Familial prion disease with Alzheimer disease-like tau pathology and clinical phenotype

Suman Jayadev, David Nochlin, Parvoneh Poorkaj, Ellen J. Steinbart, James A. Mastrianni, Thomas J. Montine, Bernardino Ghetti, Gerard D. Schellenberg, Thomas D. Bird, James B. Leverenz

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Abstract

Objective To describe the Alzheimer disease (AD)-like clinical and pathological features, including marked neurofibrillary tangle (NFT) pathology, of a familial prion disease due to a rare nonsense mutation of the prion gene (PRNP). Methods Longitudinal clinical assessments were available for the proband and her mother. After death, both underwent neuropathological evaluation. PRNP was sequenced after failure to find immunopositive Aβ deposits in the proband and the documentation of prion protein (PrP) immunopositive pathology. Results The proband presented at age 42 years with a 3-year history of progressive short-term memory impairment and depression. Neuropsychological testing found impaired memory performance, with relatively preserved attention and construction. She was diagnosed with AD and died at age 47 years. Neuropathologic evaluation revealed extensive limbic and neocortical NFT formation and neuritic plaques consistent with a Braak stage of VI. The NFTs were immunopositive, with multiple tau antibodies, and electron microscopy revealed paired helical filaments. However, the neuritic plaques were immunonegative for Aβ, whereas immunostaining for PrP was positive. The mother of the proband had a similar presentation, including depression, and had been diagnosed clinically and pathologically as AD. Reevaluation of her brain tissue confirmed similar tau and PrP immunostaining findings. Genetic analysis revealed that both the proband and her mother had a rare PRNP mutation (Q160X) that resulted in the production of truncated PrP. Interpretation We suggest that PRNP mutations that result in a truncation of PrP lead to a prolonged clinical course consistent with a clinical diagnosis of AD and severe AD-like NFTs.

Original languageEnglish
Pages (from-to)712-720
Number of pages9
JournalAnnals of Neurology
Volume69
Issue number4
DOIs
StatePublished - Mar 2011

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Prion Diseases
Clinical Pathology
Alzheimer Disease
Phenotype
Neurofibrillary Tangles
Amyloid Plaques
Depression
Pathology
tau Proteins
Mutation
Nonsense Codon
Prions
Short-Term Memory
Documentation
Electron Microscopy
Prion Proteins
Antibodies
Brain
Genes

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Jayadev, S., Nochlin, D., Poorkaj, P., Steinbart, E. J., Mastrianni, J. A., Montine, T. J., ... Leverenz, J. B. (2011). Familial prion disease with Alzheimer disease-like tau pathology and clinical phenotype. Annals of Neurology, 69(4), 712-720. https://doi.org/10.1002/ana.22264

Familial prion disease with Alzheimer disease-like tau pathology and clinical phenotype. / Jayadev, Suman; Nochlin, David; Poorkaj, Parvoneh; Steinbart, Ellen J.; Mastrianni, James A.; Montine, Thomas J.; Ghetti, Bernardino; Schellenberg, Gerard D.; Bird, Thomas D.; Leverenz, James B.

In: Annals of Neurology, Vol. 69, No. 4, 03.2011, p. 712-720.

Research output: Contribution to journalArticle

Jayadev, S, Nochlin, D, Poorkaj, P, Steinbart, EJ, Mastrianni, JA, Montine, TJ, Ghetti, B, Schellenberg, GD, Bird, TD & Leverenz, JB 2011, 'Familial prion disease with Alzheimer disease-like tau pathology and clinical phenotype', Annals of Neurology, vol. 69, no. 4, pp. 712-720. https://doi.org/10.1002/ana.22264
Jayadev S, Nochlin D, Poorkaj P, Steinbart EJ, Mastrianni JA, Montine TJ et al. Familial prion disease with Alzheimer disease-like tau pathology and clinical phenotype. Annals of Neurology. 2011 Mar;69(4):712-720. https://doi.org/10.1002/ana.22264
Jayadev, Suman ; Nochlin, David ; Poorkaj, Parvoneh ; Steinbart, Ellen J. ; Mastrianni, James A. ; Montine, Thomas J. ; Ghetti, Bernardino ; Schellenberg, Gerard D. ; Bird, Thomas D. ; Leverenz, James B. / Familial prion disease with Alzheimer disease-like tau pathology and clinical phenotype. In: Annals of Neurology. 2011 ; Vol. 69, No. 4. pp. 712-720.
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