Latest Frontotemporal Dementia Research (Frontotemporal Lobar Degeneration)

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The frontotemporal disorders are a group of rare diseases that involve shrinkage of specific areas of the brain that regulate behavior, personality, and language, a process termed frontotemporal lobar degeneration (FTLD). Frontotemporal disorders usually develop between ages 40 and 60, with early symptoms that can include personality or behavior changes, loss of ability to use or comprehend language, or difficulties with movement, followed by more general cognitive impairment and, ultimately, death. A frontotemporal disorder may sometimes be diagnosed in combination with another neurological disorder such as amyotrophic lateral sclerosis (ALS) or Parkinson’s disease. The exact prevalence of these disorders is unknown, but some researchers estimate that as many as 10 percent of all cases of dementia are actually frontotemporal disorders. [Source: National Institutes of Health Fact Sheet]

For more information on frontotemporal disorders visit The Association for Frontotemporal Degeneration (AFTD).

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  • TDP-43 in the spectrum of MND-FTLD pathologies. -
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    TDP-43 in the spectrum of MND-FTLD pathologies.

    Mol Cell Neurosci. 2017 Jul 04;83:46-54

    Authors: Heyburn L, Moussa CE

    The relationship between RNA-binding proteins, particularly TAR DNA binding protein 43 (TDP-43), and neurodegeneration is an important area of research. TDP-43 is involved in so many cellular processes that perturbation of protein homeostasis can lead to countless downstream effects. Understanding what leads to this disease-related protein imbalance and the resulting cellular and molecular effects will help to develop targets for disease intervention, whether it be prevention of protein accumulation, or addressing a secondary effect of protein accumulation. Here we review the current literature of TDP-43 and TDP-43 pathologies, the effects of TDP-43 overexpression and disruption of synaptic proteins through its binding of messenger RNA, leading to synaptic dysfunction. This review highlights some of the still-limited knowledge of the protein TDP-43 and how it can contribute to disease.

    PMID: 28687523 [PubMed - as supplied by publisher]

  • Imaging and fluid biomarkers in frontotemporal dementia. -
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    Imaging and fluid biomarkers in frontotemporal dementia.

    Nat Rev Neurol. 2017 Jul;13(7):406-419

    Authors: Meeter LH, Kaat LD, Rohrer JD, van Swieten JC

    Frontotemporal dementia (FTD), the second most common type of presenile dementia, is a heterogeneous neurodegenerative disease characterized by progressive behavioural and/or language problems, and includes a range of clinical, genetic and pathological subtypes. The diagnostic process is hampered by this heterogeneity, and correct diagnosis is becoming increasingly important to enable future clinical trials of disease-modifying treatments. Reliable biomarkers will enable us to better discriminate between FTD and other forms of dementia and to predict disease progression in the clinical setting. Given that different underlying pathologies probably require specific pharmacological interventions, robust biomarkers are essential for the selection of patients with specific FTD subtypes. This Review emphasizes the increasing availability and potential applications of structural and functional imaging biomarkers, and cerebrospinal fluid and blood fluid biomarkers in sporadic and genetic FTD. The relevance of new MRI modalities - such as voxel-based morphometry, diffusion tensor imaging and arterial spin labelling - in the early stages of FTD is discussed, together with the ability of these modalities to classify FTD subtypes. We highlight promising new fluid biomarkers for staging and monitoring of FTD, and underline the importance of large, multicentre studies of individuals with presymptomatic FTD. Harmonization in the collection and analysis of data across different centres is crucial for the implementation of new biomarkers in clinical practice, and will become a great challenge in the next few years.

    PMID: 28621768 [PubMed - in process]

  • [Genetic architecture of amyotrophic lateral sclerosis and frontotemporal dementia : Overlap and differences]. -
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    [Genetic architecture of amyotrophic lateral sclerosis and frontotemporal dementia : Overlap and differences].

    Nervenarzt. 2017 Jul;88(7):728-735

    Authors: Synofzik M, Otto M, Ludolph A, Weishaupt JH

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) overlap not only clinically, but also with respect to shared neuropathology and genes. A large number of novel genes has recently been identified which underlie both diseases, e. g., C9orf72, TARDBP, GRN, TBK1, UBQLN2, VCP, CHCHD10, or SQSTM1. In contrast, other genes are still largely associated with only one of the two diseases, e. g., SOD1 with ALS or MAPT with FTD. These genetic findings indicate a large number of shared mechanisms, yet along with still a certain cell-specific vulnerability. The recently identified genes are not only key to investigate the pathophysiology underlying ALS and FTD, but also the first step in the development of causal gene- or pathway-specific therapies. Mutations in these genes are also found in a substantial share of seemingly "sporadic" ALS and FTD patients. Given the large genetic heterogeneity with more than >25 genes having been identified for ALS and FTD, genetic diagnostics should - after exclusion of C9orf72 repeat expansions - no longer resort to single gene-diagnostics, but rather use next generation sequencing panels or whole exome sequencing.

    PMID: 28573364 [PubMed - in process]

  • New routes in frontotemporal dementia drug discovery. -
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    New routes in frontotemporal dementia drug discovery.

    Expert Opin Drug Discov. 2017 Jul;12(7):659-671

    Authors: De Conti L, Borroni B, Baralle M

    INTRODUCTION: Research into the pathogenic mechanisms behind frontotemporal dementia (FTD) has yielded several new targets for therapeutic intervention; such targets include specific new pathways uncovered by mutations as well as targets involving the modulation, formation and degradation of protein aggregates. Areas covered: Herein, the authors outline the principal molecular causes underlying FTD to date and the research that has been performed in these areas with respect to an eventual corrective strategy. Expert opinion: While it is worthwhile targeting pathways affected by specific mutations with a causative loss of function linked to FTD, research still has to contend with issues including the remaining presence of protein aggregates or that treatments are rarely universally applicable. Aiming to recover function in a downstream target caused by the protein aggregates will likely be insufficient due to the large cascade of events affected. It is our belief that the clearance of these aggregates and the inhibition of protein misfolding are more appropriate and direct routes to an eventual therapy.

    PMID: 28571480 [PubMed - indexed for MEDLINE]

  • ALS and frontotemporal dementia belong to a common disease spectrum. -
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    ALS and frontotemporal dementia belong to a common disease spectrum.

    Rev Neurol (Paris). 2017 May;173(5):273-279

    Authors: Couratier P, Corcia P, Lautrette G, Nicol M, Marin B

    ALS is now understood to be a complex multisystem neurodegenerative disease because areas other than the motor cortices of the brain undergo degeneration. Frontotemporal dementia (FTD) may be associated with motor neuron disease, and the transactive response DNA-binding protein 43 (TDP-43) is a major pathological substrate underlying both diseases. The recent discovery of a gene that can cause both FTD, ALS and FTD-ALS, C9ORF72, has modified the way for considering these two pathologies. These findings would allow the development of potential biomarkers and therapeutic targets for these devastating diseases. This review summarizes the key points leading up to our current understanding of the genetic, clinical and neuropathological overlap between FTD and ALS.

    PMID: 28449882 [PubMed - in process]

  • Frontotemporal dementia as a comorbidity to idiopathic normal pressure hydrocephalus (iNPH): a short review of literature and an unusual case. -
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    Frontotemporal dementia as a comorbidity to idiopathic normal pressure hydrocephalus (iNPH): a short review of literature and an unusual case.

    Fluids Barriers CNS. 2017 Apr 19;14(1):10

    Authors: Korhonen VE, Solje E, Suhonen NM, Rauramaa T, Vanninen R, Remes AM, Leinonen V

    Behavioural variant frontotemporal dementia (bvFTD) and idiopathic normal pressure hydrocephalus (iNPH) are neurodegenerative diseases that can present with similar symptoms. These include decline in executive functions, psychomotor slowness, and behavioural and personality changes. Ventricular enlargement is a key radiological finding in iNPH that may also be present in bvFTD caused by the C9ORF72 expansion mutation. Due to this, bvFTD has been hypothesized as a potential comorbidity to iNPH but bvFTD patients have never been identified in studies focusing in clinical comorbidities with iNPH. Here we describe a patient with the C9ORF72 expansion-associated bvFTD who also showed enlarged ventricles on brain imaging. The main clinical symptoms were severe gait disturbances and psychiatric problems with mild cognitive decline. Cerebrospinal fluid removal increased the patient's walking speed, so a ventriculoperitoneal shunt was placed. After insertion of the shunt, there was a significant improvement in walking speed as well as mild improvement in cognitive function but not in neuropsychiatric symptoms relating to bvFTD. Comorbid iNPH should be considered in bvFTD patients who have enlarged ventricles and severely impaired gait.

    PMID: 28420385 [PubMed - indexed for MEDLINE]

  • Frontotemporal Dementia. -
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    Frontotemporal Dementia.

    Neurol Clin. 2017 May;35(2):339-374

    Authors: Olney NT, Spina S, Miller BL

    Frontotemporal dementia (FTD) is a heterogeneous disorder with distinct clinical phenotypes associated with multiple neuropathologic entities. Presently, the term FTD encompasses clinical disorders that include changes in behavior, language, executive control, and often motor symptoms. The core FTD spectrum disorders include behavioral variant FTD, nonfluent/agrammatic variant primary progressive aphasia, and semantic variant PPA. Related FTD disorders include frontotemporal dementia with motor neuron disease, progressive supranuclear palsy syndrome, and corticobasal syndrome. In this article, the authors discuss the clinical presentation, diagnostic criteria, neuropathology, genetics, and treatments of these disorders.

    PMID: 28410663 [PubMed - indexed for MEDLINE]

  • Recent advances in the molecular genetics of frontotemporal lobar degeneration. -
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    Recent advances in the molecular genetics of frontotemporal lobar degeneration.

    Funct Neurol. 2017 Jan/Mar;32(1):7-16

    Authors: Rainero I, Rubino E, Michelerio A, D'Agata F, Gentile S, Pinessi L

    The term frontotemporal lobar degeneration (FTLD) describes a spectrum of neurodegenerative disorders associated with deposition of misfolded proteins in the frontal and temporal lobes. Up to 40% of FTLD patients reports a family history of neurodegeneration, and approximately 1/3 of familial cases shows an autosomal dominant pattern of inheritance of the phenotype. Over the past two decades, several causative and susceptibility genes for FTLD have been discovered, supporting the notion that genetic factors are important contributors to the disease processes. Genetic variants in three genes, MAPT, GRN and C9orf72, account for about half of familial FTLD cases. In addition, rare defects in the CHMP2B, VCP, TARDBP, SQSTM1, FUS, UBQLN, OPTN, TREM2, CHCHD10 and TBK1 genes have been described. Additional genes are expected to be found in near future. The purpose of this review is to describe recent advances in the molecular genetics of the FTLD spectrum and to discuss implications for genetic counseling.

    PMID: 28380318 [PubMed - indexed for MEDLINE]

  • Pharmacological Management of Psychiatric Symptoms in Frontotemporal Dementia: A Systematic Review. -
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    Pharmacological Management of Psychiatric Symptoms in Frontotemporal Dementia: A Systematic Review.

    J Geriatr Psychiatry Neurol. 2017 May;30(3):162-169

    Authors: Buoli M, Serati M, Caldiroli A, Galimberti D, Scarpini E, Altamura AC

    Psychiatric symptoms in patients with frontotemporal dementia (FTD) are highly prevalent and may complicate clinical management of these patients. Purpose of the present article is to present and discuss available data about the pharmacological treatment of psychiatric symptoms in patients with FTD. A research in the main database sources has been conducted to obtain an overview of the pharmacological management of psychiatric symptoms in patients with FTD. The search strategy included the following terms-"FTD and psychiatry," "FTD and behavioural disturbances," and "FTD and treatment". Pathophysiology of psychiatric symptoms in FTD is different from other types of dementia. Although drugs for Alzheimer disease appear to be ineffective for the treatment of psychiatric symptoms of FTD, preliminary evidence supports a possible usefulness of serotonergic antidepressants for these patients. Data are too scanty to draw definitive conclusions, but antidepressant treatment, particularly with serotonergic compounds, may improve psychiatric symptoms in patients with FTD. Large observational studies are needed to confirm this preliminary evidence, and a lot of effort and collaboration between neurologists and psychiatrists will be definitely crucial for future research of effective treatments for FTD.

    PMID: 28351199 [PubMed - indexed for MEDLINE]

  • The Role of Dipeptide Repeats in C9ORF72-Related ALS-FTD. -
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    The Role of Dipeptide Repeats in C9ORF72-Related ALS-FTD.

    Front Mol Neurosci. 2017;10:35

    Authors: Freibaum BD, Taylor JP

    Expansion of a hexanucleotide (GGGGCC) repeat in the gene chromosome 9 open reading frame 72 (C9ORF72) is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (FTD). Three non-exclusive mechanisms have been proposed to contribute to the pathology initiated by this genetic insult. First, it was suggested that decreased expression of the C9orf72 protein product may contribute to disease. Second, the recognition that C9ORF72-related disease is associated with accumulation of GGGGCC repeat-containing RNA in nuclear foci led to the suggestion that toxic gain of RNA function, perhaps related to sequestration of RNA-binding proteins, might be an important driver of disease. Third, it was subsequently appreciated that GGGGCC repeat-containing RNA undergoes unconventional translation to produce unnatural dipeptide repeat (DPR) proteins that accumulate in patient brain early in disease. DPRs translated from all six reading frames in either the sense or antisense direction of the hexanucleotide repeat result in the expression of five DPRs: glycine-alanine (GA), glycine-arginine (GR), proline-alanine (PA), proline-arginine (PR) and glycine-proline (GP; GP is generated from both the sense and antisense reading frames). However, the relative contribution of each DPR to disease pathogenesis remains unclear. Here, we review evidence for the contribution of each specific DPR to pathogenesis and examine the probable mechanisms through which these DPRs induce neurodegeneration. We also consider the association of the toxic DPRs with impaired RNA metabolism and alterations to the liquid-like state of non-membrane-bound organelles.

    PMID: 28243191 [PubMed - in process]

  • Disrupted Face Processing in Frontotemporal Dementia: A Review of the Clinical and Neuroanatomical Evidence. -
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    Disrupted Face Processing in Frontotemporal Dementia: A Review of the Clinical and Neuroanatomical Evidence.

    Neuropsychol Rev. 2017 Mar;27(1):18-30

    Authors: Hutchings R, Palermo R, Piguet O, Kumfor F

    Faces play an integral role in day-to-day functioning, particularly for social interactions where dynamic and rapid processing of information is vital. Analysis of faces allows an individual to ascertain a wide range of information including deciphering mood and identity, with these assessments directing an individual's subsequent response and behaviours. The prominent social and emotional deficits observed in frontotemporal dementia (FTD), a younger-onset dementia syndrome, may in part reflect a breakdown of the face processing network. Different subtypes of FTD present with divergent patterns of atrophy, although damage is predominantly confined to the frontal and temporal lobes. Specific predictions regarding the role of frontal and temporal regions in face processing have been proposed in the model outlined by Haxby et al. Trends in Cognitive Sciences, 4(6), 223-233 (2000). This model presents a parsimonious method by which to understand face processing in FTD while concurrently allowing assessment of the predictive value and applicability of such a model. By applying the Haxby model to the existing FTD literature, this review presents both direct and indirect evidence of a breakdown in key elements of the face processing network. The type and degree of breakdown appears to differ as a function of FTD subtype and associated brain atrophy. The evidence presented in this review and its relationship with predictions of the Haxby model provides impetus and direction for future research investigating face processing in FTD.

    PMID: 28116580 [PubMed - in process]

  • Oxytocin for frontotemporal dementia: a systematic review. -
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    Oxytocin for frontotemporal dementia: a systematic review.

    Ther Adv Psychopharmacol. 2017 Jan;7(1):48-53

    Authors: Tampi RR, Maksimowski M, Ahmed M, Tampi DJ

    BACKGROUND: The aim of this systematic review is to identify published randomized controlled trials (RCTs) that evaluated the use of oxytocin in individuals with frontotemporal dementia (FTD).
    METHODS: A literature search was conducted of PubMed, MEDLINE, EMBASE, PsycINFO and Cochrane collaboration databases for RCTs in any language that evaluated the use of oxytocin in individuals with FTD. Bibliographic databases of published articles were also searched for additional studies.
    RESULTS: A total of two RCTs that evaluated the use of oxytocin in individuals with FTD were identified. In one study, the use of oxytocin in individuals with FTD produced a reduction in identification of negative facial expressions (anger and fear) which can be hypothesized to improve trust and increase cooperation in these individuals. Both studies noted oxytocin was well tolerated and showed short term benefits on behavioral symptoms in individuals with FTD.
    CONCLUSIONS: Oxytocin appears to improve social aspects of cognition and behavioral symptoms in individuals with FTD and is well tolerated. However, positive data from larger and longer duration RCTs are needed before the routine use of oxytocin in individuals with FTD can be recommended.

    PMID: 28101324 [PubMed - in process]

  • Frontotemporal lobar degeneration: Pathogenesis, pathology and pathways to phenotype. -
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    Frontotemporal lobar degeneration: Pathogenesis, pathology and pathways to phenotype.

    Brain Pathol. 2017 Jan 18;:

    Authors: Mann DMA, Snowden JS

    Frontotemporal Lobar Degeneration (FTLD) is a clinically, pathologically and genetically heterogeneous group of disorders that affect principally the frontal and temporal lobes of the brain. There are three major associated clinical syndromes, behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD) and progressive non-fluent aphasia (PNFA); three principal histologies, involving tau, TDP-43 and FUS proteins; and mutations in three major genes, MAPT, GRN and C9orf72, along with several other less common gene mutations. All three clinical syndromes can exist separately or in combination with Amyotrophic Lateral Sclerosis (ALS). SD is exclusively a TDP-43 proteinopathy, and PNFA may be so, with both showing tight clinical, histological and genetic inter-relationships. bvFTD is more of a challenge with overlapping histological and genetic features, involvement of any of the three aggregating proteins, and changes in any of the three major genes. However, when ALS is present, all cases show a clear histological phenotype with TDP-43 aggregated proteins, and familial forms are associated with expansions in C9orf72. TDP-43 and FUS are nuclear carrier proteins involved in the regulation of RNA metabolism, whereas tau protein - the product of MAPT - is responsible for the assembly/disassembly of microtubules, which are vital for intracellular transport. Mutations in TDP-43 and FUS genes are linked to clinical ALS rather than FTLD (with or without ALS), suggesting that clinical ALS may be a disorder of RNA metabolism. Conversely, the protein products of GRN and C9orf72, along with those of the other minor genes, appear to form part of the cellular protein degradation machinery. It is possible therefore that FTLD is a reflection of dysfunction within lysosomal/proteasomal systems resulting in failure to remove potentially neurotoxic (TDP-43 and tau) aggregates, which ultimately overwhelm capacity to function. Spread of aggregates along distinct pathways may account for the different clinical phenotypes, and patterns of progression of disease.

    PMID: 28100023 [PubMed - as supplied by publisher]

  • Genetics insight into the amyotrophic lateral sclerosis/frontotemporal dementia spectrum. -
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    Genetics insight into the amyotrophic lateral sclerosis/frontotemporal dementia spectrum.

    J Med Genet. 2017 Mar;54(3):145-154

    Authors: Ji AL, Zhang X, Chen WW, Huang WJ

    Recent genetic discoveries have dramatically changed our understanding of two major neurodegenerative conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are common, devastating diseases of the brain. For decades, ALS and FTD were classified as movement and cognitive disorders, respectively, due to their distinct clinical phenotypes. The recent identification of chromosome 9 open reading frame 72 (C9orf72) as the major gene causative of familial forms of ALS and FTD uncovered a new reality of a continuous FTD/ALS spectrum. The finding that up to 50% of all patients present some degree of ALS and FTD phenotypes supports this ALS/FTD continuum. Now >100 genes are known to contribute to ALS/FTD, with a few major contributors that are reviewed below. The low penetrance of C9orf72 mutations, its contribution to sporadic cases, and its combination with other genes support an oligogenic model where two or more genes contribute to disease risk, onset, progression and phenotype: from 'pure' ALS or FTD to combined ALS/FTD. These advances in the genetics of ALS/FTD will soon lead to a better mechanistic understanding of the pathobiology of the disease, which should result in the development of effective therapies in the near future.

    PMID: 28087719 [PubMed - in process]

  • ALS/FTLD: experimental models and reality. -
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    ALS/FTLD: experimental models and reality.

    Acta Neuropathol. 2017 Feb;133(2):177-196

    Authors: Tan RH, Ke YD, Ittner LM, Halliday GM

    Amyotrophic lateral sclerosis is characterised by a loss of upper and lower motor neurons and characteristic muscle weakness and wasting, the most common form being sporadic disease with neuronal inclusions containing the tar DNA-binding protein 43 (TDP-43). Frontotemporal lobar degeneration is characterised by atrophy of the frontal and/or temporal lobes, the most common clinical form being the behavioural variant, in which neuronal inclusions containing either TDP-43 or 3-repeat tau are most prevalent. Although the genetic mutations associated with these diseases have allowed various experimental models to be developed, the initial genetic forms identified remain the most common models employed to date. It is now known that these first models faithfully recapitulate only some aspects of these diseases and do not represent the majority of cases or the most common overlapping pathologies. Newer models targeting the main molecular pathologies are still rare and in some instances, lack significant aspects of the molecular pathology. However, these diseases are complex and multigenic, indicating that experimental models may need to be targeted to different disease aspects. This would allow information to be gleaned from a variety of different yet relevant models, each of which has the capacity to capture a certain aspect of the disease, and together will enable a more complete understanding of these complex and multi-layered diseases.

    PMID: 28058507 [PubMed - in process]

  • Association of Mutations in TBK1 With Sporadic and Familial Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. -
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    Association of Mutations in TBK1 With Sporadic and Familial Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

    JAMA Neurol. 2017 Jan 01;74(1):110-113

    Authors: Freischmidt A, Müller K, Ludolph AC, Weishaupt JH, Andersen PM

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative syndromes that occur sporadically or have been associated with mostly dominant inheritance of mutations in more than 30 genes. A critical issue is whether all reported mutations are disease causing or are coincidental findings. In this review we analyze the pathogenicity of nonsynonymous variants in the newly discovered gene encoding TANK-binding kinase 1 (TBK1). The available data suggest that mutations in TBK1 that cause a 50% reduction of TBK1 protein levels are pathogenic. In most cases, the almost complete loss of expression of the mutated TBK1 allele is due to loss-of-function mutations creating a premature termination codon and the degradation of the mutated messenger RNA by nonsense-mediated messenger RNA decay. In addition, TBK1 protein levels reduced by 50% have been proven for specific in-frame deletions of 1 or several amino acids, probably due to increased degradation of the mutated protein. Evaluation of many of the TBK1 missense mutations found in patients with ALS or FTD is prevented by missing data demonstrating cosegregation of the variants and incomplete knowledge about the TBK1 functions relevant for neurodegeneration. These findings suggest that haploinsufficiency of TBK1 is causative for ALS and FTD regardless of the type of mutation. Evaluation of TBK1 variants that do not cause haploinsufficiency is not possible without data demonstrating cosegregation.

    PMID: 27892983 [PubMed - indexed for MEDLINE]

  • Genetics of Frontotemporal Dementia. -
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    Genetics of Frontotemporal Dementia.

    Curr Neurol Neurosci Rep. 2016 Dec;16(12):107

    Authors: Olszewska DA, Lonergan R, Fallon EM, Lynch T

    Frontotemporal dementia (FTD) is the second most common cause of dementia following Alzheimer's disease (AD). Between 20 and 50% of cases are familial. Mutations in MAPT, GRN and C9orf72 are found in 60% of familial FTD cases. C9orf72 mutations are the most common and account for 25%. Rarer mutations (<5%) occur in other genes such as VPC, CHMP2B, TARDP, FUS, ITM2B, TBK1 and TBP. The diagnosis is often challenging due to symptom overlap with AD and other conditions. We review the genetics, clinical presentations, neuroimaging, neuropathology, animal studies and therapeutic trials in FTD. We describe clinical scenarios including the original family with the tau stem loop mutation (+14) and also the recently discovered 'missing tau' mutation +15 that 'closed the loop' in 2015.

    PMID: 27878525 [PubMed - in process]

  • Frontotemporal Lobar Degeneration: Mechanisms and Therapeutic Strategies. -
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    Frontotemporal Lobar Degeneration: Mechanisms and Therapeutic Strategies.

    Mol Neurobiol. 2016 Nov;53(9):6091-6105

    Authors: Li YQ, Tan MS, Yu JT, Tan L

    Frontotemporal lobar degeneration (FTLD) is characterized by progressive deterioration of frontal and anterior temporal lobes of the brain and often exhibits frontotemporal dementia (FTD) on clinic, in <65-year-old patients at the time of diagnosis. Interdisciplinary approaches combining genetics, molecular and cell biology, and laboratory animal science have revealed some of its potential molecular mechanisms. Although there is still no effective treatment to delay, prevent, and reverse the progression of FTD, emergence of agents targeting molecular mechanisms has been beginning to promote potential pharmaceutical development. Our review summarizes the latest new findings of FTLD and challenges in FTLD therapy.

    PMID: 26537902 [PubMed - in process]

  • Pathogenic determinants and mechanisms of ALS/FTD linked to hexanucleotide repeat expansions in the C9orf72 gene. -
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    Pathogenic determinants and mechanisms of ALS/FTD linked to hexanucleotide repeat expansions in the C9orf72 gene.

    Neurosci Lett. 2017 Jan 01;636:16-26

    Authors: Wen X, Westergard T, Pasinelli P, Trotti D

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two apparently distinct neurodegenerative diseases, the former characterized by selective loss of motor neurons in the brain and spinal cord and the latter characterized by selective atrophy of frontal and temporal lobes. Over the years, however, growing evidence from clinical, pathological and genetic findings has suggested that ALS and FTD belong to the same clinic-pathological spectrum disorder. This concept has been further supported by the identification of the most common genetic cause for both diseases, an aberrantly expanded hexanucleotide repeat GGGGCC/ CCCCGG sequence located in a non-coding region of the gene C9orf72. Three hypotheses have been proposed to explain how this repeats expansion causes diseases: 1) C9orf72 haploinsufficiency-expanded repeats interfere with transcription or translation of the gene, leading to decreased expression of the C9orf72 protein; 2) RNA gain of function-RNA foci formed by sense and antisense transcripts of expanded repeats interact and sequester essential RNA binding proteins, causing neurotoxicity; 3) Repeat associated non-ATG initiated (RAN) translation of expanded sense GGGGCC and antisense CCCCGG repeats produces potential toxic dipeptide repeat protein (DPR). In this review, we assess current evidence supporting or arguing against each proposed mechanism in C9 ALS/FTD disease pathogenesis. Additionally, controversial findings are also discussed. Lastly, we discuss the possibility that the three pathogenic mechanisms are not mutually exclusive and all three might be involved in disease.

    PMID: 27619540 [PubMed - in process]

  • Pathogenesis of FUS-associated ALS and FTD: insights from rodent models. -
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    Pathogenesis of FUS-associated ALS and FTD: insights from rodent models.

    Acta Neuropathol Commun. 2016 Sep 06;4(1):99

    Authors: Nolan M, Talbot K, Ansorge O

    Disruptions to genes linked to RNA processing and homeostasis are implicated in the pathogenesis of two pathologically related but clinically heterogeneous neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations in the Fused-in-Sarcoma (FUS) gene encoding a 526 amino-acid RNA-binding protein are found in a small subset of ALS cases, but FUS mutations do not appear to be a direct cause of FTD. Structural and functional similarities between FUS and another ALS-related RNA-binding protein, TDP-43, highlight the potential importance of aberrant RNA processing in ALS/FTD, and this pathway is now a major focus of interest. Recently, several research groups have reported transgenic vertebrate models of FUSopathy, with varying results. Here, we discuss the evidence for FUS pathogenicity in ALS/FTD, review the experimental approaches used and phenotypic features of FUS rodent models reported to date, and outline their contribution to our understanding of pathogenic mechanisms. Further refinement of vertebrate models will likely aid our understanding of the role of FUS in both diseases.

    PMID: 27600654 [PubMed - in process]

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