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Annals of Neurology

Shuntong Hu, Robert C Knowlton, Brendon O Watson, Katarzyna M Glanowska, Geoffrey G Murphy, Jack M Parent, Yu Wang
Epileptogenic mechanisms in focal cortical dysplasia (FCD) remain elusive, as no animal models faithfully recapitulate FCD seizures, which have distinct electrographic features and a wide range of semiologies. Given that DEPDC5 plays significant roles in focal epilepsies with FCD, we used in utero electroporation with clustered regularly interspaced short palindromic repeats gene deletion to create focal somatic Depdc5 deletion in the rat embryonic brain. Animals developed spontaneous seizures with focal pathological and electroclinical features highly clinically relevant to FCD IIA, paving the way toward understanding its pathogenesis and developing mechanistic-based therapies...
August 6, 2018: Annals of Neurology
A Sebastian Lopez-Chiriboga, Christopher Klein, Anastasia Zekeridou, Andrew McKeon, Divanshu Dubey, Eoin P Flanagan, Vanda A Lennon, Jan-Mendelt Tillema, Elaine C Wirrell, Marc C Patterson, Avi Gadoth, J Gregory Aaen, J Nicholas Brenton, Jonathan D Bui, Amanda Moen, Catherine Otten, Amanda Piquet, Sean J Pittock
The clinical phenotype of leucine-rich glioma-inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) autoimmunity is well defined in adults. Data for children are limited (<10 cases). Among 13,319 pediatric patients serologically tested for autoimmune neurological disorders (2010-2017), 264 were seropositive for VGKC-complex-IgG (radioimmunoprecipitation). Only 13 (4.9%) were positive by transfected cell-binding assay for: LGI1-IgG (7), CASPR2-IgG (3) or both (3). This is significantly less than in adults...
August 3, 2018: Annals of Neurology
B R Turk, C L Nemeth, J S Marx, C Tiffany, R O Jones, B E Theisen, C F Murray, S P Kambhampati, R Ramireddy, S Singh, M R Rosen, M Kaufman, P A Watkins, S Kannan, R M Kannan, A Fatemi
OBJECTIVE: X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disorder due to mutations in the peroxisomal very long-chain fatty acyl-CoA transporter, ABCD1, with limited therapeutic options. ALD may manifest in a slowly progressive adrenomyeloneuropathy (AMN) phenotype, or switch to rapid inflammatory demyelinating cerebral disease (cALD), in which microglia have been shown to play a pathophysiological role. The aim of this study was to determine the role of patient phenotype in the immune response of ex-vivo monophagocytic cells to stimulation, and to evaluate the efficacy of polyamidoamine (PAMAM) dendrimer conjugated to the anti-oxidant precursor N-acetyl-cysteine (NAC) in modulating this immune response...
August 1, 2018: Annals of Neurology
E Jabbari, J Woodside, Mmx Tan, M Shoai, A Pittman, R Ferrari, K Y Mok, D Zhang, R H Reynolds, R de Silva, M J Grimm, G Respondek, U Müller, S Al-Sarraj, S M Gentleman, A J Lees, T T Warner, J Hardy, T Revesz, G U Höglinger, J L Holton, M Ryten, H R Morris
OBJECTIVE: The basis for clinical variation related to underlying Progressive Supranuclear Palsy (PSP) pathology is unknown. We performed a genome wide association study (GWAS) to identify genetic determinants of PSP phenotype. METHODS: Two independent pathological and clinically diagnosed PSP cohorts were genotyped and phenotyped to create Richardson's syndrome (RS) and non-RS groups. We carried out separate logistic regression GWAS to compare RS and non-RS groups and then combined datasets to carry out a whole cohort analysis (RS=367, non-RS=130)...
July 31, 2018: Annals of Neurology
Francesca Fardo, Nanna Brix Finnerup, Patrick Haggard
OBJECTIVE: A common symptom of neuropathy is the misperception of heat and pain from cold stimuli. Similar cold allodynic sensations can be experimentally induced using the Thermal-Grill Illusion (TGI) in humans. It is currently unclear whether this interaction between thermosensory and nociceptive signals depends on spinal or supraspinal integration mechanisms. To address this issue, we developed a non-invasive protocol to assess thermosensory integration across spinal segments. METHODS: We leveraged anatomical knowledge regarding dermatomes and their spinal projections to investigate potential contributions of spinal integration to the TGI...
July 31, 2018: Annals of Neurology
Joseph Moneim, Alasdair Coles, Gavin Giovannoni, Rachel Horne, Oliver Carr
No abstract text is available yet for this article.
July 31, 2018: Annals of Neurology
Jiaying Zhang, Sarah Gregory, Rachael I Scahill, Alexandra Durr, David L Thomas, Stéphane Lehericy, Geraint Rees, Sarah J Tabrizi, Hui Zhang
OBJECTIVE: Huntington's disease (HD) is a monogenic, fully penetrant neurodegenerative disorder, providing an ideal model for understanding brain changes occurring in the years prior to disease onset. Diffusion tensor imaging (DTI) studies show widespread white matter disorganization in the early pre-manifest stages (pre-HD). However, while DTI has proved informative, it provides only limited information about underlying changes in tissue properties. Neurite Orientation Dispersion and Density Imaging (NODDI) is a novel MRI technique for characterizing axonal pathology more specifically, providing metrics that separately quantify axonal density and axonal organization...
July 31, 2018: Annals of Neurology
Birgit Frauscher, Nicolás von Ellenrieder, Rina Zelmann, Christine Rogers, Dang Khoa Nguyen, Philippe Kahane, François Dubeau, Jean Gotman
OBJECTIVE: High-frequency oscillations (HFOs) are a promising biomarker for the epileptogenic zone. It has not been possible however to differentiate physiological from pathological HFOs, and baseline rates of HFO occurrence vary substantially across brain regions. This project establishes region-specific normative values for physiological HFOs and high-frequency activity (HFA). METHODS: Intracerebral stereo-encephalography recordings with channels displaying normal physiological activity and from non-lesional tissue were selected from two tertiary epilepsy centers...
July 26, 2018: Annals of Neurology
Samir Abu-Rumeileh, Veronica Redaelli, Simone Baiardi, Graeme Mackenzie, Otto Windl, Diane L Ritchie, Giuseppe Didato, Jorge Hernandez-Vara, Marcello Rossi, Sabina Capellari, Daniele Imperiale, Mario Giorgio Rizzone, Alessia Belotti, Sandro Sorbi, Annemieke J M Rozemuller, Pietro Cortelli, Ellen Gelpi, Robert G Will, Inga Zerr, Giorgio Giaccone, Piero Parchi
OBJECTIVE: Comprehensively describe the phenotypic spectrum of sporadic Fatal Insomnia (sFI) to facilitate diagnosis and management of this rare and peculiar prion disorder. METHODS: A survey among major prion disease reference Centres in Europe identified 13 patients diagnosed with sFI in the past 20 years. We undertook a detailed analysis of clinical and histopathological features, and the results of diagnostic investigations. RESULTS: Mean age at onset was 43 years and mean disease duration 30 months...
July 26, 2018: Annals of Neurology
Georgios Tsivgoulis, Aristeidis H Katsanos, Dimitris Mavridis, Zuzana Gdovinova, Michał Karliński, Mary Joan Macleod, Daniel Strbian, Niaz Ahmed
OBJECTIVE: We assessed the outcomes of intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) patients on dual antiplatelet therapy prior to stroke onset. METHODS: We analyzed prospectively collected data from the SITS International Stroke Thrombolysis Register (SITS-ISTR) on consecutive IVT-treated AIS patients during a seven-year period (2010-2017). In propensity-score matched groups of patients with dual antiplatelet pretreatment and no antiplatelet pretreatment we compared: 1) SICH, according to SITS-MOST, ECASS II and NINDS definitions, 2) 3-month mortality, 3) 3-month favorable functional outcome (FFO; mRS-scores:0-1), 4) 3-month functional independence (FI; mRS-scores:0-2) and 5) distribution of the 3-month mRS-scores...
July 26, 2018: Annals of Neurology
Xiao Jiang, Alexis Lupien-Meilleur, Sabrina Tazerart, Mathieu Lachance, Elena Samarova, Roberto Araya, Jean-Claude Lacaille, Elsa Rossignol
OBJECTIVE: Deletions of CACNA1A, encoding the α1 subunit of CaV 2.1 channels, cause epilepsy with ataxia in humans. While the deletion of Cacna1a in GABAergic interneurons (INs) derived from the medial ganglionic eminence (MGE) impairs cortical inhibition and causes generalized seizures in Nkx2.1Cre ;Cacna1ac/c mice, the targeted deletion of Cacna1a in somatostatin-expressing INs (SOM-INs), a subset of MGE-derived INs, does not result in seizures, indicating a crucial role of parvalbumin-expressing (PV) INs...
July 26, 2018: Annals of Neurology
Katherine D Holland, Thomas M Bouley, Paul S Horn
Sodium channelopathies are a common genetic cause of paroxysmal disorders of the brain, peripheral nervous system, muscle, and heart. The phenotypes produced depend on a combination of the channel affected and its functional consequence; unfortunately, for missense variants, the latter is not clinically available. However we will show that the location of a missense sodium channel variant can be used as a surrogate for functional studies. We present data from epilepsy to illustrate clinical and treatment implications of sodium channel variants, the relationship between function, location and treatment response, then generalize this to other sodium channelopathies...
July 26, 2018: Annals of Neurology
Ki-Wook Oh, Min-Young Noh, Min-Soo Kwon, Hyun Young Kim, Seong-Il Oh, Jinseok Park, Hee-Jin Kim, Chang-Seok Ki, Seung Hyun Kim
OBJECTIVE: To assess the safety and efficacy of two repeated intrathecal injections of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in amyotrophic lateral sclerosis (ALS). METHODS: In phase 2 randomized controlled trial (NCT01363401), 64 participants with ALS were randomly assigned treatments (1:1) of riluzole alone (control group, n = 31) or combined with two BM-MSCs injections (MSC group, n = 33). Safety was assessed based on the occurrence of adverse events...
July 26, 2018: Annals of Neurology
Eleonora Tamilia, Eun-Hyoung Park, Stefania Percivati, Jeffrey Bolton, Fabrizio Taffoni, Jurriaan M Peters, P Ellen Grant, Phillip L Pearl, Joseph R Madsen, Christos Papadelis
OBJECTIVE: In patients with medically refractory epilepsy (MRE), interictal ripples (80-250 Hz) are seen in large brain areas whose resection may be unnecessary for seizure-freedom. This limits their utility as epilepsy biomarkers for surgery. We assessed the spatiotemporal propagation of interictal ripples on intracranial electroencephalography (iEEG) in children with MRE, compared it with the propagation of spikes, identified ripples that initiated propagation (onset-ripples), and evaluated their clinical value as epilepsy biomarkers...
July 18, 2018: Annals of Neurology
Robert B Weiss, Veronica J Vieland, Diane M Dunn, Yuuki Kaminoh, Kevin M Flanigan
OBJECTIVE: Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disease caused by loss-of-function dystrophin (DMD) mutations in boys, who typically suffer loss of ambulation by age 12. Previously we reported that coding variants in latent transforming growth factor beta-binding protein 4 (LTBP4) were associated with reduced TGFβ signaling and prolonged ambulation (p-value = 1.0 × 10-3 ) in DMD patients; this result was subsequently replicated by other groups. In this study, we evaluated whether additional DMD modifier genes are observed using whole genome association in the original cohort...
July 16, 2018: Annals of Neurology
Melania Spadaro, Stephan Winklmeier, Eduardo Beltrán, Caterina Macrini, Romana Höftberger, Elisabeth Schuh, Franziska S Thaler, Lisa-Ann Gerdes, Sarah Laurent, Ramona Gerhards, Simone Brändle, Klaus Dornmair, Constanze Breithaupt, Markus Krumbholz, Markus Moser, Gurumoorthy Kirshnamoorthy, Frits Kamp, Dieter Jenne, Reinhard Hohlfeld, Tania Kümpfel, Hans Lassmann, Naoto Kawakami, Edgar Meinl
OBJECTIVE: Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) occur in a proportion of patients with inflammatory demyelinating diseases of the CNS. We analyzed their pathogenic activity by affinity-purifying these Abs from patients and transferring them to experimental animals. METHODS: Patients with Abs to MOG were identified by cell-based assay. We determined the cross-reactivity to rodent MOG and determined the recognized MOG-epitopes. We produced the correctly folded extracellular domain of MOG and affinity-purified MOG-specific Abs from the blood of patients...
July 16, 2018: Annals of Neurology
Lamia Ghezali, Carmen Capone, Céline Baron-Menguy, Julien Ratelade, Søren Christensen, Lars Østergaard Pedersen, Valérie Domenga-Denier, Jan Torleif Pedersen, Anne Joutel
OBJECTIVE: CADASIL, caused by dominant mutations in the NOTCH3 receptor, is the most aggressive small vessel disease of the brain. A key feature of its pathogenesis is accumulation of the extracellular domain of NOTCH3 receptor (Notch3ECD ) in small vessels, with formation of characteristic extracellular deposits termed granular osmiophilic material (GOM). Here, we investigated the therapeutic potential of a mouse monoclonal antibody (5E1) that specifically recognizes Notch3ECD . METHODS: The binding affinity of 5E1 towards purified NOTCH3 was assessed using Octet analysis...
July 16, 2018: Annals of Neurology
(no author information available yet)
OBJECTIVE: After the initial report of a CHCHD10 mutation in mitochondrial disease with features resembling amyotrophic lateral sclerosis (ALS), CHCHD10 mutations have been considered to be a frequent cause for ALS. However, the exact pathogenicity and clinical significance of these mutations remain unclear. Here, we aimed to determine the role of CHCHD10 mutations in ALS. METHODS: We analyzed 4,365 whole-genome sequenced ALS patients and 1,832 controls from 7 different countries and examined all non-synonymous single nucleotide variants (SNVs) in CHCHD10...
July 16, 2018: Annals of Neurology
Juho Joutsa, Ludy C Shih, Andreas Horn, Martin M Reich, Ona Wu, Natalia S Rost, Michael D Fox
Brain damage can occasionally result in paradoxical functional benefit, which could help identify therapeutic targets for neuromodulation. However, these beneficial lesions are rare and lesions in multiple different brain locations can improve the same symptom. Using a technique called lesion network mapping, we show that heterogeneous lesion locations resulting in tremor relief are all connected to common nodes in the cerebellum and thalamus, the latter of which is a proven deep brain stimulation target for tremor...
July 16, 2018: Annals of Neurology
Yen Ying Lim, Jason Hassenstab, Alison Goate, Anne M Fagan, Tammie L S Benzinger, Carlos Cruchaga, Eric McDade, Jasmeer Chhatwal, Johannes Levin, Martin R Farlow, Neill R Graff-Radford, Christoph Laske, Colin L Masters, Stephen Salloway, Peter Schofield, John C Morris, Paul Maruff, Randall J Bateman
OBJECTIVE: Previous studies suggest that the brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may influence symptom onset in Alzheimer's disease (AD). Our recent cross-sectional findings suggest that Met66 may influence clinical expression in dominantly inherited AD (DIAD) through its effects on tau. However, it remains unclear whether carriage of Met66 in DIAD results in faster increases in CSF tau and ptau181 , and whether these increases are associated with accelerated brain volume loss and memory decline...
July 16, 2018: Annals of Neurology
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