3,817 results match your criteria Dementia in Motor Neuron Disease


Excellent reliability of the ALSFRS-R administered via videoconferencing: A study of people with motor neuron disease in Scotland.

J Neurol Sci 2020 Jun 21;416:116991. Epub 2020 Jun 21.

Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, UK; Department of Clinical Neurosciences, Western General Hospital, Edinburgh, UK; Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, UK. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2020.116991DOI Listing

Morphological variability is greater at developing than mature mouse neuromuscular junctions.

J Anat 2020 Jun 13. Epub 2020 Jun 13.

Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK.

The neuromuscular junction (NMJ) is the highly specialised peripheral synapse formed between lower motor neuron terminals and muscle fibres. Post-synaptic acetylcholine receptors (AChRs), which are found in high density in the muscle membrane, bind to acetylcholine released into the synaptic cleft of the NMJ, thereby enabling the conversion of motor action potentials to muscle contractions. NMJs have been studied for many years as a general model for synapse formation, development and function, and are known to be early sites of pathological changes in many neuromuscular diseases. Read More

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http://dx.doi.org/10.1111/joa.13228DOI Listing

In Vivo Imaging of Anterograde and Retrograde Axonal Transport in Rodent Peripheral Nerves.

Methods Mol Biol 2020 ;2143:271-292

Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK.

Axonal transport, which is the process mediating the active shuttling of a variety cargoes from one end of an axon to the other, is essential for the development, function, and survival of neurons. Impairments in this dynamic process are linked to diverse nervous system diseases and advanced ageing. It is thus essential that we quantitatively study the kinetics of axonal transport to gain an improved understanding of neuropathology as well as the molecular and cellular mechanisms regulating cargo trafficking. Read More

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http://dx.doi.org/10.1007/978-1-0716-0585-1_20DOI Listing
January 2020

From basic research to the clinic: innovative therapies for ALS and FTD in the pipeline.

Mol Neurodegener 2020 Jun 1;15(1):31. Epub 2020 Jun 1.

International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano 99, 34149, Trieste, Italy.

Amyotrophic lateral sclerosis (ALS) and Frontotemporal Degeneration (FTD) are neurodegenerative disorders, related by deterioration of motor and cognitive functions and short survival. Aside from cases with an inherited pathogenic mutation, the causes of the disorders are still largely unknown and no effective treatment currently exists. It has been shown that FTD may coexist with ALS and this overlap occurs at clinical, genetic, and molecular levels. Read More

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http://dx.doi.org/10.1186/s13024-020-00373-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268618PMC

Decline of cognitive and behavioral functions in amyotrophic lateral sclerosis: a longitudinal study.

Amyotroph Lateral Scler Frontotemporal Degener 2020 Jun 2:1-7. Epub 2020 Jun 2.

ALS Center, Department of Neurology, Azienda Ospedaliera Universitaria Maggiore della Carità, Novara, Italy.

: A cognitive impairment, ranging from frontotemporal dementia (FTD) to milder forms of dysexecutive or behavioral dysfunction, is detected in 30-50% of patients affected by amyotrophic lateral sclerosis (ALS) at diagnosis. Such condition considerably influences the prognosis, and possibly impacts on the decision-making process with regards to end-of-life choices. The aim of our study is to examine the changes of cognitive and behavioral impairment in a large population of ALS from the time of diagnosis to a 6-month follow-up (IQR 5. Read More

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http://dx.doi.org/10.1080/21678421.2020.1771732DOI Listing

C9orf72 suppresses systemic and neural inflammation induced by gut bacteria.

Nature 2020 06 13;582(7810):89-94. Epub 2020 May 13.

Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.

A hexanucleotide-repeat expansion in C9ORF72 is the most common genetic variant that contributes to amyotrophic lateral sclerosis and frontotemporal dementia. The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are implicated in neural degeneration. The expansion is transcribed into a long repetitive RNA, which negatively sequesters RNA-binding proteins before its non-canonical translation into neural-toxic dipeptide proteins. Read More

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http://dx.doi.org/10.1038/s41586-020-2288-7DOI Listing

Mitigation of ALS Pathology by Neuron-Specific Inhibition of Nuclear Factor Kappa B Signaling.

J Neurosci 2020 Jun 26;40(26):5137-5154. Epub 2020 May 26.

CERVO Brain Research Centre, Québec City, Québec G1J 2G3, Canada

To investigate the role of neuronal NF-κB activity in pathogenesis of amyotrophic lateral sclerosis (ALS), we generated transgenic mice with neuron-specific expression of a super-repressor form of the NF-κB inhibitor (IκBα-SR), which were then crossed with mice of both sexes, expressing ALS-linked gene mutants for TAR DNA-binding protein (TDP-43) and superoxide dismutase 1 (SOD1). Remarkably, neuronal expression of IκBα-SR transgene in mice expressing TDP-43 or TDP-43 mice led to a decrease in cytoplasmic to nuclear ratio of human TDP-43. The mitigation of TDP-43 neuropathology by IκBα-SR, which is likely due to an induction of autophagy, was associated with amelioration of cognitive and motor deficits as well as reduction of motor neuron loss and gliosis. Read More

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http://dx.doi.org/10.1523/JNEUROSCI.0536-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314413PMC

SPG7 mutations in amyotrophic lateral sclerosis: a genetic link to hereditary spastic paraplegia.

J Neurol 2020 May 23. Epub 2020 May 23.

Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.

Amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP) are motor neuron diseases sharing clinical, pathological, and genetic similarities. While biallelic SPG7 mutations are known to cause recessively inherited HSP, heterozygous SPG7 mutations have repeatedly been identified in HSP and recently also in ALS cases. However, the frequency and clinical impact of rare SPG7 variants have not been studied in a larger ALS cohort. Read More

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http://dx.doi.org/10.1007/s00415-020-09861-wDOI Listing

Neuropsychiatric Aspects of Frontotemporal Dementia.

Psychiatr Clin North Am 2020 Jun 8;43(2):345-360. Epub 2020 Apr 8.

UCSF Memory and Aging Center, Box 1207, 675 Nelson Rising Lane, Suite 190, San Francisco, CA 94143, USA. Electronic address: https://twitter.com/brucemillerucsf.

Frontotemporal dementia (FTD) encompasses a group of clinical syndromes, including behavioral-variant FTD, nonfluent variant primary progressive aphasia, semantic variant primary progressive aphasia, FTD motor neuron disease, progressive supranuclear palsy syndrome, and corticobasal syndrome. Early on in its course, FTD is commonly seen in psychiatric clinics. We review the clinical features and diagnostic criteria in FTD spectrum disorders. Read More

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http://dx.doi.org/10.1016/j.psc.2020.02.005DOI Listing

Frontotemporal Dementia: Neuropathology, Genetics, Neuroimaging, and Treatments.

Psychiatr Clin North Am 2020 Jun 8;43(2):331-344. Epub 2020 Apr 8.

UCSF Memory and Aging Center, Box 1207, 675 Nelson Rising Lane, Suite 190, San Francisco, CA 94143, USA. Electronic address: https://twitter.com/brucemillerucsf.

Frontotemporal dementia (FTD) encompasses a group of clinical syndromes, including behavioral variant FTD, nonfluent variant primary progressive aphasia, semantic variant primary progressive aphasia, FTD motor neuron disease, progressive supranuclear palsy syndrome, and corticobasal syndrome. Early on in its course, FTD is commonly seen in psychiatric clinics. In this article the authors review the neuroimaging, pathology, genetics, and therapeutic interventions for FTD spectrum disorders. Read More

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http://dx.doi.org/10.1016/j.psc.2020.02.006DOI Listing

Use of Multimodal Imaging and Clinical Biomarkers in Presymptomatic Carriers of C9orf72 Repeat Expansion.

JAMA Neurol 2020 May 18. Epub 2020 May 18.

KU Leuven, Department of Neurosciences, Experimental Neurology, B-3000 Leuven, Belgium.

Importance: During a time with the potential for novel treatment strategies, early detection of disease manifestations at an individual level in presymptomatic carriers of a hexanucleotide repeat expansion in the C9orf72 gene (preSxC9) is becoming increasingly relevant.

Objectives: To evaluate changes in glucose metabolism before symptom onset of amyotrophic lateral sclerosis or frontotemporal dementia in preSxC9 using simultaneous fluorine 18-labeled fluorodeoxyglucose ([18F]FDG positron emission tomographic (PET) and magnetic resonance imaging as well as the mutation's association with clinical and fluid biomarkers.

Design, Setting, And Participants: A prospective, case-control study enrolled 46 participants from November 30, 2015, until December 11, 2018. Read More

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http://dx.doi.org/10.1001/jamaneurol.2020.1087DOI Listing

VCP/p97 Mediates Dynein-Dependent Retrograde Mitochondrial Motility in Axons.

Front Cell Dev Biol 2020 21;8:256. Epub 2020 Apr 21.

Department of Neurosurgery, School of Medicine, Stanford University, Stanford, CA, United States.

Valosin-containing protein (VCP), also called p97, is an evolutionarily conserved and ubiquitously expressed ATPase with diverse cellular functions. Dominant mutations in are found in a late-onset multisystem degenerative proteinopathy. The neurological manifestations of the disorder include frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Read More

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http://dx.doi.org/10.3389/fcell.2020.00256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186335PMC

Neurodegeneration and Motor Deficits in the Absence of Astrogliosis upon Transgenic Mutant TDP-43 Expression in Mature Mice.

Am J Pathol 2020 May 1. Epub 2020 May 1.

Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia. Electronic address:

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing and fatal disease characterized by muscular atrophy due to loss of upper and lower motor neurons. Pathogenic mutations in the TARDBP gene that encodes TDP-43 have been identified in familial ALS. We have previously reported transgenic mice with neuronal expression of human TDP-43 carrying the pathogenic A315T mutation (iTDP-43 mice) using a tetracycline-controlled inducible promotor system. Read More

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http://dx.doi.org/10.1016/j.ajpath.2020.04.009DOI Listing

ACR Appropriateness Criteria® Movement Disorders and Neurodegenerative Diseases.

J Am Coll Radiol 2020 May;17(5S):S175-S187

Specialty Chair, Atlanta VA Health Care System and Emory University, Atlanta, Georgia.

Movement disorders and neurodegenerative diseases are a variety of conditions that involve progressive neuronal degeneration, injury, or death. Establishing the correct diagnosis of a movement disorder or neurodegenerative process can be difficult due to the variable features of these conditions, unusual clinical presentations, and overlapping symptoms and characteristics. MRI has an important role in the initial assessment of these patients, although a combination of imaging and laboratory and genetic tests is often needed for complete evaluation and management. Read More

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http://dx.doi.org/10.1016/j.jacr.2020.01.042DOI Listing
May 2020
2.283 Impact Factor

Low-dose X-ray imaging may increase the risk of neurodegenerative diseases.

Med Hypotheses 2020 Apr 13;142:109726. Epub 2020 Apr 13.

2540 Belmont Avenue, Ardmore, PA 19003, United States. Electronic address:

The hypothesis presented here explores the possibility that X-ray imaging commonly used in dental practices may be a shared risk factor for sporadic dementias and motor-neuron diseases. As the evidence will suggest, the brain is ill-equipped to manage the intrusion of low-dose ionizing radiation (IR) beyond that which is naturally occurring. When the brain's antioxidant defenses are overwhelmed by IR, it produces an abundance of reactive oxygen species (ROS) that can lead to oxidative stress, mitochondrial dysfunction, loss of synaptic plasticity, altered neuronal structure and microvascular impairment that have been identified as early signs of neurodegeneration in Alzheimer's disease, Parkinson's, amyotrophic lateral sclerosis, vascular dementia and other diseases that progressively damage the brain and central nervous system. Read More

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http://dx.doi.org/10.1016/j.mehy.2020.109726DOI Listing

Synaptic dysfunction induced by glycine-alanine dipeptides in C9orf72-ALS/FTD is rescued by SV2 replenishment.

EMBO Mol Med 2020 May 29;12(5):e10722. Epub 2020 Apr 29.

Jefferson Weinberg ALS Center, Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA, USA.

The most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an intronic hexanucleotide repeat expansion in the C9orf72 gene. In disease, RNA transcripts containing this expanded region undergo repeat-associated non-AUG translation to produce dipeptide repeat proteins (DPRs), which are detected in brain and spinal cord of patients and are neurotoxic both in vitro and in vivo paradigms. We reveal here a novel pathogenic mechanism for the most abundantly detected DPR in ALS/FTD autopsy tissues, poly-glycine-alanine (GA). Read More

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http://dx.doi.org/10.15252/emmm.201910722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207170PMC

Altered Mitochondrial Dynamics in Motor Neuron Disease: An Emerging Perspective.

Cells 2020 Apr 24;9(4). Epub 2020 Apr 24.

Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX 77030, USA.

Mitochondria plays privotal role in diverse pathways that regulate cellular function and survival, and have emerged as a prime focus in aging and age-associated motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Accumulating evidence suggests that many amyloidogenic proteins, including MND-associated RNA/DNA-binding proteins fused in sarcoma (FUS) and TAR DNA binding protein (TDP)-43, are strongly linked to mitochondrial dysfunction. Animal model and patient studies have highlighted changes in mitochondrial structure, plasticity, replication/copy number, mitochondrial DNA instability, and altered membrane potential in several subsets of MNDs, and these observations are consistent with the evidence of increased excitotoxicity, induction of reactive oxygen species, and activation of intrinsic apoptotic pathways. Read More

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http://dx.doi.org/10.3390/cells9041065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226538PMC

CAG repeats ≥ 34 in Ataxin-1 gene are associated with amyotrophic lateral sclerosis in a Brazilian cohort.

J Neurol Sci 2020 Jul 19;414:116842. Epub 2020 Apr 19.

Department of Neurology, School of Medicine, University of Campinas - UNICAMP, Rua Tessália Vieira de Camargo, 126, Cidade Universitária "Zeferino Vaz", 13083-887 Campinas, SP, Brazil.

Little is known about the genetic basis of amyotrophic lateral sclerosis (ALS) outside Europe and US. In this study, we investigated whether intermediate CAG expansions at ATXN1 were associated to ALS in the Brazilian population. To accomplish that, representative samples from 411 unrelated patients and 436 neurologically normal controls from 6 centers spread over the territory were genotyped to quantify ATXN1 expansions. Read More

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http://dx.doi.org/10.1016/j.jns.2020.116842DOI Listing

Characteristics of People with Dementia vs Other Conditions on Admission to Inpatient Palliative Care.

J Am Geriatr Soc 2020 Apr 24. Epub 2020 Apr 24.

School of Population and Global Health, The University of Western Australia, Crawley, Australia.

Objectives: Our aim was to (1) describe the clinical characteristics and symptoms of people diagnosed with dementia at the time of admission to inpatient palliative care; and (2) compare the nature and severity of these palliative care-related problems to patients with other chronic diseases.

Design: Descriptive study using assessment data on point of care outcomes (January 1, 2013, to December 31, 2018).

Setting: A total of 129 inpatient palliative care services participating in the Australian Palliative Care Outcomes Collaboration. Read More

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http://dx.doi.org/10.1111/jgs.16458DOI Listing

Electrical impedance myography (EIM) in a natural history study of mutation carriers.

Amyotroph Lateral Scler Frontotemporal Degener 2020 Apr 21:1-7. Epub 2020 Apr 21.

EMG Section, NINDS, NIH, Bethesda, MD, USA.

Electrical Impedance Myography (EIM) was used to evaluate disease progression in subjects with expansion mutations and to assess correlations with Medical Research Council (MRC) Scale and revised ALS Functional Rating Scale (ALSFRS-R) measurements. Four types of clinical presentations were assessed; Amyotrophic Lateral Sclerosis (ALS), Frontotemporal dementia (FTD) or other dementia, ALS-FTD, and asymptomatic (ASYMP). Subjects were divided into an ALS Group (ALS/ALS-FTD) and non-ALS Group (FTD/ASYMP) based on initial visit and evaluated at 0, 6, 18, and 30 months with EIM of 4 arm and 4 leg muscles, ALSFRS-R, and MRC scales. Read More

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http://dx.doi.org/10.1080/21678421.2020.1752247DOI Listing

The role of neurofilament light chain in frontotemporal dementia: a meta-analysis.

Aging Clin Exp Res 2020 Apr 18. Epub 2020 Apr 18.

Leeds Teaching Hospitals, Leeds, UK.

Frontotemporal dementia (FTD) is the second most frequent dementia, after Alzheimer's, in patients under the age of 65. It encompasses clinical entities characterized by behavioral, language, and executive control dysfunction. Neurofilament light chain (NfL) is a new, non-disease specific, widely studied biomarker indicative of axonal injury and degeneration. Read More

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http://dx.doi.org/10.1007/s40520-020-01554-8DOI Listing

Primary lateral sclerosis: diagnosis and management.

Pract Neurol 2020 Mar 26. Epub 2020 Mar 26.

Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK.

Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder at the upper motor neurone extreme of the spectrum of motor neurone disease. The diagnosis is clinical and based on the characteristic features of slowly progressive spasticity beginning in the lower limbs, or more rarely with spastic dysarthria, typically presenting around 50 years of age. The absence of lower motor neurone involvement is considered to be a defining feature, but confident distinction of PLS from upper motor neurone-predominant forms of amyotrophic lateral sclerosis may be difficult in the first few years. Read More

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http://dx.doi.org/10.1136/practneurol-2019-002300DOI Listing

Protein transmission in neurodegenerative disease.

Nat Rev Neurol 2020 04 23;16(4):199-212. Epub 2020 Mar 23.

The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Most neurodegenerative diseases are characterized by the intracellular or extracellular aggregation of misfolded proteins such as amyloid-β and tau in Alzheimer disease, α-synuclein in Parkinson disease, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis. Accumulating evidence from both human studies and disease models indicates that intercellular transmission and the subsequent templated amplification of these misfolded proteins are involved in the onset and progression of various neurodegenerative diseases. The misfolded proteins that are transferred between cells are referred to as 'pathological seeds'. Read More

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http://dx.doi.org/10.1038/s41582-020-0333-7DOI Listing

Development of disease-modifying drugs for frontotemporal dementia spectrum disorders.

Nat Rev Neurol 2020 04 23;16(4):213-228. Epub 2020 Mar 23.

Department of Research and Development, Chiesi Farmaceutici, Parma, Italy.

Frontotemporal dementia (FTD) encompasses a spectrum of clinical syndromes characterized by progressive executive, behavioural and language dysfunction. The various FTD spectrum disorders are associated with brain accumulation of different proteins: tau, the transactive response DNA binding protein of 43 kDa (TDP43), or fused in sarcoma (FUS) protein, Ewing sarcoma protein and TATA-binding protein-associated factor 15 (TAF15) (collectively known as FET proteins). Approximately 60% of patients with FTD have autosomal dominant mutations in C9orf72, GRN or MAPT genes. Read More

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http://dx.doi.org/10.1038/s41582-020-0330-xDOI Listing
April 2020
15.358 Impact Factor

Mice Carrying ALS Mutant TDP-43, but Not Mutant FUS, Display In Vivo Defects in Axonal Transport of Signaling Endosomes.

Cell Rep 2020 Mar;30(11):3655-3662.e2

Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK; UK Dementia Research Institute, University College London, London WC1E 6BT, UK; Discoveries Centre for Regenerative and Precision Medicine, University College London Campus, London WC1N 3BG, UK. Electronic address:

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease resulting from a complex interplay between genetics and environment. Impairments in axonal transport have been identified in several ALS models, but in vivo evidence remains limited, thus their pathogenetic importance remains to be fully resolved. We therefore analyzed the in vivo dynamics of retrogradely transported, neurotrophin-containing signaling endosomes in nerve axons of two ALS mouse models with mutations in the RNA processing genes TARDBP and FUS. Read More

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http://dx.doi.org/10.1016/j.celrep.2020.02.078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090381PMC

Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy.

Acta Neuropathol Commun 2020 03 17;8(1):34. Epub 2020 Mar 17.

UCL Queen Square Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK.

Autosomal dominant missense mutations in BICD2 cause Spinal Muscular Atrophy Lower Extremity Predominant 2 (SMALED2), a developmental disease of motor neurons. BICD2 is a key component of the cytoplasmic dynein/dynactin motor complex, which in axons drives the microtubule-dependent retrograde transport of intracellular cargo towards the cell soma. Patients with pathological mutations in BICD2 develop malformations of cortical and cerebellar development similar to Bicd2 knockout (-/-) mice. Read More

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http://dx.doi.org/10.1186/s40478-020-00909-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076953PMC

[Genetic Diversity in Frontotemporal Dementia].

Mol Biol (Mosk) 2020 Jan-Feb;54(1):17-28

Research Center of Neurology, Moscow, 125367 Russia.

Frontotemporal dementia is a progressive neurodegenerative disorder with high clinical, genetic, and pathomorphological diversity It is the third most common cause of dementia in all ages and the most common cause of early onset dementia (below 65). Despite its multifactorial nature, up to 40% of patients have a family history where the autosomal dominant inheritance type is seen in a quarter of cases. In this review, we describe key genes whose mutations can result in the development of frontotemporal dementia, the possible pathogenic mechanisms of the degenerative process, and provide information on the clinical features of the disease for different genetic variants. Read More

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http://dx.doi.org/10.31857/S0026898420010139DOI Listing

Characteristic Features of FUS Inclusions in Spinal Motor Neurons of Sporadic Amyotrophic Lateral Sclerosis.

J Neuropathol Exp Neurol 2020 Apr;79(4):370-377

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Alterations of RNA metabolism caused by mutations in RNA-binding protein genes, such as transactivating DNA-binding protein-43 (TDP-43) and fused in sarcoma (FUS), have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Unlike the accumulation of TDP43, which is accepted as a pathological hall mark of sporadic ALS (sALS), FUS pathology in sALS is still under debate. Although immunoreactive inclusions of FUS have been detected in sALS patients previously, the technical limitation of signal detection, including the necessity of specific antigen retrieval, restricts our understanding of FUS-associated ALS pathology. Read More

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http://dx.doi.org/10.1093/jnen/nlaa003DOI Listing

Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington's disease.

Nat Commun 2020 02 27;11(1):1105. Epub 2020 Feb 27.

Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA, 16802, USA.

Huntington's disease (HD) is caused by Huntingtin (Htt) gene mutation resulting in the loss of striatal GABAergic neurons and motor functional deficits. We report here an in vivo cell conversion technology to reprogram striatal astrocytes into GABAergic neurons in both R6/2 and YAC128 HD mouse models through AAV-mediated ectopic expression of NeuroD1 and Dlx2 transcription factors. We found that the astrocyte-to-neuron (AtN) conversion rate reached 80% in the striatum and >50% of the converted neurons were DARPP32 medium spiny neurons. Read More

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http://dx.doi.org/10.1038/s41467-020-14855-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046613PMC
February 2020

The Pathophysiology of Tau and Stress Granules in Disease.

Adv Exp Med Biol 2019 ;1184:359-372

Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.

This chapter discusses the relationship between tau, RNA binding proteins and stress granules, which exhibit an intimate bidirectional relationship affecting the functions of both tau and the translational stress response. We describe how tau becomes hyperphosphorylated and oligomerized as part of an endogenous mechanism to promote the translational stress response through interaction with RNA binding proteins. Prior studies demonstrate that dysfunction of RNA binding proteins biology is sufficient to cause neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia. Read More

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http://dx.doi.org/10.1007/978-981-32-9358-8_26DOI Listing

l-Serine Reduces Spinal Cord Pathology in a Vervet Model of Preclinical ALS/MND.

J Neuropathol Exp Neurol 2020 Apr;79(4):393-406

Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.

The early neuropathological features of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) are protein aggregates in motor neurons and microglial activation. Similar pathology characterizes Guamanian ALS/Parkinsonism dementia complex, which may be triggered by the cyanotoxin β-N-methylamino-l-alanine (BMAA). We report here the occurrence of ALS/MND-type pathological changes in vervets (Chlorocebus sabaeus; n = 8) fed oral doses of a dry powder of BMAA HCl salt (210 mg/kg/day) for 140 days. Read More

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http://dx.doi.org/10.1093/jnen/nlaa002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092359PMC

Unveiling synapse pathology in spinal bulbar muscular atrophy by genome-wide transcriptome analysis of purified motor neurons derived from disease specific iPSCs.

Mol Brain 2020 02 19;13(1):18. Epub 2020 Feb 19.

Department of Neurology, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.

Spinal bulbar muscular atrophy (SBMA) is an adult-onset, slowly progressive motor neuron disease caused by abnormal CAG repeat expansion in the androgen receptor (AR) gene. Although ligand (testosterone)-dependent mutant AR aggregation has been shown to play important roles in motor neuronal degeneration by the analyses of transgenic mice models and in vitro cell culture models, the underlying disease mechanisms remain to be fully elucidated because of the discrepancy between model mice and SBMA patients. Thus, novel human disease models that recapitulate SBMA patients' pathology more accurately are required for more precise pathophysiological analysis and the development of novel therapeutics. Read More

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http://dx.doi.org/10.1186/s13041-020-0561-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029484PMC
February 2020

The evolving role of surface electromyography in amyotrophic lateral sclerosis: A systematic review.

Clin Neurophysiol 2020 Apr 27;131(4):942-950. Epub 2019 Dec 27.

UK Dementia Research Institute, Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.

Objective: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease that leads to inexorable motor decline and a median survival of three years from symptom onset. Surface EMG represents a major technological advance that has been harnessed in the development of novel neurophysiological biomarkers. We have systematically reviewed the current application of surface EMG techniques in ALS. Read More

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http://dx.doi.org/10.1016/j.clinph.2019.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083223PMC

Structural basis of the zinc-induced cytoplasmic aggregation of the RNA-binding protein SFPQ.

Nucleic Acids Res 2020 04;48(6):3356-3365

Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.

SFPQ is a ubiquitous nuclear RNA-binding protein implicated in many aspects of RNA biogenesis. Importantly, nuclear depletion and cytoplasmic accumulation of SFPQ has been linked to neuropathological conditions such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Here, we describe a molecular mechanism by which SFPQ is mislocalized to the cytoplasm. Read More

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http://dx.doi.org/10.1093/nar/gkaa076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102971PMC

The impact of cognitive and behavioral impairment in amyotrophic lateral sclerosis.

Expert Rev Neurother 2020 Mar 14;20(3):281-293. Epub 2020 Feb 14.

Brain and Mind Centre, The University of Sydney, Sydney, Australia.

: A spectrum of non-motor manifestations in amyotrophic lateral sclerosis (ALS) patients has been increasingly recognized, with cognitive and behavioral impairments the most prominent. Evidence suggests that ALS overlaps on a pathological, genetic, and clinical level with frontotemporal dementia (FTD), thereby suggesting a frontotemporal spectrum disorder (ALS-FTSD). Cognitive impairment has been reported in up to 75% of ALS patients, whilst the rate of behavioral dysfunction ranges up to 50%. Read More

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http://dx.doi.org/10.1080/14737175.2020.1727740DOI Listing

Sorting Rare ALS Genetic Variants by Targeted Re-Sequencing Panel in Italian Patients: , , and Variants Account for 3% of Rare Genetic Forms.

J Clin Med 2020 Feb 3;9(2). Epub 2020 Feb 3.

Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.

Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease due to motor neuron loss variably associated with frontotemporal dementia (FTD). Next generation sequencing technology revealed an increasing number of rare and novel genetic variants and interpretation of their pathogenicity represents a major challange in the diagnosis of ALS. We selected 213 consecutive patients with sporadic or familial (16%) ALS, tested negative for , , , and mutations. Read More

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http://dx.doi.org/10.3390/jcm9020412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073901PMC
February 2020

Elevated methylation levels, reduced expression levels, and frequent contractions in a clinical cohort of C9orf72 expansion carriers.

Mol Neurodegener 2020 01 30;15(1). Epub 2020 Jan 30.

Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.

Background: A repeat expansion in the C9orf72-SMCR8 complex subunit (C9orf72) is the most common genetic cause of two debilitating neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Currently, much remains unknown about which variables may modify these diseases. We sought to investigate associations between C9orf72 promoter methylation, RNA expression levels, and repeat length, their potential effects on disease features, as well as changes over time and within families. Read More

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http://dx.doi.org/10.1186/s13024-020-0359-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993399PMC
January 2020

Differential role of triggering receptors expressed on myeloid cells 2 R47H in 3 neurodegenerative diseases based on a systematic review and meta-analysis.

Medicine (Baltimore) 2020 Jan;99(5):e18921

Department of Geriatrics, Dazhou Central Hospital, Dazhou, Sichuan, China.

Background: Recent studies have suggested that the potential functional polymorphism R47H in triggering receptors expressed on myeloid cells 2 (TREM2) is associated with several neurodegenerative diseases, however, the results remain inconclusive. This meta-analysis aimed to investigate the association between TREM2 R47H and the risk for 3 typical neurodegenerative diseases: Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS).

Methods: A literature review was carried out using PubMed, Medline, and Embase. Read More

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http://dx.doi.org/10.1097/MD.0000000000018921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004756PMC
January 2020

Speech and Language Presentations of FTLD-TDP Type B Neuropathology.

J Neuropathol Exp Neurol 2020 03;79(3):277-283

From the Mesulam Center for Cognitive Neurology and Alzheimer's Disease.

Four right-handed patients who presented with an isolated impairment of speech or language had transactive response DNA-binding protein of 43 kDa (TDP-43) type B pathology. Comportment and pyramidal motor function were preserved at presentation. Three of the cases developed axial rigidity and oculomotor findings late in their course with no additional pyramidal or lower motor neuron impairments. Read More

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http://dx.doi.org/10.1093/jnen/nlz132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036652PMC

Development of the MiNDToolkit for management of cognitive and behavioral impairment in motor neuron disease.

Neurodegener Dis Manag 2020 02 24;10(1):15-25. Epub 2020 Jan 24.

Faculty of Medicine & Health Sciences, University of East Anglia, Norwich, UK.

To develop structured guidance, recommendations and techniques for nonpharmacological management of cognitive and behavioral impairments in motor neuron disease, called the MiNDToolkit. A four-round-modified Delphi method was utilized (online and face-to-face meeting), supplemented by recent research, recommendations, expertise from allied health professionals, clinicians, researchers and clients. Round 1 (N = 47) identified allied health professionals techniques. Read More

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http://dx.doi.org/10.2217/nmt-2019-0035DOI Listing
February 2020

CRISPR-mediated gene correction links the ATP7A M1311V mutations with amyotrophic lateral sclerosis pathogenesis in one individual.

Commun Biol 2020 01 20;3(1):33. Epub 2020 Jan 20.

Department of Neurosurgery, Spine & Spinal Cord Institute, College of Medicine, Yonsei University, Seoul, 03722, South Korea.

Amyotrophic lateral sclerosis (ALS) is a severe disease causing motor neuron death, but a complete cure has not been developed and related genes have not been defined in more than 80% of cases. Here we compared whole genome sequencing results from a male ALS patient and his healthy parents to identify relevant variants, and chose one variant in the X-linked ATP7A gene, M1311V, as a strong disease-linked candidate after profound examination. Although this variant is not rare in the Ashkenazi Jewish population according to results in the genome aggregation database (gnomAD), CRISPR-mediated gene correction of this mutation in patient-derived and re-differentiated motor neurons drastically rescued neuronal activities and functions. Read More

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http://dx.doi.org/10.1038/s42003-020-0755-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970999PMC
January 2020

Chitinases, neuroinflammation and biomarkers in ALS.

Authors:
Michael Swash

J Neurol Neurosurg Psychiatry 2020 Apr 14;91(4):338. Epub 2020 Jan 14.

Barts and the London School of Medicine, QMUL, The Royal London Hospital, London E1 1FR, UK

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http://dx.doi.org/10.1136/jnnp-2019-322520DOI Listing

Pre-symptomatic diagnosis in ALS.

Rev Neurol (Paris) 2020 Mar 10;176(3):166-169. Epub 2020 Jan 10.

Motoneuron Disease: Pathophysiology and Therapy, INM, University Montpellier, Montpellier, France; Laboratoire de Biochimie et Biologie Moléculaire, CHU Nîmes, Nîmes, France; Service de Biochimie et Biologie Moléculaire, CHRU Tours, France.

Pathophysiology of amyotrophic lateral sclerosis (ALS) remains partially understood even though it is accepted worldwide that motor neuron death results from a pluri-factorial process with a variable role of genetic factors. Although not distinguishable from a clinical point of view, familial forms of ALS (fALS, 10% of cases) and sporadic forms (sALS, 90% of cases) can be described. Since the identification of superoxide dismutase 1 gene (SOD1) mutations, more than 30 genes have been linked to fALS. Read More

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http://dx.doi.org/10.1016/j.neurol.2019.07.027DOI Listing

ALS phenotype is influenced by age, sex, and genetics: A population-based study.

Neurology 2020 02 6;94(8):e802-e810. Epub 2020 Jan 6.

From the ALS Center (A. Chiò, C.M., A. Canosa, U.M., F.D., R.V., M.G., M. Brunetti, M. Barberis, B.I., L.P., J.P.Z., A. Calvo), "Rita Levi Montalcini" Department of Neuroscience, University of Torino; Azienda Ospedaliero-Universitaria Città della Salute e della Scienza of Torino (A. Chiò, C.M., A. Calvo), Turin; Institute of Cognitive Sciences and Technologies (A. Chiò), National Research Council, Rome; Department of Health Sciences Interdisciplinary Research Center of Autoimmune Diseases (L.C., S.D.), "Amedeo Avogadro" University of Eastern Piedmont, Novara; ALS Center, Department of Neurology (M.F.S., V.S., F.D.M., L.M.), Azienda Ospedaliera Universitaria Maggiore della Carità, Novara; and Istituti Clinici Scientifici Maugeri (G.M.), IRCCS Milano, Milan, Italy.

Objective: To assess the determinants of amyotrophic lateral sclerosis (ALS) phenotypes in a population-based cohort.

Methods: The study population included 2,839 patients with ALS diagnosed in Piemonte, Italy (1995-2015). Patients were classified according to motor (classic, bulbar, flail arm, flail leg, predominantly upper motor neuron [PUMN], respiratory) and cognitive phenotypes (normal, ALS with cognitive impairment [ALSci], ALS with behavioral impairment [ALSbi], ALSci and ALSbi combined [ALScbi], ALS-frontotemporal dementia [FTD]). Read More

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http://dx.doi.org/10.1212/WNL.0000000000008869DOI Listing
February 2020

Long-Term Voluntary Physical Exercise Exerts Neuroprotective Effects and Motor Disturbance Alleviation in a Rat Model of Parkinson's Disease.

Behav Neurol 2019 5;2019:4829572. Epub 2019 Dec 5.

Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 33305, Taiwan.

Background: Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder affecting 7-10 million individuals. The pathologic hallmark of PD is nigrostriatal dopaminergic neuron loss, leading to several motor and nonmotor disturbances, such as akinesia, gait disturbance, depression, and anxiety. Recent animal studies have demonstrated that physical exercise improves behavioral and neuropathological deficits in PD. Read More

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http://dx.doi.org/10.1155/2019/4829572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915149PMC

Relationship between neuropsychiatric disorders and cognitive and behavioural change in MND.

J Neurol Neurosurg Psychiatry 2020 Mar 23;91(3):245-253. Epub 2019 Dec 23.

Human Cognitive Neurosciences, Department of Psychology, The University of Edinburgh, Edinburgh, UK.

Objective: In this population-based study, we aimed to determine whether neuropsychiatric history, medication or family history of neuropsychiatric disorders predicted cognitive and/or behavioural impairment in motor neuron disease (MND).

Methods: People with MND (pwMND) on the Scottish Clinical, Audit, Research and Evaluation of MND (CARE-MND) register, diagnosed from January 2015 to January 2018, with cognitive and/or behavioural data measured using the Edinburgh Cognitive and Behavioural ALS Screen were included. Data were extracted on patient neuropsychiatric, medication and family history of neuropsychiatric disorders. Read More

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http://dx.doi.org/10.1136/jnnp-2019-321737DOI Listing