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183 Cholinergic treatment of behavioral disturbances in Alzheimer's disease
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FIFTH INTERNATIONALCONFERENCE ON ALZHEIMER'S DISEASE
Alzheimer's disease (AD) can present with a variety of clinical profiles. The most common presentation is that of a progressive amnestic disorder with subsequent involvement of other cognitive functions and personality alterations. Although this is the most common presentation, there are a variety of other clinical profiles. AD can present as a focal cortical degeneration syndrome, with the clinical features dependent on the regions of the brain involved. Some of these syndromes include disturbances of language, visuospatial skills, attentional functions, executive processes, and praxis. The neuropathological substrate of these disorders is variable and can include AD. Recently, The Lewy Body Variant of AD has been described, and this clinical presentation will be discussed. Finally, other modifying features that affect the progression of AD, such as extrapyramidal symptoms and myoclonus will be discussed as well. In summary, while the progressive amnestic form of AD is the most common presentation, other variations on the clinical syndrome can be important to identify because they may have implications for prognosis and treatment.
180 The Caregiyer's Role in Alzheimer's Disease P. Rabins Department of Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA The majority of persons with Alzeimer's disease are cared for by family members in their homes. Research from several studies has shown that the care provider rates for emotional morbidity is 2-3 times the rate seen in age-similar individuals. This presentation will review the epidemiology data on the incidence and prevalence of ernotional disability in earegivers. It will also review the 11 treatment studies in the literature in which a blinded intervention was carded out. Nine of these 11 studies show that intervention was more beneficial than the placebo comparison treatment. Both educational and emotional support were effective. However, when compared to each other, emotional support was more effective; the combination is probably more effective than either alone. Preliminary evidence suggests that intervention may delay the need for institutional care.
181 Clinical Profile of Donepezil (E2020) S. Rogers Eisai America Inc., Teaneck, New Jersey, USA Donepezil, a distinct new piperidine-class agent with a long duration of action, has high selectivity for acetyl versus butyryl cholinesterase and exerts little peripheral activity. Results of randomized, double-blind, placebo-controlled trials in mild-to-moderately severe Alzheimer's Disease (AD) demonstrate that once-daily donepezil is well tolerated, and that adverse events am mild and transient. No hepatotoxicity was observed. Statistically significant improvements were seen in cognitive function, as measured by the sensitive and well-validated ADAS-cog scale, and in patient global function, as measured by the ADSU-CGIC version of CIBI-C Plus.
R O U N D T A B L E H: B E H A V I O U R EFFICACY OUTCOME
moderate Alzheimer's Disease (AD). A large scale (343 patients) 6 month study of xanomeline revealed a beneficial effect on cognition relative to placebo (completer analysis of ADAS-Cog, p = 0.045; CIBIC +, p = 0.022), as might be predicted by the cholinergic hypothesis. More surprising was a dramatic reduction of psychosis, agitation and other problematic behaviors which often complicate the course of AD. Analysis of the Alzheimer's Disease Symptomatology scale, a novel instrument used to assess problematic behaviors in AD patients, revealed significant (p~ 0.002), dose-dependent reductions in vocal outbursts, suspiciousness, delusions, agitation, and hallucinations. NOSGER, a validated instrument for the assessment of behaviors and activities of daily living in the elderly, also showed a significant dose-response relationship (p= 0.018). Recent studies in animals may provide an experimental basis for these clinical effects. In rats, chronic administration (i.e. 2-3 weeks) of a number of antipsychotic drugs reduces the number of spontaneously active dopamine neurons. Haloperidol and other typical antipsycbotics reduce the activity of both A9 and A10 dopamine neurons, whereas, atypical antipsychotic drugs, such as clozapine, selectively reduce the activity of A10 dopamine neurons. This selectivity suggests that a reduction in activity of A10 dopamine neurons may underlie the antipsychotic actions of these drugs. Recent studies have shown that xanomeline also selectively reduces the number of spontaneously active AI0 dopamine neurons. Xanomeline's effect on A10 activity is seen acutely without the requirement for chronic administration. Xanomeline may offer a new effective approach to the treatment of behavioral and cognitive symptoms in AD.
183 Cholinergie Treatment of Behavioral Disturbances in Aizheimer's Disease
JL. Cummings*, MD. UCLA School of Medicine, Los Angeles, CA, USA. The pathology of Alzheimer's Disease (AD) includes histologic changes (neuronal loss, gliosis, plaques, tangles, amyloid angiopathy) and neurochemical alterations (reductions in acetylcholine [ACh], norepinephrine, and serotonin). The objective of the study is to examine therapeutic interventions aimed at reducing the marked cholinergic deficiency in AD patients. Acetyleholine precursors, acetylcholinesterase inhibitors, cholinergic receptor agonists, and other cholinomimetic medications have been administered to AD patients. The principal outcome monitored in such treatment is improvement in memory and other cognitive deficits. The cholinergic system mediates aspects of non-cognitive emotional activities as well as intellectual function. Psychosis, agitation, and personality alterations (particularly apathy and disengagement) have been associated with cholinergic deficits. These behaviors are common in AD, are attributable to the cholinergic deficiency of AD and may be amenable to treatment with cholinergic agents. Preliminary evidence indicates that acetylcholinesterase inhibitors and cholinergic receptor agonists ameliorate behavioural changes in AD. Acetylcholinesterase inhibitors reduce apathy, anxiety and hallucinations, and cholinergic receptor agonists benefit psychoses, hallucinations and agitation. These studies indicate that behavioral alterations are primary manifestations of the neurobiological changes of AD; they are associated with the ACh deficiency of AD and that they respond to treatment with cholinomimetic agents. Mild improvements in memory and other cognitive deficits have also been realized. Further studies of the behavioral effects of cholinergic agent treatment of AD are warranted.
AS A N 184 Combining Efficacy Measures across Cultures: Report from the Activitiesof-Daily-Living (ADL) Project.
182 The Effects of Xanomeline, an MI-Selective Muscarinic Agonist, on Behavioral Symptoms in AIzheimer's Disease
N. Bodick*, W. Often, K. Rasmussen, and S. Paul. Eli Lilly and Company, Indianapolis, Indiana 46285, USA Xanomeline, a novel muscarinic agonist with high affinity for the M1 receptor subtype, is under development for the treatment of mild and
H.L Erzigkeit*. Psychiatric University Hospital Erlangen, Erlangen, Germany. Intercultural comparisons of clinical trials require the validity of the applied measurement instrument to be proven for each country or ,language. Consequently, during the last few years, increasing efforts have been made to internationally calibrate psychometric tests and scales frequently used in dementia research. Whereas considerable progress has been made in the area of symptom rating scales or cognitive performance tests, activities-of-dailyliving (ADL) measures fulfilling the standards for international application are
FIFTH INTERNATIONALCONFERENCE ON ALZHEIMER'S DISEASE
Alzheimer's disease (AD) can present with a variety of clinical profiles. The most common presentation is that of a progressive amnestic disorder with subsequent involvement of other cognitive functions and personality alterations. Although this is the most common presentation, there are a variety of other clinical profiles. AD can present as a focal cortical degeneration syndrome, with the clinical features dependent on the regions of the brain involved. Some of these syndromes include disturbances of language, visuospatial skills, attentional functions, executive processes, and praxis. The neuropathological substrate of these disorders is variable and can include AD. Recently, The Lewy Body Variant of AD has been described, and this clinical presentation will be discussed. Finally, other modifying features that affect the progression of AD, such as extrapyramidal symptoms and myoclonus will be discussed as well. In summary, while the progressive amnestic form of AD is the most common presentation, other variations on the clinical syndrome can be important to identify because they may have implications for prognosis and treatment.
180 The Caregiyer's Role in Alzheimer's Disease P. Rabins Department of Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA The majority of persons with Alzeimer's disease are cared for by family members in their homes. Research from several studies has shown that the care provider rates for emotional morbidity is 2-3 times the rate seen in age-similar individuals. This presentation will review the epidemiology data on the incidence and prevalence of ernotional disability in earegivers. It will also review the 11 treatment studies in the literature in which a blinded intervention was carded out. Nine of these 11 studies show that intervention was more beneficial than the placebo comparison treatment. Both educational and emotional support were effective. However, when compared to each other, emotional support was more effective; the combination is probably more effective than either alone. Preliminary evidence suggests that intervention may delay the need for institutional care.
181 Clinical Profile of Donepezil (E2020) S. Rogers Eisai America Inc., Teaneck, New Jersey, USA Donepezil, a distinct new piperidine-class agent with a long duration of action, has high selectivity for acetyl versus butyryl cholinesterase and exerts little peripheral activity. Results of randomized, double-blind, placebo-controlled trials in mild-to-moderately severe Alzheimer's Disease (AD) demonstrate that once-daily donepezil is well tolerated, and that adverse events am mild and transient. No hepatotoxicity was observed. Statistically significant improvements were seen in cognitive function, as measured by the sensitive and well-validated ADAS-cog scale, and in patient global function, as measured by the ADSU-CGIC version of CIBI-C Plus.
R O U N D T A B L E H: B E H A V I O U R EFFICACY OUTCOME
moderate Alzheimer's Disease (AD). A large scale (343 patients) 6 month study of xanomeline revealed a beneficial effect on cognition relative to placebo (completer analysis of ADAS-Cog, p = 0.045; CIBIC +, p = 0.022), as might be predicted by the cholinergic hypothesis. More surprising was a dramatic reduction of psychosis, agitation and other problematic behaviors which often complicate the course of AD. Analysis of the Alzheimer's Disease Symptomatology scale, a novel instrument used to assess problematic behaviors in AD patients, revealed significant (p~ 0.002), dose-dependent reductions in vocal outbursts, suspiciousness, delusions, agitation, and hallucinations. NOSGER, a validated instrument for the assessment of behaviors and activities of daily living in the elderly, also showed a significant dose-response relationship (p= 0.018). Recent studies in animals may provide an experimental basis for these clinical effects. In rats, chronic administration (i.e. 2-3 weeks) of a number of antipsychotic drugs reduces the number of spontaneously active dopamine neurons. Haloperidol and other typical antipsycbotics reduce the activity of both A9 and A10 dopamine neurons, whereas, atypical antipsychotic drugs, such as clozapine, selectively reduce the activity of A10 dopamine neurons. This selectivity suggests that a reduction in activity of A10 dopamine neurons may underlie the antipsychotic actions of these drugs. Recent studies have shown that xanomeline also selectively reduces the number of spontaneously active AI0 dopamine neurons. Xanomeline's effect on A10 activity is seen acutely without the requirement for chronic administration. Xanomeline may offer a new effective approach to the treatment of behavioral and cognitive symptoms in AD.
183 Cholinergie Treatment of Behavioral Disturbances in Aizheimer's Disease
JL. Cummings*, MD. UCLA School of Medicine, Los Angeles, CA, USA. The pathology of Alzheimer's Disease (AD) includes histologic changes (neuronal loss, gliosis, plaques, tangles, amyloid angiopathy) and neurochemical alterations (reductions in acetylcholine [ACh], norepinephrine, and serotonin). The objective of the study is to examine therapeutic interventions aimed at reducing the marked cholinergic deficiency in AD patients. Acetyleholine precursors, acetylcholinesterase inhibitors, cholinergic receptor agonists, and other cholinomimetic medications have been administered to AD patients. The principal outcome monitored in such treatment is improvement in memory and other cognitive deficits. The cholinergic system mediates aspects of non-cognitive emotional activities as well as intellectual function. Psychosis, agitation, and personality alterations (particularly apathy and disengagement) have been associated with cholinergic deficits. These behaviors are common in AD, are attributable to the cholinergic deficiency of AD and may be amenable to treatment with cholinergic agents. Preliminary evidence indicates that acetylcholinesterase inhibitors and cholinergic receptor agonists ameliorate behavioural changes in AD. Acetylcholinesterase inhibitors reduce apathy, anxiety and hallucinations, and cholinergic receptor agonists benefit psychoses, hallucinations and agitation. These studies indicate that behavioral alterations are primary manifestations of the neurobiological changes of AD; they are associated with the ACh deficiency of AD and that they respond to treatment with cholinomimetic agents. Mild improvements in memory and other cognitive deficits have also been realized. Further studies of the behavioral effects of cholinergic agent treatment of AD are warranted.
AS A N 184 Combining Efficacy Measures across Cultures: Report from the Activitiesof-Daily-Living (ADL) Project.
182 The Effects of Xanomeline, an MI-Selective Muscarinic Agonist, on Behavioral Symptoms in AIzheimer's Disease
N. Bodick*, W. Often, K. Rasmussen, and S. Paul. Eli Lilly and Company, Indianapolis, Indiana 46285, USA Xanomeline, a novel muscarinic agonist with high affinity for the M1 receptor subtype, is under development for the treatment of mild and
H.L Erzigkeit*. Psychiatric University Hospital Erlangen, Erlangen, Germany. Intercultural comparisons of clinical trials require the validity of the applied measurement instrument to be proven for each country or ,language. Consequently, during the last few years, increasing efforts have been made to internationally calibrate psychometric tests and scales frequently used in dementia research. Whereas considerable progress has been made in the area of symptom rating scales or cognitive performance tests, activities-of-dailyliving (ADL) measures fulfilling the standards for international application are