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  • An expanded parenchymal CD8+ T cell clone in GABAA receptor encephalitis
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2020-01-14
    Aline Bracher; Carmen Alcalá; Jaime Ferrer; Nico Melzer; Reinhard Hohlfeld; Bonaventura Casanova; Eduardo Beltrán; Klaus Dornmair

    The role of T cells in autoimmune encephalitis syndromes with autoantibodies against cell surface antigens is still enigmatic. Here we analyzed the T cell receptor repertoires of CD8+ and CD4+ T cells in a patient with “idiopathic” gamma‐aminobutyric‐acid‐A receptor (GABAA‐R) encephalitis by next‐generation sequencing and single‐cell analyses. We identified a CD8+ T cell clone that was strongly expanded in the cerebrospinal fluid and in the hippocampus but not in the operculo‐insular cortex. By contrast, CD4+ T cells were polyclonal in these tissues. Such a strong clonal expansion suggests that CD8+ T cells may play a significant role in the pathogenesis.

  • Relapsing–remitting clinical course expands the phenotype of Aicardi–Goutières syndrome
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2020-01-10
    Jeffrey Lambe; Olwen C. Murphy; Weiyi Mu; Krista Sondergaard Schatz; Kristin W. Barañano; Arun Venkatesan

    Aicardi–Goutières syndrome (AGS) is a rare and likely underdiagnosed genetic leukoencephalopathy, typically presenting in infancy with encephalopathy and characteristic neuroimaging features, with residual static neurological deficits. We describe a patient who, following an initial presentation at the age of 12 months in keeping with AGS, exhibited a highly atypical relapsing course of neurological symptoms in adulthood with essentially normal neuroimaging. Whole‐exome sequencing confirmed a pathogenic RNASEH2B gene variant consistent with AGS. This case highlights the expanding phenotypes associated with AGS and the potential role of whole‐exome sequencing in facilitating an increase in the rate of diagnosis.

  • Genome sequencing in persistently unsolved white matter disorders
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2020-01-07
    Guy Helman; Bryan R. Lajoie; Joanna Crawford; Asako Takanohashi; Marzena Walkiewicz; Egor Dolzhenko; Andrew M. Gross; Vladimir G. Gainullin; Stephen J. Bent; Emma M. Jenkinson; Sacha Ferdinandusse; Hans R. Waterham; Imen Dorboz; Enrico Bertini; Noriko Miyake; Nicole I. Wolf; Truus E. M. Abbink; Susan M. Kirwin; Christina M. Tan; Grace M. Hobson; Long Guo; Shiro Ikegawa; Amy Pizzino; Johanna L. Schmidt; Genevieve Bernard; Raphael Schiffmann; Marjo S. van der Knaap; Cas Simons; Ryan J. Taft; Adeline Vanderver

    Genetic white matter disorders have heterogeneous etiologies and overlapping clinical presentations. We performed a study of the diagnostic efficacy of genome sequencing in 41 unsolved cases with prior exome sequencing, resolving an additional 14 from an historical cohort (n = 191). Reanalysis in the context of novel disease‐associated genes and improved variant curation and annotation resolved 64% of cases. The remaining diagnoses were directly attributable to genome sequencing, including cases with small and large copy number variants (CNVs) and variants in deep intronic and technically difficult regions. Genome sequencing, in combination with other methodologies, achieved a diagnostic yield of 85% in this retrospective cohort.

  • Confounding effect of blood volume and body mass index on blood neurofilament light chain levels
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2020-01-01
    Ali Manouchehrinia; Fredrik Piehl; Jan Hillert; Jens Kuhle; Lars Alfredsson; Tomas Olsson; Ingrid Kockum

    Blood Neurofilament light chain (NfL) has been suggested as a promising biomarker in several neurological conditions. Since blood NfL is the consequence of leaked NfL from the cerebrospinal fluid, differences in individuals’ Body Mass Index (BMI) or blood volume (BV) might affect its correlation to other biomarkers and disease outcomes. Here, we investigated the correlation between plasma NfL, BMI, and BV in 662 controls and 2,586 multiple sclerosis cases. We found a significant negative correlation between plasma NfL, BMI/BV in both groups. Our results highlight the potential confounding effect of BMI/BV on associations between blood NfL and disease outcomes.

  • First FHM3 mouse model shows spontaneous cortical spreading depolarizations
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-12-27
    Nico A. Jansen; Anisa Dehghani; Margot M. L. Linssen; Cor Breukel; Else A. Tolner; Arn M. J. M. van den Maagdenberg

    Here we show, for the first time, spontaneous cortical spreading depolarization (CSD) events – the electrophysiological correlate of the migraine aura – in animals by using the first generated familial hemiplegic migraine type 3 (FHM3) transgenic mouse model. The mutant mice express L263V‐mutated α1 subunits in voltage‐gated NaV1.1 sodium channels (Scn1aL263V). CSDs consistently propagated from visual to motor cortex, recapitulating what has been shown in patients with migraine with aura. This model may be valuable for the preclinical study of migraine with aura and other diseases in which spreading depolarization is a prominent feature.

  • Electrical impedance myography for reducing sample size in Duchenne muscular dystrophy trials
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-12-25
    Melanie L. Leitner; Kush Kapur; Basil T. Darras; Michele Yang; Brenda Wong; Laura Dalle Pazze; Julaine Florence; Martin Buck; Laura Freedman; Jose Bohorquez; Seward Rutkove; Craig Zaidman

    To evaluate the sensitivity of electrical impedance myography (EIM) to disease progression in both ambulatory and non‐ambulatory boys with DMD.

  • Length‐dependent MRI of hereditary neuropathy with liability to pressure palsies
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-12-24
    Michael Pridmore; Ryan Castoro; Megan Simmons McCollum; Hakmook Kang; Jun Li; Richard Dortch

    Hereditary neuropathy with liability to pressure palsies (HNPP) is caused by heterozygous deletion of the peripheral myelin protein 22 (PMP22) gene. Patients with HNPP present multifocal, reversible sensory/motor deficits due to increased susceptibility to mechanical pressure. Additionally, age‐dependent axonal degeneration is reported. We hypothesize that length‐dependent axonal loss can be revealed by MRI, irrespective of the multifocal phenotype in HNPP.

  • Efficacy of atomoxetine versus midodrine for neurogenic orthostatic hypotension
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-12-19
    Jung‐Ick Byun; Do‐Yong Kim; Jangsup Moon; Hye-Rim Shin; Jun‐Sang Sunwoo; Woo‐Jin Lee; Han‐Sang Lee; Kyung‐Il Park; Soon‐Tae Lee; Keun‐Hwa Jung; Ki‐Young Jung; Manho Kim; Sang Kun Lee; Kon Chu

    The efficacy and safety of 1‐month atomoxetine and midodrine therapies were compared. Three‐month atomoxetine and combination therapies were investigated for additional benefits.

  • A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-12-18
    Edgard Verdura; Agatha Schlüter; Gorka Fernández‐Eulate; Raquel Ramos‐Martín; Miren Zulaica; Laura Planas‐Serra; Montserrat Ruiz; Stéphane Fourcade; Carlos Casasnovas; Adolfo López de Munain; Aurora Pujol

    To identify causative mutations in a patient affected by ataxia and spastic paraplegia.

  • Age of onset determines intrinsic functional brain architecture in Friedreich ataxia
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-12-18
    Gilles Naeije; Vincent Wens; Nicolas Coquelet; Martin Sjøgård; Serge Goldman; Massimo Pandolfo; Xavier P. De Tiège

    Friedreich ataxia (FRDA) is the commonest hereditary ataxia in Caucasians. Most patients are homozygous for expanded GAA triplet repeats in the first intron of the frataxin (FXN) gene, involved in mitochondrial iron metabolism. Here, we used magnetoencephalography (MEG) to characterize the main determinants of FRDA‐related changes in intrinsic functional brain architecture.

  • MCF2 is linked to a complex perisylvian syndrome and affects cortical lamination
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-12-17
    Aude Molinard‐Chenu; Joël Fluss; Sacha Laurent; Méryle Laurent; Michel Guipponi; Alexandre G. Dayer

    The combination of congenital bilateral perisylvian syndrome (CBPS) with lower motor neuron dysfunction remains unusual and suggests a potential common genetic insult affecting basic neurodevelopmental processes. Here we identify a putatively pathogenic missense mutation in the MCF2 gene in a boy with CBPS. Using in utero electroporation to genetically manipulate cortical neurons during corticogenesis, we demonstrate that the mouse Mcf2 gene controls the embryonic migration of cortical projection neurons. Strikingly, we find that the CBPS‐associated MCF2 mutation impairs cortical laminar positioning, supporting the hypothesis that alterations in the process of embryonic neuronal migration can lead to rare cases of CBPS.

  • Novel mutation in optineurin causing aggressive ALS+/−frontotemporal dementia
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-12-15
    Shu‐Man Feng; Chun‐Hui Che; Shu‐Yan Feng; Chang‐Yun Liu; Liu‐Yi Li; Yuan‐Xiao Li; Hua‐Pin Huang; Zhang‐Yu Zou

    Mutations in optineurin (OPTN) have been identified in familial and sporadic amyotrophic lateral sclerosis (ALS). We screened a cohort of Chinese patients for mutations in optineurin. We also performed an extensive literatures review of all mutations in optineurin identified previously to detect genotype–phenotype associations.

  • Transmembrane protease serine 5: a novel Schwann cell plasma marker for CMT1A
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-12-12
    Hongge Wang; Matthew Davison; Kathryn Wang; Tai‐He Xia; Martin Kramer; Katherine Call; Jun Luo; Xingyao Wu; Riccardo Zuccarino; Chelsea Bacon; Yunhong Bai; John J. Moran; Laurie Gutmann; Shawna M. E. Feely; Tiffany Grider; Alexander M. Rossor; Mary M. Reilly; John Svaren; Michael E. Shy

    Development of biomarkers for Charcot‐Marie‐Tooth (CMT) disease is critical for implementing effective clinical trials. The most common form of CMT, type 1A, is caused by a genomic duplication surrounding the PMP22 gene. A recent report (Neurology 2018;90:e518–3524) showed elevation of neurofilament light (NfL) in plasma of CMT1A disease patients, which correlated with disease severity. However, no plasma/serum biomarker has been identified that is specific to Schwann cells, the most directly affected cells in CMT1A.

  • High‐resolution metabolomic profiling of Alzheimer’s disease in plasma
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-12-11
    Megan M. Niedzwiecki; Douglas I. Walker; Jennifer Christina Howell; Kelly D. Watts; Dean P. Jones; Gary W. Miller; William T. Hu

    Alzheimer’s disease (AD) is a complex neurological disorder with contributions from genetic and environmental factors. High‐resolution metabolomics (HRM) has the potential to identify novel endogenous and environmental factors involved in AD. Previous metabolomics studies have identified circulating metabolites linked to AD, but lack of replication and inconsistent diagnostic algorithms have hindered the generalizability of these findings. Here we applied HRM to identify plasma metabolic and environmental factors associated with AD in two study samples, with cerebrospinal fluid (CSF) biomarkers of AD incorporated to achieve high diagnostic accuracy.

  • Nigrosome 1 imaging in REM sleep behavior disorder and its association with dopaminergic decline
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-12-09
    Thomas R. Barber, Ludovica Griffanti, Kevin M. Bradley, Daniel R. McGowan, Christine Lo, Clare E. Mackay, Michele T. Hu, Johannes C. Klein

    Rapid eye movement sleep behavior disorder (RBD) patients have a high risk of developing a Parkinsonian disorder, offering an opportunity for neuroprotective intervention. Predicting near‐term conversion, however, remains a challenge. Dopamine transporter imaging, while informative, is expensive and not widely available. Here, we investigate the utility of susceptibility‐weighted MRI (SWI) to detect abnormalities of the substantia nigra in RBD, and explore their association with striatal dopaminergic deficits.

  • Pallidal versus subthalamic nucleus deep brain stimulation for levodopa‐induced dyskinesia
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-12-08
    Shi‐Ying Fan, Kai‐Liang Wang, Wei Hu, Robert S. Eisinger, Alexander Han, Chun‐Lei Han, Qiao Wang, Shimabukuro Michitomo, Jian‐Guo Zhang, Feng Wang, Adolfo Ramirez‐Zamora, Fan‐Gang Meng

    To compare the efficacy of subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) on reducing levodopa‐induced dyskinesia (LID) in Parkinson’s disease, and to explore the potential underlying mechanisms.

  • RARS1‐related hypomyelinating leukodystrophy: Expanding the spectrum
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-12-08
    Marisa I. Mendes, Lydia M. C. Green, Enrico Bertini, Davide Tonduti, Chiara Aiello, Desiree Smith, Ettore Salsano, Shanice Beerepoot, Jozef Hertecant, Sarah von Spiczak, John H. Livingston, Lisa Emrick, Jamie Fraser, Laura Russell, Genevieve Bernard, Stefania Magri, Daniela Di Bella, Franco Taroni, Mary K. Koenig, Isabella Moroni, Gerarda Cappuccio, Nicola Brunetti‐Pierri, Jullie Rhee, Bryce A. Mendelsohn, Ingo Helbig, Katherine Helbig, Hiltrud Muhle, Omar Ismayl, Adeline L. Vanderver, Gajja S. Salomons, Marjo S. van der Knaap, Nicole I. Wolf

    Biallelic variants in RARS1, encoding the cytoplasmic tRNA synthetase for arginine (ArgRS), cause a hypomyelinating leukodystrophy. This study aimed to investigate clinical, neuroradiological and genetic features of patients with RARS1‐related disease, and to identify possible genotype‐phenotype relationships.

  • Neurofilament light is a treatment‐responsive biomarker in CLN2 disease
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-12-08
    Yuanbin Ru, Carley Corado, Russell K. Soon, Andrew C. Melton, Adam Harris, Guoying K. Yu, Nancy Pryer, John R. Sinclair, Martin L. Katz, Temitayo Ajayi, David Jacoby, Chris B. Russell, Sanjay Chandriani

    Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare, progressive, fatal neurodegenerative pediatric disorder resulting from deficiencies of the lysosomal enzyme tripeptidyl peptidase 1 that are caused by mutations in TPP1. Identifying biomarkers of CLN2 disease progression will be important in assessing the efficacy of therapeutic interventions for this disorder. Neurofilament light is an intrinsic component of healthy neurons; elevated circulating extracellular neurofilament light is a biomarker of neuropathology in several adult‐onset neurological diseases. Our objective was to assess whether circulating neurofilament light is a biomarker that is responsive to enzyme replacement therapy (ERT) in CLN2 disease.

  • Leukocyte telomere length in patients with myotonic dystrophy type I: a pilot study
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-12-05
    Youjin Wang, Ana Best, Roberto Fernández‐Torrón, Rotana Alsaggaf, Mikel Garcia‐Puga, Casey L. Dagnall, Belynda Hicks, Mone’t Thompson, Ander Matheu Fernandez, Miren Zulaica Ijurco, Mark H. Greene, Adolfo Lopez de Munain, Shahinaz M. Gadalla

    Myotonic dystrophy type I (DM1) is an autosomal dominant disease of which clinical manifestations resemble premature aging. We evaluated the contribution of telomere length in pathogenesis in 361 DM1 patients (12 with serial measurements) and 223 unaffected relative controls using qPCR assay. While no differences in baseline leukocyte relative telomere length (RTL) was noted, the data suggested an accelerated RTL attrition in DM1 (discovery cohort: T/S change/year = −0.013 in DM1 vs. −0.005 in controls, P = 0.04); similar trend was noted in validation cohort. Further investigations are needed to examine the role of TL in the pathophysiology of DM1.

  • Investigation of patient and observer agreement on description of seizures at initial clinical visit
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-12-05
    Maha N. Saleem, Christopher A. Arencibia, Kevin McKenna, Sabrina Cristofaro, Kamil Detyniecki, Daniel Friedman, Jacqueline French, Hal Blumenfeld,

    There have been few studies of agreement between seizure descriptions obtained from patients and observers. We investigated 220 patients and observers who completed structured questionnaires about patients’ semiological seizure features at the initial clinical visit. Inter‐rater reliability was assessed using Cohen’s kappa and indices of positive and negative agreement. Patients and observers had excellent agreement on the presence of memory impairment and generalized shaking and stiffness during seizures. In addition, patients under‐reported seizure descriptions more easily observed externally, whereas observers under‐reported change in patient location at seizure end. These findings may guide interpretation of clinical histories obtain in epilepsy care.

  • Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-12-03
    Jonathan M. Payne, Stephen J. C. Hearps, Karin S. Walsh, Iris Paltin, Belinda Barton, Nicole J. Ullrich, Kristina M. Haebich, David Coghill, Gerard A. Gioia, Alan Cantor, Gary Cutter, James H. Tonsgard, David Viskochil, Celiane Rey‐Casserly, Elizabeth K. Schorry, Joseph D. Ackerson, Laura Klesse, Michael J. Fisher, David H. Gutmann, Tena Rosser, Roger J. Packer, Bruce Korf, Maria T. Acosta, Kathryn N. North,

    Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism‐based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test‐retest reliability of the measures and the application of data reduction techniques to improve reproducibility.

  • Severe white matter damage in SHANK3 deficiency: a human and translational study
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-12-02
    Sarah Jesse, Hans‐Peter Müller, Michael Schoen, Harun Asoglu, Juergen Bockmann, Hans‐Juergen Huppertz, Volker Rasche, Albert C. Ludolph, Tobias M. Boeckers, Jan Kassubek

    Heterozygous SHANK3 mutations or partial deletions of the long arm of chromosome 22, also known as Phelan–McDermid syndrome, result in a syndromic form of the autism spectrum as well as in global developmental delay, intellectual disability, and several neuropsychiatric comorbidities. The exact pathophysiological mechanisms underlying the disease are still far from being deciphered but studies of SHANK3 models have contributed to the understanding of how the loss of the synaptic protein SHANK3 affects neuronal function.

  • APP‐derived peptides reflect neurodegeneration in frontotemporal dementia
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-12-02
    Ignacio Illán‐Gala, Jordi Pegueroles, Victor Montal, Daniel Alcolea, Eduard Vilaplana, Alexandre Bejanin, Sergi Borrego‐Écija, Frederic Sampedro, Andrea Subirana, María‐Belén Sánchez‐Saudinós, Ricard Rojas‐García, Hugo Vanderstichele, Rafael Blesa, Jordi Clarimón, Anna Antonell, Albert Lladó, Raquel Sánchez‐Valle, Juan Fortea, Alberto Lleó

    We aimed to investigate the relationship between cerebrospinal fluid levels (CSF) of amyloid precursor protein (APP)‐derived peptides related to the amyloidogenic pathway, cortical thickness, neuropsychological performance, and cortical gene expression profiles in frontotemporal lobar degeneration (FTLD)‐related syndromes, Alzheimer’s disease (AD), and healthy controls.

  • A data mining approach for classification of orthostatic and essential tremor based on MRI‐derived brain volume and cortical thickness
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-26
    Julián Benito‐León, Elan D. Louis, Virginia Mato‐Abad, Alvaro Sánchez‐Ferro, Juan P. Romero, Michele Matarazzo, J. Ignacio Serrano

    Orthostatic tremor (OT) is an extremely rare, misdiagnosed, and underdiagnosed disorder affecting adults in midlife. There is debate as to whether it is a different condition or a variant of essential tremor (ET), or even, if both conditions coexist. Our objective was to use data mining classification methods, using magnetic resonance imaging (MRI)‐derived brain volume and cortical thickness data, to identify morphometric measures that help to discriminate OT patients from those with ET.

  • Default mode network anatomy and function is linked to pediatric concussion recovery
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-22
    Kartik K. Iyer, Andrew Zalesky, Karen M. Barlow, Luca Cocchi

    To determine whether anatomical and functional brain features relate to key persistent post–concussion symptoms (PPCS) in children recovering from mild traumatic brain injuries (mTBI), and whether such brain indices can predict individual recovery from PPCS.

  • High‐frequency oscillations mirror severity of human temporal lobe seizures
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-21
    Jan Schönberger, Nadja Birk, Daniel Lachner‐Piza, Matthias Dümpelmann, Andreas Schulze‐Bonhage, Julia Jacobs

    Many patients with epilepsy have both focal and bilateral tonic‐clonic seizures (BTCSs), but it is largely unclear why ictal activity spreads only sometimes. Previous work indicates that interictal high‐frequency oscillations (HFOs), traditionally subdivided into ripples (80–250 Hz) and fast ripples (250–500 Hz), are a promising biomarker of epileptogenicity. We aimed to investigate whether HFOs correlate with the emergence of seizure activity and whether they differ between focal seizures (FSs) with impaired awareness and BTCSs.

  • Combined use of CSF NfL and CSF TDP‐43 improves diagnostic performance in ALS
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-19
    Takashi Kasai, Yuta Kojima, Takuma Ohmichi, Harutsugu Tatebe, Yukiko Tsuji, Yu‐ichi Noto, Fukiko Kitani‐Morii, Makiko Shinomoto, David Allsop, Toshiki Mizuno, Takahiko Tokuda

    To determine the diagnostic and prognostic significance of neurofilament light chain (NfL), TAR DNA‐binding protein 43 (TDP‐43), and total tau (t‐tau) in cerebrospinal fluid (CSF) and plasma of patients with amyotrophic lateral sclerosis (ALS) and to investigate whether the combined use of those biomarker candidates can improve their diagnostic performance.

  • α‐Synuclein in blood cells differentiates Parkinson’s disease from healthy controls
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-19
    Suaad Abd Elhadi, Jessica Grigoletto, Maura Poli, Paolo Arosio, David Arkadir, Ronit Sharon

    To determine whether blood cells expressed α‐Syn can differentiate Parkinson’s disease (PD) from healthy controls (HC).

  • Diet quality and chronic axonal polyneuropathy: a population‐based study
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-18
    Noor E. Taams, Trudy Voortman, Rens Hanewinckel, Judith Drenthen, Pieter A. van Doorn, Mohammad A. Ikram

    To investigate the association between diet quality and chronic axonal polyneuropathy.

  • A unified brain system of orientation and its disruption in Alzheimer’s disease
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-18
    Amnon Dafni‐Merom, Gregory Peters‐Founshtein, Shlomzion Kahana‐Merhavi, Shahar Arzy

    To investigate whether a unified brain system manages one’s orientation to different places, events and people in one’s environment, and test the hypothesis that failure of this system (disorientation) is an early sign of Alzheimer’s disease (AD).

  • Children with Narcolepsy type 1 have increased T‐cell responses to orexins
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-15
    Andrew C. Cogswell, Kiran Maski, Thomas E. Scammell, Dominique Tucker, Zachary S. Orban, Igor J. Koralnik

    Narcolepsy type 1 (NT1) is caused by severe loss of the orexin neurons, and is highly associated with HLA DQB1*06:02. Using intracellular cytokine staining, we observed a higher frequency of IFN‐γ‐ and TNF‐α‐producing CD4+ and CD8+ T‐cells in response to orexins in 27 children with NT1 compared to 15 healthy control children. Conversely, no such difference was observed between 14 NT1 and 16 HC adults. In addition, priming with flu peptides amplified the T‐cell response to orexins in children with NT1. Our data suggests that NT1 may be caused by an autoimmune T‐cell response to orexins, possibly triggered by flu antigens.

  • A CXCR4 receptor agonist strongly stimulates axonal regeneration after damage
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-14
    Giulia Zanetti, Samuele Negro, Aram Megighian, Andrea Mattarei, Florigio Lista, Silvia Fillo, Michela Rigoni, Marco Pirazzini, Cesare Montecucco

    To test whether the signaling axis CXCL12α‐CXCR4 is activated upon crush/cut of the sciatic nerve and to test the activity of NUCC‐390, a new CXCR4 agonist, in promoting nerve recovery from damage.

  • Study partner‐reported decline identifies cognitive decline and dementia risk
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-13
    Rachel L. Nosheny, Chengshi Jin, John Neuhaus, Philip S. Insel, Robert Scott Mackin, Michael W. Weiner,

    Identifying individuals at risk for cognitive decline, Mild Cognitive Impairment (MCI), and dementia due to Alzheimer’s disease (AD) is a critical need. Functional decline is associated with risk and can be efficiently assessed by participants and study partners (SPs). We tested the hypothesis that SP‐reported functional decline is an independent predictor of dementia risk and cognitive decline.

  • A machine learning algorithm successfully screens for Parkinson's in web users
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-12
    Brit Youngmann, Liron Allerhand, Ora Paltiel, Elad Yom‐Tov, David Arkadir

    To develop, apply, and evaluate, a novel web‐based classifier for screening for Parkinson disease among a large cohort of search engine users.

  • Antecedent infections in Guillain‐Barré syndrome: a single‐center, prospective study
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-12
    Yanlei Hao, Weifang Wang, Bart C. Jacobs, Baojun Qiao, Mengshi Chen, Daiqiang Liu, Xungang Feng, Yuzhong Wang

    To investigate the spectrum of antecedent infections in Chinese patients with Guillain‐Barré syndrome (GBS) and analyze the infections‐related clinical phenotypes locally.

  • Plasma urate concentrations and possible REM sleep behavior disorder
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-12
    Yun Shen, Junjuan Li, Michael Schwarzschild, Milena Pavlova, Songbin He, Alberto Ascherio, Shouling Wu, Liufu Cui, Xiang Gao

    To examine how urate concentrations are related to the risk of having possible REM sleep behavior disorder (pRBD) in a community‐based cohort.

  • SCN1B‐linked early infantile developmental and epileptic encephalopathy
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-11
    Alec Aeby, Claudine Sculier, Alexandra A. Bouza, Brandon Askar, Damien Lederer, Anne‐Sofie Schoonjans, Marc Vander Ghinst, Berten Ceulemans, James Offord, Luis F. Lopez‐Santiago, Lori L. Isom

    Patients with Early Infantile Epileptic Encephalopathy (EIEE) 52 have inherited, homozygous variants in the gene SCN1B, encoding the voltage‐gated sodium channel (VGSC) β1 and β1B non‐pore‐forming subunits.

  • Safety of slow‐pulsed transcranial electrical stimulation in acute spike suppression
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-11
    Mark D. Holmes, Rui Feng, Mackenzie V. Wise, Chengxin Ma, Ceon Ramon, Jinsong Wu, Phan Luu, Jidong Hou, Li Pan, Don M. Tucker

    We examined the effects of slow‐pulsed transcranial electrical stimulation (TES) in suppressing epileptiform discharges in seven adults with refractory epilepsy. An MRI‐based realistic head model was constructed for each subject and co‐registered with 256‐channel dense EEG (dEEG). Interictal spikes were localized, and TES targeted the cortical source of each subject's principal spike population. Targeted spikes were suppressed in five subject's (29/35 treatment days overall), and nontargeted spikes were suppressed in four subjects. Epileptiform activity did not worsen. This study suggests that this protocol, designed to induce long‐term depression (LTD), is safe and effective in acute suppression of interictal epileptiform discharges.

  • Familial deep cavitating state with a glutathione metabolism defect
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-09
    John Rendu, Laetitia Van Noolen, Catherine Garrel, Julie Brocard, Isabelle Marty, Christelle Corne, Julien Fauré, Gérard Besson

    Adult genetic disorders causing brain lesions have been mostly described as white matter vanishing diseases. We present here the investigations realized in patients referred for psychiatric disorder with magnetic resonance imaging showing atypical basal ganglia lesions. Genetic explorations of this family revealed a new hereditary disease linked to glutathione metabolism.

  • Mid‐life and late‐life vascular risk factor burden and neuropathology in old age
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-05
    Sarah C. Conner, Matthew P. Pase, Herman Carneiro, Mekala R. Raman, Ann C. McKee, Victor E. Alvarez, Jamie M. Walker, Claudia L. Satizabal, Jayandra J. Himali, Thor D. Stein, Alexa Beiser, Sudha Seshadri

    To determine whether vascular risk factor burden in mid‐ or late‐life associates with postmortem vascular and neurodegenerative pathologies in a community‐based sample.

  • MEFV gene mutations in neuro‐Behçet's disease and neuro‐Sweet disease
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-04
    Hidehiro Ishikawa, Akihiro Shindo, Yuichiro Ii, Dai Kishida, Atsushi Niwa, Yamato Nishiguchi, Keita Matsuura, Natsuko Kato, Akane Mizutani, Kei Tachibana, Yoshinori Hirata, Hirofumi Matsuyama, Ai Ogawa‐Ito, Akira Taniguchi, Hidekazu Tomimoto

    Mediterranean fever (MEFV) gene mutations are associated with familial Mediterranean fever (FMF). Recent studies have suggested that MEFV gene mutations may act as disease modifiers in neuro‐Behçet's (NBD) disease and neuro‐Sweet disease (NSD). We investigated MEFV genes and clinical features in 17 patients with NBD or NSD. MEFV gene mutations were frequently observed (70.6%). Headaches and exertional leg pain were associated with MEFV gene mutations (P < 0.05). Moreover, higher frequency of white matter lesions without sites predilection (P < 0.05) and non‐parenchymal lesions (P < 0.05) were also observed. MEFV gene mutations may be associated with particular findings and lesion sites.

  • Impact of FcγR variants on the response to alemtuzumab in multiple sclerosis
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-04
    Christian W. Keller, Tobias Ruck, Donal McHugh, Steffen Pfeuffer, Catharina C. Gross, Catharina Korsukewitz, Nico Melzer, Luisa Klotz, Sven G. Meuth, Christian Münz, Falk Nimmerjahn, Heinz Wiendl, Jan D. Lünemann

    Allelic variants of genes encoding for the Fc gamma receptors IIIA and IIA have been associated with the clinical response to cell‐depleting antibodies in lymphoma patients. Here, we tested the hypothesis that FCGR3A and FCGR2A high‐affinity polymorphisms predict clinical outcomes to alemtuzumab therapy in 85 patients with relapsing‐remitting multiple sclerosis. No differences in clinical and MRI‐based efficacy parameters, the development of severe infusion‐associated reactions and secondary autoimmune diseases during a 2 year follow‐up was observed based on FCGR3A or FCGR2A polymorphisms. This study does not support the use of FCGR genetic variants to predict clinical outcomes to alemtuzumab.

  • Intranasal midazolam as first‐line inhospital treatment for status epilepticus: a pharmaco‐EEG cohort study
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-04
    Lara Kay, Nina Merkel, Anemone von Blomberg, Laurent M. Willems, Sebastian Bauer, Philipp S. Reif, Susanne Schubert‐Bast, Felix Rosenow, Adam Strzelczyk

    We sought to evaluate the efficacy and tolerability of intranasal midazolam (in‐MDZ) as first‐line inhospital therapy in patients with status epilepticus (SE) during continuous EEG recording.

  • Phenotypes and malignancy risk of different FUS mutations in genetic amyotrophic lateral sclerosis
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-04
    Marcel Naumann, Kevin Peikert, Rene Günther, Anneke J. van der Kooi, Eleonora Aronica, Annemarie Hübers, Veronique Danel, Philippe Corcia, Francisco Pan‐Montojo, Sebahattin Cirak, Göknur Haliloglu, Albert C. Ludolph, Anand Goswami, Peter M. Andersen, Johannes Prudlo, Florian Wegner, Philip Van Damme, Jochen H. Weishaupt, Andreas Hermann

    Mutations in Fused in Sarcoma (FUS or TLS) are the fourth most prevalent in Western European familial amyotrophic lateral sclerosis (ALS) populations and have been associated with causing both early and very late disease onset. FUS aggregation, DNA repair deficiency, and genomic instability are contributors to the pathophysiology of FUS‐ALS, but their clinical significance per se and their influence on the clinical variability have yet to be sufficiently investigated. The aim of this study was to analyze genotype–phenotype correlations and malignancy rates in a newly compiled FUS‐ALS cohort.

  • De novo NSF mutations cause early infantile epileptic encephalopathy
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-01
    Hisato Suzuki, Takeshi Yoshida, Naoya Morisada, Tomoko Uehara, Kenjiro Kosaki, Katsunori Sato, Kohei Matsubara, Toshiyuki Takano‐Shimizu, Toshiki Takenouchi

    N‐ethylmaleimide‐sensitive factor (NSF) plays a critical role in intracellular vesicle transport, which is essential for neurotransmitter release. Herein, we, for the first time, document human monogenic disease phenotype of de novo pathogenic variants in NSF, that is, epileptic encephalopathy of early infantile onset. When expressed in the developing eye of Drosophila, the mutant NSF severely affected eye development, while the wild‐type allele had no detectable effect under the same conditions. Our findings suggest that the two pathogenic variants exert a dominant negative effect. De novo heterozygous mutations in the NSF gene cause early infantile epileptic encephalopathy.

  • Iron homeostasis, complement, and coagulation cascade as CSF signature of cortical lesions in early multiple sclerosis
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-11-01
    Roberta Magliozzi, Simon Hametner, Francesco Facchiano, Damiano Marastoni, Stefania Rossi, Marco Castellaro, Alberto Poli, Federico Lattanzi, Andrea Visconti, Richard Nicholas, Richard Reynolds, Salvatore Monaco, Hans Lassmann, Massimiliano Calabrese

    Intrathecal inflammation, compartmentalized in cerebrospinal fluid (CSF) and in meningeal infiltrates, has fundamental role in inflammation, demyelination, and neuronal injury in cerebral cortex in multiple sclerosis (MS). Since the exact link between intrathecal inflammation and mechanisms of cortical pathology remains unknown, we aimed to investigate a detailed proteomic CSF profiling which is able to reflect cortical damage in early MS.

  • Erratum: Hearing impairment after subarachnoid hemorrhage.
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-05-30

    [This corrects the article DOI: 10.1002/acn3.714.].

  • Erratum: Leigh syndrome caused by mutations in MTFMT is associated with a better prognosis.
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-04-26

    [This corrects the article DOI: 10.1002/acn3.725.].

  • Lysosomal abnormalities in hereditary spastic paraplegia types SPG15 and SPG11.
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2014-07-08
    Benoît Renvoisé,Jaerak Chang,Rajat Singh,Sayuri Yonekawa,Edmond J FitzGibbon,Ami Mankodi,Adeline Vanderver,Alice Schindler,Camilo Toro,William A Gahl,Don J Mahuran,Craig Blackstone,Tyler Mark Pierson

    OBJECTIVE Hereditary spastic paraplegias (HSPs) are among the most genetically diverse inherited neurological disorders, with over 70 disease loci identified (SPG1-71) to date. SPG15 and SPG11 are clinically similar, autosomal recessive disorders characterized by progressive spastic paraplegia along with thin corpus callosum, white matter abnormalities, cognitive impairment, and ophthalmologic abnormalities. Furthermore, both have been linked to early-onset parkinsonism. METHODS We describe two new cases of SPG15 and investigate cellular changes in SPG15 and SPG11 patient-derived fibroblasts, seeking to identify shared pathogenic themes. Cells were evaluated for any abnormalities in cell division, DNA repair, endoplasmic reticulum, endosomes, and lysosomes. RESULTS Fibroblasts prepared from patients with SPG15 have selective enlargement of LAMP1-positive structures, and they consistently exhibited abnormal lysosomal storage by electron microscopy. A similar enlargement of LAMP1-positive structures was also observed in cells from multiple SPG11 patients, though prominent abnormal lysosomal storage was not evident. The stabilities of the SPG15 protein spastizin/ZFYVE26 and the SPG11 protein spatacsin were interdependent. INTERPRETATION Emerging studies implicating these two proteins in interactions with the late endosomal/lysosomal adaptor protein complex AP-5 are consistent with shared abnormalities in lysosomes, supporting a converging mechanism for these two disorders. Recent work with Zfyve26-/- mice revealed a similar phenotype to human SPG15, and cells in these mice had endolysosomal abnormalities. SPG15 and SPG11 are particularly notable among HSPs because they can also present with juvenile parkinsonism, and this lysosomal trafficking or storage defect may be relevant for other forms of parkinsonism associated with lysosomal dysfunction.

  • GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine.
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2014-05-20
    Tyler Mark Pierson,Hongjie Yuan,Eric D Marsh,Karin Fuentes-Fajardo,David R Adams,Thomas Markello,Gretchen Golas,Dimitre R Simeonov,Conisha Holloman,Anel Tankovic,Manish M Karamchandani,John M Schreiber,James C Mullikin,,Cynthia J Tifft,Camilo Toro,Cornelius F Boerkoel,Stephen F Traynelis,William A Gahl

    OBJECTIVE Early-onset epileptic encephalopathies have been associated with de novo mutations of numerous ion channel genes. We employed techniques of modern translational medicine to identify a disease-causing mutation, analyze its altered behavior, and screen for therapeutic compounds to treat the proband. METHODS Three modern translational medicine tools were utilized: 1) high-throughput sequencing technology to identify a novel de novo mutation; 2) in vitro expression and electrophysiology assays to confirm the variant protein's dysfunction; and 3) screening of existing drug libraries to identify potential therapeutic compounds. RESULTS A de novo GRIN2A missense mutation (c.2434C>A; p.L812M) increased the charge transfer mediated by NMDA receptors containing the mutant GluN2A-L812M subunit. In vitro analysis with NMDA receptor blockers indicated that GLuN2A-L812M-containing NMDARs retained their sensitivity to the use-dependent channel blocker memantine; while screening of a previously reported GRIN2A mutation (N615K) with these compounds produced contrasting results. Consistent with these data, adjunct memantine therapy reduced our proband's seizure burden. INTERPRETATION This case exemplifies the potential for personalized genomics and therapeutics to be utilized for the early diagnosis and treatment of infantile-onset neurological disease.

  • 更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Erratum: Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease.
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2019-03-09

    [This corrects the article DOI: 10.1002/acn3.582.].

  • F-box/LRR-repeat protein 7 is genetically associated with Alzheimer's disease.
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2015-09-05
    Giuseppe Tosto,Hongjun Fu,Badri N Vardarajan,Joseph H Lee,Rong Cheng,Dolly Reyes-Dumeyer,Rafael Lantigua,Martin Medrano,Ivonne Z Jimenez-Velazquez,Mitchell S V Elkind,Clinton B Wright,Ralph L Sacco,Margaret Pericak-Vance,Lindsay Farrer,Ekaterina Rogaeva,Peter St George-Hyslop,Christiane Reitz,Richard Mayeux

    OBJECTIVE In the context of late-onset Alzheimer's disease (LOAD) over 20 genes have been identified but, aside APOE, all show small effect sizes, leaving a large part of the genetic component unexplained. Admixed populations, such as Caribbean Hispanics, can provide a valuable contribution because of their unique genetic profile and higher incidence of the disease. We aimed to identify novel loci associated with LOAD. METHODS About 4514 unrelated Caribbean Hispanics (2451 cases and 2063 controls) were selected for genome-wide association analysis. Significant loci were further tested in the expanded cohort that also included related family members (n = 5300). Two AD-like transgenic mice models (J20 and rTg4510) were used to study gene expression. Independent data sets of non-Hispanic Whites and African Americans were used to further validate findings, along with publicly available brain expression data sets. RESULTS A novel locus, rs75002042 in FBXL7 (5p15.1), was found genome-wide significant in the case-control cohort (odd ratio [OR] = 0.61, P = 6.19E-09) and confirmed in the related members cohorts (OR = 0.63, P = 4.7E-08). Fbxl7 protein was overexpressed in both AD-like transgenic mice compared to wild-type littermates. Publicly available microarray studies also showed significant overexpression of Fbxl7 in LOAD brains compared to nondemented controls. single-nucleotide polymorphism (SNP) rs75002042 was in complete linkage disequilibrium with other variants in two independent non-Hispanic White and African American data sets (0.0005 < P < 0.02) used for replication. INTERPRETATION FBXL7, encodes a subcellular protein involved in phosphorylation-dependent ubiquitination processes and displays proapoptotic activity. F-box proteins also modulate inflammation and innate immunity, which may be important in LOAD pathogenesis. Further investigations are needed to validate and understand its role in this and other populations.

  • Selected missense mutations impair frataxin processing in Friedreich ataxia.
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2017-08-16
    Elisia Clark,Jill S Butler,Charles J Isaacs,Marek Napierala,David R Lynch

    OBJECTIVE Frataxin (FXN) is a highly conserved mitochondrial protein. Reduced FXN levels cause Friedreich ataxia, a recessive neurodegenerative disease. Typical patients carry GAA repeat expansions on both alleles, while a subgroup of patients carry a missense mutation on one allele and a GAA repeat expansion on the other. Here, we report that selected disease-related FXN missense mutations impair FXN localization, interaction with mitochondria processing peptidase, and processing. METHODS Immunocytochemical studies and subcellular fractionation were performed to study FXN import into the mitochondria and examine the mechanism by which mutations impair FXN processing. Coimmunoprecipitation was performed to study the interaction between FXN and mitochondrial processing peptidase. A proteasome inhibitor was used to model traditional therapeutic strategies. In addition, clinical profiles of subjects with and without point mutations were compared in a large natural history study. RESULTS FXNI154F and FXNG130V missense mutations decrease FXN 81-210 levels compared with FXNWT, FXNR165C, and FXNW155R, but do not block its association with mitochondria. FXNI154F and FXNG130V also impair FXN maturation and enhance the binding between FXN 42-210 and mitochondria processing peptidase. Furthermore, blocking proteosomal degradation does not increase FXN 81-210 levels. Additionally, impaired FXN processing also occurs in fibroblasts from patients with FXNG130V. Finally, clinical data from patients with FXNG130V and FXNI154F mutations demonstrates a lower severity compared with other individuals with Friedreich ataxia. INTERPRETATION These data suggest that the effects on processing associated with FXNG130V and FXNI154F mutations lead to higher levels of partially processed FXN, which may contribute to the milder clinical phenotypes in these patients.

  • Expression of IL-33 and its epigenetic regulation in Multiple Sclerosis.
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2014-09-13
    Fanglin Zhang,John T Tossberg,Charles F Spurlock,Song-Yi Yao,Thomas M Aune,Subramaniam Sriram

    We examined the expression of IL-33 as an indicator of an innate immune response in relapsing remitting MS (RRMS) and controls. Based on our previous studies we proposed a link between the expression of IL-33 and IL-33 regulated genes to histone deacetylase (HDAC) activity and in particular HDAC3, an enzyme that plays a role in the epigenetic regulation of a number of genes including those which regulate inflammation. Our studies showed that intracellular expressions of IL-33 and IL-33 regulated genes are increased in patients with RRMS. In addition, following in vitro culture with TLR agonist lipopolysaccharide (LPS), there is increased induction of both IL-33 and HDAC3 in RRMS patients over that seen in controls. Also, culture of PBMC with IL-33 led to the expression of genes which overlapped with that seen in RRMS patients suggesting that the gene expression signature seen in RRMS may be driven by innate immune pathways. Expression of levels of IL-33 but not IL-1β (another gene regulated by TLR agonists) is completely inhibited by Trichostatin A (TSA) establishing a closer regulation of IL-33 but not IL-1β with HDAC. These results demonstrate the over expression of innate immune genes in RRMS and offer a causal link between the epigenetic regulation by HDAC and the induction of IL-33.

  • Disease-Modifying Effect of Adiponectin in Model of α-Synucleinopathies.
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2014-08-16
    Kazunari Sekiyama,Masaaki Waragai,Hiroyasu Akatsu,Shuei Sugama,Takato Takenouchi,Yoshiki Takamatsu,Masayo Fujita,Akio Sekigawa,Edward Rockenstein,Satoshi Inoue,Albert R La Spada,Eliezer Masliah,Makoto Hashimoto

    OBJECTIVE Growing evidence suggests that neurodegenerative diseases are associated with metabolic disorders, but the mechanisms are still unclear. Better comprehension of this issue might provide a new strategy for treatment of neurodegenerative diseases. We investigated possible roles of adiponectin (APN), the anti-diabetes protein, in the pathogenesis of α-synucleinopathies. METHODS Using biochemical and histological methods, we investigated autopsy brain of α-synucleinopathies including Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and analyzed the effects of APN in cellular and in mouse models of α-synucleinopathies. RESULTS We observed that APN is localized in Lewy bodies derived from α-synucleinopathies such as Parkinson's disease and dementia with Lewy bodies. In neuronal cells expressing α-synuclein (αS), aggregation of αS was suppressed by treatment with recombinant APN in an AdipoRI-AMP kinase pathway-dependent manner. Concomitantly, phosphorylation and release of αS were significantly decreased by APN, suggesting that APN may be antineurodegenerative. In transgenic mice expressing αS, both histopathology and movement disorder were significantly improved by intranasal treatment with globular APN when the treatment was initiated in the early stage of the disease. In a mouse model, reduced levels of guanosine- and inosine- monophosphates, both of which are potential stimulators of aggregation of αS, might partly contribute to suppression of aggregation of αS by APN. INTERPRETATION Taken together, APN may suppress neurodegeneration through modification of the metabolic pathway, and could possess a therapeutic potential against α-synucleinopathies.

  • Association of μ-Opioid Activation in the Prefrontal Cortex with Spontaneous Migraine Attacks - Brief Report I.
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2014-07-30
    Alexandre F DaSilva,Thiago D Nascimento,Marcos F DosSantos,Sarah Lucas,Hendrik van HolsbeecK,Misty DeBoer,Eric Maslowski,Tiffany Love,Ilkka K Martikainen,Robert A Koeppe,Yolanda R Smith,Jon-Kar Zubieta

    We evaluated in vivo the μ-opioid system during spontaneous episodic migraine headaches. Seven patients were scanned at different phases of their migraine using Positron Emission Tomography with the selective μ-opioid receptor (μOR) radiotracer [11C]carfentanil. In the ictal phase, there was μOR activation in the medial prefrontal cortex, which was strongly associated with the μOR availability level during the interictal phase. Furthermore, μ-opioid binding changes showed moderate negative correlation with the combined extension and severity of the attacks. These results indicate for the first time that there is high μOR activation in the migraineurs' brains during headache attacks in response to their pain.

  • Preventable Infections in Children with Leukodystrophy.
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2014-06-24
    Holly M Anderson,Jacob Wilkes,E Kent Korgenski,Michael A Pulsipher,Anne J Blaschke,Adam L Hersh,Rajendu Srivastava,Joshua L Bonkowsky

    Children with inherited leukodystrophies have high hospitalization rates, often associated with infection. We studied whether potentially modifiable risk factors (pre-existing in-dwelling central intravenous access, urinary catheter, hardware, or mechanical ventilation; and influenza vaccine) were associated with infection-related hospitalization in children with leukodystrophy. Central intravenous access was associated with sepsis (odds ratio (OR) 9.8); urinary catheter was associated with urinary tract infections (OR 9.0); lack of seasonal vaccination was associated with influenza (OR 6.4); and mechanical ventilation was associated with pneumonia (OR 2.7). We conclude that potentially modifiable risk factors are significantly associated with infection and hospitalization in children with leukodystrophies.

  • β1-adrenergic receptor activation enhances memory in Alzheimer's disease model.
    Ann. Clin. Transl. Neur. (IF 4.656) Pub Date : 2014-06-03
    Laurence Coutellier,Pooneh Memar Ardestani,Mehrdad Shamloo

    OBJECTIVE Deficits in social recognition and learning of social cues are major symptoms of neurodegenerative disorders such as Alzheimer's disease (AD). Here we studied the role of β1-noradrenergic signaling in cognitive function to determine whether it could be used as a potential therapeutic target for AD. METHODS Using pharmacological, biochemical and behavioral tools, we assessed social recognition and the β1-adrenergic receptor (ADR) and its downstream PKA/phospho-CREB (pCREB) signaling cascade in the medial amygdala (MeA) in Thy1-hAPPLond/Swe+(APP) mouse model of AD. RESULTS Our results demonstrated that APP mice display a significant social recognition deficit which is dependent on the β1-adrenergic system. Moreover, betaxolol, a selective β1-ADR antagonist, impaired social but not object/odor learning in C57Bl/6 mice. Our results identifies activation of the PKA/pCREB downstream of β1-ADR in MeA as responsible signaling cascade for learning of social cues in MeA. Finally, we found that xamoterol, a selective β1-ADR partial agonist, rescued the social recognition deficit of APP mice by increasing nuclear pCREB. INTERPRETATION Our data indicate that activation of β1-ADR in MeA is essential for learning of social cues, and that an impairment of this cascade in AD may contribute to pathogenesis and cognitive deficits. Therefore, selective activation of β1-ADR may be used as a therapeutic approach to rescue memory deficits in AD. Further safety and translational studies will be needed to ensure the safety of this approach.

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