Computational modeling of tau pathology spread reveals patterns of regional vulnerability and the impact of a genetic risk factor.
Eli J. Cornblath,Howard L. Li,Lakshmi Changolkar,Bin Zhang,Hannah J. Brown,Ronald J. Gathagan,Modupe F. Olufemi,John Q. Trojanowski,Danielle S. Bassett,Virginia M.-Y. Lee,Michael X. Henderson +10 more
TLDR
In this paper, the authors show that diffusion through the connectome is the best predictor of tau pathology patterns, and deviations from pure neuroanatomical spread are used to estimate regional vulnerability to tau, and identify related gene expression patterns.Abstract:
Neuropathological staging studies have suggested that tau pathology spreads through the brain in Alzheimer's disease (AD) and other tauopathies, but it is unclear how neuroanatomical connections, spatial proximity, and regional vulnerability contribute. In this study, we seed tau pathology in the brains of nontransgenic mice with AD tau and quantify pathology development over 9 months in 134 brain regions. Network modeling of pathology progression shows that diffusion through the connectome is the best predictor of tau pathology patterns. Further, deviations from pure neuroanatomical spread are used to estimate regional vulnerability to tau pathology and identify related gene expression patterns. Last, we show that pathology spread is altered in mice harboring a mutation in leucine-rich repeat kinase 2. While tau pathology spread is still constrained by anatomical connectivity in these mice, it spreads preferentially in a retrograde direction. This study provides a framework for understanding neuropathological progression in tauopathies.read more
Citations
More filters
Journal ArticleDOI
Local molecular and global connectomic contributions to cross-disorder cortical abnormalities
Justine Y. Hansen,Golia Shafiei,Jacob W. Vogel,Kelly Smart,Carrie E. Bearden,Martine Hoogman,Barbara Franke,Daan van Rooij,Jan K. Buitelaar,Carrie R. McDonald,Sanjay M. Sisodiya,Lianne Schmaal,Dick J. Veltman,Odile A. van den Heuvel,Dan J. Stein,Theo G.M. van Erp,Christopher R.K. Ching,Ole A. Andreassen,Tomas Hajek,Nils Opel,Gemma Modinos,André Aleman,Ysbrand D. van der Werf,Neda Jahanshad,Sophia I. Thomopoulos,Paul M. Thompson,Richard E. Carson,Alain Dagher,Bratislav Misic +28 more
TL;DR: Using MRI morphometry from the ENIGMA consortium, the authors constructed maps of cortical abnormalities for thirteen neurodevelopmental, neurological, and psychiatric disorders from N = 21,000 participants and N = 26,000 controls, collected using a harmonised processing protocol.
Journal ArticleDOI
Propagation of tau and α-synuclein in the brain: therapeutic potential of the glymphatic system
TL;DR: The involvement of the glymphatic system in neurodegenerative disease is yet to be fully defined; however, it is becoming increasingly clear that this pathway contributes to parenchymal solute clearance as mentioned in this paper .
Journal ArticleDOI
Propagation of tau and α-synuclein in the brain: therapeutic potential of the glymphatic system
TL;DR: The involvement of the glymphatic system in neurodegenerative disease is yet to be fully defined; however, it is becoming increasingly clear that this pathway contributes to parenchymal solute clearance as mentioned in this paper .
Journal ArticleDOI
Imaging Transcriptomics of Brain Disorders
TL;DR: The recent development of anatomically comprehensive gene expression atlases has opened new opportunities for studying the transcriptional correlates of noninvasively measured neural phenotypes, offering a rich framework for evaluating pathophysiological hypotheses and putative mechanisms as mentioned in this paper .
Journal ArticleDOI
Imaging transcriptomics of brain disorders
TL;DR: The recent development of anatomically comprehensive gene-expression atlases has opened new opportunities for studying the transcriptional correlates of non-invasive measured neural phenotypes, offering a rich framework for evaluating pathophysiological hypotheses and putative mechanisms as discussed by the authors.
References
More filters
Journal ArticleDOI
Controlling the false discovery rate: a practical and powerful approach to multiple testing
Yoav Benjamini,Yosef Hochberg +1 more
TL;DR: In this paper, a different approach to problems of multiple significance testing is presented, which calls for controlling the expected proportion of falsely rejected hypotheses -the false discovery rate, which is equivalent to the FWER when all hypotheses are true but is smaller otherwise.
Journal ArticleDOI
Neuropathological stageing of Alzheimer-related changes.
Heiko Braak,Eva Braak +1 more
TL;DR: The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations, permitting the differentiation of six stages.
Journal ArticleDOI
Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry.
TL;DR: To better meet the demands of routine laboratories this procedure is revised here by adapting tissue selection and processing to the needs of paraffin-embedded sections and by introducing a robust immunoreaction (AT8) for hyperphosphorylated tau protein that can be processed on an automated basis.
Journal ArticleDOI
A mesoscale connectome of the mouse brain
Seung Wook Oh,Julie A. Harris,Lydia Ng,Brent Winslow,Nicholas Cain,Stefan Mihalas,Quanxin Wang,Chris Lau,Leonard Kuan,Alex M. Henry,Marty Mortrud,Benjamin Ouellette,Thuc Nghi Nguyen,Staci A. Sorensen,Clifford R. Slaughterbeck,Wayne Wakeman,Yang Li,David Feng,Anh Ho,Eric Nicholas,Karla E. Hirokawa,Phillip Bohn,Kevin M. Joines,Hanchuan Peng,Michael Hawrylycz,John W. Phillips,John G. Hohmann,Paul Wohnoutka,Charles R. Gerfen,Christof Koch,Amy Bernard,Chinh Dang,Allan R. Jones,Hongkui Zeng +33 more
TL;DR: A brain-wide, cellular-level, mesoscale connectome for the mouse, using enhanced green fluorescent protein-expressing adeno-associated viral vectors to trace axonal projections from defined regions and cell types, and high-throughput serial two-photon tomography to image the EGFP-labelled axons throughout the brain.
Journal ArticleDOI
Global, regional, and national burden of Alzheimer's disease and other dementias, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016
Emma Nichols,Cassandra Szoeke,Stein Emil Vollset,Nooshin Abbasi,Foad Abd-Allah,Jemal Abdela,Miloud Taki Eddine Aichour,Rufus Akinyemi,Fares Alahdab,Solomon Weldegebreal Asgedom,Ashish Awasthi,Suzanne Barker-Collo,Bernhard T. Baune,Yannick Béjot,Abate Bekele Belachew,Derrick A Bennett,Belete Biadgo,Ali Bijani,Muhammad Shahdaat Bin Sayeed,Carol Brayne,David O. Carpenter,Félix Carvalho,Ferrán Catalá-López,Ester Cerin,Jee-Young Jasmine Choi,Anh Kim Dang,Meaza Girma Degefa,Shirin Djalalinia,Manisha Dubey,Eyasu Ejeta Duken,David Edvardsson,Matthias Endres,Sharareh Eskandarieh,André Faro,Farshad Farzadfar,Seyed-Mohammad Fereshtehnejad,Eduarda Fernandes,Irina Filip,Florian Fischer,Abadi Kahsu Gebre,Demeke Geremew,Maryam Ghasemi-Kasman,Elena V. Gnedovskaya,Rajeev Gupta,Vladimir Hachinski,Tekleberhan B. Hagos,Samer Hamidi,Graeme J. Hankey,Josep Maria Haro,Simon I. Hay,Seyed Sina Naghibi Irvani,Ravi Prakash Jha,Jost B. Jonas,Rizwan Kalani,André Karch,Amir Kasaeian,Yousef Khader,Ibrahim A Khalil,Ejaz Ahmad Khan,Tripti Khanna,Tawfik Ahmed Muthafer Khoja,Jagdish Khubchandani,Adnan Kisa,Katarzyna Kissimova-Skarbek,Mika Kivimäki,Ai Koyanagi,Kristopher J Krohn,Giancarlo Logroscino,Stefan Lorkowski,Marek Majdan,Reza Malekzadeh,Winfried März,João Massano,Getnet Mengistu,Atte Meretoja,Moslem Mohammadi,Maryam Mohammadi-Khanaposhtani,Ali H. Mokdad,Stefania Mondello,Ghobad Moradi,Gabriele Nagel,Mohsen Naghavi,Gurudatta Naik,Long H. Nguyen,Trang Huyen Nguyen,Yirga Legesse Nirayo,Molly R Nixon,Richard Ofori-Asenso,Felix Akpojene Ogbo,Andrew T Olagunju,Mayowa O. Owolabi,Songhomitra Panda-Jonas,Valéria Maria de Azeredo Passos,David M. Pereira,Gabriel David Pinilla-Monsalve,Michael A. Piradov,Constance D. Pond,Hossein Poustchi,Mostafa Qorbani,Amir Radfar,Robert C. Reiner,Stephen R. Robinson,Gholamreza Roshandel,Ali Rostami,Tom C. Russ,Perminder S. Sachdev,Hosein Safari,Saeid Safiri,Ramesh Sahathevan,Yahya Salimi,Maheswar Satpathy,Monika Sawhney,Mete Saylan,Sadaf G. Sepanlou,Azadeh Shafieesabet,Masood Ali Shaikh,Mohammad Ali Sahraian,Mika Shigematsu,Rahman Shiri,Ivy Shiue,João Pedro Silva,Mari Smith,Soheila Sobhani,Dan J. Stein,Rafael Tabarés-Seisdedos,Marcos Roberto Tovani-Palone,Bach Xuan Tran,Tung Thanh Tran,Amanuel Amanuel Tesfay Tsegay,Irfan Ullah,Narayanaswamy Venketasubramanian,Vasily Vlassov,Yuan-Pang Wang,Jordan Weiss,Ronny Westerman,Tissa Wijeratne,Grant M. A. Wyper,Yuichiro Yano,Ebrahim M Yimer,Naohiro Yonemoto,Mahmoud Yousefifard,Zoubida Zaidi,Zohreh Zare,Theo Vos,Valery L. Feigin,Christopher J L Murray +145 more
TL;DR: The first detailed analysis of the global prevalence, mortality, and overall burden of dementia as captured by the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016 is presented, to highlight the most important messages for clinicians and neurologists.