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).

Open Clinical Studies Related to Frontotemporal Degeneration on ClinicalTrials.gov.

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FTD IN THE LITERATURE
    PubMed Abstracts - Some citations may include links to full-text content from PubMed Central and publisher web sites. [Source: National Center for Biotechnology Information (NCBI), U.S. National Library of Medicine (NLM). NCBI Copyright and Disclaimers]
  • 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

    Abstract
    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 Jan 23;:

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

    Abstract
    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 - as supplied by publisher]

  • 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

    Abstract
    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 DM, Snowden JS

    Abstract
    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

    Abstract
    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

    Abstract
    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]

  • [Pathomechanisms and clinical aspects of frontotemporal lobar degeneration]. -
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    [Pathomechanisms and clinical aspects of frontotemporal lobar degeneration].

    Nervenarzt. 2017 Feb;88(2):163-172

    Authors: Bürger K, Arzberger T, Stephan J, Levin J, Edbauer D

    Abstract
    BACKGROUND: Frontotemporal lobar degeneration (FTLD) includes a spectrum of heterogeneous clinical and neuropathological diseases. In a strict sense this includes the behavioral variant of frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA) and both variants can be associated with amyotrophic lateral sclerosis (FTD-ALS). In a broader sense FTLD also includes progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). In recent years the strong genetic component of FTLD has become increasingly clear.
    OBJECTIVE: The association between clinical presentation, neuropathology, genetics and pathophysiological mechanisms of FTLD are presented.
    RESULTS: The diagnostic criteria and tools for the clinical differential diagnosis of FTLD are presented. At autopsy patients show neuronal and glial inclusions of Tau, TDP-43 or FUS. While Tau pathology is often associated with extrapyramidal symptoms, patients with TDP-43 and FUS inclusions often also show signs of ALS. Pathogenic mutations directly increase the aggregation propensity of these proteins or impair protein degradation through autophagy or the proteasome. Pathogenic mutations in most FTLD genes trigger cytoplasmic missorting and aggregation of the RNA-binding protein TDP-43 and thus lead to a nuclear loss of TDP-43 function. Microgliosis and mutations in GRN and TREM2 suggest an important role of neuroinflammation in FTLD.
    CONCLUSION: There is still no causal therapy for FTLD but preclinical studies focusing on pathogenic mutations in C9orf72, GRN and Tau may lead to clinical trials soon; therefore, establishing large well characterized patient cohorts is crucial for trial readiness.

    PMID: 27999880 [PubMed - in process]

  • 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

    Abstract
    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

    Abstract
    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

    Abstract
    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

    Abstract
    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]

  • Structural insight into C9orf72 hexanucleotide repeat expansions: Towards new therapeutic targets in FTD-ALS. -
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    Structural insight into C9orf72 hexanucleotide repeat expansions: Towards new therapeutic targets in FTD-ALS.

    Neurochem Int. 2016 Nov;100:11-20

    Authors: Kumar V, Kashav T, Islam A, Ahmad F, Hassan MI

    Abstract
    Hexanucleotide repeat expansions, (G4C2) in the C9orf72 gene are considered as the single most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). (G4C2), either as DNA or the transcribed RNA, can folds into unusual secondary structures, including G-quadruplex, R-loop, I-motif and hairpin. These structural polymorphism at both DNA and RNA levels were proposed to initiate molecular cascade leading to ALS/FTD. G-quadruplexes are composed of stacked G4 tetrads, held by hydrophobic bonds, and is highly stable secondary structure. Here, we covers the structural and functional features of G-quadruplexes with an emphasis on C9orf72-repeat-associated FTD and ALS (C9-FTD/ALS). We also highlighted tools and techniques used to study the G-quadruplexes. Current perspectives for molecules that target G-quadruplexes as potential therapeutic are discussed. Our extensive analysis of structural features of G-quadruplexes will be used for a better understanding of molecular mechanism of C9-FTD/ALS.

    PMID: 27539655 [PubMed - in process]

  • Advances in neuroimaging in frontotemporal dementia. -
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    Advances in neuroimaging in frontotemporal dementia.

    J Neurochem. 2016 Aug;138 Suppl 1:193-210

    Authors: Gordon E, Rohrer JD, Fox NC

    Abstract
    Frontotemporal dementia (FTD) is a clinically and neuroanatomically heterogeneous neurodegenerative disorder with multiple underlying genetic and pathological causes. Whilst initial neuroimaging studies highlighted the presence of frontal and temporal lobe atrophy or hypometabolism as the unifying feature in patients with FTD, more detailed studies have revealed diverse patterns across individuals, with variable frontal or temporal predominance, differing degrees of asymmetry, and the involvement of other cortical areas including the insula and cingulate, as well as subcortical structures such as the basal ganglia and thalamus. Recent advances in novel imaging modalities including diffusion tensor imaging, resting-state functional magnetic resonance imaging and molecular positron emission tomography imaging allow the possibility of investigating alterations in structural and functional connectivity and the visualisation of pathological protein deposition. This review will cover the major imaging modalities currently used in research and clinical practice, focusing on the key insights they have provided into FTD, including the onset and evolution of pathological changes and also importantly their utility as biomarkers for disease detection and staging, differential diagnosis and measurement of disease progression. Validating neuroimaging biomarkers that are able to accomplish these tasks will be crucial for the ultimate goal of powering upcoming clinical trials by correctly stratifying patient enrolment and providing sensitive markers for evaluating the effects and efficacy of disease-modifying therapies. This review describes the key insights provided by research into the major neuroimaging modalities currently used in research and clinical practice, including what they tell us about the onset and evolution of FTD and how they may be used as biomarkers for disease detection and staging, differential diagnosis and measurement of disease progression. This article is part of the Frontotemporal Dementia special issue.

    PMID: 27502125 [PubMed - in process]

  • Prion-like propagation as a pathogenic principle in frontotemporal dementia. -
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    Prion-like propagation as a pathogenic principle in frontotemporal dementia.

    J Neurochem. 2016 Aug;138 Suppl 1:163-83

    Authors: Hock EM, Polymenidou M

    Abstract
    Frontotemporal dementia is a devastating neurodegenerative disease causing stark alterations in personality and language. Characterized by severe atrophy of the frontal and temporal brain lobes, frontotemporal dementia (FTD) shows extreme heterogeneity in clinical presentation, genetic causes, and pathological findings. Like most neurodegenerative diseases, the initial symptoms of FTD are subtle, but increase in severity over time, as the disease progresses. Clinical progression is paralleled by exacerbation of pathological findings and the involvement of broader brain regions, which currently lack mechanistic explanation. Yet, a flurry of studies indicate that protein aggregates accumulating in neurodegenerative diseases can act as propagating entities, amplifying their pathogenic conformation, in a way similar to infectious prions. In this prion-centric view, FTD can be divided into three subtypes, TDP-43 or FUS proteinopathy and tauopathy. Here, we review the current evidence that FTD-linked pathology propagates in a prion-like manner and discuss the implications of these findings for disease progression and heterogeneity. Frontotemporal dementia (FTD) is a progressive neurodegenerative disease causing severe personality dysfunctions, characterized by profound heterogeneity. Accumulation of tau, TDP-43 or FUS cytoplasmic aggregates characterize molecularly distinct and non-overlapping FTD subtypes. Here, we discuss the current evidence suggesting that prion-like propagation and cell-to-cell spread of each of these cytoplasmic aggregates may underlie disease progression and heterogeneity. This article is part of the Frontotemporal Dementia special issue.

    PMID: 27502124 [PubMed - in process]

  • Common Molecular Pathways in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. -
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    Common Molecular Pathways in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

    Trends Mol Med. 2016 Sep;22(9):769-83

    Authors: Weishaupt JH, Hyman T, Dikic I

    Abstract
    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative diseases in which predominantly motor neurons and cerebral cortex neurons, respectively, are affected. Several novel ALS and FTD disease genes have been recently discovered, pointing toward a few overarching pathways in ALS/FTD pathogenesis. Nevertheless, a precise picture of how various cellular processes cause neuronal death, or how different routes leading to ALS and FTD are functionally connected is just emerging. Moreover, how the most recent milestone findings in the ALS/FTD field might lead to improved diagnosis and treatment is actively being explored. We highlight some of the most exciting recent topics in the field, which could potentially facilitate the identification of further links between the pathogenic ALS/FTD pathways related to autophagy, vesicle trafficking, and RNA metabolism.

    PMID: 27498188 [PubMed - in process]

  • Nuclear trafficking in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. -
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    Nuclear trafficking in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.

    Brain. 2017 Jan;140(Pt 1):13-26

    Authors: Prpar Mihevc S, Darovic S, Kovanda A, Bajc Česnik A, Župunski V, Rogelj B

    Abstract
    Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are two ends of a phenotypic spectrum of disabling, relentlessly progressive and ultimately fatal diseases. A key characteristic of both conditions is the presence of TDP-43 (encoded by TARDBP) or FUS immunoreactive cytoplasmic inclusions in neuronal and glial cells. This cytoplasmic mislocalization of otherwise predominantly nuclear RNA binding proteins implies a perturbation of the nucleocytoplasmic shuttling as a possible event in the pathogenesis. Compromised nucleocytoplasmic shuttling has recently also been associated with a hexanucleotide repeat expansion mutation in C9orf72, which is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and leads to accumulation of cytoplasmic TDP-43 inclusions. Mutation in C9orf72 may disrupt nucleocytoplasmic shuttling on the level of C9ORF72 protein, the transcribed hexanucleotide repeat RNA, and/or dipeptide repeat proteins translated form the hexanucleotide repeat RNA. These defects of nucleocytoplasmic shuttling may therefore, constitute the common ground of the underlying disease mechanisms in different molecular subtypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration.

    PMID: 27497493 [PubMed - in process]

  • Sleep Disturbances in Frontotemporal Dementia. -
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    Sleep Disturbances in Frontotemporal Dementia.

    Curr Neurol Neurosci Rep. 2016 Sep;16(9):85

    Authors: McCarter SJ, St Louis EK, Boeve BF

    Abstract
    Sleep disorders appear to be frequent comorbidities in patients with frontotemporal dementia (FTD). Insomnia and excessive daytime sleepiness commonly occur in patients with FTD and significantly contribute to caregiver burden and burnout. Sleep is severely fragmented in FTD patients, likely secondary to behavioral disturbances, other primary sleep disorders such as sleep disordered breathing and restless leg syndrome, and neurodegeneration of nuclei involved in sleep and wakefulness. Treatment of primary sleep disorders may improve excessive daytime sleepiness and sleep quality and may improve daytime cognitive functioning. Rapid eye movement (REM) sleep behavior disorder is rare in FTD and may be confused with excessive nocturnal activity due to disturbed circadian rhythm. The relationship between FTD, sleep quality, and sleep disorders requires further study to better understand the contribution of disturbed sleep to daytime neurocognitive functioning and quality of life in FTD. Further, future studies should focus on comparing sleep disturbances between different FTD syndromes, especially behavioral variant FTD and primary progressive aphasia. Comorbid sleep disorders should be promptly sought and treated in patients with FTD to improve patient and caregiver quality of life.

    PMID: 27485946 [PubMed - in process]

  • Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders. -
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    Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders.

    Mol Neurobiol. 2016 Jun 28;

    Authors: Mis MS, Brajkovic S, Tafuri F, Bresolin N, Comi GP, Corti S

    Abstract
    The identification of the hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in the non-coding region of the C9ORF72 gene as the most frequent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has opened the path for advances in the knowledge and treatment of these disorders, which remain incurable. Recent evidence suggests that HRE RNA can cause gain-of-function neurotoxicity, but haploinsufficiency has also been hypothesized. In this review, we describe the recent developments in therapeutic targeting of the pathological expansion of C9ORF72 for ALS, FTD, and other neurodegenerative disorders. Three approaches are prominent: (1) an antisense oligonucleotides/RNA interference strategy; (2) using small compounds to counteract the toxic effects directly exerted by RNA derived from the repeat transcription (foci), by the translation of dipeptide repeat proteins (DPRs) from the repeated sequence, or by the sequestration of RNA-binding proteins from the C9ORF72 expansion; and (3) gene therapy, not only for silencing the toxic RNA/protein, but also for rescuing haploinsufficiency caused by the reduced transcription of the C9ORF72 coding sequence or by the diminished availability of RNA-binding proteins that are sequestered by RNA foci. Finally, with the perspective of clinical therapy, we discuss the most promising progress that has been achieved to date in the field.

    PMID: 27349438 [PubMed - as supplied by publisher]

  • The Prevalence and Incidence of Frontotemporal Dementia: a Systematic Review. -
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    The Prevalence and Incidence of Frontotemporal Dementia: a Systematic Review.

    Can J Neurol Sci. 2016 Apr;43 Suppl 1:S96-S109

    Authors: Hogan DB, Jetté N, Fiest KM, Roberts JI, Pearson D, Smith EE, Roach P, Kirk A, Pringsheim T, Maxwell CJ

    Abstract
    BACKGROUND: Population-based prevalence and incidence studies are essential for understanding the burden of frontotemporal dementia (FTD).
    METHODS: The MEDLINE and EMBASE databases were searched to identify population-based publications from 1985 to 2012, addressing the incidence and/or prevalence of FTD. References of included articles and prior systematic reviews were searched for additional studies. Two reviewers screened all abstracts and full-text reviews, abstracted data and performed quality assessments.
    RESULTS: Twenty-six studies were included. Methodological limitations led to wide ranges in the estimates for prevalence (point prevalence 0.01-4.6 per 1000 persons; period prevalence 0.16-31.04 per 1000 persons) and incidence (0.0-0.3 per 1000 person-years). FTD accounted for an average of 2.7% (range 0-9.1%) of all dementia cases among prevalence studies that included subjects 65 and older compared to 10.2% (range 2.8-15.7%) in studies restricted to those aged less than 65. The cumulative numbers of male (373 [52.5%]) and female (338 [47.5%]) cases from studies reporting this information were nearly equal (p=0.18). The behavioural variant FTD (bvFTD) was almost four times as common as the primary progressive aphasias.
    CONCLUSIONS: Population-based estimates for the epidemiology of FTD varied widely in the included studies. Refinements in the diagnostic process, possibly by the use of validated biomarkers or limiting case ascertainment to specialty services, are needed to obtain more precise estimates of the prevalence and incidence of FTD.

    PMID: 27307130 [PubMed - indexed for MEDLINE]

  • Therapy and clinical trials in frontotemporal dementia: past, present, and future. -
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    Therapy and clinical trials in frontotemporal dementia: past, present, and future.

    J Neurochem. 2016 Aug;138 Suppl 1:211-21

    Authors: Tsai RM, Boxer AL

    Abstract
    Frontotemporal dementia (FTD) is a common form of dementia with heterogeneous clinical presentations and distinct clinical syndromes. This article will review currently available therapies for FTD, its related disorders and their clinical evidence. It will also discuss recent advancements in FTD pathophysiology, treatment development, biomarker advancement and their relation to recently completed or currently ongoing clinical trials as well as future implications. Frontotemporal dementia (FTD) is a type of dementia with distinct clinical syndromes. Current treatments involve off-label use of medications for symptomatic management and cannot modify disease course. Advancements in FTD pathophysiology, genetics, and biomarkers have led to development of small molecules targeting the underlying pathology in hopes of achieving a disease-modifying effect. This article will review current therapies for FTD, discuss advancements in FTD pathophysiology, therapy development, biomarker advancement, their relation to recent clinical trials and future implications. This article is part of the Frontotemporal Dementia special issue.

    PMID: 27306957 [PubMed - in process]

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