Elliott, Jonathan E.

Abstract Introduction Rapid Eye Movement (REM) Sleep Behavior Disorder (RBD) is characterized by a lack of muscle atonia during REM sleep with dream enactment. RBD is regarded as a prodromal synucleinopathy as a high proportion of patients eventually phenoconvert to Parkinson’s Disease and related synucleinopathies, suggesting RBD may be an early non-motor symptom of disease. Accordingly, patients with RBD are ideally situated to test potential therapeutic interventions to prevent phenoconversion to synucleinopathy. However, RBD itself, and associated patient registries, are rare. The North American Prodromal Synucleinopathy Consortium (formed in 2018) establishes a multisite registry of RBD patients with standardized neurological, neuropsychiatric, and neuropsychological assessments and biomarker collection. The present work reports baseline characteristics of this RBD patient database at its current state. Methods Seven participating sites have contributed n=170 polysomnographically-confirmed RBD patients. Data includes past medical and family history, self-report questionnaires, and neuropsychological, motor, sensory, and autonomic function testing. Additionally, all subjects have contributed blood, and a subset of subjects have contributed cerebrospinal fluid samples to the National Centralized Repository for Alzheimer’s Disease and Related Dementias for future analysis. A final diagnosis for each subject was determined through an adjudication process by NAPS Consortium PIs; subjects were categorized as ether: 1) isolated RBD, 2) RBD+, 3) Early Symptomatic, or 4) Phenoconverted. Results Of the n=170 subjects, there were n=39 isolated RBD, n=81 RBD+, n=45 Early Symptomatic, and n=4 Phenoconverted. Isolated RBD subjects have no other early neurodegeneration signs/symptoms, those with RBD+ have at least one other identifiable early/mild symptom. The early symptomatic group includes those with mild or subjective cognitive impairment, pure autonomic failure, or possible multiple systems atrophy. The Phenoconverted group consists of those with Dementia with Lew Bodies, Dementia NOS, Parkinson’s Disease, or Parkinson’s NOS. The distribution of impairment across the 5 major domains (motor, cognitive, autonomic, sensory, and psychiatric) for each of the 4 groups will be described. Conclusion This interim analysis presents data on n=170 subjects. The target enrollment is n=360 across the 7 original sites plus 3 new sites. Future work will follow these subjects longitudinally to assess rates and predictors of phenoconversion. Support (if any) NIH NIA R34 AG056639 (YJ, BB)

Previous work investigating respiratory system mechanics in mice has reported an aging-related increase in compliance and mean linear intercept ( Lm). However, these changes were assessed using only a young (2-mo-old) and old (20- and 26-mo-old) group yet were interpreted to reflect a linear evolution across the life span. Therefore, to investigate respiratory system mechanics and lung morphometry across a more complete spectrum of ages, we utilized 2 (100% survival, n = 6)-, 6 (100% survival, n = 12)-, 18 (90% survival, n = 12)-, 24 (75% survival, n = 12)-, and 30 (25% survival, n = 12)-mo-old C57BL/6 mice. We found a nonlinear aging-related decrease in respiratory system resistance and increase in dynamic compliance and hysteresis between 2- and 24-mo-old mice. However, in 30-mo-old mice, respiratory system resistance increased, and dynamic compliance and hysteresis decreased relative to 24-mo-old mice. Respiratory system impedance spectra were measured between 1–20.5 Hz at positive end-expiratory pressures (PEEP) of 1, 3, 5, and 7 cmH2O. Respiratory system resistance and reactance at each level of PEEP were increased and decreased, respectively, only in 2-mo-old animals. No differences in the respiratory system impedance spectra were observed in 6-, 18-, 24-, and 30-mo-old mice. Additionally, lungs were fixed following tracheal instillation of 4% paraformaldehyde at 25 cmH2O and processed for Lm and airway collagen deposition. There was an aging-related increase in Lm consistent with emphysematous-like changes and no evidence of increased airway collagen deposition. Accordingly, we demonstrate nonlinear aging-related changes in lung mechanics and morphometry in C57BL/6 mice.

New FindingsWhat is the central question of this study?Several rat models are commonly used to study the physiology of ageing (e.g. Fischer 344 and Brown Norway rats are recommended by the USA National Institute of Ageing). Diaphragm muscle sarcopenia (ageing‐related muscle weakness and atrophy) remains incompletely described in these rat models.What is the main finding and its importance?Diaphragm muscle sarcopenia is present in both the Fischer 344 and Brown Norway rat strains, but appears more pronounced in Fischer 344 rats.The risk for respiratory diseases increases in adults >65 years of age, which may be attributable in part to ageing‐related weakening and atrophy (i.e. sarcopenia) of the diaphragm muscle (DIAm). The mechanisms underlying DIAm sarcopenia remain unknown. Based on existing evidence, we hypothesized that sarcopenia is most evident in type IIx and/or IIb DIAm fibres, i.e. more fatigable motor units. Currently, the USA National Institute on Aging supports Fischer 344 (F344) and Brown Norway (BN) rat strains for ageing‐related research, yet DIAm sarcopenia has not been evaluated comprehensively in either strain. Thus, the present study examined DIAm sarcopenia in older adult F344 (24 months old, 50% survival) and BN rats (32 months old, 50% survival), compared with young adult (6‐month‐old) F344 and BN rats. Measurements of contractility, contractile protein concentration, fibre type distribution and fibre cross‐sectional area were obtained from midcostal DIAm strips. Maximal specific force was reduced by ∼24 and ∼13% in older F344 and BN rats, respectively. Additionally, although the cross‐sectional area of type I and IIa DIAm fibres was unchanged in both F344 and BN rats, the cross‐sectional area of type IIx and/or IIb DIAm fibres was reduced by ∼20 and ∼15% in F344 and BN rats, respectively. Thus, although there was ageing‐related DIAm weakness and atrophy, selective to type IIx and/or IIb DIAm fibres, in both F344 and BN rats, the sarcopenic phenotype was more pronounced in F344 rats.

Intrapulmonary arteriovenous anastomoses (IPAVA) are large diameter (>50 μm) vascular conduits, present in >95% of healthy humans. Because IPAVA are large diameter pathways that allow blood flow to bypass the pulmonary capillary network, blood flow through IPAVA (QIPAVA) can permit the transpulmonary passage of particles larger than pulmonary capillaries. IPAVA have been known to exist for over 50 years, but their physiological and clinical significance are still being established; although, currently suggested roles for QIPAVA include allowing emboli to reach the systemic circulation and providing a source of shunt. Studying QIPAVA is an important area of research and as the suggested roles become better established, detecting and quantifying QIPAVA may become significantly more important in the clinic. Several techniques that can be used to quantify and/or detect QIPAVA in animals, ex vivo human/animal lungs, and intact healthy humans; microspheres, radiolabeled macroaggregated albumin particles, and saline contrast echocardiography, are reviewed with limitations and advantages to each. The current body of literature using these techniques to study QIPAVA in animals, ex vivo lungs, and healthy humans has established conditions when QIPAVA is present, such as during exercise or with arterial hypoxemia and conditions when QIPAVA is absent, such as at rest or during exercise breathing 100% O2. Many of these physiological studies have direct application to patient populations and we discuss each of these findings in the context of their potential to influence the clinical utility, and interpretation, of the results from these techniques highlighted in this review.

AbstractIntrapulmonary arteriovenous anastomoses (IPAVA) have been known to exist in human lungs for over 60 years. The majority of the work in this area has largely focused on characterizing the conditions in which IPAVA blood flow (IPAVA) is either increased, e.g. during exercise, acute normobaric hypoxia, and the intravenous infusion of catecholamines, or absent/decreased, e.g. at rest and in all conditions with alveolar hyperoxia ( = 1.0). Additionally, IPAVA is present in utero and shortly after birth, but is reduced in older (>50 years) adults during exercise and with alveolar hypoxia, suggesting potential developmental origins and an effect of age. The physiological and pathophysiological roles of IPAVA are only beginning to be understood and therefore these data remain controversial. Although evidence is accumulating in support of important roles in both health and disease, including associations with pulmonary arterial pressure, and adverse neurological sequelae, there is much work that remains to be done to fully understand the physiological and pathophysiological roles of IPAVA. The development of novel approaches to studying these pathways that can overcome the limitations of the currently employed techniques will greatly help to better quantify IPAVA and identify the consequences of IPAVA on physiological and pathophysiological processes. Nevertheless, based on currently published data, our proposed working model is that IPAVA occurs due to passive recruitment under conditions of exercise and supine body posture, but can be further modified by active redistribution of pulmonary blood flow under hypoxic and hyperoxic conditions.