 |
|
Parkinson Disease Neuropathology
Later-Developing Dementia and Loss of the Levodopa Response
Hulya Apaydin, MD;
J. Eric Ahlskog, PhD, MD;
Joseph E. Parisi, MD;
Bradley F. Boeve, MD;
Dennis W. Dickson, MD
Arch Neurol. 2002;59:102-112.
ABSTRACT
| |
Objective To investigate the neuropathologic substrate for dementia occurring
late in Parkinson disease (PD).
Design We identified 13 patients with a clinical diagnosis of PD who experienced
dementia at least 4 years after parkinsonism onset (mean, 10.5 years) and
subsequently underwent postmortem examination. Despite levodopa therapy, 9
patients later became severely impaired and nonambulatory, requiring total
or near-total care; this included 4 patients treated with 1200 mg/d or more
of levodopa (with carbidopa), which was consistent with loss of the levodopa
response. These 13 patients were compared with 9 patients clinically diagnosed
as having PD, but without dementia, who had undergone autopsies.
Results Twelve of 13 PD patients with dementia had findings of diffuse or transitional
Lewy body disease as the primary pathologic substrate for dementia; 1 had
progressive supranuclear palsy. This pathology also apparently accounted for
the levodopa refractory state. Among the 12 PD patients with dementia, mean
and median Lewy body counts were increased nearly 10-fold in neocortex and
limbic areas compared with PD patients without dementia (P .002). Alzheimer pathology was modest. Only one patient met the
criteria defined by the National Institute on Aging and the Reagan Institute
Working Group on the Diagnostic Criteria for the Neuropathologic Assessment
of Alzheimer's Disease for "intermediate probability of Alzheimer's disease."
There were, however, significant correlations between neocortical Lewy body
counts and senile plaques as well as neurofibrillary tangles. Senile plaque
counts did not significantly correlate with tangle counts in any of the analyzed
nuclei. Arteriolar disease may have contributed to the clinical picture in
2 patients.
Conclusions Diffuse or transitional Lewy body disease is the primary pathologic
substrate for dementia developing later in PD. This same pathologic substrate
seemed to account for end-stage, levodopa refractory parkinsonism. The occurrence
of Alzheimer pathology was modest, but was highly correlated with Lewy body
pathology, suggesting common origins or one triggering the other.
INTRODUCTION
IDIOPATHIC Parkinson disease (PD) is a progressive neurodegenerative
disease of undetermined cause with characteristic motor findings that include
rest tremor, rigidity, bradykinesia, and postural disturbance. Degeneration
of the substantia nigra pars compacta is the primary anatomic substrate for
the motor symptoms; microscopic Lewy bodies within this nucleus are the pathologic
hallmark.
Dementia may complicate PD after years of an otherwise typical course.
This problem may overshadow the motor aspects of parkinsonism and become the
primary source of disability. In PD, dementia is not a presenting feature,
but is common later in the disease course. The frequency of dementia among
patients from clinic-hospital cohorts ranges from 6% to 29% (Table 1).1-7
However, this range likely underestimates the problem. Patients with dementia
are less likely to be referred to or followed up in PD clinics. In community-based
studies, prevalence figures are a little higher, ranging from 12% to 41% (Table 18-12),
but these numbers too may underestimate the magnitude of this problem. By
definition, prevalence studies ascertain cases at a single point in time.
Dementia may lead to nursing home placement and earlier death; these patients
will not be counted in subsequent prevalence analyses. Among PD patients who
do not initially experience dementia, the yearly incidence of dementia ranges
from 2.6% to 9.5% (Table 1 6, 11, 13-18).
Thus, if PD patients live long enough, the risk is substantial. One series
estimated that the cumulative risk of dementia among PD patients by the age
of 85 years was more than 65%.14
|
|
|
|
Table 1. Frequency, Prevalence, and Incidence of Dementia Among Patients
With Parkinson Disease (PD)*
|
|
|
The neuropathologic substrate for the dementia that develops in PD patients
has been debated. In the last quarter of the 20th century, more than 20 investigations
addressed this issue (Table 2).19-40
Among these publications, there has been no consensus whether this dementia
is primarily a cortical or subcortical process or whether Alzheimer disease
(AD) or Lewy body disease is the primary contributor. In some patients, the
pathologic cause for dementia was not apparent. Clinical heterogeneity may
explain some of this lack of consensus. In most series, clinical details were
sparse, including the temporal relationship between parkinsonism and dementia
(Table 2). Some of these series
may have included patients in whom the dementia was a presenting symptom.
Early dementia may have an entirely different pathologic basis than dementia
developing several years after the onset of levodopa-responsive PD. In fact,
dementia developing concurrently with parkinsonism plus other characteristic
features (including hallucinations and cognitive fluctuations) is now recognized
to typically represent dementia with Lewy bodies.41-42
Clinical parkinsonism may also complicate AD, in which case the dementia is
prominent early in the disease course.43-47
|
|
|
Table 2. Clinicopathologic Studies of Dementia Occurring in PD Before  -Synuclein
Immunohistochemical Analysis*
|
|
|
The uncertainties regarding the neuropathologic substrate for dementia
that complicates PD may also relate to histologic techniques. Lewy bodies
(especially cortical) and other cellular inclusions were underestimated based
on microscopy with the older hematoxylin-eosin and silver impregnation techniques.
With the application of ubiquitin immunohistochemical analysis, these were
more easily identified.48-49 Recently, -synuclein
immunohistochemical analysis was recognized to be a much more sensitive and
specific technique for identifying Lewy bodies and distinguishing these from
other cellular inclusions.50-51
The studies presented in Table 2
were performed before -synuclein immunohistochemical testing was available.
We were interested in a specific subset of patients whom we commonly
see in our PD clinics—those with typical early PD who later experience
dementia. We anticipated that the neuropathologic basis for this dementia
should be apparent and may be fairly uniform if (1) we restricted our PD patients
to those in whom parkinsonism preceded dementia by at least 4 years and (2)
the histologic techniques included -synuclein immunohistochemical analysis.
A preliminary report of our findings has been published, documenting diffuse
or transitional Lewy body disease as the primary substrate for the dementia
in all but one of these patients (the exception having progressive supranuclear
palsy).52 Hurtig et al53
and Mattila et al54 have also reported similar
findings.
METHODS
From the Mayo Health Sciences Research Database, we identified all patients
undergoing autopsy between 1976 and 1997 with diagnoses in life of PD and
dementia. All clinical histories were reviewed to identify those who met the
following criteria: (1) clinical picture of idiopathic PD without features
that suggest another parkinsonian disorder; (2) an initially favorable response
to levodopa therapy, if administered; and (3) dementia developing at least
4 years after PD motor symptom onset. Initially, we selected 5 years as the
minimum criterion interval between PD motor symptom onset and dementia; however,
because of the small number of patients, we reduced this to 4 years (adding
2 patients). Parkinsonism onset was dated from the time the initial symptoms
were experienced by the patient. Onset of dementia corresponded to the date
when cognitive impairment was first noted. To qualify as PD, all patients
were required to have at least 2 of the 3 cardinal PD motor symptoms (rigidity,
rest tremor, and bradykinesia) and have been diagnosed as having PD by a Mayo
Clinic physician. To qualify as having dementia, patients fulfilled criteria
for dementia according to the Diagnostic and Statistical
Manual of Mental Disorders, Revised Third Edition55
as documented in the medical histories.
From the same Mayo database, we identified all PD patients undergoing
autopsy between 1976 and 1997 who met criteria for absence of dementia and
for whom adequate brain tissue specimens were available for analysis. Criteria
for PD were the same as in the group with dementia. Nondementia status within
the last year of life was documented by fulfilling 1 of 2 criteria: (1) achieving
a score that was within normal limits on the Mini-Mental State Examination,56 Short Test of Mental Status,57
or formal psychometric examinations or (2) having been seen within a year
of death at least twice by Mayo Clinic physicians and having medical records
that documented the clinical impression of no dementia. These patients served
as the control group. Both the patients with and without dementia were selected
without knowledge of the patient's neuropathologic condition.
Brain areas examined included multiple neocortical regions (frontal,
parietal, and calcarine), anterior cingulate cortex, nucleus basalis of Meynert,
amygdala, entorhinal cortex, hippocampus, thalamus, and multiple brainstem
nuclei, including substantia nigra and locus coeruleus. Microscopic sections
were stained with hematoxylin-eosin, modified Bielschowsky and thioflavin
S stains, and immunohistochemical stains for -synuclein (polyclonal58) and tau (monoclonal, PHF-1; Peter Davies, PhD, Albert
Einstein College of Medicine, Bronx, NY). Microscopic features of these sections
were evaluated independently by 2 observers (J.E.P. and D.W.D.). Although
attempts were made to mask these observers to the clinical information, this
was not consistently possible. Assessment of AD-type pathologic features included
determination of Consortium to Establish a Registry for Alzheimer's Disease
(CERAD)59 neuritic plaque scores and Braak
and Braak staging.60 The National Institute
on Aging and the Reagan Institute Working Group on the Diagnostic Criteria
for the Neuropathologic Assessment of Alzheimer's Disease (NIA-Reagan) diagnostic
criteria were used for the diagnosis of AD.61
Criteria for the pathologic diagnosis of Lewy body dementia were from the
Consortium on Dementia With Lewy Bodies.41
Quantitative analyses included counts of Lewy bodies, senile plaques,
and neurofibrillary tangles (x200 microscopic field) in brain regions
from patients with and without dementia. Lewy body counts were performed in
the substantia nigra, neocortex, limbic cortex, amygdala, and nucleus basalis
of Meynert. Senile plaques and neurofibrillary tangles were counted in the
neocortex, the CA1 region of the hippocampus, and the entorhinal cortex with
thioflavin S fluorescent microscopy using an Olympus BH2 microscope (Olympus
America Inc, Melville, NY) with a 490-nm bandpass filter.
Statistical analyses were performed using JMP computer software (JMP
Software, version 4.0.4; SAS Institute Inc, Cary, NC).62 t Tests were used for comparison of the clinical demographic
data between groups. Preliminary analyses (Shapiro-Wilks W test) indicated that much of the pathologic data were not normally
distributed, and hence, nonparametric statistical tests were used for these
assessments. Comparisons between groups were by Wilcoxon rank sum test or,
where appropriate,  2 analysis. Spearman rank order statistics
were used for correlative assessments.
P<.05 was considered statistically significant.
RESULTS
DEMOGRAPHICS AND PRETERMINAL CLINICAL CHARACTERISTICS
From the Mayo database, 162 PD patients were identified who had undergone
autopsy between 1976 and 1997. Dementia had been coded in 64 of these patients.
Of these, 13 patients (6 men, 7 women) met the inclusion criteria for PD with
later-developing dementia (most of the remainder had dementia documented early
in the disease course). From the cohort of 162 PD patients who had undergone
autopsy, we included all 9 who met criteria for absence of dementia (5 men,
4 women). Mayo Clinic neurologists were involved in the diagnosis and care
of all patients except for a single PD patient without dementia who had rest
tremor–predominant PD. As given in Table 3, there was a trend toward earlier onset of parkinsonism
in the group with dementia, whereas the age at death was similar. Parkinsonism
duration was significantly longer in the demented group and much more severe
in the last year of life (based on the Hoehn and Yahr scores). The mean interval
from parkinsonism onset to dementia was 10.5 years. All patients in the PD
group with dementia had been administered levodopa therapy and initially were
at least moderately responsive, except for one. That patient (patient 3) developed
parkinsonism in 1959 and did not receive levodopa until 13 years later, by
which time she was experiencing dementia and hallucinating; levodopa was mildly
beneficial in lower doses but exacerbated her psychosis. In view of the otherwise
typical PD and the long interval from onset to levodopa treatment, we elected
to include her. One patient without dementia had mild clinical symptoms with
rest tremor–predominant parkinsonism and had not been administered levodopa
therapy.
|
|
|
|
Table 3. Patient Demographics*
|
|
|
Dementia severity and the clinical state within a year of death are
summarized in Table 4. Dementia
was documented by formal psychometric or office mental status testing in 7
of the 13 patients. In the rest, the clinical records revealed confusion and
unequivocal cognitive impairment; these observations are summarized in Table 4. Hallucinations or delusions were
experienced by 10 of the 13 patients after dementia onset. Dementia was at
least moderately severe in all, sufficient to substantially interfere with
activities of daily living, and very apparent to family and caregivers. Fluctuations
in cognition were clearly documented in 2; these could have been present in
others but not documented. In the group without dementia, absence of dementia
within a year of death was supported by normal performances on an office mental
status examination (5 patients) or formal psychometrics (1 patient). Nondemented
status was inferred from the medical records in the remaining 3 patients,
all of whom had been seen at least twice within the last year of life by a
Mayo Clinic physician.
|
|
|
|
Table 4. Dementia Characteristics and Condition in Last Year of Life
|
|
|
Of the 13 patients with dementia, 8 had Hoehn and Yahr stage 5 disease
at the end of their life, were severely impaired, and required total or near-total
care. Only 3 were ambulatory without assistance (patients 7, 8, and 11), including
1 who was ambulatory until preterminal hip fracture. All 13 patients with
dementia continued levodopa therapy but most had a poor response (Table 4). Among the patients with Hoehn
and Yahr stage 5 disease, 4 were treated with relatively high doses of carbidopa
levodopa-therapy (1200-2200 mg/d) and clearly had lost their levodopa responsiveness.
This contrasts with the group without dementia in which the median Hoehn and
Yahr score in the last year of life was 2 to 3. All 8 levodopa-treated patients
who did not have dementia remained responsive to levodopa, although incompletely
responsive in some patients, including 2 with medication refractory imbalance.
NEUROPATHOLOGY
On neuropathologic evaluation, one patient with dementia who had an
initially favorable response to levodopa therapy demonstrated typical histopathologic
features of progressive supranuclear palsy. One patient without dementia had
striatonigral degeneration (multiple system atrophy); she also had responded
to levodopa therapy, although late in the disease course she developed marked
imbalance. These 2 patients are not included in the subsequent analysis. The
remainder of the patients in both groups had typical Lewy body PD within the
substantia nigra.
Median and mean Lewy body counts were approximately 10 times higher
among the 12 PD patients with dementia compared with the 8 PD patients without
dementia in the neocortex, limbic cortex, and amygdala (all statistically
significant; Table 5). In the
nucleus basalis and substantia nigra, the median and mean Lewy body counts
were almost twice as high in the group with dementia, but this failed to reach
statistical significance (Table 5).
|
|
|
|
Table 5. Mean Lewy Body Counts per x200 Microscopic Field in
Patients With Parkinson Disease (PD)
|
|
|
All 12 PD patients with dementia had pathologic findings consistent
with either diffuse (neocortical) or transitional Lewy body disease.41 Transitional Lewy body disease, in which the Lewy
body pathology is primarily confined to limbic areas with sparse neocortical
involvement, was found in 7 patients; the remaining 5 patients had widespread
Lewy body pathology that included neocortex.
Among the PD patients with dementia, there was a trend toward increased
senile plaque and neurofibrillary tangle counts in the neocortex, the CA1
region of the hippocampus, and the entorhinal cortex (Table 6). However, compared with the patients without dementia,
this was only significant for neurofibrillary tangles in the CA1 region. The
CERAD59 neuritic plaque scores ranged from
sparse (CERAD A) to moderate (CERAD B).
|
|
|
|
Table 6. Senile Plaque and Neurofibrillary Tangle Counts per x200
Microscopic Field in Patients With Parkinson Disease (PD)
|
|
|
Only one PD patient with dementia met criteria for early AD as defined
by (1) NIA-Reagan criteria for "intermediate probability of AD,"61
with the presence of neocortical neurofibrillary tangles (Braak and Braak
stage IV),60 and (2) a moderate (CERAD B) plaque
score. In all other patients, neurofibrillary tangles were confined to entorhinal
and hippocampal areas (Braak and Braak stage II-III; NIA-Reagan "low probability
of AD"). Coexisting large and small vessel disease (atherosclerosis, arteriolosclerosis)
was present in all patients, with and without dementia, as commonly seen in
elderly patients. Among the patients with dementia, 2 had white matter pallor
and 1 of these had small white matter infarcts (lacunes).
Among the PD patients with dementia, 3 remained ambulatory before death
(patients 7, 8, and 11), with less advanced parkinsonism than the other patients
with dementia (Table 4). Pathologically,
these could not be distinguished from the other PD patients with dementia.
Mean Lewy body counts were similar to the group with dementia as a whole,
as were the counts of senile plaques and neurofibrillary tangles. The neuropathologic
diagnosis was diffuse Lewy body disease in 2 (patients 7 and 8) and transitional
Lewy body disease in the other (patient 11).
Among the PD patients without dementia, no substantial neuropathologic
change was found beyond the brainstem. Among these patients, Lewy bodies were
sparse in the neocortex and limbic cortex; none had more than minimal evidence
of AD pathologic change.
ASSOCIATIONS OF LEWY BODY COUNTS WITHIN BRAIN REGIONS
Lewy body counts in each of the analyzed brain regions were highly correlated
with counts in the other areas (Table 7). Patients with high counts in one brain region were likely to
have high counts in the others. The analysis given in Table 7 includes all PD patients (with and without dementia); however,
similar values were also found when the analysis was restricted to only the
patients with dementia (although less robust; data not shown).
|
|
|
|
Table 7. Association of Lewy Body Counts in Different Brain Nuclei
for All Patients With Parkinson Disease
|
|
|
ASSOCIATION OF LEWY BODY COUNTS WITH SENILE PLAQUES AND NEUROFIBRILLARY
TANGLES
In the neocortex, Lewy body counts were highly correlated with counts
of senile plaques and, to a slightly lesser extent, neurofibrillary tangles
(Table 8). This was not an artifact
of age, since age at death was not correlated with neocortical counts of Lewy
bodies, senile plaques, or neurofibrillary tangles (Spearman  values
all 0.1 and P>.60). Furthermore, senile plaque
counts were not correlated with counts of neurofibrillary tangles within any
of the analyzed brain regions (neocortex, CA1 area of hippocampus, or entorhinal
cortex). The analysis given in Table 8
included PD patients with and without dementia. When restricted to only those
patients with dementia, the outcomes were similar, except that the correlation
between neocortical Lewy body counts and neurofibrillary tangles did not reach
statistical significance ( = 0.49, P = .11).
|
|
|
|
Table 8. Association of Lewy Body Counts With Counts of Senile Plaques
and Neurofibrillary Tangles in All Patients With Parkinson Disease
|
|
|
COMMENT
Lewy body disease, either transitional or diffuse, seemed sufficient
to account for dementia in 12 of 13 patients. The exception was the single
patient with progressive supranuclear palsy. Two patients also had white matter
pallor, one with multiple lacunar infarctions, which could have contributed
to the dementia. Overall, these findings suggest that the primary cause for
dementia that develops later in the course of otherwise typical PD is the
underlying Lewy body disease. This finding is consistent with 2 recent series
that reported similar results.53-54
In contrast to multiple prior publications (Table 2), major Alzheimer changes were not found among our PD patients
with dementia. Only one patient met NIA-Reagan criteria for intermediate probability
of AD61; the remainder of the patients fell
into the NIA-Reagan category of "low probability of AD."
The mean age was similar in the groups with and without dementia, suggesting
that simple aging was not the cause for the pathologic differences. However,
the group with dementia had significantly longer disease durations. This was
likely a factor in both the clinical and neuropathologic differences; in progressive
neurodegenerative syndromes, longer disease durations typically result in
more severe outcomes.
Although AD did not seem to be the primary substrate for dementia in
these patients, it clearly was a component of the neuropathologic process.
There were trends toward higher senile plaque and neurofibrillary tangle counts
in most of the analyzed nuclei of the group with dementia, although this was
only statistically significant for tangles within the hippocampal CA1 region
(Table 6). Remarkably, neocortical
Lewy body counts were significantly correlated with counts of senile plaques
and, to a lesser extent, neurofibrillary tangles (Table 8). This is not explained by age-related changes, since there
were no trends linking age at death to counts of any of these neuropathologic
markers. Senile plaque counts did not correlate with counts of neurofibrillary
tangles within any of the analyzed nuclei.
The present findings of predominant diffuse or transitional Lewy body
disease, combined with lesser Alzheimer changes, are remarkably similar to
the findings in patients prospectively diagnosed as having dementia with Lewy
bodies.42 In the latter condition, patients
present with dementia with visual hallucinations. Parkinsonian motor findings
may develop early or later in the disease course, in contrast to the present
series with initial parkinsonism and later dementia. Despite the difference
in clinical course, the postmortem pathologic features are similar, with Lewy
body pathology predominantly of the transitional and diffuse type, plus, a
mixture of AD pathology that in most patients does not meet NIA-Reagan criteria
for AD. The findings reported herein underscore the increasing recognition
of the overlap of AD and Lewy body pathologies with a continuum of clinical
deficits from pure dementia to pure parkinsonism, but often with combinations.47, 63-65
The results of this study suggest that a generalized process that simultaneously
affects widespread brain regions is responsible for the dementia. This is
in contrast to what has been suggested by some prior investigators who have
focused on specific brain nuclei22, 24, 28
(Table 2). Lewy body counts in
the 5 analyzed brain regions were highly correlated (Table 7) with most Spearman values more than 0.7 (neocortex,
limbic, amygdala, nucleus basalis, and substantia nigra). The evolving clinical
state of the PD patients with dementia also suggests a generalized brain disorder.
Initially, the clinical picture was that of a focal process, with typical
levodopa-responsive PD. However, with time, most patients in this series not
only developed dementia, but also became levodopa refractory, nonambulatory,
and unable to care for themselves.
These findings also provide insight into the neuropathologic substrate
for underlying loss of the levodopa motor response. Prior PD clinicopathologic
studies have obviously included levodopa refractory, bed-bound patients (Hoehn
and Yahr stage 5). However, this specific group of PD patients has not been
singled out for neuropathologic analysis. In the present study, 8 of the 12
PD patients fit into this category; 3 had been treated with more than 1200
mg/d of levodopa (with carbidopa), suggesting a levodopa refractory state.
Thus, the same neuropathologic process that accounts for dementia seems to
play a critical role in the loss of the motor response to levodopa therapy.
Patient 13 also had Hoehn and Yahr stage 5 disease late in the disease course,
was unresponsive to high-dose levodopa therapy, and had progressive supranuclear
palsy.
Heterogeneous pathologic explanations for dementia developing within
the context of PD have been reported (Table
2). This contrasts with the present study in which the predominant
pathologic findings were fairly consistent among patients. At least 3 factors
account for this discrepancy. First, many of the earlier investigations summarized
in Table 2 were performed before
the availability of more modern immunohistochemical techniques. In fact, all
of the studies listed in Table 2
predate the availability of -synuclein immunohistochemical testing.
This is now recognized to be the most sensitive and specific method for identifying
Lewy bodies.50-51 Second, patients
included in these prior studies were likely heterogeneous. As is apparent
in Table 2, basic clinical features
were typically not reported and perhaps may not have been available to the
investigators. It was the rare series in which such basic information as latency
from parkinsonism to dementia or levodopa responsiveness was reported (Table 2). For those series that included
patients in whom dementia was a presenting feature, one might expect different
neuropathologic conditions, including AD. In the present series, the patients
were clinically homogeneous in that dementia was a later development and all
initially presented with what seemed to be typical levodopa responsive PD.
The only exception was patient 3, who presented with typical PD before levodopa
was available; when initiated 13 years later, the response was limited by
hallucinations. Third, many prior investigators reporting Alzheimer changes
as the substrate for PD dementia (Table
2) used the older Khachaturian neuropathologic criteria.66 Recent consensus criteria for the AD neuropathologic
substrate61 emphasize the importance of neurofibrillary
tangles, in addition to neuritic plaques. The Khachaturian criteria focused
primarily on plaques, which are now recognized as much less specific.
In summary, Lewy body pathology was the consistent and prominent finding
among these PD patients with dementia. However, the mixture of mild AD pathologic
changes raises questions about the interplay of these disorders.
AUTHOR INFORMATION
Accepted for publication August 30, 2001.
Author Contributions: Study concept and
design (Drs Apaydin, Ahlskog, Parisi, Boeve, and Dickson); acquisition
of data (Drs Apaydin, Ahlskog, Parisi, Boeve, and Dickson); analysis and interpretaion of data (Drs Apaydin, Ahlskog, Parisi, Boeve,
and Dickson); drafting of the manuscript (Drs Apaydin, Ahlskog,
Parisi, Boeve, and Dickson); critical revision of the manuscript for
important intellectual content (Drs Apaydin, Ahlskog, Parisi, Boeve,
and Dickson); statistical expertise (Dr Ahlskog); administrative,
technical, and material support (Drs Apaydin, Ahlskog, Parisi, Boeve
and Dickson); study supervision (Drs Apaydin, Ahlskog, Parisi,
Boeve, and Dickson).
Supported in part by grants AG06786 and AG16574 from the National Institute
on Aging, Bethesda, Md, and NS40256 from the National Institutes of Health,
Bethesda.
Corresponding author and reprints: J. Eric Ahlskog, PhD, MD, Department
of Neurology, Mayo Clinic, Rochester, MN 55905.
From the Department of Neurology, Istanbul University, Cerrahpa a
Medical School, Istanbul, Turkey (Dr Apaydin); Departments of Neurology (Drs
Ahlskog and Boeve) and Pathology (Dr Parisi), Mayo Clinic, Rochester, Minn;
and Department of Pathology, Mayo Clinic, Jacksonville, Fla (Dr Dickson).
REFERENCES
| |
1. Brown RG, Marsden CD. How common is dementia in Parkinson's disease? Lancet. 1984;2:1262-1265.
FULL TEXT
|
ISI
| PUBMED
2. Taylor A, Saint-Cyr JA, Lang AE. Dementia prevalence in Parkinson's disease. Lancet. 1985;1:1037.
3. Elizan TS, Sroka H, Maker H, Smith H, Yahr MD. Dementia in idiopathic Parkinson's disease: variables associated with
its occurrence in 203 patients. J Neural Transm. 1986;65:285-302.
4. Girotti F, Soliveri P, Carella F, et al. Dementia and cognitive impairment in Parkinson's disease. J Neurol Neurosurg Psychiatry. 1988;51:1498-1502.
ABSTRACT
5. Mayeux R, Stern Y, Rosenstein R, et al. An estimate of the prevalence of dementia in idiopathic Parkinson's
disease. Arch Neurol. 1988;45:260-262.
ABSTRACT
6. Biggins CA, Boyd JL, Harrop FM, et al. A controlled, longitudinal study of dementia in Parkinson's disease. J Neurol Neurosurg Psychiatry. 1992;55:566-571.
ABSTRACT
7. Friedman A, Barcikowska M. Dementia in Parkinson's disease. Dementia. 1994;5:12-16.
8. Sutcliffe RLG, Prior R, Mawby B, McQuillan WJ. Parkinson's disease in the district of the Northampton Health Authority,
United Kingdom: a study of prevalence and disability. Acta Neurol Scand. 1985;72:363-379.
ISI
| PUBMED
9. Mayeux R, Denaro J, Hemenegildo N, et al. A population-based investigation of Parkinson's disease with and without
dementia: relationship to age and gender. Arch Neurol. 1992;49:492-497.
ABSTRACT
10. Tison F, Dartigues JF, Auriacombe S, Letenneur L, Boller F, Alperovitch A. Dementia in Parkinson's disease: a population-based study in ambulatory
and institutionalized individuals. Neurology. 1995;45:705-708.
FREE FULL TEXT
11. Marder K, Tang MX, Cote L, Stern Y, Mayeux R. The frequency and associated risk factors for dementia in patients
with Parkinson's disease. Arch Neurol. 1995;52:695-701.
ABSTRACT
12. Aarsland D, Tandberg E, Larsen JP, Cummings JL. Frequency of dementia in Parkinson disease. Arch Neurol. 1996;53:538-542.
ABSTRACT
13. Rajput AH, Offord KP, Beard CM, Kurland LT. A case-control study of smoking habits, dementia, and other illnesses
in idiopathic Parkinson's disease. Neurology. 1987;37:226-232.
FREE FULL TEXT
14. Mayeux R, Chen J, Mirabello E, et al. An estimate of the incidence of dementia in idiopathic Parkinson's
disease. Neurology. 1990;40:1513-1517.
FREE FULL TEXT
15. Mahieux F, Fenelon G, Flahault A, Manifacier M-J, Michelet D, Boller F. Neuropsychological prediction of dementia in Parkinson's disease. J Neurol Neurosurg Psychiatry. 1998;64:178-183.
FREE FULL TEXT
16. Hughes TA, Ross HF, Musa S, et al. A 10-year study of the incidence of and factors predicting dementia
in Parkinson's disease. Neurology. 2000;54:1596-1602.
FREE FULL TEXT
17. Aarsland D, Andersen K, Larsen JP, Lolk A, Nielsen H, Kragh-Sorensen P. Risk of dementia in Parkinson's disease: a community-based, prospective
study. Neurology. 2001;56:730-736.
FREE FULL TEXT
18. Breteler MM, de Groot RR, van Romunde LK, Hofman A. Risk of dementia in patients with Parkinson's disease, epilepsy, and
severe head trauma: a register-based follow-up study. Am J Epidemiol. 1995;142:1300-1305.
FREE FULL TEXT
19. Hakim AM, Mathieson G. Dementia in Parkinson disease: a neuropathologic study. Neurology. 1979;29:1209-1214.
ISI
20. Boller F, Mizutani T, Roessmann U, Gambetti P. Parkinson disease, dementia, and Alzheimer disease: clinicopathological
correlations. Ann Neurol. 1980;7:329-335.
FULL TEXT
|
ISI
| PUBMED
21. Mann DMA, Yates PO. Pathological basis for neurotransmitter changes in Parkinson's disease. Neuropathol Appl Neurobiol. 1983;9:3-19.
ISI
| PUBMED
22. Whitehouse PJ, Hedreen JC, White III CL, Price DL. Basal forebrain neurons in the dementia of Parkinson's disease. Ann Neurol. 1983;13:243-248.
FULL TEXT
|
ISI
| PUBMED
23. Gaspar P, Gray F. Dementia in idiopathic Parkinson's disease. Acta Neuropathol. 1984;64:43-52.
FULL TEXT
| PUBMED
24. Perry EK, Curtis M, Dick DJ, et al. Cholinergic correlates of cognitive impairment in Parkinson's disease:
comparisons with Alzheimer's disease. J Neurol Neurosurg Psychiatry. 1985;48:413-421.
ABSTRACT
25. Chui HC, Mortimer JA, Slager U, Zarow C, Bondareff W, Webster DD. Pathologic correlates of dementia in Parkinson's disease. Arch Neurol. 1986;43:991-995.
ABSTRACT
26. Jellinger K. Overview of morphological changes in Parkinson's disease. In: Yahr MD, Bergmann KJ, eds. Advances in Neurology,
Parkinson's Disease. Vol 45. New York, NY: Raven Press; 1987:1-18.
27. Yoshimura M. Pathological basis for dementia in elderly patients with idiopathic
Parkinson's disease. Eur Neurol. 1988;28:29-35.
28. Rinne JO, Rummukainen J, Paljarvi L, Rinne UK. Dementia in Parkinson's disease is related to neuronal loss in the
medial substantia nigra. Ann Neurol. 1989;26:47-50.
FULL TEXT
|
ISI
| PUBMED
29. Braak H, Braak E. Cognitive impairment in Parkinson's disease: amyloid plaques, neurofibrillary
tangles, and neuropil threads in the cerebral cortex. J Neural Transm Park Dis Dement Sect. 1990;2:45-57.
FULL TEXT
|
ISI
| PUBMED
30. Xuereb JH, Tomlinson BE, Irving D, Perry RH, Blessed G, Perry EK. Cortical and subcortical pathology in Parkinson's disease: relationship
to parkinsonian dementia. Adv Neurol. 1990;53:35-40.
PUBMED
31. Zweig RM, Cardillo JE, Cohen M, Giere S, Hedreen JC. The locus ceruleus and dementia in Parkinson's disease. Neurology. 1993;43:986-991.
FREE FULL TEXT
32. Duyckaerts C, Gaspar P, Costa C, Bonnet AM, Hauw JJ. Dementia in Parkinson's disease: morphometric data. Adv Neurol. 1993;60:447-455.
PUBMED
33. Hughes AJ, Daniel SE, Blankson S, Lees AJ. A clinicopathologic study of 100 cases of Parkinson's disease. Arch Neurol. 1993;50:140-148.
ABSTRACT
34. Sugiyama H, Hainfellner JA, Yoshimura M, Budka H. Neocortical changes in Parkinson's disease, revisited. Clin Neuropathol. 1994;13:55-59.
ISI
| PUBMED
|
