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Genetic Variation Analysis in Parkinson Disease Patients With and Without Hallucinations
Case-Control Study
Christopher G. Goetz, MD;
Paul F. Burke, MD;
Sue Leurgans, PhD;
Elizabeth Berry-Kravis, MD;
Lucy M. Blasucci, RN;
Rema Raman, MS;
Lili Zhou, MD
Arch Neurol. 2001;58:209-213.
ABSTRACT
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Background Visual hallucinations in Parkinson disease (PD) occur in approximately
one third of patients treated long-term with dopaminergic medications. In
Alzheimer disease, hallucinations and psychosis have been linked to increased
representations of B2/B2 homozyogotes for the dopamine receptor gene DRD1 and 1/1 or 2/2 homozygotes for DRD3. In addition, a previous study of PD patients with and without
hallucinations did not show differences in D2 and D3 polymorphisms, although
careful case-control matching was not performed. Another study linked the
apolipoprotein E4 (APOE4) allele to hallucinations
in PD.
Objective To determine whether the frequency of dopamine receptor genetic variants
and APOE alleles in patients with PD with and without
chronic visual hallucinations resembles the pattern previously documented
in patients with Alzheimer disease.
Methods We conducted a case-control study of 44 patients with PD and chronic
hallucinations and 44 patients with PD who had never hallucinated. Cases and
controls were matched for current age and medications. DNA was isolated from
blood samples and assayed for DRD1, DRD2, DRD3, DRD4,
and APOE polymorphisms. Receptor polymorphisms were
genotyped by polymerase chain reaction. Genotypes in hallucinators and nonhallucinators
were compared using Mantel-Haenszel tests stratified by pair, and allele frequencies
were compared using Wilcoxon signed rank tests within pairs.
Results Neither D1 receptor genotypes (P = .37) nor
allele frequencies (P = .38) differed, and there
was no predominance of B2/B2 homozygotes in the hallucinators. For D3, there
was a higher frequency of allele 2 (P = .047), but
there was no significant difference between frequencies of homozygotes vs
heterozygotes (P = .39) as reported in Alzheimer
disease. D4 receptor distribution of long and short alleles did not differ
between the 2 patient groups, and there were too few C
alleles (3 of 86) to compare D2 allele genotypes or frequencies. For APOE, 12 cases and 12 controls carried E4 alleles (P>.99).
Conclusions With careful case-control matching, visual hallucinations in PD are
not associated with the pattern seen for patients with Alzheimer disease and
visual hallucinations. Furthermore, there was no association between hallucinations
and APOE. Similar methods using larger sample sizes
might be adapted to test whether specific dopaminergic receptor genetic variants
are associated with visual hallucinations in PD. Based on our data, the DRD3 allele 2 may merit further study.
INTRODUCTION
VISUAL hallucinations occur in approximately one third of patients with
Parkinson disease (PD) treated long-term with dopaminergic medications.1, 2 The exact neurochemical link to the
dopaminergic system, however, is not clearly delineated, and dose and duration
of dopaminergic therapy are not considered consistent risk factors for hallucinations.2 Furthermore, in patients with chronic hallucinations,
intravenous infusions of high-dose levodopa do not precipitate hallucinations.3 These observations suggest that the dopaminergic system
is involved in the pathophysiologic process of hallucinations in PD, but mechanisms
other than drug intoxication models should be explored.
In Alzheimer disease (AD), Sweet and colleagues4
found that psychosis and aggression were significantly more frequent in individuals
homozygous for the dopamine receptor gene DRD1 B2
and that patients with nonaggressive psychosis were significantly more likely
to be DRD3 1/1 or 2/2 homozygotes. In PD, although
dopamine receptors have not been extensively examined in patients with hallucinations,
one study5 showed that the apolipoprotein E4
(APOE4) allele was associated with hallucinations
in patients with nondemented PD. Because hallucinations and dementia can coexist,
it is not clear whether the APOE marker in PD was
a risk for hallucinations or later dementing illness.6
Based on these observations, we conducted a case-control study of patients
with PD and hallucinations and a control group of patients with PD who never
hallucinated to test (1) whether the pattern in AD is mimicked in patients
with PD and hallucinations and (2) whether patients with PD and chronic hallucinations
will have a significantly greater allele frequency of APOE4 than patients with PD who never hallucinated.
PATIENTS AND METHODS
PATIENT SAMPLE
In our tertiary care PD treatment center, between February 1, 1999,
and October 30, 1999, we identified all patients with PD, defined by CAPIT
(Core Assessment Program for Intracerebral Transplantations) criteria,7 who were receiving dopaminergic therapy and had documentation
of definite drug-related motor benefit. Patients with signs or a history suggesting
Lewy body dementia, such as fluctuating cognitive function or neuroleptic
sensitivity, were excluded. Using a questionnaire, we identified all white
patients who experienced visual hallucinations at least 3 times weekly for
the past 2 months and who had not experienced visual hallucinations before
dopaminergic drug treatment. We chose only white patients because previous
studies4 documented racial differences in dopamine
receptor allele frequencies and because whites were the predominant racial
group in our practice. All patients who fulfilled these entry criteria completed
a Mini-Mental State Examination, a Parkinson's Psychosis Rating Scale,8 a
Unified Parkinson's Disease Rating Scale (motor
section), and Hoehn and Yahr stage evaluation and contributed a 3-mL blood
sample for genetic testing. Of 354 patients screened, 48 met entry criteria,
and 44 consented to participate. For each case, we used our computer database
to identify potential control subjects with PD without hallucinations who
were also white, fulfilled CAPIT criteria, and showed motor benefit from dopaminergic
therapy. They were matched to individual cases for age (±3 years) and
dopaminergic medications (levodopa, an agonist, or both). These subjects were
interviewed at their next regular office visit and, if they had never hallucinated,
were invited to participate as a matched control subject for a given case.
Controls signed informed consent forms, completed the same tests, and contributed
a blood sample for genetic testing. Of 98 controls identified by the computer
search, 44 fulfilled entry criteria, and all consented. The research project
was approved by the institutional review board of Rush
University, Chicago,
Ill.
SAMPLE SIZE AND POWER CONSIDERATIONS
Estimates of effect size and required sample sizes for detecting increased
homozygosity of DRD1 and DRD3
receptor genes in patients with PD and chronic hallucinations were directly
based on the work of Sweet et al.4 They documented
a moderate effect size in detecting an increase in the DRD1 B2/B2 genotype and DRD3 homozygosity
for either 1/1 or 2/2 (for both,  2 = 4.0; P<.05; effect size, w = 0.30 expressed as g [departure from equal
probability] = 15) in individuals with AD and psychotic features compared
with those with AD and no psychotic features.9
Assuming similar effect sizes in patients with PD, our sample size of 44 individuals
in each group afforded 80% power to detect departures from equal probability
of 15 points or larger for DRD1 B2/B2 and DRD3 1/1 or 2/2 homozygosity.
GENOTYPING
Genomic DNA was extracted from venous blood samples with a DNA isolation
kit (Puregene; Gentra Systems, Minneapolis, Minn), and 100 ng was amplified
by modifications of polymerase chain reaction and restriction protocols for
genotyping DRD1, DRD2, DRD3, and DRD4 polymorphisms, as described elsewhere.10, 11, 12, 13, 14, 15
Apolipoprotein E genotyping was performed via polymerase chain reaction amplification
of 100 µg of genomic DNA followed by restriction analysis of radiolabeled
products with CfoI, as published previously.16
STATISTICAL ANALYSIS
Data are presented as counts, means (SDs), or allele frequencies as
appropriate. Cases and controls are compared using Mantel-Haenszel tests for
genotypes of each receptor subtype and for APOE genotypes. DRD1 and DRD3 polymorphisms were
analyzed by 3-category genotype and homozygosity. DRD4
genotypes were analyzed by comparing those with any long allele (6-8 repeats)
with those with only short alleles. Apolipoprotein E polymorphisms were analyzed
as exact genotype and by presence or absence of any APOE4 allele. Allele frequencies for D1, D3, and APOE within pairs were compared using Wilcoxon signed rank tests. Quantitative
clinical characteristics of cases were compared with those of their matched
controls using Wilcoxon rank sum tests.
RESULTS
CLINICAL DATA
The mean (SD) age of cases was 72.1 (8.4) years and of controls was
71.7 (7.9) years (P = .11). Cases and controls were
matched for current dopaminergic drug exposure, with 12 pairs receiving levodopa
alone, 1 pair receiving an agonist alone, and 31 pairs receiving combination
levodopa and agonist treatment. Cases did not significantly differ from controls
in mean (SD) daily doses of levodopa (655 [326] mg/d vs 613 [368] mg/d; P = .20) or agonist (pergolide equivalent,3
2.37 [1.70] mg/d vs 2.24 [1.52] mg/d; P = .48). The
mean (SD) PD duration was longer in cases (15.73 [7.0] years vs 10.25 [5.0]
years; P<.001), but at the onset of chronic hallucinations
in cases it was not significantly different from the current duration of PD
in controls (12.20 [6.5] years vs 10.25 [5.0] years; P
= .09).
Because item A of the Parkinson's Psychosis Rating Scale measured the
presence and severity of hallucinations, all controls scored 1 (absent) and
all cases scored 2, 3, or 4 (mean [SD], 2.64 [0.60]). For the total of the
remaining Parkinson's Psychosis Rating Scale items, cases scored significantly
higher than controls (mean [SD], 8.95 [2.42] vs 5.50 [0.63]; P<.001). The Mini-Mental State Examination scores of cases also
were more impaired (mean [SD], 23.7 [5.3] vs 28.8 [2.4]; P<.001). Motorically, the 2 groups differed significantly, and the
mean (SD)
Unified Parkinson's Disease Rating Scale motor score in cases was
38.5 (12.7) vs 28.2 (11.8) in controls (P<.001).
DOPAMINE RECEPTOR AND APOE GENOTYPES
For DRD1, overall allele frequencies (0.31
for B1 and 0.69 for B2 alleles) and heterozygosity (0.39) were similar to
previously reported4, 10 values
(B1 allele frequency range, 0.34-0.36; heterozygosity, 0.38-0.47) (Table 1). There was no significant difference
in allele frequencies or in the distribution of genotypes between cases and
controls, and, specifically, the B2/B2 genotype was not overrepresented in
the group with hallucinations. At the DRD2 locus,
because only 3 individuals carried the C allele (2
cases and 1 control), no meaningful comparison of C
allele frequency between the 2 study groups was possible. The overall frequency
of the C allele variant was 0.017, similar to that
reported in control groups from other studies4, 11
(range, 0.018-0.03). For DRD3, overall allele frequencies
(0.63 for allele 1 and 0.37 for allele 2) and heterozygosity (0.55) were similar
to previously reported4, 12 values
(1 allele frequency range, 0.62-0.66; heterozygosity range, 0.4-0.49) (Table 2). There was a trend toward overrepresentation
of the 2/2 genotype in cases (P = .05), but no significant
difference in representation of the combined homozygote (1/1 and 2/2) genotypes
between cases and controls (P = .45). Allele frequency
analysis showed borderline increased frequency of the DRD3 2 allele in cases compared with controls (P
= .047). This pattern did not reproduce the findings previously reported for
AD.4 For DRD4, there
was no difference in the percentage of individuals carrying at least 1 long
allele between cases (45%) and controls (39%). However, the overall frequency
of carrying at least 1 long allele was somewhat higher than reported in previous
studies13, 14 (range, 20%-31%).
Allele frequencies (2 allele, 0.05; 3 allele, 0.07; 4 allele, 0.63; 5 allele,
0.02; 6 allele, 0.0; 7 allele, 0.23; and 8 allele, 0.005) at this locus showed
a distribution similar to that in previous studies,13, 14
albeit with a slightly increased frequency of the 7-repeat allele.
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Table 1. DRD1 Genotypes and Allele Frequencies
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Table 2. DRD3 Genotypes and Allele Frequencies
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For APOE, genotypes and allele frequencies
were similar to those reported for whites from control populations living
in the
United States.16 There was no significant
difference between cases and controls for the APOE
genotype distribution, the fraction of individuals carrying an APOE4 allele (12 of 44 for both cases and controls), or the APOE4 allele frequency (Table 3).
Furthermore, there was no association of the APOE4
allele with dementia, as defined by a Mini-Mental State Examination score
of 24 or less.
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Table 3. Apolipoprotein E Genotypes and Allele Frequencies
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COMMENT
Hallucinations in PD are a frequent and clinically important problem
in patients treated long-term with medications. Once hallucinations develop
they persist, and their severity can progress to full psychotic behavior and
agitation.17 Hallucinations are a significant
risk factor for nursing home placement, and the latter is highly associated
with subsequent death.18 These observations
highlight the need for identifying patients at risk for hallucinations and
the importance of developing effective therapies for hallucinations in this
population.
Hypotheses concerning drug-induced hallucinations in PD have traditionally
focused on the role of the dopaminergic system and, specifically, on dopaminergic
hypersensitivity of mesocortical and mesolimbic D3 receptors. To date, however,
we know of no pathological studies of dopaminergic receptor populations that
have been performed in patients with PD and hallucinations.
Studies on genetic risk for hallucinations began with AD, another degenerative
condition frequently associated with visual hallucinations and psychotic behavior.
Psychosis was significantly more frequent in individuals expressing the B2/B2
homozygote pattern for DRD1.4
Likewise, psychosis was significantly more frequent in DRD3 homozygotes, either 1/1 or 2/2. Our primary aim was to test whether
this same pattern occurred in patients with PD and hallucinations. The laboratory
analytic techniques used for this documentation mirrored ours, but we were
careful to match cases and controls for clinical features that have been posited
to affect hallucinations, specifically, age and drug exposure. Our data demonstrate
that the findings in AD do not directly extrapolate to PD and further suggest
that hallucinations and psychosis in PD represent a distinct phenomenon from
those in AD and may not be directly or solely related to dopaminergic mechanisms.
In focusing our study on the detection of similar patterns in hallucinating
individuals with AD or PD, we built our power calculation and sample size
determination directly on the previously cited study.4
Although the number of cases and controls is smaller than the group comparison
study in patients with AD, the absence of any pattern of difference in the
D1 receptor system leaves us confident that patterns of polymorphism in this
receptor system do not mimic those seen in patients with AD and hallucinations.
For the D3 system, we found a higher frequency of allele 2, but, again, the
pattern seen in patients with AD did not occur.
A previous study19 examined D2 and D3
polymorphisms in patients with PD who did and did not have hallucinations
and, like our study, found no group differences. The advantage of that study
was its larger sample size of hallucinators and nonhallucinators with PD,
and it attempted to focus on detecting polymorphism patterns distinctive to
PD. It did not, however, examine the D1 or D4 systems. Our study complements
and extends this study in several ways. Although our sample size was smaller,
because we focused specifically on a comparison to the AD data already published,
we included a detailed analysis of the D1 polymorphism. Another advantage
of our study is that we carefully matched cases with controls in terms of
demographic features that have previously been associated with hallucinations
in PD, namely, age and medications. We also selected cases who were currently
hallucinating so as to safely exclude those who may have transiently hallucinated
in the past in the context of an acute infection or medication intoxication.
Together, the 2 studies underscore a clear distinction between dopamine receptor
polymorphisms in PD and those identified in patients with AD who hallucinate.
Larger sample sizes will be required to establish possible associations of
this D2 marker with hallucinations in PD because of the very low level of
polymorphism at this locus.15, 16
Apolipoprotein E polymorphisms have been extensively studied in various
neurodegenerative diseases as a result of the strong association of the APOE4 allele with AD. Whereas studies have not shown a
relation between PD and APOE4 alleles, one study5 showed that in patients with PD and this allele, 76%
had visual hallucinations compared with only 23% without the allele. This
study did not specify details of the clinical material, and it is not clear
whether the series was confounded with individuals who have Lewy body dementia,
a parkinsonian syndrome characterized by hallucinations and an overrepresentation
of the APOE4 allele.20
Our study did not confirm this finding, and we are confident that the clear
clinical separation of cases and controls (frequent and chronic hallucinators
vs patients who had never hallucinated), the long disease duration in both
groups, and the absence of fluctuating cognition or neuroleptic sensitivity
effectively eliminates Lewy body dementia as a confounding diagnosis. Our
data on the overall allele frequency of APOE4 support
previous findings that dementia in PD is not associated with an overrepresentation
of APOE4.6
Birkmayer and Riederer21 suggested that
serotonergic/dopaminergic imbalance may be of primary importance in the pathogenesis
of psychotic behavior in PD. Comparison of serotonergic receptor polymorphisms
in cases and controls remains an area for future research. Because of the
trend toward differences in the DRD3 genotype distribution
between cases and controls and overrepresentation of the 2 allele in cases,
a larger sample would be useful to determine whether the DRD3 2 allele is truly associated with hallucinations in PD. As we
expand our study to the serotonergic system, we are collecting additional
clinical pairs to enhance the analysis of this dopaminergic polymorphism.
AUTHOR INFORMATION
Accepted for publication October 2, 2000.
This work was supported by a center grant from the Parkinson's Disease
Foundation, New York, NY, and Chicago, Ill, and by an unrestricted education
grant from Elan/Athena Neurosciences, San Francisco, Calif.
We appreciate the counsel of P. Michael Conneally, PhD, Indianapolis,
Ind.
From the Departments of Neurological Sciences (Drs Goetz, Burke, Leurgans,
and Berry-Kravis and Ms Blasucci), Pharmacology (Dr Goetz), Preventive Medicine
(Dr Leurgans and Ms Raman), and Pediatrics (Drs Berry-Kravis and Zhou), Rush
University/Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill.
Corresponding author: Christopher G. Goetz, MD, Department of Neurological
Sciences, Rush
University/Rush-Presbyterian-St Luke's Medical Center, 1725
W Harrison St, Chicago, IL 60612.
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