bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration–motor neuron disease
Authors: Luty Agnes A. , Kwok John B.J. , Dobson‐Stone Carol , Loy Clement T. , Coupland Kirsten G. , Karlström Helena , Sobow Tomasz , Tchorzewska Joanna , Maruszak Aleksandra , Barcikowska Maria , Panegyres Peter K. , Zekanowski Cezary , Brooks William S. , Williams Kelly L. , Blair Ian P. , Mather Karen A. , Sachdev Perminder S. , Halliday Glenda M. , Schofield Peter R. 
Published: October 2010

AbstractObjective:Frontotemporal lobar degeneration (FTLD) is the most common cause of early‐onset dementia. Pathological ubiquitinated inclusion bodies observed in FTLD and motor neuron disease (MND) comprise trans‐activating response element (TAR) DNA binding protein (TDP‐43) and/or fused in sarcoma (FUS) protein. Our objective was to identify the causative gene in an FTLD‐MND pedigree with no mutations in known dementia genes.Methods:A mutation screen of candidate genes, luciferase assays, and quantitative polymerase chain reaction (PCR) was performed to identify the biological role of the putative mutation. Neuropathological characterization of affected individuals and western blot studies of cell lines were performed to identify the pathological mechanism of the mutation.Results:We identified a nonpolymorphic mutation (c.672*51G>T) in the 3′‐untranslated region (UTR) of the Sigma nonopioid intracellular receptor 1 (SIGMAR1) gene in affected individuals from the FTLD‐MND pedigree. The c.672*51G>T mutation increased gene expression by 1.4‐fold, corresponding with a significant 1.5‐fold to 2‐fold change in the SIGMAR1 transcript or Sigma‐1 protein in lymphocyte or brain tissue. Brains of SIGMAR1 mutation carriers displayed a unique pathology with cytoplasmic inclusions immunopositive for either TDP‐43 or FUS but not Sigma‐1. Overexpression of SIGMAR1 shunted TDP‐43 and FUS from the nucleus to the cytoplasm by 2.3‐fold and 5.2‐fold, respectively. Treatment of cells with Sigma‐1 ligands significantly altered translocation of TDP‐43 by up to 2‐fold.Interpretation:SIGMAR1 is a causative gene for familial FTLD‐MND with a unique neuropathology that differs from other FTLD and MND cases. Our findings also suggest Sigma‐1 drugs as potential treatments for the TDP‐43/FUS proteinopathies. Ann Neurol 2010;68:639–649
DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53‐dependent myopathy in vivo
Authors: Wallace Lindsay M. , Garwick Sara E. , Mei Wenyan , Belayew Alexandra , Coppee Frederique , Ladner Katherine J. , Guttridge Denis , Yang Jing , Harper Scott Q. 
Published: October 2010

AbstractObjective:Facioscapulohumeral muscular dystrophy (FSHD) is associated with D4Z4 repeat contraction on human chromosome 4q35. This genetic lesion does not result in complete loss or mutation of any gene. Consequently, the pathogenic mechanisms underlying FSHD have been difficult to discern. In leading FSHD pathogenesis models, D4Z4 contractions are proposed to cause epigenetic changes, which ultimately increase expression of genes with myopathic potential. Although no gene has been conclusively linked to FSHD development, recent evidence supports a role for the D4Z4‐encoded DUX4 gene in FSHD. In this study, our objective was to test the in vivo myopathic potential of DUX4.Methods:We delivered DUX4 to zebrafish and mouse muscle by transposon‐mediated transgenesis and adeno‐associated viral vectors, respectively.Results:Overexpression of DUX4, which encodes a transcription factor, caused abnormalities associated with muscular dystrophy in zebrafish and mice. This toxicity required DNA binding, because a DUX4 DNA binding domain mutant produced no abnormalities. Importantly, we found the myopathic effects of DUX4 were p53 dependent, as p53 inhibition mitigated DUX4 toxicity in vitro, and muscles from p53 null mice were resistant to DUX4‐induced damage.Interpretation:Our work demonstrates the myopathic potential of DUX4 in animal muscle. Considering previous studies showed DUX4 was elevated in FSHD patient muscles, our data support the hypothesis that DUX4 overexpression contributes to FSHD development. Moreover, we provide a p53‐dependent mechanism for DUX4 toxicity that is consistent with previous studies showing p53 pathway activation in FSHD muscles. Our work justifies further investigation of DUX4 and the p53 pathway in FSHD pathogenesis. Ann Neurol 2010
More severe white matter changes in the elderly with jugular venous reflux
Authors: Chung Chih‐Ping , Wang Pei‐Ning , Wu Yi‐Hui , Tsao Yu‐Chien , Sheng Wen‐Yung , Lin Ker‐Neng , Lin Shing‐Jong , Hu Han‐Hwa 
Published: October 2010

AbstractObjectiveThe etiology of age‐related white matter changes is unclear. Cerebral white matter changes on magnetic resonance imaging (MRI) and progressive dementia have been reported in patients with dural arteriovenous fistulas of the sigmoid sinus. The frequency of jugular venous reflux, which mimics a dural arteriovenous fistula, significantly increases with age. We investigated whether jugular venous reflux was associated with the severity of age‐related white matter changes in 97 persons (aged 55–90 years, mean [standard deviation]: 75.77 [8.19] years; 55 men) from a medical center memory clinic.MethodsMRI (1.5T) and the semiquantitative Scheltens scale were used to investigate the severity of white matter changes. Subjects were classified into 3 groups (no, mild, and severe jugular venous reflux) by duplex ultrasonography.ResultsSubjects with severe jugular venous reflux had more severe age‐related white matter changes in occipital subcortical, thalamus, pontine, and summed infratentorial regions compared with subjects with no jugular venous reflux (all corrected p
< 0.0166), especially subjects aged ≥75 years (corrected p
< 0.0166 in occipital subcortical; corrected p
< 0.0001 in pontine and summed infratentorial regions). In subjects ≥75 years, we further noted that the whole brain age‐related white matter changes rating scores were higher in the severe jugular venous reflux group than the no and mild jugular venous reflux groups (corrected p
< 0.0166).InterpretationPeople with severe jugular venous reflux exhibit more severe age‐related white matter changes, especially in caudal brain regions. We also demonstrate age‐dependent jugular venous reflux effects on the severity of age‐related white matter changes. These findings may provide new clues into the pathophysiology of age‐related white matter changes. ANN NEUROL 2011
CR1 is associated with amyloid plaque burden and age‐related cognitive decline
Authors: Chibnik Lori B. , Shulman Joshua M. , Leurgans Sue E. , Schneider Julie A. , Wilson Robert S. , Tran Dong , Aubin Cristin , Buchman Aron S. , Heward Christopher B. , Myers Amanda J. , Hardy John A. , Huentelman Matthew J. , Corneveaux Jason J. , Reiman Eric M. , Evans Denis A. , Bennett David A. , De Jager Philip L. 
Published: October 2010

AbstractObjectiveRecently, genome‐wide association studies have identified 3 new susceptibility loci for Alzheimer's disease (AD), CLU, CR1, and PICALM. We leveraged available neuropsychological and autopsy data from 2 cohort studies to investigate whether these loci are associated with cognitive decline and AD neuropathology.MethodsThe Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP) are longitudinal studies that enroll nondemented subjects and include annual clinical evaluations and brain donation at death. We evaluated CR1 (rs6656401), CLU (rs11136000), and PICALM (rs7110631) in 1,666 subjects. We evaluated associations between genotypes and rate of change in cognitive function as well as AD‐related pathology. Lastly, we used pathway analysis to determine whether relationships between single nucleotide polymorphisms and cognitive decline are mediated through AD pathology.ResultsAmong our study cohort, the mean years of follow‐up were 7.8 for ROS and 4.3 for MAP. Only the CR1 locus was associated with both global cognitive decline (p = 0.011) and global AD pathology (p = 0.025). More specifically, the locus affects the deposition of neuritic amyloid plaque (p = 0.009). In a mediation analysis, controlling for amyloid pathology strongly attenuated the effect of the CR1 locus on cognitive decline.InterpretationWe found that common variation at the CR1 locus has a broad impact on cognition and that this effect is largely mediated by an individual's amyloid plaque burden. We therefore highlight 1 functional consequence of the CR1 susceptibility allele and generalize the role of this locus to cognitive aging in the general population. ANN NEUROL 2011
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome mutations increase susceptibility to spreading depression
Authors: Eikermann‐Haerter Katharina , Yuzawa Izumi , Dilekoz Ergin , Joutel Anne , Moskowitz Michael A. , Ayata Cenk 
Published: October 2010

AbstractMigraine with aura is often the first manifestation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome (CADASIL), a disorder caused by NOTCH3 gene mutations expressed predominantly in vascular smooth muscle. Here, we report that cortical spreading depression (CSD), the electrophysiological substrate of migraine aura, is enhanced in mice expressing a vascular Notch 3 CADASIL mutation (R90C) or a Notch 3 knockout mutation. The phenotype was stronger in Notch 3 knockout mice, implicating both loss of function and neomorphic mutations in its pathogenesis. Our results link vascular smooth muscle Notch 3 mutations to enhanced spreading depression susceptibility, implicating the neurovascular unit in the development of migraine aura. Ann Neurol 2011
Olfaction and color vision identify impending neurodegeneration in rapid eye movement sleep behavior disorder
Authors: Postuma Ronald B. , Gagnon Jean‐François , Vendette Mélanie , Desjardins Catherine , Montplaisir Jacques Y. 
Published: October 2010

AbstractObjective:For development of neuroprotective therapy, neurodegenerative disease must be identified as early as possible. However, current means of identifying “preclinical” neurodegeneration are limited. Patients with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) are at >50% risk of synuclein‐mediated neurodegenerative disease—this provides a unique opportunity to directly observe preclinical synucleinopathy and to test potential markers of preclinical disease.Methods:Patients with RBD without neurodegenerative disease were enrolled in a prospective cohort starting in 2004. Olfaction and color vision were tested at baseline, then annually for 5 years. Test results were compared between patients who developed neurodegenerative disease and those who remained disease‐free.Results:Out of 64 patients, 62 (97%) participated in annual follow‐up. During follow‐up, 21 developed disease, and 41 remained disease‐free. Out of 21, 16 developed a combination of parkinsonism and dementia, 4 developed isolated parkinsonism (all with tremor), and 1 developed isolated dementia. Compared to those remaining disease‐free, patients destined to develop disease had worse baseline olfaction (University of Pennsylvania Smell Identification Test [UPSIT] = 58.3 ± 27.0% age/sex‐adjusted normal vs 80.2 ± 26.3%; p = 0.003) and color vision (Farnsworth‐Munsell 100‐Hue color test [FM‐100] errors 153.0 ± 82.2% normal vs 120.2 ± 26.5%; p = 0.022). Kaplan‐Meier 5‐year‐disease‐free survival in those with normal olfaction was 86.0%, vs 35.4% with impaired olfaction (p = 0.029). Disease‐free survival with normal color vision was 70.3%, vs 26.0% with impaired vision (p = 0.009). Both olfaction and color vision were reduced as much as 5 years before disease diagnosis, with only slight decline in preclinical stages.Interpretation:Olfaction and color vision identify early‐stage synuclein‐mediated neurodegenerative diseases. In most cases, abnormalities are measurable at least 5 years before disease onset, and progress slowly in the preclinical stages. Ann Neurol 2011;
Large genomic deletions: A novel cause of Ullrich congenital muscular dystrophy
Authors: Foley A. Reghan , Hu Ying , Zou Yaqun , Yang Michele , Medne Līvija , Leach Meganne , Conlin Laura K. , Spinner Nancy , Shaikh Tamim H. , Falk Marni , Neumeyer Ann M. , Bliss Laurie , Tseng Brian S. , Winder Thomas L. , Bönnemann Carsten G. 
Published: October 2010

AbstractTwo mutational mechanisms are known to underlie Ullrich congenital muscular dystrophy (UCMD): heterozygous dominant negatively‐acting mutations and recessively‐acting loss‐of‐function mutations. We describe large genomic deletions on chromosome 21q22.3 as a novel type of mutation underlying recessively inherited UCMD in 2 families. Clinically unaffected parents carrying large genomic deletions of COL6A1and COL6A2also provide conclusive evidence that haploinsufficiency for COL6A1and COL6A2is not a disease mechanism for Bethlem myopathy. Our findings have important implications for the genetic evaluation of patients with collagen VI–related myopathies as well as for potential therapeutic interventions for this patient population. Ann Neurol 2011;69:206–211
Evidence for a vascular factor in migraine
Authors: Asghar Mohammad S. , Hansen Adam E. , Amin Faisal M. , van der Geest R. J. , Koning Patrick van der , Larsson Henrik B. W. , Olesen Jes , Ashina Messoud 
Published: October 2010

AbstractObjectiveIt has been suggested that migraine is caused by neural dysfunction without involvement of vasodilatation. Because dismissal of vascular mechanisms seemed premature, we examined diameter of extra‐ and intracranial vessels in migraine without aura patients.MethodsA novel high‐resolution direct magnetic resonance angiography imaging technique was used to measure arterial circumference of the extracranial middle meningeal artery (MMA) and the intracranial middle cerebral artery (MCA). Data were obtained at baseline, during migraine attack, and after treatment with the migraine abortive drug sumatriptan (a 5‐hydroxytryptamine agonist).ResultsWe found dilatation of both MMA and MCA during migraine attack (p = 0.001). Sumatriptan administration caused amelioration of headache (p
< 0.001) and contraction of MMA (p < 0.001), but MCA remained unchanged (p = 0.16). Exploratory analysis revealed that in migraine attacks with half‐sided headache, there was only dilatation on the headache side of MMA of 12.49% (95% confidence interval [CI], 4.16–20.83%) and of MCA of 12.88% (95% CI, 3.49–22.27%) and no dilatation on the nonheadache side of MMA (95% CI, −4.27 to 11.53%) and MCA (95% CI, −6.7 to 14.28%). In double‐sided headache we found bilateral vasodilatation of both MMA and MCA (p
< 0.001).InterpretationThese data show that migraine without aura is associated with dilatation of extra‐ and intracerebral arteries and that the headache location is associated with the location of the vasodilatation. Furthermore, contraction of extracerebral and not intracerebral arteries is associated with amelioration of headache. Collectively, these data suggest that vasodilatation and perivascular release of vasoactive substances is an integral mechanism of migraine pathophysiology. ANN NEUROL 2011
Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia
Authors: Lancaster Eric , Huijbers Maartje G. M. , Bar Vered , Boronat Anna , Wong Andrew , Martinez‐Hernandez Eugenia , Wilson Christina , Jacobs Dina , Lai Meizan , Walker Russell W. , Graus Francesc , Bataller Luis , Illa Isabel , Markx Sander , Strauss Kevin A. , Peles Elior , Scherer Steven S. , Dalmau Josep 
Published: October 2010

AbstractObjectiveTo report clinical and immunological investigations of contactin‐associated protein‐like 2 (Caspr2), an autoantigen of encephalitis and peripheral nerve hyperexcitability (PNH) previously attributed to voltage‐gated potassium channels (VGKC).MethodsClinical analysis was performed on patients with encephalitis, PNH, or both. Immunoprecipitation and mass spectrometry were used to identify the antigen and to develop an assay with Caspr2‐expressing cells. Immunoabsorption with Caspr2 and comparative immunostaining of brain and peripheral nerve of wild‐type and Caspr2‐null mice were used to assess antibody specificity.ResultsUsing Caspr2‐expressing cells, antibodies were identified in 8 patients but not in 140 patients with several types of autoimmune or viral encephalitis, PNH, or mutations of the Caspr2‐encoding gene. Patients' antibodies reacted with brain and peripheral nerve in a pattern that colocalized with Caspr2. This reactivity was abrogated after immunoabsorption with Caspr2 and was absent in tissues from Caspr2‐null mice. Of the 8 patients with Caspr2 antibodies, 7 had encephalopathy or seizures, 5 neuropathy or PNH, and 1 isolated PNH. Three patients also had myasthenia gravis, bulbar weakness, or symptoms that initially suggested motor neuron disease. None of the patients had active cancer; 7 responded to immunotherapy and were healthy or only mildly disabled at last follow‐up (median, 8 months; range, 6–84 months).InterpretationCaspr2 is an autoantigen of encephalitis and PNH previously attributed to VGKC antibodies. The occurrence of other autoantibodies may result in a complex syndrome that at presentation could be mistaken for a motor neuron disorder. Recognition of this disorder is important, because it responds to immunotherapy. Ann Neurol 2011
Functional rundown of gamma‐aminobutyric acidAreceptors in human hypothalamic hamartomas
Authors: Li Guohui , Yang Kechun , Zheng Chao , Liu Qiang , Chang Yongchang , Kerrigan John F. , Wu Jie 
Published: October 2010

AbstractObjectiveHuman hypothalamic hamartomas (HHs) are highly associated with treatment‐resistant gelastic seizures. HHs are intrinsically epileptogenic, although the basic cellular mechanisms responsible for seizure activity are unknown. Altered gamma‐aminobutyric acid (GABA) function can contribute to epileptogenesis in humans and animal models. Recently, functional GABAAreceptor (GABAAR) rundown has been described in surgically resected human temporal lobe epilepsy tissue. We asked whether functional GABAAR rundown also occurs in human HH neurons.MethodsGABAAR‐mediated currents were measured using perforated patch‐clamp recordings in single neurons acutely dissociated from surgically resected HH tissue. In addition, functional GABAARs were expressed inXenopusoocytes after microinjection with membrane fractions from either HH or control hypothalamus, and were studied with 2‐electrode voltage‐clamp recordings.ResultsPerforated patch‐clamp recordings in dissociated HH neurons showed that repetitive exposure to GABA (5 consecutive exposures to 0.1 mM GABA with 1‐second duration and at 20‐second intervals) induced a time‐dependent rundown of whole‐cell currents in small HH neurons, whereas large HH neurons showed much less rundown using the same protocol. Functional rundown was not observed in HH neurons with repetitive exposure to glycine or glutamate. Two‐electrode voltage‐clamp recordings (6 consecutive exposures to 1 mM GABA with 10‐second duration and at 40‐second intervals) induced GABA current rundown inXenopusoocytes microinjected with HH membrane proteins, but not in the oocytes expressing hypothalamic membrane proteins derived from human autopsy controls. Functional rundown of GABA currents was significantly attenuated by intracellular application of adenosine triphosphate or the nonspecific phosphatase inhibitor, okadaic acid.InterpretationNeurons from surgically resected human HH demonstrate functional rundown of GABAAR‐mediated transmembrane currents in response to GABA agonist exposure. Rundown may be a marker for impaired GABAergic function and a contributing mechanism for seizure genesis within HH tissue. ANN NEUROL 2011
Reversible neural stem cell niche dysfunction in a model of multiple sclerosis
Authors: Rasmussen Stine , Imitola Jaime , Ayuso‐Sacido Angel , Wang Yue , Starossom Sarah C. , Kivisäkk Pia , Zhu Bing , Meyer Morten , Bronson Roderick T. , Garcia‐Verdugo Jose Manuel , Khoury Samia J. 
Published: October 2010

AbstractObjectiveThe subventricular zone (SVZ) of the brain constitutes a niche for neural stem and progenitor cells that can initiate repair after central nervous system (CNS) injury. In a relapsing‐remitting model of experimental autoimmune encephalomyelitis (EAE), the neural stem cells (NSCs) become activated and initiate regeneration during acute disease, but lose this ability during the chronic phases of disease. We hypothesized that chronic microglia activation contributes to the failure of the NSC repair potential in the SVZ.MethodsUsing bromodeoxyuridine injections at different time points during EAE, we quantified the number of proliferating and differentiating progenitors, and evaluated the structure of the SVZ by electron microscopy. In vivo minocycline treatment during EAE was used to address the effect of microglia inactivation on SVZ dysfunction.ResultsIn vivo treatment with minocycline, an inhibitor of microglia activation, increases stem cell proliferation in both naive and EAE animals. Minocycline treatment decreases cortical and periventricular pathology in the chronic phase of EAE, improving the proliferation of Sox2 stem cells and NG2 oligodendrocyte precursors cells originating in the SVZ and their differentiation into mature oligodendrocytes.InterpretationThese data suggest that failure of repair observed during chronic EAE correlates with microglia activation and that treatments targeting chronic microglial activation have the potential for enhancing repair in the CNS. ANN NEUROL 2011
Endogenous amyloid‐β is necessary for hippocampal synaptic plasticity and memory
Authors: Puzzo Daniela , Privitera Lucia , Fa' Mauro , Staniszewski Agnieszka , Hashimoto Gakuji , Aziz Fahad , Sakurai Mikako , Ribe Elena M. , Troy Carol M. , Mercken Marc , Jung Sonia S. , Palmeri Agostino , Arancio Ottavio 
Published: October 2010

AbstractObjective:The goal of this study was to investigate the role of endogenous amyloid‐β peptide (Aβ) in healthy brain.Methods:Long‐term potentiation (LTP), a type of synaptic plasticity that is thought to be associated with learning and memory, was examined through extracellular field recordings from the CA1 region of hippocampal slices, whereas behavioral techniques were used to assess contextual fear memory and reference memory. Amyloid precursor protein (APP) expression was reduced through small interfering RNA (siRNA) technique.Results:We found that both antirodent Aβ antibody and siRNA against murine APP reduced LTP as well as contextual fear memory and reference memory. These effects were rescued by the addition of human Aβ42, suggesting that endogenously produced Aβ is needed for normal LTP and memory. Furthermore, the effect of endogenous Aβ on plasticity and memory was likely due to regulation of transmitter release, activation of α7‐containing nicotinic acetylcholine receptors, and Aβ42 production.Interpretation:Endogenous Aβ42 is a critical player in synaptic plasticity and memory within the normal central nervous system. This needs to be taken into consideration when designing therapies aiming at reducing Aβ levels to treat Alzheimer disease. Ann Neurol 2011;