Alzheimer Disease: Doody RS

Fillit HM, Doody RS, Binaso K, Crooks GM, Ferris SH, Farlow MR, Leifer B, Mills C, Minkoff N, Orland B, Reichman WE, Salloway S. · Alzheimer's Drug Discovery Foundation and Institute for the Study of Aging New York, New York 10019, USA. · Am J Geriatr Pharmacother. · Pubmed #17157793 No free full text.

Abstract: BACKGROUND: Alzheimer's disease and related dementias (ADRDs) are increasingly recognized as important causes of impaired cognition, function, and quality of life, as well as excess medical care utilization and costs in the elderly Medicare managed care population. Evidence-based clinical practice guidelines for ADRDs were published in 2001. More recent studies have resulted in the approval of new agents and demonstrated an expanded role for antidementia therapy in various types of dementia, settings of care, stages of disease, and the use of combination therapy. However, these clinical guidelines have not been updated in the past few years. OBJECTIVE: The goal of this article was to provide practical recommendations developed by a panel of experts that address issues of early diagnosis, treatment, and care management of ADRDs. The panel also addressed the societal and managed care implications. METHODS: A panel of leading experts was convened to develop consensus recommendations for the treatment and management of dementia based on currently available evidence and the panel's informed expert opinion. The panel comprised 12 leading experts, including clinical investigators and practitioners in geriatric medicine, neurology, psychiatry, and psychology; managed care medical and pharmacy directors; a health systems medical director; and a health policy expert. In addition, articles were collected based on PubMed searches (2000-2005) that were relevant to the key issues identified. Search terms included Alzheimer's disease, dementia, clinical practice guidelines, clinical trials, screening and assessment, and managed care. RESULTS: ADRDs represent a significant clinical and economic burden to individuals and society, including Medicare managed care organizations (MCOs). Appropriate utilization of antidementia therapy and care management is vitally important to achieving quality of life and care for dementia patients and their caregivers, and for managing the excess costs of Alzheimer's disease. The recommendations address relevant, practical, and timely concerns that are faced on a daily basis by practitioners and by Medicare MCO medical management programs in the care of dementia patients. These consensus recommendations attempt to describe a reasonable current standard for the provision of quality care for patients with dementia. The panel recommendations support the use of screening for cognitive impairment and the use of antidementia therapy for ADRDs in different stages of disease and types of dementia in all clinical settings. The panel members evaluated the use of the 3 marketed cholinesterase inhibitors-donepezil, galantamine, and rivastigmine-as well as the N-methyl-D-aspartate antagonist memantine. Recommendations for using these medications are made with an appreciation of the difficulties in translating the results from investigational clinical trials into clinical practice. CONCLUSIONS: The recommendations of the expert panel represent a clear consensus that nihilism in the diagnosis, treatment, and management of ADRDs is unwarranted, impairs quality of care, and is ultimately not costeffective.

Doody RS. · Effie Marie Cain Chair in Alzheimer's Disease Research, Baylor College of Medicine, Houston, TX, USA. · Alzheimers Dement. · Pubmed #19328443 No free full text.

Abstract: Despite enormous worldwide public and private interest in improving the prevention and treatment of Alzheimer's disease (AD), we have not made as much of an impact as we would like, and the number of affected individuals continues to grow. Even more alarmingly, whereas global efforts to identify AD cases and to develop new treatments are increasing, patient-care options are disappearing, so that even if a highly efficacious therapy or prevention approach arose, it would not be used effectively. As a first step toward organizing a better way forward, we should establish AD centers of excellence that mandate both patient care and research in the same setting. These centers would benefit from changes in public health policies related to chronic-disease surveillance, Center for Medicare and Medicaid Services funding for the care of chronic diseases, institutional review boards, good clinical practice guidelines, National Institutes of Health regulations for the use of research funds, Food and Drug Administration guidelines for the approval of AD drugs, and Department of Commerce regulations related to patent protection of AD diagnostic aids and treatments. This new form of AD centers of excellence would also provide direct care to many patients and their families, model care for communities and medical trainees, enhance the voluntary recruitment of AD patients to clinical trials, and improve our understanding of AD and its management.

Doody RS. · Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, Houston, Texas, USA. · CNS Spectr. · Pubmed #18955960 links to  free full text

This publication has no abstract.

Geldmacher DS, Frolich L, Doody RS, Erkinjuntti T, Vellas B, Jones RW, Banerjee S, Lin P, Sano M. · Memory Disorders Program, Department of Neurology, University of Virginia, Box 800394, Charlottesville, Virginia 22908, USA. · J Nutr Health Aging. · Pubmed #17066215 No free full text.

Abstract: Alzheimer's disease (AD) is a progressive degenerative disease that warrants active management to delay or slow progression of its symptoms. The symptoms of AD encompass behavior and daily function as well as cognition, so clinicians should take a global view in the assessment of treatment success. Because there is currently no cure for AD, one cannot expect an initial cognitive improvement observed in the first few months of therapy to be sustained indefinitely. However, one should expect that the patient who is treated early and persistently with medication for AD will show less evidence of behavioral, functional, and cognitive deterioration over a period of time than one would expect in the absence of pharmacotherapy. Thus, treatment success includes not only short-term improvement of symptoms but also less decline over the long term. Determination of treatment success therefore also requires awareness of the typical progression of untreated AD. In this article we review the natural history of AD and evidence for the effectiveness of the treatments indicated for AD: donepezil, galantamine, rivastigmine, and memantine.

Doody RS. · Baylor College of Medicine, Houston, Texas, USA. · Geriatrics. · Pubmed #16025771 No free full text.

Abstract: The introduction of new therapies into the clinical arena often requires that prescribing clinicians determine how these new treatments should be integrated into an existing standard of care, typically with little more than clinical trial data to guide them. However, trial outcome measures may not always translate easily into useful information for the practicing physician. Since the publication of dementia treatment guidelines in 2001, new data on Alzheimer's disease (AD) therapies have become available. Notably, memantine has emerged as the first medication indicated for the moderate-to-severe stages of AD. This review summarizes pivotal clinical trial data on memantine in the treatment of moderate-to-severe AD and describes how these results may be interpreted for use in the clinical treatment setting. The studies showed that memantine, both alone and in combination with donepezil, was associated with positive, clinically relevant effects on cognitive and functional ability. Further, memantine in combination with donepezil also was significantly better than donepezil alone in management of behavioral symptoms. This review will conclude with a discussion of how new data on AD treatments will potentially change current treatment parameters.

Doody RS. · Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA. · J Clin Psychiatry. · Pubmed #12934969 No free full text.

Abstract: The current recommended standard of care for the symptomatic treatment of mild to moderate Alzheimer's disease is cholinesterase inhibitors. In short- and long-term studies, the 3 cholinesterase inhibitors most commonly used, donepezil, rivastigmine, and galantamine, have demonstrated efficacy in improving not only cognition but also function and behavior in patients suffering from mild to severe cases of Alzheimer's disease and other forms of dementia. However, the benefits of cholinesterase inhibitors in treating the broad spectrum of symptoms associated with Alzheimer's disease are not sustained indefinitely, and the illness continues to progress even while patients are receiving treatment. Additionally, while temporary stabilization may occur, there is typically only a modest improvement from baseline, and side effects from treatment with cholinesterase inhibitors can be too severe for some patients to tolerate. Therefore, additional therapies for Alzheimer's disease still need to be developed that include more tolerable agents with alternative mechanisms of action and broader efficacy.

Doody RS. · Baylor College of Medicine, Department of Neurology, Houston, Texas 77030, USA. · Alzheimer Dis Assoc Disord. · Pubmed #10622675 No free full text.

Abstract: Donepezil is an effective, well-tolerated, and easily administered symptomatic treatment for mild-to-moderate Alzheimer disease (AD). Data from Phase III clinical trials have demonstrated that donepezil improves cognition, global function, and activities of daily living. In addition, there were no clinically significant treatment-related effects on vital signs or laboratory values in any trial. Adverse events, when present, were generally mild in intensity, transient, and resolved during continued treatment with donepezil. This favorable safety profile, together with its reported clinical benefits established donepezil as one standard of AD therapy. Vitamin E is one of two anti-oxidant therapies that may help to slow the progression of AD over at least a two-year period. One large-scale clinical trial suggests that it has sufficient benefit and safety to join donepezil as a current standard of AD therapy.

Doody RS. · Baylor College of Medicine, Department of Neurology and Alzheimer's Disease Research Center, Houston, TX 77030, USA. · Eur Neuropsychopharmacol. · Pubmed #10332937 No free full text.

Abstract: Alzheimer's disease (AD) is associated with a deficiency of acetylcholine (ACh) in the forebrain that correlates with brain pathology and cognitive dysfunction. The most promising approach to enhancing central ACh neurotransmission has been the utilization of agents that inhibit cholinesterases which block its catabolism. Initially, the success of this strategy was limited by subtherapeutic levels of acetylcholinesterase (AChE) inhibition, tolerability problems and toxicity of the first agents. Donepezil HCI represents a new chemical class of AChE inhibitors, the piperidines. In clinical trials, donepezil has been shown to improve significantly cognition and global function in patients with mild to moderately severe AD, and has demonstrated an excellent tolerability and safety profile. These benefits, as well as a simple, once-daily dosing regimen, make donepezil a viable therapeutic option for AD patients.

Doody RS. · Baylor College of Medicine, Department of Neurology and Alzheimer's Disease Research Center, Houston, Tex. 77030-3498, USA. · Gerontology. · Pubmed #9876215 No free full text.

Abstract: Although the underlying pathogenesis of Alzheimer's disease (AD) is not fully understood, one of its key features is the widespread loss of central cholinergic innervation, known to be fundamental for cognitive processes. This finding led to the hypothesis that pharmacological enhancement of acetylcholine (ACh) neurotransmission may alleviate the symptoms of AD. Currently, cholinergic therapy, particularly cholinesterase (ChE) inhibition, represents the most realistic approach to the symptomatic treatment of AD. Donepezil HCl, for example, is a piperidine-based, reversible acetylcholinesterase (AChE) inhibitor, chemically distinct from other ChE inhibitors and rationally designed for the symptomatic treatment of AD. It is highly selective for centrally acting AChE, with little or no affinity for butyrylcholinesterase, present predominantly in the periphery. Phase I and II clinical trials demonstrated donepezil's favourable pharmacokinetic, pharmacodynamic and safety profile with no requirement for dose modification in the elderly or in patients with renal or hepatic impairment. Furthermore, its long half-life supports a simple and convenient once-daily dosing regimen. Subsequent to encouraging phase II clinical trial results, two pivotal, randomized, double-blind phase III trials (of 15 and 30 weeks' duration) demonstrated highly significant improvements in cognition and global function in mild to moderately severe AD patients treated with either 5 or 10 mg/day donepezil compared with placebo. Adverse events in the phase II and III trials, primarily cholinergic in nature, were transient and generally mild in severity and resolved during continued donepezil administration. Thus, the donepezil clinical trials programme has shown that this drug is a clinically effective and well-tolerated, once-daily treatment for the symptoms of mild to moderately severe AD.

Yan JH, Rountree S, Massman P, Doody RS, Li H. · Department of Kinesiology, California State University at East Bay, 25800 Carlos Bee Boulevard, Hayward, CA 94542-3062, USA. · J Psychiatr Res. · Pubmed #18280503 No free full text.

Abstract: Sensory-motor dysfunctions are often associated with Alzheimer's disease (AD) or mild cognitive impairment (MCI). This study suggests that deterioration in fine motor control and coordination characterizes sensory-motor deficiencies of AD and MCI. Nine patients with a clinical diagnosis of probable AD, 9 amnestic MCI subjects and 10 cognitively normal controls performed four types of handwriting movement on a digitizer. Movement time and smoothness were analyzed between the groups and across the movement patterns. Kinematic profiles were also compared among the groups. AD and MCI patients demonstrated slower, less smooth, less coordinated, and less consistent handwriting movements than their healthy counterparts. The theoretical relevance and practical implications of fine motor tasks, such as these movements involved in handwriting, are discussed relative to the deteriorated sensory-motor system of AD and MCI patients.

Davis RN, Massman PJ, Doody RS. · Department of Psychology, University of Houston, USA. · Psychol Aging. · Pubmed #14692868 No free full text.

Abstract: The WAIS-R is often used in neuropsychological evaluations of individuals with probable Alzheimer's disease (AD), but its factor structure in this population is unknown. Moreover, theories and past research findings make competing predictions concerning its structure. Using confirmatory factor analysis, the authors compared 5 alternative WAIS-R factor models among 516 AD patients: 1-factor (Spearman's g) and 2-factor (Verbal IQ and Performance IQ) models; a 3-factor model including Verbal Comprehension (VC), Perceptual Organization (PO), and Freedom From Distractibility (FD) factors; a 3-factor model in which Digit Symbol loads on PO rather than FD; and a 3-factor model in which Digit Symbol loads on both PO and FD. Results favored the 3-factor model in which Digit Symbol loads on PO rather than FD. Moreover, this model fit the data best among subsamples of patients defined by age, dementia severity, years of education, and gender.

Mohs RC, Doody RS, Morris JC, Ieni JR, Rogers SL, Perdomo CA, Pratt RD, Anonymous00310. · Mount Sinai School of Medicine, Bronx VA Medical Center, New York, NY 10468, USA. · Neurology. · Pubmed #11502917 No free full text.

Abstract: OBJECTIVE: To examine the effects of donepezil compared with placebo on the preservation of function in patients with AD over a 1-year period. METHODS: This was a prospective, 54-week, double-blind, placebo-controlled, survival to endpoint study. Patients were required to have at entry: a diagnosis of probable AD (National Institute of Neurological and Communicative Disorders and Stroke criteria); Mini-Mental State Examination score of 12 to 20; Clinical Dementia Rating of 1 or 2; modified Hachinski ischemia score < or =4; and capability of performing 8 of 10 instrumental activities of daily living and 5 of 6 basic activities of daily living. Patients (n = 431) were randomized to placebo or donepezil (5 mg/day for 28 days, 10 mg/day thereafter). Outcome measures were the AD Functional Assessment and Change Scale, the Mini-Mental State Examination, and Clinical Dementia Rating scale. At each visit, investigators determined whether predefined criteria for clinically evident decline in functional status had been met. Patients who met the endpoint criteria were discontinued per protocol. RESULTS: Donepezil extended the median time to clinically evident functional decline by 5 months versus placebo. The probability of patients treated with donepezil remaining in the study with no clinically evident functional loss was 51% at 48 weeks, compared with 35% for placebo. The Kaplan-Meier survival curves for the two treatment groups were different (p = 0.002, log-rank test). CONCLUSIONS: Patients with AD continue to show detectable disease progression over time, but treatment with donepezil for 1 year was associated with a 38% reduction in the risk of functional decline compared with placebo.

Doody RS, Dunn JK, Clark CM, Farlow M, Foster NL, Liao T, Gonzales N, Lai E, Massman P. · Baylor College of Medicine Alzheimer's Disease Research Center (AGO-8664), Houston, Tex 77030-3498, USA. · Dement Geriatr Cogn Disord. · Pubmed #11351141 No free full text.

Abstract: OBJECTIVE: To compare rates of cognitive decline between probable Alzheimer's disease (AD) patients treated with long-duration cholinesterase inhibitors (ChE-Is) and those who remained untreated. BACKGROUND: ChE-Is, including donepezil and tracrine, have shown beneficial effects on cognition and global functioning in patients with AD. The duration of these benefits is unknown because the longest double-blind placebo-controlled studies reported were only approximately 6 months long. Ethical concerns regarding randomization of patients to placebo for long periods make it difficult to undertake trials of longer duration. METHODS: We identified patients in 4 AD centers who were or were not consistently treated with ChE-Is and who had demographic, psychometric and follow-up data. We compared 205 ChE-I-treated and 218 untreated AD patients on baseline variables hypothesized to differ between these groups, on baseline Mini Mental Status Examination (MMSE) scores and on rates of MMSE change at 1 year. The analysis was performed initially with all ChE-I-treated patients as a single group versus untreated subjects, and then with donepezil versus untreated subjects and tacrine versus untreated subjects. RESULTS: As expected, treated and untreated patients differed with respect to age, education, ethnicity, percentage of community dwelling and exact days of follow-up (ANOVA and chi2) in several comparisons, but did not differ on baseline MMSE score. These baseline variables were highly intercorrelated. MMSE scores declined significantly more slowly after 1 year of ChE-I treatment compared to untreated patients (p = 0.05) after controlling for baseline differences in age, education, ethnicity and percentage of community dwelling. Slowing of decline was significant in the donepezil-treated patients (p = 0.007) but not in the tacrine-treated group (p = 0.33). CONCLUSIONS: This study, utilizing concurrent, nonrandomized controls, suggests that donepezil continues to have efficacy over at least the first year of therapy. Other studies are needed to determine whether the benefits are maintained beyond 1 year.

Doody RS, Massman P, Dunn JK. · Baylor College of Medicine, Department of Neurology, 6550 Fannin St., Suite 1801, Houston, TX 77030, USA. · Arch Neurol. · Pubmed #11255449 links to  free full text

Abstract: BACKGROUND: The ability to predict progression of disease in patients with Alzheimer disease (AD) would aid clinicians, improve the validation of biomarkers, and contribute to alternative study designs for AD therapies. OBJECTIVE: To test a calculated rate of initial decline prior to the first physician visit (preprogression rate) for its ability to predict progression during subsequent follow-up. METHODS: We calculated preprogression rates for 298 patients with probable or possible AD (using the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Associations (NINCDS-ADRDA) with a formula using expected Mini-Mental State Examination (MMSE) scores, scores at presentation, and a standardized estimate of duration. The patients are being followed up longitudinally in our Alzheimer Disease Research Center. The time to clinically meaningful deterioration, defined as an MMSE score drop of 5 or more points, was compared for patients stratified as slow, intermediate, and rapid progressors based on the preprogression rate. Cox regression analysis was used to examine the contribution of demographic variables (age, sex, ethnicity, and level of education), initial MMSE scores, estimated symptom duration, and the calculated preprogression rate to the time it took to reach the end point across the groups. RESULTS: Both initial MMSE (hazard ratio, 0.95 (0.002); z = 4.19; P<.001) and the calculated preprogression rate (hazard ratio, 1.06 (0.019); z = 3.16; P =.002) were significant in determining time to clinically meaningful decline during longitudinal follow-up (Cox regression analysis). Slow, intermediate, and rapid progressors (based on preprogression rates) experienced significantly different time intervals to clinically meaningful deterioration, with the slow progressors taking the longest time, the intermediate progressors in the middle, and the rapid progressors reaching the end point first (log rank chi(2)(1) = 9.81, P =.002). CONCLUSION: An easily calculable rate of early disease progression can classify patients as rapid, intermediate, or slow progressors with good predictive value, even at initial presentation.

Doody RS, Geldmacher DS, Gordon B, Perdomo CA, Pratt RD, Anonymous00078. · Department of Neurology, Baylor College of Medicine, 6550 Fannin Street, Suite 1801, Houston, TX 77030-3498, USA. · Arch Neurol. · Pubmed #11255446 links to  free full text

Abstract: BACKGROUND: Donepezil hydrochloride is a selective acetylcholinesterase inhibitor approved for the symptomatic treatment of mild to moderately severe Alzheimer disease (AD). Controlled clinical trials of up to 24 weeks have demonstrated that donepezil treatment (5 and 10 mg/d) significantly improves cognition and global function. OBJECTIVE: To investigate the long-term benefits of donepezil treatment in patients with AD. DESIGN: Multicenter, open-label, 144-week extension of 2 US phase 3, double-blind, placebo-controlled clinical trials: a 15-week study (12 weeks of treatment followed by a 3-week placebo washout) and a 30-week study (24 weeks of treatment followed by a 6-week placebo washout). INTERVENTIONS: All patients (N = 763) initially received donepezil, 5 mg/d, for 6 weeks, after which an increase to 10 mg/d was encouraged. MEASURES: Primary efficacy measures were the Alzheimer's Disease Assessment Scale-cognitive subscale and the Clinical Dementia Rating-Sum of the Boxes. RESULTS: After the shorter 3-week placebo washout, donepezil-associated benefits remained above original baseline values for an additional 24 weeks of open-label treatment. Benefits on Alzheimer's Disease Assessment Scale-cognitive subscale scores for patients who received 10 mg/d in the double-blind study were evident compared with the other groups for 108 weeks of open-label treatment. In contrast, donepezil-associated benefits were lost after the 6-week placebo washout, and scores decreased below original baseline values for all patient groups. Although scores improved relative to the new open-label study baseline scores after drug use was restarted, patients remained below original baseline values. The most common adverse events were associated with the nervous and digestive systems and were generally mild and transient; 17% of patient discontinuations were associated with adverse events. CONCLUSIONS: Donepezil is an effective and safe drug for the long-term symptomatic treatment of mild to moderately severe AD for up to 144 weeks (2.8 years), and sustained treatment may confer some advantages.

Davis RN, Massman PJ, Doody RS. · Department of Psychology, University of Houston, Texas 77204-5341, USA. · Alzheimer Dis Assoc Disord. · Pubmed #11236819 No free full text.

Abstract: The efficacy of a cognitive intervention consisting of training in face-name associations, spaced retrieval, and cognitive stimulation was tested in a sample of 37 patients (16 men, 21 women) with probable Alzheimer disease (AD). Patients with AD were randomly assigned to receive either the cognitive intervention or a mock (placebo) intervention for 5 weeks. The placebo group then crossed over to receive the intervention. During the intervention, AD patients showed significant improvement in recall of personal information, face-name recall, and performance on the Verbal Series Attention Test. Improvement did not generalize to additional neuropsychologic measures of dementia severity, verbal memory, visual memory, word generation, or motor speed, or to caregiver-assessed patient quality of life. Results suggest that although face-name training, spaced retrieval, and cognitive stimulation may produce small gains in learning personal information and on a measure of attention, improvement does not generalize to overall neuropsychologic functioning or patient quality of life.

Rogers SL, Doody RS, Pratt RD, Ieni JR. · Eisai Co. Ltd., 6-10 Koishikawa 4 chrome, Bunkyo-ku, Tokyo, Japan. · Eur Neuropsychopharmacol. · Pubmed #10793322 No free full text.

Abstract: This multicentre, open-label study evaluated the long-term efficacy and safety of donepezil in the treatment of patients with mild to moderately severe Alzheimer's disease (AD). The 133 patients who entered the study had previously completed a 14-week randomized, double-blind, placebo-controlled study with donepezil. In this open-label study, patients were treated initially with 3 mg per day donepezil, which could be increased to 5, 7 and 10 mg per day in a step-wise fashion. Patients attended the clinic for assessments at 3-week intervals for the first 12 weeks, then subsequently at 12-week intervals for up to 240 weeks (254 cumulative weeks). Efficacy was assessed using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Clinical Dementia Rating-Sum of the Boxes scale (CDR-SB), and data were compared with those predicted for historical untreated AD patients. During the first 6-9 months of the study, mean ADAS-cog and CDR-SB scores showed evidence of clinical improvement from baseline. After this time scores gradually deteriorated. Overall the decline was less than that estimated if this cohort of patients had not been treated. The most common adverse events were related to the nervous and digestive systems, and were generally mild and transient, resolving without the need for dose modifications. There was no evidence of hepatotoxicity. In conclusion, these data demonstrate that donepezil is a well-tolerated, realistic symptomatic treatment for AD over a period of up to 4.9 years. An interim report of the first 98 weeks of the study has been published previously.

Snyder PJ, Papp KV, Bartkowiak J, Jackson CE, Doody RS. · Department of Clinical Neurosciences, Warren Alpert Medical School, Brown University and Lifespan Hospitals System, Providence, RI, USA. · Alzheimers Dement. · Pubmed #19328439 No free full text.

Abstract: A major barrier to progress in Alzheimer's disease treatment research is the increasingly difficult task of recruiting elderly participants into clinical trials. We conducted an anonymous online survey of 676 adults (average age, 50 years) to examine perceived trust in different components of our healthcare-delivery and clinical-research systems, as well as willingness to participate in clinical trials. Respondents indicated the greatest amount of trust in family members, followed by family physicians. Only 3% of respondents "completely" trusted clinical researchers, whereas 62% of respondents trusted them "somewhat" to care for them during the course of a clinical trial. Trust in clinical researchers was modestly negatively correlated with income (r = -0.165, P < .001), but was not significantly related to sex, race, or education. Respondents indicated the least amount of trust in industry sponsors, followed by regulatory authorities.

Doody RS, Ferris SH, Salloway S, Sun Y, Goldman R, Watkins WE, Xu Y, Murthy AK. · Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, 6550 Fannin, Suite 1801, Houston, TX 77030, USA. · Neurology. · Pubmed #19176895 No free full text.

Abstract: BACKGROUND: Treatment of mild cognitive impairment (MCI) with cholinesterase inhibitors may improve symptoms. METHODS: In this multicenter, randomized, placebo-controlled trial, subjects with MCI entered a 3-week placebo run-in period followed by 48 weeks of double-blind donepezil (5 mg/day for 6 weeks, then 10 mg/day for 42 weeks) or placebo treatment. Primary efficacy variables included change from baseline in the modified Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-Cog) and Clinical Dementia Rating Scale-sum of boxes (CDR-SB) after 48 weeks of treatment (modified intention-to-treat analysis). Secondary efficacy measures evaluated cognition, behavior, and function. RESULTS: The dual primary efficacy endpoint was not reached. We noted a small, but significant, decrease in modified ADAS-Cog scores in favor of donepezil at study endpoint. Little change from baseline in CDR-SB and secondary variables was observed for either group. Patient Global Assessment scores favored donepezil at all time points except week 12 (p < or = 0.05). Perceived Deficits Questionnaire scores favored donepezil at week 24 (p = 0.05). Clinical Global Impression of Change-MCI scores favored donepezil only at week 6 (p = 0.04). Adverse events were generally mild or moderate. More donepezil-treated subjects (18.4%) discontinued treatment due to adverse events than placebo-treated subjects (8.3%). CONCLUSIONS: Donepezil demonstrated small but significant improvement on the primary measure of cognition but there was no change on the primary measure of global function. Most other measures of global impairment, cognition, and function were not improved, possibly because these measures are insensitive to change in MCI. Responses on subjective measures suggest subjects perceived benefits with donepezil treatment.

Na HR, Lee SH, Lee JS, Doody RS, Kim SY. · Department of Neurology, Bobath Memorial Hospital, Seongnam, Korea. · Dement Geriatr Cogn Disord. · Pubmed #19145080 No free full text.

Abstract: BACKGROUND: The Baylor Profound Mental Status Examination (BPMSE) was modeled to provide a brief patient-derived rating scale for staging and tracking patients with severe stages of Alzheimer's disease (AD). METHODS: The BPMSE was administered to 91 patients with probable AD (Korean version of the MMSE less than 16) according to the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria. The patients were also evaluated using the Korean version of the Severe Impairment Battery (SIB-Ko), Clinical Dementia Rating (CDR), Global Deterioration Scale (GDS), Barthel Activities of Daily Living (B-ADL), the Korean version of the Instrumental Activities of Daily Living (K-IADL), the Korean version of the Neuropsychiatric Inventory (K-NPI) and the Functional Assessment Staging (FAST). RESULTS: There were significant correlations between the BPMSE- Ko and K-MMSE scores (r = 0.66, p < 0.001) and between the BPMSE-Ko and SIB-Ko scores (r = 0.83, p < 0.001). The BPMSE-Ko correlated with the CDR, GDS, B-ADL, K-IADL, K-NPI and FAST scores (p < 0.001). The BPMSE-Ko scores continued to decline even after the K-MMSE reached values near 0. CONCLUSIONS: The BPMSE-Ko is a time efficient and useful tool to measure cognitive function in patients with severe AD.

Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D, Anonymous00052. · Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, Houston, TX, USA. · Lancet. · Pubmed #18640457 No free full text.

Abstract: BACKGROUND: Although treatments for Alzheimer's disease sometimes improve cognition, functional ability, or behaviour compared with baseline levels, such improvements are inconsistent across studies and measures, and effects diminish over time. More effective treatments are needed. We assessed the safety, tolerability, and efficacy of dimebon in the treatment of patients with mild-to-moderate Alzheimer's disease. METHODS: We enrolled 183 patients with mild-to-moderate Alzheimer's disease (mini-mental state examination [MMSE] scores 10-24) at 11 sites in Russia. Patients were randomly assigned by a computer-generated randomisation scheme to receive oral dimebon, 20 mg three times a day (60 mg/day [n=89]), or matched placebo (n=94). Other antidementia drugs were not allowed. The primary outcome measure assessed cognition, the difference in mean change from baseline to week 26, or last completed observation on the cognitive subscale of the Alzheimer's disease assessment scale (ADAS-cog). All patients and study personnel were blinded throughout the study. We compared dimebon with placebo with an intention-to-treat analysis, with last observation carried forward (ITT-LOCF) imputation. Analyses were repeated on the fully evaluable population, defined as all patients in the intention-to-treat population who had an ADAS-cog at week 26 and at least 80% compliance. 134 patients (68 in dimebon group, 66 in placebo group) enrolled in the 6-month blinded extension phase of the study. This trial is registered with Clinicaltrials.gov, number NCT00377715. FINDINGS: 155 (85%) patients completed the trial (78 [88%] in dimebon group, 77 [82%] in placebo group). Treatment with dimebon resulted in significant benefits in ADAS-cog compared with placebo (ITT-LOCF) at week 26 (mean drug-placebo difference -4.0 [95% CI -5.73 to -2.28]; p<0.0001). Results of the ITT-LOCF and the evaluable population analyses were much the same for all measures. Patients given dimebon were significantly improved over baseline for ADAS-cog (mean difference -1.9 [-2.92 to -0.85]; p=0.0005). Dimebon was well tolerated: dry mouth and depressed mood or depression were the most common adverse events associated with dimebon (12 [14%] patients for each symptom by week 26). The percentage of patients who had adverse events in the two groups did not differ. INTERPRETATION: Dimebon was safe, well tolerated, and significantly improved the clinical course of patients with mild-to-moderate Alzheimer's disease.

Doody RS. · Baylor College of Medicine, Houston, TX, USA. · Alzheimers Dement. · Pubmed #18631995 No free full text.

Abstract: The terms symptomatic and disease-modifying have become standard in discussions of Alzheimer's disease therapeutics, yet there is little justification for their use. Currently marketed drugs are presumed to be symptomatic because they lead to some degree of mean improvement over baseline and because of the widespread belief that their mechanisms are limited and their effects are completely reversible. Current trial methodologies cannot distinguish between symptomatic and disease-modifying effects. Furthermore, it is highly likely that many trials will demonstrate a combination of such effects at the level of the trial or at the level of the individual. The forces that drive this distinction are largely social, as opposed to scientific. It would be preferable for drugs to first seek an antidementia claim, preferably on the background of conventional therapies when possible, in trials that are as small and as short in duration as possible. Further refinements would come by demonstration of how substantial and how enduring the antidementia benefits are.

Doody RS, Corey-Bloom J, Zhang R, Li H, Ieni J, Schindler R. · Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, Houston, Texas 77030, USA. · Drugs Aging. · Pubmed #18257603 No free full text.

Abstract: BACKGROUND: Donepezil is licensed for the treatment of mild-to-moderate Alzheimer's disease (AD) at doses of 5-10 mg/day and has recently been approved in the US for severe AD. Multiple studies have suggested that donepezil 10 mg/day provides additional cognitive and functional benefits over the 5 mg/day dose. Higher doses of donepezil, if safe and well tolerated, might provide further benefits for patients with AD. OBJECTIVE: To evaluate the safety and tolerability of donepezil at doses of 15 and 20 mg/day. METHOD: A 24-week, randomized, double-blind, placebo-controlled, pilot study conducted at two investigational sites in the US. Enrolled patients (male and female; aged 50-86 years) had a diagnosis of probable AD at the mild-to-moderate stage (Mini-Mental State Examination [MMSE] score 10-26). All patients had been treated with donepezil 10 mg/day for 12-30 months prior to enrolment. Patients (n = 31) were randomized 1 : 1 to receive either a standard dose of donepezil (donepezil 10 mg/day plus placebo 5 mg/day for weeks 1-12; donepezil 10 mg/day plus placebo 10 mg/day for weeks 13-24) or a higher dose of donepezil (donepezil 15 mg/day for weeks 1-12; donepezil 20 mg/day for weeks 13-24). Primary outcome measures were tolerability (as determined by monitoring of discontinuations, dose modifications and adverse events) and safety (as determined by adverse event monitoring, physical examinations, clinical laboratory tests and ECGs). Psychometric measures (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-cog], MMSE and Clinician's Interview-Based Impression of Change with caregiver information [CIBIC+]) and pharmacokinetic/pharmacodynamic parameters were secondary outcomes. RESULTS: No patients withdrew from the study and there were no serious adverse events or deaths. By week 24, 15 of 16 patients in the higher-dose group tolerated the maximum 20 mg/day dose; one patient had a permanent dose reduction to donepezil 15 mg/day. In the standard-dose group, 14 of 15 patients tolerated donepezil 10 mg/day plus placebo 10 mg/day by the end of the study; one patient had a permanent dose reduction to donepezil 10 mg/day plus placebo 5 mg/day. Temporary dose reductions occurred in two patients (one from each group). Adverse events reported were as expected for donepezil and were all mild to moderate in intensity. Adverse events considered to be possibly or probably related to treatment were reported for three patients in the standard-dose group and six patients in the higher-dose group. One patient in the higher-dose group had weight loss reported as possibly or probably treatment related. Mean changes on ECGs were not clinically significant in either group, and the incidence of bradycardia was comparable. No treatment difference on any of the psychometric measures was observed between the groups. Pharmacokinetic analyses showed that an increased donepezil dose was associated with an increase in donepezil plasma concentrations from baseline. CONCLUSION: In this small pilot study of patients with mild-to-moderate AD already stabilized on donepezil 10 mg/day, doses of 15 and 20 mg/day of donepezil appeared safe and well tolerated. These results justify initiation of larger clinical trials designed to investigate the efficacy and safety of doses of donepezil higher than 10 mg/day in patients with AD.

Park KW, Pavlik VN, Rountree SD, Darby EJ, Doody RS. · Department of Neurology, Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, Houston, TX 77030, USA. · Dement Geriatr Cogn Disord. · Pubmed #17914262 No free full text.

Abstract: BACKGROUND: The purpose of this study is to examine baseline differences and annualized cognitive and functional change scores in mild Alzheimer's disease (AD) patients with and without impaired activities of daily living (ADL). METHODS: We recruited 267 mild probable AD patients with at least 1 year of follow-up (NINCDS-ADRDA criteria, MMSE>or=20). Based on initial ADL scores, they were divided into 2 groups: unimpaired (n=40) and impaired (n=227). We compared the differences in annualized change scores on MMSE, Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), ADL and Clinical Dementia Rating sum of box score (CDR-SB) for patients with and without functional impairment at baseline. RESULTS: The group with unimpaired ADL at baseline had a significantly shorter symptom duration (p=0.01) and better neuropsychological test scores at baseline (p<0.001) than those with impaired ADL. The annualized cognitive and functional change of each group from baseline to 1-year follow-up was not significantly different on the MMSE, ADAS-cog, CDR-SB, Physical Self-Maintenance Scale and Instrumental Activities of Daily Living. After 1 year, 56% of the initially unimpaired group and 6% of the initially impaired group reported no ADL impairment. CONCLUSIONS: Our study suggests that functional decline should not be required for the diagnosis of mild AD.

Atchison TB, Massman PJ, Doody RS. · Department of Psychology, Sociology, and Social Work, West Texas A&M University, Box 60296, Canyon, TX 79016-0001, United States. · Arch Clin Neuropsychol. · Pubmed #17174522 No free full text.

Abstract: Decline in basic self-care abilities is an important risk factor for institutionalization in individuals with dementia. The ability to predict such decline would be of clinical importance in working with families of dementia patients. Research has suggested that cognitive decline may precede loss of functional capacity. This paper utilized a large sample of probable Alzheimer's disease patients (N=150) who were evaluated longitudinally to assess the pattern of neuropsychological functioning predictive of rapid decline in self-care. The findings indicated that despite initial equality of Lawton Physical Self-Maintenance (PSM) scores, patients showing rapid decline of PSM function displayed significantly more impaired performance on neuropsychological measures at diagnosis. They also exhibited a statistically significant difference in the pattern of scores from patients who remained stable. The pattern of the rapid declining group included more severe impairment in visual spatial skills, processing speed, and concept formation. Difficulties in using individual patients' cognitive profiles to make predictions about future rate of PSM decline are discussed.