- Email: [email protected]
194 A Scale to measure impairment in severe dementia
FIFTH INTERNATIONAL CONFERENCE ON ALZHEIMER'S DISEASE filaments via reduced tan phosphorylatiou;iv) by inhibitingapoptosis [Lindenboimet al, J. Neurochem.,64:249 I, 95]; v) by restoringmemoryand learningin several animal modelsfor AD. It is not inconceivablethat restoringthe cholinergictone in AD brains may also delay the progressionof AD. Supported in part by Snow Brand, Japan.
193 ChoUnasterase Inhibitors and Musearinic Agonists: Is There a Role for Combination Therapy of Alzheimer's Disease? M. Farlow* Depat'maent of Neurology, Indiana University School of Medicine, 550 Univ~sity Boulevard, Suite 3124, Indianapolis, Indiana USA Taerine (Wamer-Lambart), a eholinesterase inhibiter (CI) is approved in the United States for treatment of mild to moderate stageAlzheimer's disease (AD) and there are several other Cls are in advanced stages of development. Milameline (CI-979, RU 35926 RousseI-UCLAF), a musearinic agonist with central nervous system activity,is also being investigated for treatment of AD. Inevitably these two drugs or other CIUs or musearinic agonists will be used in combination therapy. It is possible that CIs and muscarinic agonists taken together might increase the frequency of cholinergie side effects including bradycardia and/or syncope. However, there are potential advantages to such a combination therapy. Tacrine particularly increases aeetyleholine levels at synapses with presynaptic cholinergic inaervation, Milamelin: aetspost-synapfically, stimulating muscarinie receptors on neurons, even those whose pre~naptie irmervatlon has degenerated. Clinically, it has been suggested that muscarinic agonists have greater positive -effects on behaviur-than-¢holinesterase" inhibitcrs;- Since the-actions of taerhae and milameline at a cellular as well as the clinical level are different and potentially complementary, beneficial clinical effects may be additive. Since both compounds are stimulating the cholinergi¢ system, it is possible these benefits might occur at lower dosages than would be required if they were given individually. In a preliminary study with adult rhesus monkeys the combination of taxrine and milarneline reversed scopolamine induced impairment in behavior to a greater extent than either drug given alone and over a broader range of dosages. The side effects were similar to those seen with administration of the individual drug. (Personal communication from M, J. Callalmn) To investigate the safety of combining tacrino and milameline, a double blind placebo controlled trial has been developed that will add either placebo, milameline 2 ms/day or 4 rag/day to patients already established on taetiae therapy. Patients will be assessed by clinical and laboratory monitoring with measured by the ADAS-Cog. The sample size will probably not allow significant differences to be demonstrated but may show trends.
POSTER SESSION II
Clinical Course & Diagnosis I
194 A Scale to Measure Impairment in Severe Dementia P. Rabins
Department of Psychiatry, Johns Hopkins University Medical School, Meyer 279, 600 N. Wolfe, Balto. MD 21267-7279, Fax 1/410-614-1094 An 11 item 22 point scale that measures cognitive capacity in severely cognitive impaired individuals. The Severe Impairment Rating Scale (SIRS) has been tested in cross-sectional and longitudinal analyses of individuals with AIzheimer disease and Huntington disease. Inter-rater reliability =.992,p<.001. Two week test-retest reliabSty=.97,p<.0001. Internal consistency by Chronbach's alpha =.76. Validity is supported by correlations with the Glasgow Coma Scale (r =.866,p <.001), Mini Mental Status Examination (r=.770,p<.O01) and the SIB by prediction of mortality at one year.
$49
195 Rellability, validity and sensitivity to disease evolution of AIzheimer's Disease Assessment Scale (cognitive): a reappraisal U. Lucca*, P. Tiraboschi#, M. Tettamanti, C. A. De Fanti#, and A. Spagnoli Istituto di Rieerehe Farmacologiche "Marie Negri", Milano #1a Divisione Neurelogica, Ospedali Riuniti di Bergamo, Bergarno - Italy Worldwide use of the cognitive portion of Alzheimer's Disease Assessment Scale (ADAS-Cog) in antidementia drug trials as a comprehensive test to detect changes in core cognitive manifestations of Alzheimer's disease (AD), drove us to re.assess its reliability, concurrent validity, and sensitivity to clinical evolution. Thirty-three patients (24 F/9 M, mean age of 75+7.1 y and mean educational level 5.1+_.2.4y) meeting NINCDS-ADRDA criteria for probable AD and twentytwo elderly controls (mainly patients' relatives; 19 F/3M, mean age of 70.35:6.8 y and mean educational level 7.45:4.7 y) were evaluated by two independent raters in two clinical centers (baseline) and reassessed about one month later (followup) with ADAS-Cog (two alternate forms), MMSE, Blessed IMC (BIMC) and Dementia Scale (BDS, only the patients), and language and attention tests. Squared weighted Cohen's K for test-retest and inter-rater reliability and Pearson product moment coefficient for correlation studies were used. Moreover, data from one completed trial and the baseline of two ongoing investigations in probable AD patients (NINCDS-ADRDA criteria) were analyzed to evaluate ADAS-Cog (total and subtest scores) sensitivity to disease evolution and rate of progression, and to look for correlations with other global instruments. ADAS-Cog inter-rater and test-retest reliability were high in the AD group (K=0.99 and K=0.90, respectively) and, due to the truncation of variance, apparently lower in the control group (K=0.98 and K=0.55). Stability over time of the subtest scores however was less impressive, at times just fair. ADAS-Cog had good correlations in the AD group with both BIMC (r=0.70, p<0.0001) and MMSE (r=-0.76, p<0.0001), and, to a lesser extent, with the ADL portion of BDS (r--0.51, p=0.0046). Similar results were also seen at the baseline of each trial considered. Baseline data from an ongoing investigation showed a strong association with CDR-Sum of Boxes too (N=99, r=0.75). Mean ADAS-Cog score at baseline for all AD patients studied (N=185) was 26.9+-9.8, with significant differences among each stage group (Global Deterioration Scale, GDS): elderly controls (N=22) 7.9+-3.2, GDS3 (N=45) 18.5+-5.8, GDS4 (N=86) 26.3+-7.1, and GDS5 (N=51) 36.2+-8.9 (p<0.0001 at Bonferroni test following the ANOVA). The three language ratings and the concentration subtest (ADAS-nonCog) were much less sensitive to stage evolution and correlated poorly with comprehension, fluency, and attention tests. The results of our study go along with those of the original work by Rosen et al (1984) proving ADAS-Cog a suitable, global measure of cognitive change for clinical trials in AD, but suggesting that there is room to enhance the reliability and sensitivity to disease progression of some of its subtests.
196 Possible Problems With Clinical Selection Criteria Used in Alzheimer's Disease Clinical Trials. J. Willmer* and E. Mohr, Department of Medicine (Neurology), University of Ottawa, Elisabeth Bruyere Health Centre, 75 Bruyere St., Ottawa, Ontario, Canada, KIN 5C8 As there continues to be no definitive test for Alzheimer's disease, diagnosis has to be achieved using clinical criteria sets such as those outlined in DSM-III or NINCDS-ADRDA. Using a previously published CT scan measuring technique' which correlates well with diagnoses achieved using the NINCDS-ADRDA criteria, we chose to independently examine and reach a diagnosis in patients selected for participation in clinical trials of therapeutic agents in dementia of the Alzheimer type(DAT). Forty four CT seam from six sites across Canada were examined using the model. All patients had been diagnosed as having DAT by N1NCDS-ADRDA criteria and were deemed acceptable to participate in a clinical trial. The diagnostic concordance achieved in the original published model was 91.5%. The diagnostic concordance in the population being studied was 77.3%. However when examined by site, results ranged from 57.1% to 100%. Using the model, an index of atrophy and a probability of diagnosis of DAT can be determined. Across sites, there were statistically significant differences in these measures (p<.035). The mean probability of diagnosis of DAT across sites ranged from .56 to .94. Although the sites with lower probabilities had slightly lower mean ages and slightly less atrophy, there was no overall correlation of the atrophy measures with age. A number of explanations for these discrepancies can be suggested. It is possible that the CT measurement model used is not valid, perhaps due the fact that the scans were all done on different scanners, even though the same scanning protocol was used. The different sites maybe applying the NINCDS-ADRDA criteria differently, leading to selection of different subpopulations. Thus, different subgroups of DAT maybe present at different sites. If this explanation is valid, the selection of patients for Alzheimer clinical trials using current diagnostic criteria sets may not be adequate and conclusions with respect to agent efficacy could be flawed. ' Willmer J, Carruthers A, Guzman DA, Collins B, Pogue J, Stuss DT The usefulness of CT scanning in diagnosing dementia of the Alzheimer type. Can. J. Neurol. gel 1993; 20:210 - 216
193 ChoUnasterase Inhibitors and Musearinic Agonists: Is There a Role for Combination Therapy of Alzheimer's Disease? M. Farlow* Depat'maent of Neurology, Indiana University School of Medicine, 550 Univ~sity Boulevard, Suite 3124, Indianapolis, Indiana USA Taerine (Wamer-Lambart), a eholinesterase inhibiter (CI) is approved in the United States for treatment of mild to moderate stageAlzheimer's disease (AD) and there are several other Cls are in advanced stages of development. Milameline (CI-979, RU 35926 RousseI-UCLAF), a musearinic agonist with central nervous system activity,is also being investigated for treatment of AD. Inevitably these two drugs or other CIUs or musearinic agonists will be used in combination therapy. It is possible that CIs and muscarinic agonists taken together might increase the frequency of cholinergie side effects including bradycardia and/or syncope. However, there are potential advantages to such a combination therapy. Tacrine particularly increases aeetyleholine levels at synapses with presynaptic cholinergic inaervation, Milamelin: aetspost-synapfically, stimulating muscarinie receptors on neurons, even those whose pre~naptie irmervatlon has degenerated. Clinically, it has been suggested that muscarinic agonists have greater positive -effects on behaviur-than-¢holinesterase" inhibitcrs;- Since the-actions of taerhae and milameline at a cellular as well as the clinical level are different and potentially complementary, beneficial clinical effects may be additive. Since both compounds are stimulating the cholinergi¢ system, it is possible these benefits might occur at lower dosages than would be required if they were given individually. In a preliminary study with adult rhesus monkeys the combination of taxrine and milarneline reversed scopolamine induced impairment in behavior to a greater extent than either drug given alone and over a broader range of dosages. The side effects were similar to those seen with administration of the individual drug. (Personal communication from M, J. Callalmn) To investigate the safety of combining tacrino and milameline, a double blind placebo controlled trial has been developed that will add either placebo, milameline 2 ms/day or 4 rag/day to patients already established on taetiae therapy. Patients will be assessed by clinical and laboratory monitoring with measured by the ADAS-Cog. The sample size will probably not allow significant differences to be demonstrated but may show trends.
POSTER SESSION II
Clinical Course & Diagnosis I
194 A Scale to Measure Impairment in Severe Dementia P. Rabins
Department of Psychiatry, Johns Hopkins University Medical School, Meyer 279, 600 N. Wolfe, Balto. MD 21267-7279, Fax 1/410-614-1094 An 11 item 22 point scale that measures cognitive capacity in severely cognitive impaired individuals. The Severe Impairment Rating Scale (SIRS) has been tested in cross-sectional and longitudinal analyses of individuals with AIzheimer disease and Huntington disease. Inter-rater reliability =.992,p<.001. Two week test-retest reliabSty=.97,p<.0001. Internal consistency by Chronbach's alpha =.76. Validity is supported by correlations with the Glasgow Coma Scale (r =.866,p <.001), Mini Mental Status Examination (r=.770,p<.O01) and the SIB by prediction of mortality at one year.
$49
195 Rellability, validity and sensitivity to disease evolution of AIzheimer's Disease Assessment Scale (cognitive): a reappraisal U. Lucca*, P. Tiraboschi#, M. Tettamanti, C. A. De Fanti#, and A. Spagnoli Istituto di Rieerehe Farmacologiche "Marie Negri", Milano #1a Divisione Neurelogica, Ospedali Riuniti di Bergamo, Bergarno - Italy Worldwide use of the cognitive portion of Alzheimer's Disease Assessment Scale (ADAS-Cog) in antidementia drug trials as a comprehensive test to detect changes in core cognitive manifestations of Alzheimer's disease (AD), drove us to re.assess its reliability, concurrent validity, and sensitivity to clinical evolution. Thirty-three patients (24 F/9 M, mean age of 75+7.1 y and mean educational level 5.1+_.2.4y) meeting NINCDS-ADRDA criteria for probable AD and twentytwo elderly controls (mainly patients' relatives; 19 F/3M, mean age of 70.35:6.8 y and mean educational level 7.45:4.7 y) were evaluated by two independent raters in two clinical centers (baseline) and reassessed about one month later (followup) with ADAS-Cog (two alternate forms), MMSE, Blessed IMC (BIMC) and Dementia Scale (BDS, only the patients), and language and attention tests. Squared weighted Cohen's K for test-retest and inter-rater reliability and Pearson product moment coefficient for correlation studies were used. Moreover, data from one completed trial and the baseline of two ongoing investigations in probable AD patients (NINCDS-ADRDA criteria) were analyzed to evaluate ADAS-Cog (total and subtest scores) sensitivity to disease evolution and rate of progression, and to look for correlations with other global instruments. ADAS-Cog inter-rater and test-retest reliability were high in the AD group (K=0.99 and K=0.90, respectively) and, due to the truncation of variance, apparently lower in the control group (K=0.98 and K=0.55). Stability over time of the subtest scores however was less impressive, at times just fair. ADAS-Cog had good correlations in the AD group with both BIMC (r=0.70, p<0.0001) and MMSE (r=-0.76, p<0.0001), and, to a lesser extent, with the ADL portion of BDS (r--0.51, p=0.0046). Similar results were also seen at the baseline of each trial considered. Baseline data from an ongoing investigation showed a strong association with CDR-Sum of Boxes too (N=99, r=0.75). Mean ADAS-Cog score at baseline for all AD patients studied (N=185) was 26.9+-9.8, with significant differences among each stage group (Global Deterioration Scale, GDS): elderly controls (N=22) 7.9+-3.2, GDS3 (N=45) 18.5+-5.8, GDS4 (N=86) 26.3+-7.1, and GDS5 (N=51) 36.2+-8.9 (p<0.0001 at Bonferroni test following the ANOVA). The three language ratings and the concentration subtest (ADAS-nonCog) were much less sensitive to stage evolution and correlated poorly with comprehension, fluency, and attention tests. The results of our study go along with those of the original work by Rosen et al (1984) proving ADAS-Cog a suitable, global measure of cognitive change for clinical trials in AD, but suggesting that there is room to enhance the reliability and sensitivity to disease progression of some of its subtests.
196 Possible Problems With Clinical Selection Criteria Used in Alzheimer's Disease Clinical Trials. J. Willmer* and E. Mohr, Department of Medicine (Neurology), University of Ottawa, Elisabeth Bruyere Health Centre, 75 Bruyere St., Ottawa, Ontario, Canada, KIN 5C8 As there continues to be no definitive test for Alzheimer's disease, diagnosis has to be achieved using clinical criteria sets such as those outlined in DSM-III or NINCDS-ADRDA. Using a previously published CT scan measuring technique' which correlates well with diagnoses achieved using the NINCDS-ADRDA criteria, we chose to independently examine and reach a diagnosis in patients selected for participation in clinical trials of therapeutic agents in dementia of the Alzheimer type(DAT). Forty four CT seam from six sites across Canada were examined using the model. All patients had been diagnosed as having DAT by N1NCDS-ADRDA criteria and were deemed acceptable to participate in a clinical trial. The diagnostic concordance achieved in the original published model was 91.5%. The diagnostic concordance in the population being studied was 77.3%. However when examined by site, results ranged from 57.1% to 100%. Using the model, an index of atrophy and a probability of diagnosis of DAT can be determined. Across sites, there were statistically significant differences in these measures (p<.035). The mean probability of diagnosis of DAT across sites ranged from .56 to .94. Although the sites with lower probabilities had slightly lower mean ages and slightly less atrophy, there was no overall correlation of the atrophy measures with age. A number of explanations for these discrepancies can be suggested. It is possible that the CT measurement model used is not valid, perhaps due the fact that the scans were all done on different scanners, even though the same scanning protocol was used. The different sites maybe applying the NINCDS-ADRDA criteria differently, leading to selection of different subpopulations. Thus, different subgroups of DAT maybe present at different sites. If this explanation is valid, the selection of patients for Alzheimer clinical trials using current diagnostic criteria sets may not be adequate and conclusions with respect to agent efficacy could be flawed. ' Willmer J, Carruthers A, Guzman DA, Collins B, Pogue J, Stuss DT The usefulness of CT scanning in diagnosing dementia of the Alzheimer type. Can. J. Neurol. gel 1993; 20:210 - 216