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

    Nervenarzt. 2016 Dec 20;:

    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 - as supplied by publisher]

  • 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]

  • 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]

  • Tau physiology and pathomechanisms in frontotemporal lobar degeneration. -
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    Tau physiology and pathomechanisms in frontotemporal lobar degeneration.

    J Neurochem. 2016 Aug;138 Suppl 1:71-94

    Authors: Bodea LG, Eckert A, Ittner LM, Piguet O, Götz J

    Abstract
    Frontotemporal lobar degeneration (FTLD) has been associated with toxic intracellular aggregates of hyperphosphorylated tau (FTLD-tau). Moreover, genetic studies identified mutations in the MAPT gene encoding tau in familial cases of the disease. In this review, we cover a range of aspects of tau function, both in the healthy and diseased brain, discussing several in vitro and in vivo models. Tau structure and function in the healthy brain is presented, accentuating its distinct compartmentalization in neurons and its role in microtubule stabilization and axonal transport. Furthermore, tau-driven pathology is discussed, introducing current concepts and the underlying experimental evidence. Different aspects of pathological tau phosphorylation, the protein's genomic and domain organization as well as its spreading in disease, together with MAPT-associated mutations and their respective models are presented. Dysfunction related to other post-transcriptional modifications and their effect on normal neuronal functions such as cell cycle, epigenetics and synapse dynamics are also discussed, providing a mechanistic explanation for the observations made in FTLD-tau cases, with the possibility for therapeutic intervention. In this review, we cover aspects of tau function, both in the healthy and diseased brain, referring to different in vitro and in vivo models. In healthy neurons, tau is compartmentalized, with higher concentrations found in the distal part of the axon. Cargo molecules are sensitive to this gradient. A disturbed tau distribution, as found in frontotemporal lobar degeneration (FTLD-tau), has severe consequences for cellular physiology: tau accumulates in the neuronal soma and dendrites, leading among others to microtubule depolymerization and impaired axonal transport. Tau forms insoluble aggregates that sequester additional molecules stalling cellular physiology. Neuronal communication is gradually lost as toxic tau accumulates in dendritic spines with subsequent degeneration of synapses and synaptic loss. Thus, by providing a mechanistic explanation for the observations made in FTLD-tau cases, arises a possibility for therapeutic interventions. This article is part of the Frontotemporal Dementia special issue.

    PMID: 27306859 [PubMed - in process]

  • Molecular neuropathology of frontotemporal dementia: insights into disease mechanisms from postmortem studies. -
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    Molecular neuropathology of frontotemporal dementia: insights into disease mechanisms from postmortem studies.

    J Neurochem. 2016 Aug;138 Suppl 1:54-70

    Authors: Mackenzie IR, Neumann M

    Abstract
    Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. The past decade has seen the discovery of several new FTD-causing genetic mutations and the identification of many of the relevant pathological proteins. The current neuropathological classification is based on the predominant protein abnormality and allows most cases of FTD to be placed into one of three broad molecular subgroups; frontotemporal lobar degeneration with tau, TDP-43 or FET protein accumulation. This review will describe our current understanding of the molecular basis of FTD, focusing on insights gained from the study of human postmortem tissue, as well as some of the current controversies. Most cases of FTD can be subclassified into one of three broad molecular subgroups based on the predominant protein that accumulates as pathological cellular inclusions. Understanding the associated pathogenic mechanisms and recognizing these FTD molecular subtypes in vivo will likely be crucial for the development and use of targeted therapies. This article is part of the Frontotemporal Dementia special issue.

    PMID: 27306735 [PubMed - in process]

  • Review: Induced pluripotent stem cell models of frontotemporal dementia. -
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    Review: Induced pluripotent stem cell models of frontotemporal dementia.

    Neuropathol Appl Neurobiol. 2016 Oct;42(6):497-520

    Authors: Preza E, Hardy J, Warner T, Wray S

    Abstract
    The increasing prevalence of dementia in the ageing population combined with the lack of treatments and the burden on national health care systems globally make dementia a public health priority. Despite the plethora of important research findings published over the past two decades, the mechanisms underlying dementia are still poorly understood and the progress in pharmacological interventions is limited. Recent advances in cellular reprogramming and genome engineering technologies offer an unprecedented new paradigm in disease modeling. Induced pluripotent stem cells (iPSCs) have enabled the study of patient-derived neurons in vitro, a significant progress in the field of dementia research. The first studies using iPSCs to model dementia have recently emerged, holding promise for elucidating disease pathogenic mechanisms and accelerating drug discovery. In this review, we summarize the major findings of iPSC-based studies in frontotemporal dementia (FTD) and FTD overlapping with amyotrophic lateral sclerosis (FTD/ALS). We also discuss some of the main challenges in the use of iPSCs to model complex, late-onset neurodegenerative diseases such as dementias.

    PMID: 27291591 [PubMed - in process]

  • ALS and FTD: an epigenetic perspective. -
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    ALS and FTD: an epigenetic perspective.

    Acta Neuropathol. 2016 Oct;132(4):487-502

    Authors: Belzil VV, Katzman RB, Petrucelli L

    Abstract
    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two fatal neurodegenerative diseases seen in comorbidity in up to 50 % of cases. Despite tremendous efforts over the last two decades, no biomarkers or effective therapeutics have been identified to prevent, decelerate, or stop neuronal death in patients. While the identification of multiple mutations in more than two dozen genes elucidated the involvement of several mechanisms in the pathogenesis of both diseases, identifying the hexanucleotide repeat expansion in C9orf72, the most common genetic abnormality in ALS and FTD, opened the door to the discovery of several novel pathogenic biological routes, including chromatin remodeling and transcriptome alteration. Epigenetic processes regulate DNA replication and repair, RNA transcription, and chromatin conformation, which in turn further dictate transcriptional regulation and protein translation. Transcriptional and post-transcriptional epigenetic regulation is mediated by enzymes and chromatin-modifying complexes that control DNA methylation, histone modifications, and RNA editing. While the alteration of DNA methylation and histone modification has recently been reported in ALS and FTD, the assessment of epigenetic involvement in both diseases is still at an early stage, and the involvement of multiple epigenetic players still needs to be evaluated. As the epigenome serves as a way to alter genetic information not only during aging, but also following environmental signals, epigenetic mechanisms might play a central role in initiating ALS and FTD, especially for sporadic cases. Here, we provide a review of what is currently known about altered epigenetic processes in both ALS and FTD and discuss potential therapeutic strategies targeting epigenetic mechanisms. As approximately 85 % of ALS and FTD cases are still genetically unexplained, epigenetic therapeutics explored for other diseases might represent a profitable direction for the field.

    PMID: 27282474 [PubMed - in process]

  • Inside out: the role of nucleocytoplasmic transport in ALS and FTLD. -
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    Inside out: the role of nucleocytoplasmic transport in ALS and FTLD.

    Acta Neuropathol. 2016 Aug;132(2):159-73

    Authors: Boeynaems S, Bogaert E, Van Damme P, Van Den Bosch L

    Abstract
    Neurodegenerative diseases are characterized by the presence of protein inclusions with a different protein content depending on the type of disease. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are no exceptions to this common theme. In most ALS and FTLD cases, the predominant pathological species are RNA-binding proteins. Interestingly, these proteins are both depleted from their normal nuclear localization and aggregated in the cytoplasm. This key pathological feature has suggested a potential dual mechanism with both nuclear loss of function and cytoplasmic gain of function being at play. Yet, why and how this pathological cascade is initiated in most patients, and especially sporadic cases, is currently unresolved. Recent breakthroughs in C9orf72 ALS/FTLD disease models point at a pivotal role for the nuclear transport system in toxicity. To address whether defects in nuclear transport are indeed implicated in the disease, we reviewed two decades of ALS/FTLD literature and combined this with bioinformatic analyses. We find that both RNA-binding proteins and nuclear transport factors are key players in ALS/FTLD pathology. Moreover, our analyses suggest that disturbances in nucleocytoplasmic transport play a crucial initiating role in the disease, by bridging both nuclear loss and cytoplasmic gain of functions. These findings highlight this process as a novel and promising therapeutic target for ALS and FTLD.

    PMID: 27271576 [PubMed - in process]

  • Neurochemical biomarkers in the diagnosis of frontotemporal lobar degeneration: an update. -
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    Neurochemical biomarkers in the diagnosis of frontotemporal lobar degeneration: an update.

    J Neurochem. 2016 Aug;138 Suppl 1:184-92

    Authors: Oeckl P, Steinacker P, Feneberg E, Otto M

    Abstract
    Frontotemporal lobar degeneration (FTLD) is a spectrum of rare neurodegenerative diseases with overlapping symptoms and neuropathology. It includes the behavioral variant of frontotemporal dementia (bvFTD), the semantic and non-fluent variant of primary progressive aphasia (svPPA and nfvPPA), FTD with motor neuron disease (FTD-MND), progressive supranuclear palsy, and corticobasal syndrome. The diagnosis of the FTLD spectrum of diseases is based on clinical symptoms which hampers the differentiation of the diseases among each other and with other disorders that show a similar clinical appearance resulting in a high rate of misdiagnoses. This highlights the need for objective and selective measures in the diagnostic criteria and there is extensive research on neurochemical biomarkers in FTLD as one option to address this unmet clinical need. Here, we review the advances in CSF biomarker research in FTLD in the last 2 years with regard to the validation of previously suggested and identification of new biomarker candidates for the differential diagnosis of FTLD. New biomarkers for frontotemporal lobar degeneration (FTLD) are urgently needed to support differential diagnosis within the disease spectrum and with related neurodegenerative diseases such as Alzheimer disease (AD). Here, we review the advances in cerebrospinal fluid biomarker research in FTLD and provide a list of promising candidate markers.

    PMID: 27186717 [PubMed - in process]

  • Impaired protein degradation in FTLD and related disorders. -
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    Impaired protein degradation in FTLD and related disorders.

    Ageing Res Rev. 2016 Dec;32:122-139

    Authors: Götzl JK, Lang CM, Haass C, Capell A

    Abstract
    Impaired protein degradation has been discussed as a cause or consequence of various neurodegenerative diseases, such as Alzheimer's, Parkinson's and Huntington's disease. More recently, evidence accumulated that dysfunctional protein degradation may play a role in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Since in almost all neurodegenerative diseases, protein aggregates are disease-defining hallmarks, it is most likely that impaired protein degradation contributes to disease onset and progression. In the majority of FTD cases, the pathological protein aggregates contain either microtubuleassociated protein tau or TAR DNA-binding protein (TDP)-43. Aggregates are also positive for ubiquitin and p62/sequestosome 1 (SQSTM1) indicating that these aggregates are targeted for degradation. FTD-linked mutations in genes encoding three autophagy adaptor proteins, p62/SQSTM1, ubiquilin 2 and optineurin, indicate that impaired autophagy might cause FTD. Furthermore, the strongest evidence for lysosomal impairment in FTD is provided by the progranulin (GRN) gene, which is linked to FTD and neuronal ceroid lipofuscinosis. In this review, we summarize the observations that have been made during the last years linking the accumulation of disease-associated proteins in FTD to impaired protein degradation pathways. In addition, we take resent findings for nucleocytoplasmic transport defects of TDP-43, as discussed for hexanucleotide repeat expansions in C9orf72 into account and provide a hypothesis how the interplay of altered nuclear transport and protein degradation leads to the accumulation of protein deposits.

    PMID: 27166223 [PubMed - in process]

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