Alzheimer Disease: Raman R

Fleisher AS, Raman R, Siemers ER, Becerra L, Clark CM, Dean RA, Farlow MR, Galvin JE, Peskind ER, Quinn JF, Sherzai A, Sowell BB, Aisen PS, Thal LJ. · University of California, San Diego, La Jolla, CA 92037, USA. · Arch Neurol. · Pubmed #18695053 links to  free full text

Abstract: OBJECTIVE: To evaluate the safety, tolerability, and amyloid beta (Abeta) response to the gamma-secretase inhibitor LY450139 in Alzheimer disease. DESIGN: Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial. SETTING: Community-based clinical research centers. Patients Fifty-one individuals with mild to moderate Alzheimer disease were randomized to receive placebo (n=15) or LY450139 (100 mg [n=22] or 140 mg [n=14]), with 43 completing the treatment phase. Intervention The LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for 6 weeks, and then either 100 or 140 mg/d for 6 additional weeks. MAIN OUTCOME MEASURES: Primary outcome measures were adverse events, plasma and cerebrospinal fluid Abeta levels, vital signs, electrocardiographic data, and laboratory safety test results. Secondary outcome measures included the Alzheimer's Disease Assessment Scale cognitive subscale and the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale. RESULTS: Group differences were seen in skin and subcutaneous tissue concerns (P=.05), including 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse event-related discontinuations, including 1 transient bowel obstruction. The plasma Abeta(40) concentration was reduced by 58.2% for the 100-mg group and 64.6% for the 140-mg group (P<.001). No significant reduction was seen in cerebrospinal fluid Abeta levels. No group differences were seen in cognitive or functional measures. CONCLUSIONS: LY450139 was generally well tolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Abeta concentrations were consistent with inhibition of gamma-secretase. Trial Registration clinicaltrials.gov Identifier: NCT00244322.

Marson DC, Martin RC, Wadley V, Griffith HR, Snyder S, Goode PS, Kinney FC, Nicholas AP, Steele T, Anderson B, Zamrini E, Raman R, Bartolucci A, Harrell LE. · Department of Neurology, SC 650, University of Alabama at Birmingham, Birmingham, AL 35294, USA. · J Am Geriatr Soc. · Pubmed #19453308 No free full text.

Abstract: OBJECTIVES: To investigate financial capacity in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) using a clinician interview approach. DESIGN: Cross-sectional. SETTING: Tertiary care medical center. PARTICIPANTS: Healthy older adults (n=75) and patients with amnestic MCI (n=58), mild AD (n=97), and moderate AD (n=31). MEASUREMENTS: The investigators and five study physicians developed a conceptually based, semistructured clinical interview for evaluating seven core financial domains and overall financial capacity (Semi-Structured Clinical Interview for Financial Capacity; SCIFC). For each participant, a physician made capacity judgments (capable, marginally capable, or incapable) for each financial domain and for overall capacity. RESULTS: Study physicians made more than 11,000 capacity judgments across the study sample (N=261). Very good interrater agreement was obtained for the SCIFC judgments. Increasing proportions of marginal and incapable judgment ratings were associated with increasing disease severity across the four study groups. For overall financial capacity, 95% of physician judgments for older controls were rated as capable, compared with 82% for patients with MCI, 26% for patients with mild AD, and 4% for patients with moderate AD. CONCLUSION: Physicians and other clinicians can reliably evaluate financial capacity in cognitively impaired older adults using a relatively brief, semistructured clinical interview. Patients with MCI have mild impairment in financial capacity, those with mild AD have emerging global impairment, and those with moderate AD have advanced global impairment. Patients with MCI and their families should proactively engage in financial and legal planning, given these patients' risk of developing AD and accelerated loss of financial abilities.

Irizarry MC, Raman R, Schwarzschild MA, Becerra LM, Thomas RG, Peterson RC, Ascherio A, Aisen PS. · Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. · Neurodegener Dis. · Pubmed #19066433 No free full text.

Abstract: BACKGROUND: Impaired antioxidant defenses are implicated in neurodegenerative disease. The plasma levels of urate, a water-soluble antioxidant, are reduced in Alzheimer's disease (AD). OBJECTIVE: We aimed to test the hypotheses that high plasma urate at baseline is associated with: (1) a reduced rate of conversion from mild cognitive impairment (MCI) to AD and (2) a lower rate of cognitive decline in MCI. METHODS: Plasma urate was obtained at baseline from 747 participants in a 3-year, randomized, double-blind, placebo-controlled study of donepezil, vitamin E or placebo for delaying the progression of MCI to AD.The association between baseline urate and conversion from MCI to AD was examined by Cox proportional hazards regression. The relationship between baseline urate and cognitive change on the cognitive subscale of the Alzheimer's Disease Assessment Scale was evaluated by longitudinal analysis. RESULTS: Baseline plasma urate was not associated with the rate of conversion of MCI to AD. In the placebo arm, high plasma urate was related to a slower rate of cognitive decline over 3 years, although this was not reproduced in the other treatment arms. CONCLUSION: While plasma urate levels did not predict the progression of MCI to AD, high urate may be associated with a reduced rate of cognitive decline in MCI patients not treated with donepezil or vitamin E. The results support the investigation of biomarkers of antioxidant status as risk factors for cognitive decline in MCI.

Hamilton JM, Salmon DP, Galasko D, Raman R, Emond J, Hansen LA, Masliah E, Thal LJ. · Department of Neurosciences, University of California, USA. · Neuropsychology. · Pubmed #18999346 No free full text.

Abstract: Dementia with Lewy bodies (DLB) is often characterized by pronounced impairment in visuospatial skills, attention, and executive functions. However, the strength of the phenotypic expression of DLB varies and may be weaker in patients with extensive concomitant Alzheimer's disease (AD). To determine whether strength of the DLB clinical phenotype impacts cognitive decline, visuospatial and language tests were retrospectively used to predict 2-year rate of global cognitive decline in 22 autopsy-confirmed DLB patients (21 with concomitant AD) and 44 autopsy-confirmed "pure" AD patients. Generalized estimating equations (GEE) revealed a significant interaction such that poor baseline performances on tests of visuospatial skills were strongly associated with a rapid rate of cognitive decline in DLB but not AD (p < .001). No effect of confrontation naming was found. DLB patients with poor visuospatial skills had fewer neurofibrillary tangles and were more likely to experience visual hallucinations than those with better visuospatial skills. These results suggest that the severity of visuospatial deficits in DLB may identify those facing a particularly malignant disease course and may designate individuals whose clinical syndrome is impacted more by Lewy body formation than AD pathology.

Okonkwo OC, Griffith HR, Copeland JN, Belue K, Lanza S, Zamrini EY, Harrell LE, Brockington JC, Clark D, Raman R, Marson DC. · Department of Psychology, SC 650K, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA. · Neurology. · Pubmed #18981368 No free full text.

Abstract: OBJECTIVE: To investigate longitudinal change in the medical decision-making capacity (MDC) of patients with amnestic mild cognitive impairment (MCI) under different consent standards. METHODS: Eighty-eight healthy older controls and 116 patients with MCI were administered the Capacity to Consent to Treatment Instrument at baseline and at 1 to 3 (mean = 1.7) annual follow-up visits thereafter. Covariate-adjusted random coefficient regressions were used to examine differences in MDC trajectories across MCI and control participants, as well as to investigate the impact of conversion to Alzheimer disease on MCI patients' MDC trajectories. RESULTS: At baseline, MCI patients performed significantly below controls only on the three clinically relevant standards of appreciation, reasoning, and understanding. Compared with controls, MCI patients experienced significant declines over time on understanding but not on any other consent standard. Conversion affected both the elevation (a decrease in performance) and slope (acceleration in subsequent rate of decline) of MCI patients' MDC trajectories on understanding. A trend emerged for conversion to be associated with a performance decrease on reasoning in the MCI group. CONCLUSIONS: Medical decision-making capacity (MDC) decline in mild cognitive impairment (MCI) is a relatively slow but detectable process. Over a 3-year period, patients with amnestic MCI show progressive decline in the ability to understand consent information. This decline accelerates after conversion to Alzheimer disease (AD), reflecting increasing vulnerability to decisional impairment. Clinicians and researchers working with MCI patients should give particular attention to the informed consent process when conversion to AD is suspected or confirmed.

Okonkwo OC, Wadley VG, Griffith HR, Belue K, Lanza S, Zamrini EY, Harrell LE, Brockington JC, Clark D, Raman R, Marson DC. · Department of Psychology, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA. · Am J Geriatr Psychiatry. · Pubmed #18669943 No free full text.

Abstract: OBJECTIVE: Self and informant reports of functional abilities are weighted heavily in diagnostic decision making regarding mild cognitive impairment (MCI). However, it is unclear whether patients with MCI are fully aware and provide reliable estimates of their functional status. In this study, the authors used three different approaches to examine accuracy of self-report of financial abilities among patients with MCI. DESIGN: Cross-sectional, case-comparison group study. SETTING: University medical center. PARTICIPANTS: Seventy-four patients with MCI and their informants, and 73 cognitively healthy older adults and their informants. MEASUREMENTS: The authors compared MCI patients' report of their financial abilities with their performance on an objective measure of financial capacity. The authors also compared informant reports of patients' abilities with patients' objective test performance, and informant reports with patients' self-report. RESULTS: The authors found that the discrepancy between self-report and objective performance was higher among MCI patients compared with the cognitively healthy older adults on the financial domains of Checkbook Management, Bank Statement Management, and Bill Payment, and on overall financial capacity. The authors also found that MCI patients with poorer global cognition overestimated their financial abilities whereas those with higher depressive symptoms underestimated their financial abilities. Overall, MCI patients were better at estimating their financial abilities than their informants. CONCLUSIONS: Patients with MCI are not fully aware of deficits in their financial abilities. Both cognitive impairment and depression impact MCI patients' self-reported functioning. In addition, MCI informants misestimate patients' financial abilities. This raises concerns about the widespread use of informant report as the gold standard against which to evaluate patient self-report of functioning.

Okonkwo OC, Griffith HR, Belue K, Lanza S, Zamrini EY, Harrell LE, Brockington JC, Clark D, Raman R, Marson DC. · Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, USA. · J Int Neuropsychol Soc. · Pubmed #18282327 No free full text.

Abstract: This study investigated cognitive predictors of medical decision-making capacity (MDC) in patients with amnestic mild cognitive impairment (MCI). A total of 56 healthy controls, 60 patients with MCI, and 31 patients with mild Alzheimer's disease (AD) were administered the Capacity to Consent to Treatment Instrument (CCTI) and a neuropsychological test battery. The CCTI assesses MDC across four established treatment consent standards--S1 (expressing choice), S3 (appreciation), S4 (reasoning), and S5 (understanding)--and one experimental standard [S2] (reasonable choice). Scores on neuropsychological measures were correlated with scores on each CCTI standard. Significant bivariate correlates were subsequently entered into stepwise regression analyses to identity group-specific multivariable predictors of MDC across CCTI standards. Different multivariable cognitive models emerged across groups and consent standards. For the MCI group, measures of short-term verbal memory were key predictors of MDC for each of the three clinically relevant standards (S3, S4, and S5). Secondary predictors were measures of executive function. In contrast, in the mild AD group, measures tapping executive function and processing speed were primary predictors of S3, S4, and S5. MDC in patients with MCI is supported primarily by short-term verbal memory. The findings demonstrate the impact of amnestic deficits on MDC in patients with MCI.

Okonkwo O, Griffith HR, Belue K, Lanza S, Zamrini EY, Harrell LE, Brockington JC, Clark D, Raman R, Marson DC. · Department of Neurology, JT 1216, University of Alabama at Birmingham, Birmingham, AL 35233-7340, USA. · Neurology. · Pubmed #17923615 No free full text.

Abstract: OBJECTIVES: To empirically assess the capacity of patients with amnestic mild cognitive impairment (MCI) to consent to medical treatment under different consent standards (Ss). METHODS: Participants were 56 healthy controls, 60 patients with MCI, and 31 patients with mild Alzheimer disease (AD). Each participant was administered the Capacity to Consent to Treatment Instrument (CCTI) and a comprehensive neuropsychological battery. Group differences in performance on the CCTI and neuropsychological variables were examined. In addition, the capacity status (capable, marginally capable, or incapable) of each MCI participant on each CCTI standard was examined using cut scores derived from control performance. RESULTS: Patients with MCI performed comparably to controls on minimal consent standards requiring merely expressing a treatment choice (S1) or making the reasonable treatment choice [S2], but significantly below controls on the three clinically relevant standards of appreciation (S3), reasoning (S4), and understanding (S5). In turn, the MCI group performed significantly better than the mild AD group on [S2], S4, and S5. Regarding capacity status, patients with MCI showed a progressive pattern of capacity compromise (marginally capable and incapable outcomes) related to stringency of consent standard. CONCLUSIONS: Patients with amnestic mild cognitive impairment (MCI) demonstrate significant impairments on clinically relevant abilities associated with capacity to consent to treatment. In obtaining informed consent, clinicians and researchers working with patients with MCI must consider the likelihood that many of these patients may have impairments in consent capacity related to their amnestic disorder and related cognitive impairments.

Kurlan R, Cummings J, Raman R, Thal L, Anonymous00094. · Mt. Hope Professional Building, Rochester, NY 14620, USA. · Neurology. · Pubmed #17452579 No free full text.

Abstract: OBJECTIVE: To assess the efficacy and tolerability of quetiapine for agitation or psychosis in patients with dementia and parkinsonism. METHODS: Multicenter randomized, double-blind, placebo-controlled parallel groups clinical trial involving 40 patients with dementia with Lewy bodies (n = 23), Parkinson disease (PD) with dementia (n = 9), or Alzheimer disease with parkinsonian features (n = 8). The main outcome measure for efficacy was change in the Brief Psychiatric Rating Scale (BPRS) from baseline to 10 weeks of therapy. For tolerability it was change in the Unified PD Rating Scale (UPDRS) motor section over the same time period. The trial was confounded by the need for a design change and incomplete recruitment. RESULTS: No significant differences in the primary or secondary outcome measures of efficacy were observed. An unexpectedly large placebo effect, inadequate dosage (mean 120 mg/day), and inadequate power may have contributed to lack of demonstrable benefit. Quetiapine was generally well-tolerated and did not worsen parkinsonism, but was associated with a trend toward a decline on a measure of daily functioning. CONCLUSIONS: Quetiapine was well-tolerated and did not worsen parkinsonism. Although conclusions about efficacy may be limited, the drug in the dosages used did not show demonstrable benefit for treating agitation or psychosis in patients with dementia and parkinsonism. These findings are in keeping with prior studies reporting limited efficacy of various medications for reducing behavioral problems in demented patients.

Walsh SP, Raman R, Jones KB, Aisen PS, Anonymous00340. · Department of Neurology, Georgetown University Medical Center, Washington, DC 20057, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17135810 No free full text.

Abstract: In future research on the prevention of Alzheimer Disease (AD), a large simple prevention trial might test a safe intervention (eg, vitamins) in a very large population (eg, 10,000 subjects), powered to detect a modest treatment effect size. In a large, simple design, regular assessments must be very low cost, for example, handled by mail. The Mail-In Cognitive Function Screening Instrument (MCFSI) was developed for the Alzheimer's Disease Cooperative Study Prevention Instrument Project to evaluate whether a brief mail-in screening tool can be used as a specific and sensitive trigger for a diagnostic evaluation in the course of a prevention trial. The MCFSI consists of 2 similar sets of 14 questions mailed separately to the subject and the study partner, who are asked to complete them independently. The questions are derived from a standard clinical assessment of dementia; they ask about decline in function over the last year. We are currently evaluating the utility of the instrument in 640 subjects over the course of the "simulated" AD prevention trial. Analysis of baseline data showed significant differences in mean MCFSI scores between sex and ethnic groups (for subjects), age groups (for partners), and Clinical Dementia Rating global score groups (both subject and partner). In this nondemented population, both subject's and partner's MCFSI responses were related to cognitive performance. There was no significant association between MCFSI score for either subjects or partners and apolipoprotein E genotype. The MCFSI captures information related to cognitive and functional status in nondemented elderly individuals; the Alzheimer's Disease Cooperative Study Prevention Instrument Project will determine whether this brief, mail-in questionnaire is useful as a trigger for diagnostic evaluation in an AD primary prevention trial.

Cummings JL, Raman R, Ernstrom K, Salmon D, Ferris SH, Anonymous00338. · Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1769, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17135808 No free full text.

Abstract: BACKGROUND: There is an urgent need for the development of inexpensive, reliable, and valid instruments that can be used in large-scale primary prevention trials of compounds aimed at ameliorating progression from normal aging to mild cognitive impairment or Alzheimer disease. The Alzheimer's Disease Cooperative Study launched a Prevention Instrument Project to develop such methodologies. Behavioral changes are common in diseases causing dementia and may occur prior to a point when cognitive changes are sufficiently severe to allow diagnosis of a dementia syndrome. Experimental behavioral measures were included in the protocol to examine this hypothesis. METHODS: Six hundred forty-four individuals with CDR 0 or 0.5 were randomly assigned to receive a brief in-clinic behavioral assessment or telephonic administration of the same assessment. The questions were asked to the individual and their research partner. The Prevention Instrument Project included behavioral measures of depression, anxiety, irritability, and apathy. RESULTS: All measures demonstrated acceptable test-retest reliability at 3-month intervals except for the single-item depression screen by the subjects' research partner. Behavioral changes are significantly more common among patients with Clinical Dementia Rating (CDR) scores of 0.5 compared with CDR scores of 0. Behavioral alterations including irritability, anxiety, and apathy are more common among ethnic minorities than among the White population. Depression, irritability, anxiety, and apathy are significantly correlated with each other. CONCLUSIONS: Behavioral changes are common among those with mild degrees of cognitive compromise (CDR 0.5). Telephonic assessment of behavioral changes is feasible. The predictive value of these alterations for progression to Alzheimer disease or other dementias will be assessed longitudinally.

Schneider LS, Clark CM, Doody R, Ferris SH, Morris JC, Raman R, Reisberg B, Schmitt FA. · Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17135806 No free full text.

Abstract: BACKGROUND: Because primary prevention trials will require large samples and modest treatment effects are expected, the use of standard clinician-administered, clinic-based measures are unlikely to be feasible. There is a need for proxy-administered outcome measures. The goal of the Alzheimer's Disease Cooperative Study (ADCS) Prevention Instrument Project was to conduct a simulated Alzheimer disease prevention trial in 650 nondemented elderly (Ferris et al, 2006). This involved comparison of data acquisition from both home and clinic and the use of both informant-ratings and self-ratings. Important outcomes included clinical global impressions of change (CGIC) as indicators of clinically meaningful change. Such ratings provide verification that the effects of a medication as measured on rating scales are readily observable and clinically meaningful. One objective was to develop self-rated and study partner-rated CGICs optimized for nondemented elderly or people with very early Alzheimer disease. An important consideration was whether global assessments are specific and sensitive measures of change during a prevention trial. METHODS: A self-administered CGIC and a study partner-rated CGIC were developed to be used either in the clinic or at home. Using 3-month follow-up data, we determined its reliability and validity with 317 subject-partner pairs. We compared subject-ratings with partner-ratings, clinic-based with home-based ratings, and ratings based on severity as determined by the Clinical Dementia Rating scale. RESULTS: There were no differences between clinic and home ratings. Overall, 24% of subjects rated themselves, and 10% of study partners rated the subjects, as minimally to markedly improved. Subjects and partners agreed to within 1 point of their ratings 83% of the time on the 7-point scale. There were weak correlations, generally <0.20, with change scores of selected clinical rating scales. DISCUSSION: The CGICs behaved as expected, showing no overall change over 3 months, no difference between administrations at home compared with clinics, and concurrent validity. Some subjects tended to rate themselves better than their partners rated them. These analyses show the potential for using home-based CGICs which can be completed with minimal supervision and allow assessments of potential preventative interventions.

Tariot PN, Raman R, Jakimovich L, Schneider L, Porsteinsson A, Thomas R, Mintzer J, Brenner R, Schafer K, Thal L, Anonymous00302, Anonymous00303. · Department of Psychiatry, The Center for Aging and Developmental Biology, Univ. of Rochester Medical Center, Rochester, NY, USA. · Am J Geriatr Psychiatry. · Pubmed #16286437 No free full text.

Abstract: OBJECTIVE: Three placebo-controlled clinical trials have suggested the benefit of valproate for treatment of agitation associated with dementia; one was used as the basis for this multicenter trial, conducted by the Alzheimer's Disease (AD) Cooperative Study. It addresses the efficacy, safety, and tolerability of divalproex sodium for the treatment of agitation associated with dementia. METHODS: This was a randomized, double-blind, placebo-controlled clinical trial in 153 nursing home residents with probable or possible AD complicated by agitation; 110 (72%) completed the trial. Participants were randomized to treatment with divalproex sodium at a target dose of 750 mg/day (N = 75) or placebo (N = 78) for 6 weeks. The primary outcome measure was change from baseline on the Brief Psychiatric Rating Scale (BPRS) Agitation factor. Secondary outcomes included total BPRS, Clinical Global Impression of Change, Cohen-Mansfield Agitation Inventory score, and measures of safety and tolerability. RESULTS: Compliance averaged 88%. Participants receiving divalproex achieved a mean dose of 800 mg/day. Change in mean BPRS Agitation factor scores did not differ between patients treated with divalproex and placebo, nor did secondary behavioral measures. Measures of safety and tolerability did not reveal clinically important drug/placebo differences. CONCLUSIONS: This multicenter trial showed no benefit of divalproex sodium for treatment for agitation in dementia at a mean dose of 800 mg/day over 6 weeks. The results do not support findings from previous trials indicating possible benefit.

Raman R, Hedeker D. · Division of Biostatistics, University of California at San Diego, La Jolla, CA 92093-0949, USA. · Stat Med. · Pubmed #16206246 No free full text.

Abstract: Three-level data occur frequently in behaviour and medical sciences. For example, in a multi-centre trial, subjects within a given site are randomly assigned to treatments and then studied over time. In this example, the repeated observations (level-1) are nested within subjects (level-2) who are nested within sites (level-3). Similarly, in twin studies, repeated measurements (level-1) are taken on each twin (level-2) within each twin pair (level-3). A three-level mixed-effects regression model is described here. Random effects at the second and third level are included in the model. Additionally, both proportional odds and non-proportional odds models are developed. The latter allows the effects of explanatory variables to vary across the cumulative logits of the model. A maximum marginal likelihood (MML) solution is described and Gauss-Hermite numerical quadrature is used to integrate over the distribution of random effects. The random effects are normally distributed in this instance. Features of this model are illustrated using data from a school-based smoking prevention trial and an Alzheimer's disease clinical trial.

Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P, Masliah E, Williams DS, Goldstein LS. · Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093, USA. · Science. · Pubmed #15731448 links to  free full text

Abstract: We identified axonal defects in mouse models of Alzheimer's disease that preceded known disease-related pathology by more than a year; we observed similar axonal defects in the early stages of Alzheimer's disease in humans. Axonal defects consisted of swellings that accumulated abnormal amounts of microtubule-associated and molecular motor proteins, organelles, and vesicles. Impairing axonal transport by reducing the dosage of a kinesin molecular motor protein enhanced the frequency of axonal defects and increased amyloid-beta peptide levels and amyloid deposition. Reductions in microtubule-dependent transport may stimulate proteolytic processing of beta-amyloid precursor protein, resulting in the development of senile plaques and Alzheimer's disease.

Goetz CG, Burke PF, Leurgans S, Berry-Kravis E, Blasucci LM, Raman R, Zhou L. · Department of Neurological Sciences, Rush University/Rush-Presbyterian-St Luke's Medical Center, 1725 W Harrison St, Chicago, IL 60612, USA. · Arch Neurol. · Pubmed #11176958 links to  free full text

Abstract: 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.