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Volumetric MRI Results in a Prodromal AD Population

 

Audrey Istace, MSc1, Luc Bracoud, MSc1, Robert M. Berman, MD2, Feng Luo, PhD2, Florent Roche, MSc1, Stephen Salloway, MD3, Christopher van Dyck, MD4, Bruno Dubois, MD5, Niels Andreasen, MD6, PhD, Mark Brody, MD7,  Craig Curtis, MD8, Hilkka Soininen, MD9, Stephen Thein, PhD10, Thomas Shiovitz, MD11, Steven Ferris, PhD12,Joshua D. Grill, MD13,
Sylvain Gouttard, MSc1, Joël Schaerer, PhD1, Wendy Hayes, DO2, Stephen Kaplita, MSc2, Boubakeur Belaroussi, PhD1, Hui-Jing Yu, PhD1, Jesse M. Cedarbaum, MD2, Howard H. Feldman, MD14, Chahin Pachai, PhD1, Vlad Coric, MD2

1BioClinica, Lyon, France and Newtown, PA, USA - email: chahin.pachai@bioclinica.com   2Bristol Myers Squibb, Princeton, NJ and Wallingford, CT, USA   3Brown Medical School, Butler Hospital, Providence, RI, USA   4Yale University School of Medicine, New Haven, CT, USA   5Hôpital de la Salpêtrière, Paris, France   6Karolinska Institutet, Sweden   7Brain Matters Research, Delray Beach, FL, USA   8Compass Research, Orlando, FL, USA   9University of Eastern Finland, Kuopio, Finland
10Pacific Research Network, Inc., San Diego, CA, USA   11California Neuroscience Research Medical Group, Inc., Sherman Oaks, CA, USA   12NYU Langone Medical Center, New York City, NY, USA   13University of California - Los Angeles, Los Angeles, CA, USA   14University of British Columbia, Vancouver, British Columbia, Canada

 

INTRODUCTION

  • CN156-018 was the first prospective randomized controlled trial in subjects with prodromal AD using entry criteria based upon clinical phenotypic features and CSF biomarker criteria consistent with AD.
  • Avagacestat (BMS-708163), an oral γ-secretase inhibitor designed for selective inhibition of Aβ synthesis, was studied in predementia AD in CN156-018 Phase 2 clinical trial.
  • The purpose of this work was to assess volumetric MRI changes of Avagacestat-treated versus placebo subjects in whole brain, lateral ventricles and hippocampus over the course of this multi-year study.

METHODS
Population

  • 263 Prodromal AD subjects were selected, with the following inclusion criteria: MMSE 24 to 30, objective memory impairment, and CDR-global score of 0.5 with a memory box score ≥ 0.5, CSF Aβ42 levels < 200pg/mL or total tau/Aβ42 ratio ≥ 0.39.  Subjects were excluded if they met DSM-IV-TR criteria for dementia.
  • All subjects underwent MRI examinations composed of a high-resolution 3DT1 sequence in compliance with the ADNI-1 imaging protocol, using MP-RAGE (Siemens), 3D TFE (Philips) and 3D Fast SPGR (General Electric) pulse sequences. All MRI data were sent for central processing and safety monitoring to BioClinica once acquired.
  • 3DT1 MRI scans were collected at Baseline, Weeks 24, 56 and 104 to assess whole brain, lateral ventricle and hippocampal volumes. Subjects were also scanned more frequently for safety monitoring.
  • Only subjects with good quality scans (no significant imaging artifacts, same MRI protocol used across timepoints) were considered.
  • As a result, 82 subjects receiving 25 mg/day of BMS-708163 and 96 subjects receiving matching placebo during the study were considered.
  • 20 additional subjects that met all clinical inclusion criteria but were amyloid-negative based on CSF biomarker levels entered an observational cohort and were scanned at Baseline and Week 60.

Image analysis

  • Baseline volumes were assessed using atlas-based segmentation techniques [1,2].
  • Whole brain atrophy and lateral ventricle enlargement were assessed using Tensor Based Morphometry [3,4]. Hippocampal atrophy was assessed using the Hippocampal Boundary Shift Integral [4].

Statistical analysis

  • Mean brain volume loss was measured at each volumetric timepoint after adjusting for time between scans. T-tests were also performed in order to compare atrophy results between treated and placebo subjects (no correction for multiple comparisons was made).

RESULTS

  • Mean volume loss for each structure of interest is reported in Table 1 and Figure 1. The results of the t-tests are shown in Figure 1.
  • As expected, the amyloid-negative observational cohort subjects exhibited less atrophy compared to Prodromal AD subjects after 1 year for brain (p<0.01), ventricles (p<0.05) and hippocampus (p<0.001).
  • Volume loss was greater for Avagacestat than placebo-treated subjects at Weeks 24 and 56 for brain (p<0.01), ventricles (p<0.05) and hippocampus (p<0.01). At Week 104, the difference was not significant.

CONCLUSIONS

  • Biomarker positive Prodomal AD subjects demonstrated higher brain, ventricular and hippocampal atrophy compared to biomarker negative subjects followed in an observational cohort.
  • CSF biomarker criteria consistent with AD pathology can effectively be used to enrich clinical trials investigating AD.
  • Similar to observations reported in clinical trials with other anti-amyloid treatments, Avagacestat was associated with higher atrophy compared to placebo (statistically significant at Weeks 24 and 56 but not at Week 104).

REFERENCES

  1. Multi-Atlas Hippocampus Segmentation Refined with Intensity-based Tissue Classification, Belaroussi et al., AAIC 2012
  2. Predictive value of baseline hippocampal volume and brain amyloid burden on atrophy rates in predementia Alzheimer's Disease subjects treated with Avagacestat (study CN156-018), comparison to ADNI-1, Bracoud et al., CTAD 2013
  3. Longitudinal volumetric changes in a predementia AD study of Avagacestat (CN156-018) as compared to ADNI-1, Bracoud et al., CTAD 2013
  4. Comparison of Boundary Shift Integral (BSI) ans Tensor Based Morphometry (TBM) to assess volume changes on whole brain and lateral ventricles - Application to study CN156-018, Istace et al., CTAD 2013

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