The impact of respite care from the perspectives and experiences of people with amyotrophic lateral sclerosis and their care partners: a qualitative study.

BACKGROUND: Respite care provides caregiving support to people with amyotrophic lateral sclerosis (ALS) and their care partners by providing the care partner with temporary relief from their caregiving duties. The aim of this study was to explore the impact of respite care through the perspectives and lived experiences of people with ALS and their care partners. METHODS: Thirty-one dyads (62 participants) of people with ALS and their care partners were assigned to either the control group or the respite care intervention. Respite care was provided in the form of home-based services. Semi-structured interviews were conducted with participants at baseline and after a six-month period to gather perspectives on ALS caregiving, perceptions of respite care, and the respite care experience. Interviews were transcribed and subjected to thematic analysis. RESULTS: Caregiving challenges specific to the care partner and the patient-care partnership relationship were identified. Overall, people with ALS and care partners responded positively to in-home respite care and reported improved relationship quality, more time for the care partner to pursue personal commitments or take a break, and improved emotional well-being for both the person with ALS and the care partner. Barriers and concerns were raised surrounding privacy and staff consistency. CONCLUSION: This study highlights respite care as a critical tool to alleviate caregiving challenges and support the needs of people with ALS and their care partners. Engagement with the ALS community and formal evaluations of respite care services should be prioritized in order to minimize barriers and best meet the needs of people with ALS and their care partners.

Canadian Pioneers of Amyotrophic Lateral Sclerosis: A Brief History.

This is an historical account of Canadian pioneers working in amyotrophic lateral sclerosis (ALS) in the 1970s and 1980s. Key contributions included the development of specialized clinics, the ALS Society of Canada, human motor unit estimates in vivo, use of transcranial magnetic stimulation (TMS), the dementias of ALS, the importance of neurofilaments and axonal flow, neuroinflammation and immunity related to ALS, use of tissue culture to study pathogenesis, and the story of ALS in Guam. Their work set the stage for future generations of ALS physicians and scientists to bring about meaningful therapies and hopefully a cure for ALS.

RX-5902, a novel ß-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited systemic treatment options. RX-5902 is a novel anti-cancer agent that inhibits phosphorylated-p68 and thus attenuates nuclear ß-catenin signaling. The purpose of this study was to evaluate the ability of ß-catenin signaling blockade to enhance the efficacy of anti-CTLA-4 and anti-PD-1 immune checkpoint blockade in immunocompetent, preclinical models of TNBC. METHODS: Treatment with RX-5902, anti-PD-1, anti-CTLA-4 or the combination was investigated in BALB/c mice injected with the 4 T1 TNBC cell line. Humanized BALB/c-Rag2nullIl2rγnullSIRPαNOD (hu-CB-BRGS) mice transplanted with a human immune system were implanted with MDA-MB-231 cells. Mice were randomized into treatment groups according to human hematopoietic chimerism and treated with RX-5902, anti-PD-1 or the combination. At sacrifice, bone marrow, lymph nodes, spleen and tumors were harvested for flow cytometry analysis of human immune cells. RESULTS: The addition of RX-5902 to CTLA-4 or PD-1 inhibitors resulted in decreased tumor growth in the 4 T1 and human immune system and MDA-MB-231 xenograft models. Immunologic analyses demonstrated a significant increase in the number of activated T cells in tumor infiltrating lymphocytes (TILs) with RX-5902 treatment compared to vehicle (p < 0.05). In the RX-5902/nivolumab combination group, there was a significant increase in the percentage of CD4+ T cells in TILs and increased systemic granzyme B production (p < 0.01). CONCLUSIONS: Conclusions: RX-5902 enhanced the efficacy of nivolumab in a humanized, preclinical model of TNBC. Several changes in immunologic profiles were noted in mice treated with RX-5902 and the combination, including an increase in activated TILs and a decrease in human myeloid populations, that are often associated with immunosuppression in a tumor microenvironment. RX-5902 also was shown to potentiate the effects of checkpoint inhibitors of CTLA4 and the PD-1 inhibitor in the 4 T-1 murine TNBC model. These findings indicate that RX-5902 may have important immunomodulatory, as well as anti-tumor activity, in TNBC when combined with a checkpoint inhibitor.

Hypothesis: amyotrophic lateral sclerosis and environmental pollutants.

Genetic, epigenetic, and environmental factors are relevant in the causation of amyotrophic lateral sclerosis (ALS) in a multistep cascade. We suggest that exposure to environmental pollutants in early life is one such factor. ALS was first described in the 19th century in the context of the Industrial Revolution that began more than 50 years earlier. The rising incidence of ALS thereafter correlates with increasing longevity, but this is an incomplete association. We suggest that increasing exposure to environmental pollutants due to industrial activity, acting over a lifetime, is also important. The combination of genetic mutations and pollutant exposure, with increased life expectancy, may account for the apparent variations in incidence of the disease in different countries and continents and even regionally within a given country. This hypothesis is testable by focused epidemiological studies, evaluating early and lifelong industrial pollutant exposure of differing types, within the Bradford Hill framework.

Amyotrophic lateral sclerosis: Origins traced to impaired balance between neural excitation and inhibition in the neonatal period.

Amyotrophic lateral sclerosis (ALS) is an adult onset disease but with an increasingly recognized preclinical prodrome. A wide spectrum of investigative approaches has identified loss of inhibitory function at the heart of ALS. In developing an explanation for the onset of ALS, it remains a consideration that ALS has its origins in neonatal derangement of the γ-aminobutyric acid (GABA)-ergic system, with delayed conversion from excitatory to mature inhibitory GABA and impaired excitation/inhibition balance. If this is so, the resulting chronic excitotoxicity could marginalize cortical network functioning very early in life, laying the path for neurodegeneration. The possibility that adult-onset neurodegenerative conditions might have their roots in early developmental derangements is worthy of consideration, particularly in relation to current models of disease pathogenesis. Unraveling the very early molecular events will be crucial in developing a better understanding of ALS and other adult neurodegenerative disorders. Muscle Nerve, 2019.

Safety, pharmacokinetics, and preliminary efficacy of E6201 in patients with advanced solid tumours, including melanoma: results of a phase 1 study.

BACKGROUND: This phase 1 first-in-human study aimed to determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and safety of E6201, and to establish recommended dosing in patients with advanced solid tumours, expanded to advanced melanoma. METHODS: Part A (dose escalation): sequential cohorts received E6201 intravenously (IV) over 30 min (once-weekly [qw; days (D)1 + 8 + 15 of a 28-day cycle]), starting at 20 mg/m2, increasing to 720 mg/m2 or the MTD. Part B (expansion): patients with BRAF-mutated or wild-type (WT) melanoma received E6201 320 mg/m2 IV over 60 minutes qw (D1 + 8 + 15 of a 28-day cycle) or 160 mg/m2 IV twice-weekly (D1 + 4 + 8 + 11 + 15 + 18 of a 28-day cycle; BRAF-mutated only). RESULTS: MTD in Part A (n = 25) was 320 mg/m2 qw, confirmed in Part B (n = 30). Adverse events included QT prolongation (n = 4) and eye disorders (n = 3). E6201 exposure was dose-related, with PK characterised by extensive distribution and fast elimination. One patient achieved PR during Part A (BRAF-mutated papillary thyroid cancer; 480 mg/m2 qw) and three during Part B (2 BRAF-mutated melanoma; 1 BRAF-WT melanoma; all receiving 320 mg/m2 qw). CONCLUSIONS: An intermittent regimen of E6201 320 mg/m2 IV qw for the first 3 weeks of a 28-day cycle was feasible and reasonably well-tolerated in patients with advanced solid tumours, including melanoma with brain metastases, with evidence of clinical efficacy.

The relationship between personality disorder traits, emotional intelligence, and college adjustment.

OBJECTIVE: The current study examined the relationship between emotional intelligence, personality disorder traits, and college adjustment. METHOD: A sample of 246 first-semester, first-time freshmen (73.6% female, age mean = 18.7, standard deviation = 2.0) at a large university in the Eastern United States completed the Trait Emotional Intelligence Questionnaire (Petrides, 2009), the Schedule for Nonadaptive and Adaptive Personality-2 (Clark, Simms, Wu, & Casillas, 2014), and the Student Adaptation to College Questionnaire (Baker & Siryk, 1998). RESULTS: As predicted, personality disorder symptoms and emotional intelligence were generally related, and both were related to adjustment. Unique patterns of association between traits reflecting personality disorder clusters and emotional intelligence deficits also emerged. Contrary to expectation, however, emotional intelligence did not moderate the relationship between personality disorders and adjustment. CONCLUSION: The results suggest an alternative model implicating emotional intelligence as a mediator of the relationship between personality difficulties and college adjustment.

Species-specific effects of neuregulin-1ß (cimaglermin alfa) on glucose handling in animal models and humans with heart failure.

Neuregulin-1ß is a member of the neuregulin family of growth factors and is critically important for normal development and functioning of the heart and brain. A recombinant version of neuregulin-1ß, cimaglermin alfa (also known as glial growth factor 2 or GGF2) is being investigated as a possible therapy for heart failure. Previous studies suggest that neuregulin-1ß stimulation of skeletal muscle increases glucose uptake and, specifically, sufficient doses of cimaglermin alfa acutely produce hypoglycemia in pigs. Since acute hypoglycemia could be a safety concern, blood glucose changes in the above pig study were further investigated. In addition, basal glucose and glucose disposal were investigated in mice. Finally, as part of standard clinical chemistry profiling in a single ascending-dose human safety study, blood glucose levels were evaluated in patients with heart failure after cimaglermin alfa treatment. A single intravenous injection of cimaglermin alfa at doses of 0.8mg/kg and 2.6mg/kg in mice resulted in a transient reduction of blood glucose concentrations of approximately 20% and 34%, respectively, at 2h after the treatment compared to pre-treatment levels. Similar results were observed in diabetic mice. Treatment with cimaglermin alfa also increased blood glucose disposal following oral challenge in mice. However, no significant alterations in blood glucose concentrations were found in human heart failure patients at 0.5 and 2h after treatment with cimaglermin alfa over an equivalent human dose range, based on body surface area. Taken together, these data indicate strong species differences in blood glucose handling after cimaglermin alfa treatment, and particularly do not indicate that this phenomenon should affect human subjects.

Cortical influences drive amyotrophic lateral sclerosis.

The early motor manifestations of sporadic amyotrophic lateral sclerosis (ALS), while rarely documented, reflect failure of adaptive complex motor skills. The development of these skills correlates with progressive evolution of a direct corticomotoneuronal system that is unique to primates and markedly enhanced in humans. The failure of this system in ALS may translate into the split hand presentation, gait disturbance, split leg syndrome and bulbar symptomatology related to vocalisation and breathing, and possibly diffuse fasciculation, characteristic of ALS. Clinical neurophysiology of the brain employing transcranial magnetic stimulation has convincingly demonstrated a presymptomatic reduction or absence of short interval intracortical inhibition, accompanied by increased intracortical facilitation, indicating cortical hyperexcitability. The hallmark of the TDP-43 pathological signature of sporadic ALS is restricted to cortical areas as well as to subcortical nuclei that are under the direct control of corticofugal projections. This provides anatomical support that the origins of the TDP-43 pathology reside in the cerebral cortex itself, secondarily in corticofugal fibres and the subcortical targets with which they make monosynaptic connections. The latter feature explains the multisystem degeneration that characterises ALS. Consideration of ALS as a primary neurodegenerative disorder of the human brain may incorporate concepts of prion-like spread at synaptic terminals of corticofugal axons. Further, such a concept could explain the recognised widespread imaging abnormalities of the ALS neocortex and the accepted relationship between ALS and frontotemporal dementia.

Neuronal network disintegration: common pathways linking neurodegenerative diseases.

Neurodegeneration refers to a heterogeneous group of brain disorders that progressively evolve. It has been increasingly appreciated that many neurodegenerative conditions overlap at multiple levels and therefore traditional clinicopathological correlation approaches to better classify a disease have met with limited success. Neuronal network disintegration is fundamental to neurodegeneration, and concepts based around such a concept may better explain the overlap between their clinical and pathological phenotypes. In this Review, promoters of overlap in neurodegeneration incorporating behavioural, cognitive, metabolic, motor, and extrapyramidal presentations will be critically appraised. In addition, evidence that may support the existence of large-scale networks that might be contributing to phenotypic differentiation will be considered across a neurodegenerative spectrum. Disintegration of neuronal networks through different pathological processes, such as prion-like spread, may provide a better paradigm of disease and thereby facilitate the identification of novel therapies for neurodegeneration.

Amyotrophic lateral sclerosis: a long preclinical period?

The onset of amyotrophic lateral sclerosis (ALS) is conventionally considered as commencing with the recognition of clinical symptoms. We propose that, in common with other neurodegenerations, the pathogenic mechanisms culminating in ALS phenotypes begin much earlier in life. Animal models of genetically determined ALS exhibit pathological abnormalities long predating clinical deficits. The overt clinical ALS phenotype may develop when safety margins are exceeded subsequent to years of mitochondrial dysfunction, neuroinflammation or an imbalanced environment of excitation and inhibition in the neuropil. Somatic mutations, the epigenome and external environmental influences may interact to trigger a metabolic cascade that in the adult eventually exceeds functional threshold. A long preclinical and subsequent presymptomatic period pose a challenge for recognition, since it offers an opportunity for protective and perhaps even preventive therapeutic intervention to rescue dysfunctional neurons. We suggest, by analogy with other neurodegenerations and from SOD1 ALS mouse studies, that vulnerability might be induced in the perinatal period.

Tools and talk: an evolutionary perspective on the functional deficits associated with amyotrophic lateral sclerosis.

We propose that amyotrophic lateral sclerosis (ALS), and frontotemporal dementia may be viewed as a failure of interlinked functional complexes having their origins in key evolutionary adaptations. We discuss how hand-arm function, locomotion, brainstem function (involving vocalization/speech, swallowing and breathing), and cognitive impairment share complex, interdependent evolutionary adaptations that can be traced back several million years. Fine movements of the hand facilitated tool-making and use enhanced by development of bipedalism. Development of the larynx and integration of respiratory control were central to vocalization, which when combined with gesture are intermediary to human language. These adaptations were accompanied by progressive encephalization, with development of Theory of Mind to facilitate socialization. The varied clinical phenotypes of ALS can thus be understood in the context of inter-related functional complexes that subserve "Tools and Talk"; they have a long evolutionary history and are related to specific developmental neural and gene networks.

History of ALS and the competing theories on pathogenesis: IFCN handbook chapter.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the human motor system, first described in the 19th Century. The etiology of ALS appears to be multifactorial, with a complex interaction of genetic, epigenetic, and environmental factors underlying the onset of disease. Importantly, there are no known naturally occurring animal models, and transgenic mouse models fail to faithfully reproduce ALS as it manifests in patients. Debate as to the site of onset of ALS remain, with three competing theories proposed, including (i) the dying-forward hypothesis, whereby motor neuron degeneration is mediated by hyperexcitable corticomotoneurons via an anterograde transsynaptic excitotoxic mechanism, (ii) dying-back hypothesis, proposing the ALS begins in the peripheral nervous system with a toxic factor(s) retrogradely transported into the central nervous system and mediating upper motor neuron dysfunction, and (iii) independent hypothesis, suggesting that upper and lower motor neuron degenerated independently. Transcranial magnetic stimulation studies, along with pathological and genetic findings have supported the dying forward hypothesis theory, although the science is yet to be settled. The review provides a historical overview of ALS, discusses phenotypes and likely pathogenic mechanisms.

The glymphatic system and Amyotrophic lateral sclerosis.

The glymphatic system and the meningeal lymphatic vessels provide a pathway for transport of solutes and clearance of toxic material from the brain. Of specific relevance to ALS, this is applicable for TDP-43 and glutamate, both major elements in disease pathogenesis. Flow is propelled by arterial pulsation, respiration, posture, as well as the positioning and proportion of aquaporin-4 channels (AQP4). Non-REM slow wave sleep is the is key to glymphatic drainage which discontinues during wakefulness. In Parkinson's disease and Alzheimer's disease, sleep impairment is known to predate the development of characteristic clinical features by several years and is associated with progressive accumulation of toxic proteinaceous products. While sleep issues are well described in ALS, consideration of preclinical sleep impairment or the potential of a failing glymphatic system in ALS has rarely been considered. Here we review how the glymphatic system may impact ALS. Preclinical sleep impairment as an unrecognized major risk factor for ALS is considered, while potential therapeutic options to improve glymphatic flow are explored.

Nanoplastics and Neurodegeneration in ALS.

Plastic production, which exceeds one million tons per year, is of global concern. The constituent low-density polymers enable spread over large distances and micro/nano particles (MNPLs) induce organ toxicity via digestion, inhalation, and skin contact. Particles have been documented in all human tissues including breast milk. MNPLs, especially weathered particles, can breach the blood-brain barrier, inducing neurotoxicity. This has been documented in non-human species, and in human-induced pluripotent stem cell lines. Within the brain, MNPLs initiate an inflammatory response with pro-inflammatory cytokine production, oxidative stress with generation of reactive oxygen species, and mitochondrial dysfunction. Glutamate and GABA neurotransmitter dysfunction also ensues with alteration of excitatory/inhibitory balance in favor of reduced inhibition and resultant neuro-excitation. Inflammation and cortical hyperexcitability are key abnormalities involved in the pathogenic cascade of amyotrophic lateral sclerosis (ALS) and are intricately related to the mislocalization and aggregation of TDP-43, a hallmark of ALS. Water and many foods contain MNPLs and in humans, ingestion is the main form of exposure. Digestion of plastics within the gut can alter their properties, rendering them more toxic, and they cause gut microbiome dysbiosis and a dysfunctional gut-brain axis. This is recognized as a trigger and/or aggravating factor for ALS. ALS is associated with a long (years or decades) preclinical period and neonates and infants are exposed to MNPLs through breast milk, milk substitutes, and toys. This endangers a time of intense neurogenesis and establishment of neuronal circuitry, setting the stage for development of neurodegeneration in later life. MNPL neurotoxicity should be considered as a yet unrecognized risk factor for ALS and related diseases.

Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the motor neurons in the motor cortex, brainstem and spinal cord. A combination of upper and lower motor neuron dysfunction comprises the clinical ALS phenotype. Although the ALS phenotype was first observed by Charcot over 100 years ago, the site of ALS onset and the pathophysiological mechanisms underlying the development of motor neuron degeneration remain to be elucidated. Transcranial magnetic stimulation (TMS) enables non-invasive assessment of the functional integrity of the motor cortex and its corticomotoneuronal projections. To date, TMS studies have established motor cortical and corticospinal dysfunction in ALS, with cortical hyperexcitability being an early feature in sporadic forms of ALS and preceding the clinical onset of familial ALS. Taken together, a central origin of ALS is supported by TMS studies, with an anterograde transsynaptic mechanism implicated in ALS pathogenesis. Of further relevance, TMS techniques reliably distinguish ALS from mimic disorders, despite a compatible peripheral disease burden, thereby suggesting a potential diagnostic utility of TMS in ALS. This review will focus on the mechanisms underlying the generation of TMS measures used in assessment of cortical excitability, the contribution of TMS in enhancing the understanding of ALS pathophysiology and the potential diagnostic utility of TMS techniques in ALS.