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Dementia in Parkinson's disease Biochemical evidence for cortical involvement using the immunodetection of abnormal tau proteins.

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ORIGINAL ARTICLES
Dementia in Parkmson’s Disease:
Biochemical Evidence for Cortical
Involvement Using the Immunodetection
of Abnormal Tau Proteins
Patrick Vermersch, MD,” Andre Delacourte, PhD,* France Javoy-Agid, PhD,t
Jean-Jacques Hauw, MD,S and Yves Agid, MD, PhDt
~~~~~
In order to elucidate the neurochemical basis of the dementia of Parkinson’s disease, we compared samples of cerebral
cortex from 24 nondemented parkinsonian patients and parkinsonian patients with various degrees of dementia, with
those from patients with Alzheimer’s disease and control subjects, using a quantitative Western blot analysis. An
anti-paired helical filaments antibody was used for the immunodetection of the abnormally phosphorylated Tau
proteins 5 5 , 6 4 , and 69, which are known to be specific and reliable biochemical markers of Alzheimer-type neurofibrillary degeneration. The frequency and intensity of immunodetection of the abnormal Tau triplet were higher in the
demented parkinsonian subgroups than in the nondemented parkinsonian subgroup in the prefrontal area, temporal
cortex, and entorhinal cortex but not in either the occipital or the cingular cortex. A quantification of abnormal Tau
triplet by densitometry showed that unlike the results obtained in Alzheimer patients, the intensity of lesions in the
cerebral cortex of the most demented parkinsonian patients was more severe in the prefrontal area versus the temporal
area. This study (1) gives biochemical evidence for Alzheimer-type changes in the cortex of demented parkinsonian
patients and (2) suggests that lesions of the prefrontal cortex may significantly contribute to the occurrence of cognitive
changes at least in some patients with Parkinson’s disease.
Vermersch P, Delacourte A, Javoy-Agid F, Hauw J-J, Agid Y.Dementia in Parkinson’s disease.
biochemical evidence for cortical involvement using the immunodetection
of abnormal Tau proteins. Ann Neurol 1993;33:445-450
The prevalence of dementia in Parkinson’s disease
(PD) is greater than in the general population El, 21,
but controversy remains about the nature and neuropathological basis of cognitive deficits associated with
the disease. The dementia is generally considered to
be of the subcortical type 131, as in other disorders
with predominantly subcortical pathology 14, 5). This
is in concert with the clinical experience that, unlike
the findings in Alzheimer disease (AD)-type dementia, PD is rarely associated with language impairment,
apraxia, agnosia, or other dysfunctions of isocortical
association areas 16-8). It has been proposed that the
subcortical dysfunction of P D could be responsible for
cognitive changes 19) but the high frequency of Alzheimer pathology in P D [10-14] and the neuronal dysfunction in the nucleus basalis of Meynert in both P D
1151 and AD 116) have suggested that these two diseases might be related and that dementia in P D may
be due to coexisting AD.
We recently reported that the immunoblot detection
of three abnormally phosphorylated Tau proteins,
named Tau 55, 64, and 69, was systematically associated with the presence of neurofibrillary tangles
(NFTs) and senile plaques (SPs) in these areas [17,
18). This triplet is a specific and a reliable biochemical
marker of AD-type neurofibrillary degeneration and
the basic components of paired helical filaments
(PHFs) 119-2 1).
Using this marker, we give biochemical evidence for
a cortical involvement associated with dementia in P D
and suggest a possible role of cortical pathology in the
expression of cognitive changes.
From *Unit@INSERM 156, Lille; ?Unit6 INSERM 289, Paris; and
fLaboratoire de Neuropathologie Raymond Escourolle, HBpital de
La SalpCtrit.re, Paris, France.
Received Aug 25, 1992, and in revised form Nov 24. Accepted for
publication Dec 2, 1992.
Material and Methods
Subjects
The brains of 24 patients with antemortem diagnosis of PD
were used in this study. The mean age ( 2 standard deviation)
at death was 74.4 & 7.5 years and the mean duration of
Address correspondence to Dr Delacourte, Unite INSERM 156,
Place de Verdun, 59045 Lille cedex, France.
Copyright 0 1993 by the American Neurological Association 4 4 5
illness was 16 2 9.1 years. The mental status was retrospectively assessed and four grades were considered: grade 0 for
normal intellectual status, grade 1 for episodes of hallucinations or confusions, grade 2 for mild cognitive impairment,
and grade 3 for dementia [22]. In each patient in whom a
significative cognitive decline was found, the extrapyramidal
syndrome preceded the cognitive changes. Aphasia, apraxia,
and agnosia were not observed in any of them. The pathological diagnosis of P D was confirmed in the left hemisphere of
all brain specimens, based on a combination of the following
changes: depigmentation of the substantia nigra and of the
locus ceruleus, neuronal loss and gliosis in the same areas,
and presence of at least one Lewy body in one of the brainstem pigmented nuclei. The neuropathological data on some
patients (Patients 3, 7, 17, and 21) regarding the number of
SPs and NFTs after Bodian’s impregnation has been detailed
elsewhere 1231. The presence of cortical Lewy bodies in the
hippocampal and parahippocampal gyri, insula, and cingular
gyri was recorded after hematoxylin and eosin (HE) staining.
Immunocytochemistry with antiubiquitin was done on some
specimens and the results were concordant with the H E findings. In all PD brains, the density of cortical Lewy bodies was
very low and not correlated with mental status. Postmortem
delays averaged 14 t 3 hours.
The parkinsonian patients were compared with 6 patients
with A D and 8 control brains (Table). The clinical diagnosis
of A D was confirmed by histological examination of the hippocampus and prefrontal and occipital cortical regions for
Alzheimer-like neuropathological signs (neurofibrillary pathology and SPs). The control population consisted of neurologically and psychiatrically normal subjects matched with the
PD and A D patients with respect to age, agonal status, and
postmortem delays in tissue handling.
Methods
The right hemispheres were dissected for biochemical studies
at the time of autopsy. Samples from the prefrontal (area 9),
temporal (area 21), entorhinal (area 28), cingular (area 24),
and occipital (area 18) regions of the cortex were homogenized in the Laemmli sample buffer 1:10 (wt/vol) and heattreated [24]. For immunoblot studies, 20 p1 of each brain
homogenate was loaded in a 15-well gel (14-14 cm). Proteins were resolved on 10 to 20% sodium dodecyl sulfate
(SDS)-polyacrylamide gel gradients. They were electrophoretically transferred to nitrocellulose membranes before incubation with the anti-PHF antibodies. This anti-PHF antibody
was raised against PHF extracted from the frontal cortex of
a patient with A D of early onset. This antiserum is known
to exclusively label the neurofibrillary degeneration (optic
microscopy) and P H F structures (electron microscopy) [25J
and to specifically immunostain abnormal Tau proteins on
immunoblots [17, 26, 271.
For each sample, the blots were measured by densitometry. Blots were digitized on a Macintosh IIx (Apple Computer, Cupertino, CA) with a ScanJet IIC flatbed scanner
(Hewlett Packard, Palo Alto, CA) at a resolution of 72 dots/
in and saved on 8-bit gray-scale (256 shades of gray) TIFF
files. The images of the immunoblots were processed with
the public-domain program IMAGE 1.43 from W. Rasband
(National Institutes of Health Research Services Branch, Na-
446 Annals of Neurology Vol 33 No 5 May 1993
tional Institute of Mental Health). The areas of the peaks
corresponding to Tau 5 5 , 64, and 69 detected in some cortical homogenates were calculated and compared to each
other. The loading of brain samples was adjusted to avoid
saturation of the optical density and to obtain a linear relation
between the amount of immunodetected proteins and the
quantity of cortex samples. Using staining with 4-chloronaphtol, the linearity was obtained with quantities of homogenates
up to 20 p1. Each sample was measured at three different
concentrations ( 5 , 10, and 20 pI of SDS sample).
StatisticaE Analysis
The demographic data and the stage of cognitive changes
were stored on a computer hard disk in a format compatible
with the Statistical Analysis System (SAS, Cary, NC). We
used Fisher’s exact test to compare the frequencies of immunodetection of abnormally phosphorylated Tau proteins according to the scale of cognitive changes for the five cortical
areas between the four subgroups of PD patients. The mean
ages in the four subgroups of parkinsonian patients as well
as the A D and control groups were compared by the nonparametric Kruskall-Wallis H test. Comparison of the duration
of disease for the four subgroups of P D patients and comparison of the densitometric data were also performed.
Results
Abnormally phosphorylated Tau proteins were detected in all cortical areas from the Alzheimer patients,
in several cortical areas from parkinsonian patients, and
in a small number of entorhinal areas from the control
subjects (see Table), using a Western blot analysis
(Fig). Statistical analysis showed that the subgroups of
PD patients, as well as the AD and control groups,
were matched for age. The duration of the disease was
not statistically different in the four subgroups of PD
patients. We found significant differences between the
four subgroups of PD patients regarding the frequency
of abnormal Tau protein immunodetection in the prefrontal (area 7, p < 0.05), the temporal (area 21, p <
0.011, and the entorhinal cortical regions ( p < 0.02),
but no difference in the occipital and cingular regions
of the cortex (see Table). In 5 of 8 control subjects, 3
of 8 nondemented PD patients, and I of 4 PD patients
with grade 1 dementia (Patient 121, the abnormal Tau
triplet was only detected in the entorhinal cortex. In 1
of the nondemented PD patients (Patient 5 ) , this triplet
was also detected in the other areas. The densitometric
data (see Table) indicate that the intensity of immunodetection was not uniform among the different subgroups of patients. In the 9 PD patients in whom the
immunodetection of the abnormally phosphorylated
Tau was positive in the prefrontal area (area 7), the
intensity of detection was higher in the prefrontal area
than in the temporal area (area 21) in 7 (Patients 5 , 14,
16, 18, 20, 22, and 23). In the other 2 patients (Patients 17 and 21), it was lower in the prefrontal area.
In 6 P D patients with positive detection in the frontal
Demographic and Densitometric Data"
Cerebral Cortex
Age
(yr)
Subjects
Duration
Area 9
(yr)
Area 21
Entorhinal
Occipital
Cingular
Parkinson
Dementia = 0
1
2
3
4
5
82
75
77
72
73
6
71
7
84
8
68
Mean
SD 75.2 ? 10.3
Dementia = 1
9
67
10
79
11
59
12
81
Mean t SD 75.1 f 10.3
Dementia = 2
83
13
14
72
15
83
16
80
17
67
88
18
63
19
Mean ? SD 76.6
9.3
Dementia = 3
20
62
21
77
79
22
23
74
24
71
Mean t SD 72.6 f 6.6
Alzheimer
25
80
90
26
78
27
73
28
81
29
66
30
Mean
SD 78 t 8
*
*
*
19
0
0
0
0
8
10
13
22
17
20
12
15.1
26.8
0
0
0
?
0
0
0
0
9
3
27
5
30
18
28
2
16.1
?
f
12.6
6
* 12.6
9
8
10
8
11
2
8
?
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
10.9
17.8
0
4.1
2
7.3
12.2
13.6
17.6
0
0
8.7
f
8.2
19.3
?
17.3
0
0
0
21.9
6.7
13
13
39
17
17.6
0
12.1
0
0
0
0
0
0
0
19.7
0
0
0
0
0
0
0
46.1
0
30.0
1.2
25
14
15
15.7
14.1
7.0
0
0
0
0
0
21.1
0
0
0
3.2
0
9.8
0
25.7
7.5
23.6
0
9.5 f 11.0
11.1
8.2
11.5
6.9
6.5
19.2
12.5
31.1
8.7
0
14.3
5.2
18.9
20.1
7.8
0
10.4
29.7
36.9
25.8
36.5
25.4
30.2
30.8
*
11.6
* 5.0
0
7.8
0
f
4.7
13.2
25.8
13.2
26.7
30.2
34.2
39.5
26.1 f 9.9
20.2
34.8
49.9
27.4
0
0
13.8
0
0
9.9
* 8.8
28.4
58.6
58.3
63.1
52.0
4 1.4
59.8
55.5 f 7.8
74.8
69.8
75.5
72.2
59.9
75.2
71.1
5
15.1
~fr 5.9
25.4
33.3
30.1
19.8
26.9
29.8
27.5
* 4.6
31.1
39.7
36.8
26.3
40.2
65.2
39.8 t 13.5
Controls
31
32
33
34
35
36
37
38
Mean t SD
H value (df)
P
61
69
65
76
73
78
81
80
72.9
7.3
2.7 (5)
NS
*
0
0
0
0
0
0
0
0
19.3 (5)
<0.01
0
0
0
0
0
0
0
0
21.9 (5)
<0.001
0
15.2
5.9
10.1
0
7.5
18.9
0
7.2 f 7.2
23.5 15)
<o.oo 1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
15.2 ( 5 )
17.3 ( 5 )
<o.o 1
<0.01
"Demographic data of the 38 subjects and densitometric data (arbitrary values) of the irnrnunodetection of abnormal Tau proteins in the
prefrontal area (area 9), temporal area (area 2 l),and entorhinal, occipital, and cingular regions of the cortex. H values are from the Kruskal-Wallis
test.
df
= degree of freedom, 0 = there was no immunoderection of abnormal Tau proteins;
SD
=
standard deviation; NS
=
not significant.
Vermersch e t al: Abnormal Tau Proteins in PD
447
and temporal areas, we failed to find abnormal Tau
proteins in the occipital and cingular regions of the
cortex. In the Alzheimer group, the detection was positive in all areas including the occipital and cingular regions and in each patient, it was stronger in the temporal area than in the prefrontal area.
In Patients 3 and 7, the density of SPs and NFTs
was low even in the entorhinal-hippocampal region:
below l/mm2 for SPs and below 0.5/mm2 for NFTs.
In Patients 17 and 21, the density of SPs and NFTs
was higher than 2/mm2 in the entorhinal-hippocampal
region as well as in the first temporal and supramarginal
gyri. In Patient 21, a great abundance of neuropil
threads was also noted. Patients 1 7 and 21 were in
stage V to VI according to the neuropathoiogical A D
rating scale described by Braak and Braak 1281,
whereas the control subjects with abnormal Tau in the
entorhinal cortex were in stage I to 11.
lnzmunoblot detection of pathological Tau proteins with antipaired helical filament antibody, o n brain homogenates from a
demented (PD-Dementia, Patient 22) and a nondemented parkinsonian patient (PD, Patient 2).a control subject ( C ) ,and a
patient with Alzheimer’s disease (AD, Patient 25). The cortical
samples tested were from the prefrontal (FR), the temporal (TP),
the entorhinal (CE), the occipital (OC), and the cingular (CG)
regions of the cortex. The triplet of abnormal Tau protein is
marked by arrows. The scanning used for the densitometric
.study showed the areas of the peaks corresponding to the immunodetection of Tau 5 5 , 64, and 69. There was no detection of
Tau 5s. 64. and 69 in the control subject and a strong detection in the temporal region of the cortex from the Alzheimer patient.
448 Annals of Neurology Vol 33 N o 5 May 1993
Discussion
This study showed evidence for an Alzheimer-type
cortical involvement associated with the cognitive
changes in PD. A number of studies about the mental
symptoms observed in parkinsonism have suggested
that abnormalities in several neuronal systems may be
implicated. Biochemical analyses have shown reduced
levels of several neurotransmitters in the cerebral cortex, dopamine, norepinephrine, and serotonin 1291 as
well as choline acetyltransferase activity [30], used as
a marker for cholinergic neurons, a decrease that is
greater in those patients who are demented 130, 311.
However, the decrease of these neurotransmitter levels suggests alterations in the afferent cortical pathways
of subcortical origin. Cortical and hippocampal somatostatinergic transmission is also affected in demented
parkinsonian patients, as indicated by the subnormal
peptide levels. However, it is not clear whether the
changes in somatostatin levels indicate a change in neuronal metabolism or a degeneration of the somatostatin-containing cells, probably interneurons 1321. The
present data suggest that cortical lesions are associated
with dementia in PD; thus, the changes in chemical
marker levels may partially reflect a cortical cell loss.
To our knowledge, this is the first study using a
biochemical marker of the neurofibrillary degeneration
in PD. It was based on a specific detection of the abnormal Tau triplet, the basic component of the PHF structures that are found in NFTs, in dystrophic neurites
of neuritic plaques, and in neuropil threads C331. The
triplet corresponds to the Tau PHF described by others 120, 21). W e specifically quantified all the SDSsoluble abnormal Tau proteins. Due to the specificity
of our antibody and to the fact that Tau 64 and 69
have a molecular weight higher than normal Tau, normal Tau proteins did not interfere with our detection
1171. Furthermore, we observed that the triplet is sta-
ble and does resist to postmortem delays longer than
24 hours and to a storage in deep freeze (< - 40°C)
during years. Therefore, our biochemical quantification
of Tau 5 5 , 64, and 69 is likely to reflect with good
accuracy the quantification of PHF structures. Recently, it was demonstrated that the PHF-bound Tau
content, measured biochemically, correlates with the
neurofibrillary pathology observed immunohistochemically 134, 35). Indeed, in the few cases where a pathological study was made, we did find a good correlation
between the distribution of Tau 5 5 , 64, and 69 and
neurofibrillary pathology. In principle, it may slightly
differ from the distribution of NFTs as visualized by
thioflavine, which corresponds to “old” NFTs possessing the physical properties of the amyloid substance,
the “young” NFTs being only labeled with anti-Tau or
anti-PHF antibodies 136, 371.
The unexpectedly high level of immunodetection of
abnormal Tau proteins in certain cortical areas from
PD patients with dementia suggests that the disease is
associated with a neurofibrillary degeneration of Alzheimer type {IS, 387. This is in concert with previous
findings [ 10-12, 141, but in relative contradiction with
others 115, 39-41). Many reasons may explain these
conflicting results: First, the methods used for detecting the Alzheimer changes and the criteria permitting the diagnosis of coexisting Alzheimer’s disease
141, 423 ought to be considered. Second, in most of
the neuropathological studies, the presence of neuropil
threads is not taken into account in the quantitative
analysis of the neurofibrillary pathology 110- 121. We
must also be cautious before concluding there is a
causal relationship between the presence of Alzheimer
changes and dementia. For instance, a reanalysis C371
of Hakim and Mathieson’s data {lo] showed no statement concerning a possible correlation between the
severity of the pathological changes and mental state.
We observed that the entorhinal cortex was affected
by the degenerating process even in some of the nondemented patients and in a few control subjects, but
such lesions are frequently seen in nondemented aged
persons 128,431. However, we did find that the degenerating process in the entorhinal cortex was more frequent and more severe in the demented subgroups.
The extent of immunodetection of abnormal Tau proteins in one of the nondemented PD patients (Patient
5 ) may correspond to a misdiagnosed or to a preclinical
stage of dementia.
Even more remarkable is the detection of abnormal
Tau proteins, sometimes in large amounts, in the temporal area (area 21) and especially in the prefrontal
area (area 9) in most of the demented PD patients,
without detection in the occipital and cingular regions
of the cortex. This striking pattern is unusual in AD,
where the cortical mapping of the neurofibrillary degeneration shows a predominance of the lesions in the
primary sensory association cortex such as area 21 as
compared to some agranular cortical areas of the prefrontal lobe C44, 451, or at least an equal involvement
of all the homotypical cortices in the association areas
of the temporal, parietal, and frontal lobes C461.
Cognitive changes observed in P D evoke a frontal
lobe dysfunction {47), and appear sometimes early in
the disease [48). Frontal lobe dysfunction in P D has
been hypothesized to result primarily from a disturbance in caudate outflow as part of the “complex” loop
comprising a cortico-caudato-nigro-thalamo-cortical
circuit 149, 501. Our results suggest that the unexpected
cortical A D lesions, especially those found in the frontal lobe, may contribute to the genesis of cognitive
changes. This study gives a neurobiochemical argument for Albert’s point of view that a preferable label
for subcortical dementia would be frontosubcortical
dementia 131.
This study was supported by France Parkinson, Conseil Regional
Nord-Pas de Calais, Schering SA, Association d’Etudes et de Recherches sur la Maladie d’Alzheimer (ADERMA), and Instimt National
de la SantC et de la Recherche Medicale (INSERM) clinical network
CAR 492011.
We would like to thank Profs H. Petit and A. DestCe for their
helpful comments and Dr P. Amouyel for the statistical assessment.
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using, tau, involvement, dementia, cortical, evidence, abnormal, protein, disease, parkinson, biochemical, immunodetection
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