Alzheimer Disease: Pollock BG

Lotrich FE, Pollock BG, Ferrell RE. · Department of Psychiatry, Western Psychiatric Institute and Clinics, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA. · Am J Pharmacogenomics. · Pubmed #12083964 No free full text.

Abstract: Selective serotonin reuptake inhibitors (SSRIs) are used to treat a number of psychiatric disorders related to mood and anxiety, and variations in the serotonin transporter (5-HTT) gene may be involved in a number of these. A polymorphic site in the promoter region is associated with differences in 5-HTT gene expression. Studies suggest that the short allele of the 5-HTT promoter (5-HTTPR) site can adversely influence the antidepressant response to SSRIs, and is associated with anxiety-related traits, depression, and impulsive disorders such as alcohol abuse. Several studies do not replicate these findings; potential confounding factors include age, gender, and population stratification. Other 5-HTT polymorphisms also exist. For example, individuals with the short allele of a variable number of tandem repeats (VNTR) polymorphism, located in the second intron, may have reduced responsiveness to SSRIs, and the STin2.12 allele at this site has been associated with bipolar disorder. Findings both supporting and inconsistent with these conclusions are reviewed. The clinical effects of the polymorphisms may be associated with effects on platelets, neural 5-HTT levels, and indices of serotonergic function.

Bigos KL, Pollock BG, Coley KC, Miller del D, Marder SR, Aravagiri M, Kirshner MA, Schneider LS, Bies RR. · Department of Pharmaceutical Sciences, University of Pittsburgh, School of Pharmacy, 805 Salk Hall, 3501 Terrace St, Pittsburgh, PA 15261, USA. · J Clin Pharmacol. · Pubmed #18199892 No free full text.

Abstract: Response to antipsychotics is highly variable, which may be due in part to differences in drug exposure. The goal of this study was to evaluate the magnitude and variability of concentration exposure of olanzapine. Patients with Alzheimer's disease (n = 117) and schizophrenia (n = 406) were treated with olanzapine as part of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Combined, these patients (n = 523) provided 1527 plasma samples for determination of olanzapine concentrations. Nonlinear mixed-effects modeling was used to determine the population pharmacokinetics of olanzapine, and patient-specific covariates were evaluated as potential contributors to variability in drug exposure. The population mean olanzapine clearance and volume of distribution were 16.1 L/h and 2150 L, respectively. Elimination of olanzapine varied nearly 10-fold (range, 6.66-67.96 L/h). Smoking status, sex, and race accounted for 26%, 12%, and 7% of the variability, respectively (P < .0001). Smokers cleared olanzapine 55% faster than non/past smokers (P < .0001). Men cleared olanzapine 38% faster than women (P < .0001). Patients who identified themselves as black or African American cleared olanzapine 26% faster than other races (P < .0001). Differences in olanzapine exposure due to sex, race, and smoking may account for some of the variability in response to olanzapine.

Mulsant BH, Pollock BG, Nebes R, Miller MD, Sweet RA, Stack J, Houck PR, Bensasi S, Mazumdar S, Reynolds CF. · Intervention Research Center for the Study of Late-Life Mood Disorders, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. · Am J Geriatr Psychiatry. · Pubmed #11739067 No free full text.

Abstract: Selective serotonin reuptake inhibitors may be less efficacious than tricyclic antidepressants in the treatment of severe depression in older patients. The authors compared the 12-week clinical outcome of older depressed patients treated with nortriptyline or paroxetine in a double-blind randomized comparison in 116 psychiatric inpatients and outpatients (mean age: 72+/-8 years) who presented with a major depressive episode or melancholic depression. Discontinuation and response rates were compared in patients who began or who completed treatment. The discontinuation rate due to side effects was significantly higher with nortriptyline than with paroxetine (33% vs. 16%). There were no significant differences between the rates of response in the Intent-to-Treat analysis (nortriptyline: 57% vs. paroxetine: 55% ), or the Completer analysis (nortriptyline: 78% vs. paroxetine: 84%). Although paroxetine appears to be better tolerated than nortriptyline, the efficacy of these two drugs does not appear to differ in the acute treatment of older depressed patients, including hospitalized patients and those with melancholic features.

Schneider LS, Tariot PN, Lyketsos CG, Dagerman KS, Davis KL, Davis S, Hsiao JK, Jeste DV, Katz IR, Olin JT, Pollock BG, Rabins PV, Rosenheck RA, Small GW, Lebowitz B, Lieberman JA. · Clinical Antipsychotic Trials of Intervention Effectiveness Program of the National Institute of Mental Health at the University of North Carolina, Chapel Hill, NC, USA. · Am J Geriatr Psychiatry. · Pubmed #11739062 No free full text.

Abstract: The authors describe the development of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) protocol for Alzheimer disease (AD), a trial developed in collaboration with the National Institute of Mental Health (NIMH), assessing the effectiveness of atypical antipsychotics for psychosis and agitation occurring in AD outpatients. They provide an overview of the methodology utilized in the trial as well as the clinical-outcomes and effectiveness measures that were implemented.

Chow TW, Pollock BG, Milgram NW. · The Rotman Research Institute of Baycrest Centre for Geriatric Care, Toronto, ON, Canada. · Neuropsychiatr Dis Treat. · Pubmed #19300592 links to  free full text

Abstract: OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) have increased cognitive performance in some clinical studies of Alzheimer's disease (AD), but it is has been difficult to dissociate whether this is due to direct effects on cognition (neurochemical or disease-modifying) or a secondary effect of mood stabilization. We performed a systematic review for preclinical and human clinical trial evidence to support the use of SSRIs specifically for the management of cognitive decline in AD. DATA SOURCES: (1) PUBMED without language restrictions from 1950s until 2004 and updated August 2006, terms: "serotonin uptake inhibitors"[MeSH] AND ("Alzheimer disease"[MeSH] OR "Cognition Disorders"[MeSH]) NOT "Parkinson disease"[MeSH] AND (Clinical Trial[ptyp] OR Letter[ptyp] OR Meta-Analysis[ptyp] OR Randomized Controlled Trial[ptyp]) AND "alzheimer disease" [MESH] OR "Alzheimer*" combined with AND to "ssri*" OR "serotonin reuptake inhibitors" [MESH] NOT Review[ptyp]. (2) Cochrane Database of Systematic Reviews, keywords "SSRI" and "Alzheimer's". STUDY SELECTION: The PubMed search yielded 57 hits. Of these, 23 were included in this review for their specificity to SSRI use in AD or indications on efficacy beyond depressive symptoms. The other 34 citations were excluded because: (1) depression or other mood or behavioral disturbance severity was the reported outcome measure, (2) effects of SSRIs on cognition were confounded by concomitant use of other drugs, (3) subjects described were young adults, and/or (4) subjects had traumatic brain injury. The Cochrane Database of Systematic Reviews, 3rd Quarter 2006, yielded six citations related to SSRIs. DATA EXTRACTION: Data extracted from clinical trials included name of SSRI tested, cognitive outcome measures, and adverse events reported, which could include cognitive worsening. DATA SYNTHESIS: Preclinical evidence for use of SSRIs to enhance cognition in AD includes an effect at the hippocampus through carbonic anhydrase activation or stimulation of hippocampal neurogenesis. The chemical structure of paroxetine, and not intrinsic SSRI activity, may also affect APP ectodomain expression to reduce amyloid plaque formation. Clinical trials in AD generally have not assessed cognitive outcomes independently from mood or behavior stabilization. Currently, clinical studies in AD only indirectly support the use of SSRIs for disease modification by confirming a serotonergic deficit during the course of illness. CONCLUSIONS: Lack of supportive evidence for SSRIs as cognition enhancers or disease modifiers in AD is the result of omissions in clinical trial design, as opposed to reporting of negative outcomes. The preclinical evidence warrants the study of SSRIs in AD using mood, behavior, cognition, neurochemistry, and possibly neuroimaging as outcome variables.

Feng Y, Pollock BG, Coley K, Marder S, Miller D, Kirshner M, Aravagiri M, Schneider L, Bies RR. · Strategic Modeling and Simulation Group, Bristol-Myers Squibb Co., Princeton, NJ, USA. · Br J Clin Pharmacol. · Pubmed #18771484 No free full text.

Abstract: AIMS: To characterize pharmacokinetic (PK) variability of risperidone and 9-OH risperidone using sparse sampling and to evaluate the effect of covariates on PK parameters. METHODS: PK analysis used plasma samples collected from the Clinical Antipsychotic Trials of Intervention Effectiveness. A nonlinear mixed-effects model was developed using NONMEM to describe simultaneously the risperidone and 9-OH risperidone concentration-time profile. Covariate effects on risperidone and 9-OH risperidone PK parameters were assessed, including age, weight, sex, smoking status, race and concomitant medications. RESULTS: PK samples comprised 1236 risperidone and 1236 9-OH risperidone concentrations from 490 subjects that were available for analysis. Ages ranged from 18 to 93 years. Population PK submodels for both risperidone and 9-OH risperidone with first-order absorption were selected to describe the concentration-time profile of risperidone and 9-OH risperidone. A mixture model was incorporated with risperidone clearance (CL) separately estimated for three subpopulations [poor metabolizer (PM), extensive metabolizer (EM) and intermediate metabolizer (IM)]. Age significantly affected 9-OH risperidone clearance. Population parameter estimates for CL in PM, IM and EM were 12.9, 36 and 65.4 l h(-1) and parameter estimates for risperidone half-life in PM, IM and EM were 25, 8.5 and 4.7 h, respectively. CONCLUSIONS: A one-compartment mixture model with first-order absorption adequately described the risperidone and 9-OH risperidone concentrations. Age was identified as a significant covariate on 9-OH risperidone clearance in this study.

Saxton J, Kastango KB, Hugonot-Diener L, Boller F, Verny M, Sarles CE, Girgis RR, Devouche E, Mecocci P, Pollock BG, DeKosky ST. · Univ. of Pittsburgh, Pittsburgh, PA, USA. · Am J Geriatr Psychiatry. · Pubmed #16286444 No free full text.

Abstract: OBJECTIVE: The authors sought to develop a short form of the Severe Impairment Battery (SIB). METHODS: Authors describe the development of an empirically-derived short form of the SIB (SIB-S) by use of data from 191 subjects with severe dementia in the United States and France. RESULTS: Mean (standard deviation) Mini-Mental State Exam scores for the American and French samples were 7.7 (4.8) and 5.7 (3.4), respectively, and original SIB scores were 71.87 (18.34) and 58.38 (26.86), respectively. Exploratory factor analyses were conducted separately and in combination for the two samples, to determine the number of clinically meaningful factors. An eight-factor model, explaining 60.2% of the common variance, was selected. The eight constructs were described as: expressive language, memory (verbal and nonverbal), social interaction, color-naming, praxis, reading and writing, fluency, and attention. Derived SIB-S scores were 38.41 (9.12) and 29.79 (13.17) for the American and French samples, respectively. CONCLUSIONS: The original SIB is a valid and reliable research tool developed to enable reliable assessment of patients with severe dementia; it takes approximately 30 minutes to administer. The SIB-S takes only 10-15 minutes to administer, making it more appropriate for use in patients with very severe dementia, while it maintains the attributes of the original SIB.

Sweet RA, Devlin B, Pollock BG, Sukonick DL, Kastango KB, Bacanu SA, Chowdari KV, DeKosky ST, Ferrell RE. · Division of Geriatrics and Neuropsychiatry, Department of Psychiatry, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA. · Mol Psychiatry. · Pubmed #16027741 No free full text.

Abstract: Psychotic symptoms in subjects with Alzheimer disease (AD with psychosis, AD+P) define a phenotype characterized by greater cognitive burden than in AD without psychosis. We have proposed that genes of small effect may contribute to the risk for expression of psychosis in multiple disorders, including AD. Recently, sex-differential association of a three-locus haplotype, including a G-->A transition at codon 108/158 of catechol-O-methyltransferase (COMT) resulting in a Val-->Met substitution, has been reported to confer an increased risk for schizophrenia. The main objective of the study was to determine if COMT genetic variation is associated with risk of psychosis in AD, and included a case-control study of 373 individuals diagnosed with AD with, or without, psychosis. All subjects were characterized for alleles at the three loci associated with schizophrenia, RS737865, COMT G-->A 108/158 (RS4680), and RS165599, and for a C/T transition adjacent to an estrogen response element (ERE6) in the COMT P2 promoter region. Both single locus and haplotype tests of association were conducted. Logit models were used to examine independent and interacting effects of alleles at the associated loci. All analyses were stratified by sex. In female subjects, RS4680 demonstrated a modest association with AD+P; RS737865 demonstrated a trend towards an association. There was a highly significant association of AD+P with the four-locus haplotype, which resulted from additive effects of alleles at RS4680 and ERE6 (or RS737865, as this locus was in almost absolute linkage disequilibrium (LD) with ERE6). In male subjects, no single locus test was significant, but there remained a strong association between AD+P and the four-locus haplotype. This association appeared to result from interaction of the ERE6/RS737865, RS4680, and RS165599 loci. Genetic variation in COMT is associated with AD+P, and thus appears to contribute to psychosis risk across disorders. Sex-differential associations of COMT with psychosis may result from variation at, or in LD with, ERE6. Examination of variation at ERE6 in subjects with schizophrenia, and further examination of the independent and additive effects of variations in COMT on gene expression, is warranted.

Sweet RA, Hamilton RL, Butters MA, Mulsant BH, Pollock BG, Lewis DA, Lopez OL, DeKosky ST, Reynolds CF. · Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. · Neuropsychopharmacology. · Pubmed #15354182 links to  free full text

Abstract: Late life major depression (LLMD) is frequently associated with cognitive impairment, and increases the risk for subsequent dementia. Cerebrovascular disease, Alzheimer's disease (AD), and dementia with Lewy bodies (DLB) have all been hypothesized to contribute to this increased risk, though prospective studies have yet to examine these hypotheses with autopsy confirmation of the clinical diagnoses. The aim of this study is to examine the rates of cerebrovascular, AD, and DLB pathology among the first 10 participants in an LLMD brain tissue donation program. Subjects' psychiatric diagnoses and cognitive status were prospectively determined during their participation in clinical research protocols of the Intervention Research Center for Late Life Mood Disorders. After death, final clinical diagnoses were made using all clinical information, while blind to neuropathologic diagnoses. Neuropathologic assessments were conducted blind to final clinical diagnoses. Rates of neuropathology were compared with those in a cohort of subjects with dementia, without a history of LLMD, participating in an Alzheimer Disease Research Center. Seven (70%) subjects had evidence of onset of a dementia prior to death. LLMD with dementia was significantly associated with a neuropathologic diagnosis of AD. Cerebrovascular disease and DLB pathology were also frequent in the LLMD subjects with dementia, and were found in an LLMD subject without dementia. Rates of AD, DLB, and cerebrovascular disease were similar to those in the comparison subjects. These preliminary findings suggest that AD is the predominant neuropathologic condition in LLMD subjects with dementia. Further assessment of the role of comorbid cerebrovascular disease and comorbid DLB is needed.

Butters MA, Sweet RA, Mulsant BH, Ilyas Kamboh M, Pollock BG, Begley AE, Reynolds CF, DeKosky ST. · Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. · Int J Geriatr Psychiatry. · Pubmed #14677138 No free full text.

Abstract: OBJECTIVE: There is a recognized but poorly understood relationship between late-life depression (LLD) and progressive dementia. Both cognitive impairment co-occurring with LLD and a late age-of-onset of first lifetime depressive episode appear to be associated with subsequent progressive dementia. A history of major depression, especially when the first onset occurs in late-life, has been identified as a risk factor for Alzheimer's disease (AD). The major genetic risk factor for sporadic AD is carrying one or more apolipoprotein E4 (APOE4) alleles. We hypothesized that the association between LLD and dementia risk would be mediated by APOE4, specifically that APOE4 allele frequency would be associated with cognitive impairment and later age-of-depression-onset. We also predicted that APOE4 allele frequency would be increased among subjects with LLD. METHODS: We compared the distribution of APOE2, APOE3, and APOE4 alleles in groups of LLD (n=160), AD (n=568) and elderly control (EC; n=156) subjects. RESULTS: The allele distribution of the cognitively impaired LLD subgroup was not different from either the cognitively normal subgroup or the EC group but was different from the AD group. However, mean age-of-onset of depression in APOE4 carriers (51.4+/-20.7) was significantly lower than non-carriers (58.8+/-16.8). The allele distribution in LLD overall was significantly different from the AD but not the EC group. CONCLUSIONS: The finding that neither LLD, accompanying cognitive impairment, nor late age-of-onset was associated with an increased APOE4 allele frequency suggests that LLD acts as a risk factor for developing AD as well as non-AD dementia through mechanisms independent of APOE4. The unexpected finding that age-of-onset of LLD was significantly reduced in APOE4 carriers is similar to the association between APOE4 and age-of-onset in AD. Replication of the association of APOE4 with earlier age-of-depression-onset is indicated.

Kastango KB, Kim Y, Dew MA, Mazumdar S, Mulsant BH, Rosen J, Reynolds III CF, Pilkonis PA, Pollock BG. · Department of Biostatistics, University of Pittsburgh, PA 15213, USA. · Am J Geriatr Psychiatry. · Pubmed #12427579 No free full text.

Abstract: OBJECTIVE: Use of cognitive, psychiatric and behavioral domains to assess the effectiveness of a pharmacological or behavioral intervention in the treatment of neurodegenerative disorders (e.g., Alzheimer disease) aids the identification of specific types of impairment or distress in behavioral status and quality-of-life issues in this population. With confirmatory approaches to subscale development readily available, we can obtain a more precise understanding of the sub-components of a scale, potentially providing the basis for selecting behavioral and/or quality-of-life outcome measures that may be more sensitive to the effects of pharmacological or behavioral interventions. METHODS: The authors illustrate the use of a confirmatory factor-analytic approach to verify scale sub-domains of the Neurobehavioral Rating Scale (NBRS) in elderly patients with dementia. With data collected from two groups of patients being treated for significant psychiatric and behavioral symptoms, authors investigated the relationships among scale items in order to test several competing models, including a general one-factor model, a first-order multifactor model, and a second-order factor model. RESULTS: The first-order model, with seven factors, provided the best fit to the correlations among items in the NBRS, indicating the multidimensionality of problematic behaviors and symptoms exhibited by dementia patients. CONCLUSION: Authors advocate the use of a confirmatory factor-analytic approach to verify scale sub-domains in other, more widely used rating scales for patients with dementia.

Sweet RA, Pollock BG, Sukonick DL, Mulsant BH, Rosen J, Klunk WE, Kastango KB, DeKosky ST, Ferrell RE. · Department of Psychiatry, School of Medicine, University of Pittsburgh, Pennsylvania, USA. · Int Psychogeriatr. · Pubmed #12003247 No free full text.

Abstract: BACKGROUND: Psychotic symptoms in subjects with Alzheimer disease (AD+psychosis, AD+P) are a marker for a distinct phenotype characterized by more rapid cognitive and functional decline and a liability to aggressive behaviors. We recently found that AD subjects homozygous for long alleles (l) of an insertion/deletion polymorphism in the promoter region of the serotonin transporter (5-HTTPR) had elevated rates of aggressive behavior. OBJECTIVE: To examine whether the 5-HTTPR ll genotype confers an increased risk of AD+P, and of the combined AD+P/aggressive phenotype. METHODS: The 5-HTTPR genotype was determined in 332 subjects diagnosed with possible or probable AD. All subjects received structured psychiatric assessments and were categorized with regard to their history of aggressive behaviors and psychotic symptoms. RESULTS: Consistent with other reports, AD+P was associated with a significant increased risk for aggressive behavior. AD+P and aggression were both significantly associated with 5-HTTPR ll genotype and with an increased l allele frequency. Subjects with the combined behavioral phenotype (AD+P and aggressive behavior) had the highest rate of ll genotype and highest l allele frequency. CONCLUSION: The 5-HTTPR l allele appears to confer risk for the combined AD+P/aggressive phenotype. Confirmation of this association in a similar behaviorally well-characterized independent sample is needed.

Whyte EM, Pollock BG, Wagner WR, Mulsant BH, Ferrell RE, Mazumdar S, Reynolds CF. · Department of Psychiatry, University of Pittsburgh School of Medicine, PA, USA. · Am J Psychiatry. · Pubmed #11729031 links to  free full text

Abstract: OBJECTIVE: Depression has been associated with increased platelet activation. Variations in the serotonin-transporter-linked promoter region (5-HTTLPR) polymorphism may influence the degree of activation. The authors examined the association among depression, platelet activation, and 5-HTTLPR genotype. METHOD: Elderly subjects with (N=61) and without (N=12) major depression were assessed for cognitive impairment, cardiovascular disease, and two indices of platelet activation. The depressed subjects were genotyped for the 5-HTTLPR polymorphism. RESULTS: The depressed subjects were older, were more cognitively impaired, and had higher platelet factor 4 and beta-thromboglobulin levels; cardiovascular disease was minimal in both groups. In the depressed group, subjects with the 5-HTTLPR l/l genotype had significantly higher platelet factor 4 and beta-thromboglobulin levels. CONCLUSIONS: Platelet activation is increased in elderly depressed patients, especially those with the 5-HTTLPR l/l genotype. This finding suggests how genetic differences may influence cardiovascular mortality in depressed patients with ischemic heart disease.

Sukonick DL, Pollock BG, Sweet RA, Mulsant BH, Rosen J, Klunk WE, Kastango KB, DeKosky ST, Ferrell RE. · Division of Geriatrics and Neuropsychiatry, Department of Psychiatry, University of Pittsburgh, PA, USA. · Arch Neurol. · Pubmed #11559314 links to  free full text

Abstract: BACKGROUND: Aggressive behavior in Alzheimer disease (AD) has been linked to dysfunction of serotonin neurotransmission. Homozygosity for the long variant (*L) of an identified biallelic polymorphism of the serotonin transporter promoter region (5-HTTPR) is associated with increased expression of the transporter protein and increased speed of response to serotonin reuptake inhibitor treatment. OBJECTIVE: To determine whether the *L/*L genotype and the *L allele are associated with an increased risk of aggressive symptoms in patients with AD. DESIGN: Case-control study. SETTING: University hospital geriatric psychiatry inpatient program and Alzheimer disease research center. SUBJECTS: Fifty-eight patients with AD with a history of aggressive behavior and 79 never-aggressive patients with AD with comparable severity of cognitive impairment. MAIN OUTCOME MEASURES: The 5-HTTPR genotype and allele frequency. RESULTS: The *L/*L genotype was significantly associated with aggression in patients with AD (odds ratio, 2.8; 95% confidence interval, 1.2-6.5). Similar results were obtained for *L allele frequency. CONCLUSION: The 5-HTTPR*L allele and *L/*L genotype may predispose patients with AD to develop aggressive behavior.

Sweet RA, Hamilton RL, Healy MT, Wisniewski SR, Henteleff R, Pollock BG, Lewis DA, DeKosky ST. · University of Pittsburgh, Division of Geriatrics and Neuropsychiatry, Western Psychiatric Institute and Clinic, 3811 O'Hara St., Pittsburgh, PA 15213, USA. · Arch Neurol. · Pubmed #11255451 links to  free full text

Abstract: 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.