Hope Center Member Publications

Plasma amyloid-β42/40 and apolipoprotein E for amyloid PET pre-screening in secondary prevention trials of Alzheimer’s disease
(2023) Brain Communications, 5 (2), art. no. fcad015, . 

Cullen, N.C.^a , Janelidze, S.^a , Stomrud, E.^a b , Bateman, R.J.^c , Palmqvist, S.^a b , Hansson, O.^a b , Mattsson-Carlgren, N.^a d e

^a Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, 202 13, Sweden
^b Memory Clinic, Skane University Hospital, Malmö, 205 02, Sweden
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Neurology, Skane University Hospital, Lund, 221 85, Sweden
^e Wallenberg Center for Molecular Medicine, Lund University, Lund, 221 84, Sweden

Abstract
The extent to which newly developed blood-based biomarkers could reduce screening costs in secondary prevention trials of Alzheimer’s disease is mostly unexplored. We collected plasma amyloid-β42/40, apolipoprotein E ϵ4 status and amyloid PET at baseline in 181 cognitively unimpaired participants [the age of 72.9 (5.3) years; 61.9% female; education of 11.9 (3.4) years] from the Swedish BioFINDER-1 study. We tested whether a model predicting amyloid PET status from plasma amyloid-β42/40, apolipoprotein E status and age (combined) reduced cost of recruiting amyloid PET + cognitively unimpaired participants into a theoretical trial. We found that the percentage of cognitively unimpaired participants with an amyloid PET + scan rose from 29% in an unscreened population to 64% [(49, 79); P < 0.0001] when using the biomarker model to screen for high risk for amyloid PET + status. In simulations, plasma screening also resulted in a 54% reduction of the total number of amyloid PET scans required and reduced total recruitment costs by 43% [(31, 56), P < 0.001] compared to no pre-screening when assuming a 16× PET-to-plasma cost ratio. Total savings remained significant when the PET-to-plasma cost ratio was assumed to be 8× or 4×. This suggests that a simple plasma biomarker model could lower recruitment costs in Alzheimer’s trials requiring amyloid PET positivity for inclusion. © 2023 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.

Author Keywords
Alzheimer’s disease;  amyloid;  clinical trials;  PET;  plasma biomarkers

Document Type: Article
Publication Stage: Final
Source: Scopus

A somato-cognitive action network alternates with effector regions in motor cortex
(2023) Nature, . 

Gordon, E.M.^a , Chauvin, R.J.^b , Van, A.N.^b c , Rajesh, A.^a , Nielsen, A.^b , Newbold, D.J.^b d , Lynch, C.J.^e , Seider, N.A.^b f , Krimmel, S.R.^b , Scheidter, K.M.^b , Monk, J.^b , Miller, R.L.^b f , Metoki, A.^b , Montez, D.F.^b , Zheng, A.^b , Elbau, I.^e , Madison, T.^g , Nishino, T.^f , Myers, M.J.^f , Kaplan, S.^b , Badke D’Andrea, C.^a f h , Demeter, D.V.^h , Feigelis, M.^h , Ramirez, J.S.B.ⁱ , Xu, T.ⁱ , Barch, D.M.^a f j , Smyser, C.D.^a b k , Rogers, C.E.^e k , Zimmermann, J.^l , Botteron, K.N.^f , Pruett, J.R.^f , Willie, J.T.^b e m , Brunner, P.^c m , Shimony, J.S.^a , Kay, B.P.^b , Marek, S.^a , Norris, S.A.^a b , Gratton, C.ⁿ , Sylvester, C.M.^f , Power, J.D.^e , Liston, C.^e , Greene, D.J.^h , Roland, J.L.^m , Petersen, S.E.^{a b c j o} , Raichle, M.E.^{a b c j o} , Laumann, T.O.^f , Fair, D.A.^g p q , Dosenbach, N.U.F.^{a b c j k r}

^a Mallinckrodt Institute of Radiology, 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 Biomedical Engineering, Washington University in St. Louis, St Louis, MO, United States
^d Department of Neurology, New York University Langone Medical Center, New York, NY, United States
^e Department of Psychiatry, Weill Cornell Medicine, New York, NY, United States
^f Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^g Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States
^h Department of Cognitive Science, University of California San Diego, La Jolla, CA, United States
ⁱ Center for the Developing Brain, Child Mind Institute, New York, NY, United States
^j Department of Psychological and Brain Sciences, Washington University in St. Louis, St Louis, MO, United States
^k Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States
^l Department of Neuroscience, University of Minnesota, Minneapolis, MN, United States
^m Department of Neurosurgery, Washington University School of Medicine, St Louis, MO, United States
ⁿ Department of Psychology, Florida State University, Tallahassee, FL, United States
^o Department of Neuroscience, Washington University School of Medicine, St Louis, MO, United States
^p Masonic Institute for the Developing Brain, University of Minnesota, Minneapolis, MN, United States
^q Institute of Child Development, University of Minnesota, Minneapolis, MN 55455, United States
^r Program in Occupational Therapy, Washington University in St. Louis, St Louis, MO, United States

Abstract
Motor cortex (M1) has been thought to form a continuous somatotopic homunculus extending down the precentral gyrus from foot to face representations1,2, despite evidence for concentric functional zones3 and maps of complex actions4. Here, using precision functional magnetic resonance imaging (fMRI) methods, we find that the classic homunculus is interrupted by regions with distinct connectivity, structure and function, alternating with effector-specific (foot, hand and mouth) areas. These inter-effector regions exhibit decreased cortical thickness and strong functional connectivity to each other, as well as to the cingulo-opercular network (CON), critical for action5 and physiological control6, arousal7, errors8 and pain9. This interdigitation of action control-linked and motor effector regions was verified in the three largest fMRI datasets. Macaque and pediatric (newborn, infant and child) precision fMRI suggested cross-species homologues and developmental precursors of the inter-effector system. A battery of motor and action fMRI tasks documented concentric effector somatotopies, separated by the CON-linked inter-effector regions. The inter-effectors lacked movement specificity and co-activated during action planning (coordination of hands and feet) and axial body movement (such as of the abdomen or eyebrows). These results, together with previous studies demonstrating stimulation-evoked complex actions4 and connectivity to internal organs10 such as the adrenal medulla, suggest that M1 is punctuated by a system for whole-body action planning, the somato-cognitive action network (SCAN). In M1, two parallel systems intertwine, forming an integrate–isolate pattern: effector-specific regions (foot, hand and mouth) for isolating fine motor control and the SCAN for integrating goals, physiology and body movement. © 2023, The Author(s).

Funding details
National Science FoundationNSFBCS-2048066
National Institutes of HealthNIHDA04112, DA041148, DA047851, DA048742, EB031765, HD055741, HD088125, HD103525, MH096773, MH100019, MH113883, MH114976, MH115357, MH116961, MH118362, MH118370, MH118388, MH120194, MH120989, MH121276, MH121462, MH121518, MH122066, MH122389, MH124567, MH128177, MH128696, MH129426, MH129493, MH129616, NS088590, NS098482, NS110332, NS123345, NS124789, NS129521
Dystonia Medical Research FoundationDMRF
Intellectual and Developmental Disabilities Research CenterIDDRC
Dysphonia InternationalNSDA

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

A Phenome-Wide Association Study (PheWAS) of Late Onset Alzheimer Disease Genetic Risk in Children of European Ancestry at Middle Childhood: Results from the ABCD Study
(2023) Behavior Genetics, . 

Gorelik, A.J.^a , Paul, S.E.^a , Karcher, N.R.^b , Johnson, E.C.^b , Nagella, I.^a , Blaydon, L.^a , Modi, H.^a , Hansen, I.S.^b , Colbert, S.M.C.^b , Baranger, D.A.A.^a , Norton, S.A.^a , Spears, I.^a , Gordon, B.^c d , Zhang, W.^c , Hill, P.L.^a , Oltmanns, T.F.^a , Bijsterbosch, J.D.^c , Agrawal, A.^b , Hatoum, A.S.^a , Bogdan, R.^a

^a Department of Psychological and Brain Sciences, Washington University in Saint Louis, One Booking Drive, St. Louis, MO 63130, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Radiology, Washington University in Saint Louis, 660 South Euclid Ave, Box 8225, St. Louis, MO 63110, United States
^d Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University, St Louis, MO, United States

Abstract
Genetic risk for Late Onset Alzheimer Disease (AD) has been associated with lower cognition and smaller hippocampal volume in healthy young adults. However, whether these and other associations are present during childhood remains unclear. Using data from 5556 genomically-confirmed European ancestry youth who completed the baseline session of the ongoing the Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®), our phenome-wide association study estimating associations between four indices of genetic risk for late-onset AD (i.e., AD polygenic risk scores (PRS), APOE rs429358 genotype, AD PRS with the APOE region removed (ADPRS-APOE), and an interaction between ADPRS-APOE and APOE genotype) and 1687 psychosocial, behavioral, and neural phenotypes revealed no significant associations after correction for multiple testing (all ps &gt; 0.0002; all pfdr &gt; 0.07). These data suggest that AD genetic risk may not phenotypically manifest during middle-childhood or that effects are smaller than this sample is powered to detect. © 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Alzheimer disease;  APOE;  Imaging;  Middle childhood;  Phenome-wide association study;  Polygenic risk scores

Funding details
National Science FoundationNSFDGE-213989, F31AA029934, K01AA030083, K01DA051759, K23MH12179201
National Institutes of HealthNIHU01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, U24DA041147

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

Cerebral revascularization surgery reduces cerebrovascular events in children with sickle cell disease and moyamoya syndrome: Results of the stroke in sickle cell revascularization surgery retrospective study
(2023) Pediatric Blood and Cancer, . 

Aldana, P.R.^a , Hanel, R.A.^b , Piatt, J.^c , Han, S.H.^d , Bansal, M.M.^e , Schultz, C.^f , Gauger, C.^e , Pederson, J.M.^g h , Iii, J.C.W.ⁱ , Hulbert, M.L.^j , Jordan, L.C.^k , Qureshi, A.^l , Garrity, K.^a , Robert, A.P.^a , Hatem, A.^a , Stein, J.^d , Beydler, E.^d , Adelson, P.D.^m , Greene, S.ⁿ , Grabb, P.^o , Johnston, J.^p , Lang, S.-S.^q , Leonard, J.^r , Magge, S.N.^s , Scott, A.^t , Shah, S.^u , Smith, E.R.^v , Smith, J.^w , Strahle, J.^t , Vadivelu, S.^x , Webb, J.^y , Wrubel, D.^z

^a Department of Neurosurgery, University of Florida College of Medicine – Jacksonville and Wolfson Children’s Hospital, Jacksonville, FL, United States
^b Lyerly Neurosurgery, Baptist Neurological Institute, Jacksonville, FL, United States
^c Division of Neurosurgery, Nemours Neuroscience Center, A.I. duPont Hospital for Children, Wilmington, DE, United States
^d University of Florida College of Medicine, Gainesville, FL, United States
^e Department of Pediatric Hematology/Oncology, Nemours Children’s Health System and Wolfson Children’s Hospital, Jacksonville, FL, United States
^f Department of Pediatrics, Nemours Center for Cancer and Blood Disorders, Nemours Children’s Hospital, Wilmington, DE, United States
^g Superior Medical Experts, St. Paul, MN, United States
^h Nested Knowledge, St. Paul, MN, United States
ⁱ Division of Pediatric Neurological Surgery, Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN, United States
^j Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^k Division of Pediatric Neurology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, United States
^l Department of Neurology, Zeenat Qureshi Stroke Institute, University of Missouri, Columbia, MO, United States
^m Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, United States
ⁿ Department of Neurosurgery, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
^o Department of Neurosurgery, Children’s Mercy Hospital, Kansas, MO, United States
^p Department of Neurosurgery, Children’s Hospital of Alabama, Birmingham, AL, United States
^q Department of Neurosurgery and Pediatric Neurosurgery, University of Pennsylvania School of Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^r Department of Neurosurgery, Nationwide Children’s Hospital, Columbus, OH, United States
^s Department of Neurosurgery, CHOC Neuroscience Institute, Children’s Health of Orange County, Orange, CA, United States
^t Department of Neurosurgery, Washington University School of Medicine, Washington University in Saint Louis, St Louis, MO, United States
^u Department of Pediatric Hematology/Oncology, Phoenix Children’s Hospital, Phoenix, AZ, United States
^v Department of Neurosurgery, Children’s Hospital Boston, and Harvard Medical School, Boston, MA, United States
^w Department of Pediatric Neurosurgery, Goodman Campbell Brain and Spine, Peyton Manning Children’s Hospital, Indianapolis, IN, United States
^x Division of Neurosurgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
^y Department of Hematology/Oncology, Children’s National Hospital, Washington, DC, United States
^z Department of Neurosurgery, Children’s Healthcare of Atlanta, Egleston Hospital, Atlanta, GA, United States

Abstract
Background: Recent studies suggest that cerebral revascularization surgery may be a safe and effective therapy to reduce stroke risk in patients with sickle cell disease and moyamoya syndrome (SCD–MMS). Methods: We performed a multicenter, retrospective study of children with SCD–MMS treated with conservative management alone (conservative group)—chronic blood transfusion and/or hydroxyurea—versus conservative management plus surgical revascularization (surgery group). We monitored cerebrovascular event (CVE) rates—a composite of strokes and transient ischemic attacks. Multivariable logistic regression was used to compare CVE occurrence and multivariable Poisson regression was used to compare incidence rates between groups. Covariates in multivariable models included age at treatment start, age at moyamoya diagnosis, antiplatelet use, CVE history, and the risk period length. Results: We identified 141 patients with SCD–MMS, 78 (55.3%) in the surgery group and 63 (44.7%) in the conservative group. Compared with the conservative group, preoperatively the surgery group had a younger age at moyamoya diagnosis, worse baseline modified Rankin scale scores, and increased prevalence of CVEs. Despite more severe pretreatment disease, the surgery group had reduced odds of new CVEs after surgery (odds ratio = 0.27, 95% confidence interval [CI] = 0.08–0.94, p =.040). Furthermore, comparing surgery group patients during presurgical versus postsurgical periods, CVEs odds were significantly reduced after surgery (odds ratio = 0.22, 95% CI = 0.08–0.58, p =.002). Conclusions: When added to conservative management, cerebral revascularization surgery appears to reduce the risk of CVEs in patients with SCD–MMS. A prospective study will be needed to validate these findings. © 2023 Wiley Periodicals LLC.

Author Keywords
cerebrovascular event;  encephalo-duro-arterio-synangiosis;  moyamoya syndrome;  revascularization surgery;  sickle cell disease;  stroke

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