Prognostic relevance of gait-related cognitive functions for dementia conversion in amnestic mild cognitive impairment
Authors: Tuena Cosimo , Maestri Sara , Serino Silvia , Pedroli Elisa , Stramba-Badiale Marco , Riva Giuseppe ,   the Alzheimer’s Disease Neuroimaging Initiative, Silbert Lisa C. , Lind Betty , Crissey Rachel , Kaye Jeffrey A. , Carter Raina , Dolen Sara , Quinn Joseph , Schneider Lon S. , Pawluczyk Sonia , Becerra Mauricio , Teodoro Liberty , Dagerman Karen , Spann Bryan M. , Brewer James , Fleisher Adam , Vanderswag Helen , Ziolkowski Jaimie , Heidebrink Judith L. , Zbizek-Nulph Lisa , Lord Joanne L. , Albers Colleen S. , Petersen Ronald , Mason Sara S. , Knopman David , Johnson Kris , Villanueva-Meyer Javier , Pavlik Valory , Pacini Nathaniel , Lamb Ashley , Kass Joseph S. , Doody Rachelle S. , Shibley Victoria , Chowdhury Munir , Rountree Susan , Dang Mimi , Stern Yaakov , Honig Lawrence S. , Mintz Akiva , Ances Beau , Morris John C. , Winkfield David , Carroll Maria , Stobbs-Cucchi Georgia , Oliver Angela , Creech Mary L. , Mintun Mark A. , Schneider Stacy , Geldmacher David , Love Marissa Natelson , Griffith Randall , Clark David , Brockington John , Marson Daniel , Grossman Hillel , Goldstein Martin A. , Greenberg Jonathan , Mitsis Effie , Shah Raj C. , Lamar Melissa , Samuels Patricia , Duara Ranjan , Greig-Custo Maria T. , Rodriguez Rosemarie , Albert Marilyn , Onyike Chiadi , Farrington Leonie , Rudow Scott , Brichko Rottislav , Kielb Stephanie , Smith Amanda , Raj Balebail Ashok , Fargher Kristin , Sadowski Martin , Wisniewski Thomas , Shulman Melanie , Faustin Arline , Rao Julia , Castro Karen M. , Ulysse Anaztasia , Chen Shannon , Doraiswamy P. Murali , Petrella Jeffrey R. , James Olga , Wong Terence Z. , Borges-Neto Salvador , Karlawish Jason H. , Wolk David A. , Vaishnavi Sanjeev , Clark Christopher M. , Arnold Steven E. , Smith Charles D. , Jicha Gregory A. , Khouli Riham El , Raslau Flavius D. , Lopez Oscar L. , Oakley MaryAnn , Simpson Donna M. , Porsteinsson Anton P. , Martin Kim , Kowalski Nancy , Keltz Melanie , Goldstein Bonnie S. , Makino Kelly M. , Ismail M. Saleem , Brand Connie , Thai Gaby , Pierce Aimee , Yanez Beatriz , Sosa Elizabeth , Witbracht Megan , Kelley Brendan , Nguyen Trung , Womack Kyle , Mathews Dana , Quiceno Mary , Levey Allan I. , Lah James J. , Hajjar Ihab , Burns Jeffrey M. , Swerdlow Russell H. , Brooks William M. , Silverman Daniel H. S. , Kremen Sarah , Apostolova Liana , Tingus Kathleen , Lu Po H. , Bartzokis George , Woo Ellen , Teng Edmond , Graff-Radford Neill R. , Parfitt Francine , Poki-Walker Kim , Farlow Martin R. , Hake Ann Marie , Matthews Brandy R. , Brosch Jared R. , Herring Scott , van Dyck Christopher H. , Mecca Adam P. , Good Susan P. , MacAvoy Martha G. , Carson Richard E. , Varma Pradeep , Chertkow Howard , Vaitekunas Susan , Hosein Chris , Black Sandra , Stefanovic Bojana , Heyn Chris , Hsiung Ging-Yuek Robin , Kim Ellen , Mudge Benita , Sossi Vesna , Feldman Howard , Assaly Michele , Finger Elizabeth , Pasternak Stephen , Rachinsky Irina , Kertesz Andrew , Drost Dick , Rogers John , Grant Ian , Muse Brittanie , Rogalski Emily , Robson Jordan , Mesulam M.-Marsel , Kerwin Diana , Wu Chuang-Kuo , Johnson Nancy , Lipowski Kristine , Weintraub Sandra , Bonakdarpour Borna , Pomara Nunzio , Hernando Raymundo , Sarrael Antero , Rosen Howard J. , Miller Bruce L. , Weiner Micheal W. , Perry David , Turner Raymond Scott , Johnson Kathleen , Reynolds Brigid , MCCann Kelly , Poe Jessica , Marshall Gad A. , Sperling Reisa A. , Johnson Keith A. , Yesavage Jerome , Taylor Joy L. , Chao Steven , Coleman Jaila , White Jessica D. , Lane Barton , Rosen Allyson , Tinklenberg Jared , Belden Christine M. , Atri Alireza , Spann Bryan M. , Clark Kelly A. , Zamrini Edward , Sabbagh Marwan , Killiany Ronald , Stern Robert , Mez Jesse , Kowall Neil , Budson Andrew E. , Obisesan Thomas O. , Ntekim Oyonumo E. , Wolday Saba , Khan Javed I. , Nwulia Evaristus , Nadarajah Sheeba , Lerner Alan , Ogrocki Paula , Tatsuoka Curtis , Fatica Parianne , Fletcher Evan , Maillard Pauline , Olichney John , DeCarli Charles , Carmichael Owen , Bates Vernice , Capote Horacio , Rainka Michelle , Borrie Michael , Lee T.-Y. , Bartha Rob , Johnson Sterling , Asthana Sanjay , Carlsson Cynthia M. , Perrin Allison , Burke Anna , Scharre Douglas W. , Kataki Maria , Tarawneh Rawan , Kelley Brendan , Hart David , Zimmerman Earl A. , Celmins Dzintra , Miller Delwyn D. , Ponto Laura L. Boles , Smith Karen Ekstam , Koleva Hristina , Shim Hyungsub , Nam Ki Won , Schultz Susan K. , Williamson Jeff D. , Craft Suzanne , Cleveland Jo , Yang Mia , Sink Kaycee M. , Ott Brian R. , Drake Jonathan , Tremont Geoffrey , Daiello Lori A. , Drake Jonathan D. , Sabbagh Marwan , Ritter Aaron , Bernick Charles , Munic Donna , Mintz Akiva , O’Connelll Abigail , Mintzer Jacobo , Wiliams Arthur , Masdeu Joseph , Shi Jiong , Garcia Angelica , Sabbagh Marwan , Newhouse Paul , Potkin Steven , Salloway Stephen , Malloy Paul , Correia Stephen , Kittur Smita , Pearlson Godfrey D. , Blank Karen , Anderson Karen , Flashman Laura A. , Seltzer Marc , Hynes Mary L. , Santulli Robert B. , Relkin Norman , Chiang Gloria , Lee Athena , Lin Michael , Ravdin Lisa 
Published: July 2023

Abstract
Background
Increasing research suggests that gait abnormalities can be a risk factor for Alzheimer’s Disease (AD). Notably, there is growing evidence highlighting this risk factor in individuals with amnestic Mild Cognitive Impairment (aMCI), however further studies are needed. The aim of this study is to analyze cognitive tests results and brain-related measures over time in aMCI and examine how the presence of gait abnormalities (neurological or orthopedic) or normal gait affects these trends. Additionally, we sought to assess the significance of gait and gait-related measures as prognostic indicators for the progression from aMCI to AD dementia, comparing those who converted to AD with those who remained with a stable aMCI diagnosis during the follow-up.

Methods
Four hundred two individuals with aMCI from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database were included. Robust linear mixed-effects models were used to study the impact of gait abnormalities on a comprehensive neuropsychological battery over 36 months while controlling for relevant medical variables at baseline. The impact of gait on brain measures was also investigated. Lastly, the Cox proportional-hazards model was used to explore the prognostic relevance of abnormal gait and neuropsychological associated tests.

Results
While controlling for relevant covariates, we found that gait abnormalities led to a greater decline over time in attention (DSST) and global cognition (MMSE). Intriguingly, psychomotor speed (TMT-A) and divided attention (TMT-B) declined uniquely in the abnormal gait group. Conversely, specific AD global cognition tests (ADAS-13) and auditory-verbal memory (RAVLT immediate recall) declined over time independently of gait profile. All the other cognitive tests were not significantly affected by time or by gait profile. In addition, we found that ventricles size increased faster in the abnormal gait group compared to the normal gait group. In terms of prognosis, abnormal gait (HR = 1.7), MMSE (HR = 1.09), and DSST (HR = 1.03) covariates showed a higher impact on AD dementia conversion.

Conclusions
The importance of the link between gait and related cognitive functions in terms of diagnosis, prognosis, and rehabilitation in aMCI is critical. We showed that in aMCI gait abnormalities lead to executive functions/attention deterioration and conversion to AD dementia.