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Dementia parkinsonism and motor neuron disease Neurochemical and neuropathological correlates.

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15. Blank CL, Sara S, Iserhagen R, et al. Levels of norepinephrine
and dopamine in mouse brain regions following microwave inactivation-rapid post-morten degradation of striatal dopamine in
decapitated animals. J Neurochern 1979;33:213-2 19
16. Black IB, Green SC. Postmortem changes in brain catecholm i n e enzymes. Arch Neurol 1975;32:47-49
17. Gutman CR, Booze RM. David JN. Benefits of rapid vs. delayed autopsy in human brain catecholamine axonal morphology. Soc Neurosci Abstr 1987;13:437
18. Madrazzo I, Drucker-Colin R, Diaz V, et al. Open microsurgical
autograft of adrenal medulla to the right caudate nucleus in two
patients with intractable Parkinson’s disease. N Engl J Med
1987;316:831-834
mentia-parkinsonism-motor neuron disease (DPMN)
syndrome [ 11. This report presents the results of study
of the major neurotransmitter markers-gamrnaaminobutyric acid (GABA), glutamic acid, cholitw
acetyltransferase (ChAT, the marker enzyme for cholinergic neurons), dopamine and its metabolite homovanillic acid (HVA), serotonin and its metabolite 5-hydroxyindoleacetic acid I5-HIAA)-in
the brain of 1
patient in whom the dementia antedated the parkinsonism and motor neuron disease.
Case Report
Dementia, Parkinsonism,
and Motor Neuron
Disease: Neurochemical
and Neuropat hological
Correlates
Joseph J. Gilbert,* Stephen J. JQsh,if Li-Jan Chang,?
Caryl Morito,? Kathleen Shannak,?
and Oleh Hornykiewicz,tSP
The neurochemical markers for the major neurotransmitter systems were measured i n the brain of a patient
who died with a dementia-parkinsonism-motor neuron
disease (DPMN) syndrome complex. Moderate neuronal
loss i n t h e substantia nigra, spongiform changes i n the
frontal cortex, and moderate anterior horn cell loss
throughout the spinal cord were observed. A severe nigrostriatal dopamine deficiency provides the basis for
t h e observed parkinsonkn features. The dementia is unexplained.
Gilbert JJ, Kish SJ, Chang L-J, Morito C , Shannak K,
Hornykiewicz 0. Dementia, parkinsonism, and
motor neuron disease: neurochemical
and neuropathological correlates.
Ann Neurol 1788;24:688-671
Little is known of the brain neurochemical correlates
of the abnormal behavior of patients dying with deFrom the ‘Department of Pathology (Neuropathology), Victoria
Hospital, London, Ontario, the *Human Brain Laboratory, Clarke
lnstitute of Psychiatry, Toronto, Ontario, $Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, Ontario,
Canada, and the 9Institute of Biochemical Pharmacology, University
of Vienna, Vienna, Austria.
Received Jan 17, 1987, anil in revised form Jan 26 and Apr 27,
1988. Accepted for publication May 1, 1988.
Address correspondence CCJ D r Gilbert, Department of Pathology,
Victoria Hospital, South Street Campus, London, Ontario, N6A
4G5.
This man, who was previously well with no family hisrory of
neurological illness, was employed in a chemical plant; h e
had been monitored and at no time was subjected tc, toxic
exposure. At age 48, he lost his foreman’s job because of
progressive memory loss and the inability to organize his
thoughts.
At age 49, he had a normal examination, was fully
oriented, but had a poor fund of general knowledge; his
immediate recall was normal, but he was unable t o subtract
serial 7s. His insight was poor. Speech and cranial nerves I1
to XI1 were normal. The jaw jerk and facial reflexes were
brisk. He had palmomental responses, a “tremor” in the upper extremities, and normal power and coordination. The
deep tendon reflexes, stance, and gait were normal. The sensory examination was normal, but h e had difficulty concentrating for subjective testing.
Within 1 month he developed blunted affect, reduction in
facial movements and blink rate, impaired upward gaze, and
mild cogwheeling of the upper extremities. H e exhibited
weakness of upper limbs and prominent fasciculations o i the
arms, with marked denervation changes (electromyography).
A computed tomographic (CT)scan suggested mild ventricular dilatation; the lumbar puncture was normal. In the following month he deteriorated; he was restless with moderately
severe dementia, dysarthria, and dysphagia; wasting; wc.akness and fasciculations of the tongue, shoulders, upper arms,
and hands; brisk reflexes in all limbs; toes downgoing; ,ind
reduced arm swing.
Six weeks later he had prominent fasciculations of the
ocular, orbicular, mentalis, and tongue muscles and mild
rigidity in all four limbs. Reflexes were 2 t in the arms and
3 + in the legs. The toes were downgoing. He had a prominent glabellar tap, bilateral grasp responses, and bilatcrd palmomenta1 reflexes. H e developed aspiration pneumonia and
died 10 months after the first examination.
Methodology
At autopsy (8 hours after death) the right half of the brain
was frozen at -80°C for biochemical analysis, the left half
was immersed in neutral buffered formalin Frozen autopsic d
bran was also obtamed from 10 patients (62 i- i years,
mean age -t standard error [SE], 13 +- 3 hours postmortem
time) who died without evidence of neurological o r psychiarric disease
The amino acids GABA and glurmic a d were medsured
using a high-performance liquid chromatography (HI’LC)-
688 Copyright 0 1088 by the American Neurological Association
A
B
(A) Substantia nigra; loss of pigmented cells and pigment within
macrophages (arrow); mild gliosis ii present. (Hematoxylin-eosin
stain; x 229 before 36% reduction.) (B) Cervical spinal cord;
anterior gray matter, marked loss of anterior horn cells; a fm
cells remain (arrowhead); mild gliosis. (Hematoxylin-eosinstain;
x 92 before 369%reduction.)
fluorometric procedure [23. Dopamine, HVA, serotonin,
and 5-HIAA levels were determined using a minor modification of an HPLC electrochemical detection method [3].
ChAT activity was determined by the radiochemical procedure of Fonnum 141.
The brain, spinal cord, peripheral nerves, and muscle were
extensively sampled and stained with one or more of the
following: hematoxylin-eosin, Solochrome R for myelin,
cresyl violet, Bodian’s stain for axis cylinders, and Holzer’s
stain for glial fibers. Selective blocks were reacted for glial
fibrillary acidic protein by the immunoperoxidase technique
to demonstrate astrocytes and glial fibers.
Results
Neuropathofogicaf Findings
The left half of the brain revealed no external abnormalities. The cerebrum showed ventriculomegaly. The
substantia nigra showed a loss of pigment. The cerebellum and spinal cord were normal.
MICROSCOPIC DESCRIPTION. The anterior, medial,
and lateral frontal lobe revealed mild gliosis and
superficial spongiform changes with vacuolization in
the first and second layers of the cortex. The impression of mild neuronal loss was noted in layer 3. In the
medial anterior frontal lobe the spongiform changes
involved deeper layers of the cortex, and gliosis was
more prominent. The nucleus basalis appeared normal.
Sections through temporal, parietal, and occipital lobes
were normal. The hippocampus revealed occasional
eosinophilic neurons in the H1 sector. The amygdala
was not examined.
The caudate nucleus and claustrum showed mild
gliosis, yet the putamen and pallidum were normal in
all respects. The thalamus was either normal or revealed mild patchy gliosis near the ventricles. The substantia nigra showed moderate loss of pigmented
neurons and mild gliosis (Fig, A). In the medial pars
compacta, more astrogliosis and a few axonal spheroids
were noted. No Lewy bodies, Alzheimer’s plaques, or
neurofibrillary tangles were present. Within the substantia nigra the distribution of neuronal loss was relatively uniform, but the most caudal portion of the pars
reticulata was better preserved. The pons and medulla
were normal except for mild pigmented cell loss in the
locus ceruleus.
In the cerebellum, the vermis revealed a patchy loss
of Purkinje cells and mild Bergmann gliosis. Mild
neuronal loss and mild astrogliosis were present in the
dentate nucleus.
Moderate anterior horn cell dropout (with mild
gliosis) was noted throughout the spinal cord, being
most pronounced in the cervical cord (Fig, B). In contradistinction, the intermediolateral cell columns of the
thoracic cord were relatively well preserved. In the
lumbar cord, although the anterior horn cell loss was
not as prominent, ghosts of neurons were observed.
Throughout the spinal cord, the long tracts appeared
to be fully myelinated. All muscle sampled in the upper and lower extremities revealed marked changes of
denervation atrophy.
Neurochemical Results
Table 1 shows the mean levels of GABA, glutamic
acid, and ChAT activity in DPMN and control brain.
GABA concentration was normal (normal = within
the range of control samples) in all brain areas examined. Glutamic acid levels were normal, with the exception of a reduction in the frontal cortex ( - 30%)
and amygdala (-40%), which were at or just outside
of the lower end of the control range. ChAT activity
was normal in the cerebral cortex and hippocampus
but was reduced by about 50% in the caudate and putamen.
Serotonin and 5-HIAA levels (Table 2) were nor-
Brief Communication: Gilbert et al: Dementia, Parkinsonism, and M N D 689
Table I . GABA, Glrttamic Acid, and Choline Acetyltransferase Activity:" Control Subjects versus Patient with
Dementia-Parkinsonism-MotorNeuron Disease
GABA
Brain Region
Cortex
Frontal
Temporal
Parietal
Occipital
Caudate
Rostral
Intermediate
Caudal
Putarnen
Rostral
Intermediate
Caudal
Globus pallidus
Internal
External
Substantia nigra
Subthalamic nucleus
Red nucleus
Uncinate gyrus
Dentate gyms
Hippocampal gyrus
Ammon's horn
Amygdaloid nucleus
Glutamic Acid
-
ChAT Activity
Control
Subjects
DPMN
Control
Subjects
Control
Subjects
DPMN
20.0 t
19.8 t
17.8 t
19.3 t
1.8
1.9
1.8
2.3
19.9
17.8
23.5
23.2
95.2 ?
105.1 t
99.3 t
98.3 t
5.6
5.8
6.3
5.0
66.8
83.3
71.4
90.1
1.03 +- 0.06
1.05 t 0.09
0.79 2 0.21
0.76 t 0.10
0.94
0.94
0.63
0.81
33.1 t 2.9
29.0 t 2.8
22.7 2 2.0
31.1
27.9
27.3
126.7 2 9.6
132.7 t 5.2
114.3 t 7.5
112.7
105.4
95.8
NE
22.8 t 3.1
NE
NE
12.1
NE
41.4 i 6.7
37.1 ? 3.1
28.4 t 1.8
31.8
37.2
37.5
139.3 t 8.2
124.1 t 7.8
119.8 +- 8.8
115.0
111.9
104.7
25.8 t 4.2
NE
N E,
11.8
NE
NE
75.7 +- 4.4
75.2 t 4.6
60.1 r+ 6.5
37.6 t 2.3
16.7 t 0.8
18.3 t 1.8
25.2 ? 2.4
16.1 t 2.2
15.4 t 1.3
25.3 r+ 4.2
78.2
71.1
39.5
31.9
16.7
22.0
29.8
14.8
21.0
21.7
53.9 +- 4.1
60.9 +- 4.5
68.0 ? 6.9
57.1 t 9.3
66.0 t 11
102.0 t 6.4
112.6 ? 8.1
87.6 t 4.2
91.9 i 6.1
135.8 -t 5.7
51.3
51.5
51.5
60.4
75.8
71.8
91.6
68.9
107.2
81.9
NE
NE
NE
NE
NE
1.98 +- 0.35
1.96 t 0.39
1.60 ? 0.25
1.66 t 0.23
3.60 i 0.90
NE
NE
NE
NE
NE
2.46
1.50
2.13
1.06
1.63
DPMN
G A B A and gluramic acid concentrations (nmoumg protein) and ChAT activity (nmolimg proreid10 min) represent the mean t SE of 5 to 10
control subjects.
GABA = gamma-aminobutyric acid; ChAT
examined.
=
choline acetylrransferase; DPMN
=
dementia-parkinsonism-motor neuron disease. NE
=
not
Table 2. Neurotransmitters and Metabolites in Autopsied Human Brain: Control Subjects
versus Patient with Dementia-Parkinsonism-Motor Neuron Disease"
Dopamine
Brain Region
Caudate
Rostral
Intermediate
Caudal
Putarnen
Rostral
Intermediate
Caudal
Substantia nigra
Hypothalamus
Hornovanillic Acid
Serotonin
Control
Subjects
DPMN
Control
Subjects
DPMN
Control
Subjects
DPMN
Control
Subjects
DPMN
3.58 t 0.54
4.33 t 0.54
4.17 t 0.64
0.06
0.06
0.04
4.25 ? 0.66
5.35 t 0.67
3.90 2 0.74
1.05
1.52
0.78
0.27 t 0.03
0.28 t 0.04
0.19 ? 0.02
0.18
0.18
0.09
0.57 ? 0.14
0.52 t 0.10
0.57 r+ 0.08
0.26
0.37
0.24
5.44
5.46
6.54
0.90
0.13
0.35
0.20
0.29
0.11
0.07
9.66 t
7.14 -t
6.31 ?
4.20 ?
1.44 t
3.93
2.60
1.98
1.04
0.50
0.41
0.27
0.27
0.82
0.38
0.07
0.03
0.05
0.27
0.06
0.25
0.19
0.16
0.36
0.27
0.96 t
0.89 t
1.03 ?
2.60 ?
0.96 t
0.72
0.56
0.47
1.52
0.72
t 0.69
t 0.74
+- 0.87
i 0.35
2 0.02
1.18
0.92
1.06
0.99
0.37
t
t
t
r+
t
"Values in ndmg tissue wet weight represent the mean 2 SE of 8 to 10 control subjects.
DPMN
=
5-HIAA
ciementia-parkinsonism-moror neuron disease; 5-HIAA = 5-hydroxyindoleaceric acid
690 Annals of Neurology Vol 24
No 5
November 1988
0.19
0.08
0.17
0.45
0.12
mal in the hypothalamus and substantia nigra but were
close to the lower end of the control range in the
striatal subdivisions. Dopamine levels were profoundly
reduced in the caudate (-98 to -99%), putamen
(-94 to - 96%), and substantia nigra ( - 88%) but
were within the normal control range in the hypothalamus. Concentrations of HVA were reduced by 60
to 80% in all regions examined, with the caudate
( - 72 to - 80%) being more affected than the putamen ( - 59 to - 69%). The ratio HVNdopamine was
markedly elevated by 1,400 to 1,900% in the caudate
and by 500 to 800% in the putamen, as compared to
the control subjects (data not shown).
Discussion
The clinical and neuropathological features observed
in our patient resemble the abnormalities observed in
3 other patients { 13. In these patients, dementia, which
developed in the sixth decade, was found to antedate,
by months to several years, the parkinsonism and
motor neuron disease. The important neuropathological features were: neuronal loss in the substantia nigra,
spongiform changes in the superficial layers of cerebral
(especially frontalhemporal) cortex, normal substantia
innominata, absence of Lewy bodies, absence of Alzheimer plaques and neurofibrillary tangles, and severe
anterior horn cell loss. These 4 patients can, on both
clinical and histopathological grounds, be distinguished
from patients with classic motor neuron disease, idiopathic Parkinson’s disease, Guamanian parkinsonism
with amyotrophic lateral sclerosis and dementia, and
senile dementia of the Alzheimer type.
Parkinsonism in D P M N
The severe nigrostriatal dopamine deficiency with
moderate cell loss in the substantia nigra provides the
pathophysiological substrate for the parkinsonian
symptoms in our patient with DPMN. However, the
neurochemical findings differ from the situation in
idiopathic Parkinson’s disease in some important respects. Whereas in idiopathic Parkinson’s disease the
striatal dopamine loss is more pronounced in the putamen (-87 to -96%) than in the caudate (-62 to
-84%) {5f, in our DPMN case all subdivisions of the
caudate ( - 93 to - 98%) were more affected than the
putamen ( - 78 to - 90%), suggesting that the pattern
of substantia nigra cell loss might differ in the two
disorders. The cell loss and depigmentation were nioderate, patchy, and did not provide a selective topography to correlate with the dopamine depletion seen in
the striatum.
In this regard, it is especially interesting that, in contrast to the situation in idiopathic Parkinson’s disease,
an unusually severe dopamine deficiency was present
in the caudate nucleus (versus the putamen) in our
patient.
Dementia in DPMN
The neurochemicaL’neuropathologica1 basis for the
cognitive impairment in DPMN is unknown. Alzheimer-type changes were not seen. The cholinergic
system, the nucleus basalis, and ChAT activity were
normal as was noted by Horoupian and colleagues [ 11.
The observed gliosis, neuronal loss, and superficial
spongiform changes restricted to the frontal lobe were
quantitatively mild, but a significant loss of cortical
neurons could be an anatomical basis for the cognitive
impairment. The neurochemical correlate of the frontal cortex spongiform change is not due to loss of
GABAergic neurons because GABA levels were normal in the cortex. An unusually severe dopamine deficiency was present in the caudate nucleus of our patient as has been observed in patients with other
dementing illnesses E6-81.
Supported in part by a grant from the Parkinson Foundation of
Canada.
M e thank Drs D. Zochodne and W. McInnis for their help with the
clinical information and L. Schettler and G. Helps for their assistance.
S.J.K. is a Career Scientist of the Ministry of Health of Ontario
References
1. Horoupian DS, Thal L, Katzman R, et al. Dementia and motor
neuron disease: morphometric, biochemical, and Golgi study.
Ann Neurol 1984;16:305-313
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amino acids in serum and CSF using high performance liquid
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3. Felice LJ, Felice JD, Kssinger PD. Parkinson’s disease: determination of catecholamine in rat brain parts by reverse-phase ion
pair liquid chromatography. J Neurochem 1978;31:1461-1465
4. Fonnum F. Neurochemical method for the determination of
choline acetyltransferase. J Neurochem 1975;24:407-409
5. Kish S, Rajput A, Gilbert JJ, et al. GABA-dopamine relationship
in Parkinson’s disease striatum. Adv Neurol 1986;45:75-77
6. Ktsh SJ, Chang LJ, Mirchandani L, et al. Progressive supranuclear
palsy: relationship between extrapyramidal disturbances, dementia, and brain neurotransmitter markers. Ann Neurol 1985;18:
530-536
7. Kish SJ, Gilbert JJ, Chang LJ, et al. Brain neurotransmitter abnormalities in neuronal inrranuclear inclusion body disorder. Ann
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Brief Communication: Gilbert e t al: Dementia, Parkinsonism, and MND
691
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