EDITORIAL COMMENT
An update on movement disorders: exciting developments but
new obstacles
Susan Fox and Anthony Lang
University of Toronto and Movement Disorders Clinic, Toronto Western Hospital,
Toronto, Ontario, Canada
Correspondence to Susan Fox, Movement Disorders Clinic, Toronto Western
Hospital, 399, Bathurst St., Toronto, Ontario, Canada M5V 2S8
Tel: +1 416 603 6422; fax: +1 416 603 5004; e-mail: sfox@uhnres.utoronto.ca
Current Opinion in Neurology 2007, 20:432–433
ß 2007 Lippincott Williams & Wilkins
1350-7540
The field of movement disorders continues to expand on
the background of major advances in genetics and under-
standing of the molecular biology of protein misfolding
and its proposed role in neurodegeneration. Such
increased understanding of pathophysiology can only
lead on to newer and better treatments for patients with
these progressive neurological disorders. The following
eight reviews is a ‘smorgasbord’ of these topics with the
aim of updating the reader and highlighting important
recent publications in each subject.
The key role played by the microtubule-associated
protein tau and other proteins in the neurodegenerative
process continues to expand. Tau forms insoluble depos-
its in many diseases, including progressive supranuclear
palsy, corticobasal degeneration, postencephalitic parkin-
sonism and certain frontotemporal dementias amongst
others. New proteins are coming into the playing field in
atypical parkinsonian syndromes. As discussed by Litvan
(pp. 434–437), mutations in a growth factor, progranulin,
have been reported in frontotemporal dementia with
ubiquitin-positive inclusions (FTD-U). Such patients
often present with primary progressive aphasia associated
with mild parkinsonism [1]. The deposited protein has
been found to be TDP-43, which has also been found to
account for ubiquitin-positive inclusions in motor neuron
disease, with or without dementia. A common emerging
theme in all of these disorders seems to be that a
variety of protein deposits can result in similar clinical
phenotypes, for example a-synuclein and tau in both
parkinsonism and dementias [2] and TDP-43, tau
and a-synuclein deposits all found in frontotemporal
dementias [3].
In the field of dominantly inherited spinocerebellar atax-
ias, the number of genes continues to rise (at last count
28). Despite this growing number, recent evidence
suggests a common mechanism of toxicity to cerebellar
432
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and brainstem neurons in many of these diseases,
involving protein misfolding and damage to nuclear
mechanisms; see Soong and Paulson (pp. 438–446). What
remains unclear is the reason for the disparity in extent of
pathological damage from ‘pure’ cerebellar atrophy in
SCA 6, to involvement of the retina in SCA 7 and wide-
spread cortical and basal ganglia pathology in many other
spinocerebellar ataxias.
As discussed by Klein and Lohmann-Hedrich (pp. 453–
464), the genetic mutations responsible for monogenic
parkinsonism also shed light on possible mechanisms of
neurodegeneration in Parkinson’s disease. The clinical
phenotype of these genetic forms is remarkably similar to
sporadic Parkinson’s disease, suggesting a common final
pathway. Thus several PARK genes, including parkin,
PINK-1, LRRK2, ATP13A2 (PARK9) and Omi/HtrA2
(PARK13) are all enzymes involved in normal protein
and mitochondrial function. The extension of under-
standing the role of these proteins in dopamine cell
function to therapeutics in Parkinson’s disease is high-
lighted by Hung and Schwarzschild (pp. 477–483). The
field of neuroprotection is ever growing but is a roll-
ercoaster ride of hope and then disappointment when
many very promising drugs fail to show expected benefit
[4]. Recent National Institutes of Health initiatives to try
and expedite potential drugs into clinical use with the
introduction of the concept of ‘futility trials’ are laudable,
but the issue of preclinical testing is still the biggest
hurdle to future success in this field. At present there is a
paucity of progressive animal models of neurodegenera-
tion and no real link with the pathological process in
patients [5]. In addition, the neurodegenerative process
in Parkinson’s disease involves more than dopamine cell
loss in the substantia nigra pars compacta, and recent
pathological evidence has suggested the process starts
within the lower brainstem (medulla and pons) and
anterior olfactory structures [6]. Thus the need to initiate
neuroprotection much earlier than when patients present
with overt parkinsonism is driving the research toward
biomarkers for ‘preclinical’ disease.
What remains a major priority for patients with these
movement disorders is the need for good symptomatic
therapy. Thus, despite advances in understanding the
pathophysiology, patients with atypical parkinsonian
syndromes and spinocerebellar ataxias, to date, have no

effective treatments. This contrasts with current surgical
treatments available for patients with Parkinson’s disease
and dystonia. The reviews on modern neurosurgical
therapies for Parkinson’s disease and dystonia by
Volkmann (pp. 465–469) and Hamani and Moro
(pp. 470– 476) show the remarkable benefit these inter-
ventions can provide for well selected patients. Medical
treatment for Parkinson’s disease relies on dopamine
replacement using levodopa and dopamine agonists.
Despite the many benefits seen with dopamine agonists,
for example longer duration of action, no influence with
food or bowel function and ability to delay motor fluctu-
ations, several side effects are beginning to emerge that
are limiting usefulness. Thus the recently recognized
impulse control disorders, such as problem gambling
and hypersexuality, are discussed by Voon et al.
(pp. 484–492). These disorders affect a minority of
Parkinson’s disease patients but can be a cause of marked
morbidity. The side issue that these disorders raise is the
role of dopamine in the parkinsonian brain. Thus the role
of subtypes of dopamine receptors, (e.g.D3 versus D2),
the site of action within the brain, ventral versus dorsal
striatum or cortex continue to emphasize that basal
ganglia and other dopamine systems well beyond a motor
circuit have important roles in mood and behaviour.
The update on the most common of movement disorders,
essential tremor, by Lorenz and Deuschl (pp. 447–452)
raises some interesting new concepts. This disorder is
frequently present from an early age, is life long and often
worsens with age. Essential tremor may also involve
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Movement disorders: editorial comment Fox and Lang 433
nontremor manifestations such as ataxia and behavioural
symptoms with distinct personality traits. Pathological
studies, however, fail to show any of the typical features
expected of a progressive neurodegenerative disorder.
The authors propose that we need to reconsider this
disease as a neurotransmitter/receptor-mediated disease,
with further evidence coming from the often marked
improvement in tremor patients obtained with alcohol.
The exact mechanisms underlying essential tremor, how-
ever, remain elusive and reliably effective treatment is
lacking. Even genetic studies of this common disorder
have failed to progress beyond chromosomal linkage,
suggesting that despite approximately 50% of people
with essential tremor having a positive family history,
multiple factors may be involved in the pathogenesis.
References
1 Mackenzie IR. The neuropathology and clinical phenotype of FTD with
progranulin mutations. Acta Neuropathol (Berl) 2007; 26 April [Epub ahead
of print].
2 Galpern WR, Lang AE. Interface between tauopathies and synucleinopathies:
a tale of two proteins. Ann Neurol 2006; 59:449–458.
3 Leverenz JB, Yu CE, Montine TJ, et al. A novel progranulin mutation associated
with variable clinical presentation and tau, TDP43 and alpha-synuclein
pathology. Brain 2007; 17 April [Epub ahead of print].
4 Lang AE. Neuroprotection in Parkinson’s disease: and now for something
completely different? Lancet Neurol 2006; 5:990–991.
5 Bezard E. A call for clinically driven experimental design in assessing
neuroprotection in experimental Parkinsonism. Behav Pharmacol 2006;
17:379–382.
6 Braak H, Muller CM, Rub U, et al. Pathology associated with sporadic
Parkinson’s disease: where does it end? J Neural Transm Suppl 2006;
(70):89–87.