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Dementia in Parkinson Disease
A Proton Magnetic Resonance Spectroscopy Study
Christopher Summerfield, MSc;
Beatriz Gómez-Ansón, MD, PhD, FRCR;
Eduardo Tolosa, MD, FRCP;
José M. Mercader, MD;
M. Jose Martí, MD;
Pau Pastor, MD;
Carme Junqué, PhD
Arch Neurol. 2002;59:1415-1420.
ABSTRACT
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Background Magnetic resonance spectroscopy has been shown to be useful in differentiating
idiopathic Parkinson disease (PD) from atypical parkinsonian syndromes such
as progressive supranuclear palsy, multiple system atrophy, and corticobasal
degeneration.
Objective To systematically investigate the utility of proton magnetic resonance
spectroscopy in distinguishing between idiopathic PD with dementia (PDD) and
without dementia.
Design Group comparisons and correlations of brain metabolites with clinical
and neuropsychological variables.
Patients and Methods Metabolite concentrations were acquired from voxels localized to the
basal ganglia and occipital cortex in 14 patients diagnosed as having idiopathic
PDD, 12 patients with PD without dementia, and 13 matched control subjects.
The 3 groups underwent clinical and neuropsychological assessment.
Results In the occipital region, N-acetylaspartate
levels were significantly reduced in the PDD group relative to the PD and
control groups. N-acetylaspartate values correlated
with neuropsychological performance but not with severity of motor impairment.
Conclusions N-acetylaspartate reduction in occipital lobes
may be a marker for dementia in PD. The distribution of metabolite reduction
differs from that reported in Alzheimer disease. These findings suggest that
proton spectroscopy may serve as a metabolic marker of cognitive disturbance
in patients with PD.
INTRODUCTION
PATIENTS WITH idiopathic Parkinson disease (PD) are 6 times more likely
than healthy elderly people to develop dementia.1
Postmortem studies on brains of patients with long-standing PD who later develop
dementia (PDD) show both cortical Lewy bodies and Alzheimer-type cortical
changes.2 However, Alzheimer-type neuropathological
changes do not seem to account for dementia in PD,3
and Lewy body inclusions appear to contribute significantly to cognitive deficits
seen in several neuropathological conditions.4
Proton magnetic resonance spectroscopy (1H-MRS) allows the
noninvasive, in vivo measurement of brain metabolism. Four major hydrogen-containing
metabolites may be identified and measured by means of 1H-MRS.
One of these is N-acetylaspartate (NAA),5 which is present in functioning neurons and their
processes but absent in mature glial cell cultures,6
and has been taken as a putative neuronal marker. Other metabolites that can
be identified are creatine (Cre), related to general metabolism; choline-containing
compounds (Cho), which may be altered in processes with increased membrane
turnover; and myoinositol (MI), which is mainly contained in glial cells.
Previous studies using MRS in demented patients with Alzheimer disease
(AD) showed a consistent pattern of decreased NAA and increased MI values.7-10 In addition, 1H-MRS has been demonstrated to be useful in differentiating multiple-system
atrophy from PD11-13
and also PD from progressive supranuclear palsy.13-15
Results from studies comparing patients with PD and normal control subjects
are inconclusive, but in general, negative results have been reported for
NAA.14, 16-18
However, a reduction in the NAA/Cre ratio has been shown in the putamen13 and in the temporoparietal region,19
as have NAA/Cho reductions in the putamen of treated compared with untreated
patients with PD, suggesting that Cho levels may be affected by medication.16, 20
To our knowledge, only one study has previously examined brain metabolism
with the use of 1H-MRS, in 4 patients with PDD.21
These investigators found increased levels of lactate/NAA in the occipital
lobe in patients with PDD and PD relative to controls, but no statistically
significant differences in NAA/Cre levels among the 3 groups.
The aim of our study was to identify in vivo neurochemical markers associated
with dementia in idiopathic PD and their clinical and neuropsychological correlates.
We selected 2 brain areas for examination with 1H-MRS. The basal
ganglia was selected because it is known that striatonigral degeneration is
the principal neurochemical correlate of PD. The occipital lobe was selected
because altered metabolite concentrations observed with 1H-MRS
have been reported in the occipital cortex in AD,7-8
and also because positron emission tomographic studies have shown metabolic
changes in the occipital cortex of patients with dementia with Lewy bodies.22-23
SUBJECTS AND METHODS
SUBJECTS
A total of 42 subjects aged between 54 and 83 years participated in
the study. Patients were recruited from an outpatient movement disorders clinic
(PD and Movement Disorders Unit, Department of Neurology, Hospital Clinic,
Barcelona, Spain) during a 9-month period (November 2000 to July 2001). Subjects
were divided into 3 groups. The PDD group consisted of 14 patients with an
initial diagnosis of idiopathic PD, who years later developed cognitive decline
and fulfilled dementia criteria (see next section, "Diagnostic Criteria and
Selection"). The PD group included 14 patients with idiopathic PD who did
not meet dementia criteria. The control group consisted of 14 individuals
with no history of neurologic disease who were family members or spouses of
patients attending the clinic. None of these control subjects met dementia
criteria or had parkinsonism. Subjects in all 3 groups were matched for sex
and age. The study was approved by the local ethics committee. Written informed
consent was obtained from the patients (and, where appropriate, the caregiver)
after full explanation of the procedures involved.
DIAGNOSTIC CRITERIA AND SELECTION
Idiopathic PD was diagnosed by means of UK Brain Bank criteria.24 Care was taken to exclude patients who might have
atypical PD syndromes such as progressive supranuclear palsy or multiple-system
atrophy, and all patients had a good or excellent initial response to levodopa
treatment. To optimize PDD diagnosis, dementia was assessed with 3 standardized
instruments: the Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition,25 the Clinical
Dementia Rating scale,26 and the Mini-Mental
State Examination.27 Subjects who met dementia
criteria exhibited a Clinical Dementia Rating of 1, had a Mini-Mental State
Examination score of less than 23, and fullfilled both items specified in
the Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition. Subjects who were demented according to some but not
all of the rating scales were excluded from the study. No patients who developed
dementia before, or within 2 years after, onset of motor symptoms were included
in the PDD sample. Additional exclusion criteria for all subjects included
the following: history of stroke, cerebral tumor, traumatic brain injury,
epilepsy, or psychiatric illness other than depression. Patients with pacemakers
or prosthetic implants were excluded, as they could not undergo MRS examination.
Patients were selected according to the following procedure. One investigator
reviewed the clinical histories of patients attending the twice-weekly movement
disorders clinic. Patients with diagnosed idiopathic PD and suspected or confirmed
cognitive decline were interviewed jointly by the investigator and an experienced
neurologist. Dementia was assessed with the Mini-Mental State Examination,
Clinical Dementia Rating, and Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition. Patients who met criteria
for the PDD group were invited to participate in the study. For each patient
with PDD recruited, the next patient attending the clinic who fulfilled entry
criteria for the PD group, and the next spouse or family member who met criteria
for entry into the control group, who were matched for sex and age (±5
years) to the patient with PDD, were interviewed and invited to participate.
In this way, 14 triads of PDD-PD-control subjects were obtained. Detailed
information from the clinical history was recorded for participating patients,
including scores for the Unified Parkinson's Disease Rating Scale24 parts I, II, and III; Hoehn and Yahr stage28; Schwab and England score29;
and information about type of parkinsonism (tremor or rigid-akinetic), dyskinesias,
motor fluctuations, hallucinations, history of dopaminergic psychosis, details
of present medication, and demographics.
NEUROPSYCHOLOGICAL ASSESSMENT
All neuropsychological assessments took place in the morning while subjects
in the PD and PDD groups were in a levodopa-induced "on" state. Subjects took
the World Health Organization–University of California, Los Angeles,
auditory verbal learning test, the forward and backward digit span and block
design subtests of the Wechsler Adult Intelligence Scale–Revised,30 and phonemic, semantic, and action fluency.31 The Hamilton depression inventory32
was also administered. Neuropsychological tests were scored in the following
way. Two subscores were recorded for the World Health Organization–University
of California, Los Angeles, test33: (1) difference
between the number of words remembered on trial 1 and trial 5 (learning score)
and (2) number of words correctly recognized as old at 30 minutes (recognition
score). Block design was scored as in Wechsler.30
Forward and backward digits scores reflected span. Phonemic fluency scores
reflected the total words produced beginning with f, a, and s in 1 minute. Semantic
fluency was the number of animals named in 1 minute, and action fluency, the
number of verbs named in 1 minute. Detailed descriptions of these tests are
available in Lezak.34
MAGNETIC RESONANCE SPECTROSCOPY
All subjects underwent scanning with a 1.5-T magnetic resonance machine
(NV/Cvi 8.4 M4; General Electric Co, Milwaukee, Wis) with a head coil. First,
3-dimensional T1-weighted, inversion recovery spoiled gradient axial images
(1.5-mm thickness, 256 x 256, field of view = 24) of the entire brain
were obtained for localization purposes. On these, water-suppressed single-voxel
spectroscopy (proton brain examination–point resolved spectroscopy [PROBE-PRESS];
repetition time, 1500 milliseconds; echo time, 35 milliseconds; number of
excitations, 8; 128 averages) of 2 different brain regions and their corresponding
non–water-suppressed signals were obtained.
A rectangular voxel (30 x 20 x 20 mm) was localized on a
T1-weighted axial image, covering as much as possible of the lentiform and
caudate nuclei (Figure 1A). In patients
with PD and PDD, the voxel was placed contralateral to the most affected side,
and voxel side was alternated for control subjects. Single-voxel spectroscopy
was performed from this location by means of a semiautomated procedure. Automatic
prescan was first applied, and, if necessary, manual prescanning was also
performed. This resulted in all spectra having 6 Hz or less of full width
at half height of the unsuppressed water peak, and percentages of water suppression
higher than 96%. A second rectangular voxel of identical dimensions was then
located covering the occipital cortex of both hemispheres (Figure 1B), and single-voxel spectroscopy was again performed with
the same settings and procedure. Care was taken to minimize cerebrospinal
fluid contamination in both the basal ganglia and occipital volumes of interest.
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Figure 1. Axial magnetic resonance images
(3-dimensional spoiled gradient) at the level of the basal ganglia and occipital
cortex. A rectangular volume of interest of 3 x 2 x 2 cm is located
in the basal ganglia (A) and occipital cortex (B) for proton magnetic resonance
spectroscopy.
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All spectra were first visually assessed in a blinded fashion by an
experienced investigator. Spectra were evaluated for general quality depending
on the general noise, baseline, water suppression, and ability to identify
the 4 major metabolic peaks.
Spectra were postprocessed by means of manufacturer-provided software
(Probe Quantool 2000; General Electric Co). Curve fitting and line width normalization
were performed, and 4 major peaks were identified: NAA, Cre, Cho, and MI.
The fit amplitudes for each peak are reported as "machine numbers," these
being proportional to metabolite peak areas. Peak amplitudes are referenced
to water as an internal standard and are therefore proportional to metabolic
concentrations ("concentration equivalents").
Taking into account the fact that Cre concentrations may be altered
in patients with PD,35 we then adjusted the
concentration equivalents for NAA, Cho, and MI for each group by means of
the ß values from the regression of creatine on NAA, and according to
the following formula36: NAA(adjusted)i = {NAAi(observed)–ß[Crei(observed)–Cre(mean)]},
where i means each subject.
Statistical analysis was carried out on the concentration-equivalent
NAA values corrected for creatine ("adjusted concentration equivalents").
Analyses of variance and regression analysis were used to determine differences
between groups and the predictive value of neuropsychological and clinical
scores. Scheffé test was used for post hoc comparisons. A P value of less than .05 was used to test for significance, and all
statistical tests were 2-tailed.
RESULTS
Movement artifact prevented the acquisition of metabolite concentrations
from the basal ganglia voxel in 2 patients with PD, and 1 control subject
requested to be withdrawn from the study midway through the exploration. Statistical
analysis was thus carried out on the remaining 39 subjects (14 with PDD, 12
with PD, and 13 control subjects). These subjects did not differ in age, years
of education, or Hamilton depression inventory score. The PD and PDD groups
did not differ significantly on the number of years of evolution of the disease,
but they did differ on mean Hoehn and Yahr stage and on the scores of the
Unified Parkinson Disease Rating Scale scale part III, with patients with
PDD showing more disease severity on either measure. All patients with PDD
either exhibited visual hallucinations at the time of study or were taking
neuroleptic medication to control hallucinatory symptoms. Mean demographics
for all the subjects and clinical variables for the patient groups are presented
in Table 1.
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Table 1. Demographics and Clinical Variables*
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NEUROPSYCHOLOGICAL PERFORMANCE
Table 2 shows performance
on the neuropsychological tests used. Statistically significant differences
among the 3 groups were observed on all tests, and post hoc analysis showed
that patients with PDD were impaired relative to both patients with PD and
control subjects on all tests. No statistically reliable differences were
observed between patients with PD and control subjects on any neuropsychological
measures.
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Table 2. Neuropsychological Performance*
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MAGNETIC RESONANCE SPECTROSCOPY
Table 3 includes the means
and SDs for the adjusted values for the different brain metabolites as determined
with 1H-MRS in the occipital cortex and basal ganglia of the 3
groups.
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Table 3. Adjusted Concentration Equivalents for NAA and MI From the
Occipital Cortex and Basal Ganglia*
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Adjusted NAA concentration equivalents obtained from the voxel localized
to the occipital cortex in the 3 groups studied are plotted in Figure 2. Analysis of variance showed statistically significant
differences between the 3 groups (F2,36 = 5.00, P<.03), and post hoc tests between the PD and PDD groups achieved
statistical significance (Scheffé post hoc = 14.31, P<.05). Differences between control subjects and patients with PDD
approached significance (Scheffé post hoc = 11.67, P = .06).
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Figure 2. Adjusted occipital concentration
equivalents for N-acetylaspartate (NAA) obtained in control subjects,
patients with Parkinson disease (PD), and patients with PD with dementia (PDD).
Mean and 2 SD values are shown.
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With only patients with PDD considered, significant Spearman correlations
were observed between adjusted occipital NAA and neuropsychological scores
on backward digit span and block design tests (Table 4). No correlation was observed with any of the variables
reflecting disease severity, either for the PDD group alone or for the PDD
and PD groups combined.
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Table 4. Correlations Between Adjusted Occipital NAA and Clinical/Neuropsychological
Variables in the PDD Sample Alone*
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No significant differences were found among the 3 groups for the adjusted
concentration equivalents for Cho or MI in the occipital cortex, and no significant
correlations were observed between these values and any of the clinical or
neuropsychological variables in patients with PDD and PD.
In the basal ganglia, analysis of variance showed no significant differences
in the adjusted concentration equivalents for the different metabolites among
the 3 groups.
COMMENT
Metabolite concentrations in the occipital cortex and basal ganglia
of patients with PDD were acquired by means of 1H-MRS and compared
with those of patients with PD and control subjects. In the occipital cortex,
patients with PDD showed significantly lower NAA values than patients with
PD or control subjects. No further significant differences were found in any
of the other metabolites in the occipital region or in the basal ganglia among
the 3 groups. These results suggest predominantly cortical involvement and
are in agreement with positron emission tomography studies demonstrating cerebral
hypometabolism in the visual cortices of patients with PDD, in contrast to
patients with AD or healthy control subjects.22-23
Our failure to find a difference in metabolite concentrations between
patients with PD and control subjects is in agreement with previous studies
examining the occipital or basal ganglia regions.14-15,17, 21, 35
However, Hu et al19 obtained significant NAA/Cre
reductions in 17 nondemented patients with PD in a voxel localized to the
temporoparietal region. We selected the occipital region because it has been
demonstrated to be more sensitive to increases in MI than the parietotemporal
region,7 and it has been suggested that, in
the pathologic progression of AD, increases in MI precede decreases in NAA.10
Increased MI/Cre and decreased NAA/Cre ratios are a consistent finding
in the parietal or occipital cortex of patients with AD.7
We found decreased NAA in the occipital cortex of patients with PDD, suggesting
neuronal dysfunction or loss, but no differences in MI values. Shonk et al8 also found that in the occipital cortex of patients
with AD, absolute NAA concentrations are reduced and MI levels increased,
whereas patients with non-Alzheimer dementia syndromes showed reduced NAA
levels but relatively stable concentrations of MI. We propose that MRS may
be a useful marker of distinguishing between AD and non-AD dementia. However,
further evidence and neuropathological data are needed to confirm this hypothesis.
Increased severity of neurologic symptoms is a risk factor for dementia
in PD.37-38 As expected, we found
that patients with PDD exhibited greater severity of extrapyramidal symptoms
than did patients with PD, reflected by Hoehn and Yahr stage and scores from
part III of the Unified Parkinson Disease Rating Scale. However, motor impairment
did not correlate with NAA levels in PD or PDD. It is likely that motor impairment
in PD is associated with degeneration of the nigrostriatal pathway. However,
in the PDD group, we found correlations between NAA values and neuropsychological
performance (backward digit span and block design tests). We suggest that
the level of NAA in the occipital cortex may serve as a biological marker
for the severity of cognitive decline in patients with PDD.
While we observed significantly different occipital NAA values between
patients with PD and PDD, post hoc tests showed differences between patients
with PDD and control subjects that approached, but did not reach, 2-way statistical
significance. Larger studies are needed to confirm this result and to show
that patients with PDD can be distinguished from nondemented subjects on the
basis of occipital NAA.
In summary, we have shown that patients with PDD have metabolic changes
in the occipital cortex indicating predominant neuronal cell dysfunction or
death, with little or no glial involvement. These results support the view
that PDD is not just the result of AD developing in patients with long-standing
PD. In addition, there is a correlation between observed NAA in the occipital
cortex and the cognitive status of patients with PDD. Magnetic resonance spectroscopy
may be potentially useful in improving the diagnosis of patients with PD who
develop dementia.
AUTHOR INFORMATION
Accepted for publication March 2, 2002.
Author contributions: Study
concept and design (Mr Summerfield and Drs Tolosa, Mercader, Martí,
Pastor, and Junqué); acquisition of data (Mr
Summerfield and Drs Gómez-Ansón, Tolosa, Mercader, Martí,
and Pastor); analysis and interpretation of data
(Mr Summerfield and Drs Gómez-Ansón and Junqué); drafting of the manuscript (Mr Summerfield and Drs Gómez-Ansón
and Junqué); critical revision of the manuscript
for important intellectual content (Mr Summerfield and Drs Gómez-Ansón,
Tolosa, Mercader, Martí, Pastor, and Junqué); statistical expertise (Mr Summerfield); obtaining
funding (Dr Junqué); administrative, technical,
or material support (Drs Gómez-Ansón and Junqué); study supervision (Drs Gómez-Ansón, Tolosa,
Mercader, Martí, and Junqué); clinical assessment
and acquisition of clinical data (Dr Pastor).
This work was supported by grants 99SGR00081, 98SGR00110, and 2000FI
00471 fom the Generalitat de Catalunya, Catalunya Spain, and by the Diagnostic
Imaging Center at the Clinic Hospital, Barcelona, Spain.
Corresponding author and reprints: Eduardo Tolosa, MD, FRCP, Department
of Neurology, ICMSN, Hospital Clinic, Casanova 143, 08036 Barcelona, Spain
(e-mail: etolosa{at}clinic.ub.es).
From the Department of Psychiatry and Clinical Psychobiology (Mr Summerfield
and Dr Junqué), Neurology Department, Institut de Malalties del Sistema
Nervios, Hospital Clinic (Drs Tolosa, Martí, and Pastor), and Radiology
Department, CDI, Hospital Clinic (Drs Gómez-Ansón and Mercader),
University of Barcelona, Institut d'Investigacions Biomèdiques August
Pi i Sunyer, Barcelona, Spain.
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