Hi - We have a newly diagnosed person in Frost Texas, which is near
Corsicana Texas.  She is looking for a localish organization, support group,
neuro, really any help at all.  Anyone?  Thanks, Meg
-----Original Message-----
From: Parkinson's Information Exchange Network
[mailto:[log in to unmask]]On Behalf Of M.Schild
Sent: Monday, January 17, 2005 4:25 PM
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Subject: Unmet medical needs in Parkinson's disease



« 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.

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