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Etiolgy pathogenesis and prevention of Parkinson' disease Fourth annual symposium co-sponsored by the Parkinson Study Group and Movement Disorder Society.

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Etiology, Pathogenesis, and Prevention of
Parkinson’s Disease: Fourth Annual Symposium
Co-Sponsored by the Parkinson Study Group and
Movement Disorder Society
Sunday, October 14, 1990
Grand Ballroom A, Hilton Hotel, Atlanta, GA
Program
8:30 Introduction
-8:35 Penney
11:30 Motor Cortex Stimulation Before and After
-1 1:45 Thalamotomy in a Patient with a Unilateral
8:35 Risk Factors for Parkinson’s Disease: A Case
-8:50 Control Study of Young and Old Onset
Patients
Stern
Parkinsonian Tremor
van der Linden
11:45 Effect of Deprenyl on Neuropsychological
-12:OO Function in Early Parkinson’s Disease
Corn0
8:50 Residential Histories in Parkinson’s Disease
-9:Oj Patients
Davanipour
9:05 Smoking and Age at Onset of Parkinson’s
Abstracts
-9:20 Disease: Analysis of the DATATOP Cohort
Tanner
9:20 Death Rates Among Demented and
-9:35 Nondemented Patients with Parkinson’s
Disease
Murder
9:35 N-Methyl-D-Aspartate Antagonists Protect
-9: 50 Substantia Nigra
- from MPP+ Neurotoxicity
Tzlrski
9:50 Do Oxidation Reactions Contribute to the
-1o:oj Pathogenesis of Parkinson’s Disease?
Olanow
10:05 Break
-10:30
10:30 Acute and Persistent Parkinsonism Associated
-l0:45 with Ingestion of Petroleum Product Mixture
Tetrud
10:45 Increased Serum and Cerebrospinal Fluid
-11:oo Interferon-Gamma in Early Untreated
Parkinson’s Disease
Sheremata
11:oo Site(s) of Lesion and Resting Tremor
-11:15 Rujput
11:15 Validating Accelerometric Measures of
-11:30 Parkinsonism: Technical Aspects and
Preliminary Results
Tymn
294 Annals of Neurology
Vol 28 N o 2 August 1990
Risk Factors for Parkinson’s Disease: A Case Control
Study of Young and Old Onset Patients
&I. Stern, E . Duhney, S . Gruber, L. Golbe, M. Bergen,
P . Stalky. and H . Hurtig, Philadeiphia, FA, and Neu
Brunswick, NJ
While the etiology of Parkinson’s disease (PD) remains unknown, recent evidence suggests that certain external factors
(i.e., environmental agents) may trigger a chain of oxidative
reactions that ultimately destroy nigral cells. This hypothesis
has rekindled interest in the epidemiology of PD. Previous
studies using a variety of epidemiologicalmethods have associated rural living, well water and exposure to industrial
chemicals or pesticides with a high prevalence of PD. These
observations have been supported by other studies which
claim a higher incidence of these environmental risk factors
in young onset patients. We therefore conducted a detaded
analysis of various environmental exposures and early life
experiences in 75 patients with old onset PD (>60), 75
young onset patients (<40) and 150 age and sex matched
controls. Contrary to previous reports, we were unable to
implicate rural living, well water, exposure to herbicides,
pesticides or industrial toxins as significant PD risk factors.
On the other hand, at least one episode of head trauma
“severe enough to cause vertigo, dizziness, blurred or double
vision, seizures or convulsions, transient memory loss, personality changes or paralysis” occurred significantly more often prior to disease onset in both young and old PD patients
than controls (p <.05). Smoking was inversely associated
with PD as has been previously reported. Young onset patients were more likely to have a parent with PD than old
onset cases although no other factors distinguished young
from old onset patients. We suggest that the risk of developing PD is influenced by a variety of factors. While we were
unable to link specific environmental agents with PD, our
study suggests that head trauma and heredity should be reassessed as potential risk factors for PD.
Residential Histories in Parkinson’s Disease Patients
2. Davanipour and A. D. Will, Loma Linda, C A
Residential histories in Parkinson’s disease (PD) patients
have been investigated utilizing previously collected data
from a cohort of more than 34,000 white Seventh-day Adventists in California (Adventist Health Study). These data
are based on life-style and health-related inquiries obtained
through a self-administered questionnaire. Cases of Parkinson’s disease have been identified using the ICD code on
death certificates. Forty nine cases with PD have been
identified. Residential area was reported as rural for 56.5%
of PD patients and as non-rural for 43.5% of PD patients.
The 95% “exact” confidence interval for the percentage of
those Parkinson cases with rural residence was 4196-719Z.
The proportion of rural residence in the general Seventh-day
Adventist population is 21.3%. If rural residence were a
predisposing factor for PD, we would expect the frequency
of the rural residency to be greater in the Seventh-day Adventists PD patients than in the general Seventh-day Adventists population. Consequently, this preliminary analysis indicates that rural residency may be overrepresented (p < 0.05)
among PD patients.
Smoking and Age at Onset of Parkinson’s Disease:
Analysis of the D A T A T O P Cohort
Environmental Injuences Working Gvoup of the Parkinson
Study Gronp and The Parkinson Study Group (C. M . Tanner,
Presenter. Chicugo, IL)
Smoking tobacco has been proposed to protect against the
development of Parkinson’s disease (PD) by many investigators, although this hypothesis remains controversial. If cigarette smoking does actually protect against PD, then PD
patients who are habitual smokers should have a later age of
PD onset than those who never smoked. We tested the latter
hypothesis in patients participating in a clinical trial of preventive therapies for PD (DATATOP, total N = 800), comparing patients with early onset PD (“EARLY”, onset 2 30
5 40 years) to those with later onset PD (“LATE’, onset
2 65 and 5 80). There were no statistically significant differences in clgarette smoking between EARLY and LATE
patients. 17133 EARLY and 911222 LATE patients had
never smoked cigarettes. Although findings in this cohort
may not be applicable to all PD patients, in the DATATOP
patient group cigarette smoking did not appear to delay the
age of PD onset. By extrapolation, these data support the
suggestion that, rather than reflecting a protective biologic
action, differences in cigarette smoking between PD patients
and persons without PD may instead represent PDassociated personality traits. (Supported by USPHS Grant
NS24778.)
Death Rates Among Demented and Nondemented
Patients with Parkinson’s Disease
I(. Mardm, E. Mirubello,J . Chen, K . Bell, G. Doonezef,
L. Cote, Y . Stern, and R. Mayeux. New York, NY
The prevalence of dementia with Parkinson’s disease (PD) is
dependent upon the incidence of dementia and the duration
of coincident PD and dementia (PD D). We previously
estimated the prevalence of PD+D from a review of medical records to be 10.9%. A reexamination of the same
+
cohort, almost 5 years later revealed 65 incident cases of
dementia and 15 cases of dementia not recognized during
the prevalent period. The incidence rate of dementia was
6.65 times that expected in patients of similar ages without
PD. If P D + D reduces survival, then the prevalence of
PD D may be underestimated despite the high incidence.
Of the 15 patients who were demented during the prevalent
period but misclassified, 8 died during the follow-up period.
Of the 249 records re-reviewed for the incidence study, excluding all who were previously demented, 41 subjects died
(16.5%); 11.9% (221184) of the PD group and 29.2% (19/
65) of the P D + D group (X2, ldf = 9.56, p < .01). The
majority of deaths were due to cardiovascular disease or
pneumonia. Cause of death did not differ in the PD and
P D + D groups. The fact that P D + D patients were older,
had more severe manifestations and were significantly more
disabled than PD patients may have contributed to their
reduced survival. We conclude that incidence is a more accurate measure of the true frequency of dementia with PD.
Dementia with PD may be far more common than previously reported.
+
N-Methyl-D-Aspartate Antagonists Protect Substantia
Nigra from MPP’ Neurotoxicity
L. Turski, K. Bressler. K-J. Rettig, P.-A. Lorcbmann,
and H . Wacbtel,Berlin, West Germany
The discovery that intake of MPTP (1-methyl-4-phenyl1,2,3,6-tetrahydropyridine)leads to symptoms of Parkinson’s disease and produces degeneration of nlgrostriatal
dopaminergic neurons in humans gave rise to the hypothesis
that this invariably progressive disorder may be caused by
endogenous or environmental toxins. Thus treatments
aimed at preventing death of dopaminergic neurons may
offer a therapy for parkinsonism. As the metabolite MPP+
(1-methyl-4-phenyl-pyridinium ion) mediates MPTP toxicity, inhibition of the conversion of MPTP to MPP+ by
monoamine oxidase B ( M A 0 13) is effective in preventing
the toxic effect of MPTP in experimental animals. The excitation mediated by dicarboxylic amino acids, such as Lglutamate or L-aspartate, has been claimed repeatedly to be
involved in pathogenesis of neurodegenerative disorders.
We therefore tested whether antagonists active at subtypes
of L-glutamate receptors, such as N-methyl-D-aspartate
(NMDA) or quisqualate (QA), prevent toxicity of MPP+
or that induced by the selective dopaminergic neurotoxin
6-hydroxydopamine (6-OHDA) in the rat substantia nigra
pars compacta. 2-Amino-7-phosphonoheptanoate (AP7;
0.025-0.1 pmol), 3-(( 2 )-2-carboxypiperazin-4-yl)-propyl-lphosphonate (CPP; 0.1 pmol) and (+)-5-methyl-l0,11dihydro-5H-dibenzo-(a,d)cycloheptan-5,1O-imine maleate
(MK-801; 0.1 pmol), selective NMDA antagonists, but not
6-cyano-7-nitro-quinoxaline-2,3-dione
(CNQX; 0.1 pmol),
the preferential Q A antagonist, provided dose- and timerelated (up to 24 h) protection against MPP+ (0.025 kmol)
toxicity when co-administered into the rat substantia nigra.
Systemic administration of CPP (0.02-0.1 mmol/kg) and
MK-801 (0.002-0.01 mmoYkg) also offered temporary protection (up to 4 h) against MPPt toxicity in the nigra. Repeated systemic administration of CPP (0.1 mmoVkg) or
MK-801 (0.01 mmolikg) (6x every 4 h) prolonged protection against MPP+ challenge up to 24 h. Neurotoxicity produced by 6-OHDA (0.1 pmol) remained unaffected by AP7
(0.1 wmol). These findings indicate that processes controlled
by excitatory amino acids may be important in toxicity induced by MPP+.
Program and Abstracts, Fourth Annual Symposium, PSG/MDS 295
Do Oxidation Reactions Contribute t o the Pathogenesis
of Parkinson’s Disease?
C . W . Ohnow, Tampa, FL
Free radicals generated from oxidation reactions can damage
biological molecules including DNA, protein and lipids.
There are several reasons to be concerned that such reactions
contribute to the pathogenesis of Parkinson’s disease (PD):
(1) the brain is abundant in polyunsaturated fatty acids; ( 2 )
the brain receives a disproportionately large amount of oxygen; ( 3 )brain protective mechanisms are relatively deficient
compared to other organs; and ( 4 )iron, which facilitates oxidation reactions, accumulates in specific brain regions including the substantia nigra (SN). Dopamine undergoes oxidative
metabolism by the MAO-B enzyme to form a pool of hydrogen peroxide (H2Q2). In the brain, glutathione protects
against the further oxidation of H202. However, if there
is a stress on the oxidation system because of increased
dopamine metabolism or inadequate protective systems,
H202is further oxidized to form the free hydroxyl radical
which can induce lipid peroxidation, membrane damage and
cell death. Recent evidence suggests that such a sequence
may occur in PD. Findings include: (1)increased iron in the
SN; ( 2 ) decreased glutathione in the SN; ( 3 )increased lipid
peroxidation in the SN; and ( 4 )clinical information suggesting that the MAO-B inhibitor deprenyl may slow the rate of
progression of PD. If oxidation reactions contribute to the
pathogenesis of PD, approaches which interfere with these
reactions such as selective chelation of iron, augmentation of
glutathione, MAO-B inhibition and free radical scavengers
may permit therapy which alters the natural history of PD.
be presented. This case may be the first clue that an MPTPlike substance exists in the environment.
Increased Serum and Cerebrospinal Fluid
Interferon-Gamma in Early Untreated Parkinson’s
Disease
W. A. Shwenzata, W. Totlrtelotte, A. Sazant, C . S. k i n e .
J . Sanchez-Ramos, and W.J . Weiner, Miami, FL
Mechanisms of neuronal damage in Parkinson’s disease have
not been established but the presence of reactive microgld
cells bearing MHC Class I1 antigens in substantia nigra indicates an active destructive process. Since these MHC antigens are induced by interferon-gamma (IFN-g), which is also
a potent activator for macrophages, we sought and obtained
preliminary evidence of IFN-g abnormalities in serum and
cerebrospinal fluid (CSF). We now report results in 16 Parkinson’s ( 8 early untreated mean age 59.5 y f i :s with a mean
duration of 1.38 ? 0.74 years and mean Hoehn and Yahr
score of 1.25 2 0.38), 8 advanced patients and 107 controls.
Controls included 25 multiple sclerosis (MS) patients, 2 1
with other advanced neurodegenerative disease (NDD), 18
with retrovirus associated chronic encephalomyelopathy type
I (RACE-l), and 43 with AIDS. Serum and CSF IFN-g
values were determined using a sensitive radioimmunometric
assay. Serum values (U/mm3) for the untreated Parkinson’s
were 0.59 +. 1.24, 0.24 & 0.33 for advanced patients, 0.12
0.22 in NDD; >0.01 in MS; 0.13 ? 0.21 in RACE-1;
and 0.06 & 0.11 in AIDS. CSF I F N g (U/mm3) values in
untreated patients were 0.58 & 0.38 compared to 0.23
0.29 in advanced patients; 0.10 2 0.04 in NDD; 0.18
0.12 in MS; 0.59
0.56 in RACE-1; and 0.35 ? 0.11 in
AIDS. Serum and CSF I F N g values in Parkinson’s and
RACE-1 are significantly higher than other diseases (p <
0.01).In the present study early Parkinson patients exhibited
much higher serum and CSF I F N g values than patients with
long standing severe disease. These pilot findings are consistent with the hypothesis that immunological activation occurs
in response to acute and/or chronic viral stimulation in early
Parkinson’s disease.
*
*
Acute and Persistent Parkinsonism Associated with
Ingestion of Petroleum Product Mixture
J. W. Tetrud, J . W . Langston, I . Irwin. andB. S n w .
San.Jose, CA, and Vancouver, BC
The discovery that MPTP can induce a syndrome in human
and non-human primates mimicking Parkinson’s disease has
stimulated speculation that exposure to environmental toxins
might play a major euological role. Although other environmental agents, such as manganese, carbon monoxide and
carbon disulfide, can induce parkinsonism, the clinical syndrome rarely mimics the idiopathic disease as closely as that
induced by MPTP. We now report acute and persistent parkinsonism, highly reminiscent of the parkinsonian syndrome
induced by MFTP, associated with ingestion of a petroleum
mixture. In early January, 1990, a 20 year old laborer swallowed fluid containing a mixture of petroleum products (including kerosine, ethylene glycol, motor oil and gasoline)
while attempting to siphon off water. Within 48 hours he
developed oral-buccal-lingual dyskinesia. Over the next 8
days the dyskinesia cleared (he received 200 mg diphenhydramine per day), but signs of bilateral parkinsonism began
to emerge. Two weeks after exposure he exhibited moderate
bradykinesia, rigidity, postural instability, hypophonia, facial
masking and a postural tremor; a clinical picture compatible
with Hoehn and Yahr stage I1 parkinsonism. H e had brisk
reflexes with an equivocal right sided Babinski but no spasticity or weakness. Mentation as measured by a brief neuropsychological test battery was normal. A brain MRI was normal as were routine laboratory tests and the urine was
negative for neuroleptics. There was no past history of illicit
drug use or major medical, psychiatric or surgical illness.
Eight weeks after exposure he continued to manifest Hoehn
and Yahr stage I1 parkinsonism. Videotape and PET scan will
296 Annals of Neurology Vol 28 No 2 August 1990
*
Sit&) of Lesion and Resting Tremor
A. H . Rajput, B. Rozdihky, and L. Ang, Saskatoon,
Saskatchtwan, C a n a h
Akinesia (AK), rigidity (RG) and resting tremor (RT) are
3 main features of idiopathic Parkinson’s disease (IPD).
Marked substantia nigra (SN) neuronal loss results in striatal
dopamine (DA) deficiency which correlates with AK and
RG but not with RT. Based on that and surgical animal
models of RT, it has been postulated that SN lesion together
with lesions of cerebellofugal pathways but normal motor
cortex and thalamus are the anatomical basis of RT. Neuroleptic induced and MPTP induced Parkinsonian cases that
have no cerebellar pathology may also have prominent RT.
Additionally, the histopathological studies conducted over
70 years have not revealed significant cerebellar pathway
lesions in IPD. We report our 2 decades of clinical and
pathological observations in this regard. The tremor when
present was categorized as classical RT or mixed. All 26 IPD,
4 with severe SN cell loss but no Lewy body inclusions and 6
cases with IPD and Alzheimer’s disease had RT. On the
other hand, none of the 3 striatonigral degeneration (SN
comparable to IPD), 2 Shy Drager syndrome and 3 progressive supranuclear palsy cases had RT. In 2 SND with pos-
turd hypotension, 2 olivopontocerebellar atrophy (OPCA)
and 2 S N D & OPCA cases, mixed tremor was noted. Our
data indicate that SN pathology alone is sufficient anatomical
basis for RT in IPD. The additional pathology, we believe,
modifies the tremor-suppresses or alters its character.
Validating Accelerometric Measures of Parkinsonism:
Technical Aspects and Preliminary Results
W. W . Tryon, At. F. Brin. S. F d n , S. Guillory, L. Winfield,
and S. Bressman, New York, N Y
Valid instrumented assessments of neurological disorders are
vital instruments that supplement traditional clinical assessment. They are crucial to enhancing our understanding of
the progression of disease and the response to therapy, and
may reveal insights into pathophysiology. Any developed
instrumented tests should first be validated against well described clinical disorders with established clinical rating
scales. Using a simple, sensitive, practical, and economical
instrumented methodology, we evaluated the correlation between clinical ratings and accelerometric measurements of
tremor, bradykinesia, and the cogwheel aspect of rigidity in
patients with Parkinson’s disease. Bilateral accelerometry of
five patients revealed a correlation of r(14) = 0.84, p <
.0002 with clinical ratings of resting tremor amplitude. Frequency reductions and amplitude increases were noted with
disease progression. Large amplitude resting tremor was observed to emerge from small amplitude postural tremor after
about 5 seconds; correlation with clinical ratings was good.
Slow (0.3 Hz) wrist flexiodextensioti was shown to produce
activity bursts consistent with the cogwheel aspect of rigidity;
a correlation of r(6) = .63, p < .05 (1 tail) was obtained
between clinical ratings and accelerometric measurements of
cogging. Decreases in amplitude and frequency of finger tapping were observed and correlated well. A new “clutching”
phenomenon has been observed in tapping behavior, involving departures from monotonicity. Once validated, these instruments may be used to quantitatively assess and track the
clinical course of disease states and the response to interventional therapy. Cross correlations between different related
disorders may also be studied.
Motor Cortex Stimulation Before and After
Thalamocomy in a Patient with a Unilateral
Parkinsonian Tremor
C. van der Linden, R. Bruggeman, and H . W. Gobman,
Philadelphia, PA, and Amsterdzm, The Netherlands
To evaluate the effect of stereotactic thalamotomy on the
function of the corticospinal tract, we studied motor evoked
potentials (MEPs) recorded by surface electromyography
(EMG) in the left extensor carpi radialis (ECR) and flexor
carpi radialis (FCR) with magnetic stimulation of the contralateral motor cortex in a 38 year old patient with a severe
postural and resting tremor of the left hand. The patient was
diagnosed 8 years previously with left hemiparkinsonism.
The tremor was unresponsive to various medications. After
thalamotomy the tremor had disappeared, confirmed by
EMG studies. MEP latencies at rest were normal and did not
change after thalamotomy. Volitional contraction of either
ECR or FCR shortened the latency of the corresponding
MEP before and after thalamotomy. However, before
thalamotomy responses at rest were less well synchronized
and followed by EMG silence with subsequent long duration
tonic after discharges. Furthermore, during voluntary contraction the responses only slightly enhanced. After surgery
MEPs at rest in both muscles were more synchronized and
after discharges had disappeared. Moreover, with volitional
contraction of either ECR or FCR, the MEPs enhanced
more dramatically. The consistent MEP latencies suggest
that the conduction of the pyramidal tract is unaffected by
thalamotomy. The better synchronized responses and the
alleviation of after discharges in this patient with hemiparkinsonism following thalamotomy suggest an improved sensorimotor integration, which may be the result of a reduced
thalamic input onto either segmental or suprasegmental
levels.
Effect of Deprenyl on Neuropsychological Function in
Early Parkinson’s Disease
The Parkinson Study Group (P. G. Como, Presenter, Rochester,
NY)
Cognitive assessment was completed at baseline and every
6 months as part of the multi-center trial, Deprenyl
and Tocopherol Antioxidative Therapy of Parkinsonism
(DATATOP) consisting of 800 patients with early ParkinSD) months
son’s disease (PD). Based on 12 ? 5 (mean
of observation, preliminary results indicate that deprenyl
significantly delays disability, e.g., need for levodopa therapy
(NewEngl J Med 1989; 321:1364).Data were analyzed for
subjects who had completed at least six months of follow-up,
including N = 296 in Group A (not receiving deprenyl) and
N = 344 in Group B (receiving deprenyl). Treatment effects were analyzed comparing baseline to follow-up at 6 and
12 months and for annualized rates of decline. At baseline,
the treatment groups did not differ on any of the measures.
Regardless of treatment, subjects who reached end point
requiring levodopa declined faster than those who did not
reach end point on: total recall (p = .04), long-term storage
(p = .01), long-term recall (p = .04), and delayed recall
(p = ,004) on Selective Reminding, Symbol Digit (p =
,005) and Visual Memory (p = .03). After 6 months, subjects not assigned to deprenyl performed worse than subjects
receiving deprenyl on delayed recall (p = .02) and Symbol
Digit (p = .02). At 12 months, subjects in the non-deprenyl
group were additionally more impaired on long-term storage
(p = .02) and long-term recall (p = .008). No differences
were found between the treatment groups for annual rates of
decline on any of the cognitive tests. Subjects in Group A,
however, had a more rapid rate of decline on Hamilton Depression (p = .002) than Group B. These results suggest that
deprenyl may delay cognitive decline in early, untreated PD.
(Supported by USPHS Grant NS24778.)
*
Program and Abstracts, Fourth Annual Symposium, PSG/MDS 297
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