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June 2005 Cholinesterase Inhibitors Across Stages of Dementia and Cognitive Impairments in the Elderly
On March 5, a symposium entitled “Cholinesterase Inhibitors Across Stages of Dementia and Cognitive Impairments in the Elderly” was held at the 2005 Annual Meeting of the American Association for Geriatric Psychiatry. Presenters discussed the recognition and treatment of mild cognitive impairment; Alzheimer’s disease and its response to cholinesterase inhibitors; the management of cognitive and behavioral symptoms of dementia with Lewy bodies; and the response of Parkinson’s disease dementia to cholinesterase inhibitors.
CME Certified
CME Accreditation
This activity was developed for primary care physicians and geriatric psychiatrists.
Educational Objectives
Upon completion of this activity, participants should be able to:
• Discuss diagnostic criteria and treatment options for dementia with Lewy bodies, Parkinson’s disease with dementia, and Alzheimer’s disease.
• Identify specific symptoms that may indicate the onset of mild cognitive impairment.
• Review strategies for maximizing the use of cholinesterase inhibitors, and to identify potential future applications of cholinergic therapy for various dementias and mild cognitive impairment.
Sponsorship
This activity is sponsored by the American Association for Geriatric Psychiatry.
Accreditation
The American Association for Geriatric Psychiatry (AAGP) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. AAGP designates this continuing educational activity for a maximum of one Category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity. This CME activity was planned and produced in accordance with the ACCME Essentials. Based upon trials, the estimated time to complete this activity is 1 hour.
Educational Grant
This activity is supported by an educational grant from Novartis Pharmaceuticals Corporation.
Faculty Disclosure Information
The American Association for Geriatric Psychiatry requires that the authors participating in a continuing medical education activity disclose to participants any significant financial interest or other relationship (1) with the manufacturers of any commercial service discussed in an educational presentation, and (2) with any commercial supporters of the activity.
Soo Borson, MD, reported that she has received grant/research support from, has served as a consultant to, and/or is on the speakers’ bureau of Forest Pharmaceuticals, Inc., Janssen Pharmaceutica Products, LP, Novartis Pharmaceuticals Corporation, and Pfizer Inc. Her presentation will discuss the unapproved use of cholinesterase inhibitors for mild cognitive impairment.
Martin R. Farlow, MD, reported that he has received grants from, is a consultant to, and/or is on the speakers’ bureau of Acellera, Best Practice, Eisai/Pfizer Inc, Elan Pharmaceuticals, Inc., Eli Lilly and Company, Eunoe Inc, Forest Laboratories, Inc. and Research Institute, GlaxoSmithKline, Memory Pharmaceuticals Corp., Novartis Pharmaceuticals Corporation, Ono Pharmaceuticals, PharmaNet, LLC, and Sanofi-Synthelabo Inc. His presentation will not discuss the unapproved use of any drug or device.
George T. Grossberg, MD, reported that he has received grant/research support from and/or has served as a consultant to Abbott Laboratories, AstraZeneca Pharmaceuticals, Boehringer-Ingelheim, Bristol-Myers Squibb Company, Eli Lilly and Company, Forest Pharmaceuticals, Inc., Janssen Pharmaceutica Products, LP, KV Pharmaceutical Co., Novartis Pharmaceuticals Corporation, Ono Pharmaceuticals, Organon, Inc., Pfizer Inc, Sanofi-Aventis, Sanofi-Synthelabo Inc., and Wyeth Pharmaceuticals. His presentation will discuss the unapproved use of cholinesterase inhibitors for mild cognitive impairment.
Daniel I. Kaufer, MD, reported that he has received grant/research support from, has served as a consultant to, and/or is on the speakers’ bureau of Esai-Pfizer, Forest Pharmaceuticals, Inc., Johnson & Johnson Company, and Novartis Pharmaceuticals Corporation. His presentation will discuss the unapproved use of cholinesterase inhibitors for dementia with Lewy bodies and Parkinson’s disease dementia.
Disclaimer
The content and views presented in this educational activity are those of the faculty and do not necessarily reflect those of the American Association for Geriatric Psychiatry, Novartis Pharmaceuticals Corporation, or the publisher, HMP Communications, LLC. The authors have disclosed if any unlabeled use of products is mentioned in the material. Before prescribing any medicine, primary references and full prescribing information should be consulted.
Program Release Date: July 2005
Program Expiration Date: July 2006
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Mild Cognitive Impairment: Early Recognition and Intervention
George T. Grossberg, MD, Program Chairperson, and Samuel W. Fordyce Professor and Director, Geriatric Psychiatry, Saint Louis University School of Medicine, St. Louis, MO, discussed the definition of mild cognitive impairment (MCI), its associated biological factors, and its recognition and treatment.
Definition of MCI
Patients with MCI are generally older adults who, in addition to memory loss, have objective psychometric evidence of memory impairment compared with individuals of similar age and educational/vocational background.1 This is in contrast to patients with age-associated memory impairment (AAMI), who have memory loss but normal psychometric scores. Patients with MCI do not experience significant impairment in their activities of daily living or other cognitive functions such as language, abstract thinking, or problem solving (Table I). Ten to 15% of patients with MCI per year (50% over 5 years) will develop dementia.2 (Table I). The amnesic form of MCI is the subtype that most commonly becomes a prodrome for dementia.3 The more impaired a patient with MCI is, the higher the chance of developing dementia.
Biological Factors in MCI
Studies have shown greater hippocampal atrophy in patients with MCI, especially in those who are apolipoprotein E-4 (ApoE-4) carriers. Farlow et al4 found that the presence of ApoE-4 in patients with MCI was associated with greater impairments in memory and functional activities, and with hippocampal atrophy. Blair and colleagues5 found that ApoE-4 was associated with a greater cognitive decline in middle-aged Caucasian individuals. Functional neuroimaging studies have examined hypometabolism in different brain regions. Mosconi et al6 found that, out of eight patients with MCI who converted to Alzheimer’s disease (AD), all showed a reduced regional glucose metabolic rate in the inferior parietal cortex, as compared with 29 patients with MCI who did not convert to AD. Chetelat and associates7 compared seven patients who converted from MCI to AD with ten patients who did not convert, and found lower fluoro-deoxyglucose (FDG) uptake in the right tempoparietal cortex in the converters. Saykin et al8 used functional magnetic resonance imaging to show that patients with amnesic MCI had reduced frontoparietal activity. Medial temporal lobe atrophy, decreased entorhinal cortex, and high cerebrospinal fluid tau levels have all been shown to be potential predictors of conversion from MCI to AD.9,10
Treatment of MCI
One nonpharmacologic, 6-week study by Ball et al11 evaluated improvements in mental ability and daily functioning in elderly, independent-living adults who were randomized to memory training, reasoning training, speed of processing training, or a control group. Eighty-seven percent of those who were speed-trained, 74% of reasoning-trained individuals, and 26% of memory-trained participants demonstrated reliable cognitive improvement immediately after the intervention period. Thus, older patients may benefit from keeping mentally active. Salloway et al12 conducted a randomized, double-blind, placebo-controlled study of donepezil in 270 patients with MCI.
The New York University Paragraph Delayed Recall Test and the Alzheimer’s Disease Cooperative Study Clinician’s Global Impression of Change for MCI (ADCS CGIC-MCI) did not show significant treatment effects. However, some of the secondary efficacy measures, such as the modified Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog), the Wechsler Memory Scale-Revised (WMS-R), the Digit Span Backwards Test, and the Symbol Digit Modalities Test, all showed favorable treatment effects using donepezil versus placebo. DeKosky and colleagues13 conducted a randomized, double-blind, placebo-controlled, 24-month study of galantamine in 898 patients with MCI who were clinically at risk for AD. The ADAS-Cog developed for MCI and the Clinical Dementia Rating (CDR) scale were not statistically significant for delay of conversion to AD (although the CDR-sum of the boxes [CDR-SB] did show statistical significance). A number of secondary measures (ADCS-Activities of Daily Living [ADCS-ADL] developed for MCI and Digit Symbol Substitution Test [DSST]) showed statistical significance in delaying conversion to AD with galantamine versus placebo.
A randomized, double-blind, placebo-controlled, 24-month study of galantamine in 1062 patients with MCI aimed to improve cognition and global functioning at 12 months, and to delay conversion to dementia.14 ADAS-Cog/MCI, CDR-SB, and CDR were not statistically significant with use of galantamine versus placebo in improving cognition and function in patients with MCI. However, some of the secondary efficacy measures, such as the DSST, did show statistical significance with galantamine in improving cognition and global functioning and delaying conversion to dementia at 24 months. In a recent double-blind, placebo-controlled study of galantamine in patients with MCI, 1026 patients were randomized to galantamine, and 1022 were randomized to placebo.15 Thirteen deaths occurred in the galantamine group versus one death in the placebo group. Half of the deaths were due to either stroke, myocardial infarction, or sudden death.
Another randomized, double-blind, placebo-controlled study evaluated the safety and efficacy of vitamin E and donepezil, and their ability to delay clinical progression from MCI to AD.16 At 18 months, individuals randomized to donepezil had a delay and decreased risk of progressing to AD by about 6 months; however, at the end of the 36-month trial, the risk of progressing to AD was the same for all three groups. A randomized, double-blind, placebo-controlled study of rivastigmine, comparing the length of time of progression from MCI to AD, has recently been completed (unpublished data). The trial, involving 2000 patients, began as a 36-month study and progressed to a 48-month study. The data are currently being analyzed.
Conclusion
Progress is being made with regard to understanding the relationship between MCI and AD. More reliable methods are required to document progression or improvement of cognitive impairment or conversion to AD. More neuropathological data are needed to better understand the neuropathology and neurochemistry of MCI. Promising treatments are in the pipeline.
References
1. Petersen RC, Smith GE, Waring SC, et al. Mild cognitive impairment: Clinical characterization and outcome. Arch Neurol 1999;56: 303-308.
2. Morris JC, Storandt M, Miller JP, et al. Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol 2001;58: 397-405.
3. Knopman DS, Boeve BF, Petersen RC. Essentials of the proper diagnoses of mild cognitive impairment, dementia, and major subtypes of dementia. Mayo Clin Proc 2003;78:1290-1308.
4. Farlow MR, He Y, Tekin S, et al. Impact of APOE in mild cognitive impairment. Neurology 2004;63:1898-1901.
5. Blair CK, Folsom AR, Knopman DS, et al; Atherosclerosis Risk for Communities (ARIC) Study Investigators. APOE genotype and cognitive decline in a middle-aged cohort. Neurology 2005;64:268-276.
6. Mosconi L, Perani D, Sorbi S, et al. MCI conversion to dementia and the APOE genotype: A prediction study with FDG-PET. Neurology 2004;63: 2332-2340.
7. Chetelat G, Desgranges B, de la Sayette V, et al. Mild cognitive impairment: Can FDG-PET predict who is to rapidly convert to Alzheimer’s disease? Neurology 2003;60:1374-1377.
8. Saykin AJ, Wishart HA, Rabin LA, et al. Cholinergic enhancement of frontal lobe activity in mild cognitive impairment. Brain 2004;127:1574-1583.
9. Killiany RJ, Hyman BT, Gomez-Isla T, et al. MRI measures of entorhinal cortex vs hippocampus in preclinical AD. Neurology 2002;58: 1188-1196.
10. Riemenschneider M, Lautenschlager N, Wagenpfeil S, et al. Cerebrospinal fluid tau and beta-amyloid 42 proteins identify Alzheimer disease in subjects with mild cognitive impairment. Arch Neurol 2002;59: 1729-1734.
11. Ball K, Berch DB, Helmers KF, et al; Advanced Cognitive Training for Independent and Vital Elderly Study Group. Effects of cognitive training interventions with older adults: A randomized controlled trial. JAMA 2002;288:2271-2281.
12. Salloway S, Ferris S, Kluger A, et al; Donepezil 401 Study Group. Efficacy of donepezil in mild cognitive impairment: A randomized placebo-controlled trial. Neurology 2004;63:651-657.
13. DeKosky ST, Ikonomovic MD, Styren SD, et al. Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann Neurol 2002;51:145-155.
14. Winblad B. Maintaining functional and behavioral abilities in Alzheimer disease. Alzheimer Dis Assoc Disord 2001;15(Suppl 1):S34-S40.
15. Reminyl [package insert]. Janssen Pharmaceutica Products, LP; Titusville, NJ; 2001.
16. Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352 (23): 2379-2388.
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Alzheimer’s Disease: Response to Cholinesterase Inhibitors
Soo Borson, MD, Professor and Director of Geropsychiatry Services, University of Washington, Seattle, WA, spoke about how to predict clinical response to acetylcholinesterase inhibitors in AD, discussed data on the effectiveness of AD drugs in community populations, and concluded with methods of optimizing patient management.
Acetylcholinesterase Inhibitors: The Standard of Treatment in AD
In 32 published clinical trials, the acetylcholinesterase inhibitors donepezil, rivastigmine, and galantamine have shown consistent value; they are safe in long-term use, and there have been no major drug interactions in postmarketing surveillance (Table II). Raskind et al1 found that cognitive decline over 36 months of continuous galantamine treatment was substantially less than the predicted cognitive decline of untreated patients with mild-to-moderate dementia. Winblad et al2 found that overall decline in patients with AD—as assessed by the global rating of behavior, cognition, and function—was half as fast in donepezil-treated patients than for placebo over a 1-year period. Feldman et al3 determined that patients with AD who were treated with donepezil over a 24-week period had a sustained improvement in behavior that was superior to the placebo group. Another placebo-controlled, 2-year, primary effectiveness study of donepezil found sustained cognitive and functional benefits in the treatment group that were not seen with placebo.4 A meta-analysis of acetylcholinesterase inhibitors clinical trials showed that donepezil, galantamine, and rivastigmine were similar in cognitive efficacy, provided the drugs were used at therapeutic doses.5
Acetylcholinesterase Inhibitors: Going Beyond the Basics
Recent studies demonstrate that efficacy and patterns of cholinesterase inhibitor use are more complex than previously appreciated. Data now strongly support efficacy for cholinesterase inhibitors across the progressive stages of AD. Using combined data from three randomized, placebo-controlled rivastigmine trials, Kurz et al6 found that rivastigmine maintained ADAS-Cog scores at or above placebo levels across mild, moderate, and severe stages, and the benefits of drug therapy were increasingly apparent at more advanced stages as the rate of decline accelerated in the placebo condition. One study on rivastigmine involved 235 patients who were randomized to the study drug or placebo, 187 of whom subsequently crossed over to open-label treatment with rivastigmine.7 The study found that placebo patients who progressed faster during the double-blind phase responded more robustly to subsequent rivastigmine treatment (according to the ADAS-Cog and Progressive Deterioration Scale [PDS] scores).
Other studies have found that factors besides drug safety and efficacy influence patterns of cholinesterase inhibitor use. Gill et al,8 in comparing 6400 new users of donepezil versus 3400 subjects enrolled in ten randomized, controlled trials, found that 51-78% would not have been eligible to participate in randomized trials because of advanced age, medical comorbidities, or residence in long-term care. In addition, 28% of new users had stopped taking donepezil by 8 months of treatment, with discontinuation more likely in patients with greater comorbidities. This suggests that physicians may not be confident in prescribing acetylcholinesterase inhibitors for patients who differ from typical participants of randomized, controlled trials, and that more data are needed on clinical outcomes in these “real world” patient populations. Another study comparing results from three fixed-dose and one flexible-dose rivastigmine trials found that drug tolerability can be improved through slower escalation of dosing with individualized titration.9-12
Caregivers and sociodemographic factors also play an important role in decisions about acetylcholin-esterase inhibitor use. Belle and colleagues13 examined predictors of use by patients with dementia whose caregivers were enrolled in the multisite caregiver intervention Resources for Enhancing Alzheimer’s Caregiver Health (REACH) trial. Only 31% of care recipients used a cognitive enhancer at baseline; use was predicted by race (white), higher levels of education, less severe dementia, caregiving time, and being a spouse rather than a parent of the caregiver. Over the course of the study, a higher proportion of patients stopped taking cholinesterase inhibitors than started the treatment. This study suggests that educating caregivers about the benefits of long-term treatment could improve rates of sustained use required for optimal outcomes.
Keys to Sustaining Acetylcholinesterase Inhibitor Treatment
Sustained treatment requires consideration of individual differences between patients, the magnitude of therapeutic response, the likelihood of response to a specific drug, and tolerance for dose escalation. Active anticipation, management, and monitoring are required for comorbidities such as heart or lung disease, urinary incontinence, and complications of dementia (eg, dehydration, hypotension, obstipation, subnutrition, falls). In addition, an attitude of realistic optimism about management and a perspective rooted in principles of chronic disease management are key attributes of physicians and families caring for patients with dementia. A comprehensive, long-range, collaborative dementia care partnership— centered on the goals of slowing decline and prolonging quality of life—is the means by which overall outcomes can be optimized.
References
1. Raskind MA, Peskind ER, Truyen L, et al. The cognitive benefits of galantamine are sustained for at least 36 months: A long-term extension trial. Arch Neurol 2004;61:252-256.
2. Winblad B, Engedal K, Soininen H, et al. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001;57:489-495.
3. Feldman H, Gauthier S, Hecker J, et al; Donepezil MSAD Study Investigators Group. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer’s disease. Neurology 2001;57:613-620.
4. Courtney C, Farrell D, Gray R, et al; AD2000 Collaborative Group. Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): Randomised double-blind trial. Lancet 2004;363:2105-2115.
5. Ritchie CW, Ames D, Clayton T, Lai R. Metaanalysis of randomized trials of the efficacy and safety of donepezil, galantamine and rivastigmine for the treatment of Alzheimer disease. Am J Geriatr Psychiatry 2004;12: 358-369.
6. Kurz A, Farlow M, Quarg P, Spiegel R. Disease stage in Alzheimer disease and treatment effects of rivastigmine. Alzheimer Dis Assoc Disord 2004;18: 123-128.
7. Farlow MR, Hake A, Messina J, et al. Response of patients with Alzheimer disease to rivastigmine treatment is predicted by the rate of disease progression. Arch Neurol 2001;58:417-422.
8. Gill SS, Bronskill SE, Mamdani M, et al. Representation of patients with dementia in clinical trials of donepezil. Can J Clin Pharmacol 2004;11: e274-e285.
9. Study B351. Data on file, Novartis Pharmaceuticals Corporation.
10. Study B352. Data on file, Novartis Pharmaceuticals Corporation.
11. Study B303. Data on file, Novartis Pharmaceuticals Corporation.
12. Study B304. Data on file, Novartis Pharmaceuticals Corporation.
13. Belle SH, Zhang S, Czaja SJ, et al. Use of cognitive enhancement medication in persons with Alzheimer disease who have a family caregiver: Results from the Resources for Enhancing Alzheimer’s Caregiver Health (REACH) Project. Am J Geriatr Psychiatry 2004;12: 250-257.
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Dementia with Lewy Bodies: The Management of Cognitive and Behavioral Symptoms
Daniel Kaufer, MD, Associate Professor of Neurology, and Director of the Memory and Cognitive Disorders Program, University of North Carolina School of Medicine, Chapel Hill, NC, reviewed the antecedents, diagnostic criteria, clinical signs, pathophysiological mechanisms, and treatment options for dementia with Lewy bodies (DLB).
Core Features of DLB
DLB is a dementia syndrome that is linked pathologically to Lewy bodies occurring in the brain stem and throughout the brain. In 1996, consensus guidelines established diagnosis criteria requiring dementia plus at least two of the following three core features: fluctuating cognition, recurrent visual hallucinations, or spontaneous parkinsonian motor signs.1 They also identified a number of supportive features: repeated falls, syncope, transient loss of consciousness, neuroleptic sensitivity, systematized delusions, and other hallucinations (Table III). In comparison with AD, patients with DLB have greater deficits in attention and executive and visuo-spatial functions, but relatively preserved short-term memory. There are more severe neocortical cholinergic deficits in cortical-cortical pathways, but less severe mesial temporal cholinergic deficits in the cortical-limbic pathways. Fluctuating cognition occurs in 60-80% of patients with DLB. This may reflect cholinergic and mono-aminergic imbalances in the reticulo-thalamic-cortical pathways.
One study by Ferman et al2 attempted to characterize the key clinical manifestations of fluctuations. Four items were identified: daytime drowsiness, daytime sleep for 2 or more hours per day, staring into space, and episodic, disorganized speech. Visual hallucinations occur in 50-75% of patients with DLB. These may reflect reduced acetylcholine and preserved serotonergic function in the thalamocortical pathways. Parkinsonian motor signs are present in 80-90% of patients with DLB. Bradykinesia, limb rigidity, action tremor, and problems with gait/balance are common. This is thought to reflect nigrostriatal involvement with reduced dopaminergic function. One new criterion being proposed is rapid eye movement (REM) sleep behavior disorder, which causes patients to have a wake-like electroencephalogram, dream-like imagery, and muscle atonia. Patients with DLB have brainstem and cortical Lewy bodies; some patients have amyloid plaques, and only a few have neurofibrillary tangles. One main revision to the DLB criteria will be to count the number of tangles in the brain, because the presence of many tangles is more consistent with AD. In DLB, dementia onset occurs within 1 year of motor signs, if they are present. This is in contrast to Parkinson’s disease dementia (PDD), where cognitive or neuropsychiatric symptoms may arise 10-15 years after the onset of motor signs.
Pharmacologic Treatment of DLB
Acetylcholinesterase inhibitors often improve psychosis and cognitive function, and may have a positive effect on other neuropsychiatric symptoms and vegetative signs. They can have a mixed effect on autonomic functions, and they generally do not affect motor signs. There have been a few open-label studies of acetylcholinesterase inhibitors in DLB. Donepezil was found to markedly reduce fluctuations and hallucinations in two patients with DLB.3 In a different study, donepezil reduced hallucinations in eight of nine patients with DLB.4 A study on galantamine showed significantly reduced results in the Neuropsychiatric Inventory (NPI)-4 cluster of symptoms (delusions, hallucinations, depression, apathy), as well as cognitive and global improvement.5 There has been one large controlled study on the use of rivastigmine in DLB.6 Subjects were selected based on having neuropsychiatric symptoms. Efficacy measures showed a significant reduction in total NPI and NPI-4 cluster. NPI symptoms that dramatically improved were apathy, anxiety, and disinhibited behaviors. There was a trend toward improved cognition and global function. There was no significant worsening of parkinsonian motor signs, and the gastrointestinal effects were comparable to other AD studies.
Low-dose quetiapine is probably the most commonly used agent for psychosis treatment in DLB, followed by other atypicals. Parkinsonian motor signs should not be treated unless absolutely necessary, in which case, levodopa is the safest choice. Anticholinergics should be avoided, if possible, to treat REM sleep disorder (clonazepam and other benzodiazepines are effective). For neurogenic bladder problems, long-acting drugs should be used only when absolutely necessary because they may lead to cognitive side effects.
Conclusion
The criteria established for DLB are a work in progress. Further investigation is needed to clarify the relationships between PDD and DLB, and between DLB, AD, and Parkinson’s disease. Emerging data support cholinesterase therapy as a first-line treatment for DLB, for both cognitive and neuropsychiatric symptoms. More large placebo-controlled studies are required.
References
1. McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the consortium on DLB international workshop. Neurology 1996;47: 1113-1124.
2. Ferman TJ, Smith GE, Boeve BF, et al. DLB fluctuations: Specific features that reliably differentiate DLB from AD and normal aging. Neurology 2004;62:181-187.
3. Kaufer DI, Catt KE, Lopez OL, DeKosky ST. Dementia with Lewy bodies: Response of delirium-like features to donepezil. Neurology 1998;51:1512.
4. Shea C, MacKnight C, Rockwood K. Donepezil for treatment of dementia with Lewy bodies: A case series of nine patients. Int Psychogeriatr 1998;10(3): 229-238.
5. Edwards KR, Hershey L, Wray L, et al. Efficacy and safety of galantamine in patients with dementia with Lewy bodies: A 12-week interim analysis. Dement Geriatr Cogn Disord 2004;17(Suppl 1):40-48.
6. McKeith I, Del Ser T, Spano P, et al. Efficacy of rivastigmine in dementia with Lewy bodies: A randomized, double-blind, placebo-controlled international study. Lancet 2000;356:2031-2036.
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Parkinson’s Disease Dementia: Cognitive Response to Cholinesterase Inhibitors
Martin Farlow, MD, Professor and Vice-Chairman for Research, Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, explained that Parkinson’s disease (PD) affects 1-2% of people over age 80 years.1 Dementia is estimated to affect 20-78% of patients with PD.2-4 There is evidence that patients with PD have cholinergic deficits.3 The disorder is characterized by cognitive slowing, attention deficits, and executive, visuo-spatial, neuropsychiatric, and memory impairments. The symptoms of dementia develop after motor symptoms appear. The clinical characteristics of dementia in PD (PDD) include deficits in three or more of the following domains: language, memory, visuospatial, personality, and complex cognitive function. There can be episodes of cognitive clouding, hallucinations, delusions, depression, agitation, and sleep disturbances. Language ability, orientation, long-term memory, and calculation are relatively preserved (Table IV). Risk factors for PDD include advanced age and late onset of PD,5 severe motor findings,6 depression,7 low verbal fluency, executive dysfunction, and early onset of hallucina-tions.4 Patients with PD with postural instability and gait disorder are at higher risk than those with tremor-predominant PD.4
Therapeutic Studies in PDD
A number of open-label studies have been conducted with cholinesterase inhibitors in PDD. Small trials by Reading et al8 and Giladi et al9 have shown large improvements in cognitive functioning with rivastigmine. Bergman et al10 and Fabbrini et al11 have found improvements in psychotic symptoms with donepezil.
Donepezil
Two very small, placebo-controlled and blinded studies have shown benefits on cognition with donepezil.12,13 Another study by Brashear et al14 gave mixed results. This was a small, 12-week, double-blind, placebo-controlled, single-site study on donepezil, followed by a 33-week open-label study. In the double-blind phase, donepezil-treated patients had an improvement of 0.7 on the Mini-Mental State Examination (MMSE), and a worsening of three points on the Geriatric Depression Scale (GDS). There were no differences on CDR items. This small study suggests that donepezil has limited efficacy in PDD. It was also suggested that PD symptoms (as measured by the Unified Parkinson’s Disease Rating Scale [UPDRS]) worsened in patients taking donepezil. Rivastigmine Emre and associates15 conducted a large, double-blind, randomized, placebo-controlled, parallel-group, multicenter, multinational study of rivastigmine in 541 patients with PDD. There was no significant difference from baseline in either the rivastigmine or placebo groups on the UPDRS; thus, parkinsonian symptoms were not worsened by rivastigmine treatment. There was a two-point reduction on the ADAS-Cog in the rivastigmine group, compared with a one-point increase in the placebo group (P < 0.001). In a 24-week categorical analysis of ADCS-CGIC, more patients taking rivastigmine were clinically assessed as having improved and more patients on placebo were assessed as having worsened. At 24 weeks, rivastigmine patients had decreased one point from baseline on the ADCS-ADL scale, compared with a decrease of 3.5 points for placebo. Patients taking rivastigmine had a decrease of two points on the NPI, compared with no change in the placebo group (P = 0.015). Rivastigmine produced significant benefits across a wide range of symptoms. The drug was generally well-tolerated, and parkinsonian symptoms did not worsen.
Conclusion
In summary, PDD may, over the long-term, occur in up to 78% of patients with PD. Prominent features of PDD include parkinsonian features, episodic, cognitive clouding, and hallucinations. Risk factors for PDD include advanced age of onset of PD, severe motor findings, depression, and akinetic PD. Rivastigmine was found to significantly improve co
