Parkinson’s Disease in 2020 by Joel Raffel
The next 12 years are vital to the field of Parkinson’s disease (PD). With the UK’s aging
population, prevalence will increase from present approximations of 160 per 100,000.
But whilst pharmacological enhancement of the dopamine system provides remarkable
improvement of motor symptoms for a number of years, chronic administration is less
effective and comes with significant complications. Further, current medications do not
manage the debilitating non-motor symptoms of PD, which also correlate with advancing
age.1 The future may be one of increased prevalence, combined with less satisfactory
management.
Equally, one could be optimistic, with various novel therapeutic strategies being tested in
the laboratory and in clinical trial. This short article focuses on those strategies that aim
to modify the course of disease, rather than merely providing symptomatic relief, and
emphasises what remains to be achieved if these are to impact on PD management by the
year 2020. Many state that neuroprotective therapies will succeed only in conjunction
with novel strategies for early diagnosis; this article argues that only modest diagnostic
improvements are likely in the near future.
Disease Modification
Three main strategies to limit the progressive neural degeneration in PD - neurotrophic
drugs, cell therapies, and gene therapies – shall be discussed in turn, with particular focus
on therapies that have been trialled clinically.
Neurotrophic drugs
Monoamine oxidase B (MAO-B) inhibitors, dopamine agonists, and glial-cell-linederived neurotrophic factor (GDNF) show neuroprotective efficacy in a laboratory
setting. However, clinical research into GDNF illustrates many of the difficulties in
developing a clinically effective neuroprotective drug. Long-term GDNF infusion in 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP)-treated
monkeys
produced
significant improvements in motor symptoms, without dyskinesias, coupled with
structural restoration.2 But despite initial success in a small, open-label trial, a 34-patient
randomised control trial (RCT) of intraputaminal GDNF caused serious side-effects
without clinical benefit.3
This highlights a few important points. Most fundamentally, it demonstrates that
laboratory results do not necessarily correlate with clinical efficacy. This is likely due to
discrepancies between the MPTP monkey model and the human PD patient, and the
optimal dose, timing and route of administration in each. Indeed, the 34-patient RCT has
been criticised for its design and the dosage of GDNF utilised.
Another important dilemma is that trials continue to evaluate ‘neuroprotection’ using
clinical tools such as the Unified Parkinson’s Disease Rating Scale (UPDRS). Such
scales measure fluctuating symptoms, are biased towards motor symptoms, and have
questionable objectivity.
Moreover, clinical assessment cannot easily distinguish an
intervention’s disease-modifying effect from a direct symptomatic effect. Improved
biomarkers would make for cheaper and more reliable clinical trials of neuroprotection,
and shall be discussed later.
That said, rasagiline (2nd generation MAO-B inhibitor), does come with evidence of a
clinical neuroprotective effect. Firstly, the parent compound and its metabolite are
neuroprotective in a laboratory setting. But more crucially, in a RCT that compared 12
months of rasagiline against patients who took 6 months of placebo followed by 6 months
of rasagiline, the 12-month group had less functional decline than the 6-month group.4
This suggests that the action is not merely symptomatic, although one should note that
earlier treatment itself might provide the long-term benefit, rather than an inherent
disease-modifying quality of the drug. Nevertheless, the exciting preliminary success of
rasagiline will be investigated further in larger RCTs. With once-daily formulation and
a good safety profile making it suitable for the elderly, rasagiline may prove to be
essential in future management strategies.
Cell Therapy
Whilst neurotrophic drugs could limit disease progression, the transplantation of
functioning cells could actively reverse the pathological processes that have occurred in
advanced PD. Promising results were obtained in mice, but clinical trials have had mixed
success. A RCT of human embryonic dopamine neuron transplant surgery against sham
surgery found that younger patients (under 60 years) showed significant improvement
after the procedure.5 This was coupled with evidence of fibre outgrowth, as measured by
18F-fluorodopa uptake on positron emission tomography (PET) and post-mortem
examination.
However, older patients did not benefit clinically, despite evidence of fibre outgrowth.
This may reflect a lower degree of brain plasticity or more diffuse brain disease in the
older group, and is a significant hurdle for future widespread use, as in the invasive
nature of the procedure. Furthermore, 15% of subjects developed severe drug-resistant
dyskinesias.
Future research aims to implant exogenous stem cells, or to manipulate endogenous stem
cell, for the treatment of PD. This could offer great advantages, not least by avoiding the
practical and ethical issues surrounding the use of human fetal tissue. Major challenges
include the conversion of adult stem cells to a dopaminergic phenotype, and limiting the
teratogenic potential of embryonic stem cells. This exciting area of research is far from
ready for clinical trial, but it is optimistic rather than unrealistic to suggest that it could
contribute to management by 2020.
Gene Therapy
In comparison, gene therapy is unlikely to impact upon our clinical management as early
as 2020, although it is has great potential for the more distant future. Again, gene
therapy would aim to modify the disease, and would likely be most effective in the
presymptomatic or early symptomatic phase. Major challenges include improving the
temporal and spatial regulation of expression, not to mention identifying which genes
should be targeted in treatment.
Other Treatment Options
Whilst this article will not discuss L-Dopa and the increasing range of available
dopamine agonists, research should continue to characterise the relative efficacy and side
effect profile of different monotherapies and combined therapies, especially since the
elderly population has a greater likelihood of adverse reactions.
Neurosurgical deep brain stimulation (DBS) and ablative procedures are effective in
advanced PD, but are not disease-modifying treatments, nor are they suitable for the
elderly.
Whilst extradural motor cortex stimulation is proposed as a non-invasive
alternative to DBS, its supposed efficacy in early case reports have been disputed by
subsequent case reports.6 Until a double-blinded RCT has been conducted, its predicted
importance in the management of geriatric PD is no more than speculation.
In addition, research must continue to investigate the debilitating non-motor symptoms of
PD, including dementia, since current treatment options are limited. If neuroprotective
therapies do emerge as an important part of PD management, it will be interesting to
observe how they impact on the development of non-dopaminergic non-motor symptoms.
Diagnosis
Accurate and earlier diagnosis will become increasingly important with the advent of the
aforementioned neuroprotective therapies, since early intervention will be key. Yet a
community-based study estimates current diagnostic error to be as high as 50%.7 The
commonest causes of misdiagnosis were essential tremor, Alzheimer's disease and
vascular pseudo-parkinsonism, all of which will increase with the aging population.
Further confusion arises in that 34% of subjects over 65 years old show mild
Parkinsonian signs8, far more than the equivalent PD prevalence of 3%. 2006 NICE
guidelines recommend that all patients with suspected PD should be referred untreated to
a specialist with expertise in this field. Clinical diagnosis sensitivity is approximately
91% in this setting9, while further benefits include thorough assessment of non-motor
symptoms, mental issues, and social implications.
Nevertheless, research must strive to develop biomarkers for pathological change in PD.
Potential benefits include more accurate diagnosis, earlier and even presymptomatic
diagnosis, and improved therapeutic trials. Single-photon emission computed
tomography (SPECT) may contribute when a diagnosis is in doubt, but current imaging
techniques such as SPECT or transcranial ultrasound lack specificity for use in early
diagnosis, as do pre-motor symptoms like olfactory and autonomic dysfunction, and
neuropsychological impairment.10 Progress might come by combining several diagnostic
tests; large cohort studies are required to investigate further. But first we probably
require technological advances in imaging, genetics or metabonomics for example,
although one can only speculate at present. It is also worth noting that to be useful for
early diagnosis, a test’s predictive value must be large enough to justify the implications
of being treated incorrectly, and so until we have developed an effective neuroprotective
therapy and characterised its side effects it is impossible to know the precision of test
required.
Conclusion
With the UK’s aging population, PD in 2020 could be more prevalent, with a greater
percentage of severe PD, and increased non-motor symptoms. This article has argued
that whilst gene therapies will not and cell therapies may not, neurotrophic drugs will
impact on our management of PD by the year 2020. It is assumed that earlier diagnosis is
essential for the success of neuroprotective therapies, and so specialists should manage
early presentations of query PD. At present, the author finds little evidence for the
possibility of pre-symptomatic diagnosis in the near future, as suitable biomarkers have
so far proven elusive. Future priorities include further investigation of the debilitating
non-motor symptoms of PD, although neuroprotection might limit their development too.
If disease-modifying therapies prove successful, Parkinson’s disease in 2020 is still likely
to be more prevalent, but we can hope that disease progression will be a thing of the past.
References
1. Chaudhuri KR, Yates L, Martinez-Martin P. The non-motor symptom complex of Parkinson's disease: a
comprehensive assessment is essential. Curr Neurol Neurosci Rep. 2005 Jul;5(4):275-83. Review.
2. Grondin R, Zhang Z, Yi A, Cass WA, Maswood N, Andersen AH, Elsberry DD, Klein MC, Gerhardt
GA, Gash DM. Chronic, controlled GDNF infusion promotes structural and functional recovery in
advanced parkinsonian monkeys. Brain. 2002 Oct;125(Pt 10):2191-201.
3. Lang AE, Gill S, Patel NK, Lozano A, Nutt JG, Penn R, Brooks DJ, Hotton G, Moro E, Heywood P,
Brodsky MA, Burchiel K, Kelly P, Dalvi A, Scott B, Stacy M, Turner D, Wooten VG, Elias WJ, Laws ER,
Dhawan V, Stoessl AJ, Matcham J, Coffey RJ, Traub M. Randomized controlled trial of intraputamenal
glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol. 2006 Mar;59(3):45966. Erratum in: Ann Neurol. 2006 Dec;60(6):747.
4. Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson
disease. Arch Neurol. 2004 Apr;61(4):561-6. PMID: 15096406 [PubMed - indexed for MEDLINE]
5. Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S,
Trojanowski JQ, Eidelberg D, Fahn S. Transplantation of embryonic dopamine neurons for severe
Parkinson's disease. N Engl J Med. 2001 Mar 8;344(10):710-9.
6. Cilia R, Marotta G, Landi A, Isaias IU, Vergani F, Benti R, Sganzerla E, Gerundini P, Pezzoli G,
Antonini A. Cerebral activity modulation by extradural motor cortex stimulation in Parkinson's disease: a
perfusion SPECT study. Eur J Neurol. 2008 Jan;15(1):22-8. Epub 2007 Nov 27.
7. Meara J, Bhowmick BK, Hobson P. Accuracy of diagnosis in patients with presumed Parkinson's
disease.
Age Ageing. 1999 Mar;28(2):99-102.
8. Bennett DA, Beckett LA, Murray AM, Shannon KM, Goetz CG, Pilgrim DM, Evans DA. Prevalence of
parkinsonian signs and associated mortality in a community population of older people. N Engl J Med.
1996 Jan 11;334(2):71-6.
9. Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ. The accuracy of diagnosis of parkinsonian syndromes
in a specialist movement disorder service. Brain. 2002 Apr;125(Pt 4):861-70.
10. Michell AW, Lewis SJ, Foltynie T, Barker RA. Biomarkers and Parkinson's disease. Brain. 2004
Aug;127(Pt 8):1693-705. Epub 2004 Jun 23. Review.
Joel Raffel
Green College
Oxford
OX2 6HG