Nil Dizdar

Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease

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 Parkinsons Disease Rating Scale score decreased from 53 to 35 in favor of infusion (p < 0.05). QoL was improved, using the two instruments: Parkinsons 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.

Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease

Genome-wide association studies have identified a number of susceptibility loci in sporadic Parkinsons 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.

The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease

A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimers disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinsons disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta‐analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aβ42) and total‐tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10−25). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF‐total‐tau (P = .0110) but not Aβ42 suggesting that TREM2s role in AD may involve tau dysfunction.

Safety and tolerability of growth hormone therapy in multiple system atrophy: A double-blind, placebo-controlled study

The objective of this study was to investigate tolerability and possible neurotrophic effects of growth hormone (GH) in treatment of multiple system atrophy (MSA). In this double‐blind pilot study, MSA patients were randomized to recombinant human growth hormone (r‐hGH, n = 22), 1 mg every second day (6 months) followed by alternating daily injections of 1 mg and 0.5 mg (6 months), or matched placebo (n = 21). Safety analysis demonstrated no obvious between‐group differences. In both groups, there was progressive worsening of Unified Parkinsons Disease Rating Scale total score, which tended to be less in r‐hGH‐treated patients (12.9% at 6 months, 25.3% at 12 months) than in placebo (17.0% and 35.7%). Similarly, there was a trend to less worsening in Unified MSA Rating Scale total score with r‐hGH (13.2% and 21.2%) than with placebo (21.1% and 36.5%). Cardiovascular reflex autonomic testing also tended to show less deterioration with r‐hGH than with placebo at 12 months. However, 95% CI did not indicate treatment differences for any efficacy measures. In conclusion, r‐hGH administration in MSA patients for up to 1 year appears safe and might influence disease symptoms, signs and, possibly, progression. The results support further studies utilizing higher doses in more patients.

Interim analysis of long-term intraduodenal levodopa infusion in advanced Parkinson disease

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.

Comparison of apomorphine and levodopa infusions in four patients with Parkinson’s disease with symptom fluctuations

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.

Fine mapping and resequencing of the PARK16 locus in Parkinson's disease

The PARK16 locus, spanning five genes on chromosome 1, was among the first genetic regions to show genome-wide association in Parkinsons 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.

Stereotactic microdialysis of the basal ganglia in Parkinson's disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an efficacious treatment in patients with advanced Parkinsons 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 Parkinsons 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.

The Ronnie Gardiner Rhythm and Music Method – a feasibility study in Parkinson’s disease

Abstract 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.

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.