List of publications for the week of May 3, 2021
White matter microstructure associations with episodic memory in adults with Down syndrome: a tract-based spatial statistics study
(2021) Journal of Neurodevelopmental Disorders, 13 (1), art. no. 17, .
Bazydlo, A.a , Zammit, M.a , Wu, M.b , Dean, D.a c , Johnson, S.a c d , Tudorascu, D.b , Cohen, A.b , Cody, K.a , Ances, B.e , Laymon, C.b , Klunk, W.b , Zaman, S.f , Handen, B.b , Alexander, A.a d , Christian, B.a c d , Hartley, S.d g
a School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
b University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
c Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison, Madison, WI, United States
d Waisman Center, University of Wisconsin-Madison, Madison, WI, United States
e Washington University of St. Louis, St. Louis, MO, United States
f Cambridge Intellectual and Developmental Disabilities Research Group, University of Cambridge, Cambridge, United Kingdom
g School of Human Ecology, University of Wisconsin-Madison, Madison, WI, United States
Abstract
Background: Nearly all persons with Down syndrome will show pathology of Alzheimer’s disease in their 40s. There is a critical need for studies to identify early biomarkers of these various pathological changes of Alzheimer’s disease in the Down syndrome population and understand the relationship of these biomarkers to cognitive symptoms in order to inform clinical trials. Although Alzheimer’s disease is often considered a disease of gray matter, white matter degeneration has been documented during the preclinical stage of Alzheimer’s disease. The current study examined the association between diffusion tensor imaging (DTI) measures of white matter microstructure and episodic memory performance in 52 adults with Down syndrome. Methods: Seventy (N = 70) participants (M = 40.13, SD = 7.77 years) received baseline scans as part of the Neurodegeneration in Aging Down Syndrome (NiAD) study at two imaging facilities (36 at the University of Wisconsin-Madison [UW-Madison] and 34 at the University of Pittsburgh Medical Center [UPMC]). All participants had genetically confirmed trisomy 21. Fifty-two (N = 52) participants remained after QC. The DTI measures, fractional anisotropy (FA) and mean diffusivity (MD), were calculated for each participant. A combined measure of episodic memory was generated by summing the z-scores of (1) Free and Cued Recall test and (2) Rivermead Behavioural Memory Test for Children Picture Recognition. The DTI data were projected onto a population-derived FA skeleton and tract-based spatial statistics analysis was conducted using the FSL tool PALM to calculate Pearson’s r values between FA and MD with episodic memory. Results: A positive correlation of episodic memory with FA and a negative correlation of episodic memory and MD in the major association white matter tracts were observed. Results were significant (p < 0.05) after correction for chronological age, imaging site, and premorbid cognitive ability. Conclusion: These findings suggest that white matter degeneration may be implicated in early episodic memory declines prior to the onset of dementia in adults with Down syndrome. Further, our findings suggest a coupling of episodic memory and white matter microstructure independent of chronological age. © 2021, The Author(s).
Funding details
National Institutes of HealthNIHR01AG031110, T32CA009206, U01AG0514, U19 AG070043
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDU54 HD090256
Document Type: Article
Publication Stage: Final
Source: Scopus
Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice
(2021) Nature Communications, 12 (1), art. no. 2238, .
Caballero, B.a b k , Bourdenx, M.a b l , Luengo, E.a b c d , Diaz, A.a b , Sohn, P.D.e , Chen, X.e , Wang, C.e , Juste, Y.R.a b , Wegmann, S.f g , Patel, B.a b , Young, Z.T.h , Kuo, S.Y.h , Rodriguez-Navarro, J.A.a b m , Shao, H.h , Lopez, M.G.c d , Karch, C.M.i , Goate, A.M.j , Gestwicki, J.E.h , Hyman, B.T.f , Gan, L.e , Cuervo, A.M.a b
a Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, United States
b Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, United States
c Institute Teofilo Hernando for Drug Discovery, Department of Pharmacology, School of Medicine, Universidad Autonoma de Madrid, Madrid, Spain
d Instituto de Investigación Biosanitaria Hospital de la Princesa, Madrid, Spain
e Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY, United States
f Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
g German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany
h Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, CA, United States
i Department of Psychiatry, Washington University, St. Louis, MO, United States
j Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
k Roche Chile Pharmaceuticals, Las Condes, Region Metropolitana, Chile
l Institut des Maladies Neurodégénératives, CNRS, Université de Bordeaux, Bordeaux, France
m Instituto Ramón y Cajal de Investigaciones Sanitarias Hospital Ramón y Cajal, Madrid, Spain
Abstract
Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release. In fact, experimental blockage of CMA enhances cell-to-cell propagation of pathogenic tau in a mouse model of tauopathy. Furthermore, analysis of lysosomes isolated from brains of patients with tauopathies demonstrates similar molecular mechanisms leading to CMA dysfunction. This study reveals that CMA failure in tauopathy brains alters tau homeostasis and could contribute to aggravate disease progression. © 2021, The Author(s).
Funding details
B2017/BMD-3827–NRF24ADCM
RTI2018-095793-B-I00
National Institutes of HealthNIHAG046374, T32 GM007491
National Institute on AgingNIAAG021904, AG031782, AG036884, AG038072, AG054108, AG05681, AG058674
National Institute of Neurological Disorders and StrokeNINDSNS100717
Charles H. Revson FoundationCP13-00234
JPB Foundation
Rainwater Charitable FoundationRCF
Fundación Tatiana Pérez de Guzmán el Bueno
Document Type: Article
Publication Stage: Final
Source: Scopus
The Dystonia Coalition: A Multicenter Network for Clinical and Translational Studies
(2021) Frontiers in Neurology, 12, art. no. 660909, .
Kilic-Berkmen, G.a , Wright, L.J.b , Perlmutter, J.S.c , Comella, C.d , Hallett, M.e , Teller, J.f , Pirio Richardson, S.g , Peterson, D.A.h , Cruchaga, C.i , Lungu, C.j , Jinnah, H.A.a k
a Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Radiology, Neuroscience, Physical, Therapy and Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
e Human Motor Control Section, National Institute of Neurological, Disorders and Stroke (NINDS), National Institute of Health (NIH), Bethesda, MD, United States
f Dystonia Medical Research Foundation, Chicago, IL, United States
g Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
h Institute for Neural Computation, University of California, San Diego, La Jolla, CA, United States
i Department of Psychiatry, Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, MO, United States
j Division of Clinical Research, National Institute of Neurological, Disorders and Stroke (NINDS), National Institute of Health (NIH), Bethesda, MD, United States
k Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States
Abstract
Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal postures, repetitive movements, or both. Research in dystonia has been challenged by several factors. First, dystonia is uncommon. Dystonia is not a single disorder but a family of heterogenous disorders with varied clinical manifestations and different causes. The different subtypes may be seen by providers in different clinical specialties including neurology, ophthalmology, otolaryngology, and others. These issues have made it difficult for any single center to recruit large numbers of subjects with specific types of dystonia for research studies in a timely manner. The Dystonia Coalition is a consortium of investigators that was established to address these challenges. Since 2009, the Dystonia Coalition has encouraged collaboration by engaging 56 sites across North America, Europe, Asia, and Australia. Its emphasis on collaboration has facilitated establishment of international consensus for the definition and classification of all dystonias, diagnostic criteria for specific subtypes of dystonia, standardized evaluation strategies, development of clinimetrically sound measurement tools, and large multicenter studies that document the phenotypic heterogeneity and evolution of specific types of dystonia. © Copyright © 2021 Kilic-Berkmen, Wright, Perlmutter, Comella, Hallett, Teller, Pirio Richardson, Peterson, Cruchaga, Lungu and Jinnah.
Author Keywords
blepharospasm; cervical dystonia; dystonia; laryngeal dystonia; rare diseases; spasmodic dysphonia; torticollis; writer’s cramp
Funding details
National Institutes of HealthNIHNS065701, NS116025, TR001456
National Institute of Neurological Disorders and StrokeNINDS
National Center for Advancing Translational SciencesNCATS
Dystonia Coalition
Document Type: Review
Publication Stage: Final
Source: Scopus
Neuroskeletal Effects of Chronic Bioelectric Nerve Stimulation in Health and Diabetes
(2021) Frontiers in Neuroscience, 15, art. no. 632768, .
Beeve, A.T.a b , Shen, I.b , Zhang, X.a b , Magee, K.b , Yan, Y.c , MacEwan, M.R.c , Scheller, E.L.a b
a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
b Department of Internal Medicine, Division of Bone and Mineral Diseases, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
c Department of Neurosurgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
Abstract
Background/Aims: Bioelectric nerve stimulation (eStim) is an emerging clinical paradigm that can promote nerve regeneration after trauma, including within the context of diabetes. However, its ability to prevent the onset of diabetic peripheral neuropathy (DPN) has not yet been evaluated. Beyond the nerve itself, DPN has emerged as a potential contributor to sarcopenia and bone disease; thus, we hypothesized that eStim could serve as a strategy to simultaneously promote neural and musculoskeletal health in diabetes. Methods: To address this question, an eStim paradigm pre-optimized to promote nerve regeneration was applied to the sciatic nerve, which directly innervates the tibia and lower limb, for 8 weeks in control and streptozotocin-induced type 1 diabetic (T1D) rats. Metabolic, gait, nerve and bone assessments were used to evaluate the progression of diabetes and the effect of sciatic nerve eStim on neuropathy and musculoskeletal disease, while also considering the effects of cuff placement and chronic eStim in otherwise healthy animals. Results: Rats with T1D exhibited increased mechanical allodynia in the hindpaw, reduced muscle mass, decreased cortical and cancellous bone volume fraction (BVF), reduced cortical bone tissue mineral density (TMD), and decreased bone marrow adiposity. Type 1 diabetes also had an independent effect on gait. Placement of the cuff electrode alone resulted in altered gait patterns and unilateral reductions in tibia length, cortical BVF, and bone marrow adiposity. Alterations in gait patterns were restored by eStim and tibial lengthening was favored unilaterally; however, eStim did not prevent T1D-induced changes in muscle, bone, marrow adiposity or mechanical sensitivity. Beyond this, chronic eStim resulted in an independent, bilateral reduction in cortical TMD. Conclusion: Overall, these results provide new insight into the pathogenesis of diabetic neuroskeletal disease and its regulation by eStim. Though eStim did not prevent neural or musculoskeletal complications in T1D, our results demonstrate that clinical applications of peripheral neuromodulation ought to consider the impact of device placement and eStim on long-term skeletal health in both healthy individuals and those with metabolic disease. This includes monitoring for compounded bone loss to prevent unintended consequences including decreased bone mineral density and increased fracture risk. © Copyright © 2021 Beeve, Shen, Zhang, Magee, Yan, MacEwan and Scheller.
Author Keywords
bone; bone marrow adiposity; electrical stimulation; gait; muscle; nerves; neuropathy; type 1 diabetes (T1D)
Funding details
National Institutes of HealthNIHP30-AR074992, S10-RR0227552, T32-AR060719, U01-DK116317
Document Type: Article
Publication Stage: Final
Source: Scopus
Role of sirt1 in isoflurane conditioning‐induced neurovascular protection against delayed cerebral ischemia secondary to subarachnoid hemorrhage
(2021) International Journal of Molecular Sciences, 22 (8), art. no. 4291, .
Liu, M.a , Jayaraman, K.a , Giri, T.a , Zipfel, G.J.b , Athiraman, U.a
a Department of Anesthesiology, Washington University in Saint Louis, Saint Louis, MO 63110, United States
b Department of Neurological Surgery, Washington University in Saint Louis, Saint Louis, MO 63110, United States
Abstract
We recently reported that isoflurane conditioning provided multifaceted protection against subarachnoid hemorrhage (SAH)‐induced delayed cerebral ischemia (DCI), and this protection was through the upregulation of endothelial nitric oxide synthase (eNOS). SIRT1, an NAD‐dependent deacetylase, was shown to be one of the critical regulators of eNOS. The aim of our current study is to examine the role of SIRT1 in isoflurane conditioning‐induced neurovascular protection against SAH‐induced DCI. Mice were divided into four groups: sham, SAH, or SAH with isoflurane conditioning (with and without EX‐527). Experimental SAH via endovascular perforation was performed. Anesthetic conditioning was performed with isoflurane 2% for 1 h, 1 h after SAH. EX‐527, a selective SIRT1 inhibitor, 10 mg/kg was injected intraperitoneally immediately after SAH in the EX‐527 group. SIRT1 mRNA expression and activity levels were measured. Vasospasm, microvessel thrombosis, and neurological outcome were assessed. SIRT1 mRNA expression was downregulated, and no difference in SIRT1 activity was noted after isoflurane exposure. Isoflurane conditioning with and without EX‐527 attenuated vasospasm, microvessel thrombosis and improved neurological outcomes. Our data validate our previous findings that isoflurane conditioning provides strong protection against both the macro and micro vascular deficits induced by SAH, but this protection is likely not mediated through the SIRT1 pathway. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Author Keywords
Aneurysmal subarachnoid hemorrhage; Delayed cerebral ischemia; Isoflurane conditioning; SIRT1
Funding details
National Institutes of HealthNIHR01 NS091603
Brain Aneurysm FoundationBAF
Document Type: Article
Publication Stage: Final
Source: Scopus
Resting-State Functional Connectivity Disruption as a Pathological Biomarker in Autosomal Dominant Alzheimer Disease
(2021) Brain Connectivity, 11 (3), pp. 239-249.
Smith, R.X.a , Strain, J.F.a , Tanenbaum, A.a , Fagan, A.M.a d , Hassenstab, J.a , McDade, E.a , Schindler, S.E.a , Gordon, B.A.b d , Xiong, C.c , Chhatwal, J.e , Jack, C.f , Karch, C.d g , Berman, S.h , Brosch, J.R.i , Lah, J.J.j , Brickman, A.M.k , Cash, D.M.l , Fox, N.C.l , Graff-Radford, N.R.m , Levin, J.n , Noble, J.k , Holtzman, D.M.a d , Masters, C.L.o , Farlow, M.R.i , Laske, C.p , Schofield, P.R.q , Marcus, D.S.b , Morris, J.C.a d , Benzinger, T.L.S.b d , Bateman, R.J.a d , Ances, B.M.a d
a Department of Neurology, Washington University in Saint Louis, St. Louis, MO, United States
b Department of Radiology, Washington University in Saint Louis, St. Louis, MO, United States
c Department of Biostatistics, Washington University in Saint Louis, St. Louis, MO, United States
d Hope Center for Neurological Disorders, Knight Adrc, Washington University, St. Louis, MO, United States
e Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
f Department of Radiology, Mayo Clinic, Rochester, MN, United States
g Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
h Department of Neurology, University of Pittsburgh, Pittsburgh, PA, United States
i Department of Neurology, Indiana University, Indianapolis, IN, United States
j Department of Neurology, Emory University, Atlanta, GA, United States
k Department of Neurology, Columbia University, New York, NY, United States
l Department of Neurodegenerative Disease, Dementia Research Centre, Institute of Neurology, University College London, London, United Kingdom
m Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
n German Center for Neurodegenerative Disease (DZNE) Munich, Munich, Germany
o The Florey Institute, University of Melbourne, Parkvile, Australia
p Eberhard Karls University of Tubingen, Tubingen, Germany
q Neuroscience Research Australia and School of Medical Sciences, The University of New South Wales (UNSW) Sydney, Sydney, Australia
Abstract
Aim: Identify a global resting-state functional connectivity (gFC) signature in mutation carriers (MC) from the Dominantly Inherited Alzheimer Network (DIAN). Assess the gFC with regard to amyloid (A), tau (T), and neurodegeneration (N) biomarkers, and estimated years to symptom onset (EYO). Introduction: Cross-sectional measures were assessed in MC (n = 171) and mutation noncarrier (NC) (n = 70) participants. A functional connectivity (FC) matrix that encompassed multiple resting-state networks was computed for each participant. Methods: A global FC was compiled as a single index indicating FC strength. The gFC signature was modeled as a nonlinear function of EYO. The gFC was linearly associated with other biomarkers used for assessing the AT(N) framework, including cerebrospinal fluid (CSF), positron emission tomography (PET) molecular biomarkers, and structural magnetic resonance imaging. Results: The gFC was reduced in MC compared with NC participants. When MC participants were differentiated by clinical dementia rating (CDR), the gFC was significantly decreased in MC CDR >0 (demented) compared with either MC CDR 0 (cognitively normal) or NC participants. The gFC varied nonlinearly with EYO and initially decreased at EYO =-24 years, followed by a stable period followed by a further decline near EYO = 0 years. Irrespective of EYO, a lower gFC associated with values of amyloid PET, CSF Aβ1-42, CSF p-tau, CSF t-tau, 18F-fluorodeoxyglucose, and hippocampal volume. Conclusions: The gFC correlated with biomarkers used for defining the AT(N) framework. A biphasic change in the gFC suggested early changes associated with CSF amyloid and later changes associated with hippocampal volume. © Copyright 2021, Mary Ann Liebert, Inc.
Author Keywords
18F-fluorodeoxyglucose (FDG); amyloid; autosomal dominant Alzheimer disease; cerebrospinal fluid (CSF); estimated years to onset (EYO); hippocampus; positron emission tomography (PET); resting-state functional connectivity; tau
Document Type: Article
Publication Stage: Final
Source: Scopus
Is presymptomatic ALS perivascular?
(2021) Nature Medicine, 27 (4), pp. 585-586.
Kreple, C.J., Schoch, K.M., Miller, T.M.
Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, United States
Document Type: Note
Publication Stage: Final
Source: Scopus
Low-dose interleukin-2 and regulatory T cell treatments attenuate punctate and dynamic mechanical allodynia in a mouse model of sciatic nerve injury
(2021) Journal of Pain Research, 14, pp. 893-906.
Hu, R.a b c , Zhang, J.a b d , Liu, X.a b , Huang, D.c , Cao, Y.-Q.a b
a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
b Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, United States
c Department of Pain Management, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
d Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Abstract
Purpose: Nerve injury-induced mechanical hyper-sensitivity, in particular stroking-induced dynamic allodynia, is highly debilitating and difficult to treat. Previous studies indicate that the immunosuppressive regulatory T (Treg) cells modulate the magnitude of punctate mechanical allodynia resulting from sciatic nerve injury. However, whether enhancing Treg-mediated suppression attenuates dynamic allodynia is not known. In the present study, we addressed this knowledge gap by treating mice with low-dose interleukin-2 (ld-IL2) injections or adoptive transfer of Treg cells. Methods: Female Swiss Webster mice received daily injections of ld-IL2 (1 μg/mouse, intraper-itoneally) either before or after unilateral spared nerve injury (SNI). Male C57BL/6J mice received adoptive transfer of 1 x 106 Treg cells 3 weeks post-SNI. The responses to punctate and dynamic mechanical stimuli on the hindpaw were monitored before and up to 4–6 weeks post-SNI. We also compared the distribution of Treg cells and CD3+ total T cells after SNI and/or ld-IL2 treatment. Results: Ld-IL2 pretreatment in female Swiss Webster mice completely blocked the development of SNI-induced dynamic mechanical allodynia and reduced the magnitude of punc-tate allodynia. Delayed ld-IL2 treatment in female mice significantly attenuated the morphine-resistant punctate and dynamic allodynia at 3–5 weeks post-SNI. Adoptive transfer of Treg cells to male C57BL/6J mice 3 weeks post-SNI effectively reversed the persistent punctate and dynamic allodynia, supporting that the effect of ld-IL2 is mediated through endogenous Treg cells, and is likely independent of mouse strain and sex. Neither ld-IL2 treatment nor Treg transfer affected the basal responses to punctate or brush stimuli. Ld-IL2 significantly increased the frequency of Treg cells among total CD3+ T cells in the injured sciatic nerves but not in the uninjured nerves or the dorsal root ganglia, suggesting the injured nerve as ld-IL2’s site of action. Conclusion: Collectively, results from the present study supports Treg as a cellular target and ld-IL2 as a potential therapeutic option for nerve injury-induced persistent punctate and dynamic mechanical allodynia. © 2021 Hu et al.
Author Keywords
Chronic pain; Dynamic allodynia; Low-dose interleukin-2; Punctate allodynia; Regulatory T cell; Spared nerve injury
Funding details
National Institutes of Health NIH NS103350-02S1
Document Type: Article
Publication Stage: Final
Source: Scopus