Hope Center member publications

Substrate reduction therapy for Krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor
(2021) Scientific Reports, 11 (1), art. no. 14486, . 

Babcock, M.C.^a , Mikulka, C.R.^b , Wang, B.^a , Chandriani, S.^a , Chandra, S.^a , Xu, Y.^a , Webster, K.^a , Feng, Y.^a , Nelvagal, H.R.^d , Giaramita, A.^a , Yip, B.K.^a , Lo, M.^a , Jiang, X.^b , Chao, Q.^a , Woloszynek, J.C.^a , Shen, Y.^a , Bhagwat, S.^a , Sands, M.S.^b c , Crawford, B.E.^a

^a BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, United States
^b Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Krabbe disease (KD) and metachromatic leukodystrophy (MLD) are caused by accumulation of the glycolipids galactosylceramide (GalCer) and sulfatide and their toxic metabolites psychosine and lysosulfatide, respectively. We discovered a potent and selective small molecule inhibitor (S202) of ceramide galactosyltransferase (CGT), the key enzyme for GalCer biosynthesis, and characterized its use as substrate reduction therapy (SRT). Treating a KD mouse model with S202 dose-dependently reduced GalCer and psychosine in the central (CNS) and peripheral (PNS) nervous systems and significantly increased lifespan. Similarly, treating an MLD mouse model decreased sulfatides and lysosulfatide levels. Interestingly, lower doses of S202 partially inhibited CGT and selectively reduced synthesis of non-hydroxylated forms of GalCer and sulfatide, which appear to be the primary source of psychosine and lysosulfatide. Higher doses of S202 more completely inhibited CGT and reduced the levels of both non-hydroxylated and hydroxylated forms of GalCer and sulfatide. Despite the significant benefits observed in murine models of KD and MLD, chronic CGT inhibition negatively impacted both the CNS and PNS of wild-type mice. Therefore, further studies are necessary to elucidate the full therapeutic potential of CGT inhibition. © 2021, The Author(s).

Funding details
National Institutes of HealthNIHR01 NS100779
Office of Extramural Research, National Institutes of HealthOER
BioMarin Pharmaceutical
Office of Research Infrastructure Programs, National Institutes of HealthORIP, NIH, NIH-ORIP, ORIP

Document Type: Article
Publication Stage: Final
Source: Scopus

Transcriptional-regulatory convergence across functional MDD risk variants identified by massively parallel reporter assays
(2021) Translational Psychiatry, 11 (1), art. no. 403, . 

Mulvey, B., Dougherty, J.D.

Departments of Genetics and Psychiatry, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Family and population studies indicate clear heritability of major depressive disorder (MDD), though its underlying biology remains unclear. The majority of single-nucleotide polymorphism (SNP) linkage blocks associated with MDD by genome-wide association studies (GWASes) are believed to alter transcriptional regulators (e.g., enhancers, promoters) based on enrichment of marks correlated with these functions. A key to understanding MDD pathophysiology will be elucidation of which SNPs are functional and how such functional variants biologically converge to elicit the disease. Furthermore, retinoids can elicit MDD in patients and promote depressive-like behaviors in rodent models, acting via a regulatory system of retinoid receptor transcription factors (TFs). We therefore sought to simultaneously identify functional genetic variants and assess retinoid pathway regulation of MDD risk loci. Using Massively Parallel Reporter Assays (MPRAs), we functionally screened over 1000 SNPs prioritized from 39 neuropsychiatric trait/disease GWAS loci, selecting SNPs based on overlap with predicted regulatory features—including expression quantitative trait loci (eQTL) and histone marks—from human brains and cell cultures. We identified >100 SNPs with allelic effects on expression in a retinoid-responsive model system. Functional SNPs were enriched for binding sequences of retinoic acid-receptive transcription factors (TFs), with additional allelic differences unmasked by treatment with all-trans retinoic acid (ATRA). Finally, motifs overrepresented across functional SNPs corresponded to TFs highly specific to serotonergic neurons, suggesting an in vivo site of action. Our application of MPRAs to screen MDD-associated SNPs suggests a shared transcriptional-regulatory program across loci, a component of which is unmasked by retinoids. © 2021, The Author(s).

Funding details
National Institutes of HealthNIH
National Institute of Mental HealthNIMH1F30MH1116654, 1R01MH116999
Simons FoundationSF571009, TR002345

Document Type: Article
Publication Stage: Final
Source: Scopus

A multicenter retrospective study of heterogeneous tissue aggregates obstructing ventricular catheters explanted from patients with hydrocephalus
(2021) Fluids and Barriers of the CNS, 18 (1), art. no. 33, . 

Hariharan, P.^a , Sondheimer, J.^b , Petroj, A.^b , Gluski, J.^c , Jea, A.^d , Whitehead, W.E.^e , Sood, S.^f , Ham, S.D.^f , Rocque, B.G.^g , Marupudi, N.I.^h , McAllister, J.P., IIⁱ , Limbrick, D.^j , Del Bigio, M.R.^k , Harris, C.A.^b

^a Wayne State University Dept. of Biomedical Engineering, 6135 Woodward Avenue, Detroit, MI 48202, United States
^b Wayne State University Dept. of Chemical Engineering and Materials Science, 6135 Woodward Avenue, Detroit, MI 48202, United States
^c Dept. of Neurosurgery, Wayne State University School of Medicine, 540 E. Canfield Avenue, Detroit, MI 48201, United States
^d Riley Hospital for Children at IU Health, 705 Riley Hospital Drive, Indianapolis, IN 46202, United States
^e Texas Children’s, 6701 Fannin Street, Suite 1230.01, Houston, TX, United States
^f Departments of Neurosurgery and Pediatric Neurosurgery, Wayne State University School of Medicine and Children’s Hospital of Michigan, 3901 Beaubien Boulevard, 2nd Floor Carl’s Building, Detroit, MI 48201, United States
^g Department of Neurosurgery, University of Alabama At Birmingham, Birmingham, AL, United States
^h Children’s Hospital of Michigan Dept. of Neurosurgery, 3901 Beaubien Boulevard, 2nd Floor Carl’s Building, Detroit, MI 48201, United States
ⁱ School of Medicine Dept. of Neurological Surgery, Washington University, 425 S. Euclid Avenue, St. Louis, MO 63110, United States
^j School of Medicine Dept. of Neurological Surgery, Washington University, 660 S. Euclid Avenue, St. Louis, MO 6311, United States
^k Department of Pathology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada

Abstract
Background: Implantation of ventricular catheters (VCs) to drain cerebrospinal fluid (CSF) is a standard approach to treat hydrocephalus. VCs fail frequently due to tissue obstructing the lumen via the drainage holes. Mechanisms driving obstruction are poorly understood. This study aimed to characterize the histological features of VC obstructions and identify links to clinical factors. Methods: 343 VCs with relevant clinical data were collected from five centers. Each hole on the VCs was classified by degree of tissue obstruction after macroscopic analysis. A subgroup of 54 samples was analyzed using immunofluorescent labelling, histology and immunohistochemistry. Results: 61.5% of the 343 VCs analyzed had tissue aggregates occluding at least one hole (n = 211) however the vast majority of the holes (70%) showed no tissue aggregates. Mean age at which patients with occluded VCs had their first surgeries (3.25 yrs) was lower than in patients with non-occluded VCs (5.29 yrs, p < 0.02). Mean length of time of implantation of occluded VCs, 33.22 months was greater than for non-occluded VCs, 23.8 months (p = 0.02). Patients with myelomeningocele had a greater probability of having an occluded VC (p = 0.0426). VCs with occlusions had greater numbers of macrophages and astrocytes in comparison to non-occluded VCs (p < 0.01). Microglia comprised only 2–6% of the VC-obstructing tissue aggregates. Histologic analysis showed choroid plexus occlusion in 24%, vascularized glial tissue occlusion in 24%, prevalent lymphocytic inflammation in 29%, and foreign body giant cell reactions in 5% and no ependyma. Conclusion: Our data show that age of the first surgery and length of time a VC is implanted are factors that influence the degree of VC obstruction. The tissue aggregates obstructing VCs are composed predominantly of astrocytes and macrophages; microglia have a relatively small presence. © 2021, The Author(s).

Author Keywords
Biobank;  Hydrocephalus;  Multicenter;  Retrospective cohort;  Shunt failure;  Shunt obstruction;  Surgical outcomes;  Ventriculoperitoneal shunt

Funding details
National Institutes of HealthNIHR01NS094570
National Institute of Neurological Disorders and StrokeNINDS

Document Type: Article
Publication Stage: Final
Source: Scopus

Genome-wide chromatin accessibility analyses provide a map for enhancing optic nerve regeneration
(2021) Scientific Reports, 11 (1), art. no. 14924, . 

Pita-Thomas, W.^a , Gonçalves, T.M.^a , Kumar, A.^a , Zhao, G.^a b , Cavalli, V.^a c d

^a Department of Neuroscience, Washington University School of Medicine, St Louis, MO 63110, United States
^b Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, United States
^c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Retinal Ganglion Cells (RGCs) lose their ability to grow axons during development. Adult RGCs thus fail to regenerate their axons after injury, leading to vision loss. To uncover mechanisms that promote regeneration of RGC axons, we identified transcription factors (TF) and open chromatin regions that are enriched in rat embryonic RGCs (high axon growth capacity) compared to postnatal RGCs (low axon growth capacity). We found that developmental stage-specific gene expression changes correlated with changes in promoter chromatin accessibility. Binding motifs for TFs such as CREB, CTCF, JUN and YY1 were enriched in the regions of the chromatin that were more accessible in embryonic RGCs. Proteomic analysis of purified rat RGC nuclei confirmed the expression of TFs with potential role in axon growth such as CREB, CTCF, YY1, and JUND. The CREB/ATF binding motif was widespread at the open chromatin region of known pro-regenerative TFs, supporting a role of CREB in regulating axon regeneration. Consistently, overexpression of CREB fused to the VP64 transactivation domain in mouse RGCs promoted axon regeneration after optic nerve injury. Our study provides a map of the chromatin accessibility during RGC development and highlights that TF associated with developmental axon growth can stimulate axon regeneration in mature RGC. © 2021, The Author(s).

Funding details
National Institutes of HealthNIHR35NS122260
National Eye InstituteNEIR21EY029077
National Institute of Neurological Disorders and StrokeNINDSR01NS096034
Research to Prevent BlindnessRPB
Office of Research Infrastructure Programs, National Institutes of HealthORIP, NIH, NIH-ORIP, ORIPR03AG070474

Document Type: Article
Publication Stage: Final
Source: Scopus

Comparison of CSF biomarkers in Down syndrome and autosomal dominant Alzheimer’s disease: a cross-sectional study
(2021) The Lancet Neurology, 20 (8), pp. 615-626.

Fagan, A.M.^a , Henson, R.L.^a , Li, Y.^a , Boerwinkle, A.H.^a , Xiong, C.^b , Bateman, R.J.^a , Goate, A.^c , Ances, B.M.^a , Doran, E.^d , Christian, B.T.^e f , Lai, F.^g , Rosas, H.D.^g , Schupf, N.^h i , Krinsky-McHale, S.^j , Silverman, W.^d , Lee, J.H.^h i , Klunk, W.E.^k , Handen, B.L.^k , Allegri, R.F.^l , Chhatwal, J.P.^g , Day, G.S.^m , Graff-Radford, N.R.^m , Jucker, M.^n o , Levin, J.^p , Martins, R.N.^q , Masters, C.L.^r s , Mori, H.^t , Mummery, C.J.^u , Niimi, Y.^v , Ringman, J.M.^w , Salloway, S.^x , Schofield, P.R.^y , Shoji, M.^z , Lott, I.T.^d , Alzheimer’s Biomarker Consortium-Down Syndrome^aa ac , Dominantly Inherited Alzheimer Network^ab 

^a Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^b Division of Biostatistics, Washington University School of Medicine, St Louis, MO, United States
^c Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^d Department of Pediatrics, UC Irvine School of Medicine, Irvine, CA, United States
^e Department of Medical Physics, Waisman Center, University of Wisconsin-Madison, Madison, WI, United States
^f Department of Psychiatry, Waisman Center, University of Wisconsin-Madison, Madison, WI, United States
^g Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States
^h Department of Epidemiology, Columbia University Irving Medical Center, New York, NY, United States
ⁱ Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
^j New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, United States
^k Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
^l Department of Cognitive Neurology, Instituto Neurologico Fleni, Buenos Aires, Argentina
^m Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, United States
ⁿ Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
^o German Center for Neurodegenerative Diseases, Tübingen, Germany
^p Department of Neurology, Ludwig-Maximilians-Universität München, German Center for Neurodegenerative Diseases, Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^q School of Medical Health and Sciences, Edith Cowan University, Joondalup, WA, Australia
^r Florey Institute, Melbourne, VIC, Australia
^s University of Melbourne, Melbourne, VIC, Australia
^t Department of Clinical Neuroscience, Osaka City University Medical School, Abenoku, Osaka, Japan
^u Dementia Research Centre, Institute of Neurology, University College London, London, UK, United Kingdom
^v Unit for Early and Exploratory Clinical Development, University of Tokyo, Tokyo, Japan
^w Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
^x Memory and Aging Program, Brown University, Butler Hospital, Providence, RI, United States
^y Neuroscience Research Australia, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
^z Geriatrics Research Institute and Hospital, Maebashi, Gunma, Japan

Abstract
Background: Due to trisomy of chromosome 21 and the resultant extra copy of the amyloid precursor protein gene, nearly all adults with Down syndrome develop Alzheimer’s disease pathology by the age of 40 years and are at high risk for dementia given their increased life expectancy compared with adults with Down syndrome in the past. We aimed to compare CSF biomarker patterns in Down syndrome with those of carriers of autosomal dominant Alzheimer’s disease mutations to enhance our understanding of disease mechanisms in these two genetic groups at high risk for Alzheimer’s disease. Methods: We did a cross-sectional study using data from adults enrolled in the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS) study, a multisite longitudinal study of Alzheimer’s disease in Down syndrome, as well as a cohort of carriers of autosomal dominant Alzheimer’s disease mutations and non-carrier sibling controls enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study. For ABC-DS, participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of Jan 31, 2019, were included in the analysis. DIAN participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of June 30, 2018, were evaluated as comparator groups. CSF samples obtained from adults with Down syndrome, similarly aged carriers of autosomal dominant Alzheimer’s disease mutations, and non-carrier siblings (aged 30–61 years) were analysed for markers of amyloid β (Aβ1–40, Aβ1–42); tau phosphorylated at threonine 181-related processes; neuronal, axonal, or synaptic injury (total tau, visinin-like protein 1, neurofilament light chain [NfL], synaptosomal-associated protein 25); and astrogliosis and neuroinflammation (chitinase-3-like protein 1 [YKL-40]) via immunoassay. Biomarker concentrations were compared as a function of dementia status (asymptomatic or symptomatic), and linear regression was used to evaluate and compare the relationship between biomarker concentrations and age among groups. Findings: We assessed CSF samples from 341 individuals (178 [52%] women, 163 [48%] men, aged 30–61 years). Participants were adults with Down syndrome (n=41), similarly aged carriers of autosomal dominant Alzheimer’s disease mutations (n=192), and non-carrier siblings (n=108). Individuals with Down syndrome had patterns of Alzheimer’s disease-related CSF biomarkers remarkably similar to carriers of autosomal dominant Alzheimer’s disease mutations, including reductions (all p&lt;0·0080) in Aβ1–42 to Aβ1–40 ratio and increases in markers of phosphorylated tau-related processes; neuronal, axonal, and synaptic injury (p&lt;0·080); and astrogliosis and neuroinflammation, with greater degrees of abnormality in individuals with dementia. Differences included overall higher concentrations of Aβ and YKL-40 (both p&lt;0·0008) in Down syndrome and potential elevations in CSF tau (p&lt;0·010) and NfL (p&lt;0·0001) in the asymptomatic stage (ie, no dementia symptoms). Funding: National Institute on Aging, Eunice Kennedy Shriver National Institute of Child Health and Human Development, German Center for Neurodegenerative Diseases, and Japan Agency for Medical Research and Development. © 2021 Elsevier Ltd

Funding details
National Institutes of HealthNIH
National Institute on AgingNIA
Eli Lilly and Company
RocheK23AG064029
Massachusetts General HospitalMGH
Biogen
AbbVie
University of WashingtonUW
University of California, IrvineUCI
Japan Agency for Medical Research and DevelopmentAMED
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDU01 AG051406, U01 AG051412, UF1AG032438
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Alzheimerfonden

Document Type: Article
Publication Stage: Final
Source: Scopus

Sevoflurane and desflurane exposures following aneurysmal subarachnoid hemorrhage confer multifaceted protection against delayed cerebral ischemia
(2021) Biomedicines, 9 (7), art. no. 820, . 

Jayaraman, K.^a , Liu, M.^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
Numerous studies have demonstrated the ability of isoflurane conditioning to provide multifaceted protection against aneurysmal subarachnoid hemorrhage (SAH)-associated delayed cerebral ischemia (DCI); however, preclinical studies have not yet examined whether other commonly used inhalational anesthetics in neurological patients such as sevoflurane or desflurane are also protective against SAH-induced neurovascular deficits. We therefore sought to identify the potential for sevoflurane and desflurane conditioning to protect against DCI in an endovascular perforation mouse model of SAH. Neurological function was assessed daily via neuroscore. Large artery vasospasm and microvessel thrombosis were assessed three days after SAH or sham surgery. Four groups were examined: Sham, SAH + room air, SAH + 2% Sevoflurane, and SAH + 6% Desflurane. For the SAH groups, one hour after surgery, mice received 2% sevoflurane, 6% desflurane, or room air for one hour. We found that conditioning with sevoflurane or desflurane attenuated large artery vasospasm, reduced microvessel thrombosis, and improved neurologic function. Given their frequent clinical use and strong safety profile in patients (including those with SAH), these data strongly support further studies to validate these findings in preclinical and clinical studies and to elucidate the mechanisms by which these agents might be acting. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Aneurysmal subarachnoid hemorrhage;  Conditioning;  Delayed cerebral ischemia;  Desflurane;  Inhalational anesthesia;  Sevoflurane

Funding details
National Institutes of HealthNIHNS091603

Document Type: Article
Publication Stage: Final
Source: Scopus

Global waves synchronize the brain’s functional systems with fluctuating arousal
(2021) Science Advances, 7 (30), art. no. eabf2709, . 

Raut, R.V.^a , Snyder, A.Z.^a b , Mitra, A.^c , Yellin, D.^d , Fujii, N.^e , Malach, R.^d , Raichle, M.E.^a b

^a Department of Radiology, Washington University, St. Louis, MO 63110, United States
^b Department of Neurology, Washington University, St. Louis, MO 63110, United States
^c Department of Psychiatry, Stanford University, Stanford, CA 94305, United States
^d Department of Neurobiology, Weizmann Institute of Science, Rehovot, 76100, Israel
^e Laboratory for Adaptive Intelligence, RIKEN Brain Science Institute, Wako, 351-0198, Japan

Abstract
We propose and empirically support a parsimonious account of intrinsic, brain-wide spatiotemporal organization arising from traveling waves linked to arousal. We hypothesize that these waves are the predominant physiological process reflected in spontaneous functional magnetic resonance imaging (fMRI) signal fluctuations. The correlation structure (“functional connectivity”) of these fluctuations recapitulates the large-scale functional organization of the brain. However, a unifying physiological account of this structure has so far been lacking. Here, using fMRI in humans, we show that ongoing arousal fluctuations are associated with global waves of activity that slowly propagate in parallel throughout the neocortex, thalamus, striatum, and cerebellum. We show that these waves can parsimoniously account for many features of spontaneous fMRI signal fluctuations, including topographically organized functional connectivity. Last, we demonstrate similar, cortex-wide propagation of neural activity measured with electrocorticography in macaques. These findings suggest that traveling waves spatiotemporally pattern brain-wide excitability in relation to arousal. © 2021 American Association for the Advancement of Science. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Central triage of acute stroke patients across a distributive stroke network is safe and reduces transfer denials
(2021) Stroke, pp. 2671-2675. 

Holder, D.^a , Leeseberg, K.^c , Giles, J.A.^a , Lee, J.-M.^a b d , Namazie, S.^c , Ford, A.L.^a b

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Center for Clinical Excellence, Bjc Healthcare, St. Louis, MO, United States
^d Department of Biomedical Engineering, Washington University, St. Louis, MO, United States

Abstract
Background and Purpose: Mechanical thrombectomy has dramatically increased patient volumes transferred to comprehensive stroke centers (CSCs), resulting in transfer denials for patients who need higher level of care only available at a CSC. We hypothesized that a distributive stroke network (DSN), triaging low severity acute stroke patients to a primary stroke center (PSC) upon initial telestroke consultation, would safely reduce transfer denials, thereby providing additional volume to treat severe strokes at a CSC. Methods: In 2017, a DSN was implemented, in which mild stroke patients were centrally triaged, via telestroke consultation, to a PSC based upon a simple clinical severity algorithm, while higher acuity/severity strokes were triaged to the CSC. In an observational cohort study, data on acute ischemic stroke patients presenting to regional community hospitals were collected pre-versus post-DSN implementation. Safety outcomes and rate of CSC transfer denials were compared pre-DSN versus post-DSN. Results: The pre-DSN cohort (n=150), triaged to the CSC, had a similar rate of symptomatic intracerebral hemorrhage and discharge location compared with the post-DSN cohort (n=150), triaged to the PSC. Time to stroke unit admission was faster post-DSN (2 hours 40 minutes) versus pre-DSN (3 hours 29 minutes; P<0.001). Transfer denials were reduced post-DSN (3.8%) versus pre-DSN (1.8%; P=0.02), despite an increase in telestroke consultation volume over the same period (median, 3 calls per day pre-DSN versus 5 calls per day post-DSN; P=0.001). No patients who were triaged to the PSC required subsequent transfer to the CSC. Conclusions: A DSN, triaging mild ischemic stroke patients from community hospitals to a PSC, safely reduced transfer denials to the CSC, allowing greater capacity at the CSC to treat higher acuity stroke patients © 2021 American Heart Association, Inc.

Author Keywords
cohort studies;  ischemic stroke;  patient discharge;  telemedicine;  triage

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

Longitudinal cortex-wide monitoring of cerebral hemodynamics and oxygen metabolism in awake mice using multi-parametric photoacoustic microscopy
(2021) Journal of Cerebral Blood Flow and Metabolism, .

Sciortino, V.M.^a , Tran, A.^b , Sun, N.^a e , Cao, R.^a , Sun, T.^a e , Sun, Y.-Y.^c , Yan, P.^d , Zhong, F.^a e , Zhou, Y.^a e , Kuan, C.-Y.^c , Lee, J.-M.^d e e , Hu, S.^a e 

^a Department of Biomedical Engineering, University of Virginia, University of Virginia, Charlottesville, VA, United States
^b Department of Biology, University of Virginia, University of Virginia, Charlottesville, VA, United States
^c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Neuroscience, University of Virginia, University of Virginia, Charlottesville, VA, United States
^e Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Multi-parametric photoacoustic microscopy (PAM) has emerged as a promising new technique for high-resolution quantification of hemodynamics and oxygen metabolism in the mouse brain. In this work, we have extended the scope of multi-parametric PAM to longitudinal, cortex-wide, awake-brain imaging with the use of a long-lifetime (24 weeks), wide-field (5 × 7 mm2), light-weight (2 g), dual-transparency (i.e., light and ultrasound) cranial window. Cerebrovascular responses to the window installation were examined in vivo, showing a complete recovery in 18 days. In the 22-week monitoring after the recovery, no dura thickening, skull regrowth, or changes in cerebrovascular structure and function were observed. The promise of this technique was demonstrated by monitoring vascular and metabolic responses of the awake mouse brain to ischemic stroke throughout the acute, subacute, and chronic stages. Side-by-side comparison of the responses in the ipsilateral (injury) and contralateral (control) cortices shows that despite an early recovery of cerebral blood flow and an increase in microvessel density, a long-lasting deficit in cerebral oxygen metabolism was observed throughout the chronic stage in the injured cortex, part of which proceeded to infarction. This longitudinal, functional-metabolic imaging technique opens new opportunities to study the chronic progression and therapeutic responses of neurovascular diseases. © The Author(s) 2021.

Author Keywords
cerebral vasculature;  cranial window;  longitudinal imaging;  oxygen metabolism;  Photoacoustic microscopy

Funding details
National Science FoundationNSF2023988
National Institutes of HealthNIHNS099261
American Heart AssociationAHA15SDG25960005

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

A Multi-center Genome-wide Association Study of Cervical Dystonia
(2021) Movement Disorders, . 

Sun, Y.V.^a b , Li, C.^a , Hui, Q.^a , Huang, Y.^a , Barbano, R.^c , Rodriguez, R.^d , Malaty, I.A.^e , Reich, S.^f , Bambarger, K.^f , Holmes, K.^f , Jankovic, J.^g , Patel, N.J.^h , Roze, E.ⁱ , Vidailhet, M.ⁱ , Berman, B.D.^j , LeDoux, M.S.^k , Espay, A.J.^l , Agarwal, P.^m , Pirio-Richardson, S.ⁿ , Frank, S.A.^o , Ondo, W.G.^p , Saunders-Pullman, R.^q , Chouinard, S.^r , Natividad, S.^s , Berardelli, A.^t , Pantelyat, A.Y.^u , Brashear, A.^v , Fox, S.H.^w , Kasten, M.^x y , Krämer, U.M.^z , Neis, M.^z aa , Bäumer, T.^x ab , Loens, S.^x ab , Borsche, M.^x z , Zittel, S.^ac , Maurer, A.^ac , Gelderblom, M.^ac , Volkmann, J.^ad , Odorfer, T.^ad , Kühn, A.A.^ae , Borngräber, F.^ae , König, I.R.^af , Cruchaga, C.^ag , Cotton, A.C.^ah , Kilic-Berkmen, G.^ah , Freeman, A.^ah , Factor, S.A.^ah , Scorr, L.^ah , Bremner, J.D.^ai aj , Vaccarino, V.^a , Quyyumi, A.A.^ak , Klein, C.^x , Perlmutter, J.S.^al , Lohmann, K.^x , Jinnah, H.A.^ah am

^a Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, United States
^b Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, United States
^c Movement Disorders Division, University of Rochester, Rochester, NY, United States
^d Neurology One, Orlando, FL, United States
^e Department of Neurology, Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, United States
^f Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, United States
^g Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, United States
^h Department of Neurology, Henry Ford Health System, Henry Ford Hospital, Detroit, MI, United States
ⁱ Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle; Assistance Publique – Hôpitaux de Paris, Hôpital Salpêtrière, Département de Neurologie, Paris, France
^j Department of Neurology, Virginia Commonwealth University, Richmond, VA, United States
^k Department of Psychology, University of Memphis, Memphis, TN, United States
^l James J and Joan A Gardner Center for Parkinson’s Disease and Movement Disorders, University of Cincinnati Academic Health Center, Cincinnati, OH, United States
^m Booth Gardner Parkinson’s Care Center, Evergreen Health, Kirkland, WA, United States
ⁿ Department of Neurology, University of New Mexico, Albuquerque, NM, United States
^o Beth Israel Deaconess Medical Center, Boston, MA, United States
^p Department of Neurology, Methodist Neurological Institute, Weill Cornell Medical School, Houston, TX, United States
^q Icahn School of Medicine at Mount Sinai, Movement Disorders, Department of Neurology, Mount Sinai Beth Israel, New York, NY, United States
^r Unité des troubles du mouvement André-Barbeau, Centre Hospitalier de l’Université de Montréal, Montreal, Canada
^s Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL, United States
^t Department of Neurology and Psychiatry, Sapienza University of Rome and IRCCS Neuromed, Rome, Italy
^u Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^v Neurology, University of California, Davis, Sacramento, CA, United States
^w University of Toronto, Edmond J Safra Program in Parkinson Disease; Movement Disorder Clinic, Toronto Western Hospital, Toronto, ON, Canada
^x Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
^y Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany
^z Department of Neurology, University of Lübeck, Lübeck, Germany
^aa Institute for Health Sciences, Department of Midwifery Science, University of Lübeck, Lübeck, Germany
^ab Institute of Systemic Motor Research, University of Lübeck, Lübeck, Germany
^ac Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
^ad Department of Neurology, University Hospital Würzburg, Würzburg, Germany
^ae Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany
^af Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany
^ag Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^ah Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
^ai Atlanta VA Medical Center, Decatur, GA, United States
^aj Departments of Psychiatry & Behavioral Sciences and Radiology, Emory University School of Medicine, Atlanta, GA, United States
^ak Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA, United States
^al Department of Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University in St. Louis, St. Louis, MO, United States
^am Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States

Abstract
Background: Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility. Objective: To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach. Methods: We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal. Results: After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10−8). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10−6). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10−8, minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823). Conclusion: The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society. © 2021 International Parkinson and Movement Disorder Society.

Author Keywords
cervical dystonia;  genome-wide association study (GWAS);  movement disorder;  rare disease

Funding details
KL2 TR001080
National Institutes of HealthNIHNS067501, NS096455, NS116015
U.S. Department of DefenseDOD
National Institute of Neurological Disorders and StrokeNINDS
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Dana Foundation
National Parkinson FoundationNPF
Dystonia Medical Research FoundationDMRF
Restless Legs Syndrome FoundationRLSF
Merck
Medtronic
Biogen
CHDI FoundationCHDI
National Center for Advancing Translational SciencesNCATSNS116025, TR001456
Teva Pharmaceutical Industries
Allergan
International Parkinson and Movement Disorder SocietyMDS
Boston Scientific CorporationBSC
Benign Essential Blepharospasm Research FoundationBEBRF
Sunovion
Parkinson’s FoundationPF
Ipsen Biopharmaceuticals
National Spasmodic Dysphonia AssociationNSDA
ACADIA PharmaceuticalsACADIA
Dystonia CoalitionNS065701
Government of South Australia
Canadian Institutes of Health ResearchCIHR
European CommissionEC
Deutsche ForschungsgemeinschaftDFGFOR 2698, FOR2488
Agence Nationale de la RechercheANR
Bundesministerium für Bildung und ForschungBMBF01GM1514B, TR‐SFB134
Deutsche Krebshilfe
Federalno Ministarstvo Obrazovanja i Nauke
Parkinson Canada
European Academy of NeurologyEAN
Merz Pharmaceuticals
H. Lundbeck A/S
Werner Otto Stiftung

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

Risk of intracranial haemorrhage and ischaemic stroke after convexity subarachnoid haemorrhage in cerebral amyloid angiopathy: international individual patient data pooled analysis
(2021) Journal of Neurology, . 

Hostettler, I.C.^a , Wilson, D.^a , Fiebelkorn, C.A.^b , Aum, D.^c , Ameriso, S.F.^d , Eberbach, F.^d , Beitzke, M.^e , Kleinig, T.^f , Phan, T.^g u , Marchina, S.^h , Schneckenburger, R.ⁱ , Carmona-Iragui, M.^j , Charidimou, A.^k , Mourand, I.^l , Parreira, S.^m , Ambler, G.ⁿ , Jäger, H.R.^o , Singhal, S.^g u , Ly, J.^g u , Ma, H.^g u , Touzé, E.^p , Geraldes, R.^q r , Fonseca, A.C.^m , Melo, T.^m , Labauge, P.^l , Lefèvre, P.-H.^s , Viswanathan, A.^k , Greenberg, S.M.^k , Fortea, J.^j , Apoil, M.ⁱ , Boulanger, M.^i p , Viader, F.ⁱ , Kumar, S.^h , Srikanth, V.^g u , Khurram, A.^f , Fazekas, F.^e , Bruno, V.^d , Zipfel, G.J.^c , Refai, D.^t , Rabinstein, A.^b , Graff-Radford, J.^b , Werring, D.J.^a

^a Stroke Research Centre, University College London, National Hospital of Neurology and Neurosurgery, Institute of Neurology, Queen Square, London, WC1N, United Kingdom
^b Department of Neurology, Mayo Clinic, Rochester, MN, United States
^c Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^d Institute for Neurological Research, Fleni, Buenos Aires, Argentina
^e Department of Neurology, Medical University of Graz, Graz, Austria
^f Department of Neurology, Royal Adelaide Hospital, Adelaide, Australia
^g Department of Neurology, Monash Health and Stroke and Ageing Research Group, Melbourne, Australia
^h Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
ⁱ Department of Neurology, CHU Caen Normandie, Caen, France
^j Memory Unit, Department of Neurology, Hospital de la Santa Creu I Sant Pau, Institut Investigació Biomèdica Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
^k J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
^l Department of Neurology, CHU de Montpellier, Hôpital Gui-de-Chauliac, Montpellier, France
^m Stroke Unit, Department of Neuroscience, Hospital de Santa Maria, University of Lisbon, Lisbon, Portugal
ⁿ Department of Statistical Science, UCL, London, WC1E 6BT, United Kingdom
^o Neuroradiological Academic Unit, Department of Brain Repair & Rehabilitation, University College London, Institute of Neurology, London, United Kingdom
^p Normandy University, UNICAEN, INSERM U1237, Caen, France
^q Nuffield Department of Clinical Neurosciences, Oxford University Hospitals, Oxford, United Kingdom
^r Neurology department, Frimley Health Foundation Trust, Camberley, United Kingdom
^s Department of Neuroradiology, CHU de Montpellier, Hôpital Gui-de-Chauliac, Montpellier, France
^t Department of Neurosurgery, Emory University, Atlanta, GA, United States
^u Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, Australia

Abstract
Objective: To investigate the frequency, time-course and predictors of intracerebral haemorrhage (ICH), recurrent convexity subarachnoid haemorrhage (cSAH), and ischemic stroke after cSAH associated with cerebral amyloid angiopathy (CAA). Methods: We performed a systematic review and international individual patient-data pooled analysis in patients with cSAH associated with probable or possible CAA diagnosed on baseline MRI using the modified Boston criteria. We used Cox proportional hazards models with a frailty term to account for between-cohort differences. Results: We included 190 patients (mean age 74.5 years; 45.3% female) from 13 centers with 385 patient-years of follow-up (median 1.4 years). The risks of each outcome (per patient-year) were: ICH 13.2% (95% CI 9.9–17.4); recurrent cSAH 11.1% (95% CI 7.9–15.2); combined ICH, cSAH, or both 21.4% (95% CI 16.7–26.9), ischemic stroke 5.1% (95% CI 3.1–8) and death 8.3% (95% CI 5.6–11.8). In multivariable models, there is evidence that patients with probable CAA (compared to possible CAA) had a higher risk of ICH (HR 8.45, 95% CI 1.13–75.5, p = 0.02) and cSAH (HR 3.66, 95% CI 0.84–15.9, p = 0.08) but not ischemic stroke (HR 0.56, 95% CI 0.17–1.82, p = 0.33) or mortality (HR 0.54, 95% CI 0.16–1.78, p = 0.31). Conclusions: Patients with cSAH associated with probable or possible CAA have high risk of future ICH and recurrent cSAH. Convexity SAH associated with probable (vs possible) CAA is associated with increased risk of ICH, and cSAH but not ischemic stroke. Our data provide precise risk estimates for key vascular events after cSAH associated with CAA which can inform management decisions. © 2021, The Author(s).

Author Keywords
Cerebral amyloid angiopathy;  Intracerebral haemorrhage;  Ischemic stroke;  Non-traumatic convexity/convexal/cortical subarachnoid haemorrhage;  Stroke

Funding details
National Institutes of HealthNIH01AG026484, 01NS096730, 24 NS100591, 24 NS107154
Alzheimer’s AssociationAA
Global Brain Health InstituteGBHI
National Institute for Health ResearchNIHR
Department of Health and Social CareDH
Fondation Jérôme Lejeune
Alzheimer’s Research UKARUK
Instituto de Salud Carlos IIIISCIII
Departament de Salut, Generalitat de Catalunya
NIHR Imperial Biomedical Research CentreBRC
Fundació Víctor Grífols i Lucas76 AG057015-01

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

Effect of electroencephalogram-guided anaesthesia administration on 1 yr mortality: 1 yr follow-up of a randomised clinical trial
(2021) British Journal of Anaesthesia, . 

Fritz, B.A.^a , King, C.R.^a , Mickle, A.M.^a , Wildes, T.S.^a , Budelier, T.P.^a , Oberhaus, J.^a , Park, D.^a , Maybrier, H.R.^a , Ben Abdallah, A.^a , Kronzer, A.^a , McKinnon, S.L.^a , Torres, B.A.^a , Graetz, T.J.^a , Emmert, D.A.^a , Palanca, B.J.^a , Stevens, T.W.^a , Stark, S.L.^b , Lenze, E.J.^c , Avidan, M.S.^a , Abdallah, A.B.^a , Apakama, G.^a , Aranake-Chrisinger, A.^a , Bolzenius, J.^a , Burton, J.^a , Cui, V.^a , Goswami, S.^a , Gupta, S.^a , Jordan, K.^a , Muench, M.R.^a , Murphy, M.R.^a , Patel, A.^a , Spencer, J.W.^a , Strutz, P.^a , Tedeschi, C.M.^a , Trammel, E.R.^a , Upadhyayula, R.T.^a , Winter, A.C.^a , Lin, N.^d , Jacobsohn, E.^e , Fong, T.^f , Gallagher, J.^f , Inouye, S.K.^f , Schmitt, E.M.^f , Somerville, E.^b , Stark, S.^b , Melby, S.J.^g , Tappenden, J.^g , ENGAGES Research Group^h

^a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
^b Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Mathematics, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Anesthesiology, University of Manitoba, Winnipeg, Canada
^f Department of Medicine, Beth Israel-Deaconess Medical Center, Boston, MA, United States
^g Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Intraoperative EEG suppression duration has been associated with postoperative delirium and mortality. In a clinical trial testing anaesthesia titration to avoid EEG suppression, the intervention did not decrease the incidence of postoperative delirium, but was associated with reduced 30 day mortality. The present study evaluated whether the EEG-guided anaesthesia intervention continued to be associated with reduced 1 yr mortality. Methods: This manuscript reports 1 yr follow-up of patients from a single-centre RCT, including a post-hoc secondary outcome (1 yr mortality) in addition to pre-specified secondary outcomes. The trial included patients aged 60 yr or older undergoing surgery with general anaesthesia between January 2015 and May 2018. Patients were randomised to receive EEG-guided anaesthesia or usual care. The previously reported primary outcome was postoperative delirium. The outcome of the current study was all-cause 1 yr mortality. Results: Of the 1232 patients enrolled, 614 patients were randomised to EEG-guided anaesthesia and 618 patients to usual care. One year mortality was 57/591 (9.6%) in the guided group and 62/601 (10.3%) in the usual-care group. No significant difference in mortality was observed (adjusted absolute risk difference, –0.7%; 99.5% confidence interval, –5.8% to 4.3%; P=0.68). Conclusions: An EEG-guided anaesthesia intervention aiming to decrease duration of EEG suppression during surgery did not significantly decrease 1 yr mortality. These findings, in the context of other studies, do not provide supportive evidence for EEG-guided anaesthesia to prevent intermediate term postoperative death. Clinical trial registration: NCT02241655. © 2021 British Journal of Anaesthesia

Author Keywords
burst suppression;  depth of anaesthesia;  electroencephalogram suppression;  postoperative death;  postoperative delirium;  postoperative falls;  postoperative mortality;  quality of life

Funding details
National Institutes of HealthNIH
U.S. Food and Drug AdministrationFDAUH3 AG050312
National Institute on AgingNIA
National Institute of General Medical SciencesNIGMST32 GM108539
U.S. Department of Housing and Urban DevelopmentHUD
Patient-Centered Outcomes Research InstitutePCORI
Takeda Pharmaceutical CompanyTPC
Janssen Pharmaceuticals
National Institute on Disability, Independent Living, and Rehabilitation ResearchNIDILRR
H. Lundbeck A/S

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

Brain structure and problematic alcohol use: a test of plausible causation using latent causal variable analysis
(2021) Brain Imaging and Behavior, . 

Hatoum, A.S.^a , Johnson, E.C.^a , Agrawal, A.^a , Bogdan, R.^b

^a Department of Psychiatry, Washington University St. Louis Medical School, 825 S Taylor Ave, St. Louis, MO 63110, United States
^b Department of Psychological & Brain Sciences, Washington University St. Louis, St. Louis, MO, United States

Abstract
Associations between brain structure and problematic alcohol use may reflect alcohol-induced toxicity and/or preexisting risk. Here, we applied a latent causal variable approach to genome-wide association study summary statistics of problematic alcohol use (n = 435,563) and magnetic resonance imaging-derived brain structure phenotypes (e.g., cortical volume, cortical thickness, white matter volume; ns ranging from 17,706 to 51,665) to test whether variability in brain structure may plausibly contribute to problematic alcohol use and/or whether problematic alcohol use influences brain structure. After correction for multiple testing within each modality, we find evidence that greater volume of the pars opercularis, greater thickness of the cuneus, and lower volume of the basal forebrain may plausibly contribute to problematic alcohol use. All other nominally-significant associations identify brain structure as a potential causal contributor to problematic alcohol use; there was no evidence suggesting that problematic alcohol use may cause differences in brain structure. Collectively, these results challenge common interpretations that associations between alcohol use and brain structure reflect consequences of alcohol, instead supporting emerging work suggesting that brain structure may reflect a predispositional risk factor for alcohol involvement. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Funding details
National Institutes of HealthNIHAA027827, AG052564, DA007261-17, DA046224, F32AA027435, K02DA032573, MH109532
U.S. Department of Veterans AffairsVA
Office of Research and DevelopmentORD
Health Services Research and DevelopmentHSR&D

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

Non-motor phenotypic subgroups in adult-onset idiopathic, isolated, focal cervical dystonia
(2021) Brain and Behavior, . 

Wadon, M.E.^a , Bailey, G.A.^a , Yilmaz, Z.^a b , Hubbard, E.^c , AlSaeed, M.^c d , Robinson, A.^c , McLauchlan, D.^a , Barbano, R.L.^e , Marsh, L.^f , Factor, S.A.^g , Fox, S.H.^h i , Adler, C.H.^j , Rodriguez, R.L.^k , Comella, C.L.^l , Reich, S.G.^m , Severt, W.L.ⁿ , Goetz, C.G.^l , Perlmutter, J.S.^o , Jinnah, H.A.^g , Harding, K.E.^p , Sandor, C.^q , Peall, K.J.^a

^a Neuroscience and Mental Health Research Institute, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Maindy Road, Cardiff, CF24 4HQ, United Kingdom
^b Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, United Kingdom
^c School of Medicine, Cardiff University, Heath Park Campus, Cardiff, CF14 4YS, United Kingdom
^d Division of Neurology, University of British Columbia, Wesbrook Mall, Vancouver, BC V6T 2B5, Canada
^e Department of Neurology, University of Rochester, Elmwood Avenue, Rochester, NY NY 14642, United States
^f Menninger Department of Psychiatry, Baylor College of Medicine, Butler Boulevard, Houston, TX 77030, United States
^g Departments of Neurology & Human Genetics, Emory University, Woodruff Circle, Atlanta, GA 30322, United States
^h Edmond J Safra Program in Parkinson Disease, Movement Disorder Clinic, Toronto Western Hospital, Bathurst Street, Toronto, ON M5T 2S8, Canada
ⁱ Department of Medicine, University of Toronto, Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada
^j The Parkinson’s Disease and Movement Disorders Center, Mayo Clinic, Department of Neurology, East Shea Boulevard, Scottsdale, AZ 85259, United States
^k Department of Neurology, University of Florida, Newell Drive, Gainesville, FL 32611, United States
^l Department of Neurological Sciences, Rush University Medical Center, West Harrison Street, Chicago, IL 60612, United States
^m Department of Neurology, University of Maryland School of Medicine, south Paca Street, Baltimore, MD 21201, United States
ⁿ Beth Israel Medical Center, First Avenue, New York, NY 10003, United States
^o Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University School of Medicine, South Euclid Avenue, St. Louis, MO 63110, United States
^p Department of Neurology, Aneurin Bevan University Health Board, Corporation Road, Newport, NP19 0BH, United Kingdom
^q UK Dementia Research Institute, Cardiff University, Maindy Road, Cardiff, CF24 4HQ, United Kingdom

Abstract
Background: Non-motor symptoms are well established phenotypic components of adult-onset idiopathic, isolated, focal cervical dystonia (AOIFCD). However, improved understanding of their clinical heterogeneity is needed to better target therapeutic intervention. Here, we examine non-motor phenotypic features to identify possible AOIFCD subgroups. Methods: Participants diagnosed with AOIFCD were recruited via specialist neurology clinics (dystonia wales: n = 114, dystonia coalition: n = 183). Non-motor assessment included psychiatric symptoms, pain, sleep disturbance, and quality of life, assessed using self-completed questionnaires or face-to-face assessment. Both cohorts were analyzed independently using Cluster, and Bayesian multiple mixed model phenotype analyses to investigate the relationship between non-motor symptoms and determine evidence of phenotypic subgroups. Results: Independent cluster analysis of the two cohorts suggests two predominant phenotypic subgroups, one consisting of approximately a third of participants in both cohorts, experiencing increased levels of depression, anxiety, sleep impairment, and pain catastrophizing, as well as, decreased quality of life. The Bayesian approach reinforced this with the primary axis, which explained the majority of the variance, in each cohort being associated with psychiatric symptomology, and also sleep impairment and pain catastrophizing in the Dystonia Wales cohort. Conclusions: Non-motor symptoms accompanying AOIFCD parse into two predominant phenotypic sub-groups, with differences in psychiatric symptoms, pain catastrophizing, sleep quality, and quality of life. Improved understanding of these symptom groups will enable better targeted pathophysiological investigation and future therapeutic intervention. © 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC

Author Keywords
dystonia disorders;  phenotype;  surveys and questionnaires;  torticollis

Funding details
U54 TR001456
National Institute of Neurological Disorders and StrokeNINDSU54 NS065701, U54 NS116025
Dystonia Medical Research FoundationDMRF
Jacques und Gloria Gossweiler-StiftungJGGF
Dystonia Coalition
Rare Diseases Clinical Research NetworkRDCRN
Fight for Sight UK

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

Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for Soluble and Insoluble Amyloid β Aggregates in Alzheimer’s Disease
(2021) Journal of the American Chemical Society, . 

Sun, L.^a , Cho, H.-J.^a , Sen, S.^c , Arango, A.S.^c , Huynh, T.T.^d e , Huang, Y.^a , Bandara, N.^d , Rogers, B.E.^d , Tajkhorshid, E.^c , Mirica, L.M.^a b

^a Department of Chemistry, Beckman Institute for Advanced Science and Technology, the Neuroscience Program, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL 61801, United States
^b Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Nih Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, Center for Biophysics and Quantitative Biology, Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
^d Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, United States
^e Department of Chemistry, Washington University, St. Louis, MO 63130, United States

Abstract
Alzheimer’s Disease (AD) is the most common neurodegenerative disease, and efficient therapeutic and early diagnostic agents for AD are still lacking. Herein, we report the development of a novel amphiphilic compound, LS-4, generated by linking a hydrophobic amyloid-binding distyrylbenzene fragment with a hydrophilic triazamacrocycle, which dramatically increases the binding affinity toward various amyloid β (Aβ) peptide aggregates, especially for soluble Aβ oligomers. Moreover, upon the administration of LS-4 to 5xFAD mice, fluorescence imaging of LS-4-treated brain sections reveals that LS-4 can penetrate the blood-brain barrier and bind to the Aβ oligomers in vivo. In addition, the treatment of 5xFAD mice with LS-4 reduces the amount of both amyloid plaques and associated phosphorylated tau aggregates vs the vehicle-treated 5xFAD mice, while microglia activation is also reduced. Molecular dynamics simulations corroborate the observation that introducing a hydrophilic moiety into the molecular structure of LS-4 can enhance the electrostatic interactions with the polar residues of the Aβ species. Finally, exploiting the Cu2+-chelating property of the triazamacrocycle, we performed a series of imaging and biodistribution studies that show the 64Cu-LS-4 complex binds to the amyloid plaques and can accumulate to a significantly larger extent in the 5xFAD mouse brains vs the wild-type controls. Overall, these results illustrate that the novel strategy, to employ an amphiphilic molecule containing a hydrophilic moiety attached to a hydrophobic amyloid-binding fragment, can increase the binding affinity for both soluble and insoluble Aβ aggregates and can thus be used to detect and regulate various Aβ species in AD. © 2021 American Chemical Society.

Funding details
National Institutes of HealthNIHP41-GM104601, R01GM114588

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