Rapid eye movement sleep behavior disorder: a narrative review from a technological perspective.

STUDY OBJECTIVES: Isolated rapid eye movement sleep behavior disorder (iRBD) is a parasomnia characterized by dream enactment. It represents a prodromal state of α-synucleinopathies, like Parkinson's disease. In recent years, biomarkers of increased risk of phenoconversion from iRBD to overt α-synucleinopathies have been identified. Currently, diagnosis and monitoring rely on self-reported reports and polysomnography (PSG) performed in the sleep lab, which is limited in availability and cost-intensive. Wearable technologies and computerized algorithms may provide comfortable and cost-efficient means to not only improve the identification of patients with iRBD but also to monitor risk factors of phenoconversion. In this work, we review studies using these technologies to identify iRBD or monitor phenoconversion biomarkers. METHODS: A review of articles published until May 31, 2022 using the Medline database was performed. We included only papers in which participants with RBD were part of the study population. The selected papers were divided into four sessions: actigraphy, gait analysis systems, computerized algorithms, and novel technologies. RESULTS: In total, 25 articles were included in the review. Actigraphy, wearable accelerometers, pressure mats, smartphones, tablets, and algorithms based on PSG signals were used to identify RBD and monitor the phenoconversion. Rest-activity patterns, core body temperature, gait, and sleep parameters were able to identify the different stages of the disease. CONCLUSIONS: These tools may complement current diagnostic systems in the future, providing objective ambulatory data obtained comfortably and inexpensively. Consequently, screening for iRBD and follow-up will be more accessible for the concerned patient cohort.

Measuring Sleep, Wakefulness, and Circadian Functions in Neurologic Disorders.

Neurologic disorders impact the ability of the brain to regulate sleep, wake, and circadian functions, including state generation, components of state (such as rapid eye movement sleep muscle atonia, state transitions) and electroencephalographic microarchitecture. At its most extreme, extensive brain damage may even prevent differentiation of sleep stages from wakefulness (eg, status dissociatus). Given that comorbid sleep-wake-circadian disorders are common and can adversely impact the occurrence, evolution, and management of underlying neurologic conditions, new technologies for long-term monitoring of neurologic patients may potentially usher in new diagnostic strategies and optimization of clinical management.

An immunocompetent farmer with isolated cerebral alveolar echinococcosis: illustrative case.

BACKGROUND: Alveolar echinococcosis is a rare condition, but living or working in a rural environment is a substantial risk factor. The liver is the organ primarily affected, with additional extrahepatic manifestations in approximately 25% of cases. Primary extrahepatic disease is rare, and isolated cerebral involvement is extremely unusual. OBSERVATIONS: The authors described an illustrative case of isolated cerebral alveolar echinococcosis in an immunocompetent farmer. Magnetic resonance imaging of the brain showed a predominantly cystic lesion with perifocal edema and a "bunch of grapes" appearance in the left frontal lobe. Histology revealed sharply demarcated fragments of a fibrous cyst wall accompanied by marked inflammation and necrosis. Higher magnification showed remnants of protoscolices with hooklets and calcified corpuscles. Immunohistochemistry and polymerase chain reaction (PCR) analysis confirmed the diagnosis of cerebral alveolar echinococcosis. Interestingly, serology and thoracic and abdominal computed tomography results were negative, indicative of an isolated primary extrahepatic manifestation. LESSONS: Isolated, primary central nervous system echinococcosis is extremely rare, with only isolated case reports. As in the authors' case, it can occur in immunocompetent patients, especially persons with a rural vocational history. Negative serology results do not exclude cerebral echinococcosis, which requires histological confirmation. Immunohistochemical staining and PCR analysis are especially useful in cases without classic morphological findings.

Layer-specific integration of locomotion and sensory information in mouse barrel cortex.

During navigation, rodents continually sample the environment with their whiskers. How locomotion modulates neuronal activity in somatosensory cortex, and how it is integrated with whisker-touch remains unclear. Here, we compared neuronal activity in layer 2/3 (L2/3) and L5 of barrel cortex using calcium imaging in mice running in a tactile virtual reality. Both layers increase their activity during running and concomitant whisking, in the absence of touch. Fewer neurons are modulated by whisking alone. Whereas L5 neurons respond transiently to wall-touch during running, L2/3 neurons show sustained activity. Consistently, neurons encoding running-with-touch are more abundant in L2/3 and they encode the run-speed better during touch. Few neurons across layers were also sensitive to abrupt perturbations of tactile flow during running. In summary, locomotion significantly enhances barrel cortex activity across layers with L5 neurons mainly reporting changes in touch conditions and L2/3 neurons continually integrating tactile stimuli with running.

The biological function of the cellular prion protein: an update.

The misfolding of the cellular prion protein (PrPC) causes fatal neurodegenerative diseases. Yet PrPC is highly conserved in mammals, suggesting that it exerts beneficial functions preventing its evolutionary elimination. Ablation of PrPC in mice results in well-defined structural and functional alterations in the peripheral nervous system. Many additional phenotypes were ascribed to the lack of PrPC, but some of these were found to arise from genetic artifacts of the underlying mouse models. Here, we revisit the proposed physiological roles of PrPC in the central and peripheral nervous systems and highlight the need for their critical reassessment using new, rigorously controlled animal models.

Novel Mouse Models of Methylmalonic Aciduria Recapitulate Phenotypic Traits with a Genetic Dosage Effect.

Methylmalonic aciduria (MMAuria), caused by deficiency of methylmalonyl-CoA mutase (MUT), usually presents in the newborn period with failure to thrive and metabolic crisis leading to coma or even death. Survivors remain at risk of metabolic decompensations and severe long term complications, notably renal failure and neurological impairment. We generated clinically relevant mouse models of MMAuria using a constitutive Mut knock-in (KI) allele based on the p.Met700Lys patient mutation, used homozygously (KI/KI) or combined with a knockout allele (KO/KI), to study biochemical and clinical MMAuria disease aspects. Transgenic Mut(ki/ki) and Mut(ko/ki) mice survive post-weaning, show failure to thrive, and show increased methylmalonic acid, propionylcarnitine, odd chain fatty acids, and sphingoid bases, a new potential biomarker of MMAuria. Consistent with genetic dosage, Mut(ko/ki) mice have lower Mut activity, are smaller, and show higher metabolite levels than Mut(ki/ki) mice. Further, Mut(ko/ki) mice exhibit manifestations of kidney and brain damage, including increased plasma urea, impaired diuresis, elevated biomarkers, and changes in brain weight. On a high protein diet, mutant mice display disease exacerbation, including elevated blood ammonia, and catastrophic weight loss, which, in Mut(ki/ki) mice, is rescued by hydroxocobalamin treatment. This study expands knowledge of MMAuria, introduces the discovery of new biomarkers, and constitutes the first in vivo proof of principle of cobalamin treatment in mut-type MMAuria.

Excessively elevated C-reactive protein after surgery for temporal lobe epilepsy.

OBJECTIVE: We present a series of 87 patients who underwent anteromesial temporal lobe resections for therapy refractory temporal lobe epilepsy. In addition to seizure outcome, we observed excessively elevated CRP-levels in this patient population. METHODS: We followed 87 patients (m=39, f=48; mean age 33.73±12.92, range 5-67 years) who underwent surgery between July 2003 and November 2011. Seizure outcome was classified in all patients according to the ILAE-classification by Wieser et al. (mean follow-up: 38.72 months). CRP levels were measured in 59 patients of the epilepsy surgery group and in a control group of 44 consecutive patients with supratentorial tumors (22 glioblastomas, 22 meningiomas). RESULTS: Clinical benefit was seen in 96.6% of the patients (ILAE classes 1-4), 80.5% were completely seizure free (ILAE class 1). Post-OP CRP values were significantly higher in the epilepsy group (n=59; mean CRP peak value: 100.86 mg/l, range: 16-258 mg/l) compared to the control group (n=44; mean CRP peak value: 36.85 mg/l, range: 0.4-233 mg/l) (p<0.001), but the correlation of mean CRP value and mean temperature peak is weak (r=0.31). CONCLUSIONS: Seizure outcome after surgery for temporal lobe epilepsy was excellent, CRP levels were excessively elevated in these patients in the absence of clinical infection and significantly higher compared to resections of supratentorial lesions.

Silver-enhanced in situ hybridization for determination of EGFR copy number alterations in non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) gene mutation and high gene copy number (CN) predict response to EGFR tyrosine kinase inhibitor therapy in the adenocarcinoma subtype of non-small cell lung cancer (NSCLC). The aims of this study were first to compare automated enzyme metallographic silver-enhanced in situ hybridization (SISH) with conventionally used fluorescence in situ hybridization (FISH) in the determination of EGFR CN in NSCLC tissue sections, and second to assess the association of EGFR CN with EGFR mutations and clinicopathological parameters. FISH and SISH were performed on tissue microarrays and large sections. Samples from 56 consecutively surgically resected NSCLC patients (cohort 1) and from 60 selected lung adenocarcinoma patients (cohort 2) were analyzed. EGFR CN was classified applying the Colorado criteria, and agreement between both methods was evaluated using κ values. EGFR CN was compared with EGFR protein expression and EGFR gene mutations. The results of SISH and FISH were identical in 114 of the 116 cases examined using the 2 techniques. One case was FISH+, SISH-, and 1 case was FISH- and SISH+. The agreement between the 2 methods was good in cohort 1 (κ=0.642 [0.428, 0.823]) and excellent in cohort 2 (κ=0.963 [0.870, 1.000]). EGFR positivity by FISH and SISH was associated with high EGFR protein expression (P<0.001) and EGFR mutation (P<0.001). These results validate the use of SISH for assessing EGFR CN alterations in NSCLC. The advantage of a permanent result and the possibility of bright-field microscopy make SISH an attractive alternative to FISH.