Alzheimer Disease: Hartman R

Anand R, Hartman R, Sohn H, Danyluk J, Graham SM. · · Am J Geriatr Psychiatry. · Pubmed #12611745 No free full text.

Abstract: The authors conducted a comparative review of study designs and patient populations used in pivotal trials investigating various cholinesterase inhibitors (tacrine, donepezil, rivastigmine, galantamine, controlled-release physostigmine, and metrifionate) and their impact on outcomes reported. Study design parameters that were investigated included patient selection, definitions of adverse dropouts and serious adverse events, effective doses used, dosing flexibility (fixed versus flexible), forced titration, and titration rate. Population characteristics included medical comorbidity and disease severity. Data suggest that differences in study designs and patient populations affect outcomes. Therefore, caution should be taken before making decisions on relative efficacy, safety, and tolerability, because clinical studies are not always directly comparable.

Potki SG, Anand R, Hartman R, Veach J, Grossberg G. · Brain Imaging Center, Department of Psychiatry and Human Behavior, University of California, Irvine 92697, USA. · Prog Neuropsychopharmacol Biol Psychiatry. · Pubmed #12188104 No free full text.

Abstract: OBJECTIVES: To investigate the relationship between activities of daily living (ADL) impairment and Alzheimer's disease (AD) severity in mild to moderately severe AD patients receiving the cholinesterase (ChE) inhibitor rivastigmine. METHODS: ADLs were evaluated using the Progressive Deterioration Scale (PDS). Disease severity was assessed with the Global Deterioration Scale (GDS). Patients were participants in one of three double-blind, placebo-controlled trials with rivastigmine. RESULTS: Baseline PDS scores differed significantly (P<.001) by disease severity. At Week 26, PDS declines from baseline for placebo patients were significantly different at all disease stages. Specific ADL affected were disease stage-dependent. Rivastigmine treatment (6-12 mg/day) resulted in total PDS scores being significantly improved compared with placebo at all disease stages, although the effect on individual items differed by severity. CONCLUSIONS: ADL impairment differs across the stages of AD. Greater impairment in total ADL scores is observed with increasing severity of illness. However, the stage of illness determines the type of ADLs lost. Treatment response to rivastigmine occurs with mild, moderate and moderately severe AD, with the largest effect in patients with advancing severity of disease.

Morganroth J, Graham S, Hartman R, Anand R. · eResearch Technology, Philadelphia, PA 19103, USA. · J Clin Pharmacol. · Pubmed #12017350 No free full text.

Abstract: The electrocardiographic (ECG) effects of rivastigmine treatment were assessed in mild to moderately severe Alzheimer's disease (AD) by analysis of four 26-week, double-blind, multicenter, placebo-controlled, phase III clinical trials. Of an initial 2791 patients, 77% completed treatment. Seventy-one percent required at least one concomitant medication for conditions other than AD, with 34% requiring cardiovascular medications. Safety assessments included ECGs, adverse events, vital signs, and clinical laboratory parameters. Pooled 12-lead ECG data were analyzed by an independent cardiologist blinded to treatment group and clinical information. Heart rate, PR, QRS, and QTc intervals did not differ significantly between treatment and placebo groups. Percentage change from baseline for PR, QRS, and QTc intervals was also no different. In conclusion, rivastigmine appears not to produce adverse effects on cardiac function assessed by ECG.

Potkin SG, Anand R, Fleming K, Alva G, Keator D, Carreon D, Messina J, Wu JC, Hartman R, Fallon JH. · Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92627-3960, USA. · Int J Neuropsychopharmacol. · Pubmed #11602028 No free full text.

Abstract: In-vivo metabolic measures with positron emission tomography using (18)F-fluorodeoxyglucose (FDG-PET) have demonstrated hypometabolism in temporal, frontal, and hippocampal areas during the early stages of Alzheimer's disease (AD). Progression of the dementia in AD involves compromised cholinergic functioning. Cholinesterase inhibitors have demonstrated efficacy in improving cognition and behaviour in AD. In this study, we demonstrate the usefulness of FDG-PET in measuring the progression of untreated AD and its modification by treatment with rivastigmine (Exelon, Novartis Pharmaceuticals, East Hanover, New Jersey, USA), a centrally selective cholinesterase inhibitor of the carbamate type. Patients with mild to moderate probable AD (Mini-Mental Status Exam scores of 10-26, inclusive) were enrolled in a double-blind, placebo controlled comparison of three fixed daily doses of rivastigmine (3, 6, or 9 mg/d) or placebo for 26 wk. FDG-PET scans were obtained on 27 patients at baseline and following 26 wk of treatment using the Snodgrass Picture Naming activation task. A total of 71.4% of the patients treated with placebo deteriorated clinically compared to only 25.0% of the patients treated with rivastigmine (chi2 = 4.8; p & 0.03). Rivastigmine-responders (i.e. those who clinically improved or remained clinically stable as measured by the Clinicianaposs Interview-Based Impression of Change-plus) showed a marked increase in brain metabolism (p <0.01) involving, but not limited to, structures comprising the memory-related cortices and the prefrontal system. These metabolic changes were not observed in the placebo-treated patients or the rivastigmine non-responders. Of note is that responders increased hippocampal metabolism by 32.5% (p < 0.03) compared to a non-significant decrease in the non-responders (6.4%) and placebo-treated patients (4.1%). These results are consistent with the literature suggesting that FDG-PET can sensitively measure the progression of AD and its improvement with cholinesterase inhibitors. Rivastigmine prevented the expected deterioration in clinical status and dramatically increased brain metabolic activity in a majority of patients.

Farlow MR, Hake A, Messina J, Hartman R, Veach J, Anand R. · Department of Neurology, Indiana University School of Medicine, CL583, 541 Clinical Dr., Indianapolis, IN 46202-5111, USA. · Arch Neurol. · Pubmed #11255445 links to  free full text

Abstract: BACKGROUND: Evidence suggests that disease severity predicts the response of patients with Alzheimer disease (AD) to cholinesterase inhibitor treatment, raising the question of whether disease progression also predicts response to this treatment. OBJECTIVE: To evaluate retrospectively whether rate of disease progression during placebo treatment affects response to subsequent rivastigmine tartrate therapy for patients with mild to moderately severe AD. DESIGN: A 26-week, open-label extension study following a 26-week, double-blind, randomized, placebo-controlled trial. SETTING: Outpatient research centers at 22 sites in the United States. PATIENTS: We studied 187 of 235 patients originally randomized to receive placebo treatment in the double-blind phase of the trial who continued with open-label (rivastigmine) extension therapy. INTERVENTION: Placebo treatment for 26 weeks followed by rivastigmine treatment, 2 to 12 mg/d, for 26 weeks. MAIN OUTCOME MEASURES: Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog), Progressive Deterioration Scale, Mini-Mental State Examination, and Global Deterioration Scale scores. RESULTS: Rivastigmine administration during open-label extension therapy benefited patients who had progressed slowly and those who had progressed rapidly during initial double-blind placebo treatment. Slowly progressive patients responded with a mean 1.03-point improvement in the week 26 (ie, start of open-label rivastigmine treatment) ADAS-Cog score at 12 weeks of rivastigmine treatment (week 38 of treatment; P =.02 vs week 26). However, more rapidly progressive patients had a significantly larger mean 4.97-point improvement from the week 26 ADAS-Cog score at 12 weeks (with respect to week 26 of treatment and slowly progressive patient scores, P<.001 for both). Thus, a more rapid disease progression rate while receiving placebo treatment was predictive of a significantly stronger patient response to rivastigmine therapy. This relation also was observed with the other 3 outcome measures and was still apparent when accounting for disease severity. CONCLUSIONS: Rate of disease progression for patients with mild to moderate AD seems to predict response to rivastigmine treatment. Patients with more rapidly progressive disease might be particularly likely to benefit from rivastigmine therapy.

Farlow M, Anand R, Messina J, Hartman R, Veach J. · Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202-5111, USA. · Eur Neurol. · Pubmed #11096224 No free full text.

Abstract: The efficacy of a centrally active cholinesterase inhibitor, rivastigmine tartrate (ENA 713; Exelon, in patients with mild to moderately severe Alzheimer's disease was evaluated in a 26-week open-label extension of a 26-week, double-blind, placebo-controlled study. By 52 weeks, patients originally treated with 6-12 mg/day rivastigmine had significantly better cognitive function than patients originally treated with placebo.

Kumar V, Anand R, Messina J, Hartman R, Veach J. · Florida Institute of Neurosciences and Clinical Research, 530 S. Nokomis Avenue, Suite 14, Venice, FL 34284, USA. · Eur J Neurol. · Pubmed #10809936 No free full text.

Abstract: We evaluated the efficacy and safety of the centrally acting cholinesterase inhibitor, rivastigmine tartrate, for patients with mild to moderately severe Alzheimer's disease (AD) with or without concurrent vascular risk factors (VRF). Patients (45-90 years of age) were randomized to placebo (n = 235), low-dose rivastigmine (1-4 mg/day, n = 233), or high-dose rivastigmine (6-12 mg/day, n = 231) for 26 weeks. Efficacy measures included the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), the Clinician's Interview Based Impression of Change (CIBIC-Plus), the Progressive Deterioration Scale (PDS), the Global Deterioration Scale (GDS), and the Mini-Mental State Examination (MMSE). For efficacy and safety analysis, patients were categorized by baseline Modified Hachinski Ischemic Score (MHIS) for the determination of VRF (MHIS > 0: presence of VRF; MHIS = 0: absence of VRF). As early as 12 weeks, the mean change from the baseline ADAS-Cog score was significantly different for those patients treated with high-dose rivastigmine compared with placebo controls in both MHIS categories. However, the treatment difference between high-dose rivastigmine and placebo at each time-point was larger for patients with MHIS > 0. The proportion of responders was significantly greater in the high-dose rivastigmine group for each level of improvement. No differences were noted between treatment groups regarding safety evaluations. Rivastigmine is effective in both categories of patients, and those with VRF experience greater clinical benefit (cognition, activities of daily living, and disease severity).

Rösler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, Stähelin HB, Hartman R, Gharabawi M. · Sektion Gerontopsychiatric, Psychiatrische Universitätsklinik, Fuchsleinstrasse 15, D 97080 Würzburg, Germany. · BMJ. · Pubmed #10066203 links to  free full text

Abstract: OBJECTIVES: To assess the effects of rivastigmine on the core domains of Alzheimer's disease. DESIGN: Prospective, randomised, multicentre, double blind, placebo controlled, parallel group trial. Patients received either placebo, 1-4 mg/day (lower dose) rivastigmine, or 6-12 mg/day (higher dose) rivastigmine. Doses were increased in one of two fixed dose ranges (1-4 mg/day or 6-12 mg/day) over the first 12 weeks with a subsequent assessment period of 14 weeks. SETTING: 45 centres in Europe and North America. PARTICIPANTS: 725 patients with mild to moderately severe probable Alzheimer's disease diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, and the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association. OUTCOME MEASURES: Cognitive subscale of the Alzheimer's disease assessment scale, rating on the clinician interview based impression of change incorporating caregiver information scale, and the progressive deterioration scale. RESULTS: At the end of the study cognitive function had deteriorated among those in the placebo group. Scores on the Alzheimer's disease assessment scale improved in patients in the higher dose group when compared with patients taking placebo (P<0.05). Significantly more patients in the higher dose group had improved by 4 points or more than had improved in the placebo group (24% (57/242) v 16% (39/238)). Global function as rated by the clinician interview scale had significantly improved among those in the higher dose group compared with those taking placebo (P<0.001), and significantly more patients in the higher dose group showed improvement than did in the placebo group (37% (80/219) v 20% (46/230)). Mean scores on the progressive deterioration scale improved from baseline in patients in the higher dose group but fell in the placebo group. Adverse events were predominantly gastrointestinal, of mild to moderate severity, transient, and occurred mainly during escalation of the dose. 23% (55/242) of those in the higher dose group, 7% (18/242) of those in the lower dose group, and 7% (16/239) of those in the placebo group discontinued treatment because of adverse events. CONCLUSIONS: Rivastigmine is well tolerated and effective. It improves cognition, participation in activities of daily living, and global evaluation ratings in patients with mild to moderately severe Alzheimer's disease. This is the first treatment to show compelling evidence of efficacy in a predominantly European population.

Crawford FC, Freeman MJ, Schinka JA, Abdullah LI, Gold M, Hartman R, Krivian K, Morris MD, Richards D, Duara R, Anand R, Mullan MJ. · Roskamp Institute University of South Florida, Tampa, FL 33613, USA. · Neurology. · Pubmed #10993992 No free full text.

Abstract: OBJECTIVE: To investigate whether or not a coding polymorphism in the cystatin C gene (CST3) contributes risk for AD. DESIGN: A case-control genetic association study of a Caucasian dataset of 309 clinic- and community-based cases and 134 community-based controls. RESULTS: The authors find a signficant interaction between the GG genotype of CST3 and age/age of onset on risk for AD, such that in the over-80 age group the GG genotype contributes two-fold increased risk for the disease. The authors also see a trend toward interaction between APOE epsilon4-carrying genotype and age/age of onset in this dataset, but in the case of APOE the risk decreases with age. Analysis of only the community-based cases versus controls reveals a significant three-way interaction between APOE, CST3 and age/age of onset. CONCLUSION: The reduced or absent risk for AD conferred by APOE in older populations has been well reported in the literature, prompting the suggestion that additional genetic risk factors confer risk for later-onset AD. In the author's dataset the opposite effects of APOE and CST3 genotype on risk for AD with increasing age suggest that CST3 is one of the risk factors for later-onset AD. Although the functional significance of this coding polymorphism has not yet been reported, several hypotheses can be proposed as to how variation in an amyloidogenic cysteine protease inhibitor may have pathologic consequences for AD.