- Email: [email protected]
RESOLVING CONFLICTING CSF BIOMARKER INFORMATION IN ALZHEIMER′S DISEASE
Poster Presentations: Wednesday, July 27, 2016
hypertension and NIA-AA group (p¼0.056), in which hypertension increased the risk of cognitive decline in groups with a normal amyloid marker. Conclusions: We showed that vascular risk factors, except atherosclerotic diseases, are not associated with prodromal AD and the related cognitive decline. These findings have implications for clinical practice and intervention strategies. P4-123
RESOLVING CONFLICTING CSF BIOMARKER INFORMATION IN ALZHEIMER0 S DISEASE
Kelly D. Watts, J. Christina Howell, Patricia Herrera, Raven C. Lee, William T. Hu Emory University, Atlanta, GA, USA. Contact e-mail: [email protected] Background: Different CSF biomarker combinations can provide
conflicting diagnostic information in Alzheimer0 s disease (AD). This is often attributed to differences in sensitivity and specificity, at the cohort level, between CSF markers (Ab42, t-Tau, p-Tau181, tTau/Ab42, and p-Tau181/Ab42). When these biomarkers are analyzed against the same gold standard independently, conflicting biomarker information can also result from biomarker substructures not obvious to investigators. Previous studies have not examined conflicting biomarker information at the individual level (e.g., a profile showing normal Ab42 levels but abnormal t-Tau/Ab42 ratio may be interprted as AD-like even though the normal Ab42 level argues against amyloid pathology). The prevalence of these conflicts and ways to resolve them are unknown. Methods: We measured CSF AD biomarker levels in one consecutive series (n¼431) from Emory University using the multiplex AlzBio3 assay and surveyed the concordance rates between CSF biomarkers at the individual level. We also compared these results with those from clinical testing through a comparable ELISA. To resolve the issue of differential sensitivity and biomarker substructure, we then analyzed CSF AD biomarker levels through two-step clustering to identify naturally existing subgroups of biomarker profiles. Finally, to determine if the cluster membership or the combination of independent biomarker information confers greater information on prognosis, we analyzed if either predicted longitudinal cognitive changes in the Alzheimer’s Disease Neuro-Imaging Initiative (ADNI, n¼409). Results: Conflicting CSF biomarker information was very common: 59% of the Emory subjects and 37% of ADNI subjects had at least one biomarker providing diagnostic information distinct from the other biomarkers. Clustering analysis revealed three groupings: one characterized by p-Tau181/ Ab42>0.131 and longitudinal cognitive decline in MCI, and two others (including one characterized by Ab42>258.5pg/mL) associated with cognitive stability. Within each cluster, concordant or discordant biomarker findings did not further distinguish rates of longitudinal cognitive decline. Conclusions: Conflicting information from different CSF AD biomarkers was common. A datadriven strategy accounting for all biomarker combinations identified naturally existing groupings each characterized by similar biochemical and prognostic profiles. P4-125
COGNITIVE EVENT-RELATED POTENTIALS USED AS BIOMARKERS IN PLEODIAL-I STUDY: FIRST EVIDENCE OF A NEUROPHYSIOLOGICAL EFFECT OF PXT864 IN MILD ALZHEIMER’S DISEASE PATIENTS
Karim Bennys1, Raphael Haddad2, Catherine Scart Gres2, Peter Schmitt3, Jacques Touchon4, 1Memory Resources and Research Center, CHRU Gui de Chauliac, Montpellier, France; 2Pharnext SAS, Issy les Moulineaux, France, Paris, France; 3Pharnext, Paris, France; 4Memory Research
P1061
Resource Center for Alzheimer’s disease, University Hospital Montpellier, France, Montpellier, France. Contact e-mail: [email protected] Background: Cognitive event related potential (ERP) is a usefull biomarker for the diagnosis of Alzheimer’s Disease (AD), even from the preclinical stage. We report here the use of ERP in a phase IIa clinical study to explore in mild AD patients the symptomatic effect of PXT864, an under-development fixed combination of low doses of acamprosate and baclofen, which has shown multiple reversions of pathological alteration in cellular and animal models of AD. Methods: PLEODIAL-I is a pilot phase IIa study to assess the safety and preliminary evidence of efficacy on cognitive impairment and function of PXT864 in patients with mild AD. PXT864 was taken in single blind during 4 weeks, followed by placebo during 4 weeks, and then PXT864 during 4 last weeks. With this challenge/de-challenge/re-challenge original design, two doses of PXT864 were tested by two sets of patients. Efficacy was assessed through the 11-item Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-Cog). In one of the 6 participating investigational centers, a sub-study was added to assess also PXT864 efficacy with the ERP method. Recordings were performed on Cz, Fz, and Pz at baseline (V1, before first drug administration) and at each 4-week visit (V2, V3, and V4). 3 patients under the lower dose and 3 under the higher dose of PXT864 had completed their 4-visit ERP sessions. Results: An improvement during the 2 periods under active drug, and a worsening during the placebo period were observed in all cases in terms of latencies and amplitudes of P3b on Cz, Fz, and Pz for both doses tested. This expected “challenge, de-challenge, re-challenge” pattern was also found in a spatio-temporal principal component analysis performed on ERP raw data. Conclusions: These ERP results show first evidence of PXT864 neurophysiological activity to restore the balance between glutamate and GABA signaling disrupted by toxic Aß oligomeric peptides, which seemed also to be coupled to a global cognitive improvement in 4-week treatment periods.
P4-126
EVALUATION OF A NOVEL ARRAY OF SNP (SINGLE NUCLEOTIDE POLYMORPHISM) MARKERS IN AMYLOID-PET STRATIFIED SAMPLES FROM MCI AND COGNITIVELY NORMAL INDIVIDUALS
Maryam Shoai1, Lakshmi Radhakrishnan2, Richard Pither3, Geoff Scopes4, Valentina Escott-Price5, Simon M. Laws6,7, Julie Davis3, Harald Hampel8, Rik Vandenberghe9, Claire Bloor4, John Hardy1, 1UCL Institute of Neurology, London, United Kingdom; 2Affymetrix, Santa Clara, CA, USA; 3Cytox Ltd, UK, Oxford, United Kingdom; 4Affymetrix, High Wycombe, United Kingdom; 5MRC Centre for Neuropsychiatric Genetics & Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom; 6Edith Cowan University, Perth, Australia; 7Cooperative Research Centre for Mental Health, Melbourne, Australia; 8Universite Pierre et Marie Curie, Paris, France; 9 Laboratory for Cognitive Neurology, Department of Neurology, University of Leuven and University Hospitals Leuven Gasthuisberg, Leuven, Belgium. Contact e-mail: [email protected] Background: Considerable evidence has been accumulated that supports the role of a significant inherited risk component for the development of Late-Onset Alzheimer’s Disease (LOAD). The identification of a panel of genetic risk variants, or SNPs, which could be used in the definition of an algorithm to predict risk of future progression to Alzheimer’s Disease in early symptomatic, or pre-symptomatic individuals, would have utility to researchers, drug developers and clinicians alike. Methods: We have used whole
hypertension and NIA-AA group (p¼0.056), in which hypertension increased the risk of cognitive decline in groups with a normal amyloid marker. Conclusions: We showed that vascular risk factors, except atherosclerotic diseases, are not associated with prodromal AD and the related cognitive decline. These findings have implications for clinical practice and intervention strategies. P4-123
RESOLVING CONFLICTING CSF BIOMARKER INFORMATION IN ALZHEIMER0 S DISEASE
Kelly D. Watts, J. Christina Howell, Patricia Herrera, Raven C. Lee, William T. Hu Emory University, Atlanta, GA, USA. Contact e-mail: [email protected] Background: Different CSF biomarker combinations can provide
conflicting diagnostic information in Alzheimer0 s disease (AD). This is often attributed to differences in sensitivity and specificity, at the cohort level, between CSF markers (Ab42, t-Tau, p-Tau181, tTau/Ab42, and p-Tau181/Ab42). When these biomarkers are analyzed against the same gold standard independently, conflicting biomarker information can also result from biomarker substructures not obvious to investigators. Previous studies have not examined conflicting biomarker information at the individual level (e.g., a profile showing normal Ab42 levels but abnormal t-Tau/Ab42 ratio may be interprted as AD-like even though the normal Ab42 level argues against amyloid pathology). The prevalence of these conflicts and ways to resolve them are unknown. Methods: We measured CSF AD biomarker levels in one consecutive series (n¼431) from Emory University using the multiplex AlzBio3 assay and surveyed the concordance rates between CSF biomarkers at the individual level. We also compared these results with those from clinical testing through a comparable ELISA. To resolve the issue of differential sensitivity and biomarker substructure, we then analyzed CSF AD biomarker levels through two-step clustering to identify naturally existing subgroups of biomarker profiles. Finally, to determine if the cluster membership or the combination of independent biomarker information confers greater information on prognosis, we analyzed if either predicted longitudinal cognitive changes in the Alzheimer’s Disease Neuro-Imaging Initiative (ADNI, n¼409). Results: Conflicting CSF biomarker information was very common: 59% of the Emory subjects and 37% of ADNI subjects had at least one biomarker providing diagnostic information distinct from the other biomarkers. Clustering analysis revealed three groupings: one characterized by p-Tau181/ Ab42>0.131 and longitudinal cognitive decline in MCI, and two others (including one characterized by Ab42>258.5pg/mL) associated with cognitive stability. Within each cluster, concordant or discordant biomarker findings did not further distinguish rates of longitudinal cognitive decline. Conclusions: Conflicting information from different CSF AD biomarkers was common. A datadriven strategy accounting for all biomarker combinations identified naturally existing groupings each characterized by similar biochemical and prognostic profiles. P4-125
COGNITIVE EVENT-RELATED POTENTIALS USED AS BIOMARKERS IN PLEODIAL-I STUDY: FIRST EVIDENCE OF A NEUROPHYSIOLOGICAL EFFECT OF PXT864 IN MILD ALZHEIMER’S DISEASE PATIENTS
Karim Bennys1, Raphael Haddad2, Catherine Scart Gres2, Peter Schmitt3, Jacques Touchon4, 1Memory Resources and Research Center, CHRU Gui de Chauliac, Montpellier, France; 2Pharnext SAS, Issy les Moulineaux, France, Paris, France; 3Pharnext, Paris, France; 4Memory Research
P1061
Resource Center for Alzheimer’s disease, University Hospital Montpellier, France, Montpellier, France. Contact e-mail: [email protected] Background: Cognitive event related potential (ERP) is a usefull biomarker for the diagnosis of Alzheimer’s Disease (AD), even from the preclinical stage. We report here the use of ERP in a phase IIa clinical study to explore in mild AD patients the symptomatic effect of PXT864, an under-development fixed combination of low doses of acamprosate and baclofen, which has shown multiple reversions of pathological alteration in cellular and animal models of AD. Methods: PLEODIAL-I is a pilot phase IIa study to assess the safety and preliminary evidence of efficacy on cognitive impairment and function of PXT864 in patients with mild AD. PXT864 was taken in single blind during 4 weeks, followed by placebo during 4 weeks, and then PXT864 during 4 last weeks. With this challenge/de-challenge/re-challenge original design, two doses of PXT864 were tested by two sets of patients. Efficacy was assessed through the 11-item Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-Cog). In one of the 6 participating investigational centers, a sub-study was added to assess also PXT864 efficacy with the ERP method. Recordings were performed on Cz, Fz, and Pz at baseline (V1, before first drug administration) and at each 4-week visit (V2, V3, and V4). 3 patients under the lower dose and 3 under the higher dose of PXT864 had completed their 4-visit ERP sessions. Results: An improvement during the 2 periods under active drug, and a worsening during the placebo period were observed in all cases in terms of latencies and amplitudes of P3b on Cz, Fz, and Pz for both doses tested. This expected “challenge, de-challenge, re-challenge” pattern was also found in a spatio-temporal principal component analysis performed on ERP raw data. Conclusions: These ERP results show first evidence of PXT864 neurophysiological activity to restore the balance between glutamate and GABA signaling disrupted by toxic Aß oligomeric peptides, which seemed also to be coupled to a global cognitive improvement in 4-week treatment periods.
P4-126
EVALUATION OF A NOVEL ARRAY OF SNP (SINGLE NUCLEOTIDE POLYMORPHISM) MARKERS IN AMYLOID-PET STRATIFIED SAMPLES FROM MCI AND COGNITIVELY NORMAL INDIVIDUALS
Maryam Shoai1, Lakshmi Radhakrishnan2, Richard Pither3, Geoff Scopes4, Valentina Escott-Price5, Simon M. Laws6,7, Julie Davis3, Harald Hampel8, Rik Vandenberghe9, Claire Bloor4, John Hardy1, 1UCL Institute of Neurology, London, United Kingdom; 2Affymetrix, Santa Clara, CA, USA; 3Cytox Ltd, UK, Oxford, United Kingdom; 4Affymetrix, High Wycombe, United Kingdom; 5MRC Centre for Neuropsychiatric Genetics & Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom; 6Edith Cowan University, Perth, Australia; 7Cooperative Research Centre for Mental Health, Melbourne, Australia; 8Universite Pierre et Marie Curie, Paris, France; 9 Laboratory for Cognitive Neurology, Department of Neurology, University of Leuven and University Hospitals Leuven Gasthuisberg, Leuven, Belgium. Contact e-mail: [email protected] Background: Considerable evidence has been accumulated that supports the role of a significant inherited risk component for the development of Late-Onset Alzheimer’s Disease (LOAD). The identification of a panel of genetic risk variants, or SNPs, which could be used in the definition of an algorithm to predict risk of future progression to Alzheimer’s Disease in early symptomatic, or pre-symptomatic individuals, would have utility to researchers, drug developers and clinicians alike. Methods: We have used whole