Vincent Ries

AFQ056 treatment of levodopa‐induced dyskinesias: Results of 2 randomized controlled trials

Study objectives were to assess the efficacy, safety, and tolerability of AFQ056 in Parkinsons disease patients with levodopa‐induced dyskinesia. Two randomized, double‐blind, placebo‐controlled, parallel‐group, in‐patient studies for Parkinsons disease patients with moderate to severe levodopa‐induced dyskinesia (study 1) and severe levodopa‐induced dyskinesia (study 2) on stable dopaminergic therapy were performed. Patients received 25–150 mg AFQ056 or placebo twice daily for 16 days (both studies). Study 2 included a 4‐day down‐titration. Primary outcomes were the Lang‐Fahn Activities of Daily Living Dyskinesia Scale (study 1), the modified Abnormal Involuntary Movement Scale (study 2), and the Unified Parkinsons Disease Rating Scale–part III (both studies). Secondary outcomes included the Unified Parkinsons Disease Rating Scale–part IV items 32–33. The primary analysis was change from baseline to day 16 on all outcomes. Treatment differences were assessed. Fifteen patients were randomized to AFQ056 and 16 to placebo in study 1; 14 patients were randomized to each group in study 2. AFQ056‐treated patients showed significant improvements in dyskinesias on day 16 versus placebo (eg, Lang‐Fahn Activities of Daily Living Dyskinesia Scale, P = .021 [study 1]; modified Abnormal Involuntary Movement Scale, P = .032 [study 2]). No significant changes were seen from baseline on day 16 on the Unified Parkinsons Disease Rating Scale‐part III in either study. Adverse events were reported in both studies, including dizziness. Serious adverse events (most commonly worsening of dyskinesias, apparently associated with stopping treatment) were reported by 4 AFQ056‐treated patients in study 1, and 3 patients (2 AFQ056‐treated patient and 1 in the placebo group) in study 2. AFQ056 showed a clinically relevant and significant antidyskinetic effect without changing the antiparkinsonian effects of dopaminergic therapy.

A new dopaminergic nigro-olfactory projection

Parkinson disease (PD) is a neurodegenerative disorder characterized by massive loss of midbrain dopaminergic neurons. Whereas onset of motor impairments reflects a rather advanced stage of the disorder, hyposmia often marks the beginning of the disease. Little is known about the role of the nigro-striatal system in olfaction under physiological conditions and the anatomical basis of hyposmia in PD. Yet, the early occurrence of olfactory dysfunction implies that pathogens such as environmental toxins could incite the disease via the olfactory system. In the present study, we demonstrate a dopaminergic innervation from neurons in the substantia nigra to the olfactory bulb by axonal tracing studies. Injection of two dopaminergic neurotoxins—1-methyl-4-phenylpyridinium and 6-hydroxydopamine—into the olfactory bulb induced a decrease in the number of dopaminergic neurons in the substantia nigra. In turn, ablation of the nigral projection led to impaired olfactory perception. Hyposmia following dopaminergic deafferentation was reversed by treatment with the D1/D2/D3 dopamine receptor agonist rotigotine. Hence, we demonstrate for the first time the existence of a direct dopaminergic projection into the olfactory bulb and identify its origin in the substantia nigra in rats. These observations may provide a neuroanatomical basis for invasion of environmental toxins into the basal ganglia and for hyposmia as frequent symptom in PD.

Intravenous iron sucrose for restless legs syndrome in pregnant women with low serum ferritin

We report on two pregnant women who either had de novo restless legs syndrome (RLS) or had marked enhancement of preexisting RLS symptoms during pregnancy. Both patients had ferritin values <50 μg/L at baseline. The patients had relevant sleep disorders and daytime symptoms caused by RLS. The women were treated in an open paradigm with intravenous iron sucrose. A few weeks after therapy, both patients experienced a significant reduction or even remission of RLS symptoms. Their quality of life and sleep substantially improved and no treatment-related adverse effects were observed. According to our initial experience, intravenous iron sucrose administration appears to be an effective therapy in RLS patients with low ferritin values during pregnancy.

Long-term treatment with L-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson's disease.

Non-motor symptoms such as hyposmia and depression are often observed in Parkinsons disease (PD) and can precede the onset of motor symptoms for years. The underlying pathological alterations in the brain are not fully understood so far. Dysregulation of adult neurogenesis in the dentate gyrus of the hippocampus and the olfactory bulb has been recently suggested to be implicated in non-motor symptoms of PD. However, there is so far no direct evidence to support the relationship of non-motor symptoms and the modulation of adult neurogenesis following dopamine depletion and/or dopamine replacement. In this study, we investigated the long-term effects of l-DOPA and pramipexole, a dopamine agonist, in a mouse model of bilateral intranigral 6-OHDA lesion, in order to assess the impact of adult neurogenesis on non-motor behavior. We found that l-DOPA and pramipexole can normalize decreased neurogenesis in the hippocampal dentate gyrus and the periglomerular layer of the olfactory bulb caused by a 6-OHDA lesion. Interestingly, pramipexole showed an antidepressant and anxiolytic effect in the forced swim test and social interaction test. However, there was no significant change in learning and memory function after dopamine depletion and dopamine replacement, respectively.

Mitochondrial dysfunction as a therapeutic target in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a sporadic and progressive neurodegenerative disease, most often leading to a symmetric, akinetic-rigid syndrome with prominent postural instability, vertical supranuclear gaze palsy, and cognitive decline. It belongs to the family of tauopathies and involves both cortical and subcortical structures. There is evidence from laboratory as well as in vivo studies suggesting that mitochondrial energy metabolism is impaired in PSP. Furthermore, several findings suggest that a failure in mitochondrial energy production might act as an upstream event in the chain of pathological events leading to the aggregation of tau and neuronal cell death. Agents targeting mitochondrial dysfunction have already shown a positive effect in a phase II study; however, further studies to verify these results need to be conducted. This review will focus on the pathophysiological concept of mitochondrial dysfunction in PSP and its possible role as a therapeutic target.

Selegiline normalizes, while l-DOPA sustains the increased number of dopamine neurons in the olfactory bulb in a 6-OHDA mouse model of Parkinson's disease

Olfactory dysfunction, often preceding the cardinal motor symptoms, such as bradykinesia, rigidity, tremor at rest and postural instability, is frequently reported in Parkinsons disease. This symptom appears to be related to an increased number of dopamine neurons in the periglomerular layer of the olfactory bulb. In animal models of Parkinsons disease, adult neural progenitor cells migrating from the subventricular zone of the lateral ventricle to the olfactory bulb are evidently altered in their survival and progeny. The modulation of neural progenitor cells contributing to the number of dopamine neurons in the periglomerular layer, however, is still poorly understood. In this study, we have investigated the survival and neuronal differentiation of newly generated cells in the olfactory bulb, following treatment with the dopamine precursor l-DOPA and the monoamine oxidase-B inhibitor selegiline in a unilateral, intranigral 6-hydroxydopamine lesion model in mice. Our data show that the number of neural progenitor cells in the subventricular zone is decreased after an intranigral 6-hydroxydopamine lesion, while there is no difference from control in lesioned mice with selegiline or l-DOPA treatment. Selegiline is able to normalize the number of dopamine neurons in the periglomerular layer, while l-DOPA treatment sustains the increased number observed in 6-hydroxydopamine lesioned animals. We conclude that there is a distinct modulation of newly generated dopamine neurons of the olfactory bulb after l-DOPA and selegiline treatment. The differential effects of the two drugs might also play a role in olfactory dysfunction in Parkinsons disease patients.

The PD-associated alpha-synuclein promoter Rep1 allele 2 shows diminished frequency in restless legs syndrome

Gain-of-function mutations of alpha-synuclein (SNCA) are known to trigger Parkinson’s disease (PD) with striatal dopaminergic deficits and a reduction of spontaneous movements. The longest size variant (allele 2) of the complex microsatellite repeat Rep1 within the SNCA gene promoter is known to confer a PD risk. We now observed this Rep1 allele 2 to show significantly decreased frequency in restless legs syndrome (RLS) in a genotyping study of 258 patients versus 235 healthy controls from Germany. Given that RLS is a disease with increased spontaneous movements and with increased striatal dopamine signaling, these novel data appear plausible. The scarcity of this alpha-synuclein gain-of-function variant in RLS might suggest that a low alpha-synuclein function via the SNARE complex in presynaptic vesicle release and neurotransmission of the striatum contributes to RLS pathogenesis.

Blood RNA biomarkers in prodromal PARK4 and rapid eye movement sleep behavior disorder show role of complexin 1 loss for risk of Parkinson's disease

ABSTRACT Parkinsons disease (PD) is a frequent neurodegenerative process in old age. Accumulation and aggregation of the lipid-binding SNARE complex component α-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity have been intensely investigated. In view of the physiological roles of SNCA in blood to modulate vesicle release, we studied blood samples from a new large pedigree with SNCA gene duplication (PARK4 mutation) to identify effects of SNCA gain of function as potential disease biomarkers. Downregulation of complexin 1 (CPLX1) mRNA was correlated with genotype, but the expression of other Parkinsons disease genes was not. In global RNA-seq profiling of blood from presymptomatic PARK4 indviduals, bioinformatics detected significant upregulations for platelet activation, hemostasis, lipoproteins, endocytosis, lysosome, cytokine, Toll-like receptor signaling and extracellular pathways. In PARK4 platelets, stimulus-triggered degranulation was impaired. Strong SPP1, GZMH and PLTP mRNA upregulations were validated in PARK4. When analysing individuals with rapid eye movement sleep behavior disorder, the most specific known prodromal stage of general PD, only blood CPLX1 levels were altered. Validation experiments confirmed an inverse mutual regulation of SNCA and CPLX1 mRNA levels. In the 3′-UTR of the CPLX1 gene we identified a single nucleotide polymorphism that is significantly associated with PD risk. In summary, our data define CPLX1 as a PD risk factor and provide functional insights into the role and regulation of blood SNCA levels. The new blood biomarkers of PARK4 in this Turkish family might become useful for PD prediction. Summary: Complexin 1 is a prodromal biomarker and risk factor for REM sleep behavior disorder and PARK4-associated Parkinsons disease.

Acylated and unacylated ghrelin confer neuroprotection to mesencephalic neurons

The polypeptide ghrelin is an endogenous ligand at the growth hormone secretagogue receptor 1a. To ghrelin multiple functions have been ascribed including promotion of gastrointestinal motility. Postprandial ghrelin levels have been reported to be reduced in patients suffering from Parkinson disease (PD). Experimental studies revealed neuroprotective effects of ghrelin in different PD models. The purpose of the present study was (i) to further elucidate the mechanism underlying the neuroprotective action of ghrelin and (ii) to determine whether these effects occur with both the acylated and the unacylated form. The study was conducted in primary mesencephalic cultures treated with mitochondrial complex I and complex II inhibitors. We show that protective effects of ghrelin against complex I inhibition with MPP+ were independent of the acylation status of ghrelin, although acylated ghrelin appeared to be more potent. Protection by both forms was also observed when neurons were exposed to the complex II inhibitor 3-NP. Both forms led to higher oxygen consumption rates upon electron transport chain uncoupling, indicating that the two peptides may exert uncoupling effects themselves. We demonstrate that the rescue provided by ghrelin required calcium influx through L-type voltage-gated calcium channels. Whereas the protective effects of acylated ghrelin required receptor binding, effects of the unacylated form remained unaffected by treatment with a ghrelin receptor antagonist. Importantly, inhibition of ghrelin O-acyltransferase failed to reduce the activity of unacylated ghrelin. Overall, our data suggest that both acylated and unacylated ghrelin afford protection to dopamine neurons but through mechanisms that only partially overlap.

Rodent Toxin Models of PD: An Overview

Publisher Summary This chapter provides an overview of the rodent toxin models of Parkinsons disease (PD). This chapter focuses on the 6-hydroxydopamine (6-OHDA) 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP), rotenone model and the paraquat model. Due to its structural similarities with dopamine and norepinephrine, 6-OHDA is efficiently taken up and accumulated by neurons that have catecholaminergic plasma membrane transporters for dopamine and norepinephrine, thus accounting for its relatively selective toxicity for monoaminergic neurons. Studies suggest that within neurons, its cytotoxic actions are associated with its ease of autoxidation. This is a complex process with simultaneous formation of reactive oxygen species (ROS), like hydrogen peroxide. Unlike the other neurotoxins used to induce PD models, 6-OHDA is an endogenous metabolite of dopamine, and has been detected in the human caudate nucleus. Thus, to the extent that oxidative metabolism of endogenous dopamine may play a role in human PD, 6-OHDA may model this process. This chapter gives an overview of the rodent toxin models and elaborates the strengths and weaknesses of the neurotoxin models in detail.