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Parkinson's disease Unresolved issues.

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INTRODUCTION
Parkinson’s Disease: Unresolved Issues
There have been few neurological disorders that have
provided greater insight into the organization of the
nervous system or inspired more novel and scientifically based treatment strategies than Parkinson’s disease (PD). Indeed, PD is perhaps the ultimate neurological paradigm for the development of treatment
strategies based on rational laboratory research. The
development of the dopamine hypothesis in PD
stemmed from observations by Carlsson and colleagues in the 1950s, who showed that blocking dopamine uptake with reserpine could lead to bradykinesia in rabbits, and that this could be reversed by
dopaminergic treatment.1 This led to the demonstration that dopamine levels were markedly reduced in
the striatum of PD patients2 and to clinical trials
demonstrating the dramatic benefit of L-dopa.3 However, it was soon appreciated that L-dopa treatment
was associated with potentially disabling acute and
chronic side effects. Increased plasma dopamine levels
associated with acute L-dopa administration were associated with nausea, vomiting, and hypotension.
These symptoms are due to activation of dopamine
receptors in the area postrema that are not protected
by the blood–brain barrier, and they can usually be
prevented by coadministering L-dopa with a peripheral decarboxylase inhibitor. Chronic L-dopa treatment is associated with motor complications in the
form of fluctuating motor responses and dyskinesias.
Here, too, scientific research and novel medical and
surgical therapies have come to the rescue. Laboratory
studies have demonstrated that L-dopa–induced motor complications are associated with molecular and
neurophysiological changes in basal ganglia output
neurons, possibly because of nonphysiological replacement of striatal dopamine. Surgical lesions or deep
brain stimulation of the globus pallidus or subthalamic nucleus dramatically reduce motor complications, probably by eliminating these abnormal neuronal firing patterns.4 Research studies are currently
exploring the possibility that restoration of brain dopamine in a more physiological manner might reverse
or prevent the development of motor complications.5
The therapeutic story of PD has thus been one of
clinical success based on scientifically derived solutions, and has resulted in better treatments and better
outcomes for millions of patients around the world.
The story does not end here, however, and perhaps
we are victims of our own success. In recent years it
has become apparent that the pathology in PD ex-
tends beyond the nigrostriatal dopamine system and
affects multiple regions of the brain, spinal cord, and
peripheral autonomic nervous system. This nondopaminergic pathology translates into clinical features
such as gait disturbances with falling, sleep disturbances, autonomic dysfunction, sensory disorders,
and dementia. These features are not adequately controlled by L-dopa and can represent a major source of
disability for patients with PD. Indeed, it is our success in treating the classic dopaminergic features of
PD that has brought these nondopaminergic features
to the forefront. Thus, the development of more effective and disease-modifying therapies remains the
major unmet medical need for PD, and we must turn
our attention to laboratory and clinical research in the
hope of developing insight into the cause of why cells
degenerate, better animal models for testing new therapies, and ultimately more effective therapies for PD
patients.
It is clear that despite our many successes in PD,
there remain many unresolved issues whose resolution
is critical to our ultimate success in combating PD.
This supplement will consider some of these unresolved issues. These include our current understanding
of why cells die,6 the value of current animal models,7
and what we know about how the basal ganglia8 are
organized in the normal and dopamine-depleted states.
Clinical articles9 –14 will review new concepts on how
and when to initiate therapy in PD, treatment options
for motor complications, the nonmotor features of PD,
PD dementia, and impulse control disorders. Finally,
we address issues that offer promise for the future; the
role of cell-based and gene therapies,15 prospects of developing a viable biomarker,16 where we stand in our
attempt to develop a neuroprotective therapy, and
prospects for the premotor detection of PD.17 It is our
belief that a better understanding of these important
issues will lead to further insights into the nature of
PD, and the developments of more effective therapies
that can further minimize the disability associated with
PD so as to ultimately bring an end to this disorder.
Potential conflicts of interest: This supplement has been sponsored
by an unrestricted educational grant provided by Boehringer Ingelheim (BI). C.W.O. has served as a consultant to BI, Novartis,
Teva, Merck Serono, and Ceregene. M.B.S. has received speaking
and consulting honoraria from BI, Teva, NuPathe, Vernalis, and
Novartis.
© 2008 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
S1
C. Warren Olanow, MD, FRCPC, and
Matthew B. Stern, MD
References
1. Carlsson A, Lindqvist M, Magnusson T. 3,4-Dihydroxyphenylalanine and 5-hydroxytroptophan as reserpine antagonists. Nature 1957;180:1200.
2. Ehringer H, Hornykiewicz O. Verteilung von Noradrenalin
und Dopamin (3-Hydroxytyramin) im Gehirn des Mensachen
und ihr Verhalten bei Erkrankungen des extrapyramidalen Systems. Klin Wochenschr 1960;38:1238 –1239.
3. Cotzias GC, Van Woert MH, Schiffer LM. Aromatic amino
acids and modification of parkinsonism. New Engl J Med
1967;276:374 –379.
4. DeLong MR. Primate models of movement disorders of basal
ganglia origin. Trends Neurosci 1990;13:281–289.
5. Olanow CW, Obeso JA, Stocchi F. Continuous dopamine receptor stimulation in the treatment of Parkinson’s disease: scientific rationale and clinical implications. Lancet Neurol 2006;
5:677– 687.
6. Gupta A, Dawson VL, Dawson TM. What causes cell death in
Parkinson’s disease? Ann Neurol 2008;64(Suppl):S3–S15.
7. Jenner P. Functional models of Parkinson’s Disease: a valuable
tool in the development of novel therapies. Ann Neurol 2008;
64(Suppl):S16 –S29.
8. Obeso A, et al. The basal ganglia in Parkinson’s disease: current
concepts and unexplained observations. Ann Neurol 2008;
64(Suppl):S30 –S46.
S2
Annals of Neurology
Vol 64 (suppl)
December 2008
9. Schapira AH, Olanow CW. Drug selection and timing of initiation of treatment in early Parkinson’s disease. Ann Neurol
2008;64(Suppl):S47–S55.
10. Fahn S. How do you treat motor complications in Parkinson’s
disease: medicine, surgery, or both? Ann Neurol 2008;
64(Suppl):S56 –S64.
11. Simuni T, Sethi T. Nonmotor manifestations of Parkinson’s
disease. Ann Neurol 2008;64(Suppl):S65–S80.
12. Goetz CG, Emre M, Dubois B. Parkinson’s disease dementia:
definitions, guidelines, and research perspectives in diagnosis.
Ann Neurol 2008;64(Suppl):S81–S92.
13. Weintraub D. Dopamine and impulse control disorders in Parkinson’s disease. Ann Neurol 2008;64(Suppl):S93–S100.
14. Olanow CW, Kieburtz K. Why have we failed to achieve neuroprotection in Parkinson’s disease? Ann Neurol 2008;
64(Suppl):S101–S110.
15. Marek K, Jennings D, Tamagnan G, Seibyl J. Biomarkers for
Parkinson’s disease: tools to assess Parkinson’s disease onset and
progression. Ann Neurol 2008;64(Suppl):S111–S121.
16. Isacson O, Kordower JH. Future of cell and gene therapies
for Parkinson’s disease. Ann Neurol 2008;64(Suppl):S122–
S138.
17. Siderowf A, Stern MB. Premotor Parkinson’s disease: clinical
features, detection, and prospects for treatment. Ann Neurol
2008;64(Suppl):S139 –S147.
DOI: 10.1002/ana.21442
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