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Alterations of Striatal Dopamine Receptor Binding in Alzheimer Disease Are Associated With Lewy Body Pathology and Antemortem Psychosis
Robert A. Sweet, MD;
Ronald L. Hamilton, MD;
Matthew T. Healy, MEd;
Stephen R. Wisniewski, PhD;
Ruth Henteleff, AB;
Bruce G. Pollock, MD, PhD;
David A. Lewis, MD;
Steven T. DeKosky, MD
Arch Neurol. 2001;58:466-472.
ABSTRACT
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Background Lewy bodies (LB) are present in at least 20% to 30% of persons with
Alzheimer disease (AD) and contribute to the risk of psychosis and to excess
cognitive burden.
Objective To determine whether altered striatal dopamine receptor binding is associated
with LB and psychosis in AD.
Design Postmortem case control.
Setting Alzheimer's Disease Research Center at the University of Pittsburgh
(Pa).
Participants Consecutive cases from the Alzheimer's Disease Research Center brain
bank, neuroleptic free for at least 1 month prior to death, with neuropathologic
diagnoses of AD with LB (AD + LB, n = 14), AD without LB (AD, n = 13), or
normal brains (n = 8).
Main Outcome Measures Dopamine D1, D2, and D3 receptor densities,
and affinities as determined by selective saturation binding studies in striatal
tissue.
Results Subjects with AD + LB, compared with those with AD, demonstrated increased
D1 receptor density and decreased D2 and D3
receptor density. D3 receptor density was selectively increased,
however, in AD subjects with a history of psychosis, independent of the presence
or absence of LB. The effect of neuroleptic treatment on D3 binding
was further examined in an additional group of subjects who had received neuroleptics
near the time of death. Neuroleptic treatment reduced D3 affinity
with no effect on D3 density.
Conclusions Alzheimer disease with LB is associated with selective alterations in
dopamine receptor density, which may contribute to the distinct clinical profile
of this group. The D3 receptor may be an important target of neuroleptic
treatment of psychosis in AD.
INTRODUCTION
ALZHEIMER DISEASE (AD) is currently estimated to affect 3 to 4 million
individuals in the United States. Psychotic symptoms, delusions, and hallucinations
occur in at least 30% to 40% of AD patients.1
Patients with AD and psychotic symptoms demonstrate more severe cognitive
deficits than matched AD subjects without psychosis.2, 3
Similarly, AD subjects with psychotic symptoms are at risk for more rapid
cognitive deterioration3, 4 more
rapid decline in function,5 and premature institutionalization.5, 6
Many individuals diagnosed ante mortem with AD will demonstrate cortical
Lewy bodies (LB) at autopsy in addition to the neuropathologic findings of
AD (AD with Lewy bodies, AD + LB). Alzheimer disease with Lewy bodies has
been associated with excess cognitive burden, extrapyramidal symptoms, and
with more frequent psychotic symptoms.7 Prominent
reductions in postmortem measures of presynaptic dopamine have been reported
in AD + LB.8, 9, 10
These reductions, however, are not as severe as seen in Parkinson disease.9, 10
A limited number of studies have examined dopamine receptor density
in AD subjects who have been characterized with regard to LB. Dopamine D1, D2, and D3 receptors, but not D4
or D5 receptors, are expressed in striatum.11
Perry et al10 examined nonselective D2/D3 receptor binding using [3H]raclopride in
AD, AD + LB, and normal control (NC) subjects. Neuroleptic-naive or neuroleptic-intolerant
AD + LB subjects had reduced striatal D2/D3 receptor
binding, while AD subjects did not differ from NC subjects. Whether the observed
reductions in D2/D3 binding were due to a reduction
in D2 binding, in D3 binding, or in both cannot be directly
answered at this time. Because D3 density varies along a dorsal
to ventral gradient in striatum,12 the absence
of a significant interaction of striatal region with the diagnostic group
in the examination of D2/D3 binding reported by Perry
et al10 provides indirect evidence that both
D2 and D3 binding were reduced.
Joyce et al13 examined D1
and D2 receptor binding in striatum of AD and NC subjects. Alzheimer
disease was not associated with reduction in striatal D2 receptor
binding, unless the AD subjects also demonstrated extrapyramidal symptoms
(EPS). D1 binding in AD did not differ from controls, and there
was no association with EPS. In contrast, D1 binding is elevated
in response to the dopamine deficit found in Parkinson disease.13, 14
The hypothesis that D1 binding is also elevated in response to
the less extensive dopamine deficit seen in AD + LB has not been examined.
Although older studies reporting elevated D2/D3/D4 receptor binding to be associated with schizophrenic psychosis were
confounded by long-term neuroleptic exposure, recent evidence suggests the
D3 receptor may play a role in psychotic symptoms. There is a significant
association of schizophrenia with homozygosity for a biallelic BalI/MscI polymorphism in the D3
gene, although the magnitude of this association is modest.15
Similarly, we found homozygosity for this polymorphism to be associated with
a modest increased rate of psychosis in subjects with AD.16
Increased striatal D3 binding has been reported in subjects with
schizophrenia who are not taking neuroleptics in comparison with NC subjects,
with the largest differences in rostral-ventral striatum.12
Neuroleptic treatment was associated with normalization of D3 binding.12 In contrast to schizophrenia, the association of
D3 receptor binding with psychosis in AD has not been examined.
We undertook, therefore, saturation binding studies of D1,
D2, and D3 receptors in neuroleptic-free NC, AD, and
AD + LB subjects characterized with regard to their history of psychotic symptoms.
We hypothesized that AD + LB would be associated with reduced density of both
D2 and D3 receptors, with a corresponding increased
D1 density. We further hypothesized that increased D3
density would be associated with a history of psychotic symptoms in both AD
and AD + LB subjects.
SUBJECTS AND METHODS
MATERIALS
The radioligands iodine
[125I](R)-trans-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)amino]
tetralin ([125I]trans-7-OH-PIPAT) and [3H]-SCH23390 were obtained
from NEN Life Science Products, Boston, Mass. Ketanserin, (+)-butaclamol hydrochloride
and PD-128907 were obtained from Research Biochemicals International, Natick,
Mass. Ultima Gold scintillation fluid was obtained from Packard Instrument
Co, Meriden, Conn. Anti-ßA4 peptide was provided by the Consortium to
Establish a Registry for Alzheimer's Disease (CERAD) and purchased from Dr
Henryk Wisniewski, New York State Institute for Basic Research, Staten Island.
Antibodies to  -synuclein were provided by Dr Virginia M.-Y. Lee, University
of Pennsylvania, Philadelphia.
CLINICAL CHARACTERIZATION OF SUBJECTS
Subjects were identified through the brain bank of the Alzheimer's Disease
Research Center at the University of Pittsburgh. All studies were approved
by the institutional review board of the University of Pittsburgh. Of the
27 AD and AD + LB subjects, 25 underwent complete neurologic, neuropsychologic,
and psychiatric diagnostic evaluations at initial and annual evaluations as
part of their participation in the Alzheimer's Disease Research Center. Details
of these assessment protocols have been reported elsewhere.5, 16, 17
In addition, all available records were reviewed for evidence of delusions
and hallucinations by 1 of 2 raters (R.A.S., M.T.H.). Interrater reliability
for the classification of psychosis was established in 20 subjects and was
high ( = 0.70). Delusions and hallucinations were defined as previously
described.16, 17 No patient had
a history of schizophrenia, schizoaffective disorder, or other idiopathic
psychosis. Extrapyramidal symptoms were defined by the presence of bradykinesia,
cogwheel rigidity, or resting tremor. Extrapyramidal symptom ratings were
unavailable for 3 AD + LB subjects. Current medications were recorded at all
Alzheimer's Disease Research Center visits. In addition, psychotropic medications
used in the past (initial visit) or since the last evaluation (annual visits)
were recorded. Medications used at the time of death and during the 3 months
prior to death were reviewed, and the interval since last neuroleptic use
was recorded.
Demographic and clinical information for the 8 NC, 13 AD, and 14 AD
+ LB subjects are presented in Table 1.
All subjects were either neuroleptic naive (n = 30) or neuroleptic free for
at least 1 month (n = 5). Lifetime duration of neuroleptic treatment did not
differ between groups (exact multinomial, P = .80).
Normal control subjects were significantly younger (mean [SD], 66 [14] years,
F2 = 5.5, P<.01), with nearly significantly
longer mean [SD] postmortem intervals (6 [3] days, F2 = 3.1, P = .06), and more often men (100%, exact multinomial P<.001) compared with AD subjects. There were no significant
differences in these variables between the AD and AD + LB groups or in Braak
score,18 a measure of neurofibrillary pathology
(F1 = .03, P = .90).
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Table 1. Demographic, Clinical, and Dopamine Receptor Binding Characteristics
of Elderly Subjects
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BRAIN TISSUE PROCESSING AND NEUROPATHOLOGIC DIAGNOSES
At the time of brain removal, postmortem interval was recorded and the
brain was divided in the midsagittal plane. The right hemibrain was coronally
sectioned at 1.0-cm intervals. The majority of the right nucleus accumbens
in each case was dissected and divided into 3 frozen samples, 1 of which was
used for this study. The head of the right caudate was sampled from the same
section. All samples were stored at -80°C until assayed. The left
hemibrain was fixed in 10% formalin, then sectioned coronally. The tissue
sections examined, and the histologic and immunocytochemical methods used,
followed CERAD protocols and have been described in detail elsewhere.17 Neuritic plaques, diffuse plaques, and neurofibrillary
tangles were semiquantitatively scored and diagnoses established using CERAD
criteria.19 A diagnosis of AD + LB further
required multiple -synuclein–positive LB in limbic and/or neocortical
areas. Conversely, a diagnosis of AD indicated that no -synuclein–positive
LB were present in any area, including the substantia nigra.
SATURATION BINDING ASSAYS
For all assays, unwashed tissue was used to preserve the original tissue
density of dopamine receptors.20 Caudate and
nucleus accumbens samples were ground into powder over liquid nitrogen. At
onset of the study, samples were weighed, thawed, then homogenized and suspended
in buffer the morning of each assay day. Later the homogenization step was
performed immediately prior to addition to the assay tubes. This methodologic
change was treated as a covariate in all statistical analyses. Total and nonspecific
binding at each concentration of ligand were determined in triplicate.
D1 assays were conducted as described by Hall et al21 with minor modifications. Total volume was 500 µL,
with a final concentration of caudate tissue of 2.0 mg wet weight per milliliter.
Incubation buffer was 50-mmol/L tris-hydrochloride (pH 7.4), 120-mmol/L sodium
chloride, 1-mmol/L magnesium chloride, 2-mmol/L calcium chloride, 5-mmol/L
potassium chloride, and 0.1% ascorbic acid. Ketanserin, 200 nmol/L, was added
to block binding to serotonin2A receptors. The ligand was [3H]-SCH23390, 0.25 to 8.0 nmol/L. Nonspecific binding was defined by
1-µmol/L (+)-butaclamol. D2 assays were conducted in a total
volume of 500 µL, with a final concentration of caudate tissue of 2
mg wet weight per milliliter. Incubation buffer was 50-mmol/L tris-hydrochloride
(pH 7.4), 1-mmol/L EDTA, 120-mmol/L sodium chloride, 2-mmol/L magnesium chloride,
1.5-mmol/L calcium chloride, and 300-µmol/L guanosine triphosphate.
The ligand was [3H]raclopride, 0.07 to 40.0 nmol/L. To block D3 binding, 50 µL of 5.0-µmol/L PD128907 (final concentration,
0.50 µmol/L) was added to each tube. Nonspecific binding was defined
by 1-µmol/L domperidone. Both D1 and D2 assays
were incubated at room temperature for 60 minutes and terminated by placing
tubes in an ice water bath. Samples were harvested onto filter strips (Whatman
GF/B; Whatman Inc, Newton, Mass), which had been soaked in 0.5% poly(ethylenimine)
solution, then washed with 12-mL ice cold 50-mmol/L tris-hydrochloride solution
(pH 7.4). Filters were placed into scintillation vials with 4.0-mL scintillation
fluid and counted for 5 minutes in a scintillation counter (Beckman LS-5801;
Beckman, Fullerton, Calif).
D3 assays were conducted adapting the methods Gurevich et
al12 and Pugsley et al22
for selective labeling of D3 receptors, and used tissue from nucleus
accumbens. Total volume was 100 µL, with a final tissue concentration
of 10 mg wet weight per milliliter. Incubation buffer was 50-mmol/L tris-hydrochloride
(pH 7.4), 0.50-mmol/L EDTA, 120-mmol/L sodium chloride, 1.0-mmol/L magnesium
chloride, 1.5-mmol/L calcium chloride, and 300-µmol/L guanosine triphosphate.
The ligand was [125I]trans-7-OH-PIPAT, 0.125 to 8.0 nmol/L. Nonspecific
binding was defined by 0.50-µmol/L PD128907. Under these conditions,
binding to receptors other than D3 (eg, D2, serotonin1A, or sigma sites) is eliminated.22, 23
Assays were incubated at room temperature for 90 minutes, then terminated
and harvested as described above. Filters were counted for 1 minute in a gamma
counter (Titertek).
STATISTICAL ANALYSIS
Bmax and Kd were determined
by nonlinear regression analysis of specific binding using GraphPad Prism
software.24 All binding studies were best fit
by a 1-site model, which was confirmed by both statistical comparison of fits
and by visual inspection of Scatchard transformations. Statistical analyses
used Statistical Product and Service Solutions for Windows 9.0.0 (SPSS Inc,
Chicago, Ill). Kd was transformed to pKd (-logKd) for all analyses. Bmax and pKd for each receptor were the dependent variables. The association of
Bmax and pKd with diagnostic
group was tested by analysis of covariance, with age, postmortem interval,
and sex entered as covariates. A covariate indicating the tissue homogenization
method (see above) was entered in all analyses. Tests of the associations
of Bmax and pKd with psychosis
and EPS used 2-way analysis of covariance with diagnosis and psychosis (or
EPS) presence-absence entered as cofactors. Age, postmortem interval, and
sex were not included in tests restricted to AD and AD + LB subjects, as these
groups were matched on these variables.
RESULTS
The association of receptor densities and affinities with neuropathologic
group is presented in Figure 1.
There was a significant difference among groups in D1 density (F2 = 3.5, P = .04) and D1 affinity
(F2 = 3.5, P = .04). Mean (SEM) covariate-adjusted
D1 densities were 34% higher in AD + LB vs AD subjects, 21.7 (1.5)
vs 16.2 (1.6), respectively (P = .01). When D1 affinity was included as a covariate, the association of D1
density with diagnostic group was reduced but continued to demonstrate a significant
trend (F2 = 3.2, P = .06). D2
density also demonstrated a trend toward a significant difference among groups
(F2 = 3.2, P = .06). Mean covariate-adjusted
D2 densities were 30% lower in AD + LB than AD subjects, 11.9 (2.0)
and 18.8 (2.0), respectively (P = .02). D2
affinity differed significantly among groups (F2 = 4.1, P = .03), with significantly higher affinity in AD and AD + LB vs NC
subjects (P = .03 and P
= .009, respectively). After entering D2 affinity as a covariate,
the association of D2 density with diagnostic group was significant
(F2 = 4.2, P = .03). D3 density
did not differ among groups (F2 = 2.2, P
= .10). However, D3 affinity was significantly different among
groups (F2 = 4.3, P = .03). Post hoc comparisons
revealed a significant difference between the AD + LB and NC groups (P = .02). After inclusion of D3 affinity as
a covariate, there remained no significant association of D3 density
with diagnostic group (F2 = 2.0, P = .20).
There were no significant associations of density or affinity of any
of the receptors with EPS in AD subjects. Similarly, neither D1
density and affinity nor D2 density and affinity were associated
with psychosis in the AD subjects. In contrast, D3 density was
significantly elevated among subjects with psychosis (F1 = 5.8, P = .03, Figure 2).
Controlling for the presence of psychosis, there was also a significant reduction
of D3 density in the AD + LB compared with AD subjects (F1 = 6.9, P = .02). In contrast, D3
affinity was not associated with psychosis (F1 = 1.2, P = .30), although a significant increase in D3 affinity
was present in AD + LB compared with AD subjects (F1 = 11.0, P = .006). There was also a significant interaction of
psychosis and diagnosis (F1 = 10.5, P
= .007). The associations of D3 density with psychosis and diagnostic
group were unaltered when D3 affinity was entered as a covariate
(F1 = 5.7, P = .03 and F1 =
5.0, P = .04, respectively). Mean [SD] covariate-adjusted
D3 densities were increased by 72% in subjects with psychosis (6.9
[1.0]) compared with those without psychosis (4.0 [0.7]). In contrast, mean
covariate-adjusted D3 densities were decreased by 52% in AD + LB
subjects vs AD subjects, 3.5 (1.0) and 7.3 (1.1), respectively.
We identified 5 subjects who had been excluded from the above analyses
due to recent neuroleptic use. The clinical characteristics of these patients
are presented in Table 2. All
neuroleptic-treated subjects were diagnosed as having AD + LB. They did not
differ significantly in age, sex, race, Braak score, or history of psychosis
from the 9 AD + LB subjects not taking neuroleptics in whom D3
assays were conducted (Table 1).
D3 density and affinity for the AD + LB subjects treated with and
without neuroleptics are presented in Figure
3. There was no effect of neuroleptic treatment on D3
density (F1 = 2.0, P = 0.2). However,
D3 affinity was significantly reduced in the neuroleptic-treated
subjects (F1 = 5.8, P = .03). In 1 subject
treated with neuroleptics, neuroleptic use was 16 days prior to death. Exclusion
of this subject had almost no effect on mean [SD] D3 affinity in
the neuroleptic-treated group (pKd = 8.63
[0.3]), and the difference between groups in D3 affinity continued
to show a trend toward significance (P = .08).
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Table 2. D3 Receptor Binding Characteristics in Alzheimer
Disease Subjects With Cortical Lewy Bodies Who Were Receiving Neuroleptic
Treatment at the Time of Death*
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Figure 3. The effect of neuroleptic use
at the time of death on D3 density (A) and affinity (B). There
was no significant effect of neuroleptic treatment at time of death on D3 density. In contrast, neuroleptic treatment resulted in a significant
decrease in D3 affinity. Asterisk indicates P 
.05 for subjects taking neuroleptics vs those not taking neuroleptics.
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COMMENT
Consistent with our hypotheses, the presence of LB in AD subjects was
associated with increased density of caudate D1 receptors, reduced
density of nucleus accumbens D3 receptors, and a trend toward reduced
density of caudate D2 receptors. Alzheimer disease with LB was
also associated with an increased affinity of all 3 dopamine receptors, although
the changes in receptor density were unaffected by the observed changes in
affinity. In contrast to the association of altered receptor binding with
AD + LB, D3 receptor density was elevated in subjects with a history
of psychosis, independent of the presence or absence of Lewy bodies.
The observed alterations in D1 and D3 density
may result, in part, from a postsynaptic response to sustained striatal dopamine
deficits, which have been observed in AD + LB.8, 9, 10, 25, 26
Although we did not measure striatal dopamine concentration directly, the
observed increase in receptor affinities in AD + LB is consistent with reduced
dopamine concentration in caudate and nucleus accumbens of these subjects.27 In the prototype dopamine deficiency disorder, Parkinson
disease, caudate D1 density is typically up-regulated in untreated
subjects by 40% to 50%.14 The effect of dopamine
deficiency on the D3 receptor is not well established, although
recent evidence indicates that D3 binding is down-regulated by
about 40% to 50% in caudate and nucleus accumbens of patients with Parkinson
disease.28
In contrast to D1 and D3, the trend toward reduction
in D2 density is not consistent with a postsynaptic response to
dopamine depletion. In Parkinson disease, caudate D2 density is
typically up-regulated in untreated subjects by 15% to 80%.14, 27
The extent of dopamine deficiency in AD + LB is not as severe as is seen in
Parkinson disease.9 Thus, it is possible that
D2 receptors are not up-regulated in response to moderate concentration
decreases, possibly due to lower affinity for dopamine than D1
and D3.29 Absent up-regulation,
however, does not explain the observed reduction in D2 density.
We have described numerous -synuclein–positive neurites in striatum
of AD + LB.30 Whether this pathologic process
preferentially affects D2 pathways is not known.
We also found that having accounted for the effect of LB presence on
D3 receptor binding, there was a significant increase in D3 density in subjects with a history of psychosis. The increase in D3 density in psychosis was present in both AD and AD + LB subjects and
unaffected by D3 affinity. Overall, subjects with psychosis had
a 72% elevation of mean D3 density compared with subjects without
psychosis. The magnitude of this elevation is consistent with the report of
a 55% to 110% increase in D3 binding, measured by autoradiography,
in ventral striatum of subjects with schizophrenic psychosis who were not
taking neuroleptics.12 Guided by our studies
of the association of psychosis with genetic variation in the D3
receptor, we had hypothesized that D3 plays a permissive role in
the onset of psychotic symptoms in subjects with an underlying neurodevelopmental
or neurodegenerative condition.16, 31
The findings of the present study, taken together with those of Gurevich et
al,12 provide support for this hypothesis in
3 disorders: schizophrenia, AD, and AD + LB. The magnitude of the association
of psychosis with striatal D3 density is substantially greater
than that of the association of psychosis with homozygosity for the BalI polymorphism in the D3 gene.
This suggests that the contribution of the BalI polymorphism
to the determination of D3 density in brain is modest.
Consistent with this interpretation, we did not find a significant association
between D3 density and genotype in these subjects (data not shown).
Whether elevated D3 density in psychosis is a primary deficit
or reflects a pathologic response to other disease-related processes cannot
be determined. However, the elevations in D3 density do not appear
to be an artifact of neuroleptic treatment. In contrast to findings for the
D2 receptor in striatum, striatal D3 receptor binding
is not up-regulated by antipsychotic treatment in animals.32
Similarly, we found no effect of recent neuroleptic treatment on D3
density in our subjects. Finally, there was no corresponding up-regulation
of D2 receptors in our psychotic subjects, indicating the specificity
of our observation.
In contrast to the absence of neuroleptic effects on D3 density,
we found that D3 affinity was reduced by neuroleptic treatment.
This latter finding may explain an apparent discrepancy between the present
study and that by Gurevich et al.12 Using receptor
autoradiography, they found that neuroleptic treatment at the time of death
led to "down-regulation" of D3 binding. Because autoradiographic
binding is dependent on both receptor density and affinity, the reduced D3 binding interpreted by Gurevich et al could have resulted from an
affinity reduction. The mean D3 Kd in our subjects taking neuroleptics was 2.4 times higher than in subjects
not taking neuroleptics (3.1 nmol/L and 1.3 nmol/L, respectively). This difference
would yield an approximate 100% difference in D3 binding at the
0.30-nmol/L ligand concentration used by Gurevich et al, a value close to
the difference they observed in ventral striatum. Thus, the most parsimonious
explanation of the effect of neuroleptic treatment on D3 receptors
in both AD and schizophrenia is that it acts to increase D3 receptor
apparent affinity. Whether this occurs through simple competitive inhibition
or through an alternate mechanism (eg, posttranslational modification) remains
unknown.
An important limitation of the present study is that most AD and AD
+ LB subjects had advanced dementia at the time of autopsy. We cannot conclude
that the observed dopamine receptor changes are present in earlier stages
of illness when the clinical profiles of AD and AD + LB diverge. Another limitation
of our study is the inexact matching of the NC subjects, which may have reduced
the magnitude of detectable difference between groups because of the need
to enter covariates into the analyses. We did not find an association of decreased
D2 density with EPS in our subjects. This may have resulted from
limited power due to the small number of subjects with EPS, rather than a
lack of true association.10, 13
Strengths of the present study include the ante mortem behavioral characterization
of the subjects, examination of multiple receptor populations in the same
subjects, and the use of saturation binding methods that provide separate
information about affinity and density.
In conclusion, this study provides evidence for a distinct pattern of
expression of striatal D1, D2, and D3 receptors
in AD + LB. Future studies would benefit from inclusion of a Parkinson disease
comparison group. Further studies examining the D3 receptor as
a target of neuroleptic action are indicated.
AUTHOR INFORMATION
Accepted for publication June 12, 2000.
This work was supported in part by grants MH01153 and AG15133 from the
National Institutes of Health and grant M1998-003 from the John F. and Nancy
A. Emmerling fund of The Pittsburgh Foundation.
From the Division of Geriatrics and Neuropsychiatry (Drs Sweet, Pollock,
and DeKosky, Mr Healy, and Ms Henteleff), Department of Psychiatry (Dr Lewis),
and the Division of Neuropathology, Department of Pathology (Dr Hamilton),
School of Medicine, and the Department of Epidemiology, Graduate School of
Public Health (Dr Wisniewski), University of Pittsburgh, Pittsburgh, Pa.
Corresponding author and reprints: Robert A. Sweet, MD, Western Psychiatric
Institute and Clinic, 3811 O'Hara St, Pittsburgh, PA 15213 (e-mail: Sweetra{at}msx.upmc.edu).
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