- Email: [email protected]
External criteria comparison of global cognition test candidates from the Alzheimer's Disease Neuroimaging Initiative (ADNI) data
Oral Sessions: O1-01: Basic Science: Beta-amyloid and Stem Cells Background: Most measurements of cognitive performance, including the Alzheimer’s Disease Assessment Scale - Cognitive subscale (ADAS-Cog), are based on counts, such as counts of errors. The use of sum scores requires the implicit acceptance of untenable assumptions. These assumptions are relaxed when modern psychometric methods, including item response theory (IRT), are used to score cognitive performance data. IRT also provides a framework for the principled expansion of an instrument. The goal of this research was to evaluate the best methods for handling ADAS-Cog performance data when using IRT methods. A secondary goal was to evaluate extensions to the ADAS-Cog battery to improve measurement sensitivity. Methods: We used cognitive performance data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Measures included the ADAS-Cog, the Boston Naming Test, the Auditory Verbal Learning Test, Digit Span, Digit Symbol, Trail Making, and Clock Drawing. We estimated IRT models for cognitive performance data using item parcels (e.g., ordinal sub-task scores) and granular items (e.g., individual items from sub-tasks). We evaluated a number of distinct model and scoring permutations, varying the tests and items that were included. Results: We found that bifactor measurement models (models that account for residual correlation among items net of a general factor with orthogonal factors for sub-components) fit the cognitive performance data well. In general, we detected no benefit for estimating models using granular items relative to models using ordinal item parcels. IRT scores based on the ADAS-Cog compared favorably in internal psychometric characteristics to scores in which the ADAS-Cog was supplemented by neuropsychological tests. Differences among scales were relatively small. Conclusions: The ADAS-Cog is essentially a unidimensional cognitive performance test after parceling out selected methods factors. The measurement precision is good in the ADNI cohort overall, but measurement precision is lower among persons with none to mild impairment and very severe impairment. Internal psychometric properties of the ADAS-Cog were not substantially improved by adding items from commonly used neuropsychological tests. Further improvement of the ADAS-Cog requires investigation of cognitive performance tests not included in the ADNI protocol. F1-02-04
EXTERNAL CRITERIA COMPARISON OF GLOBAL COGNITION TEST CANDIDATES FROM THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE (ADNI) DATA
Paul Crane, University of Washington School of Medicine, Seattle, Washington, United States. Contact e-mail: [email protected] Background: ADNI provides a wealth of data for comparing different global cognition tests. In previous work, we had selected particular imaging and clinical characteristics as benchmarks for tests of memory (Crane et al., 2012), executive functioning (EF; Gibbons et al., 2012), and global cognition (Skinner et al., 2012). For this project we selected several of these and compared the candidate global cognition tests in terms of their associations with these criteria. Methods: We used several categories of external criteria. For imaging parameters, we examined global indices (ventricular (VV) and total brain volume (TBV)), as well as hippocampal (HCV) and entorhinal cortex (EC) volumes, more disease-specific indicators. For clinical parameters, we compared rates of change over time in relation to change in clinical diagnosis, and time to conversion from late mild cognitive impairment (LMCI) to Alzheimer’s disease (AD). For biomarkers, we looked at CSF Abeta1-42, tau, and ptau, and the AD pattern (low Abeta1-42 and high total tau) described in De Meyer et al. (2010). We conducted analyses separately in each diagnostic group (e.g. normal cognition, LMCI, and AD), except for time to AD and the CSF biomarker criteria, which were only examined in LMCI. Results: Differences across measures in strength of association with external criteria were small. In LMCI, scores that included memory items generally had the strongest cross-sectional associations with HCV, ECV, and TBV, but scores with EF items were best for VV. Most measures predicted conversion from LMCI to dementia with similar accuracy. For the clinical and biomarker outcomes, relationships were improved with the addition of EF items in LMCI. Most scores increased over time in NC. Scores supplemented by Boston Naming test items were
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most sensitive to change in clinical diagnosis. Overall, there was no benefit to the use of more granular item data or to Rasch scoring. Conclusions: ADNI data provide a wealth of opportunities to compare different candidate global cognition tests. For many outcomes, it would be beneficial to expand the ADAS-Cog to include additional items, particularly in the EF domain. PLENARY SESSION: PL-01 PL-01-01
AMYLOID PET IMAGING IN CLINICAL PRACTICE
Steven DeKosky, Charlottesville, Virginia, United States. Contact e-mail: [email protected] Background: Healthy debate continues about what is the “inciting event” in Alzheimer Disease (AD); multiple different and complex biological cascades having been discovered in the last 20 years. The “hallmark diagnostic findings” of AD are amyloid plaques comprised of extracellular deposition of the Amyloid Precursor Protein (APP) fragment beta-amyloid 1-42 (A b); and intraneuronal deposition of neurofibrillary tangles (NFT), comprised of hyperphosphorylated and cross-linked tau protein. If the brain does not have amyloid plaque deposition, AD cannot be diagnosed by current neurodiagnostic criteria. Methods: In late onset AD, fibrillar and oligomeric forms of A b accumulate. Concentrations of these aggregated peptides are hypothesized to increase in an early presymptomatic phase of the disease. Then, as A b aggregates into plaque, CSF Ab42 levels fall to half the normal concentration. Some aggregates assemble into fibrils and form classical neuritic plaques; others remain in the oligomeric state or form diffuse deposits. NFTs build up in nerve cells and lead to neuronal injury (reflected in membrane integrity compromise and leakage of the intracellular tau into the CSF). Amyloid plaque numbers/density do not correlate as well with cognition as do NFT; amyloid is more a marker of the presymptomatic and disease states. Results: There are multiple uses for amyloid imaging. In clinical practice a positive scan can confirm a specific dementia diagnosis of AD. In MCI, a positive scan strongly implicates AD as the cause. In normal middle aged or elderly subjects, a positive scan indicates that the AD process is ongoing in the brain. However, a positive scan does not predict the definite development of AD; 35-30% of individuals over 85 who have normal cognition have enough amyloid plaques and NFT in their brains at autopsy that they would have been diagnosed with AD had they had cognitive problems prior to death. Finally, serial amyloid PET scans can determine whether anti-amyloid medications show diminished amyloid. Conclusions: We will discuss assumptions underlying use of amyloid imaging for these purposes, the regulatory pathway by which they can be approved, and the issues of the value of amyloid imaging that present themselves to patients, physicians, regulators, and third party payers including Medicare. ORAL SESSIONS: O1-01 BASIC SCIENCE: BETA-AMYLOID AND STEM CELLS O1-01-01
BRICHOS EFFICIENTLY INHIBITS BETAAMYLOID 42 AGGREGATION AND TOXICITY IN DROSOPHILA MELANOGASTER
Erik Hermansson1, Krishnapriya Loganathan1, Damian Crowther2, Gunilla Westermark3, Bengt Winblad4, Jan Johansson1, Jenny Presto1, 1 Karolinska Institutet, Stockholm, Sweden; 2University of Cambridge, Cambridge, United Kingdom; 3Uppsala University, Uppsala, Sweden; 4 Karolinska Institute, Huddinge, Sweden. Contact e-mail: jenny.presto@ki. se Background: Alzheimer’s disease (AD) is the most common form of dementia. Hallmarks in AD are the aggregation of the Abpeptide into amyloid fibrils and plaques in the brain. The fibrils of Abare not believed to be the most neurotoxic species, instead intermediates formed during the process of Abaggregation have been shown to be more toxic. We are studying the BRICHOS domain found in 12 protein families, and focus on the BRICHOS domains in the Bri2 protein associated with familial British and Danish dementia, the neuron specific Bri3 protein and the lung specific proSP-C. Our working hypothesis is that the BRICHOS domain is a natural anti-amyloid
EXTERNAL CRITERIA COMPARISON OF GLOBAL COGNITION TEST CANDIDATES FROM THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE (ADNI) DATA
Paul Crane, University of Washington School of Medicine, Seattle, Washington, United States. Contact e-mail: [email protected] Background: ADNI provides a wealth of data for comparing different global cognition tests. In previous work, we had selected particular imaging and clinical characteristics as benchmarks for tests of memory (Crane et al., 2012), executive functioning (EF; Gibbons et al., 2012), and global cognition (Skinner et al., 2012). For this project we selected several of these and compared the candidate global cognition tests in terms of their associations with these criteria. Methods: We used several categories of external criteria. For imaging parameters, we examined global indices (ventricular (VV) and total brain volume (TBV)), as well as hippocampal (HCV) and entorhinal cortex (EC) volumes, more disease-specific indicators. For clinical parameters, we compared rates of change over time in relation to change in clinical diagnosis, and time to conversion from late mild cognitive impairment (LMCI) to Alzheimer’s disease (AD). For biomarkers, we looked at CSF Abeta1-42, tau, and ptau, and the AD pattern (low Abeta1-42 and high total tau) described in De Meyer et al. (2010). We conducted analyses separately in each diagnostic group (e.g. normal cognition, LMCI, and AD), except for time to AD and the CSF biomarker criteria, which were only examined in LMCI. Results: Differences across measures in strength of association with external criteria were small. In LMCI, scores that included memory items generally had the strongest cross-sectional associations with HCV, ECV, and TBV, but scores with EF items were best for VV. Most measures predicted conversion from LMCI to dementia with similar accuracy. For the clinical and biomarker outcomes, relationships were improved with the addition of EF items in LMCI. Most scores increased over time in NC. Scores supplemented by Boston Naming test items were
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most sensitive to change in clinical diagnosis. Overall, there was no benefit to the use of more granular item data or to Rasch scoring. Conclusions: ADNI data provide a wealth of opportunities to compare different candidate global cognition tests. For many outcomes, it would be beneficial to expand the ADAS-Cog to include additional items, particularly in the EF domain. PLENARY SESSION: PL-01 PL-01-01
AMYLOID PET IMAGING IN CLINICAL PRACTICE
Steven DeKosky, Charlottesville, Virginia, United States. Contact e-mail: [email protected] Background: Healthy debate continues about what is the “inciting event” in Alzheimer Disease (AD); multiple different and complex biological cascades having been discovered in the last 20 years. The “hallmark diagnostic findings” of AD are amyloid plaques comprised of extracellular deposition of the Amyloid Precursor Protein (APP) fragment beta-amyloid 1-42 (A b); and intraneuronal deposition of neurofibrillary tangles (NFT), comprised of hyperphosphorylated and cross-linked tau protein. If the brain does not have amyloid plaque deposition, AD cannot be diagnosed by current neurodiagnostic criteria. Methods: In late onset AD, fibrillar and oligomeric forms of A b accumulate. Concentrations of these aggregated peptides are hypothesized to increase in an early presymptomatic phase of the disease. Then, as A b aggregates into plaque, CSF Ab42 levels fall to half the normal concentration. Some aggregates assemble into fibrils and form classical neuritic plaques; others remain in the oligomeric state or form diffuse deposits. NFTs build up in nerve cells and lead to neuronal injury (reflected in membrane integrity compromise and leakage of the intracellular tau into the CSF). Amyloid plaque numbers/density do not correlate as well with cognition as do NFT; amyloid is more a marker of the presymptomatic and disease states. Results: There are multiple uses for amyloid imaging. In clinical practice a positive scan can confirm a specific dementia diagnosis of AD. In MCI, a positive scan strongly implicates AD as the cause. In normal middle aged or elderly subjects, a positive scan indicates that the AD process is ongoing in the brain. However, a positive scan does not predict the definite development of AD; 35-30% of individuals over 85 who have normal cognition have enough amyloid plaques and NFT in their brains at autopsy that they would have been diagnosed with AD had they had cognitive problems prior to death. Finally, serial amyloid PET scans can determine whether anti-amyloid medications show diminished amyloid. Conclusions: We will discuss assumptions underlying use of amyloid imaging for these purposes, the regulatory pathway by which they can be approved, and the issues of the value of amyloid imaging that present themselves to patients, physicians, regulators, and third party payers including Medicare. ORAL SESSIONS: O1-01 BASIC SCIENCE: BETA-AMYLOID AND STEM CELLS O1-01-01
BRICHOS EFFICIENTLY INHIBITS BETAAMYLOID 42 AGGREGATION AND TOXICITY IN DROSOPHILA MELANOGASTER
Erik Hermansson1, Krishnapriya Loganathan1, Damian Crowther2, Gunilla Westermark3, Bengt Winblad4, Jan Johansson1, Jenny Presto1, 1 Karolinska Institutet, Stockholm, Sweden; 2University of Cambridge, Cambridge, United Kingdom; 3Uppsala University, Uppsala, Sweden; 4 Karolinska Institute, Huddinge, Sweden. Contact e-mail: jenny.presto@ki. se Background: Alzheimer’s disease (AD) is the most common form of dementia. Hallmarks in AD are the aggregation of the Abpeptide into amyloid fibrils and plaques in the brain. The fibrils of Abare not believed to be the most neurotoxic species, instead intermediates formed during the process of Abaggregation have been shown to be more toxic. We are studying the BRICHOS domain found in 12 protein families, and focus on the BRICHOS domains in the Bri2 protein associated with familial British and Danish dementia, the neuron specific Bri3 protein and the lung specific proSP-C. Our working hypothesis is that the BRICHOS domain is a natural anti-amyloid