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Original Contribution |

The 5-HTTPR*S/*L Polymorphism and Aggressive Behavior in Alzheimer Disease FREE

Danielle L. Sukonick, BA; Bruce G. Pollock, MD, PhD; Robert A. Sweet, MD; Benoit H. Mulsant, MD; Jules Rosen, MD; William E. Klunk, MD, PhD; Kari B. Kastango, MS; Steven T. DeKosky, MD; Robert E. Ferrell, PhD
[+] Author Affiliations

From the Division of Geriatrics and Neuropsychiatry, Department of Psychiatry (Mss Sukonick and Kastango and Drs Pollock, Sweet, Mulsant, Rosen, Klunk, and DeKosky), Department of Neurology, School of Medicine (Dr DeKosky), and Department of Human Genetics, Graduate School of Public Health (Dr Ferrell), University of Pittsburgh, Pittsburgh, Pa; and the Geriatric Research, Education, and Clinical Center, Veterans Affairs Pittsburgh Health Care System (Dr Mulsant). Dr Mulsant has received grant or research support from the National Institute of Mental Health, AstraZeneca, Inc, Janssen Pharmaceutica, Pfizer, Inc/Eisai Pharmaceuticals, and GlaxoSmithKline; is a consultant to AstraZeneca, Inc, Eli Lilly and Company, Janssen Pharmaceutica, Pfizer, Inc, and GlaxoSmithKline; is on the speaker's bureau for AstraZeneca, Inc, Janssen Pharmaceutica, Pfizer, Inc/Eisai Pharmaceuticals, Searle, and GlaxoSmithKline; owns stock in Akzo-Nobel, Biogen, Inc, Celsion Corporation, Elan Corporation, Forest Laboratories, Inc, and Immune Response Corporation; is a major stock holder in Biogen, Inc; and has received honoraria from AstraZeneca, Inc, Eli Lilly and Company, Janssen Pharmaceutica, Pfizer, Inc/Eisai Pharmaceuticals, Organon, Searle, and GlaxoSmithKline.


Arch Neurol. 2001;58(9):1425-1428. doi:10.1001/archneur.58.9.1425.
Text Size: A A A
Published online

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.

ALZHEIMER disease (AD) is frequently complicated by psychiatric symptoms including verbal and physical aggression.1 Altered function of the serotonin (5-hydroxytryptamine or 5-HT) neurotransmitter system has been implicated in impulsive aggressive behavior2,3 and in aggressive behavior in patients diagnosed as having AD.47 Postmortem and biopsy studies of brains from patients with AD show a decrease in levels of 5-HT, 5-HT receptors, and the 5-HT transporter (5-HTT).810 The concentration of 5-hydroxyindoleacetic acid, a metabolite of 5-HT, has been shown to be decreased in the cerebrospinal fluid and cerebral cortex of patients with AD.4,11 A few studies have demonstrated a specific association between aggressive behavior in AD and greatly diminished cortical levels of 5-HT.4,5 Therapeutic agents that act on the 5-HT system have been shown to be helpful in the treatment of aggression in patients diagnosed as having AD.1214 Consistent with the findings of excess 5-HT loss in aggressive subjects with AD, fenfluramine challenge studies have found a hypersensitive postsynaptic response in agitated subjects with AD compared with nonagitated control subjects with AD.6,15

In 1996, a 44–base pair (bp) insertion/deletion polymorphism (5HTTPR) was discovered in the 5′ promoter region of the 5-HTT gene (HTT, SLC6A4).16 The 5HTTPR alleles are defined by differing numbers of a 44-bp GC-rich repetitive sequence. The basal transcriptional activity of the long variant (*L) is about 2.5- to 3-fold higher than that of the short variant (*S).16,17 This differential rate of transcription results in a reduction of 5-HT reuptake sites of approximately 40% in *S/*S homozygotes and a reduction of approximately 30% for heterozygotes (*S/*L), leading some to suggest that the *S allele is functionally dominant.18

We hypothesized that the *L/*L genotype would lead to a depletion of extraneuronal 5-HT and might contribute to the risk of aggression in AD. We examined this hypothesis in 137 subjects diagnosed as having possible or probable AD, 58 of whom demonstrated aggressive behavior.

PATIENTS

All patients were examined at the Geriatric Psychiatry Inpatient Program and the Alzheimer Disease Research Center of the University of Pittsburgh Medical Center, Pittsburgh, Pa, between December 5, 1991, and October 13, 1999. Subjects underwent an extensive diagnostic and behavioral assessment, which has been described in detail elsewhere,1922 and received a diagnosis of possible or probable AD by means of the criteria of the National Institute of Neurologic and Communicative Disorders and Stroke–Alzheimer Disease and Related Disorders Association.23

Aggressive subjects, as defined by the presence of physical or verbal aggression rated with the Empirical Behavioral Pathology in Alzheimer Disease scale,24 were identified among participants in a clinical trial for treatment of behavioral disturbances in dementia conducted at the Geriatric Psychiatry Inpatient Program. Because of evidence that frequency of aggression in patients with AD may increase with severity of dementia,25 a group of never-aggressive patients with AD, with similar dementia severity as rated on the Mini-Mental State Examination(MMSE),26 was also identified from subjects participating in the Alzheimer Disease Research Center. Never aggressive was defined as the absence, on initial and annual follow-up examinations, of verbal and physical aggression as defined by the Behavior Rating Scale for Dementia of the Consortium to Establish a Registry for Alzheimer Disease.1 All data collected in this study were obtained with protocols approved by the Institutional Review Board of the University of Pittsburgh.

GENOTYPING

Lymphocytes were harvested from whole blood and DNA was extracted from lymphocytes by means of a DNA blood kit (QIAamp; Qiagen Inc, Valencia, Calif). The *S and *L alleles were determined by using DNA amplification (polymerase chain reaction) and establishing flanking primers. Amplification products were resolved by electrophoresis and visualized with ethidium bromide staining and UV transillumination, according to the method of Edenberg and Reynolds.15 Samples from all 137 patients were analyzed for the 5-HTTPR*S/*L polymorphism.

STATISTICAL ANALYSIS

Pearson χ2 test (exact method) was used to compare the groups with respect to race, sex, and allele and genotype frequencies (StatXact4, version 4.0.1; Cytel Software Corp, Cambridge, Mass). Intergroup differences in age and MSSE score were assessed by t tests (SAS, version 8.0; SAS Institute Inc, Cary, NC). Equality of variance was assessed before the t tests were performed. All tests were 2-tailed, and a significance level of .05 was used.

Demographic and clinical characteristics of patients with AD exhibiting aggressive behavior (n = 58) and those with no history of aggressive behavior (n = 79) are shown in Table 1. There were no significant differences with regard to sex and race. The MMSE scores also did not differ between groups, confirming adequate matching on this variable. Mean age was significantly higher, however, in the aggressive subjects (t = 4.3, P<.001).

Table Graphic Jump LocationTable 1. Demographic and Clinical Data for Aggressive and Never-Aggressive Patients With Alzheimer Disease

Genotype and allele frequencies of the 5HTTPR polymorphism among aggressive and never-aggressive patients with AD are shown in Table 2. The increased frequency of *L alleles in the aggressive patients was highly significant (χ21 = 18.0, P<.001). There was a corresponding significant difference in genotype distribution between the aggressive and never-aggressive patients (χ21 = 7.1, P<.01). Aggressive patients with AD had a significantly higher frequency of *L/*L genotypes than the never-aggressive patients with AD. The odds ratio (95% confidence interval) for aggression associated with the *L/*L genotype was 2.8 (1.2-6.5). When genotype, age, sex, and MMSE score were entered into a stepwise logistic regression model with aggression as the dependent variable, both *L/*L genotype and age, but not sex or MMSE, demonstrated significant associations with aggression (genotype: χ21 = 6.2, P = .01; age: χ21 = 15.8, P<.001).

Table Graphic Jump LocationTable 2. Genotype and Allele Frequency Data for Aggressive and Never-Aggressive Patients With Alzheimer Disease

To our knowledge, this is the first study to relate aggressive behavior in AD to the 5-HTTPR polymorphism. As hypothesized, there was a significantly greater frequency of the *L/*L genotype in the aggressive subjects. We also found aggressive patients with AD to have a significantly higher frequency of *L alleles than never-aggressive patients with AD.

We predicted that the *L/*L genotype would be more commonly found in patients with AD with aggressive behavior because of the established relationship between 5-HT depletion and aggression.27 There is reason to believe that subjects who are of the *L/*L genotype would have less 5-HT available at the synapse because of the higher density of 5-HTT that this genotype confers.16,17 The low level of synaptic 5-HT caused by increased reuptake would therefore approximate the reduced 5-HT levels seen in subjects with impulsive aggressive behavior associated with other neuropsychiatric conditions,2,3,27 and in aggressive patients with AD.4,5 While reports of increased prolactin response to fenfluramine challenge in agitated patients with AD may initially seem to contradict these findings, they may be readily understood as an up-regulated postsynaptic state that develops in response to tonically reduced intrasynaptic 5-HT.

In addition to the hypothesized association of aggression with the *L/*L genotype, we found a significant elevation of *L allele frequency. Inspection of the rates of aggression in the genotype groups in Table 2 shows a progressive increase in aggression frequency from *S/*S to *S/*L to *L/*L subjects: aggression was present in 1 of 27 *S/*S subjects, 34 of 72 *S/*L subjects, and 23 of 38 *L/*L subjects. This pattern is not consistent with reports of *S allele dominance.18,28 The relationship between 5HTTPR genotype and 5-HTT expression in regions of human brain29,30 may differ, however, from that observed in in vitro expression systems or in peripheral tissues. In fact the 5-HTT promoter region is subject to regulation by multiple transcription factors31; thus, the effect of the *L and *S alleles on 5-HTT expression may vary in accordance with the specific transcription factors expressed in a specific tissue, region of tissue, or disease state. It is worth noting that, in some previous studies that found an association of 5HTTPR genotype with AD risk, a pattern like that of the current study, ie, more consistent with codominance than with a dominant-recessive system, has been observed.32,33

The preclinical neurochemical findings of reduced 5-HT levels in aggressive patients with AD have suggested a role for 5-HT–enhancing drugs in the treatment of aggressive behaviors in AD. Emerging clinical data suggest this may indeed be the case.12,13,34 The current genetic findings are consistent with these earlier observations. Moreover, we previously reported that, among older subjects treated for major depressive illness with the selective 5-HT reuptake inhibitor paroxetine, *L/*L subjects had a significantly earlier antidepressant response than their *S/*S and *S/*L counterparts.35 It remains to be determined whether the *L/*L genotype will similarly predict response of aggressive behaviors in AD to treatment with 5-HT reuptake inhibitors.

Previous research on the 5HTTPR polymorphism and AD found an association between the *S allele and the development of late-onset AD in European and Brazilian subjects,32,33,36 although a subsequent study failed to replicate this association.37 Our findings suggest that these inconsistent associations could result from variability in the extent to which aggressive patients with AD were included. Behavioral characterization of subjects should be considered in future 5-HTTPR research in patients with AD.

Because this is the first study relating aggression in patients with AD to the 5-HTTPR polymorphism, independent replication will be necessary to confirm the association of the *L allele with aggressive behavioral disturbance. The major potential limitation of the study is the differing referral sources for aggressive subjects (Geriatric Psychiatry Inpatient Program) and nonaggressive subjects (Alzheimer Disease Research Center), also rated by different behavioral measures (Empirical Behavioral Pathology in Alzheimer Disease and Behavior Rating Scale, respectively). If referral source is a surrogate for a subject characteristic (other than aggression) that was associated with the 5HTTPR, a false-positive association with aggression could have resulted. The current study was also limited by incomplete matching for subject age, with the aggressive AD group being 6 years older on average than the never-aggressive group. Nevertheless, the association of genotype with aggression remained significant after controlling for the effect of age. Finally, as in all genetic association studies, a type I error might result from population stratification effects.

In summary, we found the *L allele and the *L/*L genotype of the 5HTTPR polymorphism to be increased in frequency in aggressive patients with AD when compared with patients with AD who were never aggressive. This study is the first of its kind, to our knowledge, and therefore must be considered preliminary, pending independent replication. Future studies examining the association between 5-TTPR genotype and response to serotonergic treatment of aggression in AD are also warranted.

Accepted for publication March 26, 2001.

This study was supported in part by research grants MH01509, MH59666, MH52247, and MH01613 from the National Institute of Mental Health and AG05133 from the National Institute on Aging, Bethesda, Md, and by the John F. and Nancy A. Emmerling Fund of The Pittsburgh Foundation, Pittsburgh, Pa.

We gratefully acknowledge the efforts of the research staff of the Alzheimer Disease Research Center and the Geriatric Psychopharmacology Program at the University of Pittsburgh. We would like to acknowledge the assistance of Lorri Mulkerin with the preparation of the manuscript.

Corresponding author and reprints: Robert A. Sweet, MD, Western Psychiatric Institute and Clinic, 3811 O'Hara St, Pittsburgh, PA 15213 (e-mail: SweetRA@MSX.UPMC.EDU).

Tariot  PNMack  JLPatterson  MB  et al The behavior rating scale for dementia of the Consortium to Establish a Registry for Alzheimer's Disease. Am J Psychiatry.1995;152:1349-1357.
Åsberg  MTräskman  LThorén  P 5-HIAA in the cerebrospinal fluid: a biochemical suicide predictor? Arch Gen Psychiatry.1976;33:1193-1197.
Brown  GLEbert  MHGoyer  PF  et al Aggression, suicide, and serotonin: relationship to CSF amine metabolites. Am J Psychiatry.1982;139:741-746.
Palmer  AMStratmann  GCProcter  AWBowen  DM Possible neurotransmitter basis of behavioral changes in Alzheimer's disease. Ann Neurol.1988;23:616-620.
Procter  AWFrancis  PTStratmann  GCBowen  DM Serotonergic pathology is not widespread in Alzheimer patients without prominent aggressive symptoms. Neurochem Res.1992;17:917-922.
Mintzer  JEBrawman-Mintzer  OMirski  DF  et al Fenfluramine challenge test as a marker of serotonin activity in patients with Alzheimer's dementia and agitation. Biol Psychiatry.1998;44:918-921.
Lanctot  KLHerrmann  NNaranjo  CAvan Reekum  REryavec  GShulman  RW Role of serotonin in aggressive behaviors associated with Alzheimer's disease: preliminary results. Psychopharmacol Bull.1997;33:545.
Reinikainen  KJSoininen  HReikkinen  PJ Neurotransmitter changes in Alzheimer's dementia and agitation. J Neurosci Res.1990;27:576-586.
Cross  AJ Serotonin in Alzheimer-type dementia and other dementing illnesses. Ann N Y Acad Sci.1990;600:405-417.
Cheng  AVTFerrier  INMorris  CM  et al Cortical serotonin-S2 receptor binding in Lewy body dementia, Alzheimer's and Parkinson's diseases. J Neurol Sci.1991;106:50-55.
Lawlor  B Serotonin and Alzheimer's disease. Psychiatr Ann.1990;20:567-570.
Nyth  ALGottfries  CG The clinical efficacy of citalopram in treatment of emotional disturbances in dementia disorders. Br J Psychiatry.1990;157:894-901.
Sultzer  DLGray  KFGunay  IBerisford  MAMahler  ME A double-blind comparison of trazodone and haloperidol for treatment of agitation in patients with dementia. Am J Geriatr Psychiatry.1997;5:60-69.
Pollock  BGRosen  JMulsant  BH  et al Treatment of behaviors in dementia with citalopram.  In: Proceedings of the annual meeting of the American Psychiatric Association; May 13-18, 2000; Chicago, Ill. Abstract 132.
Edenberg  HJReynolds  J Improved method for detecting the long and short promoter alleles of the serotonin transporter gene HTT (SLC6A4). Psychiatr Genet.1998;8:193-195.
Heils  ATeufel  APetri  S  et al Allelic variation of human serotonin transporter gene expression. J Neurochem.1996;66:2621-2624.
Collier  DAStober  GLi  T  et al A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry.1996;1:453-460.
Lesch  KPBengel  DHeils  A  et al Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science.1996;274:1527-1531.
Lopez  OLBecker  JTKlunk  WE  et al Research evaluation and diagnosis of probable Alzheimer's disease over the last two decades, I. Neurology.2000;55:1854-1862.
Lopez  OLBecker  JTKlunk  WE  et al Research evaluation and diagnosis of possible Alzheimer's disease over the last two decades, II. Neurology.2000;55:1863-1869.
Sweet  RANimgaonkar  VLKamboh  MILopez  OLZhang  FDeKosky  ST Dopamine receptor genetic variation, psychosis, and aggression in Alzheimer's disease. Arch Neurol.1998;55:1335-1340.
Mulsant  BHMazumdar  SPollock  BGSweet  RARosen  JLo  K Methodological issues in characterizing treatment response in demented patients with behavioral disturbances. Int J Geriatr Psychiatry.1997;12:537-547.
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  EM Clinical diagnosis of Alzheimer's Disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology.1984;34:939-944.
Auer  SRMonteiro  IMReisberg  B The empirical behavioral pathology in Alzheimer's disease (E-BEHAVE-AD) rating scale. Int Psychogeriatr.1996;8:247-266.
Devanand  DPJacobs  DMTang  MX  et al The course of psychopathologic features in mild to moderate Alzheimer disease. Arch Gen Psychiatry.1997;54:257-263.
Folstein  MFFolstein  SEMcHugh  PR Mini-Mental State: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res.1975;12:189-198.
Seiver  LJBuchsbaum  MSNew  AS  et al D, 1-fenfluramine response in impulsive personality disorder assessed with [18F]fluorodeoxyglucose positron emission tomography. Neuropsychopharmacology.1999;20:413-423.
Greenberg  BDTolliver  TJHuang  SLi  QBengel  DMurphy  DL Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. Am J Med Genet.1999;88:83-87.
Little  KYMcLaughlin  DPZhang  L  et al Cocaine, ethanol, and genotype effects on human midbrain serotonin transporter binding sites and mRNA levels. Am J Psychiatry.1998;155:207-213.
Mann  JHuang  YUndie  AS  et al A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide. Arch Gen Psychiatry.2000;57:729-738.
Heils  ATeufel  APetri  S  et al Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene. J Neural Transm Gen Sect.1995;102:247-254.
Hu  MRetz  WBaader  M  et al Promoter polymorphism of the 5-HT transporter and Alzheimer's disease. Neurosci Lett.2000;294:63-65.
Li  THolmes  CSham  PC  et al Allelic functional variation of serotonin transporter expression is a susceptibility factor for late onset Alzheimer's diseases. Neuroreport.1997;8:683-686.
Houlihan  DJMulsant  BHSweet  RA  et al A naturalistic study of trazodone in the treatment of behavioral complications of dementia. Am J Geriatr Psychiatry.1994;2:78-85.
Pollock  BGFerrell  REMulsant  BH  et al Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology.2000;23:587-590.
Oliveira  JRMGallindo  RMMaia  LGS  et al The short variant of the polymorphism within the promoter region of the serotonin transporter gene is a risk factor for late onset Alzheimer's disease. Mol Psychiatry.1998;3:438-441.
Zill  PPadberg  Fde Jonge  S  et al Serotonin transporter (5-HTT) gene polymorphism in psychogeriatric patients. Neurosci Lett.2000;284:113-115.

Figures

Tables

Table Graphic Jump LocationTable 1. Demographic and Clinical Data for Aggressive and Never-Aggressive Patients With Alzheimer Disease
Table Graphic Jump LocationTable 2. Genotype and Allele Frequency Data for Aggressive and Never-Aggressive Patients With Alzheimer Disease

References

Tariot  PNMack  JLPatterson  MB  et al The behavior rating scale for dementia of the Consortium to Establish a Registry for Alzheimer's Disease. Am J Psychiatry.1995;152:1349-1357.
Åsberg  MTräskman  LThorén  P 5-HIAA in the cerebrospinal fluid: a biochemical suicide predictor? Arch Gen Psychiatry.1976;33:1193-1197.
Brown  GLEbert  MHGoyer  PF  et al Aggression, suicide, and serotonin: relationship to CSF amine metabolites. Am J Psychiatry.1982;139:741-746.
Palmer  AMStratmann  GCProcter  AWBowen  DM Possible neurotransmitter basis of behavioral changes in Alzheimer's disease. Ann Neurol.1988;23:616-620.
Procter  AWFrancis  PTStratmann  GCBowen  DM Serotonergic pathology is not widespread in Alzheimer patients without prominent aggressive symptoms. Neurochem Res.1992;17:917-922.
Mintzer  JEBrawman-Mintzer  OMirski  DF  et al Fenfluramine challenge test as a marker of serotonin activity in patients with Alzheimer's dementia and agitation. Biol Psychiatry.1998;44:918-921.
Lanctot  KLHerrmann  NNaranjo  CAvan Reekum  REryavec  GShulman  RW Role of serotonin in aggressive behaviors associated with Alzheimer's disease: preliminary results. Psychopharmacol Bull.1997;33:545.
Reinikainen  KJSoininen  HReikkinen  PJ Neurotransmitter changes in Alzheimer's dementia and agitation. J Neurosci Res.1990;27:576-586.
Cross  AJ Serotonin in Alzheimer-type dementia and other dementing illnesses. Ann N Y Acad Sci.1990;600:405-417.
Cheng  AVTFerrier  INMorris  CM  et al Cortical serotonin-S2 receptor binding in Lewy body dementia, Alzheimer's and Parkinson's diseases. J Neurol Sci.1991;106:50-55.
Lawlor  B Serotonin and Alzheimer's disease. Psychiatr Ann.1990;20:567-570.
Nyth  ALGottfries  CG The clinical efficacy of citalopram in treatment of emotional disturbances in dementia disorders. Br J Psychiatry.1990;157:894-901.
Sultzer  DLGray  KFGunay  IBerisford  MAMahler  ME A double-blind comparison of trazodone and haloperidol for treatment of agitation in patients with dementia. Am J Geriatr Psychiatry.1997;5:60-69.
Pollock  BGRosen  JMulsant  BH  et al Treatment of behaviors in dementia with citalopram.  In: Proceedings of the annual meeting of the American Psychiatric Association; May 13-18, 2000; Chicago, Ill. Abstract 132.
Edenberg  HJReynolds  J Improved method for detecting the long and short promoter alleles of the serotonin transporter gene HTT (SLC6A4). Psychiatr Genet.1998;8:193-195.
Heils  ATeufel  APetri  S  et al Allelic variation of human serotonin transporter gene expression. J Neurochem.1996;66:2621-2624.
Collier  DAStober  GLi  T  et al A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry.1996;1:453-460.
Lesch  KPBengel  DHeils  A  et al Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science.1996;274:1527-1531.
Lopez  OLBecker  JTKlunk  WE  et al Research evaluation and diagnosis of probable Alzheimer's disease over the last two decades, I. Neurology.2000;55:1854-1862.
Lopez  OLBecker  JTKlunk  WE  et al Research evaluation and diagnosis of possible Alzheimer's disease over the last two decades, II. Neurology.2000;55:1863-1869.
Sweet  RANimgaonkar  VLKamboh  MILopez  OLZhang  FDeKosky  ST Dopamine receptor genetic variation, psychosis, and aggression in Alzheimer's disease. Arch Neurol.1998;55:1335-1340.
Mulsant  BHMazumdar  SPollock  BGSweet  RARosen  JLo  K Methodological issues in characterizing treatment response in demented patients with behavioral disturbances. Int J Geriatr Psychiatry.1997;12:537-547.
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  EM Clinical diagnosis of Alzheimer's Disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology.1984;34:939-944.
Auer  SRMonteiro  IMReisberg  B The empirical behavioral pathology in Alzheimer's disease (E-BEHAVE-AD) rating scale. Int Psychogeriatr.1996;8:247-266.
Devanand  DPJacobs  DMTang  MX  et al The course of psychopathologic features in mild to moderate Alzheimer disease. Arch Gen Psychiatry.1997;54:257-263.
Folstein  MFFolstein  SEMcHugh  PR Mini-Mental State: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res.1975;12:189-198.
Seiver  LJBuchsbaum  MSNew  AS  et al D, 1-fenfluramine response in impulsive personality disorder assessed with [18F]fluorodeoxyglucose positron emission tomography. Neuropsychopharmacology.1999;20:413-423.
Greenberg  BDTolliver  TJHuang  SLi  QBengel  DMurphy  DL Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. Am J Med Genet.1999;88:83-87.
Little  KYMcLaughlin  DPZhang  L  et al Cocaine, ethanol, and genotype effects on human midbrain serotonin transporter binding sites and mRNA levels. Am J Psychiatry.1998;155:207-213.
Mann  JHuang  YUndie  AS  et al A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide. Arch Gen Psychiatry.2000;57:729-738.
Heils  ATeufel  APetri  S  et al Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene. J Neural Transm Gen Sect.1995;102:247-254.
Hu  MRetz  WBaader  M  et al Promoter polymorphism of the 5-HT transporter and Alzheimer's disease. Neurosci Lett.2000;294:63-65.
Li  THolmes  CSham  PC  et al Allelic functional variation of serotonin transporter expression is a susceptibility factor for late onset Alzheimer's diseases. Neuroreport.1997;8:683-686.
Houlihan  DJMulsant  BHSweet  RA  et al A naturalistic study of trazodone in the treatment of behavioral complications of dementia. Am J Geriatr Psychiatry.1994;2:78-85.
Pollock  BGFerrell  REMulsant  BH  et al Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology.2000;23:587-590.
Oliveira  JRMGallindo  RMMaia  LGS  et al The short variant of the polymorphism within the promoter region of the serotonin transporter gene is a risk factor for late onset Alzheimer's disease. Mol Psychiatry.1998;3:438-441.
Zill  PPadberg  Fde Jonge  S  et al Serotonin transporter (5-HTT) gene polymorphism in psychogeriatric patients. Neurosci Lett.2000;284:113-115.

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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
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