Hope Center member publications

Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol
(2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (33), art. no. e2102191118, . 

Wang, H.^a b c , Kulas, J.A.^d e , Wang, C.^f , Holtzman, D.M.^f , Ferris, H.A.^d e , Hansen, S.B.^a b

^a Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, United States
^b Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, United States
^c Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL 33458, United States
^d Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA 22908, United States
^e Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, United States
^f Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University, School of Medicine, St. Louis, MO 63110, United States

Abstract
Alzheimer’s disease (AD) is characterized by the presence of amyloid β (Aβ) plaques, tau tangles, inflammation, and loss of cognitive function. Genetic variation in a cholesterol transport protein, apolipoprotein E (apoE), is the most common genetic risk factor for sporadic AD. In vitro evidence suggests that apoE links to Aβ production through nanoscale lipid compartments (lipid clusters), but its regulation in vivo is unclear. Here, we use superresolution imaging in the mouse brain to show that apoE utilizes astrocyte-derived cholesterol to specifically traffic neuronal amyloid precursor protein (APP) in and out of lipid clusters, where it interacts with β- and γ-secretases to generate Aβpeptide. We find that the targeted deletion of astrocyte cholesterol synthesis robustly reduces amyloid and tau burden in a mouse model of AD. Treatment with cholesterol-free apoE or knockdown of cholesterol synthesis in astrocytes decreases cholesterol levels in cultured neurons and causes APP to traffic out of lipid clusters, where it interacts with α-secretase and gives rise to soluble APP-α (sAPP-α), a neuronal protective product of APP. Changes in cellular cholesterol have no effect on α-, β-, and γ-secretase trafficking, suggesting that the ratio of Aβ to sAPP-α is regulated by the trafficking of the substrate, not the enzymes. We conclude that cholesterol is kept low in neurons, which inhibits Aβ accumulation and enables the astrocyte regulation of Aβ accumulation by cholesterol signaling. © 2021 National Academy of Sciences. All rights reserved.

Author Keywords
Alzheimer’s;  ApoE;  Cholesterol;  Lipids;  Neurodegeneration

Funding details
AG047644, NS090934, T32DK764627
National Institutes of HealthNIHDP2NS087943, K08, K08DK097293, R01NS112534
Columbia University
JPB Foundation

Document Type: Article
Publication Stage: Final
Source: Scopus

A phase Ib/IIa clinical trial of dantrolene sodium in patients with Wolfram syndrome
(2021) JCI Insight, 6 (15), art. no. e145188, . 

Abreu, D.^a b , Stone, S.I.^c , Pearson, T.S.^d , Bucelli, R.C.^d , Simpson, A.N.^e , Hurst, S.^a , Brown, C.M.^a , Kries, K.^a , Onwumere, C.^a , Gu, H.^f , Hoekel, J.^g , Tychsen, L.^g , van Stavern, G.P.^g , White, N.H.^c , Marshall, B.A.^c , Hershey, T.^h , Urano, F.^a i

^a Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University, School of Medicine, St. Louis, MO, United States
^b Medical Scientist Training Program, Washington University, School of Medicine, St. Louis, MO, United States
^c Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University, School of Medicine, St. Louis, MO, United States
^d Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
^e Center for Clinical Studies, Washington University, School of Medicine, St. Louis, MO, United States
^f Division of Biostatistics, Washington University, School of Medicine, St. Louis, MO, United States
^g Department of Ophthalmology and Visual Sciences, Washington University, School of Medicine, St. Louis, MO, United States
^h Department of Psychiatry and Radiology, Washington University, School of Medicine, St. Louis, MO, United States
ⁱ Department of Pathology and Immunology, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND. Wolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial. METHODS. Based on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions. RESULTS. Dantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and isoprostane, were elevated in subjects. CONCLUSION. This study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome. Copyright: © 2021, Abreu et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Funding details
National Institutes of HealthNIH
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDKDK020579, DK112921, DK113487
Eli Lilly and Company
National Center for Advancing Translational SciencesNCATSF30DK111070, TR000448, TR002065
Institute of Clinical and Translational SciencesICTSUL1TR002345
Vanderbilt University Medical CenterVUMC

Document Type: Article
Publication Stage: Final
Source: Scopus

First in-human report of the clinical accuracy of thoracolumbar percutaneous pedicle screw placement using augmented reality guidance
(2021) Neurosurgical Focus, 51 (2), pp. 1-8. 

Yahanda, A.T.^a , Moore, E.^b , Ray, W.Z.^a , Pennicooke, B.^a , Jennings, J.W.^c , Molina, C.A.^a

^a Departments of Neurosurgery and Radiology, Washington University School of Medicine in St. LouisMissouri, United States
^b Wayne State University School of Medicine, Detroit, Michigan, United States
^c Radiology, Washington University School of Medicine in St. LouisMissouri, United States

Abstract
OBJECTIVE Augmented reality (AR) is an emerging technology that has great potential for guiding the safe and accurate placement of spinal hardware, including percutaneous pedicle screws. The goal of this study was to assess the accuracy of 63 percutaneous pedicle screws placed at a single institution using an AR head-mounted display (ARHMD) system. METHODS Retrospective analyses were performed for 9 patients who underwent thoracic and/or lumbar percutaneous pedicle screw placement guided by ARHMD technology. Clinical accuracy was assessed via the Gertzbein-Robbins scale by the authors and by an independent musculoskeletal radiologist. Thoracic pedicle subanalysis was also performed to assess screw accuracy based on pedicle morphology. RESULTS Nine patients received thoracic or lumbar AR-guided percutaneous pedicle screws. The mean age at the time of surgery was 71.9 ± 11.5 years and the mean number of screws per patient was 7. Indications for surgery were spinal tumors (n = 4, 44.4%), degenerative disease (n = 3, 33.3%), spinal deformity (n = 1, 11.1%), and a combination of deformity and infection (n = 1, 11.1%). Presenting symptoms were most commonly low-back pain (n = 7, 77.8%) and lower-extremity weakness (n = 5, 55.6%), followed by radicular lower-extremity pain, loss of lower-extremity sensation, or incontinence/urinary retention (n = 3 each, 33.3%). In all, 63 screws were placed (32 thoracic, 31 lumbar). The accuracy for these screws was 100% overall; all screws were Gertzbein-Robbins grade A or B (96.8% grade A, 3.2% grade B). This accuracy was achieved in the thoracic spine regardless of pedicle cancellous bone morphology. CONCLUSIONS AR-guided surgery demonstrated a 100% accuracy rate for the insertion of 63 percutaneous pedicle screws in 9 patients (100% rate of Gertzbein-Robbins grade A or B screw placement). Using an ARHMS system for the placement of percutaneous pedicle screws showed promise, but further validation using a larger cohort of patients across multiple surgeons and institutions will help to determine the true accuracy enabled by this technology. © AANS 2021

Author Keywords
augmented reality;  computer-assisted spine surgery;  mixed reality;  percutaneous pedicle screw;  spine navigation

Document Type: Article
Publication Stage: Final
Source: Scopus

Extradural decompression versus duraplasty in Chiari malformation type I with syrinx: Outcomes on scoliosis from the Park-Reeves Syringomyelia Research Consortium
(2021) Journal of Neurosurgery: Pediatrics, 28 (2), pp. 167-175.

Sadler, B.^a , Skidmore, A.^b , Gewirtz, J.^b , Anderson, R.C.E.^q , Haller, G.^b , Ackerman, L.L.^d , Adelson, P.D.^e , Ahmed, R.^f , Albert, G.W.^g , Aldana, P.R.^h , Alden, T.D.ⁱ , Averill, C.^b , Baird, L.C.^j , Bauer, D.F.^k , Bethel-Anderson, T.^b , Bierbrauer, K.S.^l , Bonfield, C.M.^aq , Brockmeyer, D.L.^m , Chern, J.J.ⁿ , Couture, D.E.^o , Daniels, D.J.^p , Dlouhy, B.J.^am , Durham, S.R.^r , Ellenbogen, R.G.^s , Eskandari, R.^t , Fuchs, H.E.^u , George, T.M.^v , Grant, G.A.^w , Graupman, P.C.^x , Greene, S.^y , Greenfield, J.P.^z , Gross, N.L.^aa , Guillaume, D.J.^ab , Hankinson, T.C.^ac , Heuer, G.G.^ad , Iantosca, M.^ae , Iskandar, B.J.^f , Jackson, E.M.^af , Jea, A.H.^d , Johnston, J.M.^ag , Keating, R.F.^ah , Khan, N.^aj , Krieger, M.D.^ak , Leonard, J.R.^al , Maher, C.O.^c , Mangano, F.T.^l , Mapstone, T.B.^aa , McComb, J.G.^ak , McEvoy, S.D.^b , Meehan, T.^b , Menezes, A.H.^am , Muhlbauer, M.^aj , Oakes, W.J.^ag , Olavarria, G.^an , O’Neill, B.R.^ac , Ragheb, J.^ao , Selden, N.R.^j , Shah, M.N.^ap , Shannon, C.N.^aq au , Smith, J.^d , Smyth, M.D.^b , Stone, S.S.D.^ar , Tuite, G.F.^as , Wait, S.D.^at , Wellons, J.C., III^aq au , Whitehead, W.E.^k , Park, T.S.^b , Limbrick, D.D., Jr.^a b , Strahle, J.M.^a b ai

^a Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Neurological Surgery, Washington University, School of Medicine, St. Louis, MO, United States
^c Department of Neurosurgery, University of Michigan, School of Medicine, Ann Arbor, MI, United States
^d Department of Neurological Surgery, Indiana University, School of Medicine, Indianapolis, IN, United States
^e Division of Pediatric Neurosurgery, Barrow Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ, United States
^f Department of Neurological Surgery, University of Wisconsin, Madison, WI, United States
^g Division of Neurosurgery, Arkansas Children’s Hospital, Little Rock, AR, United States
^h Division of Pediatric Neurosurgery, University of Florida, College of Medicine, Jacksonville, FL, United States
ⁱ Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children’s Hospital of ChicagoIL, United States
^j Department of Neurological Surgery, Doernbecher Children’s Hospital, Oregon Health and Science University, Portland, OR, United States
^k Division of Pediatric Neurosurgery, Texas Children’s Hospital, Houston, TX, United States
^l Division of Pediatric Neurosurgery, Cincinnati Children’s Medical Center, Cincinnati, OH, United States
^m Division of Pediatric Neurosurgery, Primary Children’s Hospital, Salt Lake City, UT, United States
ⁿ Division of Pediatric Neurosurgery, Children’s Healthcare of AtlantaGA, United States
^o Department of Neurological Surgery, Wake Forest University, School of Medicine, Winston-Salem, NC, United States
^p Department of Neurosurgery, Mayo Clinic, Rochester, MN, United States
^q Department of Neurosurgery, Columbia University, New York, NY, United States
^r Department of Neurosurgery, University of Vermont, Burlington, VT, United States
^s Division of Pediatric Neurosurgery, Seattle Children’s Hospital, Seattle, WA, United States
^t Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, United States
^u Department of Neurosurgery, Duke University, Durham, NC, United States
^v Division of Pediatric Neurosurgery, Dell Children’s Medical Center, Austin, TX, United States
^w Division of Pediatric Neurosurgery, Lucile Packard Children’s Hospital, Stanford University, School of Medicine, Palo Alto, CA, United States
^x Division of Pediatric Neurosurgery, Gillette Children’s Hospital, St. Paul, MN, United States
^y Division of Pediatric Neurosurgery, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
^z Department of Neurological Surgery, Weill Cornell Medical College, NewYork-Presbyterian Hospital, New York, NY, United States
^aa Department of Neurosurgery, University of Oklahoma, Oklahoma City, OK, United States
^ab Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN, United States
^ac Department of Neurosurgery, Children’s Hospital Colorado, Aurora, CO, United States
^ad Division of Pediatric Neurosurgery, Children’s Hospital of Pennsylvania, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^ae Department of Neurosurgery, Penn State Milton S. Hershey Medical Center, Hershey, PA, United States
^af Department of Neurosurgery, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
^ag Division of Pediatric Neurosurgery, University of Alabama, Birmingham, AL, United States
^ah Department of Neurosurgery, Children’s National Medical Center, Washington, DC, United States
^ai Department of Orthopedic Surgery, Washington University, School of Medicine, St. Louis, MO, United States
^aj Department of Neurosurgery, Le Bonheur Children’s Hospital, Memphis, TN, United States
^ak Department of Neurosurgery, Children’s Hospital, Los Angeles, CA, United States
^al Division of Pediatric Neurosurgery, Nationwide Children’s Hospital, Columbus, OH, United States
^am Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, United States
^an Division of Pediatric Neurosurgery, Arnold Palmer Hospital for Children, Orlando, FL, United States
^ao Department of Neurological Surgery, University of Miami, School of Medicine, Miami, FL, United States
^ap Division of Pediatric Neurosurgery, McGovern Medical School, Houston, TX, United States
^aq Division of Pediatric Neurosurgery, Monroe Carell Jr. Children’s Hospital of Vanderbilt University, Nashville, TN, United States
^ar Division of Pediatric Neurosurgery, Boston Children’s Hospital, Boston, MA, United States
^as Department of Neurosurgery, Neuroscience Institute, All Children’s Hospital, St. Petersburg, FL, United States
^at Carolina Neurosurgery and Spine Associates, Charlotte, NC, United States
^au Surgical Outcomes Center for Kids, Monroe Carell Jr. Children’s Hospital of Vanderbilt University, Nashville, TN, United States

Abstract
OBJECTIVE Scoliosis is common in patients with Chiari malformation type I (CM-I)-associated syringomyelia. While it is known that treatment with posterior fossa decompression (PFD) may reduce the progression of scoliosis, it is unknown if decompression with duraplasty is superior to extradural decompression. METHODS A large multicenter retrospective and prospective registry of 1257 pediatric patients with CM-I (tonsils ≥ 5 mm below the foramen magnum) and syrinx (≥ 3 mm in axial width) was reviewed for patients with scoliosis who underwent PFD with or without duraplasty. RESULTS In total, 422 patients who underwent PFD had a clinical diagnosis of scoliosis. Of these patients, 346 underwent duraplasty, 51 received extradural decompression alone, and 25 were excluded because no data were available on the type of PFD. The mean clinical follow-up was 2.6 years. Overall, there was no difference in subsequent occurrence of fusion or proportion of patients with curve progression between those with and those without a duraplasty. However, after controlling for age, sex, preoperative curve magnitude, syrinx length, syrinx width, and holocord syrinx, extradural decompression was associated with curve progression > 10°, but not increased occurrence of fusion. Older age at PFD and larger preoperative curve magnitude were independently associated with subsequent occurrence of fusion. Greater syrinx reduction after PFD of either type was associated with decreased occurrence of fusion. CONCLUSIONS In patients with CM-I, syrinx, and scoliosis undergoing PFD, there was no difference in subsequent occurrence of surgical correction of scoliosis between those receiving a duraplasty and those with an extradural decompression. However, after controlling for preoperative factors including age, syrinx characteristics, and curve magnitude, patients treated with duraplasty were less likely to have curve progression than patients treated with extradural decompression. Further study is needed to evaluate the role of duraplasty in curve stabilization after PFD. © AANS 2021, except where prohibited by US copyright law

Author Keywords
Chiari I malformation;  Posterior fossa decompression;  Scoliosis;  Spine;  Syringomyelia

Document Type: Article
Publication Stage: Final
Source: Scopus

Protein phosphatase 4 controls circadian clock dynamics by modulating CLOCK/BMAL1 activity
(2021) Genes and Development, 35 (15-16), pp. 1161-1174. Cited 1 time.

Klemz, S.^a , Wallach, T.^a , Korge, S.^a , Rosing, M.^b , Klemz, R.^a , Maier, B.^a , Fiorenza, N.C.^a , Kaymak, I.^a , Fritzsche, A.K.^a , Herzog, E.D.^c , Stanewsky, R.^b , Kramer, A.^a

^a Laboratory of Chronobiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt- Universität zu Berlin, Berlin, 10117, Germany
^b Institute of Neuro and Behavioral Biology, Westfälische Wilhelms University, Münster, 48149, Germany
^c Department of Biology, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
In all organisms with circadian clocks, post-translational modifications of clock proteins control the dynamics of circadian rhythms, with phosphorylation playing a dominant role. All major clock proteins are highly phosphorylated, and many kinases have been described to be responsible. In contrast, it is largely unclear whether and to what extent their counterparts, the phosphatases, play an equally crucial role. To investigate this, we performed a systematic RNAi screen in human cells and identified protein phosphatase 4 (PPP4) with its regulatory subunit PPP4R2 as critical components of the circadian system in both mammals and Drosophila. Genetic depletion of PPP4 shortens the circadian period, whereas overexpression lengthens it. PPP4 inhibits CLOCK/BMAL1 transactivation activity by binding to BMAL1 and counteracting its phosphorylation. This leads to increased CLOCK/BMAL1DNA occupancy and decreased transcriptional activity, which counteracts the “kamikaze” properties of CLOCK/BMAL1. Through this mechanism, PPP4 contributes to the critical delay of negative feedback by retarding PER/CRY/CK1δ- mediated inhibition of CLOCK/BMAL1. © 2021 Cold Spring Harbor Laboratory Press. All rights reserved.

Author Keywords
BMAL1;  Circadian clock;  Circadian rhythm;  CLOCK;  Phosphorylation;  Protein phosphatase 4

Funding details
Deutsche ForschungsgemeinschaftDFG278001972, SFB740, TRR186

Document Type: Article
Publication Stage: Final
Source: Scopus

Principal Component Analysis of Striatal and Extrastriatal D2 Dopamine Receptor Positron Emission Tomography in Manganese-Exposed Workers
(2021) Toxicological sciences : an official journal of the Society of Toxicology, 182 (1), pp. 132-141. 

Criswell, S.R.^a , Searles Nielsen, S.^a , Dlamini, W.W.^a , Warden, M.N.^a , Perlmutter, J.S.^{a b c d e} , Sheppard, L.^f g , Moerlein, S.M.^b h , Lenox-Krug, J.^a , Checkoway, H.^i j , Racette, B.A.^a k

^a Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, United States
^b Department of Radiology, Washington University School of Medicine, St Louis, MO 63110, United States
^c Department of Neuroscience, Washington University School of Medicine, St Louis, MO 63110, United States
^d Program in Physical Therapy, Washington University School of Medicine, St Louis, MO 63110, United States
^e Program in Occupational Therapy, Washington University School of Medicine, St Louis, MO 63110, United States
^f Department of Environmental and Occupational Health Sciences, University of Washington, School of Public Health, Seattle, WA 98195, United States
^g Department of Biostatistics, University of Washington, School of Public Health, Seattle, WA 98195, United States
^h Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO 63110, United States
ⁱ Department of Family Medicine and Public Health, University of California, School of Medicine, La Jolla, San Diego, CA 92093, United States
^j Department of Neurosciences, University of California, School of Medicine, La Jolla, San Diego, CA 92093, United States
^k School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, South Africa

Abstract
The relationships between the neurotoxicant manganese (Mn), dopaminergic pathology, and parkinsonism remain unclear. Therefore, we used [11C](N-methyl)benperidol (NMB) positron emission tomography to investigate the associations between Mn exposure, striatal and extrastriatal D2 dopamine receptors (D2R), and motor function in 54 workers with a range of Mn exposure. Cumulative Mn exposure was estimated from work histories, and all workers were examined by a movement specialist and completed a Grooved Pegboard test (GPT). NMB D2R nondisplaceable binding potentials (BPND) were calculated for brain regions of interest. We identified 2 principal components (PCs) in a PC analysis which explained 66.8% of the regional NMB BPND variance (PC1 = 55.4%; PC2 = 11.4%). PC1 was positively correlated with NMB binding in all regions and inversely correlated with age. PC2 was driven by NMB binding in 7 brain regions (all p < .05), positively in the substantia nigra, thalamus, amygdala, and medial orbital frontal gyrus and negatively in the nucleus accumbens, anterior putamen, and caudate. PC2 was associated with both Mn exposure status and exposure duration (years). In addition, PC2 was associated with higher Unified Parkinson’s Disease Rating Scale motor subsection 3 (UPDRS3) scores and slower GPT performance. We conclude Mn exposure is associated with both striatal and extrastriatal D2R binding. Multifocal alterations in D2R expression are also associated with motor dysfunction as measured by both the GPT and UPDRS3, demonstrating a link between Mn exposure, striatal and extrastriatal D2R expression, and clinical neurotoxicity. © The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology.All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
D2 receptors;  manganese;  PCA;  PET

Document Type: Article
Publication Stage: Final
Source: Scopus

Temporal Correlation of CSF and Neuroimaging in the Amyloid-Tau-Neurodegeneration Model of Alzheimer Disease
(2021) Neurology, 97 (1), pp. e76-e87. 

Boerwinkle, A.H., Wisch, J.K., Chen, C.D., Gordon, B.A., Butt, O.H., Schindler, S.E., Sutphen, C., Flores, S., Dincer, A., Benzinger, T.L.S., Fagan, A.M., Morris, J.C., Ances, B.M.

From the Departments of Neurology (A.H.B., J.K.W., O.H.B., S.E.S., C.S., A.M.F., J.C.M., B.M.A.) and Radiology (C.D.C., B.A.G., S.F., A.D., T.L.S.B.), Washington University in St. Louis, MO

Abstract
OBJECTIVE: To evaluate temporal correlations between CSF and neuroimaging (PET and MRI) measures of amyloid, tau, and neurodegeneration in relation to Alzheimer disease (AD) progression. METHODS: A total of 371 cognitively unimpaired and impaired participants enrolled in longitudinal studies of AD had both CSF (β-amyloid [Aβ]42, phosphorylated tau181, total tau, and neurofilament light chain) and neuroimaging (Pittsburgh compound B [PiB] PET, flortaucipir PET, and structural MRI) measures. The pairwise time interval between CSF and neuroimaging measures was binned into 2-year periods. Spearman correlations identified the time bin when CSF and neuroimaging measures most strongly correlated. CSF and neuroimaging measures were then binarized as biomarker-positive or biomarker-negative using Gaussian mixture modeling. Cohen kappa coefficient identified the time bin when CSF measures best agreed with corresponding neuroimaging measures when determining amyloid, tau, and neurodegeneration biomarker positivity. RESULTS: CSF Aβ42 and PiB PET showed maximal correlation when collected within 6 years of each other (R ≈ -0.5). CSF phosphorylated tau181 and flortaucipir PET showed maximal correlation when CSF was collected 4 to 8 years prior to PET (R ≈ 0.4). CSF neurofilament light chain and cortical thickness showed low correlation, regardless of time interval (Ravg ≈ -0.3). Similarly, CSF total tau and cortical thickness had low correlation, regardless of time interval (Ravg < -0.2). CONCLUSIONS: CSF Aβ42 and PiB PET best agree when acquired in close temporal proximity, whereas CSF phosphorylated tau precedes flortaucipir PET by 4 to 8 years. CSF and neuroimaging measures of neurodegeneration have low correspondence and are not interchangeable at any time interval. © 2021 American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus

Spinal V1 neurons inhibit motor targets locally and sensory targets distally
(2021) Current Biology, . 

Sengupta, M.^a , Daliparthi, V.^a , Roussel, Y.^b c , Bui, T.V.^b , Bagnall, M.W.^a

^a Washington University School of Medicine, Department of Neuroscience, St. Louis, MO, United States
^b Brain and Mind Research Institute, Centre for Neural Dynamics, Department of Biology, University of Ottawa, Ottawa, Canada
^c Blue Brain Project, École Polytechnique Fédérale de Lausanne, Geneve, Switzerland

Abstract
Rostro-caudal coordination of spinal motor output is essential for locomotion. Most spinal interneurons project axons longitudinally to govern locomotor output, yet their connectivity along this axis remains unclear. In this study, we use larval zebrafish to map synaptic outputs of a major inhibitory population, V1 (Eng1+) neurons, which are implicated in dual sensory and motor functions. We find that V1 neurons exhibit long axons extending rostrally and exclusively ipsilaterally for an average of 6 spinal segments; however, they do not connect uniformly with their post-synaptic targets along the entire length of their axon. Locally, V1 neurons inhibit motor neurons (both fast and slow) and other premotor targets, including V2a, V2b, and commissural premotor neurons. In contrast, V1 neurons make robust long-range inhibitory contacts onto a dorsal horn sensory population, the commissural primary ascending neurons (CoPAs). In a computational model of the ipsilateral spinal network, we show that this pattern of short-range V1 inhibition to motor and premotor neurons underlies burst termination, which is critical for coordinated rostro-caudal propagation of the locomotor wave. We conclude that spinal network architecture in the longitudinal axis can vary dramatically, with differentially targeted local and distal connections, yielding important consequences for function. © 2021 Elsevier Inc.

Author Keywords
differential connectivity;  motor;  rostro-caudal coordination;  spinal cord;  zebrafish

Funding details
CDI-CORE-2015-505, CDI-CORE-2019-813
McKnight Foundation
Foundation for Barnes-Jewish Hospital3770, 4642, R01 DC016413

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