Address for Correspondence:
Thyagarajan Subramanian, MD, Penn State Milton S. Hershey
Medical Center, Mail Code H109, Room C2846, 500 University
Drive, Hershey, PA 17033. E-mail: tsubram@yahoo.com
Abstract
Movement disorders is a branch of neurology that deals with
disorders of the extrapyramidal system. Most such disorders
have pathology in the basal ganglia or the cerebellum or their
connections to the rest of the brain. Parkinson's disease is
perhaps the best known example of movement disorders. Another
example is Huntington's disease, which has become one of the
most well studied genetic disorder in neurology. Other common
movement disorders include essential tremor, dystonia and
Tourette syndrome. This article will focus on 5 new
contributions to the field of movement disorders focusing on
Parkinson's disease from our research group and how these have
influenced the medical field.
Keywords: Dyskinesias,
Mucuna pruriens,
levodopa, cell transplantation
Disease Progression Markers in Parkinson's disease
Parkinson's disease (PD) is characterized by the triad of
symptoms: resting tremor, bradykinesia (slowness of movement)
and rigidity. PD occurs usually in the population that is 65
years of age or older although a significant minority can
manifest disease at a younger age. A few of the celebrities
who have had PD at young age are the Hollywood actor Mr.
Michael J. Fox and the former world heavy weight and Olympic
boxing champion Mr. Mohammed Ali. PD responds well to
dopaminergic medications in the initial years of disease, but
they develop significant complications as the disease
progresses beyond the first 5-10 years. These complications
include drug-induced dyskinesias - disabling choreioform
movements and "on/off" fluctuations when the medications could
abruptly become ineffective for a short period of time before
working again like an "on/off" switch [1, 2]. Although
there are a large number of therapeutic options for PD
including levodopa containing preparations, dopamine agonists,
monoamino oxidase inhibitors (MAO-I), carboxy-o-methyl
transferase inhibitors (COMT-I), deep brain stimulation (DBS)
of the subthalmic nucleus or the globus pallidus and
intestinal gel infusions of levodopa, all these treatments are
purely symptomatic and do not have proven disease modifying
properties. Such disease modification is necessary ultimately
to overcome the neurodegeneration that occurs in the
nigrostriatal pathway in PD.
PD is classified into 5 stages and the first stage is
characterized by the presence of symptoms only on one side of
the body (hemiparkinsonism). Typically patients are in this
stage for 3-10 years before evolving to stage II bilateral
disease. However, this is only true if the diagnosis is made
early. Also, young onset PD (<40 years of age) and early
onset PD (EOPD, >40 <60 years of age) patients tend to
have longer periods of stage I disease [3, 4]. Average age of
onset of PD has gradually inched up as shown in many recent
studies such that the mean age is 65 years. So, one idea
that came from our group is the notion that if we are able to
detect side to side differences in PD in stage I disease, then
we may have a disease progression biomarker that will allow
the clinician to detect progression of disease to stage II.
This is a particularly important concept as patients in stage
I will be symptomatically medicated with anti-PD medications
and these medications will suppress manifestation of PD
symptoms on the opposite side from clinical detection.
Further, asking the patient to stop the anti-PD medication
even temporarily would require 14-28 day drug holiday that
would cause severe disability and would be unethical.
Therefore, clinicians today are not able to reliably predict
the advancement of stage I disease to stage II.
To solve this issue, we undertook a clinical biomarker trial.
Using a human investigation committee approved protocol funded
by the Charles Dana Foundation. We recruited 32 EOPD patients
in stage I disease and had been seen for at least 24 months in
our practice to ensure stability of PD diagnosis. They
underwent MRI imaging of the brain at enrollment and at 12, 18
and 24 months post-enrollment that was analyzed without
knowledge of the clinical status of the patient by a blinded
MRI expert. We also performed blinded transcranial sonography
(TCS) on all our subjects at each of these visits. The idea
was that these imaging modalities will show clear asymmetry of
pathology in the brain and that the hemisphere that
corresponds to the side that is symptomatic will have more
pathology. For example if the patient had right hand tremor at
rest, rigidity and bradykinesia (right hemiparkinsonism) and
did not have any parkinsonism on the left hand or leg then we
predicted that this patient will have pathology predominantly
on the left substantia nigra (left hemisphere controls right
side of the body) and its connections. Indeed this is what we
found. This was the first study to show that MRI abnormalities
where unilaterally predominant in early stage I PD patients if
they had early onset of disease. To perform this study,
we used MRI techniques called transverse relaxation and
diffusion tensor imaging (DTI). DTI is a method that detects
overall freedom of water movement at the tissue level. This
technique allows images to show mean diffusivity (MD) of water
and direction of water diffusion that is called fractional
anisotropy (FA). Transverse relaxation is a method to detect
iron in the brain and in PD there is clear evidence of iron
accumulation in the substantia nigra. Our study was able to
show for the first time that there was clearly quantifiable
and statistically significant difference between the effected
hemisphere and the unaffected hemisphere in transverse
relaxation at the level of the substantia nigra and in FA and
MD at the level of the putamen - the target of the substantia
nigra dopaminergic neurons [4].
The TCS studies were even more dramatic in these EOPD patients
showing that TCS based hyperechogenicity (increase in signal)
in the corresponding substantia nigra was much larger to meet
the criteria for abnormal pathology. We also showed that
hyperechogenicity in the less effected substantia nigra
progressed slowly over the course of next 24 months to reach
the threshold for pathology even before the clinician could
detect the clinical change to stage II bilateral disease [5].
This suggests that we may have for the first time a way to
detect disease progression in PD at least from stage I to
stage II in EOPD patients. This is a small but significant
gain in a disease where there are no disease progression
markers that are reliable. To put in context, there have been
numerous MRI studies, positron emission tomography (PET),
single photon emission (SPECT) and TCS studies and they have
failed to provide disease progression biomarkers. This is
different from their ability to diagnose PD and differentiate
it from other conditions. In this task many modalities
especially SPECT, PET and TCS have made a lot of strides.
However, our study is the first promise as a disease
progression biomarker in EOPD.
Pathophysiology of Drug Induced Dyskinesias in Parkinson's
disease
For many decades the pathophysiology of drug induced
dyskinesias in PD have been attributed to the loss of dopamine
producing cells in the substantia nigra due to
neurodegeneration and the subsequent loss of axonal
connections to the putamen and caudate nuclei (collectively
called the striatum). This loss of continuous
dopaminergic stimulation (CDS) has been attributed to the
cause of drug induced dyskinesias. The argument goes as
follows: Initially there is loss of a few substantia nigra
neurons, this causes the dopamine receptors in the striatum to
undergo changes (plasticity) to accommodate for the loss of
dopamine. Then as the patient receives large doses of levodopa
given 2 or 3 times a day orally as medications this causes an
overwhelming amount of dopamine to flood the striatum
intermittently followed by periods of very low levels when the
medication effects wear off. Since the effective clinical half
life of levodopa, the most powerful dopaminergic medication is
only about 4 hours in most humans and much shorter in PD
patients, they go through multiple upswings followed by
downswings of dopamine in the brain on a daily basis. This
causes the dopamine receptors to become supersensitive - a
process caused by neuronal and receptor plasticity. This
process is thought to take 3-5 years, which coincides roughly
to the time period over which drug induced dyskinesias occur
in PD patients. This hypothesis had received support from
experiments performed in the early 1990's that suggested that
intravenous or intrajejunal infusion of levodopa may solve the
problem of drug induced dyskinesias and on/off fluctuations in
later stages of PD [1, 2]. This is the basis of some of the
newer treatments that have come for PD including longer acting
dopamine agonists like Ropinirole, Rotigotine and
Pramipexole. However, these longer acting agents are
clearly not as potent as levodopa formulations and the idea
that delaying the use of levodopa preparations allows for
delaying disease progression has been roundly discredited in
multiple clinical trials [6, 7].
However, this theory of loss of CDS followed by intermittent
high dose levodopa therapy as the basis of drug induced
dyskinesias and motor fluctuations has many drawbacks [1, 2].
The most prominent of these is the fact that DBS surgery and
other functional surgeries in the brain for PD dramatically
improve drug induced dyskinesias. The proponents of the CDS
hypothesis have tried to explain this beneficial effect of DBS
is due to reduction of levodopa doses in such patients.
However, many patients who receive DBS or other functional
surgery experience reduction in dyskinetic symptoms even
without reducing the dose of levodopa [8]. To understand this
issue further, we undertook a series of studies in animal
models of PD and showed that traditional oral medical therapy
with levodopa or even systemic injections of levodopa does not
normalize electrophysiological changes that occur in the brain
in PD [9]. Further, we showed in a study published in
Brain,
that dopamine producing grafts placed in the brain of
parkinsonian rats can normalize the electrophysiological
abnormalities whereas levodopa administered multiple times in
a day or even round the clock for 24 hours is incapable of
normalizing electrophysiological changes in the brain [10].
What these studies mean is that in the case of the brain
disorders like PD, effectiveness of pharmacotherapy cannot be
adequately assessed based on behavioral or clinical
improvements alone. Such an approach is likely to cause
long-term negative side effects like drug induced dyskinesias
and on/off phenomenon. Drugs for PD need to be evaluated using
electrophysiology as much as pharmacology and clinical
outcomes. Normalizing electrophysiology is equally important
as pharmacological considerations and clinical behavioral
improvements. This approach to experimental therapeutics is
becoming better accepted in recent years with a number of
papers using electrophysiological outcomes in addition to
traditional clinical and pharmacological outcome studies.
Mucuna pruriens for Parkinson's disease
Mucuna pruriens, a legume that grows very well in many
countries including India. It is known in Sanskrit as
Atmagupta and in Malayalam as
Naikurna. It is a
medicinal plant that is frequently used in Ayurveda for the
treatment of PD or other disorders characterized by tremor
(Kampavata). Interestingly, PD had been described in Charaka
Samhita and other Ayurvedic literature as early as 1000 B.C.
and L-dopa had been isolated from
Mucuna pruriens in
1937 well before synthetic L-dopa use in PD patients [11, 12].
Since Ayurvedic medications are often combinations of multiple
plant products administered at variable doses it has not been
clear how
Mucuna is effective in PD. Anecdotal data
from various Ayurvedic physicians suggest that PD patients
that receive only Ayurvedic medications do not exhibit drug
induced dyskinesias. However, it is also clear that this form
of treatment is not standardized and the treatment
effectiveness is highly variable [13, 14].
Mucuna endocarp powder when administered to PD
patients at comparable doses as synthetic levodopa caused a
lot of gastrointestinal discomfort and could not be well
tolerated. Despite these difficulties with the endocarp
powder,
Mucuna pruriens has been investigated as a
putative anti-dyskinetic and anti-PD treatment. A single dose
small study of
Mucuna pruriens endocarp powder failed
to show anti-dyskinetic effects. But a growing body of
literature has shown that
Mucuna pruriens does appear
to have anti-dyskinetic properties. It had been hypothesized
that the beneficial effects of
Mucuna pruriens are
mediated via the natural presence of 4% by weight of
levodopa. The claim had been that because of this low
concentration of levodopa in
Mucuna pruriens, the
improved side effect profile is just an indication of under
dosing.
To disprove this contention, we prepared a water extract of
Mucuna
pruriens and showed that this water extract retains all
the beneficial effects of the endocarp powder. This water
extraction technique removed all the gastrointestinal side
effects of the endocarp powder of
Mucuna pruriens. We
also showed that the water extract has the same 4% by weight
of levodopa that is present in the whole endocarp powder. Next
we compared the effects of administering the same exact dose
of levodopa in the synthetic form versus
Mucuna pruriens
water extract in animal models. These experiments showed that
these animals had exactly equal improvement in parkinsonism,
but
Mucuna pruriens water extract treated animals had
no drug induced dyskinesias while the synthetic levodopa
treated animals had severe drug induced dyskinesias
[13]. This finding suggests that
Mucuna pruriens contains
additional ingredients that are anti-dyskinetic and that the
effects of this medicinal compound are not mediated solely by
levodopa. In addition,
Mucuna pruriens appears to
normalize the electrophysiological changes in the brain that
does not appear to occur when treatments are done with
synthetic levodopa alone [12]. These experiments suggest that
Mucuna pruriens water extract maybe an effective
treatment for PD. However, additional studies need to be
completed to determine the mechanism of action of these
additional ingredients.
What does this mean for contemporary treatment of PD? Although
there is promise,
Mucuna pruriens is not ready for
primetime treatment in patients with PD. This is so because
there continues to be uncertainty on the correct dosing and
standardization of this medicinal product.
Mucuna pruriens
is sold under various brand names over the Internet and we
frequently get phone calls on how to use this medication. Our
standard answer is that this medicinal product is not
standardized and that it is quite variable in its efficacy.
Therefore, we do not recommend taking it as a treatment at the
present time for PD. However, we do think that this medicinal
product holds enormous promise and that further development of
this medicine can help it become a modern therapeutic in the
near future.
Experimental Therapeutics for Disease Modification and
Pharmacotherapy in Parkinson's disease
There is a long history of attempts to modify disease
progression in PD. One of the best examples was the DATATOP
study, which tested Deprenyl (Seligiline, a MAO-B Inhibitor)
and vitamin E for their disease modifying abilities in early
PD. This study showed that the progression of PD symptoms were
not influenced by either selegiline or vitamin E. Subsequently
a number of other agents have been tested as possible disease
prevention agents in PD. One of the latest such study that we
participated was the co-enzyme Q10 double blind
placebo-controlled study. This is one of the largest PD
studies to date. Results showed that patients on placebo were
doing better than patients receiving co-enzyme Q10 and the
study had to be terminated early [15]. These studies are good
examples of futility of trying vitamins and similar agents in
PD. The recommendation to clinicians is to not prescribe any
additional vitamins as preventative therapy in PD.
We have also participated in several clinical trials that
validated new therapeutics in PD. One example is the PRESTO
study in which subjects were given Rasagiline mesylate, a
MAO-B inhibitor or placebo as add-on therapy against "on/off"
fluctuations. This study showed that Rasagiline could be used
as add-on therapy in PD patients to mitigate on/off
fluctuations [16-20]. Although its effects are mild and it is
an expensive medication, in selected patients, this add-on
therapy can be beneficial and can improve quality of life.
This is especially true for people who have difficulty in
taking multiple doses of medications as Rasagiline is a once a
day medication and does not have the amphetamine like
metabolites produced by Seligiline (Deprenyl). We are
currently involved in experimental therapeutic trials for drug
induced dyskinesias mitigation and disease modification in PD.
Cell transplantation for Parkinson's disease
One of the methods by which dopamine can be replenished in PD
is by transplanting dopaminergic cells into the striatum. One
of the first attempts to do such experiments was to use the
patient's own adrenal medulla as an autograft. Such
transplants required initial abdominal surgery to remove one
adrenal gland and then stereotactic placement of autologous
adrenal medullary cells into the striatum. After initial
enthusiasm there was a major disappointment when there was
excessive morbidity from such surgical interventions and
failure in blinded placebo controlled studies. To overcome
this morbidity and to improve cell survival we cografted sural
nerve that contains schwann cells that provide nerve growth
factor (NGF) along with the adrenal medullary issue as
cotransplants. In this small clinical trial we showed that
such cografts could potentially improve cell survival and
clinical outcome [21]. This technique never took off because
of the excessive morbidity associated with these open
surgeries. Next there was an attempt to transplant fetal
mesencephalic tissue (the precursors to the substantia nigra
in the fully developed brain) that contained dopaminergic
cells in patients with PD. This tissue was obtained from first
semester abortions. Several lines of research including
seminal clinical trials showed that such fetal grafts provide
limited benefits and that several graft recipients had to
undergo DBS surgery because they developed graft-induced
dyskinesias - a disabling side effect that occurred 5-10 years
after transplantation of fetal mesencephalic tissue [22, 23].
Later a few of these patients died from natural causes and
came up for brain pathological examination. These autopsy
studies showed that the newly grafted fetal tissue had
acquired pathological changes that are normally seen in PD.
This finding has the lead to a hypothesis that PD is a prion
like disease. Conceptually, the notion here is that abnormal
folded proteins like alpha-synuclein that are seen in fully
established PD can be released from degenerating dopaminergic
neutrons and such released abnormally folded proteins can act
as infective particles. This allows for disease to spread
within the substantia nigra and beyond. This brings
caution to surgical procedures as prion like spread could
potentially be an iatrogenic issue [24-27].
To overcome this disadvantage, and also to minimize the
ethical objections to using tissue derived from human
abortions we have tried to use human fetal retinal pigment
epithelial cells (RPEC) as transplants in PD [22, 23]. This
approach has numerous advantages and in particular it was
attractive in that RPEC derived from a single fetal donation
could be expanded in tissue culture such that over 50,000
patients can be transplanted from such a single source. We
were the first to demonstrate this new technique where RPEC
attached to microcarriers were transplanted into the
dopamine-depleted striatum for PD [28]. After initial success
in animal models we performed the first human trial [29]. In
this trial we were able to demonstrate safety and efficacy for
such transplants. Immediately after the results of this
study came out, this technology was purchased by Schering AG,
a German pharmaceutical company for further development.
German regulations did not permit the use of fetal tissue of
any kind and as a poor chemical alternative; they substituted
postnatal RPEC for the definitive trials without any
preclinical animal experimentation. Unfortunately this change
created major issues, as postnatal RPEC do not appear to have
the same survival and neurochemical properties as prenatal
RPEC. In this pivotal study both placebo in the test groups
demonstrated clinical benefit that where not statistically
different [30]. One subject enrolled in this study came up for
autopsy because of death unrelated to the study.
Interestingly, these pathologists only published the analysis
of a single hemisphere, which showed very poor cell survival
[31]. For reasons that are not clear the results from the
second hemisphere were never published. However, reports filed
by Titan Pharmaceuticals indicate that the second hemisphere
autopsy did show much better survival of transplanted RPEC
attached to microcarriers. Several other studies that used
fetal RPEC attached to microcarriers have shown that such
transplants are efficacious and without any side effects
[32-38]. Additional work from our laboratory shows that the
key to successful involvement of RPEC is to use first or
second trimester fetal origin cells as we did in all our
animal studies and in the first human trial. It is difficult
to explain the rather surprising finding that the placebo
group that received sham surgery (patients actually got
general anesthesia and stereotactic frame placement and burr
holes but never got the transplants) had remarkable
improvement in symptoms. This placebo effect has come to the
attention of the PD research community and PD patients. There
has been intense debate whether such placebo controlled
surgical trials are necessary? [39]. Also there is debate if
PD therapies have such great benefits from placebo, can we
take advantage of such placebo effects to help our patients or
to preselect patients who may be susceptible to placebo
effects from clinical trials especially if they are double
blind placebo controlled such that a placebo bias does not
negate any real effects of the experimental surgery [40, 41].
As a result of these experiments a moratorium on cell
transplantation trials was placed in 2011 [42]. Soon,
thereafter, a large meta-analysis of all transplantation
studies showed that at least in the case of fetal tissue
transplantation there is considerable optimism. Therefore, the
moratorium on fetal tissue testing has been lifted and a
European consortium of scientists, neurologists, and
neurosurgeons have opened up a patient registry to track
outcomes in continued clinical research studies [43]. In
the meantime, many new techniques that allow stem cells to be
created or derived in such a fashion as to make them
dopaminergic have been accomplished. Another new technology
that allows skin cells from patients with PD called inducible
pluripotent stem cells (IPSC) to be converted into
dopaminergic neurons has also been successful. These new
technologies need to be meticulously tested in preclinical and
clinical trials. Such studies are underway. In addition,
studies that allow remote control of grafted issue, using
optogenetics and chemogenetics are also ongoing.
Therefore, there is tremendous potential for these new
techniques to translate into new forms of therapies in PD.
In summary, the field of movement disorders is making
tremendous progress. We have touched upon only a small
fraction of research studies that are making an impact in this
field. There is progress in other movement disorders beyond PD
that we have not touched upon in this brief review.
Disorders like Huntington's disease, dystonia and Tourette
syndrome have you benefited from that introduction of
tetrabenazine and its derivatives. Newer studies show that
combination of pharmacotherapy and chemodenervation using
botulinium toxins can be highly effective in these movement
disorders [44]. The incremental progress we have made in
understanding the pathophysiology of PD and in experimental
therapeutics for PD has been the most impressive. A
modern era of pharmacotherapy that is closely monitored with
electrophysiology and modulated by optogenetics or
chemogenetics is just round the corner. We believe that this
is one of the most exciting times to be involved in movement
disorders, a field that did not had a large number of
interventions, which is rapidly changing for the better.
Although challenges remain there is a clear path for drug
discovery and experimental therapeutics that gives hope for
modern medicine to overcome the disabilities associated with
movement disorders.
Acknowledgements
This work was supported in part by research grants from the
National Institutes of Health (NIH) - National Center for
Complementary and Alternative Medicine (NCCAM) R21AT001607 and
National Institute of Neurological Disorders and Stroke
(NINDS) R01NS42402, Health Resources and Services
Administration DIBTH0632, and Pennsylvania Tobacco Settlement
Funds Biomedical Research grants to Dr. T. Subramanian The
Pennsylvania Department of Health specifically disclaims
responsibility for any analyses, interpretations, or
conclusions. Penn State University Brain Repair Research Fund
provided additional funding.
Conflict of Interest Disclosure: Dr.
Subramanian has served in the speaker's bureau for Teva
Pharmaceuticals as a paid consultant and received financial
compensation for his services after the approval of Rasagiline
as a therapeutic in PD. Teva pharmaceuticals currently holds
worldwide patent on Rasagiline. Dr. Subramanian is also the
founder and President of StereoRx, which holds intellectual
property rights on modified RPEC. Dr. Subramanian is currently
serving and/or has in the past served on advisory boards for
Novartis, UCB Pharma, Allergan, Merz, Boehringer-Ingelhiem and
GlaxoSmithKline. He is currently funded for part of his
research studies by Merz, Ipsen, NIH and Allergan. Dr.
Subramanian is married to Dr. Venkiteswaran. There are no
separate conflicts to disclose for Dr. Venkiteswaran.
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