Subregional neuroanatomical change as a biomarker for Alzheimer's disease
Authors: Holland Dominic , Brewer James B. , Hagler Donald J. , Fennema-Notestine Christine , Dale Anders M. ,   the Alzheimer's Disease Neuroimaging Initiative, Weiner Michael , Thal Leon , Petersen Ronald , Jack Clifford R. , Jagust William , Trojanowki John , Toga Arthur W. , Beckett Laurel , Green Robert C. , Gamst Anthony , Potter William Z. , Montine Tom , Anders Dale , Bernstein Matthew , Felmlee Joel , Fox Nick , Thompson Paul , Schuff Norbert , Alexander Gene , Bandy Dan , Koeppe Robert A. , Foster Norm , Reiman Eric M. , Chen Kewei , Shaw Les , Lee Virginia M.-Y. , Korecka Magdalena , Crawford Karen , Neu Scott , Harvey Danielle , Kornak John , Kachaturian Zaven , Frank Richard , Snyder Peter J. , Molchan Susan , Kaye Jeffrey , Vorobik Remi , Quinn Joseph , Schneider Lon , Pawluczyk Sonia , Spann Bryan , Fleisher Adam S. , Vanderswag Helen , Heidebrink Judith L. , Lord Joanne L. , Johnson Kris , Doody Rachelle S. , Villanueva-Meyer Javier , Chowdhury Munir , Stern Yaakov , Honig Lawrence S. , Bell Karen L. , Morris John C. , Mintun Mark A. , Schneider Stacy , Marson Daniel , Griffith Randall , Badger Beverly , Grossman Hillel , Tang Cheuk , Stern Jessica , deToledo-Morrell Leyla , Shah Raj C. , Bach Julie , Duara Ranjan , Isaacson Richard , Strauman Silvia , Albert Marilyn S. , Pedroso Julia , Toroney Jaimie , Rusinek Henry , de Leon Mony J. , De Santi Susan M. , Doraiswamy P. Murali , Petrella Jeffrey R. , Aiello Marilyn , Clark Christopher M. , Pham Cassie , Nunez Jessica , Smith Charles D. , Given Curtis A. , Hardy Peter , DeKosky Steven T. , Oakley MaryAnn , Simpson Donna M. , Ismail M. Saleem , Porsteinsson Anton , McCallum Colleen , Cramer Steven C. , Mulnard Ruth A. , McAdams-Ortiz Catherine , Diaz-Arrastia Ramon , Martin-Cook Kristen , DeVous Michael , Levey Allan I. , Lah James J. , Cellar Janet S. , Burns Jeffrey M. , Anderson Heather S. , Laubinger Mary M. , Bartzokis George , Silverman Daniel H. S. , Lu Po H. , Fletcher Rita , Parfitt Francine , Johnson Heather , Farlow Martin , Herring Scott , Hake Ann M. , van Dyck Christopher H. , MacAvoy Martha G. , Bifano Laurel A. , Chertkow Howard , Bergman Howard , Hosein Chris , Black Sandra , Graham Simon , Caldwell Curtis , Feldman Howard , Assaly Michele , Hsiung Ging-Yuek R. , Kertesz Andrew , Rogers John , Trost Dick , Bernick Charles , Gitelman Darren , Johnson Nancy , Mesulam Marsel , Sadowsky Carl , Villena Teresa , Mesner Scott , Aisen Paul S. , Johnson Kathleen B. , Behan Kelly E. , Sperling Reisa A. , Rentz Dorene M. , Johnson Keith A. , Rosen Allyson , Tinklenberg Jared , Ashford Wes , Sabbagh Marwan , Connor Donald , Obradov Sanja , Killiany Ron , Norbash Alex , Obisesan Thomas O. , Jayam-Trouth Annapurni , Wang Paul , Auchus Alexander P. , Huang Juebin , Friedland Robert P. , DeCarli Charles , Fletcher Evan , Carmichael Owen , Kittur Smita , Mirje Seema , Johnson Sterling C. , Borrie Michael , Lee T.-Y. , Asthana Sanjay , Carlsson Cynthia M. , Potkin Steven G. , Highum Diane , Preda Adrian , Nguyen Dana , Tariot Pierre N. , Hendin Barry A. , Scharre Douglas W. , Kataki Maria , Beversdorf David Q. , Zimmerman Earl A. , Celmins Dzintra , Brown Alice D. , Gandy Sam , Marenberg Marjorie E. , Rovner Barry W. , Pearlson Godfrey , Blank Karen , Anderson Karen , Saykin Andrew J. , Santulli Robert B. , Pare Nadia , Williamson Jeff D. , Sink Kaycee M. , Potter Huntington , Ashok Raj B. , Giordano Amy , Ott Brian R. , Wu Chuang-Kuo , Cohen Ronald , Wilks Kerri L. , Safirstein Beth E. 
Published: November 2009

Regions of the temporal and parietal lobes are particularly damaged in Alzheimer's disease (AD), and this leads to a predictable pattern of brain atrophy. In vivo quantification of subregional atrophy, such as changes in cortical thickness or structure volume, could lead to improved diagnosis and better assessment of the neuroprotective effects of a therapy. Toward this end, we have developed a fast and robust method for accurately quantifying cerebral structural changes in several cortical and subcortical regions using serial MRI scans. In 169 healthy controls, 299 subjects with mild cognitive impairment (MCI), and 129 subjects with AD, we measured rates of subregional cerebral volume change for each cohort and performed power calculations to identify regions that would provide the most sensitive outcome measures in clinical trials of disease-modifying agents. Consistent with regional specificity of AD, temporal-lobe cortical regions showed the greatest disease-related changes and significantly outperformed any of the clinical or cognitive measures examined for both AD and MCI. Global measures of change in brain structure, including whole-brain and ventricular volumes, were also elevated in AD and MCI, but were less salient when compared to changes in normal subjects. Therefore, these biomarkers are less powerful for quantifying disease-modifying effects of compounds that target AD pathology. The findings indicate that regional temporal lobe cortical changes would have great utility as outcome measures in clinical trials and may also have utility in clinical practice for aiding early diagnosis of neurodegenerative disease.