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Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neuropathologic subtypes of frontotemporal lobar degeneration with tau inclusions (FTLD-tau), primary tauopathies in which intracellular tau aggregation contributes to neurodegeneration. Gosuranemab (BIIB092) is a humanized monoclonal antibody that binds to N-terminal tau. While Gosuranemab passive immunotherapy trials for PSP failed to demonstrate clinical benefit, Gosuranemab reduced N-terminal tau in the cerebrospinal fluid of transgenic mouse models and PSP patients. However, the neuropathologic sequelae of Gosuranemab have not been described. In this present study, we examined the brain tissue of three individuals who received Gosuranemab. Post-mortem human brain tissues were studied using immunohistochemistry to identify astrocytic and microglial differences between immunized cases and a cohort of unimmunized PSP, CBD and aging controls. Gosuranemab immunotherapy was not associated with clearance of neuropathologic FTLD-tau inclusions. However, treatment-associated changes were observed including the presence of perivascular vesicular astrocytes (PVA) with tau accumulation within lysosomes. PVAs were morphologically and immunophenotypically distinct from the tufted astrocytes seen in PSP, granular fuzzy astrocytes (GFA) seen in aging, and astrocytic plaques seen in CBD. Additional glial responses included increased reactive gliosis consisting of bushy astrocytosis and accumulation of rod microglia. Together, these neuropathologic findings suggest that Gosuranemab may be associated with a glial response including accumulation of tau within astrocytic lysosomes.

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While behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA) remain unrelenting and universally fatal conditions, there is a framework for supportive treatment in patients diagnosed with these frontotemporal dementia (FTD) syndromes and the larger spectrum of clinical syndromes associated with frontotemporal lobar degeneration (FTLD) pathology on autopsy. A managing physician has an important role in weighing therapeutic options, organizing caregiver support, and framing long-term expectations for patients and caregivers. Additionally, a dedicated neurologist may assist patients and caregivers in navigating a growing range of FTD research, including exciting opportunities in clinical therapeutic trials. This chapter will review current therapeutic options for patients with bvFTD and PPA and detail the landscape of potential new disease-modifying therapies targeting the pathophysiology or FTLD.

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Following the discovery of the involvement of the ribonucleoprotein TDP-43 in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), a major research focus has been to develop treatments that can prevent or alleviate these disease conditions. One pharmacological approach has been to use TDP-43-based disease models to test small molecules and drugs already known to have some therapeutic effect in a variety of neurodegenerative conditions. In parallel, various disease models have been used to perform high-throughput screens of drugs and small compound libraries. The aim of this review will be to provide a general overview of the compounds that have been described to alter pathological characteristics of TDP-43. These include expression levels, cytoplasmic mis-localization, post-translational modifications, cleavage, stress granule recruitment and aggregation. In parallel, this review will also address the use of compounds that modify the autophagic/proteasome systems that are known to target TDP-43 misfolding and aggregation. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc.

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Withaferin-A, an active withanolide derived from the medicinal herbal plant Withania somnifera induces autophagy, reduces TDP-43 proteinopathy, and improves cognitive function in transgenic mice expressing mutant TDP-43 modelling FTLD. TDP-43 is a nuclear DNA/RNA-binding protein with cellular functions in RNA transcription and splicing. Abnormal cytoplasmic aggregates of TDP-43 occur in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). To date, no effective treatment is available for TDP-43 proteinopathies. Here, we tested the effects of withaferin-A (WFA), an active withanolide extracted from the medicinal herbal plant Withania somnifera, in a transgenic mouse model of FTLD expressing a genomic fragment encoding mutant TDP-43G348C. WFA treatment ameliorated the cognitive performance of the TDP-43G348C mice, and it reduced NF-κB activity and neuroinflammation in the brain. WFA alleviated TDP-43 pathology while it boosted the levels of the autophagic marker LC3BII in the brain. These data suggest that WFA and perhaps other autophagy inducers should be considered as potential therapy for neurodegenerative diseases with TDP-43 pathology.

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Genetic mutations in FUS, a DNA/RNA-binding protein, are associated with inherited forms of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). A novel transgenic FUS[1-359]-tg mouse line recapitulates core hallmarks of human ALS in the spinal cord, including neuroinflammation and neurodegeneration, ensuing muscle atrophy and paralysis, as well as brain pathomorphological signs of FTLD. However, a question whether FUS[1-359]-tg mouse displays behavioural and brain pro-inflammatory changes characteristic for the FTLD syndrome was not addressed. Here, we studied emotional, social and cognitive behaviours, brain markers of inflammation and plasticity of pre-symptomatic FUS[1-359]-tg male mice, a potential FTLD model. These animals displayed aberrant behaviours and altered brain expression of inflammatory markers and related pathways that are reminiscent to the FTLD-like syndrome. FTLD-related behavioural and molecular Journal of Cellular and Molecular Medicine features were studied in the pre-symptomatic FUS[1-359]-tg mice that received standard or new ALS treatments, which have been reported to counteract the ALS-like syndrome in the mutants. We used anti-ALS drug riluzole (8 mg/kg/d), or anti-inflammatory drug, a selective blocker of cyclooxygenase-2 (celecoxib, 30 mg/kg/d) for 3 weeks, or a single intracerebroventricular (i.c.v.) infusion of human stem cells (Neuro-Cells, 500 000-CD34+ ), which showed anti-inflammatory properties. Signs of elevated anxiety, depressive-like behaviour, cognitive deficits and abnormal social behaviour were less marked in FUS-tg-treated animals. Applied treatments have normalized protein expression of interleukin-1ß (IL-1ß) in the prefrontal cortex and the hippocampus, and of Iba-1 and GSK-3ß in the hippocampus. Thus, the pre-symptomatic FUS[1-359]-tg mice demonstrate FTLD-like abnormalities that are attenuated by standard and new ALS treatments, including Neuro-Cell preparation.

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Non-Alzheimer's dementias constitute 30% of all dementias and present with major cognitive and behavioral disturbances. Cholinesterase inhibitors improve memory by increasing brain acetylcholine levels and are approved symptomatic therapies for Alzheimer's disease (AD). They have also been investigated in other types of dementias with potential cholinergic dysfunction. There is compelling evidence for a profound cholinergic deficit in Lewy Body dementia (LBD) and Parkinson's disease dementia (PDD), even to a greater extent than AD. However, this deficit is difficult to objectivize in vascular dementia (VaD) given the increased comorbidity with AD. Furthermore, there is minimal to no evidence for cholinergic loss in frontotemporal dementia (FTD). Although cholinesterase inhibitors showed significant improvement in cognitive, behavioral, and functional measures in both LBD and PDD clinical trials, only rivastigmine is approved for PDD, due to the heterogeneity of the scales used, the duration of trials, and the limited sample sizes impacting data interpretation. Similarly, the interpretation of findings in VaD trials are limited by the lack of pre-defined inclusion criteria for 'pure VaD' and the wide heterogeneity of patients enrolled with respect to location and extent of cerebrovascular disease. In FTD patients, cholinesterase inhibitors were mostly associated with worsening of cognitive and behavioral symptoms. In non-AD dementias, cholinesterase inhibitors were well tolerated, with increased reports of mild to moderate cholinergic side effects and a non-significant trend for increased cardio and cerebrovascular events with rivastigmine in VaD, justifying their cautious use on a case-by-case basis, especially when there is evidence for cholinergic deficit.

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INTRODUCTION: Tauopathies are heterogeneous clinicopathological entities characterized by abnormal neuronal and/or glial inclusions of the microtubule-binding protein tau. Primary tauopathies considered to be diseases correspond to a major class of frontotemporal lobar degeneration (FTLD) neuropathology (FTLD-Tau), including several forms of frontotemporal dementia (FTD) clinical syndromes. Little progress has been made in the past 20 years in developing effective disease-modifying drugs for primary tauopathies and available symptomatic treatments have limited efficacy. Areas covered: Potential disease-modifying drugs in clinical development to slow neuropathological progression of primary tauopathies. Expert opinion: Since the underlying pathology of primary tauopathies consists of abnormal tau protein aggregates, treatments are being developed to interfere with the aggregation process or to promote the clearance of this protein. Unfortunately, disease-modifying treatments remain years away as demonstrated by the recent negative Phase III findings of a tau aggregation inhibitor (LMTM) for treating the behavioral variant of FTD. Further evidence will come from ongoing Phase I/II trials on novel drugs and immunotherapeutics with various targets - prevention of deposition or removal of tau aggregates, inhibition of tau phosphorylation/acetylation, modulation of O-GlcNAcylation, activation of autophagy or ubiquitin-proteasome system pathways, and rescue of selected tau loss of function or suppression of tau gene expression.

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Frontotemporal lobar degeneration causes a spectrum of complex degenerative disorders including frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome, each of which is associated with changes in the principal neurotransmitter systems. We review the evidence for these neurochemical changes and propose that they contribute to symptomatology of frontotemporal lobar degeneration, over and above neuronal loss and atrophy. Despite the development of disease-modifying therapies, aiming to slow neuropathological progression, it remains important to advance symptomatic treatments to reduce the disease burden and improve patients' and carers' quality of life. We propose that targeting the selective deficiencies in neurotransmitter systems, including dopamine, noradrenaline, serotonin, acetylcholine, glutamate and gamma-aminobutyric acid is an important strategy towards this goal. We summarize the current evidence-base for pharmacological treatments and suggest strategies to improve the development of new, effective pharmacological treatments.

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Progranulin, a secreted glycoprotein, is encoded in humans by the single GRN gene. Progranulin consists of seven and a half, tandemly repeated, non-identical copies of the 12 cysteine granulin motif. Many cellular processes and diseases are associated with this unique pleiotropic factor that include, but are not limited to, embryogenesis, tumorigenesis, inflammation, wound repair, neurodegeneration and lysosome function. Haploinsufficiency caused by autosomal dominant mutations within the GRN gene leads to frontotemporal lobar degeneration, a progressive neuronal atrophy that presents in patients as frontotemporal dementia. Frontotemporal dementia is an early onset form of dementia, distinct from Alzheimer's disease. The GRN-related form of frontotemporal lobar dementia is a proteinopathy characterized by the appearance of neuronal inclusions containing ubiquitinated and fragmented TDP-43 (encoded by TARDBP). The neurotrophic and neuro-immunomodulatory properties of progranulin have recently been reported but are still not well understood. Gene delivery of GRN in experimental models of Alzheimer's- and Parkinson's-like diseases inhibits phenotype progression. Here we review what is currently known concerning the molecular function and mechanism of action of progranulin in normal physiological and pathophysiological conditions in both in vitro and in vivo models. The potential therapeutic applications of progranulin in treating neurodegenerative diseases are highlighted.

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Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders, related by signs of deteriorating motor and cognitive functions, and short survival. The causes are still largely unknown and no effective treatment currently exists. It has been shown that FTLD may coexist with ALS. The overlap between ALS and frontotemporal dementia (FTD), the clinical syndrome associated with FTLD, occurs at clinical, genetic, and pathological levels. The hallmark proteins of the pathognomonic inclusions are SOD-1, TDP-43 or FUS, rarely the disease is caused by mutations in the respective genes. Frontotemporal lobar degenerations (FTLD) is genetically, neuropathologically and clinically heterogeneous and may present with behavioural, language and occasionally motor disorder, respectively. Almost all cases of ALS, as well as tau-negative FTLD share a common neuropathology, neuronal and glial inclusion bodies containing abnormal TDP-43 protein, collectively called TDP-43 proteinopathy. Recent discoveries in genetics (e.g. C9orf72 hexanucleotide expansion) and the subsequent neuropathological characterization have revealed remarkable overlap between ALS and FTLD-TDP indicating common pathways in pathogenesis. For ALS, an anti-glutamate agent riluzole may be offered to slow disease progression (Level A), and a promising molecule, arimoclomol, is currently in clinical trials. Other compounds, however, are being trailed and some have shown encouraging results. As new therapeutic approaches continue to emerge by targeting SOD1, TDP-43, or GRN, we present some advances that are being made in our understanding of the molecular mechanisms of these diseases, which together with gene and stem cell therapies may translate into new treatment options.

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A group of neurodegenerative diseases referred to as tauopathies are characterized by the presence of brain cells harboring inclusions of pathological species of the tau protein. These disorders include Alzheimer's disease and frontotemporal lobar degeneration due to tau pathology, including progressive supranuclear palsy, corticobasal degeneration, and Pick's disease. Tau is normally a microtubule (MT)-associated protein that appears to play an important role in ensuring proper axonal transport, but in tauopathies tau becomes hyperphosphorylated and disengages from MTs, with consequent misfolding and deposition into inclusions that mainly affect neurons but also glia. A body of experimental evidence suggests that the development of tau inclusions leads to the neurodegeneration observed in tauopathies, and there is a growing interest in developing tau-directed therapeutic agents. The following review provides a summary of strategies under investigation for the potential treatment of tauopathies, highlighting both the promises and challenges associated with these various therapeutic approaches.

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Mutations in SQSTM1, encoding for the protein SQSTM1/p62, have been recently reported in 1-3.5% of patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS/FTLD). Inclusions positive for SQSTM1/p62 have been detected in patients with neurodegenerative disorders, including ALS/FTLD. In order to investigate the pathogenic mechanisms induced by SQSTM1 mutations in ALS/FTLD, we developed a zebrafish model. Knock-down of the sqstm1 zebrafish ortholog, as well as impairment of its splicing, led to a specific phenotype, consisting of behavioral and axonal anomalies. Here, we report swimming deficits associated with shorter motor neuronal axons that could be rescued by the overexpression of wild-type human SQSTM1. Interestingly, no rescue of the loss-of-function phenotype was observed when overexpressing human SQSTM1 constructs carrying ALS/FTLD-related mutations. Consistent with its role in autophagy regulation, we found increased mTOR levels upon knock-down of sqstm1. Furthermore, treatment of zebrafish embryos with rapamycin, a known inhibitor of the mTOR pathway, yielded an amelioration of the locomotor phenotype in the sqstm1 knock-down model. Our results suggest that loss-of-function of SQSTM1 causes phenotypic features characterized by locomotor deficits and motor neuron axonal defects that are associated with a misregulation of autophagic processes.

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Frontotemporal lobar degeneration (FTLD) encompasses a spectrum of neurodegenerative disorders characterized by behavioral, executive and language impairment, with a common overlap with parkinsonism and motor-neuron disease. Despite an increased understanding of its genetic background and molecular pathophysiology, FTLD is still an orphan disorder and there are currently no effective therapies available. In this brief overview we report the results obtained by several high-throughput and bioinformatic studies aimed at discovering impairment in the transcriptional profiles in brain and peripheral tissues from FTLD patients and in animal models. Taken together, all these results provide an interesting but still fragmentary list of genes and miRNAs whose role in FTLD should be thoroughly investigated.

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Loss-of-function progranulin (PGRN) mutations have been identified as the major cause of frontotemporal lobar degeneration with TDP-43 protein inclusions (FTLD-TDP). Previously, we reported cell cycle-related alterations in lymphoblasts from FTLD-TDP patients, carrying the c.709-1G>A null PGRN mutation, suggesting aberrant cell cycle activation in affected neurons. Here we report that PGRN haploinsufficiency activates the extracellular signal-regulated protein kinases 1 and 2 pathway in a Ca(2+), protein kinase C-dependent, and pertussis toxin-sensitive manner. Addition of exogenous PGRN or conditioned medium from control cells normalized the response of PGRN-deficient lymphoblasts to serum activation. Our data indicated that noncanonical Wnt5a signaling might be overactivated by PGRN deficiency. We detected increased cellular and secreted levels of Wnt5a in PGRN-deficient lymphoblasts associated with enhanced phosphorylated calmodulin kinase II. Moreover, treatment of control cells with exogenous Wingless-type 5a (Wnt5a)-activated Ca(2+)/calmodulin kinase II (CaMKII), increased extracellular signal-regulated protein kinases 1 and 2 activity and cell proliferation up to the levels found in c.709-1G>A carrier cells. PGRN knockdown SH-SY5Y neuroblastoma cells also show enhanced Wnt5a content and signaling. Taken together, our results revealed an important role of Wnt signaling in FTLD-TDP pathology and suggest a novel target for therapeutic intervention.

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Expanded hexanucleotide repeats in the chromosome 9 open reading frame 72 (C9orf72) gene are the most common genetic cause of ALS and frontotemporal degeneration (FTD). Here, we identify nuclear RNA foci containing the hexanucleotide expansion (GGGGCC) in patient cells, including white blood cells, fibroblasts, glia, and multiple neuronal cell types (spinal motor, cortical, hippocampal, and cerebellar neurons). RNA foci are not present in sporadic ALS, familial ALS/FTD caused by other mutations (SOD1, TDP-43, or tau), Parkinson disease, or nonneurological controls. Antisense oligonucleotides (ASOs) are identified that reduce GGGGCC-containing nuclear foci without altering overall C9orf72 RNA levels. By contrast, siRNAs fail to reduce nuclear RNA foci despite marked reduction in overall C9orf72 RNAs. Sustained ASO-mediated lowering of C9orf72 RNAs throughout the CNS of mice is demonstrated to be well tolerated, producing no behavioral or pathological features characteristic of ALS/FTD and only limited RNA expression alterations. Genome-wide RNA profiling identifies an RNA signature in fibroblasts from patients with C9orf72 expansion. ASOs targeting sense strand repeat-containing RNAs do not correct this signature, a failure that may be explained, at least in part, by discovery of abundant RNA foci with C9orf72 repeats transcribed in the antisense (GGCCCC) direction, which are not affected by sense strand-targeting ASOs. Taken together, these findings support a therapeutic approach by ASO administration to reduce hexanucleotide repeat-containing RNAs and raise the potential importance of targeting expanded RNAs transcribed in both directions.

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Encephalitis associated with antibodies against N-methyl-d-aspartic acid (NMDA) receptor is characterized by severe memory deficits, decreased consciousness, epileptic seizures and movement disorders and occurs most commonly in young women. Recovery is mostly good but little is known about the disease course in patients whose treatment has been delayed severely. We present a 16-year-old girl with a 36-month follow-up. A single course of methylprednisolone attenuated some symptoms but severe and incapacitating frontotemporal syndrome remained. Second-line treatment with rituximab was initiated 12months after the onset of symptoms. A surprising recovery occurred 18months after treatment and 30months after onset. Recovery in NMDA receptor antibody-associated encephalitis can be severely delayed and does not have to be linear. Whether delayed therapy contributed to recovery in this patient cannot be answered with certainty. Spontaneous recovery independent of therapy is possible, as it has been observed previously as late as 3years after onset. Although serum antibodies disappeared with recovery in this patient, previous cases have shown serum antibodies to be unreliable markers of disease activity. Second-line treatment, especially with substances as well tolerated as rituximab, should at least be considered in NMDA receptor encephalitis with persistent neuropsychiatric syndromes after first-line therapy.

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BACKGROUND: Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26-week open-label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the neuropsychiatric inventory (NPI). We aimed to determine whether memantine is an effective treatment for FTD. METHODS: We did a randomised, parallel group, double-blind, placebo-controlled trial of 20 mg memantine taken orally daily for 26 weeks in patients with FTD. Participants met Neary criteria for behavioural variant FTD (bvFTD) or semantic dementia and had characteristic brain atrophy. Use of acetylcholinesterase inhibitors was prohibited. Individuals were randomly assigned to receive either memantine or matched placebo tablets (1:1) in blocks of two and four patients. All patients and study personnel were masked to treatment assignment. Primary endpoints were the change in total NPI score and clinical global impression of change (CGIC) score after 26 weeks and were analysed by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00545974. FINDINGS: Of 100 patients screened, 81 were randomly assigned to receive memantine (39 patients) or placebo (42 patients). Five (6%) patients discontinued, and 76 completed the 26-week treatment. Enrolment numbers were lower than planned because of many patients' preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. Memantine treatment had no effect on either the NPI (mean difference 2·2, 95% CI -3·9 to 8·3, p=0·47) or CGIC (mean difference 0·0, -0·4 to 0·4, p=0·90) after 26 weeks of treatment. Memantine was generally well tolerated; however, patients in the memantine group had more frequent cognitive adverse events (six patients) than those in the placebo group (one). INTERPRETATION: Memantine treatment showed no benefit in patients with FTD. These data do not support memantine use in FTD. FUNDING: Forest Research Institute.

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