Randomized controlled trial of cognitive behavioral therapy versus health education for sleep disturbance and fatigue following stroke and traumatic brain injury.

Objective: Evaluate efficacy of cognitive behavioural therapy for sleep and fatigue adapted for brain injury relative to health education control in alleviating sleep disturbance and fatigue after acquired brain injury.

Design: Parallel groups randomized controlled trial.

Subjects: 126 community dwelling adults with stroke or traumatic brain injury.

RNA sequencing of peripheral blood in amyotrophic lateral sclerosis reveals distinct molecular subtypes: Considerations for biomarker discovery.

Aim: Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease with limited therapeutic options. A key factor limiting the development of effective therapeutics is the lack of disease biomarkers. We sought to assess whether biomarkers for diagnosis, prognosis or cohort stratification could be identified by RNA sequencing (RNA-seq) of ALS patient peripheral blood.

Characterising the Genetic Landscape of Amyotrophic Lateral Sclerosis: A Catalogue and Assessment of Over 1,000 Published Genetic Variants.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with genetic and phenotypic heterogeneity. Pathogenic genetic variants remain the only validated cause of disease, the majority of which were discovered in familial ALS patients. While causal gene variants are a lesser contributor to sporadic ALS, an increasing number of risk alleles (low penetrance genetic variants associated with a small increase in disease risk) and variants of uncertain significance have been reported.

Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia.

Pathogenic short tandem repeat (STR) expansions cause over 20 neurodegenerative diseases. To determine the contribution of STRs in sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), we used ExpansionHunter, REviewer, and polymerase chain reaction validation to assess 21 neurodegenerative disease-associated STRs in whole-genome sequencing data from 608 patients with sporadic ALS, 68 patients with sporadic FTD, and 4703 matched controls. We also propose a data-derived outlier detection method for defining allele thresholds in rare STRs.

Co-deposition of SOD1, TDP-43 and p62 proteinopathies in ALS: evidence for multifaceted pathways underlying neurodegeneration.

Multiple neurotoxic proteinopathies co-exist within vulnerable neuronal populations in all major neurodegenerative diseases. Interactions between these pathologies may modulate disease progression, suggesting they may constitute targets for disease-modifying treatments aiming to slow or halt neurodegeneration. Pairwise interactions between superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43) and ubiquitin-binding protein 62/sequestosome 1 (p62) proteinopathies have been reported in multiple transgenic cellular and animal models of amyotrophic lateral sclerosis (ALS), however corresponding examination of these relationships in patient tissues is lacking.

NEK1 and STMN2 short tandem repeat lengths are not associated with Australian amyotrophic lateral sclerosis risk.

Sporadic amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a complex genetic architecture. The lengths of two short tandem repeats (STRs), at the NEK1 and STMN2 loci, were recently associated with ALS risk in cohorts of European descent. The STMN2 STR was proposed to be predictive of clinical features including the age of onset and disease duration in bulbar onset cases.

Altered SOD1 maturation and post-translational modification in amyotrophic lateral sclerosis spinal cord.

Aberrant self-assembly and toxicity of wild-type and mutant superoxide dismutase 1 (SOD1) has been widely examined in silico, in vitro and in transgenic animal models of amyotrophic lateral sclerosis. Detailed examination of the protein in disease-affected tissues from amyotrophic lateral sclerosis patients, however, remains scarce. We used histological, biochemical and analytical techniques to profile alterations to SOD1 protein deposition, subcellular localization, maturation and post-translational modification in post-mortem spinal cord tissues from amyotrophic lateral sclerosis cases and controls.

Simultaneous Isolation of High-Quality RNA and DNA From Postmortem Human Central Nervous System Tissues for Omics Studies.

Multi-omics approaches are increasingly being adopted to understand the complex networks underlying disease. The coisolation of high-quality nucleotides from affected tissues is paramount for the parallel analysis of transcriptomic, genomic, and epigenomic data sets. Although nucleotides extracted from postmortem central nervous system (CNS) tissue are widely used in the study of neurodegenerative disease, assessment of methods for the simultaneous isolation of DNA and RNA is limited.

Rare germline variants in childhood cancer patients suspected of genetic predisposition to cancer.

Identification of cancer-predisposing germline variants in childhood cancer patients is important for therapeutic decisions, disease surveillance and risk assessment for patients, and potentially, also for family members. We investigated the spectrum and prevalence of pathogenic germline variants in selected childhood cancer patients with features suggestive of genetic predisposition to cancer. Germline DNA was subjected to exome sequencing to filter variants in 1048 genes of interest including 176 known cancer predisposition genes (CPGs).

Cognitive Behavioral Therapy for Sleep Disturbance and Fatigue Following Acquired Brain Injury: Predictors of Treatment Response.

Objective: To identify factors associated with treatment response to cognitive behavioral therapy for sleep disturbance and fatigue (CBT-SF) after acquired brain injury (ABI).

Setting: Community dwelling.

Participants: Thirty participants with a traumatic brain injury or stroke randomized to receive CBT-SF in a parent randomized controlled trial.

Cognitive behavioural therapy versus health education for sleep disturbance and fatigue after acquired brain injury: A pilot randomised trial.

Background: Sleep disturbance and fatigue are highly prevalent after acquired brain injury (ABI) and are associated with poor functional outcomes. Cognitive behavioural therapy (CBT) is a promising treatment for sleep and fatigue problems after ABI, although comparison with an active control is needed to establish efficacy.

Objectives: We compared CBT for sleep disturbance and fatigue (CBT-SF) with a health education (HE) intervention to control for non-specific therapy effects.

Splicing factor proline and glutamine rich intron retention, reduced expression and aggregate formation are pathological features of amyotrophic lateral sclerosis.

Aim: Splicing factor proline and glutamine rich (SFPQ) is an RNA-DNA binding protein that is dysregulated in Alzheimer's disease and frontotemporal dementia. Dysregulation of SFPQ, specifically increased intron retention and nuclear depletion, has been linked to several genetic subtypes of amyotrophic lateral sclerosis (ALS), suggesting that SFPQ pathology may be a common feature of this heterogeneous disease. Our study aimed to investigate this hypothesis by providing the first comprehensive assessment of SFPQ pathology in large ALS case-control cohorts.

ALS/FTD-causing mutation in cyclin F causes the dysregulation of SFPQ.

Previously, we identified missense mutations in CCNF that are causative of familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Hallmark features of these diseases include the build-up of insoluble protein aggregates as well as the mislocalization of proteins such as transactive response DNA binding protein 43 kDa (TDP-43). In recent years, the dysregulation of SFPQ (splicing factor proline and glutamine rich) has also emerged as a pathological hallmark of ALS/FTD.

The bidirectional relationship between sleep and physical activity following traumatic brain injury.

Sleep and physical activity are both modifiable behavioural factors that are associated with better health and are potentially related. Following traumatic brain injury, damage to the brain caused by an external force, sleep disturbances are common. Exploring bidirectional relationships between sleep and physical activity might provide insight into whether increasing physical activity could decrease these sleep disturbances.

Poorer sleep quality predicts melatonin response in patients with traumatic brain injury: findings from a randomized controlled trial.

Study Objectives: A recent clinical trial demonstrated that melatonin treatment was effective in improving self-perceived sleep quality in patients with traumatic brain injury (TBI); however, it remains unclear which patients benefited from melatonin treatment. To that end, findings from the clinical trial were re-examined to identify possible predictors of treatment response.

Methods: Hierarchical multiple regression was used to identify patient characteristics, TBI injury characteristics, and self-report measures assessing sleep, fatigue, mood, and anxiety symptomatology that may uniquely explain a change in self-reported sleep quality scores (follow-up minus baseline score) as assessed by the Pittsburgh Sleep Quality Index (PSQI).

Impaired NHEJ repair in amyotrophic lateral sclerosis is associated with TDP-43 mutations.

Background: Pathological forms of TAR DNA-binding protein 43 (TDP-43) are present in motor neurons of almost all amyotrophic lateral sclerosis (ALS) patients, and mutations in TDP-43 are also present in ALS. Loss and gain of TDP-43 functions are implicated in pathogenesis, but the mechanisms are unclear. While the RNA functions of TDP-43 have been widely investigated, its DNA binding roles remain unclear.

A Simple Differentiation Protocol for Generation of Induced Pluripotent Stem Cell-Derived Basal Forebrain-Like Cholinergic Neurons for Alzheimer's Disease and Frontotemporal Dementia Disease Modeling.

The study of neurodegenerative diseases using pluripotent stem cells requires new methods to assess neurodevelopment and neurodegeneration of specific neuronal subtypes. The cholinergic system, characterized by its use of the neurotransmitter acetylcholine, is one of the first to degenerate in Alzheimer's disease and is also affected in frontotemporal dementia. We developed a differentiation protocol to generate basal forebrain-like cholinergic neurons (BFCNs) from induced pluripotent stem cells (iPSCs) aided by the use of small molecule inhibitors and growth factors.

Evidence for polygenic and oligogenic basis of Australian sporadic amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with phenotypic and genetic heterogeneity. Approximately 10% of cases are familial, while remaining cases are classified as sporadic. To date, >30 genes and several hundred genetic variants have been implicated in ALS.

Amyotrophic lateral sclerosis-linked UBQLN2 mutants inhibit endoplasmic reticulum to Golgi transport, leading to Golgi fragmentation and ER stress.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases that are related genetically and pathologically. Mutations in the UBQLN2 gene, encoding the ubiquitin-like protein ubiquilin2, are associated with familial ALS/FTD, but the pathophysiological mechanisms remain unclear. Here, we demonstrate that ALS/FTD UBQLN2 mutants P497H and P506T inhibit protein transport from the endoplasmic reticulum (ER) to the Golgi apparatus in neuronal cells.

Insomnia management.

Background: Insomnia is a common condition affecting individuals of various ages that can be addressed using a range of validated treatments.

Objective: The aim of this review is to outline current treatment approaches for insomnia disorder.

Discussion: Current guidelines suggest cognitive behavioural therapy is the first-line treatment for insomnia.

Insomnia theory and assessment.

Background: Insomnia is a common condition affecting individuals of various ages. It is diagnosed on the basis of a self-reported complaint of poor sleep quality concomitant with daytime disturbances. If left untreated, insomnia is associated with a number of adverse health outcomes.

Semi-automated fact-checking of nucleotide sequence reagents in biomedical research publications: The Seek & Blastn tool.

Nucleotide sequence reagents are verifiable experimental reagents in biomedical publications, because their sequence identities can be independently verified and compared with associated text descriptors. We have previously reported that incorrectly identified nucleotide sequence reagents are characteristic of highly similar human gene knockdown studies, some of which have been retracted from the literature on account of possible research fraud. Because of the throughput limitations of manual verification of nucleotide sequences, we developed a semi-automated fact checking tool, Seek & Blastn, to verify the targeting or non-targeting status of published nucleotide sequence reagents.