title: White Matter Degeneration in Atypical Alzheimer Disease.
abstract: OBJECTIVE
  To assess white matter (WM) tract damage in patients with atypical Alzheimer disease (AD), including early-onset AD (EOAD), logopenic variant of primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA), by using diffusion-tensor magnetic resonance (MR) imaging and to identify similarities and differences across the AD spectrum.
  
  
  METHODS
  This study was approved by the local ethical committees on human studies, and written informed consent from all subjects was obtained prior to enrollment. WM tract damage and cortical atrophy were assessed by using diffusion-tensor MR imaging and voxel-based morphometry, respectively, in 28 patients with EOAD, 12 patients with lvPPA, and 13 patients with PCA relative to age- and sex-matched healthy subjects. Conjunction and interaction analyses were used to define overlapping and syndrome-specific patterns of brain damage.
  
  
  RESULTS
  Patients with EOAD, lvPPA, and PCA shared a common pattern of WM damage that involved the body of the corpus callosum, fornix, and main anterior-posterior pathways (P < .05). They also shared cortical atrophy of the left temporoparietal regions and precuneus (P < .05, family-wise error corrected). Patients with EOAD also had specific damage to the genu and splenium of the corpus callosum and parahippocampal tract bilaterally (P < .05). In all patients with AD, particularly in the two focal forms (lvPPA and PCA), WM damage was more severe and widely distributed than expected on the basis of cortical atrophy.
  
  
  CONCLUSIONS
  In atypical AD clinical phenotypes, the distribution of WM damage exceeds cortical atrophy and may reflect the pathologic dissemination through structural connections from atrophic to unaffected cortical regions. WM degeneration may be an early marker of AD pathologic changes in EOAD and focal AD forms.
authors.affiliation: From the Neuroimaging Research Unit (F.C., F.A., D.M., E.C., M. Filippi), Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (G.M., M. Falautano, G.C., M. Filippi), Department of Clinical Neurosciences (A.M.), and Department of Neuroradiology and CERMAC (A.F.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy; INSERM, U1127, Institut du Cerveau et de la Moelle Epinière (ICM), Hôpital de la Pitié-Salpêtrière, Paris, France (R.M.); Department of Neurology, Institut de la Mémoire et de la Maladie d'Alzheimer, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France (R.M.); and Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.).
authors.forename: Francesca
authors.initials: F
authors.lastname: Caso
authors.affiliation: From the Neuroimaging Research Unit (F.C., F.A., D.M., E.C., M. Filippi), Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (G.M., M. Falautano, G.C., M. Filippi), Department of Clinical Neurosciences (A.M.), and Department of Neuroradiology and CERMAC (A.F.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy; INSERM, U1127, Institut du Cerveau et de la Moelle Epinière (ICM), Hôpital de la Pitié-Salpêtrière, Paris, France (R.M.); Department of Neurology, Institut de la Mémoire et de la Maladie d'Alzheimer, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France (R.M.); and Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.).
authors.forename: Federica
authors.initials: F
authors.lastname: Agosta
authors.affiliation: From the Neuroimaging Research Unit (F.C., F.A., D.M., E.C., M. Filippi), Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (G.M., M. Falautano, G.C., M. Filippi), Department of Clinical Neurosciences (A.M.), and Department of Neuroradiology and CERMAC (A.F.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy; INSERM, U1127, Institut du Cerveau et de la Moelle Epinière (ICM), Hôpital de la Pitié-Salpêtrière, Paris, France (R.M.); Department of Neurology, Institut de la Mémoire et de la Maladie d'Alzheimer, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France (R.M.); and Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.).
authors.forename: Daniele
authors.initials: D
authors.lastname: Mattavelli
authors.affiliation: From the Neuroimaging Research Unit (F.C., F.A., D.M., E.C., M. Filippi), Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (G.M., M. Falautano, G.C., M. Filippi), Department of Clinical Neurosciences (A.M.), and Department of Neuroradiology and CERMAC (A.F.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy; INSERM, U1127, Institut du Cerveau et de la Moelle Epinière (ICM), Hôpital de la Pitié-Salpêtrière, Paris, France (R.M.); Department of Neurology, Institut de la Mémoire et de la Maladie d'Alzheimer, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France (R.M.); and Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.).
authors.forename: Raffaella
authors.initials: R
authors.lastname: Migliaccio
authors.affiliation: From the Neuroimaging Research Unit (F.C., F.A., D.M., E.C., M. Filippi), Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (G.M., M. Falautano, G.C., M. Filippi), Department of Clinical Neurosciences (A.M.), and Department of Neuroradiology and CERMAC (A.F.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy; INSERM, U1127, Institut du Cerveau et de la Moelle Epinière (ICM), Hôpital de la Pitié-Salpêtrière, Paris, France (R.M.); Department of Neurology, Institut de la Mémoire et de la Maladie d'Alzheimer, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France (R.M.); and Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.).
authors.forename: Elisa
authors.initials: E
authors.lastname: Canu
authors.affiliation: From the Neuroimaging Research Unit (F.C., F.A., D.M., E.C., M. Filippi), Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (G.M., M. Falautano, G.C., M. Filippi), Department of Clinical Neurosciences (A.M.), and Department of Neuroradiology and CERMAC (A.F.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy; INSERM, U1127, Institut du Cerveau et de la Moelle Epinière (ICM), Hôpital de la Pitié-Salpêtrière, Paris, France (R.M.); Department of Neurology, Institut de la Mémoire et de la Maladie d'Alzheimer, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France (R.M.); and Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.).
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Magnani
authors.affiliation: From the Neuroimaging Research Unit (F.C., F.A., D.M., E.C., M. Filippi), Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (G.M., M. Falautano, G.C., M. Filippi), Department of Clinical Neurosciences (A.M.), and Department of Neuroradiology and CERMAC (A.F.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy; INSERM, U1127, Institut du Cerveau et de la Moelle Epinière (ICM), Hôpital de la Pitié-Salpêtrière, Paris, France (R.M.); Department of Neurology, Institut de la Mémoire et de la Maladie d'Alzheimer, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France (R.M.); and Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.).
authors.forename: Alessandra
authors.initials: A
authors.lastname: Marcone
authors.affiliation: From the Neuroimaging Research Unit (F.C., F.A., D.M., E.C., M. Filippi), Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (G.M., M. Falautano, G.C., M. Filippi), Department of Clinical Neurosciences (A.M.), and Department of Neuroradiology and CERMAC (A.F.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy; INSERM, U1127, Institut du Cerveau et de la Moelle Epinière (ICM), Hôpital de la Pitié-Salpêtrière, Paris, France (R.M.); Department of Neurology, Institut de la Mémoire et de la Maladie d'Alzheimer, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France (R.M.); and Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.).
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Copetti
authors.affiliation: From the Neuroimaging Research Unit (F.C., F.A., D.M., E.C., M. Filippi), Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (G.M., M. Falautano, G.C., M. Filippi), Department of Clinical Neurosciences (A.M.), and Department of Neuroradiology and CERMAC (A.F.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy; INSERM, U1127, Institut du Cerveau et de la Moelle Epinière (ICM), Hôpital de la Pitié-Salpêtrière, Paris, France (R.M.); Department of Neurology, Institut de la Mémoire et de la Maladie d'Alzheimer, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France (R.M.); and Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.).
authors.forename: Monica
authors.initials: M
authors.lastname: Falautano
authors.affiliation: From the Neuroimaging Research Unit (F.C., F.A., D.M., E.C., M. Filippi), Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (G.M., M. Falautano, G.C., M. Filippi), Department of Clinical Neurosciences (A.M.), and Department of Neuroradiology and CERMAC (A.F.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy; INSERM, U1127, Institut du Cerveau et de la Moelle Epinière (ICM), Hôpital de la Pitié-Salpêtrière, Paris, France (R.M.); Department of Neurology, Institut de la Mémoire et de la Maladie d'Alzheimer, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France (R.M.); and Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.).
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.affiliation: From the Neuroimaging Research Unit (F.C., F.A., D.M., E.C., M. Filippi), Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (G.M., M. Falautano, G.C., M. Filippi), Department of Clinical Neurosciences (A.M.), and Department of Neuroradiology and CERMAC (A.F.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy; INSERM, U1127, Institut du Cerveau et de la Moelle Epinière (ICM), Hôpital de la Pitié-Salpêtrière, Paris, France (R.M.); Department of Neurology, Institut de la Mémoire et de la Maladie d'Alzheimer, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France (R.M.); and Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.).
authors.forename: Andrea
authors.initials: A
authors.lastname: Falini
authors.affiliation: From the Neuroimaging Research Unit (F.C., F.A., D.M., E.C., M. Filippi), Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (G.M., M. Falautano, G.C., M. Filippi), Department of Clinical Neurosciences (A.M.), and Department of Neuroradiology and CERMAC (A.F.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy; INSERM, U1127, Institut du Cerveau et de la Moelle Epinière (ICM), Hôpital de la Pitié-Salpêtrière, Paris, France (R.M.); Department of Neurology, Institut de la Mémoire et de la Maladie d'Alzheimer, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France (R.M.); and Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.).
authors.forename: Massimo
authors.initials: M
authors.lastname: Filippi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D018888:Aphasia, Primary Progressive / Q000473:pathology*; D001284:Atrophy; D002540:Cerebral Cortex / Q000473:pathology*; D003430:Cross-Sectional Studies; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D066127:White Matter / Q000473:pathology*