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Depletion of catecholaminergic neurons of the rostral ventrolateral medulla in multiple systems atrophy with autonomic failure.

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Depletion of Catecholaminergic Neurons
of the Rostra1 Ventrolateral Medulla
in Multiple Systems Atrophy
with Autonomic Failure
Eduardo E. Benarroch, MD, DSci,* Inge L. Smithson, MS,* Phillip A. Low, MD,* and Joseph E. Parisi, MDt
The ventrolateral portion of the intermediate reticular formation of the medulla (ventrolateral medulla, VLM), including
the CllAl groups of catecholaminergic neurons, is thought to be involved in control of sympathetic cardiovascular
outaow, cardiorespiratory interactions, and reflex control of vasopressin release. As all these functions are affected in
patients with multiple systems atrophy (MSA) with autonomic failure, we sought to test the hypothesis that catecholaminergic (tyrosine hydroxylase [THI-positive) neurons of the VLM are depleted in these patients. Medullas were
obtained at autopsy from 4 patients with MSA with prominent autonomic failure and 5 patients with no neurological
disease. Patients with MSA had laboratory evidence of severe adrenergic sudomotor and cardiovagal failure. Tissue was
immersion fixed in 2% paraformaldehyde at 4°C for 24 hours and cut into 1-cm blocks in the coronal plane from
throughout the medulla. Serial 50-pm sections were collected and one section every 300 p m was stained for TH. There
was a pronounced depletion of TH neurons in the rostral VLM in all cases of MSA. There was also significant reduction
of TH neurons in the caudal VLM in 3 MSA patients compared with 3 control subjects. In 2 MSA cases and in 2 control
subjects, the thoracic spinal cord was available for study. There was also depletion of TH fibers and sympathetic preganglionic neurons (SPNs) in the 2 MSA cases examined. Thus, depletion of catecholaminergic neurons in the VLM may
provide a substrate for some of the autonomic and endocrine manifestations of MSA.
Benarroch EE, Smithson IL, Low PA, Parisi JE. Depletion of catecholaminergic neurons of the rostral ventrolateral
medulla in multiple systems atrophy with autonomic failure. Ann Neurol 1998;43:156-163
Multiple systems atrophy (MSA) includes the syndromes of striatonigral degeneration (parkinsonism),
olivopontine cerebellar atrophy (ataxia), and autonomic
failure, in several combinations, and is characterized
by the presence of argyrophilic inclusion bodies in glial
cells and neurons.2
Patients with MSA and autonomic failure have severe disturbance in tonic and reflex control of arterial
pressure, as well as impotence, bladder dysfunction,
and other manifestations of pandysa~tonomia.~
Depletion of sympathetic preganglionic neurons (SPNs) in
the intermediolateral cell column of the spinal cord is
thought to be the main substrate of sympathetic failure
in MSA.4 Nevertheless, other features of MSA, including impairment of hypothalamic responses to hemodynamic and other s t r e s ~ e s , ~baroreflex
and abnormal cardiorespiratory control, particularly
during sleep,* indicate an involvement of brainstem autonomic centers in these patients.
Catecholamine-containing neurons of the ventrolat-
era1 medulla (VLM) are thought to be involved in control of these several functions. For example, neurons of
the Cl group of the rostral VLM project massively to
the intermediolateral cell column9 and are critically involved in control of SPNs," and, together with A1
neurons of the caudal VLM, project to hypothalamic
nuclei secreting vasopressin1' and other hormones. C1
neurons also innervate brainstem areas presumably
involved in control of cardiorespiratory interactions
and sleep.9 In humans, the VLM contains abundant
catecholamine-synthesizing neurons, corresponding to
the C l / A l group^,'^-'^ and may contribute to the
abundant catecholaminergic innervation of SPNs, l 6
other brainstem areas,l 3 and the hypothalamus.
Loss of catecholaminergic neurons in the VLM of
patients with MSA was previously reported by Malessa
and colleague^'^ and Kato and associates. However,
in these studies, the sampling of the rostral VLM was
limited, and this may affect interpretation of the results, given the functional heterogeneity of vasomotor
From the Departments of *Neurology and TPathology, Mayo
Clinic, Rochester, MN.
Address correspondence to Dr Benarroch, Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, M N 55905.
Received Jun 9, 1997, and in revised form Aug 27. Accepted for
publication Aug 29, 1997.
156 Copyright 0 1998 by the American Neurological Association
neurons in this region. l9 Furthermore, laboratory evaluation of autonomic failure was not reported in these
W e sought to determine whether there is a consistent loss of catecholaminergic neurons at different levels of the rostral VLM, in patients with clinical and
laboratory evidence of widespread autonomic failure
and with pathological features of MSA. O u r results indicate that severe loss of catecholaminergic neurons
throughout the rostral VLM is indeed a consistent
finding in patients with MSA and laboratory documented evidence of autonomic failure.
Materials and Methods
Obtentioion of Tissue
Brains were obtained at autopsy from 4 patients with history
and examination findings consistent with MSA with autonomic failure and from 5 subjects with no history of neurological disease (Table 1). The clinical features of the MSA
patients are summarized in Table 2. Three of the 4 patients
were evaluated at the Autonomic Laboratory of the Mayo
Clinic, Rochester, Minnesota. Autonomic testing included
thermoregulatory sweat test, quantitative sudomotor axon reflex test (QSART), heart rate response to deep breathing,
and beat-to-beat arterial pressure and heart rate response to
head-up tilt and Valsalva maneuver. Two patients underwent
polysomnographic study. Written informed consent for autopsy was obtained from all subjects or their spouses.
Brains were removed as soon as possible after death, immersion fixed immediately in 2% buffered paraformaldehyde, and sent to our laboratory. After 24 hours of fixation,
the brains were transferred to sucrose for another 24 hours.
Postmortem delay was 1 1 to 55 hours (average, 35.2 hours)
for MSA cases and 5.5 to 31 hours (average, 20 hours) for
control subjects (see Table 1).
Each brain was divided into two portions. The larger portion, including the rostral brainstem above the mid pons,
cerebellum, and forebrain, was processed for routine neuropathological examination, including Gallyas staining for intracellular inclusion bodies.' In all cases, the pathological
findings were consistent with MSA. The second portion, including the brainstem from the mid pons to the pyramidal
decussation, was further processed for the immunocytochemical study. The lower portion of the medulla below the obex
was not available in 2 control subjects and in 1 MSA patient.
In 2 MSA cases (MSAs 1 and 3) and in 2 control subjects
(Controls 4 and 5), the thoracic spinal cord was available for
Medullas were sliced into 1-cm-thick sections and frozen
on dry ice. Serial 50-pm cryostat sections were divided into
sets and stained for tyrosine hydroxylase (TH) or thionine.
Sections were obtained throughout the medulla and every
sixth section (300 p m apart) was stained for TH. Quantitation was restricted to the midolivary region between 0 and
10 mm above the obex, in the region containing most THimmunoreactive neurons. 14,15 These neurons define the intermediate reticular zone, and those located ventrolateral to
Table 1. Demographic Characteristics of the Patients and Postmortem Delay for Obtention of Tissue
Subject No.
Age (yr)lSex
Postmortem Delay (hr)
Disseminated lymphoma
Ruptured abdominal aortic aneurysm
Prostate cancer
Coronary artery disease; lung cancer
Malignant melanoma
multiple systems atrophy.
Table 2. Clinical Features of MSA Patients
Duration (yr)
multiple systems atrophy; OH
Autonomic Manifestations
Motor Manifestations
Other Features
Incontinence; OH
Impotence; urinary retention;
Urinary retention; OH
Urinary incontinence;
anhidrosis; OH; GI
Obstructive sleep apnea
REM behavior disorder
Cerebellar parkinsonism
Severe dysphagia
orthostatic hypotension; REM
rapid eye movement; GI = gastrointestinal.
Benarroch et al: Cl Neurons in MSA
was chosen as a marker because it tolerates postmortem
delay better than phenylethanolamine-N-methyltransferase
(PNMT), a more selective marker of epinephrine-synthesizing
body diluted 1:3,000 (made in mouse; Incstar, Stitlwater,
MN) for 60 hours at 4°C. Sections were then incubated in
biotin-labeled secondary antibody diluted 1:100 (made in
goat; Biosource, Caniarillo, CA), streptavidin-conjugated
dase solution with or without nickel enhancement for 8 minutes. Nickel enhancement was used to avoid confusion of the
reaction product with the endogenous pigment neuromelanin. l 4 Sections were mounted, dehydrated, cleared in Histoclear (National Diagnostics, Atlanta, GA), and coverslipped
The entire reaction was performed at room temperature,
except where otherwise stated. Sections were rinsed in a 0.1
M phosphate buffer, 0.15 M NaCl, and 0.5% Tween 20,
p H 7.4, for 20 minutes, with agitation after each incubation.
Antibodies and streptavidin-HRP were diluted in the same
buffer plus 1Yo BSA. The immunocytochemical specificity
was tested by substituting normal sera for the primary antibody. N o peroxidase reaction product was observed.
Image Analysis
Images from sections stained for TH and thionine were captured separately on a video camera and digitized into the
IBAS image analysis system (Kontron Elektronik, Everett,
MA). The section perimeter and nucleus ambiguus were outlined from the captured image of the thionine section. Each
immunostained section was aligned and superimposed with
the displayed section perimeter, then the positively stained
TH cell body positions were manually recorded. Quantitation was restricted to TH cells distributed between 0 and 10
mm rostral to the obex. Sections were obtained 300 p m
apart. TH cells were subdivided into two groups with respect
to their relation to the nucleus ambiguus. Cells located ventrolaterally to this reference, corresponding to the ventrolatera1 intermediate reticular zone (Cl group), were counted on
both sides. Because there was not significant difference between cell counts between sides in either patients or control
Annals of Neurology
Vol 43
No 2
February 1998
--------- ----_________
150 -
Fig 1. Beat-to-beat systolic arterial pressure and heart rate in
response to head-up tilt (top), Vnlsalva maneuver (middle),
and deep breathing (bottom) in a 66year-old woman with
MSA. The profound fall of systolic arterial pressure during tilt
and Valsalva maneuuer are consistent with severe sympathetic
vasomotor failure; the blunted respunses o f heart rate to tilt,
Valsalva maneuver, and deep breathing indicate severe cardiovagalfailure. The test was performed about 1 year before the
woman > death.
subjects, the total cell number per section was computed for
comparison. Because the objective of the study was to compare numbers of TH cells between MSA and control subjects, and there was no significant difference in size between
TH-labeled cells in control and MSA cases, no correction
factor for split cell error was used. Because the size of T H reactive neurons varies from 10 to 50 pm, the thickness of
the sections analyzed (50 pm) exceeds the greatest nuclear
height by a factor of more than 1.5, so the error introduced
by the different nuclear height is negligible.
StatisticaJ Analysis
Comparison between the numbers of TH cells per section in
patients with MSA and those in control subjects was performed by using analysis of variance.
Autonomic Testing
Three of the 4 patients with histories suggestive of
MSA were studied in the autonomic laboratory. All exhibited changes consistent with generalized autonomic
failure, including impaired sudomotor responses, markedly reduced heart rate variability during respiration,
abnormal blood pressure and heart rate profile during
the Valsalva maneuver, and orthostatic hypotension
with no heart rate response (Fig 1).
Pathological Conjrmation of MSA
The four brains examined showed changes typical of
MSA, including depletion of neurons in the inferior
olivary nucleus, putamen, and substantia nigra, presence of argyrophilic glial inclusion bodies, and absence
of Lewy bodies. In the 2 cases of MSA where spinal
cord was available for examination (MSAs 1 and 3),
there was a profound depletion of NADPH-d-reactive
SPNs in the intermediolateral cell column (Fig 2A).
Numbers of TH Cells in the Rostra1 VLM
Cells were counted in sections obtained 300 p m apart,
between 0 and 10 mm above the obex. Within the
control group, postmortem delay, but not age, appeared to correlate with the total numbers of THlabeled cells. There was a significant reduction in the
total number of TH cells in the rostral VLM of patients with MSA (Fig 3). This was a consistent finding,
regardless of the patient's age and the postmortem delay. For example, the total cell number per section at 2
to 6 mm above the obex was 28 +- 2 in a control
subject (84 years old; postmortem delay, 31 hours)
compared with 6 +- 4 in an MSA patient (66 years old;
postmortem delay, 11 hours) (Fig 4). Cells were
counted at 0 to 3 mm below the obex in the 3 control
subjects and 3 MSA cases where the lower medulla was
available. There was a significant reduction of total
number of TH (presumably A l ) cells in the caudal
VLM of MSA patients. In the 2 MSA cases, there was
a pronounced depletion of TH-immunoreactive fibers
in the intermediolateral cell column, at the same levels
where the severe depletion of SPNs was observed (see
Fig 2E and F). In both normal control subjects and
MSA patients, the TH fibers contacted the NADPH-d
neurons in the intermediolateral column. In the MSA
cases, despite the depletion of fibers, surviving neurons
appeared to receive the remaining TH terminals (see
Fig 2G and H). Precise quantitation was not possible,
given the small number of cases. In a single patient
with autopsy-proved Parkinson's disease and spinal
muscular atrophy, but no autonomic failure, the total
number of TH cells per section and SPNs was similar
to that for control subjects.
Our results indicate that there is a severe depletion of
catecholaminergic neurons in the rostral VLM in patients with clinical, laboratory, and pathological features of MSA with autonomic failure. Our findings are
consistent with previous
and extend these
observations to include the bulk of catecholaminergic
neurons projecting to the intermediolateral column in
patients with laboratory-supported generalized autonomic failure. Our findings also provide, for the first
time, evidence that there is a depletion of descending
catecholaminergic fiber projection to the intermediolateral cell column. This indicates that the VLM
catecholamine-containing neurons depleted in MSA
project to the SPNs.
Our study, like other quantitative studies on postmortem human tissue, has the limitarions imposed by
the effects of age, postmortem delay, and fixation time
before processing.14 Most TH-immunoreactive neurons in the area of the rostral VLM synthesize epinephrine (C1 group), and therefore, PNMT would have
been a more selective marker to identify this population. However, PNMT is less resistant than TH to the
effects of postmortem delay, and thus, the lack of
staining would have been difficult to interpret, particularly in the cases with a postmortem delay of more
than 12 hours. Our findings in the caudal medulla indicate that the number of A1 (norepinephrine) neurons
is also reduced in MSA. Thus, depletion of A1 neurons
could have contributed to the reduced number of T H
cells in the rostral VLM. However, this contribution is
likely to be minor, as at least 70% of TH-positive neurons in the rostral VLM correspond to the PNMT
TH is less affected than other
p o p ~ l a t i o n . 'Although
immunocytochemical markers by postmortem delay
and fixation time, findings in our control subjects suggest that postmortem delay, more than age, affects the
number of labeled neurons. It is unlikely that the
longer median postmortem delay in our MSA patients,
compared with control subjects, could contribute to
our findings. The number of TH-labeled cells within
the MSA group did not appear to correlate with postmortem delay and was consistently lower than in control subjects with longer postmortem delays. A second
apparent limitation of our study is the small number of
patients. However, our study has the advantage of laboratory support of generalized autonomic failure and
focus on quantitation of T H cells throughout a welldefined region of the VLM, and thus allows more pre-
Benarroch et al: C1 Neurons in MSA
160 Annals of Neurology
Vol 43
No 2
February 1998
Fig 2. Coronal (A and B) and horizontal (C-H) sections of the thoracic spinal cord obtained from a 77-year-old man (Control 4)
1 with no neurological disease (A, C, E, and G) and from a 53-year-old woman with M S A (MSA 1; B, D, F, and H). Sections
were processed for NADPH-d histochemistry to identzfj, preganglionic sympathetic neurons in the intermediolateral cell column
(A-D), f o r tyrosine hydroxylase (TH) immunocytochemistry to identzfi descending catecholaminergicfibers (E and F,), or for both
(G and H). NADPH-d-reactive neurons are concentrated in the intermediolateral column and are depleted in M S A (B and 0 ) .
There is a clear reduction of TH-immunoreactive fibers in the MSA patient (8.
The depleted T H fibers correspond to the distribution of the preganglionic neurons. TH-immunoreactive fibers are not simply fibers of passage, but contact the preganglionic neurons
(G). In the M S A patient, the remaining TH-reactive processes are concentrated onto the f . w surviving NADPH-d preganglionic
neurons (H). Arrows mark the position of some of the TH-positive fibers and varicosities. Bar = 200 p m (C-F,) and 50 p m
(G and H).
cise assessment of the relation between depletion of
catecholamine neurons and autonomic failure in MSA
than previous studies. 17218 Depletion of catecholaminergic neurons of the rostral VLM may reflect selective
vulnerability of central catecholaminergic neurons, retrograde degeneration secondary to SPNs depletion, or
both. For example, there is depletion of catecholaminergic neurons of the substantia nigra and locus ceruleus
in MSA,’ but these regions do not provide direct innervation to the intermediolateral column.
Catecholaminergic denervation may reduce excitability of the surviving SPNs and thus contribute to
sympathetic vasomotor failure in MSA. 10319 Activation of a,-adrenoreceptors (presumably by descending
catecholaminergic pathways) increases excitability of
SPNs.” Loss of catecholaminergic neurons of the
VLM may contribute to other features of MSA, including impaired baroreflex response^,^ blunted cardiorespiratory interactions,’ and hypothalamic d y s f u n ~ t i o n . ~ ~ ’
Neurons of the rostral VLM constitute the efferent
limb of baroreceptor-induced sympathoinhibition.’.’
They receive inhibitory inputs from the caudal VLM
(relaying baroreceptor information from the nucleus of
the solitary tract, NTS), as well as direct (presumably
excitatory) inputs from the NTS.’’
Ascending catecholaminergic projections to the hypothalamus have been implicated in reflex control of
vasopressin release2’ and in stress-induced activation of
the adrenocortical axis.’l Denervation of the hypothalamus secondary to loss of these neurons may explain
three typical findings in patients with MSA, ie, the lack
of vasopressin increase in response to tilt-induced hyp~tension,~,‘the impaired corticotropin (adrenocorticotropic hormone or ACTH) response to hypoglycemia,’ and the impaired growth hormone response to
the au,-agonist clonidine.22 Hypothalamic inputs arise
from the caudal (Al) as well as the rostral (C1)
VLM.” Although our present study focused on the
rostral (ie, spinal projecting) catecholaminergic groups,
we studied the TH neurons in the caudal VLM in 3
control subjects and 3 MSA patients. Our results indicate that there is also a significant loss of T H immunoreactive neurons below the obex, corresponding to the A1 population. Depletion of ascending
noradrenergic inputs is consistent with the finding of
reduced concentrations of norepinephrine in the hypothalarn~s.’~
Catecholaminergic inputs from the VLM reach the
raphe nuclei, locus ceruleus, and pontine cholinergic
groups’ and neurons of the ventral respiratory group.24
Thus, depletion of catecholaminergic VLM neurons
may contribute to disturbances in sleep control (in-
rnrn above obex
0 Control
rn MSA
rnrn aboveobex
Fig 3. (A) Number of tyrosine hydrojcylase (TH)-immunoreactive neurons on the ventrolateral medulla between 0 and 10
mm above the obex, in each of the 4 M S A patients and 5
control subjects. (B) Mean (5 SEM) numbers o f T H immunoreactive cells in the ventrolateral medulla at 3 to 5
mm above the level of the obex (corresponding to the shaded
area in A, the level of the nucleus ambiguus). There was a
consistent depletion of TH neurons at all levels studied in
M S A patients. 9 < 0.05.
Benarroch et al: C1 Neurons in MSA
Fig 4. (Top) Computer-generated composite of j v e conseczitive tyrosine hydroxylare (TH)-stained sections (300 p m apart) corresponding to an 84-year-old control subject (lefi; postmortem delay, 31 hours) and a 66-year-old patient with multiple system atrophy (MSA) (right; postmortem delay, 11 hours). (Bottom) Photomicrographs of TH-immunostained sections corresponding to these
cases and showing a pronounced depletion of catecholaminergic neurons in the ventrolateral medulla of the MSA patient. This typical example demonstrates that depletion of catecholamine neurons of the ventrolateral medulla in MSA patients occurred independent& of age and postmortem delay. Bar = 50 pm.
20 7
ili ii L\
mm below obex
Fig 5. Number (mean plushinus SEM) of tyrosine hydroxylase-immunoreactiue neurons in the caudal ventrolateral medulla, at 0 to 3 mm below the obex in 3 MSA patients and
3 control subjects. There was a signiJicant reduction of these
neurons in MSA patients. p < 0.05.
162 Annals of Neurology Vol 43
No 2
February 1998
cluding abnormalities during rapid eye movement
sleep) and cardiorespiratory interactions' in patients
with MSA.
Depletion of catecholaminergic neurons of the rostral VLM is dramatic in patients with MSA and autonomic failure but may not be specific for the disease.
Reduced numbers of catecholaminergic neurons in the
rostral VLM have been found in Parkinson's disease in
some18.25but not
studies. It appears that depletion of these neurons occurs when Parkinson's disease is associated with severe orthostatic hypotension";
this is similar to what occurs with SPNs in this group
of patients.* Catecholaminergic neurons of the rostral
VLM may not be the only group of central sympathoexcitatory neurons depleted in MSA. Inputs to the
SPNs arise from several sources in addition to the C1
area, including the pataventricular nucleus, A5 neurons
of the ventrolateral pons, and serotonergic neurons of
the caudal raphe and ventromedial medulla.26 These
neurons receive inputs from the C1 area and may also
be primarily involved in the disease. Further studies,
including quantitation of serotonergic neurons of the
caudal raphe are needed to address this issue.
In summary, our study indicates strongly that depletion of catecholamine neurons in the rostral VLM is a
consistent finding in patients with MSA and autonomic failure. Depletion of TH-immunoreactive fibers
in the intermediolateral cell column indicates that these
neurons project to SPNs. We have also found a significant reduction of the caudal TH-immunoreactive neurons (A1 group) that, together with the rostral C1
group of the rostral VLM, project to the hypothalamus. Thus, in addition to failure of sympathetic cardiovascular outflow, loss of catecholaminergic VLM
neurons may explain other features of MSA, including
impaired hypothalamic response to hemodynamic
or clogidine,22 as well as
disturbances in cardiorespiratory control, particularly
during sleep.8 One possible implication is that these
patients may benefit from replacement of central norepinephrine or epinephrine with precursors such as dihydroxyphenylserine. This drug has proved useful in
managing orthostatic hypotension in patients with
MSA; but whether it is due to effects on central or
peripheral catecholaminergic systems, or both, is still
Supported in part by grants from NINDS (PO1 NS32352), NASA,
and Mayo Funds.
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