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Basal forebrain neurons in the dementia of Parkinson disease.

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Basal Forebrain Neurons
in the Dementia of Parhnson Disease
Peter J. Whitehouse, MD, PhD,' John C. Hedreen, MD,? Charles L. White 111, MD,$
and Donald L. Price, MDfi
Demented patients with Parkinson disease share certain neuropathological and neurochemical features with patients
suffering from Alzheimer disease. Recently, loss of cholinergic neurons in the basal forebrain, particularly the nucleus
basalis of Meynert, has been implicated i n the pathophysiology of Alzheimer disease. The present investigation of 12
patients with Parkinson disease demonstrates that the demented patients with this disease also show a selective loss of
cells in the nucleus basalis of Meynert, thus providing an important link between the dementias of Alzheimer disease
and Parkinson disease.
Whitehouse PJ, Hedreen JC, White CL 111, Price DL: Basal forebrain neurons in the dementia of Parkinson
disease. Ann Neurol 13:243-248, 1983
Parkinson disease (PD) has been recognized as a prime
example of selective involvement of a transmitterspecific nerve cell population since the initial description of loss of neurons in the substantia nigra early in
this century [9, 341 and the demonstration of reduced
levels of dopamine in the nigrostriatal system in the
1960s [7]. In addition, PD has been a model for pharmacological replacement therapy; administration of
levodopa ameliorates the tremor, bradykinesia, and
rigidity occurring in these patients [13}. Afthough
levodopa dramatically improves motor abnormalities, it
does not prevent or relieve the dementia that eventually develops in as many as 55% of these patients [ 5 ,
19, 331. These observations suggest that other populations of nerve cells may be affected in P D and that
changes in these cells may be responsible for the dementia. Because a majority of demented PD patients
show the senile plaques and neurofibrillary tangles typical of Alzheimer disease (AD) [Z, 4, 101 and because
studies from our laboratory have shown that A D selectively affects a population of cholinergic neurons in the
basal forebrain [27, 38, 371, we decided to examine
this neuronal population in demented and nondemented patients with PD. Located in the medial septum, diagonal band of Broca (dbB), and nucleus basalis
of Meynert (nbM) [S, 221,these cholinergic neurons,
distinguished by their large size, dark staining with
cresyl violet, and content of acetylcholinesterase
(AChE) [231 and choline acetyltransferase (CAT) r17,
From the *Departments of Neurology and Neuroscience, the
TNeuropathology Laboratory, Department of Pathology, the $DeOf
and the 'Neuropathology Laboratory' Departments of Pathology and Neurology, The Johns Hopkins Universiry School of Medicine, Baltimore, M D 21205.
201, are known to project to the neocortex [14, 16,
2 I}, hippocampus, and amygdala.
Methods
Ten cases of PD and 10 age-matched controls without
neurological disease were obtained from the Yakovlev Collection of the Armed Forces Institute of Pathology (AFIP)
(Series 1). Two additional P D cases and controls were obtained through the courtesy of D r Richard Lindenberg from
the Office of the Maryland State Medical Examiner (Series 2).
Using clinical records, the type of P D was classified as follows: idiopathic P D without dementia (4 cases); idiopathic
P D with dementia ( 5 cases); and postencephalitic P D (3
cases) (Table 1). The presence or absence of dementia was
ascertained by reviewing the clinical records for evidence of
progressive intellectual decline in association with parkinsonian symptoms (Table 2). The quality of available records
varied but included, in most cases, the results of neurological
or psychiatric evaluation (or both). Series 1 brains had been
fixed in formalin, embedded in celloidin, and sectioned in the
laboratory of Dr Paul Yakovlev. Sections (35 bm) were cut
coronally or sagittally and mounted, and every twentieth section was stained by cresyl violet and the adjacent section with
a modified Weigert stain. Using maps of human basal forebrain established in our laboratory Ella), we selected three
closely matched sections cut in either the sagittal or coronal
plane from each case. In the specimens cut in the coronal
plane, we examined the following: the midportion of the
nbM at a level containing the largest number of nerve cells;
the anterior part of this cholinergic cortical projection system
containing the nucleus of the dbB and the medial septum;
Received July 6, 1982, and in revised form Sept 16. Accepted for
publication Sept 20, 1982.
Address reprint requests to D r Whitehouse, Neuroparhology Laboratory, The Johns Hopkins University School of Medicine, 5-185
Meyer Bldg, 600 N Wolfe St, Bairimore, MD 2 1205.
243
Table I . Clinical and Demographic Characteristics of Patient Groups"
Subjects
Ageb
(yr)
Disease
Duration
(yr)
Type
of
Section'
69
70"
73
52
58
13
14
4
5
4
S
70
76
7
5
48
10
51
13
26
Type of Surgery
Series 1
P D patients
Idiopathic
(demented)
Idiopathic
(nondemented)
Postencep halitic
(nondemented)
52
32
44
Controls
C
L chernopallidectomy
C
C
L anterior choroidal ligation
L stereothalamotomy
L chernopallidectomy
R thalamotomy
L pallidotomy
R chemothalamotomy
R craniotorny with
fiber undercutting
C
C
S
C
S
S
C
C
C
50
53
54
66
67
78
80
S
C
S
C
S
C
88
C
~
Series 2
PD patients
Idiopathic
(demented 1
Controls
65
>2
1 '12
70
50
59
C
C
C
C
T h e left nbM was counted in all cases unless the patient had stereotactic surgery on that side nfthe brain. N o effects of the surgical procedures o n
the regions studied were noted.
Series 1, the mean age of P D patients and controls was identical (62 years). In Series 2, the mean age of the control patients (54 years) was less
than that of the PD patients (67 years).
'Coronal (C) or sagittal (S). Control cases were matched by plane of section as well as age.
'Inadequate clinical data led to a designation of probably demented in this case.
PD = Parkinson diseiise; R
=
right; L
=
left.
and a section midway between these two regions. In the
sagittally sectioned brains, three slides were examined per
case: the section containing the grossly visible largest number
of neurons in the nbM; and the sections 3.5 mm lateral and
3.5 mm medial to this plane. The brains in Series 2 were fixed
in formalin, embedded in paraffin, sectioned (16 pm) coronally, and stained with cresyl violet and Bodian silver stains.
Only one section from the midportion of the nbM was available in these cases. Since section thickness was about half that
of Series 1 patients, direct comparison of the number of cells
was not possible. In both series, the slides were counted by
two independent observers who were unaware of the diag-
244 Annals of Neurology Vol 13 N o 3 March 1983
nosis. Cells were counted using a Bausch and Lomb TriSimplex microprojector with a 19 mm lens. A neuron was
counted as being a member of the magnocellular basal forebrain system if it was large (>30 p m in diameter) and darkly
stained with cresyl violet. Slides of parietal cortex, hippocampus, and substantia nigra were reviewed to confirm the diagnosis of P D and to search for the histopathological stigmata
of AD, for example, senile plaques and neurofibrillary tangles. Loss of neurons and free pigment was observed in the
substantia nigra, although it was difficult in the available
cresyl violet preparations to fully assess the presence of Lewy
bodies, senile plaques, and neurofibrillary tangles. In Series
Table 2. Characteristicsof Demented PD Patients
Patient’s
Age (yr)
Clinical Characteristics
Series 1
~
~~
Slowly progressive neurological disorder for
13 years resulting in “loss of ability to walk,
talk, and eat”; “fixation of facies”; “loss of
intellectual function”
Seven-year history of “tremor starting in
right hand”; some suggestion of intellectual
deterioration; several chemopallidecromies;
preterminally “incontinent and
unresponsive”
Four-year history of “shaking of the left
hand, a shuffling gait, and mental
deterioration”; pneumoencephalogram
showed “symmetrical dilatation of the
ventricles consistent with brain atrophy”
69
70
73
Series 2
~~
~~
65
70
“Chronic brain syndrome with confusion,
disorientation, and agitation” for at least 2
years; pneumoencephalogram showed
“marked dilatation of lateral ventricles” and
“some cerebral atrophy”
One and one-half year history of “gradual
impairment of ability to understand,
reduction in memory and periods of
confusion”; “face was typical of Parkinson’s
mask”; “unable to do quick motions”;
“regular rhythmic resting tremor”
2, silver stains of the cortex and hippocampus did show
neurofibrillary tangles and senile plaques, consistent with a
diagnosis of AD.
Results
Quantitative analysis of nerve cells in the nbM and
septum in 12 patients with P D and 12 age-matched
controls showed that the demented PD patients had a
significant loss of neurons in the nbM (Fig 1, Table 3).
The postencephalitic patients did not show loss of cells
in the nbM. The data from the nondemented idiopathic
patients were somewhat more difficult to interpret.
There did not appear to be significant loss of nerve cells
in septa1 areas, but in the main body of the nbM, the
idiopathic cases seemed consistently to have fewer
neurons than the control cases. While only a limited
statistical analysis could be performed on the data because of the small number of patients in each group,
t tests revealed a significant difference between
idiopathic demented PD cases and controls in all regions of the nbM. The difference between the
idiopathic nondemented PD patients and controls was
significant when the counts of all three slides studied
were pooled and averaged. The correlations between
age and average count of neurons for all three coronal
sections in the PD patients were not significant in
either group of patients. In Series 1, a negative correlation ( Y = -0.66) between duration of disease and
average number of cells in the nbM was not quite
significant (p < 0.10).
Discussion
These results support the hypothesis that there is a
selective loss of large nerve cells in the basal forebrain
in demented patients with PD. Review of the literature
discloses that the nbM has been implicated in P D for
many years, for example, the original observations of
Lewy bodies, the classic intracytoplasmic inclusion almost pathognomonic of idiopathic PD, were made not
in the substantia nigra but in the substantia innominata,
an area encompassing the nbM [IS]. Several authors
have described loss of neurons in the nbM in PD, particularly in the idiopathic form of the disease { 1, 9, 11,
311. Consistent with our findings, the absence of
significant cell loss has been reported in the postencephalitic form of PD [36]. Moreover, Hassler Ell]
suggested that loss of cells in the nbM was associated
with “bradyphrenia,” a term he used to describe the
slowness of motor and cognitive functions in patients
with PD. However, the claim of nerve cell loss in the
nbM has not been assessed by quantitative studies, nor
is there documentation of the association of loss of
these neurons with dementia.
In the present study, neuron loss was most marked
in both the septum/dbB and nbM in demented individuals with idiopathic disease. The large cells of the nucleus of the dbB and medial septum seem to be generally intact in all patients with P D except for those with a
history of dementia. Our finding of a loss of nerve cells
in the dbB/nbM in demented patients with P D is similar to that which we have documented in A D (38, 393.
Recently, loss of cells in the nbM in the parkinsonismdementia complex has also been found r22a). Dysfunction of the cholinergic septaIldbB pathways to the hippocampal formation may be involved in the memory
abnormalities in PD 143, whereas the loss of nbM
neurons may also play an important role in the
pathogenesis of other cognitive deficits such as speed
or efficiency of cognitive processing.
These observations are consistent with recent investigations from our laboratory which suggest that the
loss of neurons in the nbM is the principal pathological
substrate of the consistently demonstrated (6, 25, 29,
373 loss of presynaptic cholinergic markers in the cortex in A D C27, 28, 38, 391. Moreover, in studies of
aged monkeys, we have provided evidence for a model
of senile plaque formation in which degenerating
AChE-rich axons, some of which are thought to arise
Whitehouse et al: Dementia of Parkinson Disease
245
Photomicrographs A and B show neurons in corresponding areas
of the midportion of the nbM in the brains of a control (A)and a
demented PD patient (B).Note the normal complement of nerve
cells in A and a profound reduction of neurons in 8 . Photomicrographs C and D demonstrate the nucleus of the dbB in a control (C) and in a demented PD patient (D).Note seoere depletion
of large neurons in the patient with PD. (SAS = subarachnoid
space; BV = blood vessel.) (Cresyl violet x 37.5.)
from cholinergic neurons in the basal forebrain, comprise, in part, the neurites in cortical plaques [27, 321.
Both the numbers of senile plaques and the magnitude
of the reduction in CAT activity have been shown to
correlate with the presence of dementia in A D [26).
Similarly, some patients with P D also show cholinergic
deficiencies in the cortex [ 3 , 301 which appear to correlate with the severity of their dementia {30}. In this
retrospective study, assessment of dementia was based
on clinical records of varying degrees of completeness.
All patients assigned to the demented category had
evidence of progressive intellectual deterioration, as
recorded by attending neurologists and psychiatrists.
246
Annals of Neurology
Vol 1 3
NO 3
March 1983
A prospective study, including standardized neuropsychological assessment of patients prior to death and
quantification of neuropathological alterations in silver
stains, would more precisely assess the relationships
between the severity of dementia and alterations in the
dbB/nbM.
Since demented patients with P D have plaques and
neurofibrillary tangles {a, 4 , 10, 12, 351 and show loss
of neurons in the nbM, we believe that similar
pathophysiological mechanisms may operate in the dementias of A D and PD. Clinically, the cognitive symptoms in AD and PD have been referred to as examples
of cortical and subcortical dementias, respectively [ 151.
The overlap in clinical, pathological, and neurochemical features between A D and PD, coupled with the
demonstration of neuron loss in the septaVnbM system
in both diseases, may require reworking of this concept, especially in the light of recent findings from our
laboratory that another “subcortical” dementia, Huntington disease, does not show loss of neurons in the
nbM [24} nor does it share the other neurochemical
and pathological features of A D and PD.
The present study demonstrates that some demented patients with PD show selective destruction of
SeptaVdbBlnbM neurons. Future investigations of the
transmitter-specific circuitry and physiology of this re-
Table 3. Loss of Basal Forebrain Neurons in the Dementia of PD"
Total Cell C o u n t s
Coronal
Subjects
N u c l e u s of
Midportion
dbB
of nbM
Sagittal
Maximal Density
C o u n r s in Coronal
Midportion of n b M
(neuronsigrid j
Average
C o u n t s for
3 Sections
~
Series 1 (35 Km)
PD patients
Idiopathic
186 i- 27 (2)'
dementedb
Idiopathic
343
nondemented
Postencephalitic
All
Controls
Series 2
*
191 ( 3 )
441
1,283
?
221 (2)""
* 634 (3)
624 (1)
337 L 201 ( 6 )
1,624 ( 1 )
1,059 i- 646 ( 6 )
361
1,926
&
434 ( 7 )
238
*
102 ( 2 )
822
?
428 ( 2 )
&
208 ( 7 )
265 (1)'
791
*
122 (3)"
979 (1)
723 2 282 ( 5 )
1,024
&
237 ( 7 )
187 ( 1 )
30
2
1.4 (2)""
677 ( 1 )
68
t_
13.5 ( 3 )
656 ( 2 )
544
274 ( 4 )
63 ( 1 )
55 2 20.9 (6)
576
64
*
*
58 ( 3 )
?
10.7 ( 7 )
(16 F m )
PD patients
Idiopathic
7.9
?
2.7 ( 2 )
demented
Controls
32.9 t 2.7 ( 2 )
"Counts are given as mean ? standard deviation. Two methods of cell counting were used. First, images of the dbB and nhM were projected onto
a sheet of paper, and individual neurons were marked and rabulated (manual counter) if they were large (> 30 pm) and stained intensely with
cresyl violet 138). Second, neurons with visible nucleoli were counted using a microscope and an ocular grid (500 x 500 pm) with the maximum
density of cells determined in a total of four grids examined by two independent observers unaware of the results of total cell counts of the same
slides. Interobserver reliability ranged from 0.87 to 0.96. Bcith methods of cell population assessment, e.g., total cell counts and maximal density
counts in the midportion of the nbM, produced the same pattern of results, with the correlation between the two measures being 0.58 ( p < 0.05)
in Series 1 cases. t Test comparisons were made between control and P D patients: *p < 0.05; **p < 0.001.
!This group includes 1 patient who was probably demented but about whom incomplete clinical data exists.
'One patient lacked an intermediate-level slide, so average counts for all three sections could not be calculated.
Numbers in parentheses represent number of patients examined for the particular cell
gion should provide new information about the role of
this basal forebrain system in health and disease and
may lead to new therapeutic approaches to the cognitive abnormality.
Funded by US Public Health Service Grants NS 10580, N S 15721,
NS 07179, and M H 15330.
The authors gratefully acknowledge helpful discussions with Drs
Mahlon R. DeLong, Joseph T. Coyle, Michael Mcknney, Linda C.
Cork, Robert G. Struble, and Arthur W. Clark, who have contributed to our thinking about the role of the basal forebrain in dementia. We thank Ms Nancy Cook for her help in preparation of the
manuscript and D r Paul Yakovlev, Mr Mohamed Haleem, and the
staff at the AFIP for allowing us to use the Yakovlev collection. In
addition, we are grateful to Dr Richard Lindenberg for providing the
cases from his personal collection.
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