Thomas Willows

Strong association between glucocerebrosidase mutations and Parkinson's disease in Sweden

Several genetic studies have demonstrated an association between mutations in glucocerebrosidase (GBA), originally implicated in Gauchers disease, and an increased risk of Parkinsons 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 Gauchers 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.

Association of a protective paraoxonase 1 (PON1) polymorphism in Parkinson's disease

Pesticide exposure has been suggested to increase the risk to develop Parkinsons 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 Parkinsons 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.

Validity and Responsiveness of At-Home Touch Screen Assessments in Advanced Parkinson's Disease

The aim of this study was to investigate if a telemetry test battery can be used to measure effects of Parkinsons 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.

CMV-associated encephalitis and antineuronal autoantibodies - a case report

BackgroundHuman 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 presentationA 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.ConclusionsA 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.

Genetic studies of the protein kinase AKT1 in Parkinson's disease.

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 AKT family has been found to be phosphorylated to a lesser extent in the dopaminergic cells of Parkinsons 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 Parkinsons 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 Parkinsons 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 Parkinsons 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 Parkinsons disease.

The HLA-DRA variation rs3129882 is not associated with Parkinson's disease in Sweden

Caroline Ran, Thomas Willows, Olof Sydow, Anders Johansson, Peter Soderkvist, Nil Dizdar, Ahmad Ahmadi, Lars Olson and Carmine Belin, The HLA-DRA variation rs3129882 is not associated with Parkinsons disease in Sweden, 2013, Parkinsonism & Related Disorders, (19), 7, 701-702. http://dx.doi.org/10.1016/j.parkreldis.2013.03.001 Copyright: Elsevier. Under a Creative Commons license http://www.elsevier.com/

Initiation of Levodopa-Carbidopa Intestinal Gel Infusion Using Telemedicine (Video Communication System) Facilitates Efficient and Well-Accepted Home Titration in Patients with Advanced Parkinson’s Disease

BACKGROUND Levodopa-carbidopa intestinal gel (LCIG; Duodopa®) is used for continuous infusion in advanced Parkinsons 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.

DJ-1 Mutations are Rare in a Swedish Parkinson Cohort

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.

Self-reported symptoms and motor tests via telemetry in a 36-month levodopa-carbidopa intestinal gel infusion trial

Objective:To define and evaluate a Computer-Vision (CV) method for scoring Paced Finger-Tapping (PFT) in Parkinsons disease (PD) using quantitative motion analysis of index-fingers and to compare the obtained scores to the UPDRS (Unified Parkinsons Disease Rating Scale) finger-taps (FT).Background:The naked-eye evaluation of PFT in clinical practice results in coarse resolution to determine PD status. Besides, sensor mechanisms for PFT evaluation may cause patients discomfort. In order to avoid cost and effort of applying wearable sensors, a CV system for non-invasive PFT evaluation is introduced.Methods:A database of 221 PFT videos from 6 PD patients was processed. The subjects were instructed to position their hands above their shoulders besides the face and tap the index-finger against the thumb consistently with speed. They were facing towards a pivoted camera during recording. The videos were rated by two clinicians between symptom levels 0-to-3 using UPDRS-FT.The CV method incorporates a motion analyzer and a face detector. The method detects the face of testee in each video-frame. The frame is split into two images from face-rectangle center. Two regions of interest are located in each image to detect index-finger motion of left and right hands respectively. The tracking of opening and closing phases of dominant hand index-finger produces a tapping time-series. This time-series is normalized by the face height. The normalization calibrates the amplitude in tapping signal which is affected by the varying distance between camera and subject (farther the camera, lesser the amplitude). A total of 15 features were classified using K-nearest neighbor (KNN) classifier to characterize the symptoms levels in UPDRS-FT. The target ratings provided by the raters were averaged.Results:A 10-fold cross validation in KNN classified 221 videos between 3 symptom levels with 75% accuracy. An area under the receiver operating characteristic curves of 82.6% supports feasibility of the obtained features to replicate clinical assessments.Conclusions:The system is able to track index-finger motion to estimate tapping symptoms in PD. It has certain advantages compared to other technologies (e.g. magnetic sensors, accelerometers etc.) for PFT evaluation to improve and automate the ratingsObjective: To compare the efficacy of botulinum toxin type A (BTX-A) treatment for patients with primary versus secondary blepharospasm (BS) associated with Parkinson’s disease (PD), with or without deep brain stimulation (DBS). Background: BS, a focal eyelid dystonia, can be idiopathic (primary) or secondary to other disorders such as PD. Furthermore eyelid-opening disorders are common in patients with PD undergoing deep brain stimulation (DBS). BTX-A is the treatment of choice for these conditions. Methods: 27 patients [15 males, age: 65.11 6 13.66 years, disease duration 7.7 6 8.2], newly or routinely treated with BTX-A were recruited including patients with primary BS (N 5 10), secondary BS associated with PD (N 5 6), PD1DBS (N 5 5), and other various types of BS (N 5 6). Patients were evaluated before and 4 weeks following BTX-A injections, using the Blepharospam Disability Scale (BDS), the Blepharospasm Disability Index (BDI), the Jankovic Rating Scale (JRS), the Blepharospasm Movement Scale (BMS), and the Clinical Global Impression of improvement (CGI-I). Additionally all were recorded on a 5-minute videotape and scored by a blinded rater. Results: Following BTX-A injections, our sample as a whole showed a statistically significant improvement in Severity of Illness (2.34 6 1.05 vs. 1.74 6 1.27, p 5 0.013), JRS severity scale (1.96 6 1.22 vs. 1.37 6 1.04, p 5 0.002), BMS severity scale (5.04 6 1.79 vs. 4 6 2.35, p 5 0.04), and the severity rating scale (1.61 6 0.8 vs. 1.19 6 0.84, p 5 0.013). When efficacy was compared by diagnosis group, the best effect was evident in patients with BS secondary to PD and was maximal for the PD patients without DBS who demonstrated significant improvement in Severity of Illness compared to the other two groups. Conclusions: In this study BTX-A was an effective treatment for BS. Patients with PD associated BS showed a better response than those with primary BS.Objective: To develop fMRI-based tools in tremor diagnostics and to demonstrate their clinical applicability. Background: Due to overlapping features of tremor disorders, clinical diagnostic tools are limited. Although seldomly used in diagnostic assessment of tremor, fMRI of pathological brain networks underlying tremor could aid accurate and early diagnosis. fMRI of the closed loop behaviour of the sensorimotor system may manifest itself differently with different tremor disorders and has not been fully explored yet in diagnostics. Methods: Following a literature review that we performed on neuroimaging studies in essential tremor (ET), we developed a novel fMRI setup to investigate pathological brain networks related to tremor. An MR-compatible wrist manipulator, to perturb the sensorimotor loop, is combined with movement measures. Results: Our review showed that current findings are consistent with the hypothesis that the cerebellothalamo-cortical network is involved in ET with a major role for the cerebellum. To date, imaging techniques roughly are divided into structural (n=11) and functional methods (n=24). Limitations include heterogeneity of ET symptoms, spatial resolution and inability to directly relate tremor to functional images. The typical nature of a sensorimotor loop is generally not taken into account. We have developed a high-end novel experimental setup within the MR-environment including artifact-free movement measures (EMG, accelerometry) and a MR-compatible wrist manipulator to apply perturbations. Perturbations applied close to pathological tremor frequencies provide sensory input in passive conditions and manipulate motor action in active conditions. Conclusions: We introduce a multimodal fMRI set-up manipulating the sensorimotor loop to identify faulty brain circuitries. This system can potentially lead to a novel quantitative diagnostic tool for differentiating tremor and other movement disorders.

Genetic Screening of the Mitochondrial Rho GTPases MIRO1 and MIRO2 in Parkinson's Disease.

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.