Diverging patterns of amyloid deposition and hypometabolism in clinical variants of probable Alzheimer’s disease
Manja Lehmann,Manja Lehmann,Manja Lehmann,Pia Ghosh,Pia Ghosh,Cindee Madison,Robert Laforce,Robert Laforce,Chiara Corbetta-Rastelli,Michael W. Weiner,Michael D. Greicius,William W. Seeley,Maria Luisa Gorno-Tempini,Howard J. Rosen,Bruce L. Miller,William J. Jagust,William J. Jagust,William J. Jagust,Gil D. Rabinovici,Gil D. Rabinovici,Gil D. Rabinovici +20 more
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TLDR
Alzheimer's disease syndromes are associated with degeneration of specific functional networks, and that fibrillar amyloid-β deposition explains at most a small amount of the clinico-anatomic heterogeneity in Alzheimer's disease.Abstract:
The factors driving clinical heterogeneity in Alzheimer’s disease are not well understood. This study assessed the relationship between amyloid deposition, glucose metabolism and clinical phenotype in Alzheimer’s disease, and investigated how these relate to the involvement of functional networks. The study included 17 patients with early-onset Alzheimer’s disease (age at onset <65 years), 12 patients with logopenic variant primary progressive aphasia and 13 patients with posterior cortical atrophy [whole Alzheimer’s disease group: age = 61.5 years (standard deviation 6.5 years), 55% male]. Thirty healthy control subjects [age = 70.8 (3.3) years, 47% male] were also included. Subjects underwent positron emission tomography with 11C-labelled Pittsburgh compound B and 18F-labelled fluorodeoxyglucose. All patients met National Institute on Ageing–Alzheimer’s Association criteria for probable Alzheimer’s disease and showed evidence of amyloid deposition on 11C-labelled Pittsburgh compound B positron emission tomography. We hypothesized that hypometabolism patterns would differ across variants, reflecting involvement of specific functional networks, whereas amyloid patterns would be diffuse and similar across variants. We tested these hypotheses using three complimentary approaches: (i) mass-univariate voxel-wise group comparison of 18F-labelled fluorodeoxyglucose and 11C-labelled Pittsburgh compound B; (ii) generation of covariance maps across all subjects with Alzheimer’s disease from seed regions of interest specifically atrophied in each variant, and comparison of these maps to functional network templates; and (iii) extraction of 11C-labelled Pittsburgh compound B and 18F-labelled fluorodeoxyglucose values from functional network templates. Alzheimer’s disease clinical groups showed syndrome-specific 18F-labelled fluorodeoxyglucose patterns, with greater parieto-occipital involvement in posterior cortical atrophy, and asymmetric involvement of left temporoparietal regions in logopenic variant primary progressive aphasia. In contrast, all Alzheimer’s disease variants showed diffuse patterns of 11C-labelled Pittsburgh compound B binding, with posterior cortical atrophy additionally showing elevated uptake in occipital cortex compared with early-onset Alzheimer’s disease. The seed region of interest covariance analysis revealed distinct 18F-labelled fluorodeoxyglucose correlation patterns that greatly overlapped with the right executive-control network for the early-onset Alzheimer’s disease region of interest, the left language network for the logopenic variant primary progressive aphasia region of interest, and the higher visual network for the posterior cortical atrophy region of interest. In contrast, 11C-labelled Pittsburgh compound B covariance maps for each region of interest were diffuse. Finally, 18F-labelled fluorodeoxyglucose was similarly reduced in all Alzheimer’s disease variants in the dorsal and left ventral default mode network, whereas significant differences were found in the right ventral default mode, right executive-control (both lower in early-onset Alzheimer’s disease and posterior cortical atrophy than logopenic variant primary progressive aphasia) and higher-order visual network (lower in posterior cortical atrophy than in early-onset Alzheimer’s disease and logopenic variant primary progressive aphasia), with a trend towards lower 18F-labelled fluorodeoxyglucose also found in the left language network in logopenic variant primary progressive aphasia. There were no differences in 11C-labelled Pittsburgh compound B binding between syndromes in any of the networks. Our data suggest that Alzheimer’s disease syndromes are associated with degeneration of specific functional networks, and that fibrillar amyloid-β deposition explains at most a small amount of the clinico-anatomic heterogeneity in Alzheimer’s disease.read more
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Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria
Bruno Dubois,Bruno Dubois,Howard Feldman,Claudia Jacova,Harald Hampel,Harald Hampel,José Luis Molinuevo,Kaj Blennow,Steven T. DeKosky,Serge Gauthier,Dennis J. Selkoe,Randall J. Bateman,Stefano F. Cappa,Sebastian J. Crutch,Sebastiaan Engelborghs,Giovanni B. Frisoni,Nick C. Fox,Douglas Galasko,Marie-Odile Habert,Gregory A. Jicha,Agneta Nordberg,Florence Pasquier,Gil D. Rabinovici,Philippe Robert,Christopher C. Rowe,Stephen Salloway,Marie Sarazin,Stéphane Epelbaum,Stéphane Epelbaum,Leonardo Cruz de Souza,Leonardo Cruz de Souza,Leonardo Cruz de Souza,Bruno Vellas,Pieter Jelle Visser,Lon S. Schneider,Yaakov Stern,Philip Scheltens,Jeffrey L. Cummings +37 more
TL;DR: It is proposed that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease.
Journal ArticleDOI
Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease.
Rik Ossenkoppele,Rik Ossenkoppele,Rik Ossenkoppele,Daniel R. Schonhaut,Daniel R. Schonhaut,Michael Schöll,Michael Schöll,Samuel N. Lockhart,Nagehan Ayakta,Nagehan Ayakta,Suzanne L. Baker,James P. O'Neil,Mustafa Janabi,Andreas Lazaris,Averill Cantwell,Jacob W. Vogel,Miguel Santos,Zachary A. Miller,Brianne M. Bettcher,Brianne M. Bettcher,Keith A. Vossel,Joel H. Kramer,Maria Luisa Gorno-Tempini,Bruce L. Miller,William J. Jagust,William J. Jagust,Gil D. Rabinovici,Gil D. Rabinovici +27 more
TL;DR: Results are consistent with and expand upon findings from post-mortem, animal and cerebrospinal fluid studies, and suggest that the pathological aggregation of tau is closely linked to patterns of neurodegeneration and clinical manifestations of Alzheimer's disease.
Journal ArticleDOI
Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer's disease.
Alexandre Bejanin,Daniel R. Schonhaut,Renaud La Joie,Joel H. Kramer,Suzanne L. Baker,Natasha Sosa,Nagehan Ayakta,Averill Cantwell,Mustafa Janabi,Mariella Lauriola,James P. O'Neil,Maria Luisa Gorno-Tempini,Zachary A. Miller,Howard J. Rosen,Bruce L. Miller,William J. Jagust,William J. Jagust,Gil D. Rabinovici,Gil D. Rabinovici,Gil D. Rabinovici +19 more
TL;DR: Results show that tau pathology is related in a region-specific manner to cognitive impairment in Alzheimer's disease, and regional relationships are weakly related to amyloid burden, but are in part mediated by grey matter volumes.
Journal ArticleDOI
Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease:
TL;DR: It is concluded that BBB dysfunction contributes to AD through a number of mechanisms that could be initiated in the presence or absence of Aβ pathology.
Journal ArticleDOI
Amyloid biomarkers in Alzheimer's disease.
Kaj Blennow,Kaj Blennow,Niklas Mattsson,Niklas Mattsson,Niklas Mattsson,Michael Schöll,Michael Schöll,Oskar Hansson,Henrik Zetterberg,Henrik Zetterberg +9 more
TL;DR: Amyloid biomarkers will be of special value in the clinic to identify patients with brain amyloid deposition at risk for progression to AD dementia, to enable initiation of treatment before neurodegeneration is too severe, and to monitor drug effects on Aβ metabolism or pathology to guide dosage.
References
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