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Epilepsy Behav 2022 Jun 22;133:108783. Epub 2022 Jun 22.

Institute of Neurology, Azienda Ospedaliero Universitaria di Cagliari, Cagliari, Italy; Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.

C9orf72 mutation is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. Recently, several reports of patients with FTD who carried the C9orf72 mutation and also manifested epilepsy have been published, since seizures occur in FTD at a higher rate than in the general population, the possible association between epilepsy and C9orf72 mutation remains to be clarified. In the attempt to understand whether epilepsy contributes to the phenotype of the C9orf72 mutation, we compared epilepsy occurrence in patients with FTD who carried the C9orf72 mutation and those who did not. Read More

Tijdschr Psychiatr 2022 ;64(5):306-311

Background: Frontotemporal dementia (FTD) is a neurodegenerative disorder leading to dementia. Because of predominant behavioural and emotional features it often presents to the psychiatrist. AIM: Provide an overview of the genetic background of FTD with recommendations for the clinician. Read More

Neuropathol Appl Neurobiol 2022 Jun 21:e12829. Epub 2022 Jun 21.

Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.

Objectives: It has long been considered that accumulation of pathological alpha-synuclein (aSyn) leads to synaptic/neuronal loss which then results in behavioural and cognitive dysfunction. To investigate this claim, we investigated effects downstream of aSyn preformed fibrils (PFF) and 6-hydroxydopamine (6-OHDA), because aSyn PFFs induce spreading/accumulation of aSyn, and 6-OHDA rapidly causes local neuronal loss.

Materials And Methods: We injected mouse aSyn PFFs into the medial forebrain bundle (MFB) of Sprague-Dawley rats. Read More

Front Neurol 2022 27;13:890203. Epub 2022 May 27.

Division of Neurology, Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.

Amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) are neurodegenerations with evolutionary underpinnings, expansive clinical presentations, and multiple genetic risk factors involving a complex network of pathways. This perspective considers the complex cellular pathology of aging motoneuronal and frontal/prefrontal cortical networks in the context of evolutionary, clinical, and biochemical features of the disease. We emphasize the importance of evolution in the development of the higher cortical function, within the influence of increasing lifespan. Read More

Curr Top Behav Neurosci 2022 Jun 17. Epub 2022 Jun 17.

Division of Radiological Sciences, Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA.

Parkinson disease (PD) dementia, pathologically featured as nigrostriatal dopamine (DA) neuronal loss with motor and non-motor manifestations, leads to substantial disability and economic burden. DA therapy targets the DA D3 receptor (D3R) with high affinity and selectivity. The pathological involvement of D3R is evidenced as an effective biomarker for disease progression and DA agnostic interventions, with compensations of increased DA, decreased aggregates of α-synuclein (α-Syn), enhanced secretion of brain-derived neurotrophic factors (BDNF), attenuation of neuroinflammation and oxidative damage, and promoting neurogenesis in the brain. Read More

Nat Commun 2022 Jun 13;13(1):3380. Epub 2022 Jun 13.

Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

A G4C2 hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of ALS and FTLD (C9-ALS/FTLD) with cytoplasmic TDP-43 inclusions observed in regions of neurodegeneration. The accumulation of repetitive RNAs and dipeptide repeat protein (DPR) are two proposed mechanisms of toxicity in C9-ALS/FTLD and linked to impaired nucleocytoplasmic transport. Nucleocytoplasmic transport is regulated by the phenylalanine-glycine nucleoporins (FG nups) that comprise the nuclear pore complex (NPC) permeability barrier. Read More

Front Cell Dev Biol 2022 27;10:915931. Epub 2022 May 27.

Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two major neurodegenerative diseases. FTD is the second most common cause of dementia and ALS is the most common form of motor neuron disease. These diseases are now known to be linked. Read More

Nucleic Acids Res 2022 Jun 10. Epub 2022 Jun 10.

Division of Oncogenomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Recent studies have revealed multiple mechanisms that can lead to heterogeneity in ribosomal composition. This heterogeneity can lead to preferential translation of specific panels of mRNAs, and is defined in large part by the ribosomal protein (RP) content, amongst other things. However, it is currently unknown to what extent ribosomal composition is heterogeneous across tissues, which is compounded by a lack of tools available to study it. Read More

Neurobiol Dis 2022 Jun 5;171:105783. Epub 2022 Jun 5.

Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia. Electronic address:

Increasing evidence suggests that kynurenine pathway (KP) dyshomeostasis may promote disease progression in dementia. Studies in Alzheimer's disease (AD) patients confirm KP dyshomeostasis in plasma and cerebrospinal fluid (CSF) which correlates with amyloid-β and tau pathology. Herein, we performed the first comprehensive study assessing baseline levels of KP metabolites in participants enrolling in the Australian Imaging Biomarkers Flagship Study of Aging. Read More

Cell Rep 2022 Jun;39(10):110913

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Ludwig-Maximilians-University Munich, Graduate School of Systemic Neurosciences (GSN), Munich, Germany. Electronic address:

An intronic (GC) expansion in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal dementia primarily through gain-of-function mechanisms: the accumulation of sense and antisense repeat RNA foci and dipeptide repeat (DPR) proteins (poly-GA/GP/GR/PA/PR) translated from repeat RNA. To therapeutically block this pathway, we screen a library of 1,430 approved drugs and known bioactive compounds in patient-derived induced pluripotent stem cell-derived neurons (iPSC-Neurons) for inhibitors of DPR expression. The clinically used guanosine/cytidine analogs decitabine, entecavir, and nelarabine reduce poly-GA/GP expression, with decitabine being the most potent. Read More

Prog Neurobiol 2022 Aug 4;215:102297. Epub 2022 Jun 4.

Department of Zoology and Physiology, University of Wyoming, 1000 E University Avenue, Laramie, WY 82071, USA. Electronic address:

Mislocalization of TAR DNA binding protein 43 kDa (TARDBP, or TDP-43) is a principal pathological hallmark identified in cases of neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As an RNA binding protein, TDP-43 serves in the nuclear compartment to repress non-conserved cryptic exons to ensure the normal transcriptome. Multiple lines of evidence from animal models and human studies support the view that loss of TDP-43 leads to neuron loss, independent of its cytosolic aggregation. Read More

Stem Cell Res 2022 Jul 1;62:102825. Epub 2022 Jun 1.

Section of Genomic Medicine, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy; Unit of Medical Genetics, Department of Laboratory and Infectious Disease Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that selectively affects motor neurons. In 20% of cases, ALS appears in comorbidity with frontotemporal dementia (FTD). We generated patient-derived-induced Pluripotent Stem Cells (iPSCs), from an ALS/FTD patient. Read More

Brain 2022 Jun 3. Epub 2022 Jun 3.

Université Côte d'Azur, Inserm U1081, CNRS UMR7284, IRCAN, CHU de Nice, Nice, France.

CHCHD10 is an amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) gene that encodes a mitochondrial protein whose precise function is unclear. Here we show that CHCHD10 interacts with the Stomatin-Like Protein 2 (SLP2) and participates to the stability of the Prohibitin (PHB) complex in the inner mitochondrial membrane. By using patient fibroblasts and mouse models expressing the same CHCHD10 variant (p. Read More

eNeuro 2022 May-Jun;9(3). Epub 2022 Jun 8.

Department of Physiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan

Transactivating response element DNA-binding protein of 43 kDa (TDP-43), which is encoded by the gene, is an RNA-binding protein with fundamental RNA processing activities, and its loss-of-function (LOF) has a central role in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). mutations are postulated to inactivate TDP-43 functions, leading to impaired RNA processing. However, it has not been fully examined how mutant TDP-43 affects global RNA regulation, especially in human cell models. Read More

Zh Nevrol Psikhiatr Im S S Korsakova 2022 ;122(5):36-42

Buyanov Moscow city clinical hospital, Moscow, Russia.

Neuropsychiatric presentations are observed in a substantial number of patients with amyotrophic lateral sclerosis (ALS). Severe behavioral disorders develop in ALS combined with frontotemporal dementia, which are considered to be a disease continuum. Psychiatric disorders in ALS with predominantly motor symptoms are less prominent and mostly presented with apathy. Read More

Neuroimage Clin 2022 May 8;35:103037. Epub 2022 May 8.

Neuromuscular Center, Department of Neurology, Neurological Institute, United States; Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States; Neuromuscular Division, The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States. Electronic address:

Objective: Our routine clinical neuroimaging showed hyperintense signal along the corticospinal tract only in some but not all patients with upper motor neuron (UMN)-predominant ALS. ALS patients with CST hyperintensity (ALS-CST+) and those without CST hyperintensity (ALS-CST-) present with nearly identical clinical UMN-predominant symptoms. Some previous studies have suggested that ALS patients with frontotemporal dementia (FTD) are on a continuum with ALS patients without FTD, while others have not. Read More

Mol Psychiatry 2022 May 20. Epub 2022 May 20.

Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

This study investigated the relationship between emotion processing and resting-state functional connectivity (rs-FC) of the brain networks in frontotemporal lobar degeneration (FTLD). Eighty FTLD patients (including cases with behavioral variant of frontotemporal dementia, primary progressive aphasia, progressive supranuclear palsy syndrome, motor neuron disease) and 65 healthy controls underwent rs-functional MRI. Emotion processing was tested using the Comprehensive Affect Testing System (CATS). Read More

Med (N Y) 2022 04;3(4):226-227

Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA; The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Genetic variants in chromosome 19 are strongly associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Ma et al. and Brown et al. Read More

Nat Commun 2022 May 19;13(1):2799. Epub 2022 May 19.

Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

GGGGCC repeat expansion in C9ORF72, which can be translated in both sense and antisense directions into five dipeptide repeat (DPR) proteins, including poly(GP), poly(GR), and poly(GA), is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we developed sensitive assays that can detect poly(GA) and poly(GR) in the cerebrospinal fluid (CSF) of patients with C9ORF72 mutations. CSF poly(GA) and poly(GR) levels did not correlate with age at disease onset, disease duration, or rate of decline of ALS Functional Rating Scale, and the average levels of these DPR proteins were similar in symptomatic and pre-symptomatic patients with C9ORF72 mutations. Read More

Nat Commun 2022 May 19;13(1):2776. Epub 2022 May 19.

RNA Therapeutics Institute, UMass Chan Medical School, 368 Plantation Street, Worcester, MA, 01605, USA.

Toxic dipeptide-repeat (DPR) proteins are produced from expanded GC repeats in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two DPR proteins, poly-PR and poly-GR, repress cellular translation but the molecular mechanism remains unknown. Here we show that poly-PR and poly-GR of ≥20 repeats inhibit the ribosome's peptidyl-transferase activity at nanomolar concentrations, comparable to specific translation inhibitors. Read More

Sci Rep 2022 May 17;12(1):8180. Epub 2022 May 17.

Department of Biological Sciences, Columbia University, New York, NY, 10027, USA.

Fused in Sarcoma (FUS) is a nuclear RNA/DNA binding protein that mislocalizes to the cytoplasm in the neurodegenerative diseases ALS and FTD. Despite the existence of FUS pathogenic mutations that result in nuclear import defects, a subset of ALS/FTD patients display cytoplasmic accumulation of wild-type FUS, although the underlying mechanism is unclear. Here we confirm that transcriptional inhibition, specifically of RNA polymerase II (RNAP II), induces FUS cytoplasmic translocation, but we show that several other stresses do not. Read More

Comp Biochem Physiol B Biochem Mol Biol 2022 Aug-Sep;261:110756. Epub 2022 May 14.

Department of Neurology and Neurosurgery, Montreal Neurological Institute, Faculty of Medicine, McGill University. Electronic address:

Many of the modern advances in cellular biology have been made by the expression of engineered constructs with epitope tags for subsequent biochemical investigations. While the utility of epitope tags has permitted insights in cellular and animal models, these are often expressed using traditional transgenic approaches. Using the CRISPR/Cas9 system and homology directed repair we recombine a single myc epitope sequence following the start codon of the zebrafish ortholog of TARDBP (TDP-43). Read More

Front Cell Neurosci 2022 29;16:844211. Epub 2022 Apr 29.

UK Dementia Research Institute, University College London, London, United Kingdom.

Several neurodegenerative diseases are characterized by the accumulation of aggregated misfolded proteins. These pathological agents have been suggested to propagate in the brain mechanisms similar to that observed for the prion protein, where a misfolded variant is transferred from an affected brain region to a healthy one, thereby inducing the misfolding and/or aggregation of correctly folded copies. This process has been characterized for several proteins, such as α-synuclein, tau, amyloid beta (Aβ) and less extensively for huntingtin and TDP-43. Read More

Front Aging Neurosci 2022 27;14:786420. Epub 2022 Apr 27.

Centre for Motor Neuron Disease Research, Faculty of Medicine, Macquarie Medical School, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.

DNA is under constant attack from both endogenous and exogenous sources, and when damaged, specific cellular signalling pathways respond, collectively termed the "DNA damage response." Efficient DNA repair processes are essential for cellular viability, although they decline significantly during aging. Not surprisingly, DNA damage and defective DNA repair are now increasingly implicated in age-related neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Read More

Life Sci Alliance 2022 09 13;5(9). Epub 2022 May 13.

Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience, University of Sheffield, Sheffield, UK

Dipeptide repeat (DPR) proteins are aggregation-prone polypeptides encoded by the pathogenic GGGGCC repeat expansion in the gene, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. In this study, we focus on the role of poly-GA DPRs in disease spread. We demonstrate that recombinant poly-GA oligomers can directly convert into solid-like aggregates and form characteristic β-sheet fibrils in vitro. Read More

Clin Transl Med 2022 May;12(5):e818

Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating human neurodegenerative diseases. A hallmark pathological feature of both diseases is the depletion of the RNA-binding protein TDP-43 from the nucleus in the brain and spinal cord of patients. A major function of TDP-43 is to repress the inclusion of cryptic exons during RNA splicing. Read More

Int J Mol Sci 2022 Apr 25;23(9). Epub 2022 Apr 25.

Pharmacology and Toxicology Unit, Department of Pharmacy, University of Genoa, Viale Cembrano 4, 16148 Genoa, Italy.

MicroRNAs (miRNAs) are essential post-transcriptional gene regulators involved in various neuronal and non-neuronal cell functions and play a key role in pathological conditions. Numerous studies have demonstrated that miRNAs are dysregulated in major neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease. Hence, in the present work, we constructed a comprehensive overview of individual microRNA alterations in various models of the above neurodegenerative diseases. Read More

Front Neurol 2022 26;13:861585. Epub 2022 Apr 26.

Movement Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

The progressive supranuclear palsy (PSP) syndrome encompasses different entities. PSP disease of sporadic origin is the most frequent presentation, but different genetic mutations can lead either to monogenic variants of PSP disease, or to other conditions with a different pathophysiology that eventually may result in PSP phenotype. PSP syndrome of monogenic origin is poorly understood due to the low prevalence and variable expressivity of some mutations. Read More

Rev Neurol (Paris) 2022 May 5;178(5):426-436. Epub 2022 May 5.

Sorbonne Université, Paris Brain Institute-Institut du Cerveau-ICM, Inserm U1127, CNRS UMR 7225, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France; Reference Centre for Rare or Early Dementias, IM2A, Département de Neurologie, AP-HP-Hôpital Pitié-Salpêtrière, Paris, France.

Repeat expansions in C9orf72 gene are the main genetic cause of frontotemporal dementia, amyotrophic lateral sclerosis and related phenotypes. With the advent of disease-modifying treatments, the presymptomatic disease phase is getting increasing interest as an ideal time window in which innovant therapeutic approaches could be administered. Recommendations issued from international study groups distinguish between a preclinical disease stage, during which lesions accumulate in absence of any symptoms or signs, and a prodromal stage, marked by the appearance the first subtle cognitive, behavioral, psychiatric and motor signs, before the full-blown disease. Read More

Eur J Neurol 2022 May 7. Epub 2022 May 7.

"Rita Levi Montalcini" Department of Neuroscience, Amyotrophic Lateral Sclerosis Center, University of Turin, Turin, Italy.

Background And Purpose: Social cognition (SC) deficits are included in amyotrophic lateral sclerosis (ALS)-frontotemporal spectrum disorder revised diagnostic criteria. However, SC performance among ALS patients is heterogeneous due to the phenotypic variability of the disease and the wide range of neuropsychological tools employed. The aim of the present study was to assess facial emotion recognition and theory of mind in ALS patients compared to controls and to evaluate correlations with the other cognitive domains and degree of motor impairment. Read More