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.

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.

Levodopa-induced dyskinesias in Parkinson disease are independent of the extent of striatal dopaminergic denervation: a pharmacological and SPECT study.

The physiopathology of levodopa-induced dyskinesias (LIDs) is unclear. Presynaptic pharmacokinetic and postsynaptic pharmacodynamic mechanisms may be involved. We have analyzed several clinical and pharmacological parameters, as well as the status of the presynaptic dopamine nigrostriatal pathway by using DaTSCAN, in 14 patients with Parkinson disease who developed early and severe LID despite using low doses of levodopa and 10 patients without this complication despite the use of high levodopa doses. Patients were matched for age at onset, duration, and severity of Parkinson disease. Statistically significant differences were observed only in the duration of LID during the levodopa challenge. However, clear differences were also observed in weight and sex distribution (women with low weight predominate in the group with dyskinesia), severity and duration of LID, and total levodopa dosage. The pattern of response to levodopa and the uptake of (123I)N-w-fluoropropyl-2[beta]-carbomethoxy-3[beta]-(4-iodophenyl)nortropane were similar in both groups. These results indicate that the development of LID needs additional contributions beyond nigrostriatal denervation. Factors related to sex and body weight could play an important role. However, these findings should be considered cautiously because of the limited statistical power of the study.

II Encuentro Nacional de Expertos en Enfermedad de Parkinson: Madrid, 6-7 de Febrero de 2009 / 2nd National Parkinson's Disease Expert Meeting

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Dopamine dysregulation syndrome and levodopa-induced dyskinesias in Parkinson disease: common consequences of anomalous forms of neural plasticity.

Four to 10% of patients with Parkinson disease and chronically treated with levodopa undergo an addictionlike behavioral disturbance named dopamine dysregulation syndrome (DDS). This article suggests that patients with Parkinson disease could be especially prone to develop DDS due to the dopamine deficiency and the "priming" of neural networks by the chronic use of drugs with a short half-life, such as levodopa. These suggestions are based on the clinical and molecular similarities between levodopa-induced dyskinesias and behavioral alterations seen in DDS and addiction to illegal drugs. Motor and behavioral abnormalities can be seen as the consequence of common mechanisms involving anomalous forms of neural plasticity. These forms affect parts of the cortical-basal ganglia-thalamocortical circuits that are topographically organized to differently modulate emotional and motor functions. Recent evidence using positron emission tomography provides support to this idea. By contrast, molecular data suggest that functional segregation may be lost in addiction, DDS, and dyskinesias. The existence of common pathogenic mechanisms for both phenomena could provide the basis for common therapeutic strategies.

I Encuentro Nacional de Expertos en Enfermedad de Parkinson: Madrid 28-29 de Marzo de 2008 / 1st National Parkinson's Disease Expert Meeting

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Conversion from dopamine agonists to cabergoline: an open-label trial in 128 patients with advanced Parkinson disease.

BACKGROUND: Cabergoline is an ergotic dopamine agonist with D2 receptor activity and a very long half-life. This pharmacological profile may result in clinically different effects. Small clinical trials indicate that overnight switching from 1 agonist to another can be performed safely. OBJECTIVE: To determine safety and efficacy of overnight switching from dopamine agonists to cabergoline in patients with advanced Parkinson disease (PD). METHODS: Patients with advanced PD and motor complications not optimally controlled by levodopa and a stable dose of bromocriptine, pergolide, pramipexole, and ropinirole were converted to cabergoline overnight. Patients were assessed by using an on-off diary, Unified Parkinson Disease Rating Scale (subscales I-IV), Parkinson's Disease Quality of Life 8 (PDQ-8), an ad hoc sleep questionnaire and an ad hoc off-period severity questionnaire. All rating scales were administered just before conversion and after 2, 6, and 12 weeks of treatment, when patients were on an optimal dose of cabergoline. Adverse effects were assessed at every visit following a check list. RESULTS: One hundred twenty-eight patients were included in the trial. Forty were on pergolide (mean dose, 2.8 mg/d), 38 on pramipexole (mean dose, 2.1 mg/d), and 32 on ropinirole (mean dose, 8.1 mg/d). Patients on bromocriptine (n = 18) were excluded from the analysis because of the small sample size. Three patients reported serious side effects (respiratory arrest, dyskinesias, and face edema and abdominal pain). Twenty-eight patients reported 41 adverse events. Twelve patients were withdrawn due to adverse effects (hallucinations [n = 5], dyspnea [n = 1], dizziness [n = 4], and vascular problems [n = 2]). A significant improvement in assessed parameters was obtained (P < 0.0001). Mean levodopa dose remained unchanged. After 12 weeks, the mean dose of cabergoline was 3.2 mg, and 25% of patients were taking the drug twice a day. CONCLUSIONS: Switching from pergolide, ropinirole, and pramipexole to cabergoline in an overnight schedule is safe. The observed clinical improvement may be related to a placebo effect, to the use of low doses of dopamine agonists, or to a direct effect of cabergoline.

Tratamiento quirúrgico de la enfermedad de Parkinson: ¿es hora de cambiar el momento de la indicación? / No disponible

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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.

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.

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.

Prevalence of tic disorder in two schools in the Basque country: Results and methodological caveats.

Different studies have shown that the prevalence of tic disorder is highly variable, depending on the methodology employed. The aim of this study was to determine the prevalence of tic disorder among children of two schools. The study was conducted in three successive steps: information to parents and teachers by way of speeches and projection of videotapes; anonymous fulfilling of an ad hoc questionnaire by teachers and parents and identification of children as "possible tic disorder" according to the questionnaire; and confirmation of the presence of tics by direct observation of children at school (20 minutes in each classroom). Eight hundred sixty-seven children were included. Age ranged from 4 to 16 years. Ninety percent of parents and 99% of teachers fulfilled the questionnaire. Seventy-one children had tics according to parents' and 50 according to teachers' opinion (both coincided in 23 cases). Fifty-seven cases were identified after direct observation in the classroom (prevalence of 6.5%). The vast majority of tics were mild in severity and duration. Prevalence obtained in this study was comparable with data reported in studies using a similar methodology, which is higher than results shown in early studies addressed with less rigid methodology. Most of identified cases were quite mild, not leading to major functional disability. In spite of the methodology employed, it is possible that some cases were lost.

Impact of fatigue in Parkinson's disease: the Fatigue Impact Scale for Daily Use (D-FIS).

The Fatigue Impact Scale for Daily Use (D-FIS) was used in a cross-sectional study including 142 consecutive Parkinson's disease (PD) patients. Usual clinical measures for PD, the Montgomery-Asberg Depression Rating Scale and the Parkinson's Disease Questionnaire-8 items were applied. In addition to the D-FIS, patients with fatigue (67.6%, PWF) completed the Multidimensional Fatigue Inventory (MFI), a visual analogue scale for fatigue (VAS-F) and a Global Perception of Fatigue scale (GPF). Relevant psychometric D-FIS results were: floor effect = 4.2%; ceiling effect = 1.1%; skewness = 0.44; item homogeneity = 0.63; Cronbach's alpha = 0.93; item-total correlation = 0.68 (item 1)-0.82 (item 8); standard error of measurement = 2.15; convergent validity with other fatigue measures = 0.54 [GPF]-0.62 [VAS-F] (p<0.001). In a multiple linear regression model, fatigue, depression, and disability independently influenced HRQoL, as measured by the PDQ-8. Patients on amantadine had lower prevalence of fatigue. In PD, D-FIS is a consistent and valid measure for fatigue, a frequent symptom previously found to impair patients' HRQoL. Fatigue was also linked to depression and disability in this study.