- Email: [email protected]
Choice of threshold hippocampal volume as a selection criterion in prodromal Alzheimer's disease
Poster Presentations: P3 by volunteers while reading a script; ii) prolonged wearing of a contact microphone by AD patients; and iii) submitting patient recordings to signal processing analysis. Methods: Perseverators were identified in a memory clinic using a cognitive symptom questionnaire. A contact microphone was affixed to the skin above the Temporo-Mandibular Joint to record speech related vibrations during description of a pictured scene. Subjects then wore the device during the course of a normal day. Recorded signals were pre-processed to reduce background noise and remove silence periods. A variety of signal features were extracted from each recorded signal and combined using Principal Component Analysis to obtain a one-dimensional feature vector. Results: Frequently occurring patterns in the feature vector were detected using a motif discovery algorithm. Some of the recorded samples were manually analyzed and examples of the repeated sequences are presented. Conclusions: We have established the feasibility of continuous recording of bone-conducted speech, and the possibility of defining distinct patterns of perseverative speech. In the next stage of the study we aim to associate the frequency of verbal repetitions with the stage, progression and type of dementia. It is possible that the method could contribute to the assessment of disease-modifying treatments.
P3-111
A RETURN TO CLINICAL SKILLS IN THE EARLY DIAGNOSIS OF ALZHEIMER’S DISEASE
Cassandra Szoeke1, Kathryn Ellis2, Ping Zhang3, Christopher Rowe4, Ralph Martins5, Colin Masters6, David Ames7, AIBL Research Group,8, 1National Ageing Research Institute, Faculty of Medicine, University of Melbourne, Melbourne, Australia; 2Mental Health Research Institute, Parkville, Australia; 3CSIRO, Parkville, Australia; 4Austin Health, Melbourne, Australia; 5ECU, Perth, Australia; 6University of Melbourne, Melbourne, Australia; 7National Ageing Research Institute, Parkville, Australia; 8Mental Health Research Institute, Parkville, Australia. Background: Preventing or delaying the onset of dementia due to Alzheimer’s disease (AD) requires an ability to identify those in early prodromal stages of disease, for inclusion in treatment and prevention trials. We have identified a sub-group within the healthy cognition (HC) category at an increased risk of progression to manifest cognitive impairment over 18 to 36 months, compared to others in the healthy control category that is independent of known risk factors. Methods: We modeled the cognitive scores of the 704 AIBL HC subjects at baseline to see if clear classes were apparent within this group. Two groups were distinguished within the HC population for cognitive performance. We then tested the predictive significance of this classification at 18 and 36 month follow-up. Association between class and risk of transition from baseline clinical state (HC) to cognitive impairment (MCI or AD) within 18 and 36 months of follow-up was approximated by an odds ratio (OR) using logistic regression. Results: Being in the lower performing group was a significant risk for converting to MCI or AD over 18 months with an odds ratio of 7.5 (CI 2.6-27.3). Three-year follow-up maintained and strengthened the risk of conversion for those in the lower performing group with OR 8.8 (CI 3.6-24.5). Being in the lower performing group at 18 months was the highest risk for conversion at three years with OR 10.2 (CI 3.4-38.1) All analyses were ad-
P491
justed for age, education, sex and APOE-ε4. Being in the lower performing group was not associated with APOE status or brain amyloid load measured by Pittsburgh compound B Positron Emission Tomography. Conclusions: In this sample a clinical cognitive test acts as a discriminator to extract an enriched subsample who has about 10 times higher risk of progression to manifest cognitive impairment within 18-36 months. Identification of this AIBL subgroup offers the potential for risk-based “filtering” in clinical trials, allowing focus on those individuals with a relative greater risk of conversion to disease in the cohort.
P3-113
CHOICE OF THRESHOLD HIPPOCAMPAL VOLUME AS A SELECTION CRITERION IN PRODROMAL ALZHEIMER’S DISEASE
Gerald Novak1, Hui Jing Yu2, Steven Einstein3, Spencer Guthrie3, Richard Margolin3, Luc Bracoud4, Boubakeur Balaroussi2, Charles S. Decarli5, Chahin Pachai6, 1Janssen Pharmaceutical Research and Development, Titusville, New Jersey, United States; 2Bioclinica, Lyon, France; 3Janssen Alzheimer Immunotherapy, South San Francisco, California, United States; 4BioClinica, Lyon, France; 5University of California-Davis, Sacramento, California, United States; 6Bioclinica, Lyon, France. Background: Hippocampal atrophy may serve to select subjects with greater likelihood of clinical progression in prodromal Alzheimer’s disease clinical trials, but the optimal cutoff hippocampal volume (HCV) for this purpose is unknown. Methods: The Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort of subjects with amnestic mild cognitive impairment (aMCI) served as a reference dataset. Included subjects had an MRI at baseline and clinical status known or inferred at 36 months. Mean right and left HCV were adjusted for age and total intracranial volume. It was assumed that progression to dementia is the primary outcome of interest and that subjects are selected for smaller HCV. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and annualized change from baseline to conversion or month 36 in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) scores were calculated for all observed HCVs, generating a receiver operating characteristic (ROC) curve. Results: Of 265 subjects, 142 (54%) progressed to dementia by 36 months. They were more likely than stable subjects to have 1-2 APOE-ε4 alleles (67 vs 41%, respectively), a smaller HCV (2872 6 412 mm 3 vs 3175 6 439 mm 3), and a higher baseline CDR-SOB score (1.84 6 0.95 vs 1.28 6 0.64). The area under the ROC curve was 0.695. Operating characteristics of several potential HCV cutoffs (and percentiles relative to ADNI controls) are given in the table. A selection criterion set at the 10th percentile included more than half of aMCI subjects and enriched the proportion of progressors from 0.535 to 0.685 (PPV). A slightly more liberal criterion increased sensitivity and annual change in CDR-SOB score at the cost of a slightly lower specificity and PPV. Conclusions: Smaller baseline HCV identified aMCI subjects with greater likelihood of progression to dementia. However, utility will depend on the acceptable tradeoffs among sensitivity, PPV and risk of propagation of overly proscriptive guidelines into clinical practice.
Table 1 Normal Percentile
HCV Cutoff, mm3
% Subjects Included
Sensitivity
Specificity
PPV
NPV
DCDRSOB (sd)
5th 10th 15th 20th
2835 3026 3141 3200
37 54 60 65
0.479 0.690 0.746 0.782
0.764 0.634 0.569 0.512
0.701 0.685 0.667 0.649
0.560 0.639 0.660 0.670
1.40 (1.43) 1.47 (1.96) 1.49 (2.00) 1.43 (1.96)
P3-111
A RETURN TO CLINICAL SKILLS IN THE EARLY DIAGNOSIS OF ALZHEIMER’S DISEASE
Cassandra Szoeke1, Kathryn Ellis2, Ping Zhang3, Christopher Rowe4, Ralph Martins5, Colin Masters6, David Ames7, AIBL Research Group,8, 1National Ageing Research Institute, Faculty of Medicine, University of Melbourne, Melbourne, Australia; 2Mental Health Research Institute, Parkville, Australia; 3CSIRO, Parkville, Australia; 4Austin Health, Melbourne, Australia; 5ECU, Perth, Australia; 6University of Melbourne, Melbourne, Australia; 7National Ageing Research Institute, Parkville, Australia; 8Mental Health Research Institute, Parkville, Australia. Background: Preventing or delaying the onset of dementia due to Alzheimer’s disease (AD) requires an ability to identify those in early prodromal stages of disease, for inclusion in treatment and prevention trials. We have identified a sub-group within the healthy cognition (HC) category at an increased risk of progression to manifest cognitive impairment over 18 to 36 months, compared to others in the healthy control category that is independent of known risk factors. Methods: We modeled the cognitive scores of the 704 AIBL HC subjects at baseline to see if clear classes were apparent within this group. Two groups were distinguished within the HC population for cognitive performance. We then tested the predictive significance of this classification at 18 and 36 month follow-up. Association between class and risk of transition from baseline clinical state (HC) to cognitive impairment (MCI or AD) within 18 and 36 months of follow-up was approximated by an odds ratio (OR) using logistic regression. Results: Being in the lower performing group was a significant risk for converting to MCI or AD over 18 months with an odds ratio of 7.5 (CI 2.6-27.3). Three-year follow-up maintained and strengthened the risk of conversion for those in the lower performing group with OR 8.8 (CI 3.6-24.5). Being in the lower performing group at 18 months was the highest risk for conversion at three years with OR 10.2 (CI 3.4-38.1) All analyses were ad-
P491
justed for age, education, sex and APOE-ε4. Being in the lower performing group was not associated with APOE status or brain amyloid load measured by Pittsburgh compound B Positron Emission Tomography. Conclusions: In this sample a clinical cognitive test acts as a discriminator to extract an enriched subsample who has about 10 times higher risk of progression to manifest cognitive impairment within 18-36 months. Identification of this AIBL subgroup offers the potential for risk-based “filtering” in clinical trials, allowing focus on those individuals with a relative greater risk of conversion to disease in the cohort.
P3-113
CHOICE OF THRESHOLD HIPPOCAMPAL VOLUME AS A SELECTION CRITERION IN PRODROMAL ALZHEIMER’S DISEASE
Gerald Novak1, Hui Jing Yu2, Steven Einstein3, Spencer Guthrie3, Richard Margolin3, Luc Bracoud4, Boubakeur Balaroussi2, Charles S. Decarli5, Chahin Pachai6, 1Janssen Pharmaceutical Research and Development, Titusville, New Jersey, United States; 2Bioclinica, Lyon, France; 3Janssen Alzheimer Immunotherapy, South San Francisco, California, United States; 4BioClinica, Lyon, France; 5University of California-Davis, Sacramento, California, United States; 6Bioclinica, Lyon, France. Background: Hippocampal atrophy may serve to select subjects with greater likelihood of clinical progression in prodromal Alzheimer’s disease clinical trials, but the optimal cutoff hippocampal volume (HCV) for this purpose is unknown. Methods: The Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort of subjects with amnestic mild cognitive impairment (aMCI) served as a reference dataset. Included subjects had an MRI at baseline and clinical status known or inferred at 36 months. Mean right and left HCV were adjusted for age and total intracranial volume. It was assumed that progression to dementia is the primary outcome of interest and that subjects are selected for smaller HCV. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and annualized change from baseline to conversion or month 36 in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) scores were calculated for all observed HCVs, generating a receiver operating characteristic (ROC) curve. Results: Of 265 subjects, 142 (54%) progressed to dementia by 36 months. They were more likely than stable subjects to have 1-2 APOE-ε4 alleles (67 vs 41%, respectively), a smaller HCV (2872 6 412 mm 3 vs 3175 6 439 mm 3), and a higher baseline CDR-SOB score (1.84 6 0.95 vs 1.28 6 0.64). The area under the ROC curve was 0.695. Operating characteristics of several potential HCV cutoffs (and percentiles relative to ADNI controls) are given in the table. A selection criterion set at the 10th percentile included more than half of aMCI subjects and enriched the proportion of progressors from 0.535 to 0.685 (PPV). A slightly more liberal criterion increased sensitivity and annual change in CDR-SOB score at the cost of a slightly lower specificity and PPV. Conclusions: Smaller baseline HCV identified aMCI subjects with greater likelihood of progression to dementia. However, utility will depend on the acceptable tradeoffs among sensitivity, PPV and risk of propagation of overly proscriptive guidelines into clinical practice.
Table 1 Normal Percentile
HCV Cutoff, mm3
% Subjects Included
Sensitivity
Specificity
PPV
NPV
DCDRSOB (sd)
5th 10th 15th 20th
2835 3026 3141 3200
37 54 60 65
0.479 0.690 0.746 0.782
0.764 0.634 0.569 0.512
0.701 0.685 0.667 0.649
0.560 0.639 0.660 0.670
1.40 (1.43) 1.47 (1.96) 1.49 (2.00) 1.43 (1.96)