodules. Various chemically non-identical apomorphine formulations are available. Anecdotal experiences have suggested that shifting from one of these (Apo-Go PumpFill®; apoGPF) to another (Apomorphine PharmSwed®; apoPS) may influence the occurrence and severity of s.c. nodules. We, therefore, followed 15 people with advanced PD (median PD-duration, 15 years; median “off”-phase Hoehn and Yahr, IV) on apoGPF and with troublesome s.c. nodules who were switched to apoPS. Data were collected at baseline, at the time of switching, and at a median of 1, 2.5, and 7.3 months post-switch. Total nodule numbers (P < 0.001), size (P < 0.001), consistency (P < 0.001), skin changes (P = 0.058), and pain (P ≤ 0.032) improved over the observation period. PD severity and dyskinesias tended to improve and increase, respectively. Apomorphine doses were stable, but levodopa doses increased by 100 mg/day. Patient-reported apomorphine efficacy tended to increase and all participants remained on apoPS throughout the observation period; with the main patient-reported reason being improved nodules. These observations suggest that patients with s.c. nodules caused by apoGPF may benefit from switching to apoPS in terms of s.c. nodule occurrence and severity. Alternatively, observed benefits may have been due to the switch itself. As nodule formation is a limiting factor in apomorphine treatment, a controlled prospective study comparing local tolerance with different formulations is warranted.

Background: Levodopa-carbidopa intestinal gel (LCIG; Duodopa ® ) is used for continuous infusion in advanced Parkinson’s disease. To achieve optimal effect, the LCIG dose is individually titrated, traditionally conducted during hospitalization in Sweden. However, dose adjustment depends on surrounding conditions, physical activity, and emotional stress, which is why titration at home could be beneficial. Telemedicine (TM) using a video communication system offers alternative titration procedures, allowing LCIG initiation at home. Objective: Study objectives were to show the feasibility of TM for LCIG home titration, evaluate resource use, and assess patient, neurologist, and nurse satisfaction. Methods: Four clinics enrolled 15 patients to observe efficiency and feasibility of TM-based monitoring. Results: Patient median (range) age was 67 (52–73) years and time since diagnosis was 10 (7–23) years. Median time between LCIG initiation and end of TM-assisted titration was 2.8 (2.0–13.8) days. Median time required for home titration by neurologists, nurses, and patients was (hours:minutes) 1 : 14 (0 : 29–1 : 52), 5 : 49 (2 : 46–10 : 3), and 8 : 53 (4 : 11–14 : 11), respectively. Neurologists and nurses considered this to be less time than required for hospital titration. TM allowed patients 92% free time from start to end of titration. Technical problems associated with TM contacts were rare, mostly related to digital link, and quickly resolved. Patients, neurologists, and nurses were satisfied using TM. No serious adverse events were reported; there was one device complaint (tube occlusion). Conclusions: In this study, TM-assisted LCIG titration at home was resource-efficient, technically feasible, well-accepted and was deemed satisfactory by patients, neurologists, and nurses.

Nuclear factor erythroid 2-like 2 (NRF2) encodes a transcription factor regulating mechanisms of cellular protection and is activated by oxidative stress. NRF2 has therefore been hypothesized to confer protection against Parkinson’s disease and so far an NRF2 haplotype has been reported to decrease the risk of developing disease and delay disease onset. Also NRF2 adopts a nuclear localization in Parkinson’s disease, which is indicative of increased NRF2 activity. We have investigated the association between NRF2 and Parkinson’s disease in a Swedish case-control material and whether NRF2 expression levels correlate with NRF2 genetic variants, disease, or disease onset. Using pyrosequencing, we genotyped one intronic and three promoter variants in 504 patients and 509 control subjects from Stockholm. Further, we quantified NRF2 mRNA expression in EBV transfected human lymphocytes from patients and controls using quantitative real-time reverse transcription PCR. We found that one of the promoter variants, rs35652124, was associated with age of disease onset (Χ2 = 14.19, p value = 0.0067). NRF2 mRNA expression levels however did not correlate with the rs35652124 genotype, Parkinson’s disease, or age of onset in our material. More detailed studies on NRF2 are needed in order to elucidate how this gene affects pathophysiology of Parkinson’s disease.

Several genetic studies have demonstrated an association between mutations in glucocerebrosidase (GBA), originally implicated in Gaucher's disease, and an increased risk of Parkinson's disease (PD). We have investigated the possible involvement of genetic GBA variations in PD in the Swedish population. Three GBA variants, E326K, N370S, and L444P were screened in the largest Swedish Parkinson cohort reported to date; 1625 cases and 2025 control individuals. We found a significant association with high effect size of the rare variant L444P with PD (odds ratio 8.17; 95% confidence interval: 2.51-26.23; p-value = 0.0020) and a significant association of the common variant E326K (odds ratio 1.60; 95% confidence interval: 1.16-2.22; p-value = 0.026). The rare variant N370S showed a trend for association. Most L444P carriers (68%) were found to reside in northern Sweden, which is consistent with a higher prevalence of Gaucher's disease in this part of the country. Our findings support the role of GBA mutations as risk factors for PD and point to lysosomal dysfunction as a mechanism contributing to PD etiology. (C) 2016 The Author(s). Published by Elsevier Inc.

Purpose: Telemedicine can be used to find more cost and time efficient solutions, for both caregivers and patients. In an attempt to turn inpatient care to outpatient care, we have explored and evaluated a telemedicine solution where the patient can be at home during treatment periods. We have also introduced video visits, in outpatient care, as a complement to physical meetings. Both initiatives is expected to lead to considerable benefits for both the patient and Karolinska University Hospital (Karolinska).Context: Traditionally, patients with Parkinson’s disease have been hospitalized during the titration period of a new drug. Using telemedicine, these patients can stay at home. The patient meets with the neurologist and a nurse continuously during the titration period, using dedicated HD-video conferencing equipment at the hospital, with the nurse and at the patient’s home. A medical tube is placed through the nose of the patient to adjust the medication. The neurologist continuously assesses the impact of the drug through video meetings. Once it is proven that the treatment has the sought effect the medical tube is surgically placed.In addition, patients in ordinary outpatient care are offered video visits by the neurology nurses for continuous check-ups. This requires that the patient has a computer with a camera or a mobile device, and enough bandwidth at his/her location. Client based video conferencing tools are used for the video visits.Methods: A proof-of-concept (PoC) was conducted in 2012 with three patients being titrated at home [1]. To verify the results from the PoC, a national study with four hospitals were conducted in 2015. The level of quality needed for the video conferencing equipment were tested with neurologists. Patients and staff were interviewed after the PoC and responded to a questionnaire after the national study. To enable video visits, we used a combination of systems already available at Karolinska, a computer based and a web based video client. A pilot was conducted in the Fall 2015. Patients and staff responded to a questionnaire after the video visits.Results and discussion: Both home titration and video visits are implemented at Karolinska. Two neurologists use home titration when their patients need the specific drug as part of advanced treatment. Nurses at the outpatient clinic within the neurology department have recently started to offer patients video visits instead of physical meetings. Video visits have also been implemented at other patient flows at Karolinska, e.g, speech therapy, obesity treatment, diabetes, heart failure.The home titration solution was proven to be efficient. Although expensive equipment is needed, the PoC showed a return of investment after four patients per year. The experience has been positive for the patients that could stay at home in a familiar environment and continue to work. The PoC showed that the total time per day the neurologist spends with the patient is about the same as in traditional care, but the number of days of treatment is shorter with home titration. Also, the nurse can spend time with the patient in a more flexible way than with the hospitalized patients.Video visits were considered to be of more benefit to the patient than to Karolinska. However, we have seen new ways of meeting with and treating the patients, and indications of fewer missed meetings. The technology used can be improved, e.g., with additional functionality such as feedback on waiting time and removing unnecessary functionality that may lead to unnecessary information noise for the users. [1] Willows, T., Groth, K., Björkehag, J., Andersson, M., Larsson, J. & Permert, J. (2015) Moving health care to the patients home: An innovative approach to introduce levodopa-carbidopa intestinal gel (LCIG) treatment. Abstract at The MDS 19th Int. Congress of Parkinson’s Disease and Movement Disorders.

The aim of this study was to investigate if a telemetry test battery can be used to measure effects of Parkinson's disease (PD) treatment intervention and disease progression in patients with fluctuations. Sixty-five patients diagnosed with advanced PD were recruited in an open longitudinal 36-month study; 35 treated with levodopa-carbidopa intestinal gel (LCIG) and 30 were candidates for switching from oral PD treatment to LCIG. They utilized a test battery, consisting of self-assessments of symptoms and fine motor tests (tapping and spiral drawings), four times per day in their homes during week-long test periods. The repeated measurements were summarized into an overall test score (OTS) to represent the global condition of the patient during a test period. Clinical assessments included ratings on unified PD rating scale (UPDRS) and 39-item PD questionnaire (PDQ-39) scales. In LCIG-naïve patients, the mean OTS compared to baseline was significantly improved from the first test period on LCIG treatment until month 24. In LCIG-nonnaïve patients, there were no significant changes in the mean OTS until month 36. The OTS correlated adequately with total UPDRS (rho = 0.59) and total PDQ-39 (0.59). Responsiveness measured as effect size was 0.696 and 0.536 for OTS and UPDRS, respectively. The trends of the test scores were similar to the trends of clinical rating scores but the dropout rate was high. Correlations between OTS and clinical rating scales were adequate indicating that the test battery contains important elements of the information of well-established scales. The responsiveness and reproducibility were better for OTS than for total UPDRS.

Objective: The aim of this study was to investigate if a telemetry test battery can be used to measure effects of Parkinson’s disease (PD) treatment intervention and disease progression.Methods: Si ...

Objective: To determine if a home environment test battery can be used to measure effects of Parkinson’s disease (PD) treatment intervention and disease progression.Background: Sixty-five patients ...

There is an increasing evidence for genetic contribution to Parkinson's disease (PD). Genes responsible for monogenetic hereditary PD have been discovered to carry less devastating mutations associated with “idiopathic” PD, suggesting that common molecular pathways are involved in the pathogenesis of monogenetic and “idiopathic” PD. Recently, genome wide association studies (GWAS) have revealed new PARK loci, potentially harboring genes conferring an increased or decreased risk of developing PD. We have studied PARK18, for which HLA-DRA, a class II human leukocyte antigen, was proposed as a candidate gene. Hamza et al. [[1]Hamza T.H. Zabetian C.P. Tenesa A. Laederach A. Montimurro J. Yearout D. et al.Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease.Nat Genet. 2010; 42: 781-785Crossref PubMed Scopus (601) Google Scholar] reported that the G allele of the single nucleotide polymorphism (SNP) rs3129882 (A/G) in HLA-DRA, associates with increased risk for PD in an American cohort. Attempts to replicate the association have shown conflicting results [2Chiang H.L. Lee-Chen G.J. Chen C.M. Chen Y.C. Lee C.M. Liao M.H. et al.Genetic analysis of HLADRA region variation in Taiwanese Parkinson's disease.Parkinsonism Relat Disord. 2012; 18: 391-393Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 3Puschmann A. Verbeeck C. Heckman M.G. Soto-Ortolaza A.I. Lynch T. Jasinska-Myga B. et al.Human leukocyte antigen variation and Parkinson's disease.Parkinsonism Relat Disord. 2011; 17: 376-378Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 4Mata I.F. Yearout D. Alvarez V. Coto E. de M.L. Ribacoba R. et al.Replication of MAPT and SNCA, but not PARK16-18, as susceptibility genes for Parkinson's disease.Mov Disord. 2011; 26: 819-823Crossref PubMed Scopus (66) Google Scholar, 5Pihlstrøm L, Axelsson G, Bjørnarå KA, Dizdar N, Fardell C, Forsgren L, et al. Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease. Neurobiol Aging, published online 12 Nov 2012, http://dx.doi.org/10.1016/j.neurobiolaging.2012.10.019.Google Scholar]; not only were there lack of associations in several cohorts [2Chiang H.L. Lee-Chen G.J. Chen C.M. Chen Y.C. Lee C.M. Liao M.H. et al.Genetic analysis of HLADRA region variation in Taiwanese Parkinson's disease.Parkinsonism Relat Disord. 2012; 18: 391-393Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 3Puschmann A. Verbeeck C. Heckman M.G. Soto-Ortolaza A.I. Lynch T. Jasinska-Myga B. et al.Human leukocyte antigen variation and Parkinson's disease.Parkinsonism Relat Disord. 2011; 17: 376-378Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 4Mata I.F. Yearout D. Alvarez V. Coto E. de M.L. Ribacoba R. et al.Replication of MAPT and SNCA, but not PARK16-18, as susceptibility genes for Parkinson's disease.Mov Disord. 2011; 26: 819-823Crossref PubMed Scopus (66) Google Scholar, 4Mata I.F. Yearout D. Alvarez V. Coto E. de M.L. Ribacoba R. et al.Replication of MAPT and SNCA, but not PARK16-18, as susceptibility genes for Parkinson's disease.Mov Disord. 2011; 26: 819-823Crossref PubMed Scopus (66) Google Scholar], but the GG genotype has also been found to be protective [[3]Puschmann A. Verbeeck C. Heckman M.G. Soto-Ortolaza A.I. Lynch T. Jasinska-Myga B. et al.Human leukocyte antigen variation and Parkinson's disease.Parkinsonism Relat Disord. 2011; 17: 376-378Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]. Variable findings in different studies point to the presence of geographical and ethnical differences and hence the importance of validating GWAS findings in independent homogenous case–control materials. We have performed a replication study on the HLA-DRA SNP rs3129882 in a homogenous Swedish case–control material in order to further investigate the possible contribution of rs3129882 to PD. Blood samples were collected at the Karolinska and Linköping University Hospitals after informed consent and approval of the Regional Ethical Review Board. DNA was obtained from samples using standard protocols. We genotyped rs3129882 in 511 PD patients and 636 neurologically healthy controls (Table 1). A subset of the patients (172) and controls (279) from Linköping was previously genotyped for rs3129882 in another study [[5]Pihlstrøm L, Axelsson G, Bjørnarå KA, Dizdar N, Fardell C, Forsgren L, et al. Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease. Neurobiol Aging, published online 12 Nov 2012, http://dx.doi.org/10.1016/j.neurobiolaging.2012.10.019.Google Scholar]. Control individuals were neurologically healthy spouses of patients (4%), individuals visiting hospitals for non-neurological disorders (54%) and from the SNAC-K project (The Swedish National Study on Aging and Care in Kungsholmen http://www.snac-k.se/) (42%). All samples are unrelated Caucasians from urban areas from the rather small population of Sweden, likely to represent a homogenous case–control material. Genotyping was performed by real-time polymerase chain reaction (PCR) (7500 fast system using standard cycling conditions, TaqMan® genotyping master mix and Genotyping Assay C_2455644_10, Applied Biosystems/Life Technologies, Carlsbad, California, USA). Due to a non-negligible level of heterogeneity in the read-out in a subset of the Linköping samples with lower DNA concentration, these samples were re-sequenced with the pyrosequencing technique to confirm genotyping results. A PCR was run with Taq polymerase enzyme and two primers, one of which was biotinylated at the 5′ end (Thermo Fisher Scientific, Ulm, Germany), (sequences are available upon request). The PCR product was purified according to manufacturer's instructions, incubated with a sequencing primer and analyzed by PYRO-sequencing (PSQ 96MA system, BIOTAGE AB Uppsala, Sweden) using PyroMark Gold Q96 Reagents (QIAGEN AB, Solna, Sweden). Three PD patients were excluded from the analysis since they were carriers of the pathogenic G2019S mutation LRRK2. Association was evaluated with Chi-square (χ2) and Fisher's exact test, significance level 5%, two-sided P-values (GraphPad Prism 5.03, GraphPad Software, San Diego California USA). Power and sample size software PS 3.0 was used for power analysis (http://biostat.mc.vanderbilt.edu/wiki/Main/PowerSampleSize). With our sample size we can detect an odds ratio of <0.712 and >1.390 with a power of 80% (α = 0.05).Table 1Demographic information.Parkinson's diseaseControlTotal no.511636Age (years)68.572.5Age of onset (years)61.0NaFemale no. (%)194 (38.0)354 (55.7)Early onset no. (%)92 (18.0)NaHeredity no. (%)39 (7.6)NaNa = not applicable, early onset = 50 years or less at diagnosis. Open table in a new tab Na = not applicable, early onset = 50 years or less at diagnosis. We genotyped a total of 511 PD patients and 636 neurologically healthy controls from Sweden and searched for possible genotypic and allelic association between rs3129882 and PD. Rs3129882 was in Hardy Weinberg equilibrium for all subjects (data not shown). We first analyzed the entire material for which we found no genotypic (data not shown) or allelic association for rs3129882 and PD (Table 2). In order to investigate variability in subgroups of patients, we stratified the material with respect to age of onset, sex and self-reported family history. Female and male patients were compared to the whole control group since genotype and allele frequencies were similar in the control groups (P > 0.5). Patients with maximum one first-, second- or third-degree relative were included in the group designated as having no known heredity, while familial PD was defined as patients with two or more relatives with PD. Applying these stringent selection criteria corresponding to those used in the report by Hamza et al. [[1]Hamza T.H. Zabetian C.P. Tenesa A. Laederach A. Montimurro J. Yearout D. et al.Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease.Nat Genet. 2010; 42: 781-785Crossref PubMed Scopus (601) Google Scholar], we discovered no further association for rs3129882 with PD (Table 2).Table 2Allele frequencies for rs3129882 in Parkinson's disease patients and control subjects analyzed with Fisher's exact test.PD (no.)Ctrl (no.)MAF PDMAF CtrlP-valueOR (95%CI)StrataStockholm3142060.4250.4220.911.02 (0.81–1.27)Linköping1943300.3810.3980.60.93 (0.72–1.2)All subjects5086360.4080.4100.991.00 (0.85–1.19)PD-associated strataNo heredity4690.4030.791.03 (0.87–1.22)Familial390.4740.280.77 (0.49–1.22)Late onset4140.4020.771.03 (0.86–1.23)Early onset910.4340.570.90 (0.66–1.24)Female1930.4020.811.03 (0.82–1.30)Male3150.4130.920.99 (0.81–1.20)PD = Parkinson's disease, Ctrl = controls, MAF = minor allele frequency, OR = odds ratio, CI = confidence interval. Open table in a new tab PD = Parkinson's disease, Ctrl = controls, MAF = minor allele frequency, OR = odds ratio, CI = confidence interval. Previous replication studies on HLA-DRA show very heterogeneous results [1Hamza T.H. Zabetian C.P. Tenesa A. Laederach A. Montimurro J. Yearout D. et al.Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease.Nat Genet. 2010; 42: 781-785Crossref PubMed Scopus (601) Google Scholar, 2Chiang H.L. Lee-Chen G.J. Chen C.M. Chen Y.C. Lee C.M. Liao M.H. et al.Genetic analysis of HLADRA region variation in Taiwanese Parkinson's disease.Parkinsonism Relat Disord. 2012; 18: 391-393Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 3Puschmann A. Verbeeck C. Heckman M.G. Soto-Ortolaza A.I. Lynch T. Jasinska-Myga B. et al.Human leukocyte antigen variation and Parkinson's disease.Parkinsonism Relat Disord. 2011; 17: 376-378Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 4Mata I.F. Yearout D. Alvarez V. Coto E. de M.L. Ribacoba R. et al.Replication of MAPT and SNCA, but not PARK16-18, as susceptibility genes for Parkinson's disease.Mov Disord. 2011; 26: 819-823Crossref PubMed Scopus (66) Google Scholar, 5Pihlstrøm L, Axelsson G, Bjørnarå KA, Dizdar N, Fardell C, Forsgren L, et al. Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease. Neurobiol Aging, published online 12 Nov 2012, http://dx.doi.org/10.1016/j.neurobiolaging.2012.10.019.Google Scholar]. These variations might be explained by ancestry; allele frequencies for rs3129882 vary greatly in different geographical regions. Hamza et al. [[1]Hamza T.H. Zabetian C.P. Tenesa A. Laederach A. Montimurro J. Yearout D. et al.Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease.Nat Genet. 2010; 42: 781-785Crossref PubMed Scopus (601) Google Scholar] reported a significant substructure in American subjects of European decent correlating with the country of origin of the subjects' ancestors. Association was stronger in subjects with ancestors from Northern Europe. However, no replication has yet been reported in European cohorts. We found no association in our exclusively Swedish material which is in agreement with recent findings in a Scandinavian (Sweden, Norway) population [[5]Pihlstrøm L, Axelsson G, Bjørnarå KA, Dizdar N, Fardell C, Forsgren L, et al. Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease. Neurobiol Aging, published online 12 Nov 2012, http://dx.doi.org/10.1016/j.neurobiolaging.2012.10.019.Google Scholar]. According to Hamza et al. [[1]Hamza T.H. Zabetian C.P. Tenesa A. Laederach A. Montimurro J. Yearout D. et al.Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease.Nat Genet. 2010; 42: 781-785Crossref PubMed Scopus (601) Google Scholar], association was stronger in sporadic PD patients with late onset. To mimic their study we performed an age of onset stratified analysis, but failed to detect any further significant differences. Therefore, our results do not suggest a role for HLA-DRA variants for PD in Sweden. Variable results in genetic replication studies can also be explained by different Linkage Disequilibrium (LD). Association can be found with an SNP which is in LD with the true disease causing SNP, while in another population these two SNPs are not in LD. HLA genes, being closely located on chromosome 6, could exert a joint effect. Rs3129882 is for example believed to influence expression levels of HLA-DRA, HLA-DQA2 and HLA-DRB5 [[1]Hamza T.H. Zabetian C.P. Tenesa A. Laederach A. Montimurro J. Yearout D. et al.Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease.Nat Genet. 2010; 42: 781-785Crossref PubMed Scopus (601) Google Scholar]. Published data on HLA-DR associations with PD are so far more in favor of association with HLA-DRB loci, which are also more polymorphic, than with the rather invariable HLA-DRA. We thank Professor Laura Fratiglioni for providing SNAC-K control samples and Dr. Fengqing Xiang for technical assistance. This study was supported by the Swedish Research Council, The Swedish Parkinson Foundation, The Swedish Brain Foundation, Swedish Brain Power, the Åke Wiberg Foundation, the Karolinska Institute Distinguished Professor Award, StratNeuro and Karolinska Institutet Funds.

Pesticide exposure has been suggested to increase the risk to develop Parkinson's disease (PD). The arylesterase paraoxonase 1 (PON1) is mainly expressed in the liver and hydrolyzes organophosphates such as pesticides. The polymorphism Leu54Met (rs854560) in PON1, impairing enzyme activity and leading to decreased PON1 expression levels, has been reported to be associated with Parkinson's disease (PD). PON1 is part of a cluster on chromosome 7q21.3 together with PON2 and PON3. We investigated the occurrence of four additional polymorphisms in PON1 and two in PON2 in a Swedish PD case-control material. We found a significant association (p = 0.007) with a PON1 promoter polymorphism, rs854571. The minor allele was more common among controls than PD cases which suggest a protective effect. This is strengthened by the fact that rs854571 is in strong linkage disequilibrium with another PON1 promoter polymorphism, rs854572, reported to increase PON1 gene expression. Our findings support the hypothesis that PON1 is involved in the etiology of PD and that higher PON1 levels are reducing the risk for PD. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

MIRO1 and MIRO2 (mitochondrial Ras homolog gene family, member T1 and T2) also referred to as RHOT1 and RHOT2, belong to the mitochondrial Rho GTPase family and are involved in axonal transport of mitochondria in neurons. Because mitochondrial dysfunction is strongly implicated in Parkinson's disease (PD), MIRO1 and MIRO2 can be considered as new candidate genes for PD. We analyzed two non-synonymous polymorphisms and one synonymous polymorphism in MIRO1 and two non-synonymous polymorphisms in MIRO2, in a Swedish Parkinson case-control material consisting of 241 patients and 307 neurologically healthy controls. None of the analyzed polymorphisms in MIRO1 and MIRO2 were significantly associated with PD. Although we did not find a significant association with PD in our Swedish case-control material, we cannot exclude these Rho GTPases as candidate genes for PD or other neurodegenerative disorders.

Background: Human cytomegalovirus (CMV) is an ubiquitous pathogen capable of modulating the host immune system. Immune dysfunction is common during CMV infection and includes autoimmune phenomena. Here we focus on a case of primary CMV infection associated with encephalopathy in a patient with a rudimentary spleen. We discuss diagnostic challenges and immunological aspects as well as the hypothesis that CMV may break tolerance and induce potentially encephalitogenic autoantibodies.Case presentation: A 33-year-old woman was admitted with features of encephalitis, rapidly progressing into a catatonic state. The patient tested negative for presence of herpes simplex virus DNA in cerebrospinal fluid (CSF), and had elevated liver enzymes and hepatomegaly at computed tomography scan (CT) examination. CT scan and magnetic resonance imaging (MRI) showed only a rudimentary spleen. Initially, serum was negative for anti-CMV IgM, but borderline for anti-CMV IgG by enzyme-linked immunosorbent assay. However, a more sensitive assay resulted in a positive specific IgM Western blot profile and low IgG avidity, suggesting primary CMV infection. Further, CMV DNA was retrospectively detected in a CSF sample collected at admission. We also detected antineuronal autoantibodies, which stained GAD-positive neurons in the hippocampus. The patient was treated by a combination of prednisone, intravenous immunoglobulins (IVIg) and antivirals, which resulted in a dramatic amelioration of the patient's neurological status. One year after admission the patient exhibited a nearly complete recovery with mild deficits in attention and memory.Conclusions: A possible reason for the critical course of CMV infection could be the lack of a functional spleen in this patient, a condition previously associated with severe CMV infection. Prompt treatment with antiviral drugs, steroids and IVIg was most likely important for the positive outcome in this case and should be considered for similar cases of severe primary CMV infection associated with immunopathological phenomena.

Mutations in the PARK7 gene, DJ-1, have been reported to cause early-onset and familial Parkinson's disease (PD). The function of DJ-1 and how it contributes to the development of the disease is not clear today, but several studies report that DJ-1 is responsive to oxidative stress and important for the maintenance of mitochondria. We have screened three coding regions of DJ-1 (exon 2, 5 and 7) in a Swedish Parkinson cohort. The Swedish PD material consisted of 67 patients with a self reported positive family history of PD and 77 patients with early-onset of disease (≤50 years old). We detected two patients with the previously reported synonymous mutation, Ala167Ala (c.501A>G, rs71653621), in exon 7. No Ala167Ala carriers were identified among 213 neurologically healthy Swedish controls. Mechanisms by which the synonymous Ala167Ala mutation can have consequences are unknown. It may affect the mRNA stability, secondary structure of mRNA, synthesis, turnover, protein folding and function. We could show a 1.3% decrease in DJ-1 mRNA folding energy in the A<G substituted sequence compared to the wild type sequence in silico, suggesting a possible small effect of Ala167Ala on DJ-1 gene function. This is the first report on an identified DJ-1 mutation in Swedish PD patients. Our results, in combination with those of previous studies, strengthen the hypothesis that alterations in DJ-1 are not a common cause of familial and early-onset PD world-wide.

The protein kinase AKT1 belongs to the Akt family and is a potent mediator of cell growth and survival and fully activated when phosphorylated. The Ala family has been found to be phosphorylated to a lesser extent in the dopaminergic cells of Parkinson's disease patients compared to control individuals, which might influence cell survival. Several publications support the implication of AKT1 in disorders of the dopaminergic system including bipolar disease and schizophrenia. In 2008 an association study performed in a Greek Parkinson's disease case-control material reported the identification of a protective AKT1 haplotype. Based on their work we have performed a replication study in a Swedish Parkinson's disease cohort. We genotyped the four single nucleotide polymorphims (SNPs): rs2494743, rs2498788, rs2494746 and rs1130214 in a case-control material consisting of 243 Parkinson patients and 315 controls. We did not find any associations with Parkinson's disease for either the individual SNPs or any of the haplotypes. In contrast to previously published results, our data do not support the hypothesis of genetic variants in AKT1 confering protection against Parkinson's disease. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DNA polymerase gamma (POLG1) is coding for the catalytic subunit of the heterotrimeric mitochondrial DNA polymerase and involved in replication and repair of mitochondrial DNA. In addition to its 5' to 3' polymerase activity, POLG1 has a 3' to 5' exonuclease activity important in the repair process. Mitochondrial dysfunction has been implicated in neurodegenerative disorders like Parkinson's disease (PD). Dopamine neurons, which degenerate in PD, are believed to be particularly susceptible to mitochondrial dysfunction, which makes POLG1 a possible candidate gene for the disease. POLG1 has a polyglutamine tract (poly-Q) in the N-terminal, encoded by a CAG sequence in exon 2. Most commonly the poly-Q tract comprises 10 repeats (10Q, frequency >80%) or moderately common 11Q (frequency 6-12%); however the composition of poly-Q alleles has been reported to vary from 6Q to 14Q. We analyzed this POLG1 trinucleotide repeat in a Swedish PD case-control material and detected variations from 5Q to 15Q. We report a significant association between the non-10/11Q repeats with PD (p=0.002). In silico analysis of poly-Q length effect on mRNA folding energy show a decrease in energy for <10/11Q mRNA (4.6%) and an increase for >10/11Q mRNA (4.8%) compared to 10/11Q mRNA. Our results strengthen the evidence for involvement of POLG1 and mitochondrial dysfunction in PD.