A Placebo-Controlled Trial of AQW051 in Patients With Moderate to Severe Levodopa-Induced Dyskinesia.

BACKGROUND: This phase 2 randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of the nicotinic acetylcholine receptor α7 agonist AQW051 in patients with Parkinson's disease and levodopa-induced dyskinesia. METHODS: Patients with idiopathic Parkinson's disease and moderate to severe levodopa-induced dyskinesia were randomized to AQW051 10 mg (n = 24), AQW051 50 mg (n = 24), or placebo (n = 23) once daily for 28 days. Coprimary end points were change in Modified Abnormal Involuntary Movement Scale and Unified Parkinson's Disease Rating Scale part III scores. Secondary outcomes included pharmacokinetics. RESULTS: In total, 67 patients completed the study. AQW051-treated patients experienced no significant improvements in Modified Abnormal Involuntary Movement Scale or Unified Parkinson's Disease Rating Scale part III scores by day 28. AQW051 was well tolerated; the most common adverse events were dyskinesia, fatigue, nausea, and falls. CONCLUSIONS: AQW051 did not significantly reduce dyskinesia or parkinsonian severity. © 2016 International Parkinson and Movement Disorder Society.

Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects.

In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-ß1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-ß1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-ß amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal fluid amyloid-ß1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE ε4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-ß1-42 values and APOE ε2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-ß1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-ß1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology.

Efficacy of levodopa/carbidopa/entacapone versus levodopa/carbidopa in patients with early Parkinson's disease experiencing mild wearing-off: a randomised, double-blind trial.

To compare the efficacy and safety of levodopa/carbidopa/entacapone (LCE) with levodopa/carbidopa (LC) on Parkinson's disease (PD) patients with mild, or only minimally disabling motor complications. A prospective 3-month, multicentre, parallel-group, double-blind, and randomised phase IV study was performed. The primary endpoint was to assess the efficacy of LCE compared to LC on ADLs using the UPDRS part II. Secondary endpoints were assessed by the UPDRS (I, III and IV) scores, QUICK and PDQ-39 questionnaires, and patient and investigator clinical global impression (CGI). Ninety-five patients were randomly assigned to treatment with LCE (100/25/200 or 150/37.5/200 mg tablets, n = 46) or LC (100/25 mg tablets, n = 49), at the same levodopa dose that were administered before randomization. Treatment with LCE resulted in significantly greater improvement in UPDRS part II (ADLs) scores compared to treatment with LC (adjusted mean difference between groups of -1.5 points) (p = 0.0288). Amelioration was also observed in UPDRS part III scores (p = 0.010), and CGI (patient and investigator) scores (p = 0.015, and p = 0.028, respectively). LCE and LC were generally well tolerated with 78 % of subjects completing the study. Most AEs (50 % in LCE and 71.4 % in LC) were classified as mild. No serious AEs were related to the treatment. Treatment with LCE results in improved efficacy compared to LC in PD patients with mild, or minimally disabling motor fluctuations, maintaining a good safety and tolerability profile.

Lewy bodies under atomic force microscope.

Lewy bodies are the hallmark of Parkinson disease and their sophisticated analysis will undoubtedly elucidate the pathogenic process. They have been studied by using different microscopic tools. The authors have used atomic force microscopy (AFM) to study the ultramicrotom cut postmortem brain tissue of Parkinson disease patients. Under the same preparation conditions, they have found aggregated fibrillary nanostructures in Lewy bodies, as well as a loss of connections between neurons located in other parts of the substantia nigra. Although these results are preliminary and descriptive in nature, this paper reports the application of a novel and intriguing technique. Further studies including the study of cortical LB and Lewy neurites will be needed to determine the full potential of AFM in the study of the pathogenesis of cell death in Parkinson disease and other synucleinopathies.

Mutations in the Na+/K+ -ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism.

Rapid-onset dystonia-parkinsonism (RDP, DYT12) is a distinctive autosomal-dominant movement disorder with variable expressivity and reduced penetrance characterized by abrupt onset of dystonia, usually accompanied by signs of parkinsonism. The sudden onset of symptoms over hours to a few weeks, often associated with physical or emotional stress, suggests a trigger initiating a nervous system insult resulting in permanent neurologic disability. We report the finding of six missense mutations in the gene for the Na+/K+ -ATPase alpha3 subunit (ATP1A3) in seven unrelated families with RDP. Functional studies and structural analysis of the protein suggest that these mutations impair enzyme activity or stability. This finding implicates the Na+/K+ pump, a crucial protein responsible for the electrochemical gradient across the cell membrane, in dystonia and parkinsonism.

The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene.

Rapid-onset dystonia-parkinsonism (RDP) (also known as DYT12) is characterized by the abrupt onset of dystonia and parkinsonism and is caused by mutations in the ATP1A3 gene. We obtained clinical data and sequenced the ATP1A3 gene in 49 subjects from 21 families referred with 'possible' RDP, and performed a genotype-phenotype analysis. Of the new families referred for study only 3 of 14 families (21%) demonstrated a mutation in the ATP1A3 gene, but no new mutations were identified beyond our earlier report of 6. Adding these to previously reported families, we found mutations in 36 individuals from 10 families including 4 de novo mutations and excluded mutations in 13 individuals from 11 families. The phenotype in mutation positive patients included abrupt onset of dystonia with features of parkinsonism, a rostrocaudal gradient, and prominent bulbar findings. Other features found in some mutation carriers included common reports of triggers, minimal or no tremor at onset, occasional mild limb dystonia before the primary onset, lack of response to dopaminergic medications, rare abrupt worsening of symptoms later in life, stabilization of symptoms within a month and minimal improvement overall. In comparing ATP1A3 mutation positive and negative patients, we found that tremor at onset of symptoms, a reversed rostrocaudal gradient, and significant limb pain exclude a diagnosis of RDP. A positive family history is not required. Genetic testing for the ATP1A3 gene is recommended when abrupt onset, rostrocaudal gradient and prominent bulbar findings are present.

Long-term survival of encapsulated GDNF secreting cells implanted within the striatum of parkinsonized rats.

Several findings suggest that glial cell line-derived neurotrophic factor (GDNF) may be a useful tool to treat parkinsonism by acting as a neuroprotective and neurotrophic factor for dopaminergic neurotransmission systems. In the present study, we implanted alginate-poly-L-lysine-alginate microcapsules containing immobilized Fischer rat 3T3 fibroblasts transfected to produce GDNF in vitro into the striatum of 6-hydroxydopamine (6-OHDA) lesioned rats. Microencapsulated GDNF secreting cells were stable for at least 3 weeks in vitro. Intrastriatal implantation of microencapsulated GDNF secreting cells into 6-OHDA lesioned rats resulted in a decrease in apomorphine-induced rotations by 84%, 64%, 84%, 60% and 52% (2, 5, 8, 16 and 24 weeks, respectively) with respect to the value before implantation and with respect to the value obtained from the empty microcapsule implanted-group at each time point. Six months after transplantation, immunohistochemical detection of GDNF revealed strong immunoreactivity in the striatal tissue surrounding the microcapsules in the absence of tissue damage due to microcapsule implantation. No changes in the levels of dopamine and its metabolites or of tyrosine hydroxylase immunoreactivity were detected in the striatum. In summary, the implantation of microencapsulated GDNF secreting cells allows the delivery of this molecule into the rat striatum for at least 6 months and results in substantial behavioral improvement.

New ideas on the origin of L-dopa-induced dyskinesias: age, genes and neural plasticity.

More than 50% of Parkinson's disease (PD) patients treated with L-dopa develop L-dopa-induced dyskinesias (LIDs) in the long term. Some patients exhibit severe dyskinesias soon after starting low doses of L-dopa, whereas other patients remain free of this disabling complication despite treatment with L-dopa. Avoiding or delaying the appearance of LIDs is one of the main objectives of the management of PD. Plasticity of the brain to adapt to a progressive disease, together with a non-physiological treatment strategy, might be the key physiopathological element that underlies LIDs. Neural plasticity varies among patients according to age and genetics. Thus, I propose that this variation explains the observed differences in the occurrence of LIDs in PD patients. Furthermore, I suggest that denervation and L-dopa treatment act as modulating and triggering factors of LIDs, respectively. In this article, the practical implications of these ideas and the role of pharmacogenetics in PD treatment are discussed. Treatment decisions are likely to rely on this information, challenging the relevance of current 'hot' debates about how to start treatment in PD.

Cell therapy for Parkinson's disease: only young onset patients allowed? Reflections about the results of recent clinical trials with cell therapy and the progression of Parkinson's disease.

The selection of the best candidates for surgery among Parkinson's disease (PD) patients is a debated topic. This could be particularly important for transplantation studies in which patients with advanced PD and motor complications refractory to conventional pharmacological treatments are usually included. The development of lesions in nondopaminergic structures, which apparently are unaffected by the intervention, could eventually lead to the appearance of disabling, treatment-resistant symptoms. This has been considered as the crucial factor responsible for the outcome of any therapeutic procedure. However, other factors might be involved. It is suggested in this article that the rate of progression of PD and the effects of ageing are more important than the extradopaminergic involvement in the final outcome. Rate of progression of PD is critically related to the power of compensatory mechanisms, which are age related and under the control of still unknown genes. Thus, patients with young onset parkinsonism (YOP), either caused by gene mutations or not, could be the best candidates for surgery because they have a slower disease progression and more competent compensatory mechanisms. On the other hand, this can also explain the appearance of unexpected side effects such as the "runaway" dyskinesias reported following transplantation.

Electrophysiological characterization of substantia nigra dopaminergic neurons in partially lesioned rats: effects of subthalamotomy and levodopa treatment.

Progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta is the main histopathological characteristic of Parkinson's disease. We studied the electrophysiological characteristics of the spontaneous activity of substantia nigra pars compacta dopaminergic neurons in rats with a partial, unilateral, 6-hydroxydopamine lesion of the nigrostriatal pathway. In addition, the effects of subthalamotomy and prolonged levodopa treatment on the activity of dopaminergic neurons were investigated. As a result of the lesion ( approximately 50% neuronal loss), the number of spontaneously active neurons was significantly reduced. Basal firing rate, burst firing and responsiveness to intravenously administered apomorphine remained unchanged. In contrast, the variation coefficient, a measure of interspike interval regularity, was significantly increased. Ibotenic acid (10 microg) lesion of the ipsilateral subthalamic nucleus in lesioned rats did not modify the electrophysiological parameters. However, prolonged levodopa treatment (100 mg/kg/day + benserazide 25 mg/kg/day, 14 days) reversed the irregularity observed in cells from lesioned rats, while it induced an irregular firing pattern in cells from intact rats. Our results using an experimental model of moderate Parkinson's disease indicate that surviving substantia nigra pars compacta dopaminergic neurons fire irregularly. In this model, subthalamotomy does not modify the firing pattern while levodopa treatment efficiently restores normal firing of SNpc neurons and does not appear to be toxic to them.

The SCOPA-Motor Scale for assessment of Parkinson's disease is a consistent and valid measure.

OBJECTIVE: The SCOPA-Motor Scale (S-MS) for assessment of Parkinson's disease (PD), contains 21 items in three domains: Motor examination, Disability, and Complications. Our objective was to validate the S-MS Spanish version. STUDY DESIGN AND SETTING: This validation study was based on a multicenter, cross-sectional, one-point-in-time evaluation design. The applied measures were: Unified Parkinson's Disease Rating Scale-3.0 (UPDRS); S-MS; PD Global Evaluation (PDGE); and Clinical Global Impression of severity (CGI). Completeness of data collection, floor and ceiling effect, internal consistency, precision, and construct and discriminative validity were analyzed in 151 PD patients. RESULTS: Scores from S-MS were fully computable. Floor effect was high for Complications (43.7%). Cronbach's alpha was > 0.90 for every domain, and item-total correlation was > 0.70 except for Examination. Standard error of measurement (SEM) ranged from 0.40 to 2.4. Convergent validity with corresponding UPDRS sections yielded coefficients > 0.90. Discriminative validity across Hoehn and Yahr (HY) and CGI stages was significant (Kruskal-Wallis, P < .0001). Insofar as internal consistency was concerned, alpha-values of the Examination sections were marginally higher for the UPDRS than for the S-MS (a finding perhaps accounted for by redundancy in this part of the UPDRS). CONCLUSION: The S-MS is a consistent and valid scale, shorter by almost half than the UPDRS.

Efficacy and safety of donepezil in the treatment of executive dysfunction in Parkinson disease: a pilot study.

Cognitive disturbances in Parkinson's disease (PD) are dominated by troubles in executive functions which affects to a vast majority of parkinsonian patients since the onset of the disease. A common clinical observation is that parkinsonian patients, who eventually develop dementia, exhibit subtle cognitive disturbances quite earlier. The main biochemical substrate of cognitive dysfunction in PD, even of the early dysexecutive syndrome, might be a cholinergic deficiency. The aim of this pilot study was to determine the efficacy and safety of donepezil in the treatment of 10 patients with PD and dysexecutive alterations without dementia. All the items of the Clinical Global Impression were significantly improved. An improvement on both the modified Wisconsin Card Sorting Test and DIGIT Span was found. Parkinsonism remained unchanged during the study. Only 1 out of 10 patients experienced transient and mild gastrointestinal side effects. This study suggests that donepezil may be useful in the treatment of the dysexecutive syndrome associated with PD.

Neuroprotective role of dopamine agonists: evidence from animal models and clinical studies.

Parkinson disease is a progressive neurodegenerative disease that affects, among other neurotransmitter systems, the nigrostriatal dopaminergic projection. Palliative treatment with levodopa and/or dopamine agonists improves motor symptoms even though patients continue to get clinically worse by the neurodegenerative process that continues to act as the major factor of physiological aging. Studies (in vitro and in vivo) with experimental models have shown that dopamine agonists have neuroprotective effects, directly or indirectly mediated by their ability to stabilize mitochondria, antioxidant effects, synthesis of growth factors, stabilization of the ubiquitin-proteasome system, activation of autophagy, antiapoptotic induction of Bcl2 family, or enhancement of neurogenesis (proliferation and migration) in the subventricular zone. Clinical studies have not completely confirmed these effects. Analysis in better characterized groups of patients with similar clinical symptoms, identical treatments, and the same evolution time are required. Technological advances which enable the learning of the etiology and the pathogenesis (genetic and environmental) of the disease, together with clinical assessment methods, bring hope to the development of new molecules in the symptomatic treatment of Parkinson disease. These molecules must display neuroprotective potential (prophylactic and/or therapeutic) which must be able to maintain the brain's physiological function and to modify or slow the natural course of the disease.

Nigrostriatal denervation changes the effect of cannabinoids on subthalamic neuronal activity in rats.

RATIONALE: It is known that dopaminergic cell loss leads to increased endogenous cannabinoid levels and CB1 receptor density. OBJECTIVE: The aim of this study was to evaluate the influence of dopaminergic cell loss, induced by injection of 6-hydroxydopamine, on the effects exerted by cannabinoid agonists on neuron activity in the subthalamic nucleus (STN) of anesthetized rats. RESULTS: We have previously shown that Δ(9)-tetrahydrocannabinol (Δ(9)-THC) and anandamide induce both stimulation and inhibition of STN neuron activity and that endocannabinoids mediate tonic control of STN activity. Here, we show that in intact rats, the cannabinoid agonist WIN 55,212-2 stimulated all recorded STN neurons. Conversely, after dopaminergic depletion, WIN 55,212-2, Δ(9)-THC, or anandamide inhibited the STN firing rate without altering its discharge pattern, and stimulatory effects were not observed. Moreover, anandamide exerted a more intense inhibitory effect in lesioned rats in comparison to control rats. CONCLUSIONS: Cannabinoids induce different effects on the STN depending on the integrity of the nigrostriatal pathway. These findings advance our understanding of the role of cannabinoids in diseases involving dopamine deficits.