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Progressive amnestic dementia, hippocampal sclerosis, and mutation in C9ORF72

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Abstract

The most common cause of familial frontotemporal lobar degeneration with TAR DNA-binding protein-43 pathology (FTLD-TDP) has been found to be an expansion of a hexanucleotide repeat (GGGGCC) in a noncoding region of the gene C9ORF72. Hippocampal sclerosis (HpScl) is a common finding in FTLD-TDP. Our objective was to screen for the presence of C9ORF72 hexanucleotide repeat expansions in a pathologically confirmed cohort of “pure” hippocampal sclerosis cases (n = 33), outside the setting of FTLD-TDP and Alzheimer’s disease (AD). Using a recently described repeat-associated non-ATG (RAN) translation (C9RANT) antibody that was found to be highly specific for c9FTD/ALS, we identified a single “pure” HpScl autopsy case with a repeat expansion in C9ORF72 (c9HpScl). Mutation screening was also performed with repeat-primed polymerase chain reaction and further confirmed with Southern blotting. The c9HpScl patient had a 14-year history of a slowly progressive amnestic syndrome and a clinical diagnosis of probable AD. Neuropsychological testing revealed memory impairment, but no deficits in other cognitive domains. Autopsy showed hippocampal sclerosis with TDP-43 immunoreactive neuronal inclusions relatively limited to limbic lobe structures. Neuritic pathology immunoreactive for p62 was more frequent than TDP-43 in amygdala and hippocampus. Frequent p62-positive neuronal inclusions were present in cerebellar granule neurons as is typical of C9ORF72 mutation carriers. There was no significant FTLD or motor neuron disease. C9RANT was found to be sensitive and specific in this autopsy-confirmed series of HpScl cases. The findings in this patient suggest that the clinical and pathologic spectrum of C9ORF72 repeat expansion is wider than frontotemporal dementia and motor neuron disease, including cases of progressive amnestic dementia with restricted TDP-43 pathology associated with HpScl.

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Acknowledgments

We are grateful to all patients, family members, and caregivers who agreed to brain donation, without which these studies would have been impossible. We also acknowledge the expert technical assistance of Linda Rousseau and Virginia Phillips for histology, and Monica Castanedes-Casey for immunohistochemistry. We would like to thank Martha Purdy, John Gonzalez, and Beth Marten for brain bank coordination. Additionally, we appreciate the council of John A. Lucas for his recommendation of normative percentiles for neuropsychological scores. This research was funded by Mayo Foundation (Jacoby Professorship of Alzheimer Research); National Institutes of Health (P50-AG16574, P50-NS72187, P01-AG03949, R01-AG37491, R01-NS080882 and R01-AG026251); the ALS Therapy Alliance; and the State of Florida Alzheimer Disease Initiative. MEM is supported by a fellowship from the Robert and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program.

Conflict of interest

Dr. Rademakers and Mrs. Dejesus-Hernandez have a patent on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9ORF72.

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Authors and Affiliations

  1. Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Melissa E. Murray, Kevin F. Bieniek, M. Banks Greenberg, Mariely DeJesus-Hernandez, Nicola J. Rutherford, Marka van Blitterswijk, Ellis Niemantsverdriet, Peter E. Ash, Tania F. Gendron, Naomi Kouri, Matt Baker, Leonard Petrucelli, Rosa Rademakers & Dennis W. Dickson

  2. Department of Neuroscience, Compass Research, 100 West Gore Street, Orlando, FL, 32806, USA

    Ira J. Goodman

  3. Department of Neurology, University of Central Florida College of Medicine, 6850 Lake Nona Boulevard, Orlando, FL, 32827, USA

    Ira J. Goodman

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  1. Melissa E. Murray
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Correspondence to Dennis W. Dickson.

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Murray, M.E., Bieniek, K.F., Banks Greenberg, M. et al. Progressive amnestic dementia, hippocampal sclerosis, and mutation in C9ORF72 . Acta Neuropathol 126, 545–554 (2013). https://doi.org/10.1007/s00401-013-1161-2

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