Clinician Perspectives of Gene Therapy as a Treatment Option for Duchenne Muscular Dystrophy.

Background: Duchenne muscular dystrophy (DMD) is a progressive, life-limiting, neuromuscular disorder. Clinicians play an important role in informing families about therapy options, including approved gene therapies and clinical trials of unapproved therapies.

Objective: This study aimed to understand the perspectives of clinicians about gene therapy for DMD, which has not previously been studied.

CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia.

Background: Neuroinflammation has been shown to be an important pathophysiological disease mechanism in frontotemporal dementia (FTD). This includes activation of microglia, a process that can be measured in life through assaying different glia-derived biomarkers in cerebrospinal fluid. However, only a few studies so far have taken place in FTD, and even fewer focusing on the genetic forms of FTD.

Differential chemokine alteration in the variants of primary progressive aphasia-a role for neuroinflammation.

Background: The primary progressive aphasias (PPA) represent a group of usually sporadic neurodegenerative disorders with three main variants: the nonfluent or agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA). They are usually associated with a specific underlying pathology: nfvPPA with a primary tauopathy, svPPA with a TDP-43 proteinopathy, and lvPPA with underlying Alzheimer's disease (AD). Little is known about their cause or pathophysiology, but prior studies in both AD and svPPA have suggested a role for neuroinflammation.

Idiopathic intracranial hypertension presenting as iron deficiency anemia: a case report.

Background: The presentation of idiopathic intracranial hypertension (IIH) in association with iron deficiency anemia (IDA) is rare.

Case Presentation: This case report depicts the unusual case of a 31-year-old woman of mixed Jamaican and English heritage with IIH who presented initially as IDA in the context of menorrhagia. Subsequent ophthalmic review, lumbar puncture, cerebrospinal fluid analysis and neuroimaging studies revealed severe bilateral optic disc swelling and raised intracranial pressure in keeping with IIH.

Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration.

Background: Microglial dysfunction is implicated in frontotemporal lobar degeneration (FTLD). Although studies have reported excessive microglial activation or senescence (dystrophy) in Alzheimer's disease (AD), few have explored this in FTLD. We examined regional patterns of microglial burden, activation and dystrophy in sporadic and genetic FTLD, sporadic AD and controls.

Cerebrospinal Fluid YKL-40 and Chitotriosidase Levels in Frontotemporal Dementia Vary by Clinical, Genetic and Pathological Subtype.

Background: Chronic glial dysfunction may contribute to the pathogenesis of frontotemporal dementia (FTD). Cerebrospinal fluid (CSF) levels of glia-derived proteins YKL-40 and chitotriosidase are increased in Alzheimer's disease (AD) but have not been explored in detail across the spectrum of FTD.

Methods: We investigated whether CSF YKL-40 and chitotriosidase levels differed between FTD patients and controls, across different clinical and genetic subtypes of FTD, and between individuals with a clinical FTD syndrome due to AD versus non-AD (frontotemporal lobar degeneration, FTLD) pathology (based on CSF neurodegenerative biomarkers).

Two pathologically confirmed cases of novel mutations in the MAPT gene causing frontotemporal dementia.

MAPT mutations were the first discovered genetic cause of frontotemporal dementia (FTD) in 1998. Since that time, over 60 MAPT mutations have been identified, usually causing behavioral variant FTD and/or parkinsonism clinically. We describe 2 novel MAPT mutations, D252V and G389_I392del, each presenting in a patient with behavioral variant FTD and associated language and cognitive deficits.

CSF synaptic protein concentrations are raised in those with atypical Alzheimer's disease but not frontotemporal dementia.

Background: Increased CSF levels of a number of synaptic markers have been reported in Alzheimer's disease (AD), but little is known about their concentrations in frontotemporal dementia (FTD). We investigated this in three synaptic proteins, neurogranin, SNAP-25, and synaptotagmin-1.

Methods: CSF samples were analysed from 66 patients with a disorder in the FTD spectrum and 19 healthy controls.

White matter hyperintensities in progranulin-associated frontotemporal dementia: A longitudinal GENFI study.

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD.

Sleep symptoms in syndromes of frontotemporal dementia and Alzheimer's disease: A proof-of-principle behavioural study.

Sleep disruption is a key clinical issue in the dementias but the sleep phenotypes of these diseases remain poorly characterised. Here we addressed this issue in a proof-of-principle study of 67 patients representing major syndromes of frontotemporal dementia (FTD) and Alzheimer's disease (AD), in relation to 25 healthy older individuals. We collected reports on clinically-relevant sleep characteristics - time spent overnight in bed, sleep quality, excessive daytime somnolence and disruptive sleep events.

Clinical value of cerebrospinal fluid neurofilament light chain in semantic dementia.

Background: Semantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of disease-modifying agents may be facilitated by the relative clinical and pathological homogeneity of SD, but we need robust monitoring biomarkers to measure their efficacy. In different FTLD subtypes, neurofilament light chain (NfL) is a promising marker, therefore we investigated the utility of cerebrospinal fluid (CSF) NfL in SD.

Searching for novel cerebrospinal fluid biomarkers of tau pathology in frontotemporal dementia: an elusive quest.

Background: Frontotemporal dementia (FTD) is a pathologically heterogeneous neurodegenerative disorder associated usually with tau or TDP-43 pathology, although some phenotypes such as logopenic variant primary progressive aphasia are more commonly associated with Alzheimer's disease pathology. Currently, there are no biomarkers able to diagnose the underlying pathology during life. In this study, we aimed to investigate the potential of novel tau species within cerebrospinal fluid (CSF) as biomarkers for tau pathology in FTD.

Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia.

White matter hyperintensities (WMH) are often seen on MRI brain scans in frontotemporal dementia (FTD) due to progranulin (GRN) mutations, but their pathological correlates are unknown. We examined the histological changes underlying WMH in a patient with GRN mutation associated behavioral variant FTD. In vivo and cadaveric MRI showed progressive, asymmetric frontotemporal and parietal atrophy, and asymmetrical WMH predominantly affecting frontal mid-zones.

Cerebrospinal fluid soluble TREM2 levels in frontotemporal dementia differ by genetic and pathological subgroup.

Background: Reliable biomarkers of frontotemporal dementia (FTD) are currently lacking. FTD may be associated with chronic immune dysfunction, microglial activation and raised inflammatory markers, particularly in progranulin (GRN) mutation carriers. Levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) are elevated in Alzheimer's disease (AD), but they have not been fully explored in FTD.

The clinical, neuroanatomical, and neuropathologic phenotype of -associated frontotemporal dementia: A longitudinal case report.

Introduction: Mutations in the TANK-binding kinase 1 () gene have recently been shown to cause frontotemporal dementia (FTD). However, the phenotype of -associated FTD is currently unclear.

Methods: We performed a single case longitudinal study of a patient who was subsequently found to have a novel A705fs mutation in the gene.

Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia.

Objective: To investigate serum neurofilament light chain (NfL) concentrations in frontotemporal dementia (FTD) and to see whether they are associated with the severity of disease.

Methods: Serum samples were collected from 74 participants (34 with behavioral variant FTD [bvFTD], 3 with FTD and motor neuron disease and 37 with primary progressive aphasia [PPA]) and 28 healthy controls. Twenty-four of the FTD participants carried a pathogenic mutation in C9orf72 (9), microtubule-associated protein tau (MAPT; 11), or progranulin (GRN; 4).

The clinical spectrum of sporadic and familial forms of frontotemporal dementia.

The term frontotemporal dementia (FTD) describes a clinically, genetically and pathologically diverse group of neurodegenerative disorders. Symptoms of FTD can present in individuals in their 20s through to their 90s, but the mean age at onset is in the sixth decade. The most common presentation is with a change in personality and impaired social conduct (behavioural variant FTD).

Compulsive versifying after treatment of transient epileptic amnesia.

Compulsive production of verse is an unusual form of hypergraphia that has been reported mainly in patients with right temporal lobe seizures. We present a patient with transient epileptic amnesia and a left temporal seizure focus, who developed isolated compulsive versifying, producing multiple rhyming poems, following seizure cessation induced by lamotrigine. Functional neuroimaging studies in the healthy brain implicate left frontotemporal areas in generating novel verbal output and rhyme, while dysregulation of neocortical and limbic regions occurs in temporal lobe epilepsy.

C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins.

An expanded GGGGCC repeat in C9orf72 is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. A fundamental question is whether toxicity is driven by the repeat RNA itself and/or by dipeptide repeat proteins generated by repeat-associated, non-ATG translation. To address this question, we developed in vitro and in vivo models to dissect repeat RNA and dipeptide repeat protein toxicity.

The C9ORF72 expansion mutation: gene structure, phenotypic and diagnostic issues.

The discovery of the C9ORF72 hexanucleotide repeat expansion in 2011 and the immediate realisation of a remarkably high prevalence in both familial and sporadic frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) triggered an explosion of interest in studies aiming to define the associated clinical and investigation phenotypes and attempts to develop technologies to measure more accurately the size of the repeat region. This article reviews progress in these areas over the subsequent 2 years, focussing on issues directly relevant to the practising physician. First, we summarise findings from studies regarding the global prevalence of the expansion, not only in FTLD and ALS cases, but also in other neurological diseases and its concurrence with other genetic mutations associated with FTLD and ALS.

When do psychogenic nonepileptic seizures occur on a video/EEG telemetry unit?

To maximize the efficiency of diagnostic video/EEG telemetry, we retrospectively studied the occurrence of clinical events during admission in 254 patients. One hundred fifty-nine patients had psychogenic nonepileptic seizures (PNES) and 95 had epileptic seizures (ES). Twenty-five with PNES and none with ES had an event before or during electrode placement (P<0.