title: Biochemical, neuropathological, and neuroimaging characteristics of early-onset Alzheimer's disease due to a novel PSEN1 mutation.
abstract: Familial Alzheimer's disease (AD) due to PSEN1 mutations provides an opportunity to examine AD biomarkers in persons in whom the diagnosis is certain. We describe a 55 year-old woman with clinically probable AD and a novel PSEN1 mutation who underwent genetic, clinical, biochemical and magnetic resonance and nuclear imaging assessments. We also describe neuropathological findings in her similarly affected brother. Neuropsychological testing confirmed deficits in memory, visuospatial and language function. CSF t-tau and p-tau181 were markedly elevated and Aβ(42) levels reduced. FDG-PET revealed hypometabolism in the left parietotemporal cortex. FDDNP-PET showed increased binding of tracer in medial temporal and parietal lobes and in the head of the caudate and anterior putamen bilaterally. Neuropathological examination of her brother showed the typical findings of AD and the striatum demonstrated amyloid pathology and marked neurofibrillary pathology beyond that typically seen in late-onset AD. A novel S212Y substitution in PSEN1 was present in the index patient and her affected brother but not in an older unaffected sister. An in vitro assay in which the S212Y mutation was introduced in cell culture confirmed that it was associated with increased production of Aβ(42). We describe biochemical, imaging, and neuropathological changes in a pedigree with a novel PSEN1 mutation. This allows us to validate the pathogenicity of this mutation and the indices used to assess AD.
authors.affiliation: Mary S. Easton Center for Alzheimer's Disease Research, UCLA Department of Neurology, Los Angeles, CA, United States. jringman@mednet.ucla.edu
authors.forename: John M
authors.initials: JM
authors.lastname: Ringman
authors.forename: Karen H
authors.initials: KH
authors.lastname: Gylys
authors.forename: Luis D
authors.initials: LD
authors.lastname: Medina
authors.forename: Michelle
authors.initials: M
authors.lastname: Fox
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kepe
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Flores
authors.forename: Liana G
authors.initials: LG
authors.lastname: Apostolova
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Barrio
authors.forename: Gary
authors.initials: G
authors.lastname: Small
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Silverman
authors.forename: Erin
authors.initials: E
authors.lastname: Siu
authors.forename: Stephen
authors.initials: S
authors.lastname: Cederbaum
authors.forename: Silva
authors.initials: S
authors.lastname: Hecimovic
authors.forename: Martina
authors.initials: M
authors.lastname: Malnar
authors.forename: Suma
authors.initials: S
authors.lastname: Chakraverty
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.forename: James B
authors.initials: JB
authors.lastname: Leverenz
mesh_terms: D000328:Adult; D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009483:Neuropsychological Tests; D010375:Pedigree; D049268:Positron-Emission Tomography; D053764:Presenilin-1 / Q000235:genetics*
chemical_list: C508853:PSEN1 protein, human; D053764:Presenilin-1