World Congress on PD & Related Disorders

Both case-control and incident epidemiological studies in different ethnic populations have shown that tea drinking is associated with a dose-dependent reduction of risk for Parkinson´s disease (PD). To evaluate the safety, tolerability, and efficacy of green tea polyphenols (GTP) in slowing disease progression in patients with early PD, we carried out a multi-center, double-blind, randomized, placebo‑controlled, delayed start study in 32 Chinese Parkinson Study Group (CPSG) sites. Four hundred and ten untreated PD patients with disease duration < 5 years and Hoehn & Yahr Stage < 3 who were not heavy tea drinkers were randomized to one of three doses of GTP (0.4, 0.8 or 1.2 grams daily given in 2 equal oral doses) or matching placebo. After 6 months, placebo was switched to 1.2 grams daily of GTP. All patients were treated for 12 months. The change in total UPDRS score from randomization to 6 months was significantly improved in GTP treated groups as compared to the placebo group but this was not observed at 12 months. In the delayed start group, the change in UPDRS at 6 months (the start of active GTP) to 12 months was significantly improved. Insomnia was slightly increased in GTP treated patients, but there were no other significant differences in adverse effects. In conclusion, GTP is well tolerated and appears to provide, at least, a mild symptomatic benefit in early untreated PD.

Supported by the Michael J Fox Foundation

Author(s): P. Chan^1,2,3,4, Z. Qin^1,2, Z. Zheng¹, L. Zhang², X. Fang^1,5, F. Sun^1,5, Z. Gu², S. Chen⁶, J. Ma², C. Meng⁷, J.W. Langston⁷, C.M. Tanner⁷, Chinese Parkinson Study Group

¹Beijing Institute of Geriatrics, ²Neurology, ³Neurobiology, ⁴Geriatrics, ⁵Epidemiology and Social Medicine, Xuanwu Hospital of Capital Medical University, Beijing, ⁶Neurology, Ruijin Hospital of Shanghai Jiaotong University, Shanghai, China, ⁷The Parkinson's Institute, Sunnyvale, CA, USA

P1.217 Decreased putamen aldehyde dehydrogenase in Parkinson disease

D. Goldstein, P. Sullivan, C. Holmes, I. Kopin, M. Basile

NINDS, NIH Bethesda, MD and University of Miami Miller School of Medicine, Miami

Aldehyde dehydrogenase (ALDH) might be a new answer to the old question: What is special about dopaminergic neurons (of the substantia nigra) that they undergo cell death to a greater extent than other neuronal phenotypes.  They have dopamine and the dopamine transporter, but they also rely on ALDH to convert the highly toxic dopamine metabolite dihydroxyphenylacetaldehyde (DOPAL) to dihydroxyphenylacetic acid (DOPAC). A build up of DOPAL caused by lower activity or expression of ALDH would be severely toxic for the cell and could be a key player in dopaminergic neuron cell death (“catecholaldehyde hypothesis”, see discussions by Dr. Burke on the topic on PD online for references). Surely this idea can and has been tested in models, but is it relevant to human patients? Dr. Goldstein is able to answer this question by using a novel HPLC assay, sensitive enough to pick up DOPAL in post-mortem brain tissue of PD patients and controls. He showed that the severe loss of dopamine in his patients (2% of controls) was accompanied by 10 times higher DOPAL levels (related to given dopamine content) compared to control. A 25% lower DOPAC/DOPAL ratio suggests that the conversion of DOPAL to DOPAC is reduced, indicating a malfunction of the ALDH pathway. Interestingly, this effect was greater in the putamen than in caudate. During the discussion Dr. Goldstein pointed out, that DOPAL could also be converted by another enzyme, DOPAC reductase to dihydroxyphenylethanol (DOPET), which has been shown to be neuroprotective (Hydroxytyrosol, in Olives). He knows that this enzyme happens to be the key enzyme in catecholamine metabolism of noradrenergic neurons (toxic metabolite here: 3,4-Dihydroxyphenylglycolaldehyde (DOPEGAL)). Dr. Goldstein hypothesized that if there is a specific defect in the ALDH pathway, dopaminergic neurons would be more affected than noradrenergic neurons. Indeed, ALDH expression has been shown to be reduced in microarray (see Moussa Youidim on the topic with relation to rasagiline for references) studies on patient material.

The second poster presented by the author relates to these findings:

P1.013 Independence of striatal dopaminergic and cardiac noradrenergic denervation in synucleinopathies

D. Goldstein, CNP/DIR/NINDS/NIH, Bethesda, MD, USA

Here Dr. Goldstein compares patients with PD and pure autonomic failure (PAF) regarding their 6-[18F]-Fluorodopa radioactivity in the interventricular septal myocard and the putamen. This is relevant to further describe cardio-vascular deficits as e.g. orthostatic hypotension (OH) as common symptom in Parkinson’s disease. As expected, PAF patients and PD patients with orthostatic hypotension show reduced radioactivity in the heart. However, only PD patients show reduced radioactivity in the putamen although PAF patients did show a reduction in the substantia nigra. This indicates that in the nigrostriatal system, different mechanisms are involved. Dr. Goldstein points out that in PAF the pathology predominantly affects the noradrenergic system. Why do some PD patients express more of the features of PAF than others? Dr. Goldstein said that one explanation might be the pathogenesis. If for example a lower function of the vesicular monoamine transporter is present, one would find higher levels of different catecholamines in the cytoplasm which might lead to increased levels of toxic metabolites in noradrenergic neurons as well. Surely, there are many experiments that need to be done, but we have the in vivo and in vitro models to solve those intriguing questions. And just to make it a little more complex, glia cells could be involved as well.

Many exciting things at the WFN Congress in Miami today, but for me the highlight was a newly nominated gene for PD, EIF4G1, presented in both poster and platform forums by Matt Farrer, Mayo Clinic Jacksonville.  Matt, working with Marie-Christine Chartier-Harlin in Lille and several other groups worldwide, reported that several different mutations in dominantly inherited PD were found by a combination of linkage analysis and whole exome sequencing.  Additional mutations were found in smaller families, all of which appear to have typical age of onset PD with Lewy bodies.

As well as the excitement of a new gene, there is a bigger potential impact because eIF4G1 is known to interact with other proteins in the 4EBP/eIF4E system.  This is interesting as eIF4E is important in control of protein translation particular under stressful situtations.  This system has been proposed to be a potential point of convergence in several PD models.  Matt presented functional work in cell models that suggested mutant eIF4G1 protein has a loss of function.  The presented implication is that several 'types' of PD are actually related by virtue of impact on a common molecular pathway.  Obvious next steps for the geneticists will be to find additional families and characterize normal polymorphic variation so that further functional studies can be directed towards pathogenic mutations.

In several discussions at this WFN conference it was emphasized that non-motor symptoms are critical for the quality of life in patients. In the poster cited below, Lena and Meike found that the patient perception of quality of life (WHO scale) is mostly correlated with non-motor symptoms, whereby the score in Beck Depression Inventory (BDI) had a high impact on all outcomes. Meike explained that although depression is common in PD it is often under-diagnosed and the specific symptoms are poorly described. Only some of the symptoms are covered by the UPDRS. In a detailed assessment using BDI she could show that PD patients express symptoms of depression similar to major depression, although “feeling less dispirited” and “guilty” were perceived as less important. “Mood” and “motivation” as assessed in UPDRS might therefore be less sensitive to depressive syndromes in PD. Being part of the departments of Psychiatry and Neurology, Lena and Meike are convinced that PD patients would greatly benefit from the more thorough use of diagnostic tools and therapeutic interventions available for major depression. Lena emphasizes that she found a higher impairment in the quality of life in patients with an onset age < 50 years, indicating that this group deserves more attention.

P1.044/P1.139: Characteristics of Depression in PD/Determinants of Quality of Life in PD.  Lena Kertelge, Meike Kasten et al., Psychiatry and Psychotherapy, Neurology, University of Luebeck, Germany

At WFN, in the poster cited below, neurologist Dr. Mandar Jog and speech language pathologists Angie South and Stephanie Somers of the London Health Sciences Centre (LHSC) investigate possible treatments for a specific symptom of PD that severely impacts the life quality of PD patients: drooling. The cause of drooling is a reduced swallowing frequency leading to saliva overflow, although saliva production itself is lower compared to controls. Neurologists often recommend the use of chewing gum to their patient as this seems to have a beneficial effect. However, there is currently no empirical study published on outcome in patients, and the mechanisms involved are not clear. The team conducted a study in 20 PD patients measuring swallowing before, during and after gum chewing. The patients have not been informed about the purpose of the study and which measures are taken. The examiners carefully controlled for olfactory or visual cues that could increase saliva flow. Angela explained to me that it is not sufficient to only record the movement of the larynx, as PD patients often show a laryngeal wave that is not accompanied by a completed swallow. She used an additional bellow around the chest to measure swallowing apnoe, visible as a flattening of the respiratory wave.

Five minutes of gum chewing significantly increased the frequency and decreased the latency of swallowing compared to baseline. Interestingly, the effect was still present for another 5 minutes after the gum was removed. This indicates that chewing might directly modulate the sensory-motor system involved in the swallowing deficits in patients and that this effect can last beyond the treatment. Angela says that the swallowing frequency and latency achieved by gum chewing was comparable to control subjects described in the literature of dental care. Dentist find that gum chewing increases the production of saliva and Angela hypothesizes that this could take part in the induction of swallowing in her patients. Interestingly, positive effects known by dentists as e.g. reducing the acidity of saliva could be beneficial for PD patients as well. Gum chewing can lead to extensive exercise of facial and pharyngeal muscles as well as the tongue, which could have further beneficial effects. Based on these initial data the group will now start a more extensive study with longer treatment and post treatment periods in on and off state, including measures of saliva production and visualizing of muscle contractions using imaging techniques. Angela proposes that this study will help to better understand the symptoms involving larynx, pharynx and tongue movements and the beneficial effects of gum chewing.

P2.162 Chewing gum significantly improves swallow frequency and latency in patients with Parkinson’s disease.  Angela South, Mandar Jog, Stephanie Somers, University of Western Ontario, ON, Canada

Dr. Stefanis argued that it is the synergy of multiple pieces of evidence from Mendelian genetics, population genetics, human pathology, animal models and biochemistry that suggests that alpha-synuclein is critical in PD pathogenesis.  The recent GWAS study cementing the relationship of alpha-synuclein to sporadic disease was highlighted in this context.  This study, together with the duplication and triplication cases, which show that excess of even WT alpha-synuclein leads to PD, suggest that elements within the SNCA gene involved in transcriptional control may be key factors in PD pathogenesis.  Little is known, however, regarding factors in the SNCA gene regulating alpha-synuclein transcription.  Apart from the regulatory role of the NACP/Rep1 region, recent evidence indicates that areas within the Intron 1 of the gene, and in particular the transcription factors GATA2 and ZSCAN21, are also involved in alpha-synuclein transcriptional control.  Protein levels however are regulated also by rates of degradation.  Recent evidence suggests that alpha-synuclein in cultured primary neurons, including those derived from ventral midbrain, is degraded by two lysosomal pathways: Chaperone-Mediated Autophagy (CMA) and macroautophagy.  Although monomeric alpha-synuclein is not degraded by the 26S proteasome, very select soluble oligomeric species of alpha-synuclein are degraded by this pathway, while simultaneously inhibiting it.  A similar picture emerges for the effects of alpha-synuclein on lysosomes: aberrant monomeric alpha-synuclein impacts lysosomal function and survival via inhibition of CMA, the pathway that degrades it.  A compensatory induction of macroautophagy that occurs in this setting is deleterious, and leads to autophagic death.  Therefore, caution was suggested against approaches that may boost macroautophagy, as these may accelerate autophagic cell death in the context of aberrant alpha-synuclein. These studies lend support to the notion that enhancing CMA degradation may “kill two birds with one stone”, on the one hand by promoting alpha-synuclein degradation and, on the other, by attenuating alpha-synuclein-mediated toxicity.   Indeed, preliminary data suggest that overexpression of Lamp2a, the rate-limiting step in the CMA pathway, offers resistance against alpha-synuclein-mediated neurotoxicity in neuroblastoma cells.   

Dr. Sulzer presented the concept of the potentially deleterious effects of raised cytosolic dopamine.  He made the point that all humans engage macroautophagy in order to sequester potentially toxic conformers of dopamine and its metabolites in neuromelanin granules, which are actually autophagic vacuoles. Through a technique developed in his lab, Dr. Sulzer has been able to reliably measure cytosolic dopamine.  The toxic effects of extracellular dopamine applied to the cultures depend on the amount of cytosolic dopamine.  L-type Calcium channel blockers are able to suppress cytosolic dopamine accumulation and death induced by dopamine in primary ventral midbrain cultures, although the mechanism through which such blockers influence cytosolic dopamine concentration is unclear.  Interestingly, in such studies, noradrenergic and SN dopaminergic neurons underwent L-type Calcium channel-dependent neurodegeneration, whereas VTA doapminergic neurons did not.

Now, to alpha-synuclein: In addition from the well-known rescue effect of lack of alpha-synuclein on MPTP-induced neurodegeneration, lack of alpha-synuclein is also protective against dopamine-induced toxicity in cultured ventral midbrain neurons, even though cytosolic dopamine is equally elevated.  This suggests effects of alpha-synuclein downstream of cytsolic dopamine accumulation.  What could these effects be?  An answer may lie in the formation of wild type alpha-synuclein-dopamine adducts, that, according to a recent paper by Martinez-Vicente et al. (2008), inhibit the process of CMA mentioned earlier.  In order to assess alpha-synuclein-dopamine interactions in an in vivo setting, Dr. Sulzer has been applying Dopamine, together with benserazide, to mice overexpressing alpha-synuclein under the TH promoter.  Preliminary data show that these mice manifest motor deficits and loss of striatal dopamine, supporting the idea of an aberrant dopamine-alpha-synuclein interaction.  Taken together, these studies provide rationale for therapies, especially, in the context of alpha-synuclein, directed against the interaction of alpha-synuclein with dopamine and the deleterious effects on CMA.  

Dr. Chesselet presented data regarding the analysis of the Masliah mice expressing wild type alpha-synuclein, under the Thy-1 promoter.  These mice demonstrate progressive loss of striatal dopamine, which is apparent at 14 months of age.   Importantly, however, at younger ages these mice demonstrate a host of other abnormalities, including impaired olfaction and anxiety/depression-related behaviours.  Furthermore, at this early stage, they also demonstrate a variety of sensorimotor deficits that are detected by challenging motor tasks, and are non-dopaminergic.  Around the same time, deficits emerge in the noradrenergic system, which may be in part responsible for the observed phenotypes.  The constellation of these early abnormalities may have analogies to pre-manifest PD, and may offer the opportunity for testing therapies targeted at these early stages of the disease process. Dr. Chesselet clarified that these early abnormalities are not linked to overt neuronal degeneration, and are likely due to neuronal circuit dysfunction, presumably due to the aberrant folding of alpha-synuclein, whose deposition in the form of aggregates and inclusions occurs within the first two months of life of these mice.   Interestingly, laser capture microdissection of SN neurons at the early stages reveals significant, likely beneficial, compensatory responses in various pathways, including autophagy and antioxidant responses, which may serve to protect these neurons from the alpha-synuclein insult.  Collectively, these studies indicate that the widespread dysfunction of many systems in these mice has analogies to the situation in PD.

Highlights:

A)    Preliminary results suggest that boosting of the CMA pathway via Lamp2a overexpression may represent a therapeutic strategy against the toxic effects of alpha-synuclein.

B)    Preliminary results suggest that the concept of synergistic toxicity between dopamine and alpha-synuclein in dopaminergic neurons may hold true in a mouse model.

C)    Preliminary results suggest that noradrenergic, but not dopaminergic, deficits may be related to early defects in widespread neuronal circuits due to aberrant accumulation of alpha-synuclein in the Thy-1 mouse model.

Dr. Anthony Lang has posted his slides from his introductory presentation on "How Do We Define PD?" at the 2009 WFN World Congress:

At present, the thalamus has been regarded as a relay station between the basal ganglia output and the cerebral cortex. However, more recently it has been realized that the thalamus also is an important source of glutamatergic innervation reaching most of the basal ganglia nuclei, those including the striatum and the subthalamic nucleus. Indeed, neurons giving rise to thalamostriatal and thalamosubthalamic projections are known to be hyperactive following dopaminergic depletion. Furthermore and besides thalamic hyperactivity, it has also been shown the presence of primary, non-dopaminergic, ongoing neurodegenerative changes in several thalamic nuclei, with special incidence at the level of the caudal intralaminar nuclei.

Taken together, these data have settled the basis for an ongoing debate focused on whether or not the caudal intralaminar nuclei could be regarded as a potential surgical target for deep brain stimulation within the context of movement disorders of basal ganglia origin.

Three outstanding speakers have participated in the Parallel Session entitled “Thalamic Changes in PD”

First speaker was Dr. Glenda Halliday from Sydney University, Australia. Dr. Halliday is one of the best known neuropathologists in the field of movement disorders. In the year 2000 her group has published two seminal papers (one in Brain, the other one in Annals of Neurology) reporting for the first time the existence of neurodegenerative changes at the level of the centromedian-parafascicular thalamic complex in brains of patients suffering from Parkinson’s disease. Her findings have also been confirmed by several laboratories using animal models of Parkinson’s disease. Within her talk, Dr. Halliday has reviewed her most recent data showing the presence of a remarkable number of neurodegenerative changes within the thalamic intralaminar nuclei, those comprising –among others- deposits of alpha-synuclein, Lewy body-like pathologies and neuronal cell loss.

Second speaker was Dr. Yoland Smith from the Yerkes National Primate Research Center at Emory University, Atlanta. Dr. Smith has a deep expertise in basal ganglia neuromorphology and the work he has been carried out during the past Decades is a source of inspiration for all of us. I am proud to say that most of our current understanding on the thalamostriatal pathway has been gathered from his contributions. In his talk, Dr. Smith’s talk was focused on the analysis of plastic changes induced in dendritic spines of striatal medium-sized spiny neurons as a consequence of dopaminergic lesion in MPTP-treated monkeys.

Finally, last speaker was Dr. Ariel Deutch from Vanderbilt University, Tennessee. He has published a number of outstanding contributions in basal ganglia morphology, with a strong background on striatal plasticity. Within his talk he has introduced to the audience a new protein from the cerebellum that is selectively expressed in the caudal intralaminar nuclei. This particular expression of the protein is so selective that in fact the protein could be considered as a new marker for the accurate delineation of the boundaries of these nuclei. Moreover, by taking advantage of knockout mice in which the expression of this protein has been selectively removed, he has been able to generate a striking number of fascinating findings.

The dystonia session highlighted DBS as this has really revolutionized our treatment over the last 5-6 years. Marie Vidailhet and Tipu Aziz reviewed current findings - confirming and extending initial positive results and raising the questions of best sites for stimulation and clinical and genetic features that are associated with DBS benefit. David Standaert discussed the pathophysiology, especially the role of the striatum, but also touched on other pathways (which have become a hot topic, especially the cerebello- thalamic).

This forum-style symposium dealt with the question whether neurotrophic factors or growth factors remain a viable approach to PD therapy despite earlier setbacks.

Franz Hefti started with a historical and conceptual introduction into the field, pointing out that growth factor therapy for PD was based on the seminal discovery and conceptualization of nerve growth factor, neurotrophins and other protein families, including that of glial cell-derived neurotrophic factor (GDNF). These growth factors were recognized to be potent regulators of survival and differentiation of neurons during development, and they were then tested for therapeutic benefits in adult neurodegeneration, however, several clinical trials failed. To increase the probability of success in clinical studies, future trials need to be based on robust preclinical data in animal models of adult neurodegeneration rather than developmental processes, and on the demonstrated ability of the proteins to reach their intended target in the nervous system with the chosen route of administration.

Jeffrey Kordower summarized findings obtained with GDNF and the related protein neurturin. He presented a wealth of data showing that neurturin provided by gene therapy to the brain of monkeys results in stable expression of the protein and robust neuroprotective effects on dopaminergic neurons in adult animals. A first clinical trial with this approach failed to produce clinically meaningful beneficial effects. However, recent data obtained in monkeys make a strong case that alternative application sites and produces of neurturin gene therapy may have the desired therapeutic effects in PD.

Roger Barker presented a detailed analysis of the clinical data obtained with GDNF so far. He provided several examples of effective drugs, which failed in the initial clinical studies, but were fund to be efficacious in subsequent, refined trials. GDNF, which showed positive effects in exploratory studies in PD, produced only marginal effects in a further, blinded and controlled Phase II study. Nevertheless, the positive data with GDNF in many animal studies remain tantalizing and may warrant further clinical studies of this neurotrophic factor.

The session ended with a lively discussion and the conclusion that opinions remain divided even in the expert community about the expected benefits of GDNF and neurturin therapy for PD.

Non motor effects of pedunculopontine nucleus stimulation

Dr. Stefani (University Tor Vergata, Rome, Italy) reviewed his experience on low frequency stimulation of the peduculopontine nucleus (PPD) in Parkinson’s disease (PD). This target has raised interest for the possibility to control gait impairment in parkinsonian patients, clinical results are inconclusive. Dr. Stefani reported on his experience on a small group of subjects implanted simultaneously in PPT and the subthalamic nucleus (STN). The motor effects of low frequency (25 Hz) PPT stimulation were mild, because stride length was consistently better ameliorated by STN DBS than by PPT DBS. However, PPT DBS had a peculiar impact on several non-motor domains.

First, PPT stimulation induced a consistent increased glucose utilization in bilateral prefrontal areas including the dorsolateral prefrontal cortex and the orbitofrontal cortex. A significant increase of uptake and consumption of glucose occurred also in the left ventral striatum. In the same patients, PPT DBS ameliorated delayed recall, executive functions and working memory. In addition, sleep structure was dramatically changed as revealed by REM phase restoration. To note, one patient developed a severe impulse control disorder, characterized by compulsive buying of non useful items, hyper-sexuality and pathological gambling; switching off PPT stimulation abolished abnormal behavior.

PPN stimulation likely alters the functional activity of multiple ascending pathways related to limbic and associative domains. In particular, PPT might activate the ventral tegmental area and the nucleus accumbens, whose imbalance is critical for reward.

New targets for DBS: can DBS modulate non-motor symptoms?

Dr. Moro (University of Toronto, Ontario, Canada) reviewed the efficacy of DBS on non-motor symptoms (NMS) of Parkinson’s disease. Cognitive and behavioral issues, sleep disturbances, urinary and gastrointestinal disorders are the most frequent complains. Although DBS deep brain stimulation of the STN and the globus pallidus internus (GPi) has been proven to be very effective in improving PD motor signs, much less is known about the effects of DBS on non-motor symptoms. When reported, DBS effects on NMS have also been controversial (especially for urinary dysfunction, cognition and some impulsive control disorders).

The PPN is thought to modulate locomotion, movement control, sleep and cognition. Recently, the PPN area has been investigated as a possible new DBS target to treat disabling levodopa-resistant motor signs not improved with STN-DBS. To date only small case series of PD patients have had unilateral or bilateral PPN DBS. From this limited research PPN DBS has shown to increase REM sleep duration in PD and progressive supranuclear palsy (PSP) patients. Some evidence also suggests that PPN DBS might facilitate the speed of information processing for working memory tasks. Other non-motor symptoms, such as depression, pain, and weight gain may require in the future the targeting of other brain areas (subgenual cingulated region, motor cortex, hypothalamus) that are currently under investigations for other diseases.

Rationale for targeting the thalamic centre-median parafascicular complex in the surgical treatment of Parkinson’s disease

Dr. Kerkerian-Le Goff (University of Marseille, France) evaluated the rationale for targeting the centre median-parafascicular complex (CM/Pf) in PD. This is a major input and output station of the basal ganglia, that has long been forgotten in basal ganglia models and has recently attracted new interest. CM/Pf undergoes partial neurodegeneration in PD patients and in different rodent models. Cellular evidence has been provided in experimental animals that thalamic degeneration may not aggravate, but rather counteract the effects of dopamine lesion. Functional changes in the circuits involving the spared neurons could play a detrimental role. This view fits with converging anecdotic and recent direct experience in patients that CM/Pf DBS may alleviate motor disorders, notably tremor and dyskinesias, and point to this thalamic target in the context of the development of multisite stimulation strategies for PD.

The functional impact of subchronic Pf DBS (6 days of continuous stimulation) was evaluated in the 6-hydroxydopamine hemiparkinsonian rat model of PD. When testing different frequencies (25, 60, 130 Hz), only high frequency stimulation had significant anti-akinetic action as evidenced by alleviation of limb use asymmetry in the cylinder test. Although less efficient than STN DBS in the latter task, Pf DBS completely corrected lateralized neglect in the corridor task, a test of sensorimotor integration highly sensitive to impaired dopamine transmission. This potent action is to be considered in relationship with the proposed role of CM/Pf-striatal system as the incoming information with attentional value to the basal ganglia circuits. Unlike STN DBS, Pf DBS did not induce per se dyskinesias at increasing intensities and directly, although partially, alleviated L-DOPA-induced dyskinesias. Preliminary data, however, suggest that the antiparkinsonian action of Pf DBS might be limited by the L-DOPA treatment.

Pf DBS partially reversed the increase in preproenkephalin mRNA levels induced by the dopamine depletion in the striatal neurons at the origin of the indirect pathway, without significantly modifying the effects of the dopamine lesion on the markers of the direct pathway (mRNA levels of substance P and dynorphin precursors). Reversal was partial in the entopeduncular nucleus (the rodent homologous of the internal globus pallidus) and complete in (external) globus pallidus, STN and substantia nigra pars reticulata. Compared to previous data on STN DBS Pf DBS appears to have more widespread action on basal ganglia networks, with additional impact on the striatal neurons of the indirect pathway and on the entopeduncular nucleus. These data demonstrate that CM/Pf is an important node for modulating basal ganglia functioning, including the entopenduncular nucleus.

On December 14, 2009, at the XVIII WFN World Congress on Parkinson’s Disease and Related Disorders in Miami, Drs. Jose Obeso, Pedro Chana, and Andres Lozano provided an update on the pathophysiology, and medical and surgical treatment of Parkinson’s disease (PD). Dr. Obeso indicated that there is compelling evidence supporting the view that increased neuronal activity in both the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) is a crucial pathophysiological feature of the parkinsonian state. This explains why STN and GPi are two major targets in the surgical treatment of PD. Dr. Chana reviewed the pharmacological treatment of PD. While levodopa remains the most potent symptomatic treatment for PD, non-ergot dopamine agonists play a major role, particularly in younger PD subjects. It remains unclear whether dopamine agonists and rasagiline (a monoamine oxidase B inhibitor) could also have neuroprotective properties. Dr. Lozano reviewed the targets for deep brain stimulation (DBS) currently used in the surgical treatment of PD. Multiple studies have shown that both STN-DBS and GPi-DBS improve motor function in subjects with advanced PD. In addition, preliminary observations suggest that DBS in the pedunculopontine nucleus (PPN) is efficacious in treating gait disturbances in PD, and may also have positive effects on sleep and cognition.

Find Dr. Joseph Jankovic's slides from his session on "Treatment of PD-related Dysautonomia" at the WFN World Congress on Parkinson's Disease and Related Disorders. -PDOR Editor

A drug that slows disease progression or is “neuroprotective” is the most urgent priority in the management of Parkinson’s disease. At the recent International Parkinson Disease Conference held in Miami, a symposium was held addressing this issue focusing on prospects for the development of effective new disease-modifying therapies.

Dr. R. Hauser of the University of South Florida reviewed the trials that have been performed to date. He pointed out that while there are many candidate neuroprotective drugs, none has been demonstrated to have a disease-modifying effect in PD patients. One of the major obstacles has been the difficulty in discriminating possible disease-modifying effects from confounding symptomatic or pharmacological effects of a study intervention. For example, while selegiline delayed the time until disability developed warranting levodopa therapy in the DATATOP study, it could not be established if this was because the drug slowed the rate of disease progression or if the drug merely had symptomatic effects that masked ongoing neurodegeneration.

Dr. Olivier Rascol of the University of Toulouse then reviewed the delayed-start design which was developed to try and differentiate symptomatic from disease modifying effects. In this 2 period design, patients are randomized to receive active treatment or placebo in the first period. In the second period, patients in both groups receive the active medication. For the study to be positive, the change from baseline to final visit at the end of period two must be less in the early-start than in the delayed-start group even though patients in both groups are receiving the same treatment. This is consistent with a disease-modifying effect. In addition, the rate of deterioration of UPDRS score must be non-inferior in the early-start compared to the delayed-start group indicating that the groups are not converging and that the results are not due to a delayed symptomatic effect. He pointed out that rasagiline 1mg/day met these results in the ADAGIO study consistent with the possibility that the drug has a disease-modifying effect. Interestingly the 2mg dose was negative.

Dr. C. Warren Olanow of Mount Sinai school of Medicine in New York talked about the potential problems with the delayed-start study and steps that can be taken to try and avoid them. These include ensuring that period one is long enough to ensure that a disease modifying effect can occur if it is there, and that period two is long enough to obtain the full symptomatic effect of the study medication. Obviously, drop outs must be avoided as data is required from both period one and period two. Dr. Olanow, who was the PI of the ADAGIO study noted that multiple sensitivity analyses supported the primary efficacy analyses of rasagiline 1mg. He also noted that greater or more prolonged symptomatic effects of rasagiline 2mg may have masked a disease-modifying effect in this very mild population of patients. Indeed, he pointed out that a subset analyses of those with the highest UDPRS scores at baseline had positive results in the primary analyses despite the small sample size. Finally, it was noted that the delayed start study does not address the clinical relevance of a possible disease-modifying drug, and that other trials such as the long-term simple study are required in order to test the effect of the study intervention on cumulative disability.

Aims: Depth recordings from the basal ganglia of Parkinson patients and dystonic patients have revealed exaggerated local field potential (LFP) activity at alpha (α), beta (β) and gamma (γ) frequency bands. LFP recordings also allow us to know the differences in power spectra in basal ganglia (BG) during rest and different motor tasks. The objective of the current study is to investigate the nature of LFPs, recorded from the subthalamic nucleus (STN) and globus pallidus internus (GPi), over defined motor tasks.

Methods: We recorded bilateral LFP activity from STN of patients with Parkinson’s disease (PD) (n = 7) and from GPi patients with dystonia (n = 5).  Recording was done after withdrawal of medication while they performed repetitive passive, active and ballistic fast extension and flexion of the hand. In addition, we also recorded LFP during resting condition.

Results: LFP activity at α, β and γ band with movement illustrated that LFP activity was more modulated in amplitude. Amplitude modulation was higher in ballistic fast movement compared to rest, passive and active performance in both STN and GPi. The most modulations were seen over alpha frequency at the contact pair that showed the highest power and was implanted in the STN and GPi.

Conclusions: Basal ganglia activity in the alpha range is more modulated during complex movement compared to simple movements. Both the STN and GPi are part of the cortico-basal ganglia-thalamocortical circuit, which may affect the motor cortical activity. In both pathophysiological conditions, this circuit is affected in a similar way during complex motor activities.