Motor neuron disease can be viewed as an umbrella term describing a heterogeneous group of conditions, all of which are relentlessly progressive and ultimately fatal. The average life expectancy is 2 years, but with a broad range of months to decades. Biomarker research deepens disease understanding through exploration of pathophysiological mechanisms which, in turn, highlights targets for novel therapies. It also allows differentiation of the disease population into sub-groups, which serves two general purposes: (a) provides clinicians with information to better guide their patients in terms of disease progression, and (b) guides clinical trial design so that an intervention may be shown to be effective if population variation is controlled for. Biomarkers also have the potential to provide monitoring during clinical trials to ensure target engagement. This review highlights biomarkers that have emerged from the fields of systemic measurements including biochemistry (blood, cerebrospinal fluid, and urine analysis); imaging and electrophysiology, and gives examples of how a combinatorial approach may yield the best results. We emphasize the importance of systematic sample collection and analysis, and the need to correlate biomarker findings with detailed phenotype and genotype data.

Succinate-driven reverse electron transport (RET) is one of the main sources of mitochondrial reactive oxygen species (mtROS) in ischemia-reperfusion injury. RET is dependent on mitochondrial membrane potential (Δψm) and transmembrane pH difference (ΔpH), components of the proton motive force (pmf); a decrease in Δψm and/or ΔpH inhibits RET. In this study we aimed to determine which component of the pmf displays the more dominant effect on RET-provoked ROS generation in isolated guinea pig brain and heart mitochondria respiring on succinate or α-glycerophosphate (α-GP). Δψm was detected via safranin fluorescence and a TPP+ electrode, the rate of H2O2 formation was measured by Amplex UltraRed, the intramitochondrial pH (pHin) was assessed via BCECF fluorescence. Ionophores were used to dissect the effects of the two components of pmf. The K+/H+ exchanger, nigericin lowered pHin and ΔpH, followed by a compensatory increase in Δψm that led to an augmented H2O2 production. Valinomycin, a K+ ionophore, at low [K+] increased ΔpH and pHin, decreased Δψm, which resulted in a decline in H2O2 formation. It was concluded that Δψm is dominant over ∆pH in modulating the succinate- and α-GP-evoked RET. The elevation of extramitochondrial pH was accompanied by an enhanced H2O2 release and a decreased ∆pH. This phenomenon reveals that from the pH component not ∆pH, but rather absolute value of pH has higher impact on the rate of mtROS formation. Minor decrease of Δψm might be applied as a therapeutic strategy to attenuate RET-driven ROS generation in ischemia-reperfusion injury.

Background Much progress has been made in mapping genetic abnormalities linked to amyotrophic lateral sclerosis (ALS), but the majority of cases still present with no known underlying cause. Furthermore, even in families with a shared genetic abnormality there is significant phenotypic variability, suggesting that non-genetic elements may modify pathogenesis. Identification of such disease-modifiers is important as they might represent new therapeutic targets. A growing body of research has begun to shed light on the role played by the gut microbiome in health and disease with a number of studies linking abnormalities to ALS. Main body The microbiome refers to the genes belonging to the myriad different microorganisms that live within and upon us, collectively known as the microbiota. Most of these microbes are found in the intestines, where they play important roles in digestion and the generation of key metabolites including neurotransmitters. The gut microbiota is an important aspect of the environment in which our bodies operate and inter-individual differences may be key to explaining the different disease outcomes seen in ALS. Work has begun to investigate animal models of the disease, and the gut microbiomes of people living with ALS, revealing changes in the microbial communities of these groups. The current body of knowledge will be summarised in this review. Advances in microbiome sequencing methods will be highlighted, as their improved resolution now enables researchers to further explore differences at a functional level. Proposed mechanisms connecting the gut microbiome to neurodegeneration will also be considered, including direct effects via metabolites released into the host circulation and indirect effects on bioavailability of nutrients and even medications. Conclusion Profiling of the gut microbiome has the potential to add an environmental component to rapidly advancing studies of ALS genetics and move research a step further towards personalised medicine for this disease. Moreover, should compelling evidence of upstream neurotoxicity or neuroprotection initiated by gut microbiota emerge, modification of the microbiome will represent a potential new avenue for disease modifying therapies. For an intractable condition with few current therapeutic options, further research into the ALS microbiome is of crucial importance.

IntroductionThere are no disease-modifying treatments for Parkinson’s disease (PD). We undertook the first drug screen in PD patient tissue and idntified ursodeoxycholic acid (UDCA) as a promising mitochondrial rescue agent. The aims of this trial are to determine safety and tolerability of UDCA in PD at 30 mg/kg, confirm the target engagement of UDCA, apply a novel motion sensor-based approach to quantify disease progression objectively, and estimate the mean effect size and its variance on the change in motor severity.Methods and analysisThis is a phase II, two-centre, double-blind, randomised, placebo-controlled trial of UDCA at a dose of 30 mg/kg in 30 participants with early PD. Treatment duration is 48 weeks, followed by an 8-week washout phase. Randomisation is 2:1, drug to placebo. Assessments are performed at baseline, week 12, 24, 36, 48 and 56. The primary outcome is safety and tolerability. Secondary outcomes will compare the change between baseline and week 48 using the following three approaches: the Movement Disorders Society Unified Parkinson’s Disease Rating Scale Part 3 in the practically defined ‘OFF’ medication state; confirmation of target engagement, applying 31Phosphorus MR Spectroscopy to assess the levels of ATP and relevant metabolites in the brain; and objective quantification of motor impairment, using a validated, motion sensor-based approach. The primary outcome will be reported using descriptive statistics and comparisons between treatment groups. For each secondary outcome, the change from baseline will be summarised within treatment groups using summary statistics and appropriate statistical tests assessing for significant differences. All outcomes will use an intention-to-treat analysis population.Ethics and disseminationThis trial has been approved by the East of England – Cambridgeshire and Hertfordshire Research Ethics committee. Results will be disseminated in peer-reviewed journals, presentations at scientific meetings and to patients in a lay-summary format.Trial registration numberNCT03840005.

Mitochondrial dysfunction is postulated to be central to amyotrophic lateral sclerosis (ALS) pathophysiology. Evidence comes primarily from disease models and conclusive data to support bioenergetic dysfunction in vivo in patients is currently lacking. This study is the first to assess mitochondrial dysfunction in brain and muscle in individuals living with ALS using 31P-magnetic resonance spectroscopy (MRS), the modality of choice to assess energy metabolism in vivo. We recruited 20 patients and 10 healthy age and gender-matched control subjects in this cross-sectional clinico-radiological study. 31P-MRS was acquired from cerebral motor regions and from tibialis anterior during rest and exercise. Bioenergetic parameter estimates were derived including: ATP, phosphocreatine, inorganic phosphate, adenosine diphosphate, Gibbs free energy of ATP hydrolysis (ΔGATP), phosphomonoesters, phosphodiesters, pH, free magnesium concentration, and muscle dynamic recovery constants. Linear regression was used to test for associations between brain data and clinical parameters (revised amyotrophic functional rating scale, slow vital capacity, and upper motor neuron score) and between muscle data and clinico-neurophysiological measures (motor unit number and size indices, force of contraction, and speed of walking). Evidence for primary dysfunction of mitochondrial oxidative phosphorylation was detected in the brainstem where ΔGATP and phosphocreatine were reduced. Alterations were also detected in skeletal muscle in patients where resting inorganic phosphate, pH, and phosphomonoesters were increased, whereas resting ΔGATP, magnesium, and dynamic phosphocreatine to inorganic phosphate recovery were decreased. Phosphocreatine in brainstem correlated with respiratory dysfunction and disability; in muscle, energy metabolites correlated with motor unit number index, muscle power, and speed of walking. This study provides in vivo evidence for bioenergetic dysfunction in ALS in brain and skeletal muscle, which appears clinically and electrophysiologically relevant. 31P-MRS represents a promising technique to assess the pathophysiology of mitochondrial function in vivo in ALS and a potential tool for future clinical trials targeting bioenergetic dysfunction.

Objectives Intracranial pressure (ICP) has been thought to vary diurnally. This study evaluates diurnal ICP measurements and quantifies changes in ICP occurring with changes in body posture in active idiopathic intracranial hypertension (IIH). Methods This prospective observational study utilized telemetric ICP monitoring in people with active IIH. Participants had the Raumedic p-Tel ICP intraparenchymal device (Raumedic, Hembrechts, Germany) surgically inserted. Changes in ICP in the supine position were evaluated. Then, the ICP was measured in the standing, sitting, supine, left lateral decubitus positions and with coughing and bending. Ultimately, changes in ICP over the course of 24 h were recorded. ISRCTN registration number 12678718. Results 15 women were included, mean (standard deviation) age 29.5 (9.5) years, body mass index 38.1 (6.2) kg/m2, and baseline mean ICP of 21.2 (4.8) mmHg (equivalent to 28.8 (6.5) cmCSF). Mean ICP rose with the duration in the supine position 1.2 (3.3) mmHg over 5-minutes (p = 0.175), 3.5 (2.8) mmHg over 30-minutes (p = 0.0002) and by a further 2.1 (2.2) mmHg over 3 h (p = 0.042). Mean ICP decreased by 51% when moving from the supine position to standing (21.2 (4.8) mmHg to 10.3 (3.7) mmHg respectively, p = 0.0001). Mean ICP increased by 13% moving from supine to the left lateral decubitus position (21.2 (4.8) mmHg to 24.0 (3.8) mmHg, p = 0.028). There was no significant difference in ICP measurements at any point during the daytime, or between 5-minute standing or supine recordings and prolonged ambulatory daytime and end of night supine recordings respectively. ICP, following an initial drop, increased progressively in conjunction with lying supine position from 23:00 h to 07:00 h by 34% (5.2 (1.9) mmHg, p = 0.026). Conclusion This analysis demonstrated that ICP does not appear to have a diurnal variation in IIH, but varies by position and duration in the supine position. ICP rose at night whilst the patient was continuously supine. Furthermore, brief standing and supine ICP measures in the day predicted daytime prolonged ambulatory measures and end of night peak ICP respectively. This knowledge gives reassurance that ICP can be accurately measured and compared at any time of day in an ambulant IIH patient. These are useful findings to inform clinical measurements and in the interpretation of ICP analyses in IIH. Trial registration ISTCRN (12678718).

There is strong evidence of a key role for mitochondrial dysfunction in both sporadic and all forms of familial Parkinson's disease (PD). However, none of the clinical trials carried out with putative mitochondrial rescue agents have been successful. Firm establishment of a wet biomarker or a reliable readout from imaging studies detecting mitochondrial dysfunction and reflecting disease progression is also awaited. We will provide an overview of our current knowledge about mitochondrial dysfunction in PD and related drug screens. We will also summarise previously undertaken mitochondrial wet biomarker studies and relevant imaging studies with particular focus on 31P-MRI spectroscopy. We will conclude with an overview of clinical trials which tested putative mitochondrial rescue agents in PD patients.

Background : Idiopathic intracranial hypertension (IIH) is characterized by increased intracranial pressure occurring predominantly in women with obesity. The pathogenesis is not understood. We have applied untargeted metabolomic analysis using ultrahigh-performance liquid chromatography–mass spectrometry to characterize the cerebrospinal fluid (CSF) and serum in IIH compared to control subjects. Methods and findings : Samples were collected from IIH patients ( n = 66) with active disease at baseline and again at 12 months following therapeutic weight loss. Control samples were collected from gender- and weight-matched healthy controls ( n = 20). We identified annotated metabolites in CSF, formylpyruvate and maleylpyruvate/fumarylpyruvate, which were present at lower concentrations in IIH compared to control subjects and returned to values observed in controls following weight loss. These metabolites showed the opposite trend in serum at baseline. Multiple amino acid metabolic pathways and lipid classes were perturbed in serum and CSF in IIH alone. Serum lipid metabolite pathways were significantly increased in IIH. Conclusions : We observed a number of differential metabolic pathways related to amino acid, lipid, and acylpyruvate metabolism, in IIH compared to controls. These pathways were associated with clinical measures and normalized with disease remission. Perturbation of these metabolic pathways provides initial understanding of disease dysregulation in IIH.