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Dementia in Parkinson's disease is related to neuronal loss in the medial substantia nigra.

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Dementia in Parhson’s Disease
Is Related to Neuronal Loss in the
Medial Substantia Nigra
Juha 0. Rinne, MD,” Jaana Rummukainen, MLic,? Leo P a l j h i , MD,: and Urpo K. Rinne, MD”
5
Regional neuronal loss in the substantia nigra was studied in relation to extrapyramidal symptoms and dementia in 12
patients with idiopathic Parkinson’s disease (PD) and in 18 control subjects. Four areas of the right substantia nigra
were investigated at the level of the superior colliculus and caudal red nucleus. In Parkinson’s disease, the percentages
of neurons, from the medial to the lateral part of the substantia nigra, were reduced to 4996, 3196,4195, and 25% of the
control values. The number of neurons in the lateral part showed a negative correlation with the severity of rigidity
and hypokinesia, whereas tremor was less noticeable in patients with few neurons. The degree of dementia of the
patients had a significant correlation only with neuronal loss in the medial part of the substantia nigra, suggesting, in
view of the topographical organization of the neurons in the substantia nigra, that intact projections to the caudate
nucleus and limbic and cortical areas are a prerequisite for normal cognitive functioning and that their dysfunction
leads to clinical dementia.
Rinne JO, Rummukainen J, Paljirvi L, Rinne UK. Dementia in Parkinson’s disease is related to neuronal
loss in the medial substantia nigra. Ann Neurol 1989;26:/17-50
In addition to motor symptoms, cognitive impairment
and dementia are common in patients with Parkinson’s
disease (PD), especially in the later stages of the disease, and it has been suggested that they are due to the
natural course of the disease [l-41. The cognitive impairment in PD is characterized by visuospatial and
memory disorders and bradyphrenia, and has been described as subcortical dementia; aphasia, agnosia, and
apraxia, which are typical of cortical dementias such as
Alzheimer’s disease, are absent [5].
Neurons in the substantia nigra (SN) show topographical organization in which the neurons in the lateral part project primarily to the putamen, whereas the
caudate nucleus receives its nigral input mainly from
the medial part [GI. According to recent evidence, the
putamen seems to be a part of a cortical-subcortical
neuronal loop with predominantly motor relationships
(the “motor loop”). The caudate nucleus, in contrast, is
closely connected to the frontal association cortex,
which is related to psychomotor function and motivation (the “complex loop”) [7, 81. Thus, the striatal
nuclei and consequently nigrostriatal projections may
have separate functional roles. While a clear link has
been established between the motor symptoms in PD
and the degeneration of nigrostriatal dopamine
neurons, which results in a deficiency of dopa-
From the *Department of Neurology, University of Turku, Turku,
and the t h p a r t m e n t of Pathology, University of Kuopio, Kuopio,
Finland.
mine in the striatum [GI, the role of nigral degeneration in relation to dementia is unknown. It has been
suggested, however, that cognitive alterations seen in
P D are a consequence of dysfunction of the caudate
nucleus and that the neuropsychological impairments
found in patients with PD parallel those that are typical
for dysfunction of the frontal cortex [9, 101.
In a semiquantitative study [ll] no correlation was
found between mental impairment in PD and overall
cell loss in the SN. Since the cell groups in the medial
and lateral part of the SN may have different functional roles, we investigated the regional number of
neurons in the SN in relation to extrapyramidal symptoms and dementia in patients with PD.
Patients and Methods
Neuron densities in the SN were studied in 12 brains from
patients with idiopathic PD and 18 control brans. The age,
sex distribution, and clinical characteristics of the patients are
shown in the Table. The diagnosis of dementia was based on
the criteria of the Diagnostic and Statistical Manlralfor Mental
Disorders, 3rd edition (DSM-HI), and its severity was scored
on a 6-point scale (from 0 to 5), using the global deterioration scale described by Reisberg {12}, with a modification
combining the patients in classes 1 and 2 to form a single
class. The extrapyramidal symptoms were scored according
Received Sep 29, 1988, and in revised form Dec 15. Accepted for
publication Dec 19, 1988.
Address correspondence to: Dr Rinne, Department of Neurology,
University of Turku, SF-20520 Turku, Finland.
Copyright 62 1989 by the American Neurological Association 47
Age, Sex, and Clinical Variables of tbe Patients
0Controls
Neuronshrn2
Stage of
~
i
Group
Duration
ofDisease
W M ) (yr)"
111 IV
Age
(yr)"
Sex
Control
77.6 ? 6.9 1216
Parkinson's 74.0 k 7.3 616
disease
~
v
ao
~
~
~
~
b
T
PD
1
60
8.8 +- 3.0
2
2
8
40
'Mean 2 SD.
bAccording to Hoehn and Yahr {40].
20
0
Ia
Ib
I1
I11
** P C 0.01, M*PC 0.001
Fig 2. Numbers of neurons in four areas oftbe sztbstnnlia nigra.
P values refer to comparisons between controls and patients with
Parkinson? disease (PO,. la = most medial dorsal. Ilr = medial
ventral, II and 111 = ventral areas.
correlation of the degree of dementia and the severity of the
extrapyramidal symptoms with the neurond count in the SN
was determined by the Spearman rank correlation test.
Ia Ib
I1
III
Ftg 1. Diagram oftbe midbrain sectioned at the level of the
superior colliculus (sc) and caudal part of the red nucleus (nr).
The rectangles show the Position and orientation of tbefaur test
areas in the substantia nigra where neuronal density was
studied. aq = cerebral aqueduct, cc = crus cerebri, la = most
medialdorsal, 16 = medial ventral, I1 and III = ventralareas.
to the Columbia University rating scale. After death the right
half of the brain was fixed in formalin for several weeks and
was subjected to neuropathologicalanalysis as described previously { 131; special attention was given to Alzheimer lesions
by quantifying the neurofibrillary tangles and neuritic
plaques in sections that were taken from seven standard areas
and stained with Bielschowsky's stain. To quantify SN degeneration, transverse 5-bm-thick sections were taken from
the right half of the midbrain at the level of the superior
colliculus and caudal red nucleus, and then were stained with
hematoxylin and eosin. The pars compacta of the SN was
divided into quarters, numbered from medial to lateral as I,
11, 111, or IV. The most lateral quarter (IV) had only a few
cells and therefore neurons were not quantified in this quarter. The quantification of neurons was carried out in the
medial three-quarters of the SN: the most medial dorsal (Ia),
medial ventral (Ib), and ventral areas in I1 and 111 (Fig 1).
Neurons hitting the rectangular test area (1.37 mm2) as delineated by an ocular grid were counted in these neuron-rich
standard locations. We counted all perikarya recognizable
based on the presence of Nissl substance andlor melanin.
Cell profiles falling on grid boundaries were treated according to Gundersen's rule {14].
Student's E test was used to estimate the differences in
neuron counts between PD brains and control brains. The
48 Annals of Neurology Vol 26 No 1 July 1989
Results
Lewy bodies as well as qudtative loss of neurons and
pigment were found in all PD patients. All but two had
no Alzheimer-type changes (see below). The control
samples were free of Alzheimer o r PD pathological
changes. In the PD patients, the numbers of neurons,
from the medial to the lateral parts of the SN, were
49% ( p = 0.008), 31% ( p < 0.001), 41% ( p <
0.001) and 25% ( p < 0.001) of the control values (Fig
2). Thus, the decrease was greatest in the lateral part of
the SN.
Of the extrapyramidal symptoms, rigidity and hypokinesia were associated with low neuronal densities
predominantly in the lateral parts of the SN ( Y ~ =
-0.62 and -0.64, respectively; p < 0.05), whereas
tremor, by contrast, was less noticeable in patients with
0.66, p < 0.05). The degree of
few neurons (1; =
dementia showed a negative correlation with the
neuronal count in the cell groups from the most medial
dorsal part (Ia) (Fig 3) but no correlation with neuronal count in cell groups from the more lateral
parts (Ib, 11, and 111). Two PD patients had a low to
moderate number of senile plaques ( 5 - 2 0 / m 2 and
2-5/mm2) and solitary neurofibrillary tangles in the
neocortex; when these 2 patients with coincident
Alzheimer-type pathological lesions were excluded
from the analysis, the correlation bemeen dementia
and the neuronal count in the most medial dorsal part
(Ia) still remained highly significant (Y, = -0.80, p =
0.006).Correlation analyses showed that the degree of
dementia was not explained by the age of the patients
or duration of PD symptoms.
+
AD patients C22-241. Moreover, although the presence and severity of dementia in PD patients have
Neuronslm2
50-
8
40 30
I0
2o
8
-
I
OL
8
1
I
I
,
I
I
0
1
2
3
4
5
Dementia
Fig 3. Number of neurons in the medialpart of the substantia
nigra (area la) in rekation to dementia in patients with Parkinson’sdiseme(r, = -0.77, p = 0.004).
Discussion
In this study, both the extrapyramidal symptoms and
the dementia in patients with PD were found to show a
distinct correlation with regional neuronal loss in the
SN.
Of the extrapyramidal symptoms, rigidity and hypokinesia had a positive correlation with the number
of neurons in the lateral part of the SN. This is in
agreement with previous findings that showed a link
between both dopamine deficiency {6) and decreased
levels of homovandlic acid in the cerebrospinal fluid
[l5} and hypokinesia in PD patients. Tremor, in contrast, was less severe in patients with few neurons.
Indeed, it has been suggested that neural mechanisms
other than degeneration of the nigrosuiatal system are
also involved in the pathophysiology of tremor [6, 16,
17). This is consistent with the finding that the activity
of tyrosine hydroxylase shows a negative correlation
with the severity of hypokinesia and rigidity but not
with tremor { 183. The positive correlation between
tremor and the nigral neuron count in the present
study may partially be due to the fact that during the
course of the disease the clinical picture shifts from
tremor dominant to hypokinesia dominant [191, with
many patients at the later stages of the disease showing
mild or no tremor at all.
The pathological basis of dementia in PD has been a
controversial issue. The dysfunction of the ascending
cholinergic system, seen as neuronal loss in the nucleus
basalis of Meynert, is more pronounced in demented
PD patients as compared with nondemented ones 111,
20-221, suggesting that a certain threshold of neuronal
loss must be exceeded before dementia becomes evident. This neuronal loss in the nucleus basalis of Meynert in PD patients is, however, not associated with
cortical plaque and tangle counts, as is seen in brains of
been found to have a high correlation with the degree
of Alzheimer-type pathological lesions (senile plaques
and neurofibrillary tangles) in the brain [ l l , 22), dementia can also occur with plaque and tangle counts
comparable to those of nondemented control subjects
[25). It seems that in PD patients subcortical cholinergic degeneration may develop without concomitant
cortical pathological changes. Thus, Alzheimer-type
pathological changes in the brain are common in demented P D patients, but their presence does not seem
to be necessary for dementia to occur.
The role of the brain dopaminergic system in cognitive functions has often been overlooked, although
evidence from animal studies links dysfunction of the
dopaminergic system and defects of higher cerebral
functions [26, 27). Moreover, it has been found that
neuropsychological deficits in PD patients can be alleviated by the administration of levodopa during the
early stages of the disease [3, 28, 291. The loss of
suiatal dopamine in brains of PD patients is uneven,
with greater diminishment in the putamen than in the
caudate nucleus [b, 301, which reflects more complete
cell loss in the lateral than in the medial part of the SN.
This greater loss of neurons in the lateral part of the
SN was also seen in the present study. In addition to
depletion of dopamine in the striatum, there is evidence of dopamine loss in the limbic and cortical areas
in P D patients, indicating that the mesolimbic and
mesocortical dopaminergic systems are also affected
131-331. The loss of neurons in the ventral tegmental
area also suggests the involvement of these neuronal
systems in PD [34, 351. The dopamine loss in the
mesolimbic and mesocortical systems in PD patients
has not yet, however, been investigated in relation to
mental impairment of the patients.
In this study the negative correlation found between
the neuronal count in the SN and the degree of dementia suggests that the degeneration of nigral projections may constitute a subcortical component contributing to the dementia process in PD. As distinct
from motor symptoms, which were mainly associated
with cell loss in the more lateral parts of the SN, dementia correlated only with cell loss in the medial part
of the SN. This pattern may be explained by the topographical organization of the SN. The lateral portion of
the SN projects largely to the striatum, especially to
the putamen, whereas the neurons in the medial part
project more to the caudate nucleus and-together
with the neurons of the ventral tegmental area-to the
limbic and cortical areas [36-391. The results of the
present study suggest that intact nigral projections to
the caudate nucleus and limbic and cortical areas are a
prerequisite for normal cognitive functioning and that
their loss may lead to clinical dementia.
Rime et al: Dementia and Nigral Degeneration 49
This study was supported by a grant (No. 091037) from the Medical
Research Council of the Academy of Finland.
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