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« Unmet medical needs in Parkinson's disease »* from Koller, William C. et Tse, Winona Neurology, Volume 62(1) Supplement 1, 13 January 2004, pp S1-S8) Dr William C. Koller , Department of Neurology, Mt. Sinai School of Medicine, New York, NY,USA Dr C.Warren Olanow, Barrow Neurological Institute, Phoenix, AZ 85013-4496, USA. Dr José A. Obeso, Movement Disorders and Basal Ganglia Unit, Department of Neurology and Neurosurgery, Neuroscience Program, Clinica Universitaria and Medical School, Universidad de Navarra, 31008 Pamplona, Spain Dr Robert A. Hauser, Director, Parkinson's Disease And Movement Disorders Center, Tampa General Hospital; Professor, Departments Of Neurology, Pharmacology, And Experimental Therapeutics, University Of South Florida, USA Dr. Peter LeWitt, Professor of Neurology at Wayne State University School of Medicine, director of a National Parkinson Foundation Center of Excellence in Southfield, Michigan, USA Dr Fabrizio Stocchi - Dipartimento di Scienze Neurologiche, Università "La Sapienza", Roma, Italy Dr Peter Jenner, King's College London, Manresa Road, London, UK SW3 6LX, England ( * "Buts thérapeutiques non atteints dans la MP" in Neurology, Volume 62(1) Supplement 1, 13 January 2004, pp S1-S8) Dr. Olanow: I think it is important to appreciate that PD is not just a disorder of motor function. There are many non-motor features that can be important sources of disability for PD patients and are important to recognize and treat. These include depression, dementia, anxiety, mood disturbances, problems with sleep, sensory dysfunction, and a host of autonomic disturbances such as sexual dysfunction, bowel and bladder problems, constipation, and orthostatic hypotension. They are important because they may vary in severity in "on" and "off" stages, and may not respond at all to dopaminergic treatment. Many consider these to reflect more widespread degeneration than just the nigrostriatal system and when a neuroprotective therapy is designed it is important to appreciate that pathology in PD can be widespread and can affect neurons using multiple neurotransmitter systems. Dr. Koller: It is interesting to consider whether non-motor or non-dopaminergic PD features could result from dopamine denervation and if they could be prevented if you provided levodopa in a more continuous and physiologic manner. Dr. Olanow: You raise a good point. It is certainly possible that some of the features we consider non-dopaminergic may result initially from dopamine depletion. The SNc provides dopaminergic innervation throughout the basal ganglia and not just the striatum. There is also widespread dopamine innervation of the cerebral cortex, and it is intriguing to consider that a loss of dopamine may play a role in the evolution of dementia. Dopamine depletion also leads to overactivity of the subthalamic nucleus, which uses glutamate as a transmitter and could cause excitotoxic damage to target neurons. In the final analysis, however, I think you need to consider that, in sporadic PD, degeneration is more widespread than just the SNc, and this likely contributes to these other features. For example, patients with a Parkin mutation experience a relatively selective and severe SNc dopaminergic neuron loss with a young age of onset, but their subsequent course is relatively benign and they do not go on to develop non-motor features. If the problems were entirely a result of dopamine depletion, they would be expected to have a higher frequency of non-motor problems. That they do not suggests that it is the more widespread degeneration that occurs in sporadic PD that is the likely cause. Dr. Obeso: I agree that it is important to consider non-nigral degeneration if we are to deal with the real unmet needs for PD, i.e., stopping disease progression. We see neuron degeneration and Lewy bodies in many brain areas, not just those with dopaminergic neurons. It is also interesting to consider whether PD starts in the nigra and spreads from there or if it is a multisystem process. I think it is possible that other areas degenerate first but represent clinically silent areas or are associated with clinical features that are not readily detected or not looked for. Dr. Koller: But dementia is a later symptom in the disease. Does that not suggest that it is sequential? Dr. Olanow: It is only a later feature because we choose to define it as such. If someone presents with dementia and develops Parkinsonism, we call it something else. Dr. Hauser: It is also a matter of how you define dementia. We typically define dementia as cognitive impairment that impairs functional activities. If we look for more subtle changes, they are found in a higher percentage of patients and also much earlier. Further dementia correlates with the presence of cortical Lewy bodies. This suggests that dementia is part of the disease process. It may therefore be that it will be harder to develop good symptomatic treatments than to slow the disease process and prevent onset and progression. Dr. Olanow: Just to clarify, virtually all PD patients have cortical Lewy bodies. Some suggest that the more Lewy bodies you have, the more likely that you may have dementia, in the same way that the more nigral degeneration you have, the more likely you are to have motor disturbances. Frontal executive dysfunction may be an early feature of what will be dementia, just as a bit of rigidity may predict the development of postural instability. What we need to determine is if the degenerative changes in cortical neurons are taking place at a different time and at a different rate than what is occurring in the nigra. There is no doubt that degeneration in PD is widespread. You get degeneration of cholinergic neurons with Lewy bodies in the nucleus basalis, norepinephrine neurons with Lewy bodies in the locus ceruleus in addition to dopamine neurons in the SNc. Therefore, non-dopaminergic features may be controlled with dopamine therapies. But it is clear that PD is more than just dopamine degeneration and that to meet the unmet need we will have to find a way to stop the degenerative process. Dr. Jenner: I agree with you. We have become fixated on the nigrostriatal pathway and dopamine and have not adequately considered involvement of other neuron systems. It is clear that the more you look at the PD brain, the more pathology you see in a variety of areas with Lewy bodies, and we do not know how to relate the wider spread pathology to individual patients and the symptoms they exhibit. It is my sense that dementia is not common in young-onset patients. Young-onset patients seem to have more severe nigral degeneration when they present because they are more plastic and can compensate better. This may be the reason that they are at greater risk for motor complications. If dopamine depletion was the cause, they should have a greater frequency of dementia. Is that correct? Dr. Olanow: I think that is correct. People over the age of 70 are much more likely to have dementia and young-onset people are much less likely to. That could be because the older cortex is more vulnerable to degeneration. I think it is noteworthy that patients with Parkin mutations have damage that appears to be confined to the nigra and locus ceruleus, with very little damage elsewhere. They get severe depletion and then run a stable course. This suggests that dopamine depletion does not contribute to or cause the dementia. Dr. Obeso: We should not forget that there are several types of PD. At one extreme you have the Parkin mutation, in which damage is confined to the nigra and the course is predominantly motor. At the other extreme are patients who present with dementia and develop PD late. One feature that is becoming clear is that the longer the evolution, the more patients develop both motor and dementia features. Dr. Koller: One could make similar comments with respect to autonomic function. Here, too, there appear to be cases in which autonomic dysfunction is an important and even early feature of the illness. We have now seen patients who present with pure autonomic failure and then go on to develop classic features of PD. It appears that there is a continuum between these findings and that what you see may depend on what you look for and how you classify the patient. Sleep abnormalities are also common in PD and may reflect brainstem changes. We are in the infancy of understanding these conditions and have to learn more about their pathophysiology in order to design appropriate treatments. Dr. Hauser: One of the unmet needs that has become of great interest to me is the complaint of fatigue. In preliminary studies we saw a high correlation with sleep disorders and particularly with sleep apnea. Dr. Olanow: Do you think that the fatigue is related to depression? Dr. Hauser: It can be related to depression, but only a small number of our patients had changes on a depression scale. I think that depression can cause fatigue, but we need to think more about sleep disorders. Dr. Koller: There is one study of fatigue in which half the patients were clinically depressed and in the other half there was no clear explanation. Dr. LeWitt: Fatigue may also occur as a result of motor dysfunction. We found that the sense of fatigue in PD patients disappeared at the same time as the levodopa-induced improvement in motor function occurred. This implies that there may be a central motor element in fatigue. Dr. Stocchi: I think it is important to differentiate fatigue that responds to levodopa from that which does not. Some patients do not show clear motor deficit but report exhaustion and fatigue. I think it is also worth commenting that bladder dysfunction, constipation, and speech dysfunction can sometimes be helped by levodopa. . Dr. Olanow: Dr. Koller also commented on the scales that are used to assess treatments for PD. We typically rely on UPDRS scales, which primarily look at motor features. We have recently completed studies in mild patients in which improvement was captured on a variety of quality of life scales but not on the UPDRS. There are also several studies comparing dopamine agonists to levodopa that have shown improved UPDRS scores in levodopa-treated patients even though the agonist-treated patients could add levodopa if they wanted and were comparable in quality of life assessments. The question there is whether the UPDRS is failing to capture some aspect of benefit, especially related to non-motor functions. Dr. Jenner: I think these non-motor features are important sources of disability to PD patients. At support group meetings, patients frequently complain about drooling, sweating, bladder, constipation, sleep disturbances, and daytime somnolence. I don't often get asked about rigidity, bradykinesia, or dyskinesia, or "getting me going again." It is interesting that their perception of what is important is totally different from ours. Dr. Koller: We really do not have one excellent, composite scale that captures all the disability in Parkinson's disease, mainly because we have concentrated too much on the motor aspect. UPDRS is the most widely used scale but, as has been pointed out, it does not always correlate with other scales and does not capture all the disability in PD, particularly for the non-motor aspects of the disease. Dr. Olanow: Even with respect to quality of life scales, we tend to use those that are disease-specific. In disorders such as ALS, scales are used that measure what is most important to the patient-such as religion, family, friendships-and then we ask how treatment affects that. Dr. LeWitt: What do you make of patients in the recent agonist trials that had normal PET or SPECT scans. Do you think they have PD? Dr. Olanow: There is very little data to suggest that anyone with clear-cut PD has a normal imaging study. I suspect it is more likely that these cases were misdiagnosed. Indeed, repeat scans at later time intervals remained normal. ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn