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Disease-specific patterns of locus coeruleus cell loss.

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Disease-specific Patterns
of Locus Coeruleus Cell Loss
Dwight C. German, PhD," Kebreten F. Manaye, MD," Charles L. White 111, MD,P
Donald J. Woodward, PhD,S Donald D. McIntire, PhD,§ Wade K. Smith, MD)'
Rajesh N. Kalaria, MD,"" and David M. A. Mann, MDT'r
Computer visualization techniques were used to map and to quantitatively reconstruct the entire locus coeruleus,
including the nucleus subcoeruleus, to compare the topographic patterns of cell loss in postmortem brains from
patients with Parkinson's disease, Alzheimer's disease, and Down syndrome. There was comparable cell loss in all
three diseases (approximately 60%) compared with aged normal subjects, and there was a significant loss of nucleus
subcoeruleus cells specifically in patients with Parkinson's disease (63%). There was a significant positive correlation
between the magnitude of locus coeruleus cell loss and the duration of Alzheimer's disease, but no such correlation
was found for Parkinson's disease. In patients with Parkinson's disease, there was comparable cell loss throughout the
rostral-caudal extent of the nucleus; however, in patients with Alzheimer's disease and Down syndrome, the greatest
cell loss always occurred within the rostral portion of the nucleus, with a relative sparing of caudal cells. These data
are consistent with the hypothesis that cell loss in Parkinson's disease is the result of a pathological process that attacks
the catecholaminergic cells of the locus coeruleus and the subcoeruleus in general; in Alzheimer's disease and Down
syndrome, however, the pathological process only affects the rostral, cortical-projecting locus coeruleus cells and spares
the caudal, noncortical-projecting cells.
German DC, Manaye KF, White CL 111, Woodward DJ, McIntire DD,
Smith WK, Kalaria RN, Mann DMA. Disease-specific patterns
of locus coeruleus cell loss. Ann Neurol 1992;32:667-676
The locus coeruleus (LC) is located in the pontine tegmentum and is composed of norepinephrine-containing neurons that innervate widespread areas of the
central nervous system (CNS) 11-11]. Each LC neuron
sustains a widely divergent axon that innervates a large
terminal field. Certain regions of the LC project to
specific terminal fields topographically, although there
is much overlap. For example, in rodents and primates,
the rostral and dorsal LC cells innervate forebrain and
cerebral cortical structures; the more caudal and ventral cells innervate the cerebellum and the spinal cord
{5-111. Some LC axons collateralrte and innervate
more than one terminal field; for example, the cerebellum and the spinal cord, or the cerebral cortex and the
spinal cord {lo}. Because of its divergent and ubiquitous projections, the LC has been proposed to subserve global functions such as modulation of neuronal
activity 112-141; aspects of cortical development {l5,
161, plasticity 1171, metabolism {18-21}, and cogni-
tion/memory 1221 for the forebrain projections; and
modulation of motoneuron function {23-251 for the
spinal cord projections.
There is marked LC cell loss in patients with Parkinson's disease (PD) 126, 271, Alzheimer's disease (AD)
127-331, and Down syndrome (DS) 133-351. Although it has been known for some time that all these
diseases are characterized by loss of LC noradrenergic
neurons, detailed anatomical studies are needed to examine and compare the pattern of cell loss in the three
diseases. The purpose of our study was to determine
whether LC neurons are randomly or systematically
lost in PD, AD, and DS, and whether certain subgroups of cells are more susceptible to any of the specific diseases. For this purpose, computer visualization
techniques {27, 33, 36, 371 were used to reconstruct
the two-dimensional patterns of cell loss in PD, AD,
and DS brains compared with aged normal brains. Preliminary results have been previously published C381.
From the Departments of 'Psychiatry, tPathology (Neuropathology
Laboratory), $Cell Biology and Neuroscience, and §Academic Computing Services,The University of Texas Southwestern Medical Center; and "BiogcaphicsInc, Dallas, Tx; the '*Department of Neuralogy, Case Western Reserve School of Medicine, Cleveland, OH;
and the ttDepartment of Pathology, University of Manchester, ManChester, UK.
Received Dec 11, 1991, and in revised form Mar 13 and May 1,
1992. Accepted for publication May 3, 1992.
Address correspondence to Dr
Department of psychiatry, University of Texas Southwestem Medic- Center, Dallas, TX
75235-9070,
Copyright 0 1992 by the American Neurological Association 667
Locus Coerukus CeiY Loss in Neumdgenerative Diseases
Brains
Normal subjects
DA-24
DA-33
DA-34
DA-39
DA-5 1
M62A
DA-136
Alzheimer's disease
DA-4 3
DA-77d
DA-8 1
DA-88
DA-92
DA- 104
DA-120
DA-130
DA-131
Parkinson's disease
DA-49
DA-70
DA-72
DA-74
DA-9 1
DA-133
Down syndrome
DA- 108
DA-119
DA-121
Agea/Sex
Disease Durationa
Brain Weightb
LC Cell Number'
761M
6OIM
641M
721F
701M
621M
631F
...
...
...
...
...
...
...
1,720
1,430
1,330
1,260
1,250
NA
1,170
18,020
18,444
20,549
18,834
12,113
15,418
14,030
781F
791M
741M
75lF
74lF
791F
821F
6lIF
701M
4
NA
3.5
2
1.5
2
5
8
3
NA
1,215
1,100
1,070
1,150
1,100
820
NA
1,130
7,301
9,209
6,833
10,395
5,477
9,283
2,886
1,991
3,286
741M
66lF
771F
631M
771M
66lM
9
5
5
15
16
15
1,430
1,430
1,275
1,590
1,165
1,470
13,285
1,720
8,546
7,280
1,110
3,42 1
...
1,018
990
860
3,086
7,480
5,474
591M
571M
58lF
'Age and disease duration in years.
bBrainweight in grams.
'LC cell number, including subcoeruleus cell number, on one side of the brain, from the frenulum to the motor nucleus of the trigeminal nerve,
and corrected for split-cell counting error.
dDA-77 had both Alzheimer's and Parkinson's disease.
LC = locus coeruleus; NA = not available.
Materials and Methods
A total of 7 normal brains, 6 PD brains, 8 AD brains, and 3
DS brains were examined. One brain was from a patient with
both AD and PD (DA-77). Normal subjects ranged in age
from 62 to 76 years (67 -C 2 years, mean 2 SEM); patients
with PD were from 63 to 77 years old (7 1 2 3 years), patients
with AD were from 61 to 82 years old (75 k 2 years), and
patients with DS were from 57 to 59 years old (58 2 1 year)
(Table). P D brains were from patients with the neurological
symptoms of PD, a marked loss of midbrain dopaminergic
neurons, and the presence of Lewy bodies in some of the
remaining pigmented neurons in the midbrain and the LC.
AD brains were from patients with dementia and senile
plaques and neurofibrillary tangles of sufficient density and
distribution in the cerebral cortex. DS brains were from patients with the clinical and physical signs of the disease.
The brains were fixed in 10% neutral-buffered formalin
for several weeks, often suspended by the basilar artery to
minimize tissue distortion. After the entire brain was fixed,
the brainstem was dissected free and fixed for an additional
7 to 10 days. The brainstem was placed on the stage of
a freezing microtome, and 50-km-thick sections were cut
throughout the rostral-caudal extent of the LC (3 brains were
sectioned using 20 km thickness, and 1 brain was cut in the
sagittal plane). Care was taken to cut the brains in a plane
approximately perpendicular to the long axis of the brainstem. Sections were mounted onto glass slides at 0.5- to
1.0-mm intervals for the cell mapping studies. Most sections
were stained with cresyl violet or for neuromelanin pigment
(Schmorl's ferricyanide). Some brain sections were also
stained with an antibody against the rate-limiting enzyme
in catecholamine biosynthesis, tyrosine hydroxylase (1: 1000,
Eugene Tech Intl, Allendale, NJ) using the immunoperoxidase method. There was a good correlation between tyrosine
hydroxyiase-stained cells and neuromelanin-containing cells,
as previously described 132, 371.
LC cells were mapped and quantified using software developed by Biographics Inc (Dallas, TX;CARP software).
These methods have been previously described in detail 136,
391. The locations of all neuromelanin-containing LC and
subcoeruleus (SC) cells (the noradrenergic cells ventrolateral
to the caudal LC)-within sections spaced 0.5 to 1.0 mm
apart from just rostral to the frenulum (between the caudal
portion of the inferior colliculi) to just caudal to the motor
nucleus of the trigeminal nerve nucleus-were entered into
a SUN-31260 computer (SUN Microsystems Inc, Mountain
668 Annals of Neurology Vol 32 N o 5 November 1992
View, CA). Lines were drawn around the perimeter of each
tissue section, and the location of each cell was mapped
within the section. All sections were then aligned with the
adjacent sections so that cellular and pontine tissue landmarks overlapped. This procedure was necessary for the 3
two-dimensional reconstructions of the entire nucleus. The
long and short axes of LC cells were also measured. Measurements were made on cells with clearly visible nuclei in the
caudal portion of the nucleus. Ten to 20 cells were measured
in each brain at a magrdication of 400 x .
The pattern of cell loss was examined in several ways. First,
they were examined as a function of the number of LC and
SC cells per section across the rostral-caudal length of the
nucleus. Because the rostral-caudal length of the nucleus varied from brain to brain (7.5-13.6 mm), LC length was normalized such that a rostral portion of the nucleus was identified as 0% (at the level of the frenulum) and a caudal portion
of the nucleus was identified as 100% (at the rostral portion
of the motor nucleus of the trigeminal nerve). Cell numbers
were also corrected for split-cell counting error 1401. Second,
the number of cells within nucleus SC were compared across
diseases. Third, two-dimensional reconstructions of the cell
frequencies in normal and diseased brains were examined in
the horizontal plane (XZplane; the plane horizontal to the
long axis of the brainstem), the frontal plane (XY plane), and
the sagittal plane (YZ plane).
The XZ two-dimensional cell frequency maps were generated by taking the number of cells within 250-pm-wide bins
across the medial-lateral extent of a tissue section and plotting a cell frequency histogram. The frequency histograms
of adjacent tissue sections were then connected (taking into
consideration the actual distance between tissue sections) and
smoothed. Finally, the cell frequencies were divided into 5
domains; each frequency domain was color-coded, and the
frequency map was viewed from directly above the dorsal
surface of the brainstem. The YZ two-dimensional cell frequency maps were generated in the same manner as the XZ
maps, except that the frequency histograms were constructed
from 250-pm bins across the dorsal-ventral extent of a tissue
section and viewed from the midsagittal perspective. The
XY two-dimensional cell frequency maps were generated by
determining the number of cells within 250 x 250-pm bins
in each tissue section and by summing the respective bins
across all tissue sections from the frenulum of the inferior
colliculus to the rostral portion of the motor nucleus of the
trigeminal nerve. Cell densities for the X Y maps are presented as cells/mm3.
Results
In normal brains, there was an average of 16,773 k
1,133 cells (mean 2 SEM) within the LC complex on
one side of the brain (see Table). The normal nucleus
spanned a rostral-caudal distance of 10.8 to 13.6 mm.
Figure 1 illustrates the location and distribution of LC
and SC cells across the rostral-caudal length of the nucleus in a normal brain. The cells began rostrally at the
level of the inferior colliculus and sllghtly rostral to
the frenulum, and were situated ventral-lateral to the
cerebral aqueduct in the periaqueductal gray matter
(see Fig 1A). The LC cell numbers increased, moving
caudally within the nucleus, and the nucleus was displaced laterally with the opening of the cerebral aqueduct into the full extent of the fourth ventricle (see Fig
1F). The SC cells were located ventral-lateral to the
caudal portion of the LC (see Fig lE, F).
In PD brains, the rosual-caudal length of the nucleus
was 7.5 to 13.6 mm, and there was considerable variability in the magnitude of LC cell loss, ranging from
21 to 93% compared with normal brains (see Table).
For clarity of display in visualizing the rostral-caudal
extent of LC cell loss, the 6 brains were divided into
three groups based on the total amount of LC cell loss.
The 2 brains with the highest cell loss were assigned
to the high cell loss group, the 2 brains with moderate
cell loss were assigned to the medium cell loss group,
and the 2 brains with the lowest cell loss were assigned
to the low cell loss group. As the severity of total cell
loss increased from low to high, an almost complete
loss of cells resulted from rostral to caudal within the
nucleus (Fig 2). The magnitude of cell loss across
the rostral-caudal extent of the LC was analyzed as the
percent cell loss from normal. In the PD brains, there
was approximately 30,60, and 90% loss of LC cells in
the low, medium, and high cell loss groups, respectively, across all rostral-caudal portions of the nucleus.
Using a two-way analysis of variance (ANOVA), there
was no overall difference in cell loss from rostral to
caudal in the nucleus (F = 2.26; p > 0.05), and there
was no significant interaction between magnitude of
cell loss and rostral-caudal position within the nucleus
(F = 0.63). However, there was a significant difference
in the magnitude of cell lass between the three groups
(F = 17.11;p = 0.022).
The LC in the AD brains spanned a rostral-caudal
distance of 8.0 to 12.8 mm, and cell loss ranged from
38 to 88% compared with normal brains (see Table).
As in the PD brains, the 9 AD brains were combined
into three groups based on the magnitude of total LC
cell loss. In all three cell loss groups, the magnitude of
cell loss was always greatest within the rostral portion
of the nucleus; magnitude of cell loss was more than
90% in the rosual portion in the high cell loss group
(Fig 3). In the caudal portion of the nucleus, however,
there was always a sparing of some cells regardless
of how severe total cell loss was. Using a two-way
ANOVA, there was a significant difference between
the three groups in the magnitude of percent cell loss
from normal (F = 15.13;p = 0.004) and a significant
difference in percent cell loss as a function of the
rostral-caudal position within the nucleus (F = 14.76;
p = O.OOl), but no significant interaction between
these two variables (F = 0.56).
Patient DA-77 had AD and PD, defined both clinically and neuropathologically. This brain, like the other
AD brains, showed a marked loss of r o s d cells and
relative sparing of caudal cells.
German et al: Disease-specific LC Cell Loss 669
Fig 1. The location of locus coeruleus (LC) cells from rostral (A)
to cauahl (F) within a norvnul human brain. Each section is
separated b~2.4 mm, and each cell is illustrated as a dot. The
cells begin 0.5 to 1.0 mm rostra1 to the frenulum (F) of the injirior colliculus. As the cerebral aqueduct (CA) opens into the full
extent of the fourth ventrzcle (IV V), the LC cells are displaced
laterally. The caudal extent of the LC is marked by the presence
of subcoeruleus (SC) ceh and the rostral portion of the motor nucleus ofthe trigeminal nerve (not shmun), which is located just
lateral and cauahl to the location of the SC celh as illustrated
in (F). The grid size is 2 mm, and the number of cells in each
column appears at the bottom of each panel. IC = inferior colliculus; SMV = superior medullaiy velum.
670 Annals of Neurology Vol 32 No 5 November 1992
1
I.."
~
11-
~
I
~~~~~
&
LOW CELL LOSS 04-2)
-f
MEDIUM CELL LOSS (N-2)
HIQH CELL LOSS IN-21
.
I'
n
B
.
I
I
100
9
z
50
n
0
50
100
*
Fig 2. The number of locus coeruleus (LC) neurons (mean
SEM) in PD brains,fmm rostral to caudal. For comparison purposes, the number of LC cells is also presentedfor the normal
group (mean f SEM). All cell numbers represent unilateral cell
counts. Three groups are presented, based on the total percent
LC cell loss. Notice that as LC cell Loss progressed from lvw to
medium to high, there was an almost complete loss of cells from
rostral to caudzl. Cell counts have been corrected for split-cell
counting error, and rostral-cauakldistance refers to the location
of the frenulum (at 0%) and the rostral portion of the motor
nucleus of the trigeminal nerve (at 100%).
L
100 --
p"
s
z
0
50
100
Rostral-Caudal Dlstance (Percent)
Fig 3. The number of locus coeruleus (LC)neurons (mean sf:
SEMI in A D brains, from mstral to caudal. For comparison
purposes, the number of LC cells is also presentedfor the n o w l
group (mean SEM). All cell numbers represent unilateral cell
counts. The A D brains were divided into three groups based on
the total percent of LC cell loss. Note that even when there is severe cell loss in the rostral portion of the nucleus, there is still
preservation of cells in the cauakl portion of the nucleus. The ubscissa is the same as in Figure 2.
*
0
100
Rostral-Caudal Dlstanca (PerCenl)
Rostral-Caudal Dlstanca (Percent)
*
Fig 4. The number of locus coeruleus (LC)neurons (mean
SEM) in DS brains, from rostral to caudal, For comparison purposes, the number of LC cells is also presentedfor the normal
group (mean 2 SEM). All cell numbers represent unilateral cell
counts. Note that LC cell loss is most pronounced in the rostral
portion of the nucleus, with sparing of caudal cells, which is
very similar to that observed in the AD medium cell loss group.
The abscissa is the same as in Figure 2.
In A D brains, there was a significantpositive correlation between the rank order of total LC cell loss and
the duration of dementia (Pearson's r = 0.75; p <
0.03). In PD brains, however, there was no significant
correlation between the rank order of LC cell loss and
the duration of PD.
In DS brains, the LC had a rostral-caudal distance of
8.8 to 10.0 mm, and there was 55 to 82% total cell
loss compared with normal brains (Fig 4; see Table).
The pattern of LC cell loss was similar to that observed
in AD brains. The greatest cell loss occurred uniformly
within the rostral portion of the nucleus (approximately 7 5%), whereas there was always preservation
of cells within the caudal portion of the nucleus (approximately 15% cell loss). The magnitude of LC cell
loss in DS brains was comparable to that in the AD
medium cell loss group. Using a one-way ANOVA,
there was a significant difference in the magnitude of
percent cell loss from normal brains across the rosualcaudal extent of the nucleus in DS (F = 27.09; p =
0.006).
Counting the number of SC cells within 3 to 4 sections spanning a distance of 1.6 to 2.4 mm and correcting for split-cell counting error, the estimated total
number of SC cells on one side of the brain was 911.4
+- 107.4 (mean -t SEM) for normal brains (n = 7),
607.2 ? 63.0 for A D brains (n = 9), 638.0 -t 94.0
for DS brains (n = 3), and 340.7 -+ 138.9 for PD
brains (n = 6). There was a significant difference in
German et al: Disease-specific LC Cell Loss 671
SC cell number among the 4 groups (ANOVA, F =
5.30; p = 0.007). There was a significant 63% loss of
SC cells in the PD brains compared with age-matched
normal brains (Newman-Keuls multiple comparison
test, p < 0.05); however, there was no significant loss
of these cells in AD or DS brains compared with normal brains.
The size of the LC cells (measured in the caudal
portion of the nucleus) differed sllghtly between the 3
disease groups. The cells in the normal brains had a
mean diameter of 34.9 & 1.4 Fm, in the AD brains
33.7
1.5 p,m, in the PD brains 39.9 2 1.5 Fm, and
in the DS brains 36.2 k 1.1 Frn (ANOVA, F = 3.45;
p < 0.037). Newman-Keuls multiple comparison tests
indicated that there was no difference between ceI1
sizes in normal, AD, and DS brains, but there was a
significant difference between cell sizes in A D and PD
brains ( p < 0.05).
The two-dimensional reconstructions of the LC
complex provide visual appreciation of the diseasespecific patterns of cell loss (Fig 5). DS brain reconstructions were similar to the A D brain reconstructions; therefore, only the AD brain reconstruction is
presented. In the AD brain, there is almost complete
loss of cells in the rostral half of the nucleus that is
clearly observed in both the XZ and the Y Z planes.
Cells were spared in the caudal portion of the nucleus
(see Fig 5; top and middle panels). Also, the mediallateral and dorsal-ventral dimensions are reduced by
approximately 25% in the AD brain compared with
the normal brain (see Fig 5; XY plane, bottom panel).
In the PD brain, there is marked cell loss throughout
the rostral-caudal extent of the nucleus, as observed
from both the XZ and the YZ perspectives (see Fig
5; top and middle panels), and the medial-lateral and
dorsal-ventral dimensions of the LC complex are also
reduced by approximately 25% compared with the
normal brain (see Fig 5; X Y plane).
*
Discussion
LC cell loss has been reported to occur in several neurodegenerative diseases, including PD, AD, and DS. It
has been known for more than 20 years that there is
LC cell loss in patients with AD 1411 and PD [42),and
LC cell loss has also been observed in DS 133-353
Our results extend these observations by providing a
topographic analysis of the pattern of cell loss in all
three diseases. These results indicate that LC cell loss
in PD is distinctly different from that in AD and DS.
In the most severe instances of cell loss in PD, there
was approximately 90% loss of LC cells from rostral
to caudal; however, in mild cell loss, there was only
approximately 30% loss of LC cells from rostral to
caudal. In AD and DS, however, the magnitude of cell
loss varied as a function of the rostral-caudal position
within the nucleus. Cell loss was greatest rostrally; even
with the most severe cell loss, there was always preservation of caudal LC and SC cells. These disease-specific
patterns of LC cell loss are similar to those previously
observed by ourselves and others for AD E27, 281 and
PD 127).
The pattern of LC cell loss in each disease may be
related to the topographic arrangement of LC axonal
projections. LC axons, examined in both rats [5-8, 10,
11, 251 and monkeys {4, 91, have been shown to project to cortical, cerebellar, and spinal cord regions topographically. The rostral portion of the LC contains
cells that project to the cerebral cortex, the hypothalamus, and the forebrain. The ventrocaudal portions of
the LC, including the nucIeus SC, contain cells that
project to the spinal cord and the cerebellum. In AD,
it appears that there is sparing of cells in those LC
regions that in animal experiments project to the spinal cord, the cerebellum, or both. Even with the most
severe LC cell loss in AD, there is uniform sparing of
caudal LC and SC cells, in contrast to PD, in which
there is often a marked loss of caudal LC and SC cells.
It has been speculated that LC cell loss in A D is
the result of retrograde degeneration of the corticalprojecting cells, with sparing of spinal- and cerebellarprojecting LC cells 1431. Consistent with this hypothesis, it has been observed that there is neurofibrillary
pathology in 11 subcortical nuclei in AD, which all
project to the cerebral cortex [44,45],and the loss of
cortical synapses may be an early feature of AD 1461
that signals the beginning of retrograde changes within
Fig 5 . Two-dimensional cell frequency maps illustrating the distribution of locus coeruleus (LC)and subcoeruleus (SC) cells in
normal, PD, and AD brains. The maps illustrate cells on the
right side of the brain, and the cell distributions are viewed
fmm the horizontal plane (XZ plane, top), the sagittal plane
(YZ plane, middle), and the frontal plane (XU plane, bottom). The top two panels illustrate the cell distributions from
rostral (at O%, the location of the frenulum) to caudzl (at
loo%, the location o f the rostral pole of the motor nucleus of
the trigeminal nerve). The nucleus SC cells can be observed as
the white region to the ldt ofthe cauahl LC in the top panel,
to the ldt of the LC in the bottom panel, and to the right of the
LC in the middle panel. The number of cells within the horizontal plane (top),for examph, is color-coded; red areas represent regions containing 2,571 to 3,312 cellslmn?, and white areas
represent regions containing 1 to 642 celldmd. The cellular distance from the midline (i.e., the right-hand k& in the individual maps in the top and bottom panels) is indicated in mm.
In the sagittal plane (middle), cells are illustrated as in the horizontalphne, except the celh are illustrated wirh &rence to the
ventral-most extent of the cerebral aqueductlfourth ventricle (blue
vertical line in the middle of each map, at 0 mm). In the frontal plane (bottom), the colors represent the number of celhlmd,
D = dorsal; L = lateral; R = rostral.
672 Annals of Neurology Vol 32 No 5 November 1992
b
German et al: Disease-specific LC Cell Loss 673
cortical-projecting subcortical nuclei (e.g., within the
LC, dorsal raphe nucleus, nucleus basalis of Meynert).
Our data, which illustrate a significant loss of rostral
cells and sparing of caudal cells within the LC, are also
consistent with this hypothesis.
The pattern of LC cell loss in DS is similar to that
observed in AD. It has been previously observed that
there is LC cell loss in DS E33-357; however, our study
extends these observations by demonstrating that the
pattern of cell loss within the entire nucleus is similar
to that observed in AD. This similarity in LC pathology
may be related to other similarities between AD and
DS, such as the fact that cortical senile plaques, neurofibrillary tangles, and chromosome 2 1 abnormalities
also develop in older patients with DS 147-491.
Unlike AD and DS, there is a significant loss of LC
cells in all rostral-caudal portions of the nucleus in PD,
including the SC cells. In 2 of the 6 PD brains, cell
loss was markedly greater in the caudal portion as compared with the rostral portion of the nucleus. Consistent with these data, it has been previously reported
that patients with PD exhibit a trend, although not
significant, toward greater loss of caudal LC cells than
rostral LC cells [27}, as well as significant reductions
in spinal cord concentrations of norepinephrine [SO}
compared with control subjects. It is possible that degeneration of the caudal LC and SC cells, which project
to the cerebellum and the spinal cord, is responsible
for part of the PD syndrome. This hypothesis could
also explain why there was no correlation between total
LC cell loss and duration of PD symptoms, because
only the caudal portion of the nucleus (and not the
entire nucleus) is related to the motor symptoms used
to diagnose the disease. In contrast, degeneration of
the more rostral cells, which project to the forebrain,
may be related to dementia, because it has been reported that there is a greater decrease of norepinephrine levels in the LC [5l), a greater loss of LC cells
1261, and a greater loss of rostral LC cells 127) in patients with PD and dementia compared with nondemented patients with PD.
A significant loss of LC cells is correlated with dementia in several diseases (e.g., PD, AD, DS, Pick's
disease) [52}; however, in multiinfarct dementia, there
is no significant loss of LC cells f311. This observation
suggests that loss of LC nerve terminals in the cerebral
cortex is not sufficient to induce retrograde degeneration of cortical-projecting LC cells, as may occur in
AD, DS, and Pick's disease. We have previously speculated 1437 that the cell loss in AD and other neurodegenerative diseases may be the result of retrograde
degenerative processes, due either to the lack of trophic factors or to the presence of toxic substances (such
as p-amyloid in AD) within the cerebral cortex. In
multiinfarct dementia, in which degeneration of cerebral cortical neurons is triggered by the loss of blood
supply, the cortical environment must not be sufficiently damaged to destroy afferent inputs, because
there are still normal numbers of LC neurons in these
patients.
There was a significant correlation between the duration of dementia and the magnitude of LC cell loss in
AD brains ( Y = 0.75). In brains from 3 individuals
with 1.5- to 2.0-year histories of dementia, there was
48 to 69% LC cell loss, whereas in the 5 patients with
3 to 8 years of dementia, there was 58 to 89% LC
cell loss. Consistent with this observation, it has been
previously observed that there is a positive correlation
between dementia scores and LC cell loss (measured
in one portion of the nucleus); the most demented
patients showed 81% cell loss, whereas the least demented patients exhibited less than 20% cell loss 130).
Other investigators have reported positive correlations
between LC cell loss and senile plaque densities in the
cerebral cortex [29}, as well as significant decreases in
cerebral cortical norepinephrine levels in postmortem
AD brains [32). In addition, Palmer and colleagues
153) reported more than 50% reductions in temporal
neocortical norepinephrine concentrations in biopsies
from patients with AD with as little as a 2-year history
of dementia. These observations, as well as the upregulation of postsynaptic neuronal [54] and cerebral microvessel155) adrenergic receptor sites in AD, suggest
that LC dysfunction presumably occurs early in the
disease and precedes the retrograde degenerative process that results in a gradual loss of cortical-projecting
LC neurons. Our observations on the diffuse loss of
neurons throughout the LC in PD brains, as well as
the different cell sizes remaining in PD compared with
AD brains, underscore the hypothesis that a different
neurodegenerative process characterizes PD.
Dysfunction and subsequent loss of noradrenergic
LC neurons in neurodegenerative diseases such as PD,
AD, and DS may contribute to the degeneration observed within several other brain nuclei in these diseases. The LC axon terminals in the cerebral cortex
make few direct synaptic contacts with postsynaptic
neurons; rather, they appear to influence targets within
a circumscribed microenvironment, with norepinephrine acting as a neuromodulator (in contrast to a neurotransmitter) 156). The targets that are influenced in this
way include neurons 1141, astrocytes [56], and cerebral
blood vessels 121). Recent studies have shown that LC
neuronal destruction markedly worsens the neurodegenerative effects produced by both N-methyl-4phenyl-l,2,3,6-tetrahydropyridine [57] and cerebral
ischemia 1587. Such data indicate that a lack of LC
innervation can potentiate neurodegenerative processes in general. By understanding further the mechanisms by which LC cell loss can potentiate neurodegeneration, additional insight may be gained into the
pathophysiology of dementia.
674 Annals of Neurology Vol 32 No 5 November 1992
This research was supported by grants from the National Institutes
of Health (AG-08013; AG-08072 to R. N. K.), the Dallas Area
Parkinsonism Society, Biological Humanics Foundation, the John
Schemmerhorn Fund, the Alzheimer’s Disease and Related Disorders Association, the James Webb Fund of the Dallas Foundation,
and a gift from Mr and Mrs Richard Eiseman to D. C. G.
We wish to thank Dr Sadeq Hassan, John Brown, and Diane Gonzalez for histological assistance; Dr Malcolm Stewart for clinical information on the patients with PD; and Ms Judy Burdette for secretarial
assistance.
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