Transdermal Nicotine Treatment and Progression of Early Parkinson's Disease.

BACKGROUND: Epidemiologic studies show that smokers have a lower incidence of Parkinson's disease. Nicotine has been hypothesized to slow progression in early Parkinson's disease. METHODS: In a double-blind, placebo-controlled multicenter trial, we randomly assigned patients with Parkinson's disease, diagnosed within 18 months, who were in Hoehn and Yahr disease stage less than or equal to 2 (range from 0 to 5; higher scores indicate greater impairment), who were therapy naïve (except for stable monoamine-oxidase-B inhibition), and not requiring dopaminergic therapy, to transdermal nicotine or placebo. The primary end point was change in Unified Parkinson's Disease Rating Scale parts I­III (Total UPDRS) score (range from 0 to 172; higher scores indicate greater impairment) between baseline and 60 weeks (52 weeks of trial therapy, 8 weeks of washout). The first secondary end point was change in Total UPDRS from baseline to 52 weeks. Differences between groups were estimated using the Hodges­Lehmann (HL) method and tested with the exact two-sided stratified Mann­Whitney­Wilcoxon test according to the intention-to-treat principle. RESULTS: Among 163 participants, 101 were assessed for the primary end point. Mean worsening of Total UPDRS was 3.5 in the placebo versus 6.0 in the nicotine group (HL-difference with 95% CI: ­3 [­6 to 0], P=0.06). For the first secondary end point, analysis of 138 participants showed a mean worsening of 5.4 in the placebo versus 9.1 in the nicotine group (HL-difference with 95% CI: ­4 [­7 to ­1]). Dropout was mainly because of early treatment discontinuation or adverse events. Cutaneous adverse effects at the patch application site were common. In all, 34.6% of participants initiated dopaminergic therapy during participation. CONCLUSIONS: One-year transdermal nicotine treatment did not slow progression in early Parkinson's disease. (Funded by the Michael J. Fox Foundation for Parkinson's Research and others; ClinicalTrials.gov number, NCT01560754; EudraCT number, 2010-020299-42.)

Perampanel, an AMPA antagonist, found to have no benefit in reducing "off" time in Parkinson's disease.

BACKGROUND: Perampanel is a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor antagonist. Two multicenter randomized, double-blind, placebo-controlled, parallel-group phase III studies assessed the efficacy and safety of adjunctive perampanel in patients with Parkinson's disease and motor fluctuations. METHODS: In both phase III studies (301 and 302), levodopa-treated patients were randomized and treated with once-daily oral placebo (n = 504), perampanel 2 mg (n = 509), or perampanel 4 mg (n = 501). The primary end point was change in daily "off" time from baseline. The treatment period was 30 weeks in study 301 and 20 weeks in study 302. RESULTS: For any efficacy end point, perampanel 2 or 4 mg was not superior to placebo. Perampanel was well tolerated up to 4 mg/day. CONCLUSIONS: Perampanel failed to significantly improve motor symptoms versus placebo. There was also no effect on the duration or disability of levodopa-induced dyskinesia.

Patients with idiopathic rapid-eye-movement sleep behavior disorder show normal gastric motility assessed by the 13C-octanoate breath test.

BACKGROUND: Delayed gastric emptying is a non-motor symptom of Parkinson's disease. Few data exist on gastric emptying in early-stage Parkinson's disease. In idiopathic rapid-eye-movement sleep behavior disorder, a presumable pre-motor stage of Parkinson's disease, gastric emptying has not yet been investigated. METHODS: Twenty healthy controls, 13 patients with idiopathic rapid-eye-movement sleep behavior disorder, and 39 patients with Parkinson's disease patients underwent standardized testing for gastric emptying with the (13)C-octanoate breath test. RESULTS: Gastric emptying was significantly delayed in drug-naïve (P < .001) and in treated Parkinson's disease patients (P < .001), but normal in patients with idiopathic rapid-eye-movement sleep behavior disorder. CONCLUSIONS: Our study confirms delayed gastric emptying in drug-naïve, early-stage Parkinson's disease. Normal gastric emptying in idiopathic rapid-eye-movement sleep behavior disorder might be explained by the fact that neurodegenerative changes in structures modulating gastric motility are not severe enough to cause a functional deficit that can be detected by the (13)C-octanoate breath test.

Postprandial ghrelin response is reduced in patients with Parkinson's disease and idiopathic REM sleep behaviour disorder: a peripheral biomarker for early Parkinson's disease?

Ghrelin, an orexigenic peptide, has multiple functions, which include promoting gastrointestinal motility and influencing higher brain functions. Experimental data suggest that ghrelin has neuroprotective potential in the MPTP mouse model of Parkinson's disease (PD). PD patients show delayed gastric emptying and other symptoms that may relate to disturbed excretion of ghrelin. No data are available on postprandial ghrelin response in patients with PD and idiopathic REM sleep behaviour disorder (iRBD)--a condition considered a putative preclinical stage of PD. We measured fasting and postprandial ghrelin serum concentrations in 20 healthy controls, 39 (including 19 drug-naïve) PD patients and 11 iRBD patients using a commercial radioimmunoassay for total ghrelin. For statistical analysis we employed ANCOVA and post-hoc testing with Bonferroni's method. Controls showed a decrease of mean fasting ghrelin serum concentrations in the early postprandial phase, followed by a recuperation starting 60 min after the test meal and reaching a maximum at 300 min. This recuperation was less pronounced in PD and iRBD; the slope of relative postprandial ghrelin recovery was different between the investigated groups (p = 0.007). Post-hoc testing showed a difference between controls and PD patients (p = 0.002) and between controls and iRBD patients (p = 0.037). The dynamic regulation of ghrelin in response to food intake is partially impaired in subjects at putative preclinical (iRBD) and clinical stages of PD. Reduced ghrelin excretion might increase the vulnerability of nigrostriatal dopaminergic neurons as suggested by animal studies. The impaired ghrelin excretion might qualify as a peripheral biomarker and be of diagnostic or therapeutic value.

In vivo demonstration of microstructural brain pathology in progressive supranuclear palsy: a DTI study using TBSS.

We investigated DTI changes, potentially indicating alterations of microstructure and brain tissue integrity in 13 patients with probable progressive supranuclear palsy (PSP, Richardson syndrome) at stage III or less and 10 age-matched controls using a whole brain analysis of diffusion tensor imaging (DTI) data. DTI images were analyzed using tract-based spatial statistics, a hypothesis-free technique. Fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) were determined. In patients with PSP, significant increases in FA (P < 0.0001), an unspecific measure of microstructural tissue integrity, were found in the cerebellum and in the superior cerebellar peduncle bilaterally, in the fornix, the body of the corpus callosum and the olfactory region, when compared with age-matched healthy controls. Further, regional reductions in AD (P < 0.0001), an indicator of altered axonal integrity, were observed in the pons, the right substantia nigra and the cerebellar white matter bilaterally. Significant increases in RD (P < 0.0001), a potential measure of altered myelin integrity, occurred bilaterally in the superior cerebellar peduncle, the cerebellar white matter, the vermis of the cerebellum, the fornix, the body of the corpus callosum, and the olfactory region. RD values in the superior cerebellar peduncle discriminated patients with PSP and controls with high sensitivity (0.92) and specificity (1.0). The findings are supported by neuropathological studies. Our data suggest the usefulness of this clinically available new technique as a possible tool for differential diagnosis.

Nigrostriatal upregulation of 5-HT2A receptors correlates with motor dysfunction in progressive supranuclear palsy.

A dysfunction of multiple neurotransmitter systems is assumed as a neurochemical basis of the akinetic-rigid syndrome of progressive supranuclear palsy (PSP). In vitro studies have produced conflicting results on the serotoninergic system in PSP. We, therefore, studied the binding potential of the serotonin 2A (5-HT(2A)) receptor ligand [18F]altanserin in 8 patients with clinically probable PSP and 13 healthy controls using positron emission tomography. We found an up-regulation of 5-HT(2A) receptors in the substantia nigra and, to a lower degree, in the striatum, while neocortical 5- HT(2A) receptor densities showed no changes upon partial-volume correction. Nigral and striatal receptor changes were significantly correlated with patients' scores of motor dysfunction (UPDRS III, PSP-rating scale) pointing to a functional relevance of the described findings.

In vivo evidence for cerebral depletion in high-energy phosphates in progressive supranuclear palsy.

Indirect evidence from laboratory studies suggests that mitochondrial energy metabolism is impaired in progressive supranuclear palsy (PSP), but brain energy metabolism has not yet been studied directly in vivo in a comprehensive manner in patients. We have used combined phosphorus and proton magnetic resonance spectroscopy to measure adenosine-triphosphate (ATP), adenosine-diphosphate (ADP), phosphorylated creatine, unphosphorylated creatine, inorganic phosphate and lactate in the basal ganglia and the frontal and occipital lobes of clinically probable patients (N=21; PSP stages II to III) and healthy controls (N=9). In the basal ganglia, which are severely affected creatine in PSP patients, the concentrations of high-energy phosphates (=ATP+phosphorylated creatine) and inorganic phosphate, but not low-energy phosphates (=ADP+unphosphorylated creatine), were decreased. The decrease probably does not reflect neuronal death, as the neuronal marker N-acetylaspartate was not yet significantly reduced in the early-stage patients examined. The frontal lobe, also prone to neurodegeneration in PSP, showed similar alterations, whereas the occipital lobe, typically unaffected, showed less pronounced alterations. The levels of lactate, a product of anaerobic glycolysis, were elevated in 35% of the patients. The observed changes in the levels of cerebral energy metabolites in PSP are consistent with a functionally relevant impairment of oxidative phosphorylation.

Cost effectiveness of pharmacotherapies in early Parkinson's disease.

Parkinson's disease is one of the most common chronic neurodegenerative diseases. The progression of disease and the psychosocial consequences exert a major impact on patients' health-related quality of life. Although levodopa provides the best symptomatic benefit with the fewest short-term adverse effects, long-term treatment results in motor complications that are associated with both higher costs and considerable increase in patients' discomfort. The introduction of dopamine agonists early in the treatment of Parkinson's disease leads to a delay of these motor complications, but the treatment is associated with higher costs.In this review we evaluate available cost-effectiveness analyses of the dopamine agonists pramipexole, pergolide, bromocriptine, ropinirole, cabergoline and levodopa in the treatment of early Parkinson's disease. Considerable methodological differences in the identified studies complicate a comparison and impede clear evidence as to which dopamine agonist treatment is the most cost effective in early Parkinson's disease. Novel head-to-head comparisons considering the actual treatment guidelines are necessary to identify the most cost-effective alternative in treating de novo Parkinson's disease patients.

Real-life evaluations of compliance with mandatory drug safety monitoring exemplified with tolcapone in Parkinson's disease.

BACKGROUND/AIMS: In 1998, the European Medicines Agency suspended the approval for tolcapone in Parkinson's disease (PD) with motor complications due to the drug's implication in fulminant liver failure and the consequent death of 3 patients. Clinical data obtained by ongoing use of tolcapone in other countries proved that adequate safety can be achieved if liver enzymes are strictly monitored. In 2005, tolcapone was relaunched in the European Union under the prerequisite of biweekly liver enzyme monitoring. The objective of this study was to evaluate the compliance with mandatory drug safety monitoring under real-life conditions. METHODS: Twenty-one Parkinson's disease patients receiving tolcapone were analyzed with regard to their compliance in performing and reporting the required laboratory tests. RESULTS: Tolcapone was effective and well tolerated. Yet, less than 25% of the patients regularly performed and reported the required laboratory tests and the compliance declined when comparing the first and second half-years of therapy. CONCLUSIONS: Our data shed light on the incongruity between requirements of postmarketing drug surveillance and every-day reality. The depicted noncompliance is most likely a general problem in postmarketing drug surveillance with an impact for physicians, manufacturers and legal authorities. Practical, legal and ethical aspects will be discussed.

Short-term effects of coenzyme Q10 in progressive supranuclear palsy: a randomized, placebo-controlled trial.

Mitochondrial complex I appears to be dysfunctional in progressive supranuclear palsy (PSP). Coenzyme Q(10) (CoQ(10)) is a physiological cofactor of complex I. Therefore, we evaluated the short-term effects of CoQ(10) in PSP. We performed a double-blind, randomized, placebo-controlled, phase II trial, including 21 clinically probable PSP patients (stage < or = III) to receive a liquid nanodispersion of CoQ(10) (5 mg/kg/day) or matching placebo. Over a 6-week period, we determined the change in CoQ(10) serum concentration, cerebral energy metabolites (by (31)P- and (1)H-magnetic resonance spectroscopy), motor and neuropsychological dysfunction (PSP rating scale, UPDRS III, Hoehn and Yahr stage, Frontal Assessment Battery, Mini Mental Status Examination, Montgomery Asberg Depression Scale). CoQ(10) was safe and well tolerated. In patients receiving CoQ(10) compared to placebo, the concentration of low-energy phosphates (adenosine-diphosphate, unphosphorylated creatine) decreased. Consequently, the ratio of high-energy phosphates to low-energy phosphates (adenosine-triphosphate to adenosine-diphosphate, phospho-creatine to unphosphorylated creatine) increased. These changes were significant in the occipital lobe and showed a consistent trend in the basal ganglia. Clinically, the PSP rating scale and the Frontal Assessment Battery improved slightly, but significantly, upon CoQ(10) treatment compared to placebo. Since CoQ(10) appears to improve cerebral energy metabolism in PSP, long-term treatment might have a disease-modifying, neuroprotective effect.

Health-related quality of life in multiple system atrophy.

Although multiple system atrophy (MSA) is a neurodegenerative disorder leading to progressive disability and decreased life expectancy, little is known about patients' own evaluation of their illness and factors associated with poor health-related quality of life (Hr-QoL). We, therefore, assessed Hr-QoL and its determinants in MSA. The following scales were applied to 115 patients in the European MSA-Study Group (EMSA-SG) Natural History Study: Medical Outcome Study Short Form (SF-36), EQ-5D, Beck Depression Inventory (BDI), Mini-Mental state examination (MMSE), Unified MSA Rating Scale (UMSARS), Hoehn & Yahr (H&Y) Parkinson's disease staging scale, Composite Autonomic Symptom Scale (COMPASS), and Parkinson's Disease Sleep Scale (PDSS). Forty-six percent of patients had moderate to severe depression (BDI > or = 17); Hr-QoL scores on the SF-36 and EQ-5D were significantly impaired. Pain, the only domain with similar scores in MSA and published PD patients, was reported more frequently in patients with MSA-P (predominantly parkinsonian motor subtype) than MSA-C (predominantly cerebellar motor subtype; 76% vs. 50%; P = 0.005). Hr-QoL scores correlated most strongly with UMSARS motor, COMPASS, and BDI scores but not with MMSE scores, age at onset, or disease duration. The COMPASS and UMSARS activities of daily living scores were moderate-to-strong predictors for the SF-36 physical summary score and the BDI and UMSARS motor scores for the SF-36 mental summary score. This report is the first study to show that Hr-QoL is significantly impaired in MSA. Although not all possible factors related to impaired Hr-QoL in MSA could be assessed, autonomic dysfunction, motor impairment, and depression were most closely associated with poor Hr-QoL, and therapeutic management, therefore, should concentrate upon these aspects of the disease.

Progression of multiple system atrophy (MSA): a prospective natural history study by the European MSA Study Group (EMSA SG).

The disease-specific Unified Multiple System Atrophy Rating Scale (UMSARS) has been developed recently and validated for assessing disease severity in multiple system atrophy (MSA). Here, we aimed at (1) assessing rates of disease progression in MSA and (2) validating UMSARS for sensitivity to change over time. Impairment was assessed at two time points 12 months apart using UMSARS Part I (historical review), UMSARS Part II (motor examination), as well as measures of global disease severity, including UMSARS Part IV, Hoehn and Yahr (HY) Parkinson's disease staging, Schwab England Activities of Daily Living (SE ADL), and a three-point global Severity Scale (SS3). Fifty patients (male:female ratio, 1:0.9; possible MSA, 16%; probable MSA, 84%; MSA-parkinsonian, 58%; MSA-cerebellar, 42%) were assessed twice with an interval of 12.3 months. UMSARS II scores progressed by 57.3% (P<0.0001) and UMSARS I scores by 35.6% (P<0.0001) in relation to the respective baseline scores with no differences between motor subtypes, diagnostic categories and gender. Significant inverse correlations between (1) UMSARS I or UMSARS II progression and (2) baseline disability measures (i.e., the respective UMSARS or SS3 scores) and disease duration were found. Furthermore, the increases in HY staging, SE ADL and SS3 correlated significantly with UMSARS I, UMSARS II, and UMSARS IV progression. This report is the first prospective study showing rapid annual UMSARS rates of decline in MSA. Our data contribute to the ongoing validation process of UMSARS, and they facilitate the planning and implementation of future neuroprotective intervention trials.

Role of dopamine transporter SPECT for the practitioner and the general neurologist.

The accurate clinical diagnosis of parkinsonism may be impeded by atypical presentations and confounding comorbidity. The presence of parkinsonism is misdiagnosed in up to a quarter of cases in general practice. Movement disorder specialists misdiagnose parkinsonian syndromes using histopathological findings as the "gold standard" in up to 10% of cases. Dopamine transporter SPECT represents a simple and fast method to confirm nigrostriatal degeneration in a given patient. This study provides several case reports to illustrate when dopamine transporter SPECT might be carried out and discusses whether dopamine transporter SPECT should be used in primary health care practice or by general neurologists in uncertain cases. Ideally, all possible cases of parkinsonism should be referred to a neurologist experienced in the field of movement disorders. If this could be achieved then the role of dopamine transporter SPECT in the general practitioner's or local neurologist's practice would be extremely limited. Future studies must clarify whether it is cost effective to generously perform dopamine transporter SPECTs to minimize the time until parkinsonism can be diagnosed.