Hope Center member publications

Plasma phosphorylated-tau181 as a predictive biomarker for Alzheimer’s amyloid, tau and FDG PET status
(2021) Translational Psychiatry, 11 (1), art. no. 585, . 

Shen, X.-N.^a , Huang, Y.-Y.^a , Chen, S.-D.^a , Guo, Y.^b , Tan, L.^b , Dong, Q.^a , Yu, J.-T.^a , Weiner, M.W.^c , Aisen, P.^d , Petersen, R.^e , Jack, C.R., Jr^e , Jagust, W.^f , Trojanowki, J.Q.^g , Toga, A.W.^d , Beckett, L.^h , Green, R.C.ⁱ , Saykin, A.J.^j , Morris, J.C.^k , Perrin, R.J.^k , Shaw, L.M.^g , Carrillo, M.^l , Potter, W.^m , Barnes, L.ⁿ , Bernard, M.^o , González, H.^p , Ho, C.^q , Hsiao, J.K.^r , Jackson, J.^s , Masliah, E.^o , Masterman, D.^t , Okonkwo, O.^u , Perrin, R.^v , Ryan, L.^o , Silverberg, N.^o , Fleisher, A.^w , Fockler, J.^c , Conti, C.^x , Veitch, D.^x , Neuhaus, J.^c , Jin, C.^c , Nosheny, R.^c , Ashford, M.^x , Flenniken, D.^x , Kormos, A.^x , Jimenez, G.^d , Donohue, M.^d , Gessert, D.^d , Salazar, J.^d , Zimmerman, C.^d , Cabrera, Y.^d , Walter, S.^d , Miller, G.^d , Coker, G.^d , Clanton, T.^d , Hergesheimer, L.^d , Smith, S.^d , Adegoke, O.^d , Mahboubi, P.^d , Moore, S.^d , Pizzola, J.^d , Shaffer, E.^d , Sloan, B.^d , Harvey, D.^h , Borowski, B.^y , Ward, C.^y , Schwarz, C.^y , Jones, D.^y , Gunter, J.^y , Kantarci, K.^y , Senjem, M.^y , Vemuri, P.^y , Reid, R.^y , Fox, N.C.^z , Malone, I.^z , Thompson, P.^aa , Thomopoulos, S.I.^aa , Nir, T.M.^aa , Jahanshad, N.^aa , DeCarli, C.^h , Knaack, A.^h , Fletcher, E.^h , Tosun-Turgut, D.^c , Chen, S.R.^x , Choe, M.^x , Crawford, K.^aa , Yushkevich, P.A.^g , Das, S.^g , Koeppe, R.A.^ab , Reiman, E.M.^ac , Chen, K.^ac , Mathis, C.^ad , Landau, S.^f , Perrin, R.^k , Cairns, N.J.^k , Householder, E.^k , Franklin, E.^k , Bernhardt, H.^k , Taylor-Reinwald, L.^k , Shaw, L.M.^ae , Trojanowki, J.Q.^ae , Korecka, M.^ae , Figurski, M.^ae , Crawford, K.^d , Neu, S.^d , Saykin, A.J.^af , Nho, K.^af , Risacher, S.L.^af , Apostolova, L.G.^af , Shen, L.^ag , Foroud, T.M.^ah , Nudelman, K.^ah , Faber, K.^ah , Wilmes, K.^ah , Thal, L.^p , Khachaturian, Z.^ai , Hsiao, J.K.^aj , Silbert, L.C.^ak , Lind, B.^ak , Crissey, R.^ak , Kaye, J.A.^ak , Carter, R.^ak , Dolen, S.^ak , Quinn, J.^ak , Schneider, L.S.^d , Pawluczyk, S.^d , Becerra, M.^d , Teodoro, L.^d , Dagerman, K.^d , Spann, B.M.^d , Brewer, J.^p , Vanderswag, H.^al , Fleisher, A.^al , Ziolkowski, J.^ab , Heidebrink, J.L.^ab , Zbizek-Nulph, L.^ab , Lord, J.L.^ab , Albers, C.S.^e , Knopman, D.^e , Johnson, K.^e , Villanueva-Meyer, J.^am , Pavlik, V.^am , Pacini, N.^am , Lamb, A.^am , Kass, J.S.^am , Doody, R.S.^am , Shibley, V.^am , Chowdhury, M.^am , Rountree, S.^am , Dang, M.^am , Stern, Y.^an , Honig, L.S.^an , Mintz, A.^an , Ances, B.^ao , Winkfield, D.^ao , Carroll, M.^ao , Stobbs-Cucchi, G.^ao , Oliver, A.^ao , Creech, M.L.^ao , Mintun, M.A.^ao , Schneider, S.^ao , Geldmacher, D.^ap , Love, M.N.^ap , Griffith, R.^ap , Clark, D.^ap , Brockington, J.^ap , Marson, D.^ap , Grossman, H.^aq , Goldstein, M.A.^aq , Greenberg, J.^aq , Mitsis, E.^aq , Shah, R.C.^ar , Lamar, M.^ar , Samuels, P.^ar , Duara, R.^as , Greig-Custo, M.T.^as , Rodriguez, R.^as , Albert, M.^at , Onyike, C.^at , Farrington, L.^at , Rudow, S.^at , Brichko, R.^at , Kielb, S.^at , Smith, A.^au , Raj, B.A.^au , Fargher, K.^au , Sadowski, M.^av , Wisniewski, T.^av , Shulman, M.^av , Faustin, A.^av , Rao, J.^av , Castro, K.M.^av , Ulysse, A.^av , Chen, S.^av , Sheikh, M.O.^av , Singleton-Garvin, J.^av , Doraiswamy, P.M.^aw , Petrella, J.R.^aw , James, O.^aw , Wong, T.Z.^aw , Borges-Neto, S.^aw , Karlawish, J.H.^g , Wolk, D.A.^g , Vaishnavi, S.^g , Clark, C.M.^g , Arnold, S.E.^g , Smith, C.D.^ax , Jicha, G.A.^ax , El Khouli, R.^ax , Raslau, F.D.^ax , Lopez, O.L.^ad , Oakley, M.A.^ad , Simpson, D.M.^ad , Porsteinsson, A.P.^ay , Martin, K.^ay , Kowalski, N.^ay , Keltz, M.^ay , Goldstein, B.S.^ay , Makino, K.M.^ay , Ismail, M.S.^ay , Brand, C.^ay , Thai, G.^az , Pierce, A.^az , Yanez, B.^az , Sosa, E.^az , Witbracht, M.^az , Kelley, B.^ba , Nguyen, T.^ba , Womack, K.^ba , Mathews, D.^ba , Quiceno, M.^ba , Levey, A.I.^bb , Lah, J.J.^bb , Hajjar, I.^bb , Cellar, J.S.^bb , Burns, J.M.^bc , Swerdlow, R.H.^bc , Brooks, W.M.^bc , Silverman, D.H.S.^bd , Kremen, S.^bd , Apostolova, L.^bd , Tingus, K.^bd , Lu, P.H.^bd , Bartzokis, G.^bd , Woo, E.^bd , Teng, E.^bd , Graff-Radford, N.R.^be , Parfitt, F.^be , Poki-Walker, K.^be , Farlow, M.R.^j , Hake, A.M.^j , Matthews, B.R.^j , Brosch, J.R.^j , Herring, S.^j , van Dyck, C.H.^bf , Mecca, A.P.^bf , Good, S.P.^bf , MacAvoy, M.G.^bf , Carson, R.E.^bf , Varma, P.^bf , Chertkow, H.^bg , Vaitekunis, S.^bg , Hosein, C.^bg , Black, S.^bh , Stefanovic, B.^bh , Heyn, C.C.^bh , Hsiung, G.-Y.R.^bi , Kim, E.^bi , Mudge, B.^bi , Sossi, V.^bi , Feldman, H.^bi , Assaly, M.^bi , Finger, E.^bj , Pasternak, S.^bj , Rachinsky, I.^bj , Kertesz, A.^bj , Drost, D.^bj , Rogers, J.^bj , Grant, I.^bk , Muse, B.^bk , Rogalski, E.^bk , Robson, J.^bk , Mesulam, M.-M.^bk , Kerwin, D.^bk , Wu, C.-K.^bk , Johnson, N.^bk , Lipowski, K.^bk , Weintraub, S.^bk , Bonakdarpour, B.^bk , Pomara, N.^bl , Hernando, R.^bl , Sarrael, A.^bl , Rosen, H.J.^c , Miller, B.L.^c , Perry, D.^c , Turner, R.S.^bm , Johnson, K.^bm , Reynolds, B.^bm , MCCann, K.^bm , Poe, J.^bm , Sperling, R.A.^bn , Johnson, K.A.^bn , Marshall, G.A.^bn , Belden, C.M.^bo , Atri, A.^bo , Spann, B.M.^bo , Clark, K.A.^g , Zamrini, E.^bo , Sabbagh, M.^bo , Killiany, R.^bp , Stern, R.^bp , Mez, J.^bp , Kowall, N.^bp , Budson, A.E.^bp , Obisesan, T.O.^bq , Ntekim, O.E.^bq , Wolday, S.^bq , Khan, J.I.^bq , Nwulia, E.^bq , Nadarajah, S.^bq , Lerner, A.^br , Ogrocki, P.^br , Tatsuoka, C.^br , Fatica, P.^br , Fletcher, E.^bs , Maillard, P.^bs , Olichney, J.^bs , DeCarli, C.^bs , Carmichael, O.^bs , Bates, V.^bt , Capote, H.^bt , Rainka, M.^bt , Borrie, M.^bu , Lee, T.-Y.^bu , Bartha, R.^bu , Johnson, S.^bv , Asthana, S.^bv , Carlsson, C.M.^bv , Perrin, A.^ac , Burke, A.^ac , Scharre, D.W.^bw , Kataki, M.^bw , Tarawneh, R.^bw , Kelley, B.^bw , Hart, D.^bx , Zimmerman, E.A.^bx , Celmins, D.^bx , Miller, D.D.^by , Boles Ponto, L.L.^by , Smith, K.E.^by , Koleva, H.^by , Shim, H.^by , Nam, K.W.^by , Schultz, S.K.^h , Williamson, J.D.^bz , Craft, S.^bz , Cleveland, J.^bz , Yang, M.^bz , Sink, K.M.^bz , Ott, B.R.^ca , Drake, J.^ca , Tremont, G.^ca , Daiello, L.A.^ca , Drake, J.D.^ca , Sabbagh, M.^cb , Ritter, A.^cb , Bernick, C.^cb , Munic, D.^cb , Mintz, A.^cb , O’Connelll, A.^cc , Mintzer, J.^cc , Wiliams, A.^cc , Masdeu, J.^cd , Shi, J.^ce , Garcia, A.^ce , Sabbagh, M.^ce , Newhouse, P.^cf , Potkin, S.^cg , Salloway, S.^ch , Malloy, P.^ch , Correia, S.^ch , Kittur, S.^ci , Pearlson, G.D.^cj , Blank, K.^cj , Anderson, K.^cj , Flashman, L.A.^ck , Seltzer, M.^ck , Hynes, M.L.^ck , Santulli, R.B.^ck , Relkin, N.^cl , Chiang, G.^cl , Lin, M.^cl , Ravdin, L.^cl , Lee, A.^cl , Petersen, R.^y , Neylan, T.^c , Grafman, J.^cm , Montine, T.^cn , Danowski, S.^d , Nguyen-Barrera, C.^d , Finley, S.^a , Harvey, D.^f , Donohue, M.ⁿ , Bernstein, M.^c , Foster, N.^co , Foroud, T.M.^j , Potkin, S.^cp , Shen, L.^j , Faber, K.^j , Kim, S.^j , Nho, K.^j , Wilmes, K.^cq , Vanderswag, H.^p , Fleisher, A.^p , Sood, A.^ar , Blanchard, K.S.^ar , Fleischman, D.^ar , Greig, M.T.^as , Goldstein, B.^ay , Martin, K.S.^ay , Thai, G.^cr , Pierce, A.^cr , Reist, C.^cr , Yanez, B.^cr , Sosa, E.^cr , Witbracht, M.^cr , Sadowsky, C.^cs , Martinez, W.^cs , Villena, T.^cs , Rosen, H.^c , Peskind, E.R.^cn , Petrie, E.C.^cn , Li, G.^cn , Yesavage, J.^ct , Taylor, J.L.^ct , Chao, S.^ct , Coleman, J.^ct , White, J.D.^ct , Lane, B.^ct , Rosen, A.^ct , Tinklenberg, J.^ct , Jimenez-Maggiora, G.^d , Drake, E.^cu , Donohue, M.^d , Nelson, C.^c , Bickford, D.^c , Butters, M.^ad , Zmuda, M.^ad , Borowski, B.^e , Gunter, J.^e , Senjem, M.^e , Kantarci, K.^e , Ward, C.^e , Reyes, D.^e , Faber, K.M.^j , Nudelman, K.N.^j , Au, Y.H.^c , Scherer, K.^c , Catalinotto, D.^c , Stark, S.^c , Ong, E.^c , Fernandez, D.^c , Zmuda, M.^ad , Alzheimer’s Disease Neuroimaging Initiative^cv

^a Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
^b Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
^c University of California, San Francisco, San Francisco, United States
^d University of Southern California, Los Angeles, United States
^e Mayo Clinic, Rochester, Rochester, United States
^f University of California, Berkeley, Berkeley, United States
^g University of Pennsylvania, Philadelphia, United States
^h University of California, Davis, Davis, United States
ⁱ BWH/HMS, Boston, United States
^j Indiana University, Bloomington, United States
^k Washington University St. Louis, St. Louis, United States
^l Alzheimer’s Association, Chicago, United States
^m National Institute of Mental Health, Rochville, United States
ⁿ Rush University, Chicago, United States
^o NIA, Bethesda, United States
^p University of California, San Diego, San Diego, United States
^q Denali Therapeutics, South San Francisco, United States
^r NIH, Bethesda, United States
^s Massachusetts General Hospital, Boston, United States
^t Biogen, Cambridge, United States
^u University of Wisconsin, Madison, Madison, United States
^v Washington University, St. Louis, United States
^w Eli Lilly, Indianapolis, United States
^x NCIRE/The Vererans Health Research Institute, San Francisco, United States
^y Mayo Clinic, Scottsdale, United States
^z University College London, London, United Kingdom
^aa University of Southern California School of Medicine, Los Angeles, United States
^ab University of Michigan, Ann Arbor, United States
^ac Banner Alzheimer’s Institute, Phoenix, United States
^ad University of Pittsburgh, Pittsburgh, United States
^ae Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
^af Indiana University School of Medicine, Indianapolis, United States
^ag UPenn School of Medicine, Philadelphia, United States
^ah NCRAD/Indiana University School of Medicine, Indianapolis, United States
^ai Prevent Alzheimer’s Disease, Rockville, 2020, United States
^aj National Institute on Aging, Bethesda, United States
^ak Oregon Health & Science University, Portland, United States
^al University of California – San Diego, San Diego, United States
^am Baylor College of Medicine, Houston, United States
^an Columbia University Medical Center, New York, United States
^ao Washington University, St. Louis, St. Louis, United States
^ap University of Alabama – Birmingham, Birmingham, United States
^aq Mount Sinai School of Medicine, New York, United States
^ar Rush University Medical Center, Chicago, United States
^as Wien Center, Miami Beach, United States
^at Johns Hopkins University, Baltimore, United States
^au University of South Florida: USF Health Byrd Alzheimer’s Institute, Tampa, United States
^av New York University, New York, United States
^aw Duke University Medical Center, Durham, United States
^ax University of Kentucky, Lexington, United States
^ay University of Rochester Medical Center, New York, United States
^az University of California Irvine IMIND, Irvine, United States
^ba University of Texas Southwestern Medical School, Dallas, United States
^bb Emory University, Atlanta, United States
^bc University of Kansas, Medical Center, Kansas, United States
^bd University of California, Los Angeles, Los Angeles, United States
^be Mayo Clinic, Jacksonville, Jacksonville, United States
^bf Yale University School of Medicine, New Haven, United States
^bg McGill Univ., Montreal-Jewish General Hospital, Montréal, Canada
^bh Sunnybrook Health Sciences, Ontario, Toronto, Canada
^bi U.B.C. Clinic for AD & Related Disorders, Vancouver, Canada
^bj St. Joseph’s Health Care, Petaluma, United States
^bk Northwestern University, Evanston, United States
^bl Nathan Kline Institute, Orangeburg, United States
^bm Georgetown University Medical Center, Washington, United States
^bn Brigham and Women’s Hospital, Boston, United States
^bo Banner Sun Health Research Institute, Sun City, United States
^bp Boston University, Boston, United States
^bq Howard University, Washington, United States
^br Case Western Reserve University, Cleveland, United States
^bs University of California, Davis – Sacramento, Sacramento, United States
^bt Dent Neurologic Institute, Orchard Park, United States
^bu Parkwood Institute, London, Canada
^bv University of Wisconsin, Madison, United States
^bw Ohio State University, Columbus, United States
^bx Albany Medical College, Albany, United States
^by University of Iowa College of Medicine, Iowa City, United States
^bz Wake Forest University Health Sciences, Winston Salem, United States
^ca Rhode Island Hospital, Providence, United States
^cb Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, United States
^cc Roper St. Francis Healthcare, Charleston, United States
^cd Houston Methodist Neurological Institute, Houston, United States
^ce Barrow Neurological Institute, Phoenix, United States
^cf Vanderbilt University Medical Center, Nashville, United States
^cg Long Beach VA Neuropsychiatric Research Program, Long Beach, United States
^ch Butler Hospital Memory and Aging Program, Providence, United States
^ci Neurological Care of CNY, East Syracuse, United States
^cj Hartford Hospital, Olin Neuropsychiatry Research Center, Hartford, United States
^ck Dartmouth-Hitchcock Medical Center, Lebanon, United States
^cl Cornell University, Ithaca, United States
^cm Rehabilitation Institute of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, United States
^cn University of Washington, Seattle, United States
^co University of Utah, Salt Lake City, United States
^cp UC Irvine, Irvine, United States
^cq NCRAD, Indianapolis, United States
^cr University of California, Irvine, Irvine, United States
^cs Premiere Research Inst (Palm Beach Neurology), West Palm Beach, United States
^ct Stanford University, Stanford, United States
^cu BWM/HMS, Boston, United States

Abstract
Plasma phosphorylated-tau181 (p-tau181) showed the potential for Alzheimer’s diagnosis and prognosis, but its role in detecting cerebral pathologies is unclear. We aimed to evaluate whether it could serve as a marker for Alzheimer’s pathology in the brain. A total of 1189 participants with plasma p-tau181 and PET data of amyloid, tau or FDG PET were included from ADNI. Cross-sectional relationships of plasma p-tau181 with PET biomarkers were tested. Longitudinally, we further investigated whether different p-tau181 levels at baseline predicted different progression of Alzheimer’s pathological changes in the brain. We found plasma p-tau181 significantly correlated with brain amyloid (Spearman ρ = 0.45, P < 0.0001), tau (0.25, P = 0.0003), and FDG PET uptakes (−0.37, P < 0.0001), and increased along the Alzheimer’s continuum. Individually, plasma p-tau181 could detect abnormal amyloid, tau pathologies and hypometabolism in the brain, similar with or even better than clinical indicators. The diagnostic accuracy of plasma p-tau181 elevated significantly when combined with clinical information (AUC = 0.814 for amyloid PET, 0.773 for tau PET, and 0.708 for FDG PET). Relationships of plasma p-tau181 with brain pathologies were partly or entirely mediated by the corresponding CSF biomarkers. Besides, individuals with abnormal plasma p-tau181 level (>18.85 pg/ml) at baseline had a higher risk of pathological progression in brain amyloid (HR: 2.32, 95%CI 1.32–4.08) and FDG PET (3.21, 95%CI 2.06–5.01) status. Plasma p-tau181 may be a sensitive screening test for detecting brain pathologies, and serve as a predictive biomarker for Alzheimer’s pathophysiology. © 2021, The Author(s).

Funding details
National Institutes of HealthNIHU01 AG024904
U.S. Department of DefenseDODW81XWH-12-2-0012
National Institute on AgingNIA
National Institute of Biomedical Imaging and BioengineeringNIBIB
Alzheimer’s Disease Neuroimaging InitiativeADNI
National Outstanding Youth Science Fund Project of National Natural Science Foundation of ChinaIUSS81771148, 91849126
National Natural Science Foundation of ChinaNSFC81571245, 9184910220
Fudan University
Science and Technology Commission of Shanghai MunicipalitySTCSM2018SHZDZX01
National Key Research and Development Program of ChinaNKRDPC2018YFC1314700

Document Type: Article
Publication Stage: Final
Source: Scopus

Cognitive deficits and impaired hippocampal long-term potentiation in KATPinduced DEND syndrome
(2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (45), art. no. e2109721118, . 

Yahil, S.^a , Wozniak, D.F.^b c , Yan, Z.^a , Mennerick, S.^b c , Remedi, M.S.^a d

^a Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO 63110, United States
^c Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Cell Biology and Physiology, Washington University, School of Medicine, St. Louis, MO 63110, United States

Abstract
ATP-sensitive potassium (KATP) gain-of-function (GOF) mutations cause neonatal diabetes, with some individuals exhibiting developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. Mice expressing KATP-GOF mutations pan-neuronally (nKATP-GOF) demonstrated sensorimotor and cognitive deficits, whereas hippocampus-specific hKATP-GOF mice exhibited mostly learning and memory deficiencies. Both nKATP-GOF and hKATP-GOF mice showed altered neuronal excitability and reduced hippocampal long-term potentiation (LTP). Sulfonylurea therapy, which inhibits KATP, mildly improved sensorimotor but not cognitive deficits in KATP-GOF mice. Mice expressing KATP-GOF mutations in pancreatic β-cells developed severe diabetes but did not show learning and memory deficits, suggesting neuronal KATP-GOF as promoting these features. These findings suggest a possible origin of cognitive dysfunction in DEND and the need for novel drugs to treat neurological features induced by neuronal KATP-GOF. © 2021 National Academy of Sciences. All rights reserved.

Author Keywords
Behavior;  Cognition;  DEND;  Electrophysiology;  KATP

Funding details
National Institutes of HealthNIHR01DK098584, R01DK123163, R01MH123748
National Institute of Child Health and Human DevelopmentNICHDU54HD087011/ P50HD103425

Document Type: Article
Publication Stage: Final
Source: Scopus

Sirtuin 1 mediates protection against delayed cerebral ischemia in subarachnoid hemorrhage in response to hypoxic postconditioning
(2021) Journal of the American Heart Association, 10 (20), art. no. e021113, . 

Diwan, D.^a , Vellimana, A.K.^a , Aum, D.J.^a , Clarke, J.^a , Nelson, J.W.^a , Lawrence, M.^a , Han, B.H.^c , Gidday, J.M.^d , Zipfel, G.J.^a b

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Pharmacology, A.T. Still, University of Health Sciences, Kirksville College of Osteopathic Medicine, Kirksville, MO, United States
^d Departments of Ophthalmology, Physiology, Biochemistry, and Neuroscience, Louisiana State University, New Orleans, LA, United States

Abstract
BACKGROUND: Many therapies designed to prevent delayed cerebral ischemia (DCI) and improve neurological outcome in an-eurysmal subarachnoid hemorrhage (SAH) have failed, likely because of targeting only one element of what has proven to be a multifactorial disease. We previously demonstrated that initiating hypoxic conditioning before SAH (hypoxic preconditioning) provides powerful protection against DCI. Here, we expanded upon these findings to determine whether hypoxic conditioning delivered at clinically relevant time points after SAH (hypoxic postconditioning) provides similarly robust DCI protection. METHODS AND RESULTS: In this study, we found that hypoxic postconditioning (8% O2 for 2 hours) initiated 3 hours after SAH provides strong protection against cerebral vasospasm, microvessel thrombi, and neurological deficits. By pharmacologic and genetic inhibition of SIRT1 (sirtuin 1) using EX527 and global Sirt1−/− mice, respectively, we demonstrated that this mul-tifaceted DCI protection is SIRT1 mediated. Moreover, genetic overexpression of SIRT1 using Sirt1-Tg mice, mimicked the DCI protection afforded by hypoxic postconditioning. Finally, we found that post-SAH administration of resveratrol attenuated cerebral vasospasm, microvessel thrombi, and neurological deficits, and did so in a SIRT1-dependent fashion. CONCLUSIONS: The present study indicates that hypoxic postconditioning provides powerful DCI protection when initiated at clinically relevant time points, and that pharmacologic augmentation of SIRT1 activity after SAH can mimic this beneficial ef-fect. We conclude that conditioning-based therapies administered after SAH hold translational promise for patients with SAH and warrant further investigation. © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Author Keywords
Delayed cerebral ischemia;  Microvessel thrombi;  Postconditioning;  Resveratrol;  Sirt1;  Subarachnoid hemorrhage;  Vasospasm

Funding details
National Institutes of HealthNIHR01 NS091603, R25 NS090978
Neurosurgery Research and Education FoundationNREF

Document Type: Article
Publication Stage: Final
Source: Scopus

Sleep and longitudinal cognitive performance in preclinical and early symptomatic Alzheimer’s disease
(2021) Brain, 144 (9), pp. 2852-2862. Cited 1 time.

Lucey, B.P.^a b , Wisch, J.^a , Boerwinkle, A.H.^a , Landsness, E.C.^a , Toedebusch, C.D.^a , McLeland, J.S.^a , Butt, O.H.^a , Hassenstab, J.^a b c , Morris, J.C.^a b c , Ances, B.M.^a b , Holtzman, D.M.^a b c

^a Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, United States
^b Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO 63110, United States
^c Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO 63110, United States

Abstract
Sleep monitoring may provide markers for future Alzheimer’s disease; however, the relationship between sleep and cognitive function in preclinical and early symptomatic Alzheimer’s disease is not well understood. Multiple studies have associated short and long sleep times with future cognitive impairment. Since sleep and the risk of Alzheimer’s disease change with age, a greater understanding of how the relationship between sleep and cognition changes over time is needed. In this study, we hypothesized that longitudinal changes in cognitive function will have a non-linear relationship with total sleep time, time spent in non-REM and REM sleep, sleep efficiency and non-REM slow wave activity. To test this hypothesis, we monitored sleep-wake activity over 4-6 nights in 100 participants who underwent standardized cognitive testing longitudinally, APOE genotyping, and measurement of Alzheimer’s disease biomarkers, total tau and amyloid-β42 in the CSF. To assess cognitive function, individuals completed a neuropsychological testing battery at each clinical visit that included the Free and Cued Selective Reminding test, the Logical Memory Delayed Recall assessment, the Digit Symbol Substitution test and the Mini-Mental State Examination. Performance on each of these four tests was Z-scored within the cohort and averaged to calculate a preclinical Alzheimer cognitive composite score. We estimated the effect of cross-sectional sleep parameters on longitudinal cognitive performance using generalized additive mixed effects models. Generalized additive models allow for non-parametric and non-linear model fitting and are simply generalized linear mixed effects models; however, the linear predictors are not constant values but rather a sum of spline fits. We found that longitudinal changes in cognitive function measured by the cognitive composite decreased at low and high values of total sleep time (P < 0.001), time in non-REM (P < 0.001) and REM sleep (P < 0.001), sleep efficiency (P < 0.01) and <1 Hz and 1-4.5 Hz non-REM slow wave activity (P < 0.001) even after adjusting for age, CSF total tau/amyloid-β42 ratio, APOE ϵ4 carrier status, years of education and sex. Cognitive function was stable over time within a middle range of total sleep time, time in non-REM and REM sleep and <1 Hz slow wave activity, suggesting that certain levels of sleep are important for maintaining cognitive function. Although longitudinal and interventional studies are needed, diagnosing and treating sleep disturbances to optimize sleep time and slow wave activity may have a stabilizing effect on cognition in preclinical or early symptomatic Alzheimer’s disease. © 2021 The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

Author Keywords
Alzheimer’s disease;  biomarkers;  EEG;  memory;  mild cognitive impairment

Document Type: Article
Publication Stage: Final
Source: Scopus

Distinct epilepsy phenotypes and response to drugs in KCNA1 gain- and loss-of function variants
(2021) Epilepsia, . 

Miceli, F.^a , Guerrini, R.^b , Nappi, M.^a , Soldovieri, M.V.^c , Cellini, E.^b , Gurnett, C.A.^d , Parmeggiani, L.^e , Mei, D.^b , Taglialatela, M.^a

^a Department of Neuroscience, University of Naples “Federico II”, Naples, Italy
^b Neuroscience Department, A. Meyer Children’s Hospital, University of Florence, Florence, Italy
^c Department of Medicine and Health Science “V. Tiberio”, University of Molise, Campobasso, Italy
^d Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Pediatric Neurology, Bolzano Hospital, Bolzano, Italy

Abstract
A wide phenotypic spectrum of neurological diseases is associated with KCNA1 (Kv1.1) variants. To investigate the molecular basis of such a heterogeneous clinical presentation and identify the possible correlation with in vitro phenotypes, we compared the functional consequences of three heterozygous de novo variants (p.P403S, p.P405L, and p.P405S) in Kv1.1 pore region found in four patients with severe developmental and epileptic encephalopathy (DEE), with those of a de novo variant in the voltage sensor (p.A261T) identified in two patients with mild, carbamazepine-responsive, focal epilepsy. Patch-clamp electrophysiology was used to investigate the functional properties of mutant Kv1.1 subunits, both expressed as homomers and heteromers with wild-type Kv1.1 subunits. KCNA1 pore mutations markedly decreased (p. P405S) or fully suppressed (p. P403S, p. P405L) Kv1.1-mediated currents, exerting loss-of-function (LoF) effects. By contrast, channels carrying the p.A261T variant exhibited a hyperpolarizing shift of the activation process, consistent with a gain-of-function (GoF) effect. The present results unveil a novel correlation between in vitro phenotype (GoF vs LoF) and clinical course (mild vs severe) in KCNA1-related phenotypes. The excellent clinical response to carbamazepine observed in the patients carrying the A261T variant suggests an exquisite sensitivity of KCNA1 GoF to sodium channel inhibition that should be further explored. © 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Author Keywords
developmental encephalopathies;  epilepsy;  gain-of-function variants;  KCNA1;  loss-of-function variants;  potassium channels

Funding details
DECODE‐EE
Seventh Framework ProgrammeFP7N602531
European CommissionECUNICOM – 875299
Ministero della SaluteRF‐2019‐12370491
Ministero dell’Istruzione, dell’Università e della RicercaMIURPRIN 2017ALCR7C, PRIN 2017YH3SXK

Document Type: Article
Publication Stage: Article in Press
Source: Scopus