Objective Sleep Profile in LGI1/CASPR2 Autoimmunity

Study Objectives Rapid eye movement (REM) sleep behavior disorder (RBD) and other sleep disturbances are frequent in leucine-rich, glioma inactivated protein 1-IgG (LGI1) and contactin-associated protein 2-IgG (CASPR2) autoimmunity, yet polysomnographic analyses of these disorders remain limited. We aimed to characterize clinical presentations and analyze polysomnographic manifestations, especially quantitative REM sleep without atonia (RSWA) in LGI1/CASPR2-IgG seropositive (LGI/CASPR2+) patients. Methods We retrospectively analyzed clinical and polysomnographic features and quantitative RSWA between LGI1+/CASPR2+ patients and age-sex matched controls. Groups were compared with Wilcoxon rank-sum and chi-square tests. Combined submentalis and anterior tibialis (SM+AT) RSWA was the primary outcome Results Among 11 (LGI1+, n=9; CASPR2+, n=2) patients, Morvan syndrome sleep features were present in 7 (63.6%) LGI1+/CASPR2+ patients, with simultaneous insomnia and DEB in 3 (27.3%), and the most common presenting sleep disturbances were dream enactment behavior (DEB, n=5), insomnia (n=5), and sleep apnea (n=8; median apnea hypopnea index=15/hour). Median Epworth Sleepiness Scale (ESS) was 9 (range 3-24; n=10), with hypersomnia in 4 (36.4%). LGI1+/CASPR2+ patients had increased N1 sleep (p=0.02), decreased REM sleep (p=0.001), and higher levels of SM+AT any RSWA (p < 0.001). Eight of 9 (89%) LGI1+ exceeded RBD RSWA thresholds (DEB, n=5; isolated RSWA, n=3). RSWA was greater in anterior tibialis than submentalis. All 10 LGI1+/CASPR2+ patients treated with immunotherapy benefitted, and 5/10 had improved sleep disturbances. Conclusion LGI1/CASPR2-IgG autoimmunity is associated with prominent dream enactment, insomnia, RSWA, sleep apnea, and shallower sleep. Polysomnography provides objective disease markers in LGI1+/CASPR2+ autoimmunity and immunotherapy may benefit associated sleep disturbances.

P028 The Nox A1 ambulatory system is reliable when self-applied

Background Home Sleep Apnea Tests (HSAT) increases access to SDB diagnostic testing (Safadi, 2014). A previous study defined a reliable HSAT if: ≥4hours total recording time, an intelligible position signal and respiratory effort, airflow and oximetry for at least 80% of the night were recorded, however, admits no standardized criteria in the literature (Domingo, 2010). Aim To test the reliability of a self-applied HSAT using the Nox-A1 ambulatory system (NOX Medical, Iceland). Method Patients self-applied the HSAT guided by industry produced video and written instructions. Signals for the HSAT included; two electro-occulagrams (EOG), two sub-mental electromyograms (EMG), a single modified frontal encephalogram (EEG), a lead I ECG, single leg anterior tibialis EMG, chest and abdominal inductance respiratory effort, nasal pressure airflow, WristOx 2 3150 SpO2 (Nonin Medical, Inc., USA) and 3-D accelerometer and body position sensor. Analysed with ProFusion PSG 4 (Compumedics Limited, Australia) after importing data into Nexus. 33 consecutive studies were recorded during lock-down. Recording satisfactory if SpO2 signal and EEG present >80% of study, it was considered a failure if doctor requested test repeat. Results 33 subjects, age 43.1 ± 13.7 years, BMI 27.4 ± 6.0 kg/m2, 66.6% male. 81.8% of studies satisfactory. 6% of studies needed a repeat in-lab PSG due to 1) loss of oximetry & EEG and 2) loss of EEG Discussion 6% doctor request repeat in-lab PSG is comparable to a study (Lloberes, 2001) of partially self-applied HSAT. Demonstrated good reliability with this self-applied COVID-safe method of HSAT.

Structure-function Specialisation of the Interfascicular Matrix in the Human Achilles Tendon

ABSTRACTObjectiveTendon consists of highly aligned collagen-rich fascicles surrounded by interfascicular matrix (IFM). Some tendons act as energy stores to improve locomotion efficiency; these tendons are prone to debilitating injuries, the incidence of which increases with ageing. In equine tendons, energy storage is achieved primarily through specialisation of the IFM. However, no studies have investigated IFM structure-function specialisation in human tendons. Here, we compare the positional anterior tibialis and energy storing Achilles tendons, testing the hypothesis that the Achilles IFM has specialised composition and mechanical properties, which are lost with ageing.MethodsWe used a multidisciplinary combination of mechanical testing, immunolocalisation and proteomics to investigate structure-function specialisations in functionally distinct human tendons and how these are altered with ageing.ResultsThe IFM in the energy storing Achilles tendon is more elastic and fatigue resistant than the IFM in the positional anterior tibialis tendon, with a trend towards decreased fatigue resistance with age in the Achilles IFM. With ageing, alterations occur predominantly to the proteome of the Achilles IFM.ConclusionThe Achilles tendon IFM is specialised for energy storage, and changes to its proteome with ageing are likely responsible for the observed trends towards decreased fatigue resistance. Knowledge of key energy storing specialisations and their changes with ageing offers insight towards developing effective treatments for tendinopathy.Key messagesWhat is already known about this subject?Energy storing tendons in animals and humans are particularly prone to injury and the incidence increases with increasing age.Previous work in some animal models has shown that the specialisation of tendon properties for energy storage is achieved primarily through adaptation of the interfascicular matrix, with specialisation lost in ageing. However, the structural specialisations that provide the human Achilles tendon with its energy storing ability, and how these are affected by ageing, remain to be established.What does this study add?We demonstrate that the interfascicular matrix in the human Achilles tendon is specialised for energy storing, with increased elastic recoil and fatigue resistance, and that these specialisations are partially lost with ageing, likely due to alterations to the proteome of the interfascicular matrix.How might this impact on clinical practice or future developments?Short term, the specialist IFM mechanics we have demonstrated can be detected with new developments in ultrasound functional imaging, offering improved opportunities for contextual tendinopathy diagnostics. Personalised rehabilitation programmes can now be explored and designed specifically to target IFM mechanics.Longer term, the knowledge of key specialisations in injury prone energy storing tendons and how they are affected by ageing, offers crucial insight towards developing cell or tissue engineering treatments targeted at restoring tendon structure and function post-injury, specifically targeted at the IFM.

REM sleep atonia loss distinguishes synucleinopathy in older adults with cognitive impairment

ObjectiveTo determine whether quantitative polysomnographic REM sleep without atonia (RSWA) distinguishes between cognitive impairment phenotypes.BackgroundNeurodegenerative cognitive impairment in older adults predominantly correlates with tauopathy or synucleinopathy. Accurate antemortem phenotypic diagnosis has important prognostic and treatment implications; additional clinical tools might distinguish between dementia syndromes.MethodsWe quantitatively analyzed RSWA in 61 older adults who underwent polysomnography including 46 with cognitive impairment (20 probable synucleinopathy), 26 probable non-synucleinopathy (15 probable Alzheimer disease, 11 frontotemporal lobar dementia), and 15 age- and sex-matched controls. Submentalis and anterior tibialis RSWA metrics and automated REM atonia index were calculated. Group statistical comparisons and regression were performed, and receiver operating characteristic curves determined diagnostic RSWA thresholds that best distinguished synucleinopathy phenotype.ResultsSubmentalis—but not anterior tibialis RSWA—was greater in synucleinopathy than nonsynucleinopathy; several RSWA diagnostic thresholds distinguished synucleinopathy with excellent specificity including submentalis tonic, 5.6% (area under the curve [AUC] 0.791); submentalis any, 15.0% (AUC 0.871); submentalis phasic, 10.8% (AUC 0.863); and anterior tibialis phasic, 31.4% (AUC 0.694). In the subset of patients without dream enactment behaviors, submentalis RSWA was also greater in patients with synucleinopathy than in those without synucleinopathy. RSWA was detected more frequently by quantitative than qualitative methods (p = 0.0001).ConclusionElevated submentalis RSWA distinguishes probable synucleinopathy from probable nonsynucleinopathy in cognitively impaired older adults, even in the absence of clinical dream enactment symptoms.Classification of evidenceThis study provides Class III evidence that quantitative RSWA analysis is useful for distinguishing cognitive impairment phenotypes. Further studies with pathologic confirmation of dementia diagnoses are needed to confirm the diagnostic utility of RSWA in dementia.

HyPer2 imaging reveals temporal and heterogeneous hydrogen peroxide changes in denervated and aged skeletal muscle fibers in vivo

To determine the role of denervation and motor unit turnover in the age-related increase in skeletal muscle oxidative stress, the hydrogen peroxide (H2O2) specific, genetically-encoded, fluorescent cyto-HyPer2 probe was expressed in mouse anterior tibialis (AT) muscle and compared with ex vivo measurements of mitochondrial oxidant generation. Crush of the peroneal nerve induced increased mitochondrial peroxide generation, measured in permeabilised AT fibers ex vivo and intra vital confocal microscopy of cyto-HyPer2 fluorescence showed increased cytosolic H2O2 in a sub-set (~24%) of individual fibers associated with onset of fiber atrophy. In comparison, mitochondrial peroxide generation was also increased in resting muscle from old (26 month) mice compared with adult (6–8 month) mice, but no age effect on fiber cytosolic H2O2in vivo was seen. Thus ageing is associated with an increased ability of muscle fibers to maintain cytosolic redox homeostasis in the presence of denervation-induced increase in mitochondrial peroxide generation.