AUTHOR=Yang Zhengshi , Caldwell Jessica Z. K. , Cummings Jeffrey L. , Ritter Aaron , Kinney Jefferson W. , Cordes Dietmar , The Alzheimer's Disease Neuroimaging Initiative (ADNI) , Weiner Michael , Aisen Paul , Weiner Michael , Aisen Paul , Petersen Ronald , Jack Clifford R. , Jagust William , Trojanowki John Q. , Toga Arthur W. , Beckett Laurel , Green Robert C. , Saykin Andrew J. , Morris John , Liu Enchi , Green Robert C. , Montine Tom , Petersen Ronald , Aisen Paul , Gamst Anthony , Thomas Ronald G. , Donohue Michael , Walter Sarah , Gessert Devon , Sather Tamie , Beckett Laurel , Harvey Danielle , Gamst Anthony , Donohue Michael , Kornak John , Jack Clifford R. , Dale Anders , Bernstein Matthew , Felmlee Joel , Fox Nick , Thompson Paul , Schuff Norbert , Alexander Gene , DeCArli Charles , Jagust William , Bandy Dan , Koeppe Robert A. , Foster Norm , Reiman Eric M. , Chen Kewei , Mathis Chet , Morris John , Cairns Nigel J. , Taylor-Reinwald Lisa , Trojanowki J. Q. , Shaw Les , Lee Virginia M.Y. , Korecka Magdalena , Toga Arthur W. , Crawford Karen , Neu Scott , Saykin Andrew J. , Foroud Tatiana M. , Potkin Steven , Shen Li , Khachaturian Zaven , Frank Richard , Snyder Peter J. , Molchan Susan , Kaye Jeffrey , Quinn Joseph , Lind Betty , Dolen Sara , Schneider Lon S. , Pawluczyk Sonia , Spann Bryan M. , Brewer James , Vanderswag Helen , Heidebrink Judith L. , Lord Joanne L. , Petersen Ronald , Johnson Kris , Doody Rachelle S. , Villanueva-Meyer Javier , Chowdhury Munir , Stern Yaakov , Honig Lawrence S. , Bell Karen L. , Morris John C. , Ances Beau , Carroll Maria , Leon Sue , Mintun Mark A. , Schneider Stacy , Marson Daniel , Griffith Randall , Clark David , Grossman Hillel , Mitsis Effie , Romirowsky Aliza , deToledo-Morrell Leyla , Shah Raj C. , Duara Ranjan , Varon Daniel , Roberts Peggy , Albert Marilyn , Onyike Chiadi , Kielb Stephanie , Rusinek Henry , Leon Mony J de , Glodzik Lidia , Doraiswamy P. Murali , Petrella Jeffrey R. , Coleman Edward R. , Arnold Steven E. , Karlawish Jason H. , Wolk David , Smith Charles D. , Jicha Greg , Hardy Peter , Lopez Oscar L. , Oakley MaryAnn , Simpson Donna M. , Porsteinsson Anton P. , Goldstein Bonnie S. , Martin Kim , Makino Kelly M. , Ismail M. Saleem , Brand Connie , Mulnard Ruth A. , Thai Gaby , Mc-Adams-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 , Swerdlow Russell H. , Apostolova Liana , Lu Po H. , Bartzokis George , Silverman Daniel H.S. , Graff-Radford Neill R , Parfitt Francine , Johnson Heather , Farlow Martin , Herring Scott , Hake Ann M. , van Dyck Christopher H. , Carson Richard E. , MacAvoy Martha G. , Chertkow Howard , Bergman Howard , Hosein Chris , Black Sandra , Stefanovic Bojana , Caldwell Curtis , Hsiung Ging-Yuek Robin , Feldman Howard , Assaly Michele , KertesZ Andrew , Rogers John , Trost Dick , Bernick Charles , Munic Donna , Kerwin Diana , Mesulam Marek-Marsel , Lipowski Kristine , Wu Chuang-Kuo , Johnson Nancy , Sadowsky Carl , Martinez Walter , Villena Teresa , Turner Raymond Scott , Johnson Kathleen , Reynolds Brigid , Sperling Reisa A. , Johnson Keith A. , Marshall Gad , Frey Meghan , Rosen Allyson , Tinklenberg Jared , Sabbagh Marwan , Belden Christine , Jacobson Sandra , Kowall Neil , Killiany Ronald , Budson Andrew E. , Norbash Alexander , Johnson Patricia Lynn , Obisesan Thomas O. , Wolday Saba , Bwayo Salome K. , Lerner Alan , Hudson Leon , Ogrocki Paula , Fletcher Evan , Carmichael Owen , Olichney John , DeCarli Charles , Kittur Smita , Borrie Michael , Lee T-Y , Bartha Rob , Johnson Sterling , Asthana Sanjay , Carlsson Cynthia M. , Potkin Steven G. , Preda Adrian , Nguyen Dana , Tariot Pierre , Fleisher Adam , Reeder Stephanie , Bates Vernice , Capote Horacio , Rainka Michelle , Hendin Barry A. , Scharre Douglas W. , Kataki Maria , Zimmerman Earl A. , Celmins Dzintra , Brown Alice D. , Pearlson Godfrey D. , Blank Karen , Anderson Karen , Saykin Andrew J. , Santulli Robert B. , Schwartz Eben S. , Sink Kaycee M. , Williamson Jeff D. , Garg Pradeep , Watkins Franklin , Ott Brian R. , Querfurth Henry , Tremont Geoffrey , Salloway Stephen , Malloy Paul , Correia Stephen , Rosen Howard J. , Miller Bruce L. , Mintzer Jacobo , Longmire Crystal Flynn , Spicer Kenneth TITLE=Sex Modulates the Pathological Aging Effect on Caudate Functional Connectivity in Mild Cognitive Impairment JOURNAL=Frontiers in Psychiatry VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2022.804168 DOI=10.3389/fpsyt.2022.804168 ISSN=1664-0640 ABSTRACT=Purpose

To assess the pathological aging effect on caudate functional connectivity among mild cognitive impairment (MCI) participants and examine whether and how sex and amyloid contribute to this process.

Materials and Methods

Two hundred and seventy-seven functional magnetic resonance imaging (fMRI) sessions from 163 cognitive normal (CN) older adults and 309 sessions from 139 participants with MCI were included as the main sample in our analysis. Pearson's correlation was used to characterize the functional connectivity (FC) between caudate nuclei and each brain region, then caudate nodal strength was computed to quantify the overall caudate FC strength. Association analysis between caudate nodal strength and age was carried out in MCI and CN separately using linear mixed effect (LME) model with covariates (education, handedness, sex, Apolipoprotein E4, and intra-subject effect). Analysis of covariance was conducted to investigate sex, amyloid status, and their interaction effects on aging with the fMRI data subset having amyloid status available. LME model was applied to women and men separately within MCI group to evaluate aging effects on caudate nodal strength and each region's connectivity with caudate nuclei. We then evaluated the roles of sex and amyloid status in the associations of neuropsychological scores with age or caudate nodal strength. An independent cohort was used to validate the sex-dependent aging effects in MCI.

Results

The MCI group had significantly stronger age-related increase of caudate nodal strength compared to the CN group. Analyzing women and men separately revealed that the aging effect on caudate nodal strength among MCI participants was significant only for women (left: P = 6.23 × 10−7, right: P = 3.37 × 10−8), but not for men (P > 0.3 for bilateral caudate nuclei). The aging effects on caudate nodal strength were not significantly mediated by brain amyloid burden. Caudate connectivity with ventral prefrontal cortex substantially contributed to the aging effect on caudate nodal strength in women with MCI. Higher caudate nodal strength is significantly related to worse cognitive performance in women but not in men with MCI.

Conclusion

Sex modulates the pathological aging effects on caudate nodal strength in MCI regardless of amyloid status. Caudate nodal strength may be a sensitive biomarker of pathological aging in women with MCI.