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Background and Objectives: Intestinal levodopa/carbidopa gel infusion (LCIG) is superior to oral treatment in advanced Parkinson disease. The primary objective of this trial was to investigate whether continuous subcutaneous or intravenous infusion with a continuously buffered acidic levodopa/carbidopa solution yields steady-state plasma concentrations of levodopa that are equivalent in magnitude, and noninferior in variability, to those obtained with LCIG in patients with advanced Parkinson disease., Methods: A concentrated acidic levodopa/carbidopa (8:1) solution buffered continuously and administered intravenously (DIZ101) or subcutaneously (DIZ102) was compared with an approved LCIG in a randomized, 3-period crossover, open-label, multicenter trial. Formulations were infused for 16 hours to patients with Parkinson disease who were using LCIG as their regular treatment. Patients were recruited from several university neurology clinics but came to the same phase I unit for treatment. Pharmacokinetic variables and safety including dermal tolerance are reported. The primary outcomes were bioequivalence and noninferior variability of DIZ101 and DIZ102 vs LCIG with respect to levodopa plasma concentrations., Results: With dosing adjusted to estimated bioavailability, DIZ101 and DIZ102 produced levodopa plasma levels within standard bioequivalence limits compared with LCIG in the 18 participants who received all treatments. Although the levodopa bioavailability for DIZ102 was complete, it was 80% for LCIG. Therapeutic concentrations of levodopa were reached as quickly with subcutaneous administration of DIZ102 as with LCIG and remained stable throughout the infusions. Owing to poor uptake of LCIG, carbidopa levels in plasma were higher with DIZ101 and DIZ102 than with the former. All individuals receiving any of the treatments (n = 20) were included in the evaluation of safety and tolerability. Reactions at the infusion sites were mild and transient., Discussion: It is feasible to rapidly achieve high and stable levodopa concentrations by means of continuous buffering of a subcutaneously administered acidic levodopa/carbidopa-containing solution., Trial Registration Information: ClinicalTrials.gov identifier: NCT03419806. Registration first posted on February 5, 2018, first patient enrolled on February 16, 2018., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

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.

Persons with Parkinson's disease and their care partners want support from health care to develop the skills to handle everyday life with the long-term condition. Earlier findings indicate that participants of the self-management program Swedish National Parkinson School experience several benefits of the program. The purpose of this qualitative observational study was to explore if participants had implemented the strategies of self-monitoring included in the program and use them to communicate health care status and needs in clinical encounters. Data were collected 3 to 15 months after participation in the program and analyzed using constant comparative analysis. Three categories were evident: "Self-observation in everyday life," "Self-care activities to promote health," and "Managing emotional impact of Parkinson's Disease." Categories were linked together in a core category that highlight the use of self-management strategies described by participants during clinical encounters. Results confirmed that persons with Parkinson's disease and care partners use the techniques of self-observation in their everyday lives. Observations of effects in clinical care can be a valuable approach to evaluate the outcomes educational interventions and their benefits for individuals and health care., (© 2020 The Authors Nursing & Health Sciences Published by John Wiley & Sons Australia, Ltd.)

Background: IRL752 is a novel small-molecule compound that acts to regioselectively enhance norepinephrine, dopamine, and acetylcholine neurotransmission in the cerebral cortex., Objective: The primary objective of the trial was to investigate the safety and tolerability of IRL752 in patients with Parkinson's disease and dementia., Methods: Patients with Parkinson's disease and dementia were randomized to IRL752 or placebo treatment (3:1 ratio) for 28 days. The study drug was given as an adjunct treatment to the patients' regular stable antiparkinsonian medication. Dosing was individually titrated for 14 days after which the dose was kept stable for an additional 14 days., Results: A total of 32 patients were randomized to treatment, and 29 patients completed the 4-week treatment. Adverse events were generally mild and transient and were mostly reported during the dose titration phase. There were 2 serious adverse events, and none of them were related to the experimental treatment. The average dose achieved in the stable dose phase was 600 mg daily, yielding a 2-hour postdose plasma concentration of about 4 μM on day 28. Exploratory assessment of secondary outcomes indicated efficacy for symptoms and signs known to be poorly responsive to levodopa., Conclusions: IRL752 appears to be safe and well tolerated for a 4-week treatment in patients with Parkinson's disease and dementia. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Objective: To evaluate a group-based music intervention in patients with Parkinson's disease., Design: Parallel group randomized controlled trial with qualitative triangulation., Setting: Neurorehabilitation in primary care., Subjects: Forty-six patients with Parkinson's disease were randomized into intervention group ( n  = 26), which received training with the music-based intervention, and control group ( n  = 20) without training., Interventions: The intervention was delivered twice weekly for 12 weeks., Main Measures: Primary outcome was Timed-Up-and-Go subtracting serial 7's (dual-task ability). Secondary outcomes were cognition, balance, concerns about falling, freezing of gait, and quality of life. All outcomes were evaluated at baseline, post-intervention, and three months post-intervention. Focus groups and individual interviews were conducted with the intervention group and with the delivering physiotherapists., Results: No between-group differences were observed for dual-task ability. Between-group differences were observed for Falls Efficacy Scale (mean difference (MD) = 6.5 points; 95% confidence interval (CI) = 3.0 to 10.0, P  = 0.001) and for Parkinson Disease Questionnaire-39 items (MD = 8.3; 95% CI = 2.7 to 13.8, P  = 0.005) when compared to the control group post-intervention, but these were not maintained at three months post-intervention. Three themes were derived from the interviews: Expectations versus Results, Perspectives on Treatment Contents , and Key Factors for Success ., Conclusion: Patient-reported outcomes and interviews suggest that the group-based music intervention adds value to mood, alertness, and quality of life in patients with Parkinson's disease. The study does not support the efficacy in producing immediate or lasting gains in dual-tasking, cognition, balance, or freezing of gait.

Parkinson's disease is the second most common neurodegenerative disease. Lewy bodies with alpha-synuclein as the major component and loss of dopaminergic nerve cells in substantia nigra are neuropathological features. The diagnosis of Parkinson's disease is based on the occurrence of bradykinesia, rigidity and resting tremor. The disease is also associated with several non-motor symptoms. The therapy is mainly based on pharmacological treatment to increase dopamine signaling and neurosurgical deep brain stimulation. The symptoms and signs of the progressive disease change over time, requiring treatment adjustments. Patients should be followed by a physician, nurse and a multidisciplinary team with expertise in Parkinson's disease.

Olfactory dysfunction is an early manifestation of Parkinson's disease (PD). The present study aimed to illustrate potential differences between PD patients and healthy controls in terms of neural activity and functional connectivity within the olfactory brain network. Twenty PD patients and twenty healthy controls were examined with olfactory fMRI and resting-state fMRI. Data analysis of olfactory fMRI included data-driven tensorial independent component (ICA) and task-driven general linear model (GLM) analyses. Data analysis of resting-state fMRI included probabilistic ICA based on temporal concatenation and functional connectivity analysis within the olfactory network. ICA of olfactory fMRI identified an olfactory network consisting of the posterior piriform cortex, insula, right orbitofrontal cortex and thalamus. Recruitment of this network was less significant for PD patients. GLM analysis revealed significantly lower activity in the insula bilaterally and the right orbitofrontal cortex in PD compared to healthy controls but no significant differences in the olfactory cortex itself. Analysis of resting-state fMRI did not reveal any differences in the functional connectivity within the olfactory, default mode, salience or central executive networks between the two groups. In conclusion, olfactory dysfunction in PD is associated with less significant recruitment of the olfactory brain network. ICA could demonstrate differences in both the olfactory cortex and its main projections, compared to GLM that revealed differences only on the latter. Resting-state fMRI did not reveal any significant differences in functional connectivity within the olfactory, default mode, salience and central executive networks in this cohort., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims and Objective: To identify and describe experiences valuable for managing daily life after participation in the NPS self-management intervention. The second part was to explore the applicability of the Self- and family management framework by Grey and colleagues for persons with Parkinson's Disease and their relatives., Background: The impact of PD is evident on the lives of both patients and relatives. The National Parkinson School (NPS) is a Swedish self-management programme designed for patients and relatives, aiming at teaching strategies helpful for the ability of self-management, in order to promote life satisfaction., Design: Qualitative explorative with inductive and deductive analysis., Methods: Five group discussions with NPS participants were audio-recorded. Verbatim transcriptions were analysed inductively with thematic analysis according to Braun and Clarke, and the findings were then applied deductively to the existing model for patients with chronic disease., Results: Through the first step of inductive analysis, three themes capturing the meaning, value and experience of being a participant at the NPS were identified: exchanging experiences and feeling support, adjustment and acceptance of PD for managing daily life and promoting life satisfaction. The deductive analysis applied the inductive findings to the Self- and family management framework of chronically ill to explore the fit to persons with PD and relatives attending the NPS programme., Conclusions: The NPS programme is a promising approach for helping persons with PD and their relatives to achieve better self-management of disease and improved life satisfaction. Further evaluations of programme outcomes in clinical practice are warranted., Relevance of Clinical Practice: Self-management programmes like the NPS is a promising approach in facilitating a positive mindset and outlook on life and gain knowledge to understand, adapt and handle chronic disease, such as PD, better., (© 2018 John Wiley & Sons Ltd.)

Background: In this study we investigated the association between SNPs in the S100B gene and Parkinson's disease (PD) in two independent Swedish cohorts. The SNP rs9722 has previously been shown to be associated with higher S100B concentrations in serum and frontal cortex in humans. S100B is widely expressed in the central nervous system and has many functions such as regulating calcium homeostasis, inflammatory processes, cytoskeleton assembly/disassembly, protein phosphorylation and degradation, and cell proliferation and differentiation. Several of these functions have been suggested to be of importance for the pathophysiology of PD., Methods: The SNPs rs9722, rs2239574, rs881827, rs9984765, and rs1051169 of the S100B gene were genotyped using the KASPar® PCR SNP genotyping system in a case-control study of two populations (431 PD patients and 465 controls, 195 PD patients and 378 controls, respectively). The association between the genotype and allelic distributions and PD risk was evaluated using Chi-Square and Cox proportional hazards test, as well as logistic regression. Linear regression and Cox proportional hazards tests were applied to assess the effect of the rs9722 genotypes on age of disease onset., Results: The S100B SNPs tested were not associated with the risk of PD. However, in both cohorts, the T allele of rs9722 was significantly more common in early onset PD patients compared to late onset PD patients. The SNP rs9722 was significantly related to age of onset, and each T allele lowered disease onset with 4.9 years. In addition, allelic variants of rs881827, rs9984765, and rs1051169, were significantly more common in early-onset PD compared to late-onset PD in the pooled population., Conclusions: rs9722, a functional SNP in the 3'-UTR of the S100B gene, was strongly associated with age of onset of PD.

Background: Olfactory impairment is an early manifestation of Parkinson's disease (PD). Diffusion Tensor Imaging (DTI) and Magnetization Transfer (MT) are two imaging techniques that allow noninvasive detection of microstructural changes in the cerebral white matter., Objective: To assess white matter alterations associated with olfactory impairment in PD, using a binary imaging approach with DTI and MT., Methods: 22 PD patients and 13 healthy controls were examined with DTI, MT and an odor discrimination test. DTI data were first analyzed with tract-based spatial statistics (TBSS) in order to detect differences in fractional anisotropy, mean, radial and axial diffusivity between PD patients and controls. Voxelwise randomized permutation was employed for the MT analysis, after spatial and intensity normalization. Additionally, ROI analysis was performed on both the DTI and MT data, focused on the white matter adjacent to olfactory brain regions., Results: Whole brain voxelwise analysis revealed decreased axial diffusivity in the left uncinate fasciculus and the white matter adjacent to the left olfactory sulcus of PD patients. ROI analysis demonstrated decreased axial diffusivity in the right orbitofrontal cortex, as well as decreased mean diffusivity and axial diffusivity in the white matter of the left entorhinal cortex of PD patients. There were no significant differences regarding fractional anisotropy, radial diffusivity or MT between patients and controls., Conclusions: ROI analysis of DTI could detect microstructural changes in the white matter adjacent to olfactory areas in PD patients, whereas MT imaging could not.

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.

Background: Continuous infusion of levodopa-carbidopa intestinal gel (LCIG) can effectively manage motor and non-motor complications in advanced Parkinson's disease (PD). Healthcare costs, quality of life (QoL), effectiveness, and tolerability were assessed in routine care treatment with LCIG., Methods: The seventy-seven patients enrolled in this prospective, open-label, 3-year study in routine medical care were LCIG-naïve (N = 37), or had previous LCIG treatment for <2 (N = 22), or ≥2 (N = 18) years. Healthcare costs were collected monthly. PD symptoms and QoL were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS), 39-item Parkinson's Disease Questionnaire (PDQ-39), and EuroQoL 5-Dimension Visual Analog Scale (EQ-5D VAS); LCIG dose, safety, and tolerability were monitored., Results: Mean monthly costs per patient (€8226 ± 5952) were similar across cohorts, remained steady during 3-year follow-up, and increased with PD severity and QoL impairment. In LCIG-naïve patients, significant improvements compared to baseline were observed on the UPDRS total score and PDQ-39 summary index score through 18 months (n = 24; UPDRS, p = 0.033; PDQ-39, p = 0.049). Symptom control was maintained during 3-year follow-up in LCIG-experienced cohorts. Small changes in mean daily LCIG dose were observed. Adverse events were common and generally related to the device, procedure, levodopa, or laboratory evaluations., Conclusions: Costs in LCIG-treated patients were stable over 3 years. LCIG treatment led to significant improvements in motor function and QoL over 18 months in LCIG-naïve patients and no worsening was observed in LCIG-experienced patients over 3 years despite natural PD progression over time. The long-term safety was consistent with the established LCIG profile., (Copyright © 2016 AbbVie Inc. Published by Elsevier Ltd.. All rights reserved.)

The aim of the study was to compare the efficacy of olfactory testing and presynaptic dopamine imaging in diagnosing Parkinson's disease (PD) and atypical parkinsonian syndromes (APS); to evaluate if the combination of these two diagnostic tools can improve their diagnostic value. A prospective investigation of 24 PD patients, 16 APS patients and 15 patients with non-parkinsonian syndromes was performed during an 18-month period. Single photon emission computed tomography with the presynaptic radioligand (123)I-FP-CIT (DaTSCAN(®)) and olfactory testing with the Brief 12-item Smell Identification Test (B-SIT) were performed in all patients. DaTSCAN was analysed semi-quantitatively, by calculating two different striatal uptake ratios, and visually according to a predefined ranking scale. B-SIT score was significantly lower for PD patients, but not significantly different between APS and non-parkinsonism. The visual assessment of DaTSCAN had higher sensitivity, specificity and diagnostic accuracy compared to olfactory testing. Most PD patients (75%) had visually predominant dopamine depletion in putamen, while most APS patients (56%) had visually severe dopamine depletion both in putamen and in caudate nucleus. The combination of DaTSCAN and B-SIT led to a higher rate of correctly classified patients. Olfactory testing can distinguish PD from non-parkinsonism, but not PD from APS or APS from non-parkinsonism. DaTSCAN is more efficient than olfactory testing and can be valuable in differentiating PD from APS. However, combining olfactory testing and DaTSCAN imaging has a higher predictive value than these two methods separately.

The PARK16 locus, spanning five genes on chromosome 1, was among the first genetic regions to show genome-wide association in Parkinson's disease (PD). Subsequent investigations have found variability in PARK16 top-hits and association patterns across populations, and the implicated genes and mechanisms are currently unclear. In the present study, we aimed to explore the contribution of PARK16 variability to PD risk in a Scandinavian population. We genotyped 17 single-nucleotide polymorphisms in a case-control sample set of 2570 individuals from Norway and Sweden to fine map the locus. Targeted resequencing of the full coding regions of SLC45A3, NUCKS1, RAB7L1, SLC41A1 and PM20D1 was performed in DNA pools from a subset of 387 patient samples. We find evidence for an association with PD for rs1775143 as well as a haplotype located around the 5' region of RAB7L1, implicating variants which are not in high linkage disequilibrium with the strongest signal from a recent large meta-analysis in Caucasians. We also provide suggestive support for epistasis between RAB7L1 and LRRK2 as previously hypothesized by others. Comparing our results with previous work, allelic heterogeneity at PARK16 appears likely, and further studies are warranted to disentangle the complex patterns of association and pinpoint the functionally relevant variants.

Objective: To verify if (123)I-FP-CIT, DaTSCAN(®) can differentiate early stages of Parkinson's disease (PD) as well as patients with Atypical Parkinsonian syndromes (APS) from manifest Parkinson's disease., Methods: 128 consecutive patients were investigated with (123)I-FP-CIT SPECT during a 4-year period. All patients were diagnosed according to the established consensus criteria for diagnosis of PD (n = 53) and APS (n = 19). Remaining patients were grouped early PD (before onset of L-DOPA medication), (n = 20), vascular PD (n = 6), and non-PD syndromes (n = 30) and SWEDD (n = 1). SPECT images were analyzed visually according to a predefined ranking scale of dopaminergic nerve cell degeneration, distinguishing a posterior-anterior degeneration pattern (egg shape) from a more global and severe degeneration pattern (burst striatum). Striatum uptake ratios were quantitatively analyzed with the 3D software, EXINI., Results: In the group of APS patients, the burst striatum pattern was most frequent and found in 61 % (11/18 patients). In PD patients, the egg shape pattern was dominating, especially in early PD where it was present in 95 % (19/20 patients). The positive predictive value for the egg shape pattern to diagnose PD was 92 % in this material (APS and all PD patients) and the specificity 90 % for the burst striatum pattern to exclude APS. The uptake ratios were reduced in both PD and APS patients and closely related to the image ranking., Conclusion: In this study, we found that in more than half of the patients it was possible to differentiate between PD and APS by visual interpretation only. Similar results were obtained using semi-quantitative uptake ratios. Combining visual assessment with uptake ratios did not add to the discriminating power of DaTSCAN(®) SPECT in this material.

Genome-wide association studies have identified a number of susceptibility loci in sporadic Parkinson's disease (PD). Recent larger studies and meta-analyses have greatly expanded the list of proposed association signals. We performed a case-control replication study in a Scandinavian population, analyzing samples from 1345 unrelated PD patients and 1225 control subjects collected by collaborating centers in Norway and Sweden. Single-nucleotide polymorphisms representing 18 loci previously reported at genome-wide significance levels were genotyped, as well as 4 near-significant, suggestive, loci. We replicated 11 association signals at p < 0.05 (SNCA, STK39, MAPT, GPNMB, CCDC62/HIP1R, SYT11, GAK, STX1B, MCCC1/LAMP3, ACMSD, and FGF20). The more recently nominated susceptibility loci were well represented among our positive findings, including 3 which have not previously been validated in independent studies. Conversely, some of the more well-established loci failed to replicate. While future meta-analyses should corroborate disease associations further on the level of common markers, efforts to pinpoint functional variants and understand the biological implications of each risk locus in PD are also warranted., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To assess the feasibility of the novel intervention, Ronnie Gardiner Rhythm and Music (RGRM™) Method compared to a control group for patients with Parkinson's disease (PD)., Method: Eighteen patients, mean age 68, participating in a disability study within a neurological rehabilitation centre, were randomly allocated to intervention group (n = 12) or control group (n = 6). Feasibility was assessed by comparing effects of the intervention on clinical outcome measures (primary outcome: mobility as assessed by two-dimensional motion analysis, secondary outcomes: mobility, cognition, quality of life, adherence, adverse events and eligibility)., Results: Univariable analyses showed no significant differences between groups following intervention. However, analyses suggested that patients in the intervention group improved more on mobility (p = 0.006), cognition and quality of life than patients in the control group. There were no adverse events and a high level of adherence to therapy was observed., Conclusions: In this disability study, the use of the RGRM™ Method showed promising results in the intervention group and the adherence level was high. Our results suggest that most assessments chosen are eligible to use in a larger randomized controlled study for patients with PD., Implications for Rehabilitation: The RGRM™ Method appeared to be a useful and safe method that showed promising results in both motor and cognitive functions as well as quality of life in patients with moderate PD. The RGRM™ Method can be used by physiotherapists, occupational, speech and music therapists in neurological rehabilitation. Most measurements were feasible except for Timed-Up-and-Go.

Background: This interim 12-month analysis is a part of an open-label, observational, prospective study on health outcomes and cost impact of levodopa/carbidopa intestinal gel (LCIG, Duodopa) in Parkinson disease (PD). The specific aim was to investigate clinical and health-related quality of life (HRQoL) effects in routine care., Methods: Unified PD rating scale (UPDRS) was the primary efficacy measurement. PD QoL questionnaire 39 (PDQ-39) assessed HRQoL. Subjects were assessed at baseline, ≥3 months after surgery, and then every 3 months., Results: Twenty-seven treatment-naïve subjects when started with LCIG showed a decrease in UPDRS score that was statistically significant throughout the year: UPDRS total score (mean ± SD), baseline = 52.1 ± 16.1, N = 27, month 0 (first visit; at least 3 months after permanent LCIG) = 43.1 ± 16.7, N = 27, P = 0.003; month 12 = 42.5 ± 22.6, n = 25, P = 0.017. PDQ-39 results also showed a tendency for improvement: PDQ-39 (mean ± SD), baseline = 33.6 ± 10.8, N = 27, month 0 = 27.1 ± 11.8, N = 27, P = 0.001; 12 months = 28.8 ± 12.8, n = 23, P = 0.126., Conclusions: LCIG provides functional improvement beginning at first visit that is sustained for 12 months., (© 2012 John Wiley & Sons A/S.)

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., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an efficacious treatment in patients with advanced Parkinson's disease, yet the mechanisms of STN DBS are poorly understood. The aims of this study were to develop a useful method for studying neurotransmitter alterations during DBS and for the pharmacokinetics of L-dopa in brain tissue. Ten patients with Parkinson's disease participated, whereof two had no previous L-dopa medication. The electrodes and catheters were placed using MRI-guided stereotaxic targeting. Two microdialysis probes were placed, one in the right internal globus pallidus, and one in a brachial vein. The quadripolar deep brain electrodes were placed in the right STN. Microdialysates from brain tissue and blood were collected in 15-min fractions at baseline and during DBS. After stimulation new baseline fractions were taken and finally three fractions during continuous intravenous infusion of L-dopa. Clinical evaluation showed that both DBS and L-dopa infusion gave good relief of rigidity and tremor in all ten patients. During DBS the L-dopa levels in the brain increased in some of the patients but did not persist during the whole stimulation period. The concentration in brain increased substantially during intravenous L-dopa infusion. A number of catecholamines and their metabolites were analysed with high pressure liquid chromatography (HPLC). With our study we could show that this model is suitable for the monitoring of neurotransmitters and for pharmacokinetic studies in human brain, although we found that the sampling time was too short to follow the possible alterations in brain activity caused by DBS., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Levodopa combined with a dopa-decarboxylase inhibitor, such as carbidopa, shifts the metabolism to the COMT pathway. Adding the peripheral acting COMT inhibitor entacapone provides improvement for patients with PD suffering from motor fluctuations. We studied the effects of the enzyme inhibitors entacapone and carbidopa on the levodopa concentrations in CSF and in blood. Five PD patients with wearing-off underwent lumbar drainage and intravenous microdialysis. Samples were taken 12 h daily for 3 days. Day 1; intravenous levodopa was given, day 2; additional oral entacapone 200 mg tid, day 3; additional oral entacapone 200 mg tid and carbidopa 25 mg bid. Levodopa in CSF and in dialysates was analysed. The AUC for levodopa increased both in blood and CSF when additional entacapone was given alone and in combination with carbidopa. The C(max) of levodopa in both CSF and blood increased significantly. Additional entacapone to levodopa therapy gives an increase of C(max) in CSF and in blood. The increase is more evident when entacapone is combined with carbidopa., ((c) 2010 Movement Disorder Society.)

Background: Motor fluctuations in patients with advanced Parkinson's disease may be successfully treated with subcutaneous apomorphine infusion or intraduodenal levodopa/carbidopa infusion. No comparative trials of these two alternatives were performed., Aims of the Study: We present a subanalysis from a randomized crossover clinical trial where levodopa infusion as monotherapy was compared with any other combination of pharmacotherapy in fluctuating patients. Four patients used apomorphine infusion and oral levodopa in the comparator arm. The results of these four patients are presented in detail., Methods: The duration of the trial was 3 + 3 weeks. Patients were video-recorded half-hourly on two non-consecutive days of both treatment arms. Blinded video ratings were used. Patient self-assessments of motor function and quality-of-life (QoL) parameters were captured using an electronic diary., Results: Ratings in moderate to severe "off" state ranged 0-44% on apomorphine infusion and 0-6% on levodopa infusion. Moderate to severe dyskinesias were not recorded in any of the treatments. QoL was reported to be improved in all patients on duodenal levodopa infusion., Conclusions: Monotherapy with duodenal infusion of levodopa was more efficacious and brought greater QoL than combination therapy with apomorphine infusion in these fluctuating patients.

Objectives: To compare daytime intraduodenal levodopa/carbidopa infusion as monotherapy with individually optimized conventional combination therapies in patients with advanced Parkinson disease (PD) for motor fluctuations and quality of life (QoL)., Methods: Twenty-four patients with motor fluctuations and dyskinesia were studied in a randomized crossover design to compare individualized conventional treatment and intraduodenal infusion of a levodopa/carbidopa gel for 3 + 3 weeks. Video scoring of motor function was assessed by blinded assessors on a global Treatment Response Scale from -3 to 0 to +3 (from severe "off" to "on" to "on" with severe dyskinesia). Patient self-assessment of motor performance and QoL was done using an electronic diary., Results: Median percentage of ratings in a functional "on" interval (-1 to +1) was increased from 81 to 100% by infusion therapy (p < 0.01). This improvement was accompanied by a decrease in "off" state (p < 0.01) and no increase in dyskinesia. Median Unified Parkinson's Disease Rating Scale score decreased from 53 to 35 in favor of infusion (p < 0.05). QoL was improved, using the two instruments: Parkinson's Disease Questionnaire-39 and 15D Quality of Life Instrument (p < 0.01). Adverse events were similar for both treatment strategies., Conclusions: Continuous intraduodenal infusion of the levodopa/carbidopa enteral gel as monotherapy is safe and clinically superior to a number of individually optimized combinations of conventional oral and subcutaneous medications in patients with motor fluctuations. Intraduodenal infusion of levodopa offers an important alternative in treating patients with advanced Parkinson disease.

Hair and plasma from patients on long-term selegiline medication were analyzed to evaluate the relationships between plasma and hair melanin concentrations and the incorporation of the selegiline metabolites methamphetamine and amphetamine in hair, and to evaluate hair analyses for determining compliance in medication. Analyses were performed on both the whole hairs, as well as pigmented and non-pigmented hairs from gray-haired patients. Melanin was quantitated by spectrophotometry, and metabolites were quantitated by gas chromatography-mass spectrometry. Concentrations in pigmented and non-pigmented hairs differed significantly for both methamphetamine (p < 0.01) and amphetamine (p < 0.02), with mean concentration ratios being 3.69 +/- 1.88 and 2.95 +/- 1.16 for methamphetamine and amphetamine, respectively. Segmental analysis indicated that some patients had not been compliant with medication. We concluded that the incorporation of methamphetamine and amphetamine into hair of single individuals shows a preference for pigmented hairs over white hairs and that segmental analysis of hair may be useful when measuring compliance with medication.

Objectives: The pharmacokinetics of free L-dopa in blood and tissue of five parkinsonian patients with malignant melanoma was studied with microdialysis. In one case the effect of L-dopa treatment on 5-S-cysteinyldopa and the melanoma was studied. Gastric emptying and its effects on free L-dopa in blood were also investigated in one of the patients., Methods: Five patients were given 100 mg L-dopa with 25 mg benserazide. Blood and dialysates from the circulation and fatty tissue were collected for analysis. [13C]-Octanoic breath test was used for analyzing gastric half-emptying time., Results: Four of the patients had similar pharmacokinetic patterns for L-dopa and a significant (P < 0.05) increase of serum 5-S-cysteinyldopa occurring 30 min after L-dopa intake. Delayed L-dopa peaks and slow gastric half-emptying time were found in 1 patient. A dose-dependent increase of 5-S-cysteinyldopa occurred but no melanoma metastases were seen during long-term L-dopa therapy., Conclusion: L-dopa therapy increases 5-S-cysteinyldopa levels but does not seem to cause progress of melanomas. Gastric emptying impacts L-dopa pharmacokinetics.

It has earlier been claimed that clinical improvement of patients with Parkinson's disease is obtained by treatment with NADH. This has to be verified by double-blind, clinical studies and measurement of biochemical effects of the treatment. In a double blind study five patients with clinically moderate Parkinson's disease were treated with NADH, 25 mg, given intravenously once a day for four days. Then they were given 25 mg NADH intramuscularly after 2 and 4 weeks. Disability scores were determined before each treatment and two weeks after the final injection. A control group (n = 4) with the same degree of Parkinson's disease obtained sodium chloride with the same schedule. According to the Unified Parkinson's Disease Rating Scale a tendency to clinical improvement was seen after the iv infusions in both treatment and placebo groups. However, the changes were not statistically significant, and no changes occurred during the following weeks. No changes were found neither in the study nor the control group regarding cerebrospinal fluid concentrations of dynorfin, metenkefalin, somatostatin, hydroxy-methoxy-phenylglycol, homovanillic acid and 5-hydroxyindole acetic acid. The results indicate that no great changes are obtained after short-term treatment of parkinsonian patients with NADH, neither clinically nor biochemically.