Accelerometer-derived movement features as predictive biomarkers for muscle atrophy in neurocritical care: a prospective cohort study.

BACKGROUND: Physical inactivity and subsequent muscle atrophy are highly prevalent in neurocritical care and are recognized as key mechanisms underlying intensive care unit acquired weakness (ICUAW). The lack of quantifiable biomarkers for inactivity complicates the assessment of its relative importance compared to other conditions under the syndromic diagnosis of ICUAW. We hypothesize that active movement, as opposed to passive movement without active patient participation, can serve as a valid proxy for activity and may help predict muscle atrophy. To test this hypothesis, we utilized non-invasive, body-fixed accelerometers to compute measures of active movement and subsequently developed a machine learning model to predict muscle atrophy. METHODS: This study was conducted as a single-center, prospective, observational cohort study as part of the MINCE registry (metabolism and nutrition in neurointensive care, DRKS-ID: DRKS00031472). Atrophy of rectus femoris muscle (RFM) relative to baseline (day 0) was evaluated at days 3, 7 and 10 after intensive care unit (ICU) admission and served as the dependent variable in a generalized linear mixed model with Least Absolute Shrinkage and Selection Operator regularization and nested-cross validation. RESULTS: Out of 407 patients screened, 53 patients (age: 59.2 years (SD 15.9), 31 (58.5%) male) with a total of 91 available accelerometer datasets were enrolled. RFM thickness changed - 19.5% (SD 12.0) by day 10. Out of 12 demographic, clinical, nutritional and accelerometer-derived variables, baseline RFM muscle mass (beta - 5.1, 95% CI - 7.9 to - 3.8) and proportion of active movement (% activity) (beta 1.6, 95% CI 0.1 to 4.9) were selected as significant predictors of muscle atrophy. Including movement features into the prediction model substantially improved performance on an unseen test data set (including movement features: R2 = 79%; excluding movement features: R2 = 55%). CONCLUSION: Active movement, as measured with thigh-fixed accelerometers, is a key risk factor for muscle atrophy in neurocritical care patients. Quantifiable biomarkers reflecting the level of activity can support more precise phenotyping of ICUAW and may direct tailored interventions to support activity in the ICU. Studies addressing the external validity of these findings beyond the neurointensive care unit are warranted. TRIAL REGISTRATION: DRKS00031472, retrospectively registered on 13.03.2023.

Clinical heterogeneity within the ALS-FTD spectrum in a family with a homozygous optineurin mutation.

OBJECTIVE: Mutations in the gene encoding for optineurin (OPTN) have been reported in the context of different neurodegenerative diseases including the amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum. Based on single case reports, neuropathological data in OPTN mutation carriers have revealed transactive response DNA-binding protein 43 kDa (TDP-43) pathology, in addition to accumulations of tau and alpha-synuclein. Herein, we present two siblings from a consanguineous family with a homozygous frameshift mutation in the OPTN gene and different clinical presentations. METHODS: Both affected siblings underwent (i) clinical, (ii) neurophysiological, (iii) neuropsychological, (iv) radiological, and (v) laboratory examinations, and (vi) whole-exome sequencing (WES). Postmortem histopathological examination was conducted in the index patient, who deceased at the age of 41. RESULTS: The index patient developed rapidly progressing clinical features of upper and lower motor neuron dysfunction as well as apathy and cognitive deterioration at the age of 41. Autopsy revealed an ALS-FTLD pattern associated with prominent neuronal and oligodendroglial TDP-43 pathology, and an atypical limbic 4-repeat tau pathology reminiscent of argyrophilic grain disease. The brother of the index patient exhibited behavioral changes and mnestic deficits at the age of 38 and was diagnosed with behavioral FTD 5 years later, without any evidence of motor neuron dysfunction. WES revealed a homozygous frameshift mutation in the OPTN gene in both siblings (NM_001008212.2: c.1078_1079del; p.Lys360ValfsTer18). INTERPRETATION: OPTN mutations can be associated with extensive TDP-43 pathology and limbic-predominant tauopathy and present with a heterogeneous clinical phenotype within the ALS-FTD spectrum within the same family.

PRDM12: New Opportunity in Pain Research.

PRDM12 is a newly identified causative gene for a type of congenital insensitivity to pain disorder, which is characterized by the inability to perceive pain. Here, we discuss the (patho)physiology of PRDM12 function and the opportunities and challenges those data provide for novel therapeutic approaches in various pain disorders.

Modeling cell-autonomous motor neuron phenotypes in ALS using iPSCs.

Amyotrophic lateral sclerosis (ALS) is an aggressive and uniformly fatal degenerative disease of the motor nervous system. In order to understand underlying disease mechanisms, researchers leverage a host of in vivo and in vitro models, including yeast, worms, flies, zebrafish, mice, and more recently, human induced pluripotent stem cells (iPSCs) derived from ALS patients. While mouse models have been the main workhorse of preclinical ALS research, the development of iPSCs provides a new opportunity to explore molecular phenotypes of ALS within human cells. Importantly, this technology enables modeling of both familial and sporadic ALS in the relevant human genetic backgrounds, as well as a personalized or targeted approach to therapy development. Harnessing these powerful tools requires addressing numerous challenges, including different variance components associated with iPSCs and motor neurons as well as concomitant limits of reductionist approaches. In order to overcome these obstacles, optimization of protocols and assays, confirmation of phenotype robustness at scale, and validation of findings in human tissue and genetics will cement the role for iPSC models as a valuable complement to animal models in ALS and more broadly among neurodegenerative diseases.

Sialic Acid-Containing Glycans as Cellular Receptors for Ocular Human Adenoviruses: Implications for Tropism and Treatment.

Human adenoviruses (HAdV) are the most common cause of ocular infections. Species B human adenovirus type 3 (HAdV-B3) causes pharyngoconjunctival fever (PCF), whereas HAdV-D8, -D37, and -D64 cause epidemic keratoconjunctivitis (EKC). Recently, HAdV-D53, -D54, and -D56 emerged as new EKC-causing agents. HAdV-E4 is associated with both PCF and EKC. We have previously demonstrated that HAdV-D37 uses sialic acid (SA)-containing glycans as cellular receptors on human corneal epithelial (HCE) cells, and the virus interaction with SA is mediated by the knob domain of the viral fiber protein. Here, by means of cell-based assays and using neuraminidase (a SA-cleaving enzyme), we investigated whether ocular HAdVs other than HAdV-D37 also use SA-containing glycans as receptors on HCE cells. We found that HAdV-E4 and -D56 infect HCE cells independent of SAs, whereas HAdV-D53 and -D64 use SAs as cellular receptors. HAdV-D8 and -D54 fiber knobs also bound to cell-surface SAs. Surprisingly, HCE cells were found resistant to HAdV-B3 infection. We also demonstrated that the SA-based molecule i.e., ME0462, designed to bind to SA-binding sites on the HAdV-D37 fiber knob, efficiently prevents binding and infection of several EKC-causing HAdVs. Surface plasmon resonance analysis confirmed a direct interaction between ME0462 and fiber knobs. Altogether, we demonstrate that SA-containing glycans serve as receptors for multiple EKC-causing HAdVs, and, that SA-based compound function as a broad-spectrum antiviral against known and emerging EKC-causing HAdVs.