title: Selective disruption of the cerebral neocortex in Alzheimer's disease.
abstract: BACKGROUND
  Alzheimer's disease (AD) and its transitional state mild cognitive impairment (MCI) are characterized by amyloid plaque and tau neurofibrillary tangle (NFT) deposition within the cerebral neocortex and neuronal loss within the hippocampal formation. However, the precise relationship between pathologic changes in neocortical regions and hippocampal atrophy is largely unknown.
  
  
  RESULTS
  In this study, combining structural MRI scans and automated image analysis tools with reduced cerebrospinal fluid (CSF) Aβ levels, a surrogate for intra-cranial amyloid plaques and elevated CSF phosphorylated tau (p-tau) levels, a surrogate for neocortical NFTs, we examined the relationship between the presence of Alzheimer's pathology, gray matter thickness of select neocortical regions, and hippocampal volume in cognitively normal older participants and individuals with MCI and AD (n = 724). Amongst all 3 groups, only select heteromodal cortical regions significantly correlated with hippocampal volume. Amongst MCI and AD individuals, gray matter thickness of the entorhinal cortex and inferior temporal gyrus significantly predicted longitudinal hippocampal volume loss in both amyloid positive and p-tau positive individuals. Amongst cognitively normal older adults, thinning only within the medial portion of the orbital frontal cortex significantly differentiated amyloid positive from amyloid negative individuals whereas thinning only within the entorhinal cortex significantly discriminated p-tau positive from p-tau negative individuals.
  
  
  CONCLUSIONS
  Cortical Aβ and tau pathology affects gray matter thinning within select neocortical regions and potentially contributes to downstream hippocampal degeneration. Neocortical Alzheimer's pathology is evident even amongst older asymptomatic individuals suggesting the existence of a preclinical phase of dementia.
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America. rahul@nmr.mgh.harvard.edu
authors.forename: Rahul S
authors.initials: RS
authors.lastname: Desikan
authors.forename: Mert R
authors.initials: MR
authors.lastname: Sabuncu
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schmansky
authors.forename: Martin
authors.initials: M
authors.lastname: Reuter
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Cabral
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Hess
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
authors.forename: Alessandro
authors.initials: A
authors.lastname: Biffi
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Anderson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosand
authors.forename: David H
authors.initials: DH
authors.lastname: Salat
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Kemper
authors.forename: Anders M
authors.initials: AM
authors.lastname: Dale
authors.forename: Reisa A
authors.initials: RA
authors.lastname: Sperling
authors.forename: Bruce
authors.initials: B
authors.lastname: Fischl
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D019579:Neocortex / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D011859:Radiography; D016875:tau Proteins / Q000134:cerebrospinal fluid / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins