Swedish guidelines for device-aided therapies in Parkinson's disease -Economic evaluation and implementation.

OBJECTIVES: The National Board of Health and Welfare in Sweden published the national guidelines for Parkinson's Disease 2016. The aim of this study was to summarize this evidence review and development of the guidelines, focusing on the economic evaluation of device-aided therapies (deep brain stimulation, pump-based infusion of levodopa-carbidopa intestinal gel or apomorphine) for Parkinson's disease, and the rate of implementation after 3 years in Sweden. MATERIAL AND METHODS: The evidence review underlying the guidelines-including systematic literature searches of clinical and economic evidence, model-based economic evaluation, and formal analysis and guideline development-was examined, condensed, and translated. The impact of the guidelines was assessed with treatment use statistics from 2009 to 2019. RESULTS: All device-aided therapies were assigned high priority. Based on a relatively low proportion of device-aided therapies (30%) in Parkinson's disease, a 5-year increase of 500 patients was recommended. This was estimated to reduce total costs by SEK 14 million (€1.7 million). Follow-up data found an increase of 217 patients between 2017 and 2019, following the same trend as before the guidelines. CONCLUSION: Three years after the guidelines were published, the use of device-aided therapies has increased in Sweden, albeit not in pace with recommendations. One reason for slow implementation may be poor incentivization related to budget silos in which the costs for device-aided therapies are borne by the regions but the cost offsets (eg, reduced need for home care) are reaped by local stakeholders.

EuroInf: a multicenter comparative observational study of apomorphine and levodopa infusion in Parkinson's disease.

Subcutaneous apomorphine infusion (Apo) and intrajejunal levodopa infusion (IJLI) are two treatment options for patients with advanced Parkinson's disease (PD) and refractory motor complications, with varying cost of treatment. There are no multicenter studies comparing the effects of the two strategies. This open-label, prospective, observational, 6-month, multicenter study compared 43 patients on Apo (48.8% males, age 62.3 ± 10.6 years; disease duration: 14 ± 4.4 years; median H & Y stage 3; interquartile range [IQR]: 3-4) and 44 on IJLI (56.8% males, age 62.7 ± 9.1 years; disease duration: 16.1 ± 6.7 years; median H & Y stage 4; IQR, 3-4). Cohen's effect sizes (≥0.8 considered as large) were "large" with both therapies with respect to total motor, nonmotor, and quality-of-life scores. The Non-Motor Symptoms Scale (NMSS) with Apo showed moderate improvement, whereas sleep/fatigue, gastrointestinal, urinary, and sexual dimensions of the NMSS showed significantly higher improvement with IJLI. Seventy-five percent on IJLI improved in their quality-of-life and nonmotor symptoms (NMS), whereas in the Apo group, a similar proportion improved in quality of life, but 40% in NMS. Adverse effects included peritonitis with IJLI and skin nodules on Apo. Based on this open-label, nonrandomized, comparative study, we report that, in advanced Parkinson's patients, both IJLI and Apo infusion therapy appear to provide a robust improvement in motor symptoms, motor complications, quality-of-life, and some NMS. Controlled, randomized studies are required.

Associations Between Fluctuations in Daytime Sleepiness and Motor and Non-Motor Symptoms in Parkinson's Disease.

BACKGROUND: Non-motor fluctuations are a major concern in Parkinson's disease (PD), and they have been categorized into neuropsychiatric, autonomic and sensory fluctuations. However, this categorization does not include sleep and sleep-related features, and the association between daytime sleepiness and other motor and/or non-motor fluctuations in PD remains to be elucidated. OBJECTIVE: To investigate the relationship between daytime sleepiness and other non-motor and motor fluctuations in people with PD. METHODS: A three-day home diary recording daytime sleepiness, mood, anxiety, and motor symptoms was used along with the Karolinska Sleepiness Scale (KSS) and 6 days of accelerometer (Parkinson's KinetiGraph™; PKG™) registration to detect motor fluctuations among people with a DaTSCAN verified clinical PD diagnosis (32 men; mean PD duration, 8.2 years). Participants were categorized as motor fluctuators or non-fluctuators according to the UPDRS part IV and/or the presence of motor and non-motor fluctuations. RESULTS: Fifty-two people with PD participated. Daytime sleepiness correlated significantly with motor symptoms, mood and anxiety among those classified as motor fluctuators (n = 28). Motor fluctuators showed stronger correlations between the individual mean level of all diary variables (daytime sleepiness, anxiety, mood and motor symptoms) when compared to the non-fluctuators (n = 24). Stronger positive within-individual correlations were found among fluctuators in comparison to non-fluctuators. In general, PKG data did not correlate with diary data. CONCLUSION: Episodes of daytime sleepiness, as reported by home diaries, were associated with other self-reported non-motor and motor fluctuations, but were not supported by PKG data.

A 10-Year Follow-Up of Excessive Daytime Sleepiness in Parkinson's Disease.

INTRODUCTION: The aim of this prospective study was to investigate excessive daytime sleepiness (EDS) over time and in relation to other PD symptoms among people with Parkinson's disease (PD). METHODS: Thirty participants younger than 65 years with PD were randomly selected. At inclusion, mean (SD) disease duration was 6.2 (4.8) years and median (min-max) severity of PD was classified as stage II (stages I-III) according to Hoehn and Yahr. Participants were followed annually for 10 years with clinical assessments of their PD status, medications, comorbidities, and a standardized interview about their sleep habits and occurrence of daytime sleepiness. EDS was assessed by the self-reported Epworth Sleepiness Scale (ESS). Seventeen participants completed the 10-year longitudinal follow-up. RESULTS: Fifteen of 30 persons were classified to suffer from EDS (ESS > 10) at baseline. At the group level, EDS remained stable over 10 years and did not deteriorate in parallel with worsening of motor symptoms. Furthermore, EDS was associated with sleep quality, fatigue, anxiety, depression, and axial/postural/gait impairments. CONCLUSIONS: EDS did not worsen over 10 years, although other PD aspects did. EDS in PD seems to be a complex nonmotor symptom that is unrelated to deterioration of motor symptoms in PD.

Support for dopaminergic hypoactivity in restless legs syndrome: a PET study on D2-receptor binding.

Clinical observations support a central role of the dopamine system in restless legs syndrome (RLS) but previous imaging studies of striatal dopamine D2-receptors have yielded inconclusive results. Extrastriatal dopaminergic function has hitherto not been investigated. Sixteen RLS patients naïve to dopaminergic drugs and sixteen matched control subjects were examined with PET. [11C]Raclopride and [11C]FLB 457 were used to estimate D2-receptor availability in striatum and extrastriatal regions, respectively. Examinations were performed both in the morning (starting between 10:00 and 12:00 h) and evening (starting at 18:00 h). Measures were taken to monitor and control for head movement during data acquisition. In the striatum, patients had significantly higher [11C]raclopride binding potential (BP) values than controls. In extrastriatal regions, [11C]FLB 457 BP was higher in patients than controls, and in the regional analysis the difference was statistically significant in subregions of thalamus and the anterior cingulate cortex. The diurnal variability in BP with [11C]FLB 457 and [11C]raclopride was within the previously reported test-retest reproducibility for both radioligands. The study supports involvement of the dopamine system in both striatal and extrastriatal brain regions in the pathophysiology of RLS. The brain regions where differences in D2-receptor binding were shown are implicated in the regulation of affective and motivational aspects of sensory processing, suggesting a possible pathway for sensory symptoms in RLS. Increased D2-receptor availability in RLS may correspond to higher receptor densities or lower levels of endogenous dopamine. Both interpretations are consistent with the hypothesis of hypoactive dopaminergic neurotransmission in RLS, as increased receptor levels can be owing to receptor upregulation in response to low levels of endogenous dopamine. The results do not support variations in dopamine D2-receptor availability as a correlate to the diurnal rhythm of RLS symptoms.

Neuropeptide Y and Calcitonin Gene-Related Peptide in Cerebrospinal Fluid in Parkinson's Disease with Comorbid Depression versus Patients with Major Depressive Disorder.

Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. The diagnosis of PD is based on movement dysfunctions. Many patients also suffer from comorbid depression in spite of adequate treatment with dopamine replacement, indicating that also other non-dopaminergic mechanisms are involved. Indeed, neuropeptides are critically implicated in the pathophysiology of major depressive disorder (MDD). To increase our understanding of the biochemical basis of depression in PD patients, we examined the levels of neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) in cerebrospinal fluid (CSF) from PD patients, with or without comorbid depression, and compared them to the levels in patients with MDD. We also compared the levels of NPY and CGRP with 5-hydroxyindoleacetic acid (5-HIAA), the major serotonin metabolite. Both NPY and CGRP were higher in PD patients with comorbid depression compared to MDD patients. No similar difference was found in 5-HIAA levels. Accordingly, there were no correlations between NPY and 5-HIAA or CGRP and 5-HIAA levels. The finding of higher NPY and CGRP CSF levels in PD patients with MDD raises the possibility that different pathophysiological processes may underlie depression in PD and MDD.

Levodopa-carbidopa intestinal gel (LCIG) treatment in routine care of patients with advanced Parkinson's disease: An open-label prospective observational study of effectiveness, tolerability and healthcare costs.

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.

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 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.

Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients.

BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinson's disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 µg rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen. CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD. TRIAL REGISTRATION. Clinical Trials.gov NCT00866502. FUNDING. Newron Sweden AB (former NeuroNova AB) and Swedish Governmental Agency for Innovation Systems (VINNOVA).

The influence of preanalytical conditions on the DJ-1 concentration in human cerebrospinal fluid.

AIM: The purpose of this study was to establish the influence of centrifugation and protease activity on the cerebrospinal fluid (CSF) concentrations of DJ-1 and hemoglobin. MATERIALS & METHODS: The concentrations of DJ-1 and hemoglobin were determined in 12 (DJ-1) and six (hemoglobin) pairs of CSF samples, with one sample being stored without centrifugation and the other being centrifuged at 2000 × g before storage. The DJ-1 concentration was also determined in centrifuged and uncentrifuged CSF containing protease inhibitors and compared with values determined in centrifuged and uncentrifuged CSF samples without protease inhibitors. Furthermore, specific protein concentrations were determined in CSF from two groups, each comprising 23 patients with Parkinson's disease. In one group the CSF was centrifuged at 1300-1800 × g, 4°C, 10 min, and in the other at 2000 × g, 4°C, 10 min. RESULTS: Centrifugation at 2000 × g resulted in significantly lower CSF DJ-1 concentrations compared with no centrifugation and centrifugation at a lower g-force. There was a significant difference in the hemoglobin concentration between centrifuged and uncentrifuged CSF. In all centrifuged samples the hemoglobin concentration was <200 ng/ml including blood contaminated samples centrifuged at 2000 × g. When a protease inhibitor cocktail was added to the CSF prior to centrifugation, the DJ-1 concentration was significantly higher. CONCLUSION: Preanalytical factors such as centrifugation and protease inhibition must be carefully controlled when handling CSF for analysis of DJ-1 and other biomarkers, as DJ-1 was influenced by blood contamination, centrifugation and protease activity.

Oxysterols and Parkinson's disease: evidence that levels of 24S-hydroxycholesterol in cerebrospinal fluid correlates with the duration of the disease.

Oxysterols are important for cholesterol homeostasis in the brain and may be affected in neurodegenerative diseases. The levels of the brain-derived oxysterol 24S-hydroxycholesterol (24S-OH) have been reported to be markedly reduced in the circulation of patients with Parkinson's disease (PD) (Lee et al., Antioxid. Redox Signal. 11 (2009) 407-420). The finding is surprising in view of the fact that other neurodegenerative diseases are associated with relatively modest effects on the circulating levels of 24S-OH. We determined the plasma and cerebrospinal fluid (CSF) levels of 24S-OH and 27-hydroxycholesterol (27-OH) in patients with PD with different disease duration using a highly accurate method based on isotope dilution-mass spectrometry. All the patients had plasma levels of the different oxysterols within the normal range. When analyzing CSF, 10% of the PD patients were found to have levels of 24S-OH above the cut-off level and interestingly there was a significant correlation between levels of 24S-OH in CSF and duration of the disease (r=0.40, P<0.05). The CSF level of 27-OH was found to be above the cut-off level in 10% of the patients, indicating a defect blood-brain barrier function. There was no correlation between levels of 27-OH in CSF and duration of the disease. These data indicates that oxysterol levels in CSF may be of value to follow disease progression.

A comparison of gray matter density in restless legs syndrome patients and matched controls using voxel-based morphometry.

BACKGROUND: Restless legs syndrome (RLS) is a common neurological disorder the pathophysiology of which is incompletely understood. Four studies have examined structural differences between the brains of RLS patients and healthy controls, using voxel-based morphometry (VBM). All 4 studies have provided different results. METHODS: Optimized VBM was used to search for structural differences in gray matter density. Sixteen RLS patients naïve to dopaminergic drugs and 16 age- and sex-matched controls received structural T1-weighted MR scans. Structural data were analyzed using FSL-VBM. RESULTS: No difference in gray matter density was detected between the two groups (voxel-wise significance: no significant voxels at P= .89 (whole brain Family Wise Error (FWE) corrected); no significant voxels at P < .05 (whole brain False Discovery Rate (FDR) corrected; smallest achievable FDR threshold .99). CONCLUSION/DISCUSSION: The present study did not replicate (confirm) previous findings of structural brain changes in RLS, but instead supported the findings of a recent study showing a lack of gray matter alteration in an elderly RLS population. More specifically, the results do not support neuronal loss as an underlying disease mechanism in RLS. Potential limitations in the application of VBM are also discussed.

A pharmacokinetic-pharmacodynamic model for duodenal levodopa infusion.

OBJECTIVE: The purpose of this work was to identify and estimate a population pharmacokinetic- pharmacodynamic model for duodenal infusion of a levodopa/carbidopa gel (Duodopa) to examine pharmacological properties of this treatment. METHODS: The modeling involved pooling data from 3 studies (on advanced Parkinson disease) and fixing some parameters to values found in literature. The first study involved 12 patients studied on 3 occasions each and was previously published. The second study involved 3 patients on 2 occasions. A bolus dose was given after a washout during night. Plasma samples and motor ratings (clinical assessment of motor function on a 7-point treatment response scale ranging from "very off" to "very hyperkinetic") were collected until the clinical effect returned to baseline. The third study involved 5 patients on 3 occasions receiving 5 different dose levels. Different structural models were evaluated using the nonlinear mixed-effects modeling program NONMEM VI. Population mean parameter values, and interindividual, interoccasion, and residual variabilities were estimated. RESULTS: Absorption of the levodopa/carbidopa gel can be adequately described with first-order absorption with bioavailability and lag time. Estimated population parameter values were a mean absorption time of 28.5 minutes, a lag time of 2.9 minutes, and a bioavailability of 88%. The pharmacodynamic model for motor ratings had the following population values: a half-life of effect delay of 21 minutes, a concentration at 50% effect of 1.55 mg/L, an Emax of 2.39 U on the treatment response scale, and a sigmoidicity of the Emax function of 11.6. CONCLUSIONS: For the typical unmedicated subject, it will take 51.4 minutes until the peak levodopa effect is reached after a bolus dose. This delay is, like the magnitude of the effect, highly variable in this patient group. The residual error magnitudes of 20% for levodopa concentrations and 0.92 U (SD) for motor ratings indicate that the models developed provide predictions of a relevant quality. The developed model may be a first step toward model-guided treatment individualization of duodenal infusion of levodopa.

Monoamines, BDNF, IL-6 and corticosterone in CSF in patients with Parkinson's disease and major depression.

The biochemical basis of major depression (MD) in Parkinson's disease (PD) is largely unknown. To increase our understanding of MD in PD patients, the levels of monoamine metabolites (HVA, 5-HIAA and MHPG), BDNF, orexin-A, IL-6 and corticosterone were examined in cerebrospinal fluid. The analyses were performed in MD patients with (n = 11) and without (n = 12) PD at baseline and after 12 weeks' of treatment with the antidepressant citalopram, and in patients with solely PD (n = 14) at baseline and after 12 weeks. The major findings were that PD patients with MD had significantly lower baseline levels of MHPG, corticosterone and IL-6 when compared to patients with solely MD. In response to citalopram treatment, patients with solely MD exhibited an expected decrease in 5-HIAA and MHPG levels which was not found in PD patients with MD. Moreover, the levels of BDNF and IL-6 were lower in PD patients with MD compared with patients with solely MD after treatment with citalopram. Thus, the biochemical basis and the response to citalopram differ between PD patients with MD and patients with solely MD.

HMPAO SPECT in Parkinson's disease (PD) with major depression (MD) before and after antidepressant treatment.

Previously we suggested that major depression (MD) in Parkinson's disease (PD) could be an indication of a more advanced and widespread neurodegenerative process, as PD symptoms were more severe in those with depression. We also found a different antidepressant response with SSRI medication in PD patients with depression compared to depressed patients without PD. This indicates diverse underlying pathophysiological mechanisms. Investigations using single-photon emission computed tomography (SPECT), measuring regional cerebral blood flow (rCBF), may contribute to enlighten the neurobiological substrates linked to depressive symptoms. SPECT was performed in order to compare rCBF in MD patients with and without PD. The study included 11 MD patients with PD, 14 non-depressed PD patients and 12 MD patients without PD. All patients were followed for 12 weeks with repeated evaluation of depressive as well as PD symptoms. Anti-Parkinsonian treatment remained unchanged during the study. Antidepressant treatment with SSRI (citalopram) was given to all patients with MD. SPECT was performed before and after 12 weeks of antidepressant treatment. rCBF was found to differ between PD patients with and without MD, as well as between MD patients with and without PD, both at baseline and concerning the response to treatment with SSRI (citalopram). In patients with PD the rCBF was found to be decreased in preoccipital and occipital regions, a finding more common when PD was combined with MD. In summary, larger cortical areas were found to be involved in depressed PD patients, both with hyperactivity (reciprocal to basal degeneration in PD and maybe dopaminergic treatment) and with hypoactivity (probably due to organic lesions leading to hypoperfusion). These observations support our hypothesis that PD combined with MD is an expression of a more advanced and widespread neurodegenerative disorder.