Wassilios G. Meissner

Priorities in Parkinson's disease research

The loss of dopaminergic neurons in the substantia nigra pars compacta leads to the characteristic motor symptoms of Parkinsons disease: bradykinesia, rigidity and resting tremors. Although these symptoms can be improved using currently available dopamine replacement strategies, there is still a need to improve current strategies of treating these symptoms, together with a need to alleviate non-motor symptoms of the disease. Moreover, treatments that provide neuroprotection and/or disease-modifying effects remain an urgent unmet clinical need. This Review describes the most promising biological targets and therapeutic agents that are currently being assessed to address these treatment goals. Progress will rely on understanding genetic mutations or susceptibility factors that lead to Parkinsons disease, better translation between preclinical animal models and clinical research, and improving the design of future clinical trials.>

Dopamine depletion increases the power and coherence of β-oscillations in the cerebral cortex and subthalamic nucleus of the awake rat

Local field potentials (LFPs) recorded from the subthalamic nucleus (STN) of untreated patients implanted with stimulation electrodes for the treatment of Parkinsons disease (PD) demonstrate strong coherence with the cortical electroencephalogram over the β‐frequency range (15–30 Hz). However, studies in animal models of PD emphasize increased temporal coupling in cortico‐basal ganglia circuits at substantially lower frequencies, undermining the potential usefulness of these models. Here we show that 6‐hydroxydopamine (6‐OHDA) lesions of midbrain dopamine neurons are associated with significant increases in the power and coherence of β‐frequency oscillatory activity present in LFPs recorded from frontal cortex and STN of awake rats, as compared with the healthy animal. Thus, the pattern of synchronization between population activity in the STN and cortex in the 6‐OHDA‐lesioned rodent model of PD closely parallels that seen in the parkinsonian human. The peak frequency of coherent activity in the β‐frequency range was increased in lesioned animals during periods of spontaneous and sustained movement. Furthermore, administration of the dopamine receptor agonist apomorphine to lesioned animals suppressed β‐frequency oscillations, and increased coherent activity at higher frequencies in the cortex and STN, before producing the rotational behaviour indicative of successful lesion. Taken together, these results support a crucial role for dopamine in the modulation of population activity in cortico‐basal ganglia circuits, whereby dopaminergic mechanisms effectively filter out synchronized, rhythmic activity at β‐frequencies at the systems level, and shift temporal couplings in these circuits to higher frequencies. These changes may be important in regulating movement.

Competition between Feedback Loops Underlies Normal and Pathological Dynamics in the Basal Ganglia

Experiments performed in normal animals suggest that the basal ganglia (BG) are crucial in motor program selection. BG are also involved in movement disorders. In particular, BG neuronal activity in parkinsonian animals and patients is more oscillatory and more synchronous than in normal individuals. We propose a new model for the function and dysfunction of the motor part of BG. We hypothesize that the striatum, the subthalamic nucleus, the internal pallidum (GPi), the thalamus, and the cortex are involved in closed feedback loops. The direct (cortex–striatum–GPi–thalamus–cortex) and the hyperdirect loops (cortex–subthalamic nucleus–GPi–thalamus–cortex), which have different polarities, play a key role in the model. We show that the competition between these two loops provides the BG–cortex system with the ability to perform motor program selection. Under the assumption that dopamine potentiates corticostriatal synaptic transmission, we demonstrate that, in our model, moderate dopamine depletion leads to a complete loss of action selection ability. High depletion can lead to synchronous oscillations. These modifications of the network dynamical state stem from an imbalance between the feedback in the direct and hyperdirect loops when dopamine is depleted. Our model predicts that the loss of selection ability occurs before the appearance of oscillations, suggesting that Parkinsons disease motor impairments are not directly related to abnormal oscillatory activity. Another major prediction of our model is that synchronous oscillations driven by the hyperdirect loop appear in BG after inactivation of the striatum.

The natural history of multiple system atrophy: a prospective European cohort study

Summary Background Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA. Methods Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years. Vital status was ascertained 2 years after study completion. Disease progression was assessed using the unified MSA rating scale (UMSARS), a disease-specific questionnaire that enables the semiquantitative rating of autonomic and motor impairment in patients with MSA. Additional rating methods were applied to grade global disease severity, autonomic symptoms, and quality of life. Survival was calculated using a Kaplan-Meier analysis and predictors were identified in a Cox regression model. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Sample size estimates were calculated using a paired two-group t test. Findings 141 patients with moderately severe disease fulfilled the consensus criteria for MSA. Mean age at symptom onset was 56·2 (SD 8·4) years. Median survival from symptom onset as determined by Kaplan-Meier analysis was 9·8 years (95% CI 8·1–11·4). The parkinsonian variant of MSA (hazard ratio [HR] 2·08, 95% CI 1·09–3·97; p=0·026) and incomplete bladder emptying (HR 2·10, 1·02–4·30; p=0·044) predicted shorter survival. 24-month progression rates of UMSARS activities of daily living, motor examination, and total scores were 49% (9·4 [SD 5·9]), 74% (12·9 [8·5]), and 57% (21·9 [11·9]), respectively, relative to baseline scores. Autonomic symptom scores progressed throughout the follow-up. Shorter symptom duration at baseline (OR 0·68, 0·5–0·9; p=0·006) and absent levodopa response (OR 3·4, 1·1–10·2; p=0·03) predicted rapid UMSARS progression. Sample size estimation showed that an interventional trial with 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power. Interpretation Our prospective dataset provides new insights into the evolution of MSA based on a follow-up period that exceeds that of previous studies. It also represents a useful resource for patient counselling and planning of multicentre trials. Funding Fifth Framework Programme of the European Union, the Oesterreichische Nationalbank, and the Austrian Science Fund.

Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson's disease.

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa (L-dopa) therapy for Parkinsons disease (PD). L-dopa-induced dyskinesia (LID) are ultimately experienced by the vast majority of patients. In addition, psychiatric conditions often manifested as compulsive behaviours, are emerging as a serious problem in the management of L-dopa therapy. The present review attempts to provide an overview of our current understanding of dyskinesia and other L-dopa-induced dysfunctions, a field that dramatically evolved in the past twenty years. In view of the extensive literature on LID, there appeared a critical need to re-frame the concepts, to highlight the most suitable models, to review the central nervous system (CNS) circuitry that may be involved, and to propose a pathophysiological framework was timely and necessary. An updated review to clarify our understanding of LID and other L-dopa-related side effects was therefore timely and necessary. This review should help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptoms.

Late emergence of synchronized oscillatory activity in the pallidum during progressive parkinsonism

Parkinsons disease is known to result from basal ganglia dysfunction. Electrophysiological recordings in parkinsonian patients and animals have shown the emergence of abnormal synchronous oscillatory activity in the cortico‐basal ganglia network in the pathological condition. In addition, previous studies pointed out an altered response pattern during movement execution in the pallidum of parkinsonian animals. To investigate the dynamics of these changes during disease progression and to relate them to the onset of the motor symptoms, we recorded spontaneous and movement‐related neuronal activity in the internal pallidum of nonhuman primates during a progressive dopamine depletion process. Parkinsonian motor symptoms appeared progressively during the intoxication protocol, at the end of which both animals displayed severe akinesia, rigidity and postural abnormalities. Spontaneous firing rates did not vary significantly after intoxication. During the early phase of the protocol, voluntary movements were significantly slowed down and delayed. At the same time, the neuronal response to movement execution was modified and inhibitory responses disappeared. In contrast, the unitary and collective dynamic properties of spontaneous neuronal activity, as revealed by spectral and correlation analysis, remained unchanged during this period. Spontaneous correlated activity increased later, after animals became severely bradykinetic, whereas synchronous oscillatory activity appeared only after major motor symptoms developed. Thus, a causality between the emergence of synchronous oscillations in the pallidum and main parkinsonian motor symptoms seems unlikely. The pathological disruption of movement‐related activity in the basal ganglia appears to be a better correlate at least to bradykinesia and stands as the best candidate to account for this motor symptom.

Targeting α-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations

Progressive neuronal cell loss in a small subset of brainstem and mesencephalic nuclei and widespread aggregation of the α-synuclein protein in the form of Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinsons disease. Most cases occur sporadically, but mutations in several genes, including SNCA, which encodes α-synuclein, are associated with disease development. The discovery and development of therapeutic strategies to block cell death in Parkinsons disease has been limited by a lack of understanding of the mechanisms driving neurodegeneration. However, increasing evidence of multiple pivotal roles of α-synuclein in the pathogenesis of Parkinsons disease has led researchers to consider the therapeutic potential of several strategies aimed at reduction of α-synuclein toxicity. We critically assess the potential of experimental therapies targeting α-synuclein, and discuss steps that need to be taken for target validation and drug development.

Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria.

Background: PSP is a neuropathologically defined disease entity. Clinical diagnostic criteria, published in 1996 by the National Institute of Neurological Disorders and Stroke/Society for PSP, have excellent specificity, but their sensitivity is limited for variant PSP syndromes with presentations other than Richardsons syndrome.

Coordinated reset has sustained aftereffects in Parkinsonian monkeys

Coordinated reset neuromodulation consists of the application of consecutive brief high‐frequency pulse trains through the different contacts of the stimulation electrode. In theoretical studies, by achieving unlearning of abnormal connectivity between neurons, coordinated reset neuromodulation reduces pathological synchronization, a hallmark feature of Parkinsons disease pathophysiology. Here we show that coordinated reset neuromodulation of the subthalamic nucleus has both acute and sustained long‐lasting aftereffects on motor function in parkinsonian nonhuman primates. Long‐lasting aftereffects were not observed with classical deep brain stimulation. These observations encourage further development of coordinated reset neuromodulation for treating motor symptoms in Parkinson disease patients. ANN NEUROL 2012;72:816–820

High-frequency stimulation of the subthalamic nucleus enhances striatal dopamine release and metabolism in rats

High‐frequency stimulation of the subthalamic nucleus is believed to exert its main effects via the basal ganglia output structures. Previously, we have shown a concomitant increase in striatal dopamine (DA) metabolites in normal and 6‐hydroxydopamine‐lesioned rats. The present study was designed to determine whether this increase in striatal DA metabolites reflects enhanced intraneuronal DA turnover or, alternatively, is due to increased DA release with subsequent rapid and efficient reuptake and/or metabolism. Thus, high‐frequency stimulation of the subthalamic nucleus was performed in normal rats after inhibition of DA reuptake, metabolism or DA depletion. Extracellular levels of striatal DA and its metabolites were assessed using microdialysis. Our data suggest that subthalamic high‐frequency stimulation increases striatal DA release and activates independent striatal DA metabolism. Since such changes could be triggered by modification of either the activity or the gene expression of the rate‐limiting enzyme tyrosine hydroxylase, an activity assay and RT‐PCR of striatal and nigral samples were performed. Subthalamic stimulation increased striatal tyrosine hydroxylase activity without affecting gene expression. We, therefore, conclude that the application of subthalamic high‐frequency stimulation could partially compensate for the DA deficit by inducing increased striatal DA release and metabolism.