Cuprizone administration in mice provides a reproducible model of demyelination and spontaneous remyelination, and has been useful in understanding important aspects of human disease, including multiple sclerosis. In this study, we apply high spatial resolution quantitative MRI techniques to establish the spatio-temporal patterns of acute demyelination in C57BL/6 mice after 6 weeks of cuprizone administration, and subsequent remyelination after 6 weeks of post-cuprizone recovery. MRI measurements were complemented with Black Gold II stain for myelin and immunohistochemical stains for associated tissue changes. Gene expression was evaluated using the Allen Gene Expression Atlas. Twenty-five C57BL/6 male mice were split into control and cuprizone groups; MRI data were obtained at baseline, after 6 weeks of cuprizone, and 6 weeks post-cuprizone. High-resolution (100μm isotropic) whole-brain coverage magnetization transfer ratio (MTR) parametric maps demonstrated concurrent caudal-to-rostral and medial-to-lateral gradients of MTR decrease within corpus callosum (CC) that correlated well with demyelination assessed histologically. Our results show that demyelination was not limited to the midsagittal line of the corpus callosum, and also that opposing gradients of demyelination occur in the lateral and medial CC. T2-weighted MRI gray/white matter contrast was strong at baseline, weak after 6 weeks of cuprizone treatment, and returned to a limited extent after recovery. MTR decreases during demyelination were observed throughout the brain, most clearly in callosal white matter. Myelin damage and repair appear to be influenced by proximity to oligodendrocyte progenitor cell populations and exhibit an inverse correlation with myelin basic protein gene expression. These findings suggest that susceptibility to injury and ability to repair vary across the brain, and whole-brain analysis is necessary to accurately characterize this model. Whole-brain parametric mapping across time is essential for gaining a real understanding of disease processes in-vivo. MTR increases in healthy mice throughout adolescence and adulthood were observed, illustrating the need for appropriate age-matched controls. Elucidating the unique and site-specific demyelination in the cuprizone model may offer new insights into in mechanisms of both damage and repair in human demyelinating diseases.

Pantothenate kinase-associated neurodegeneration (PKAN) is a progressive movement disorder that is due to mutations in PANK2. Pathologically, it is a member of a class of diseases known as neurodegeneration with brain iron accumulation (NBIA) and features increased tissue iron and ubiquitinated protein aceous aggregates in the globuspallidus. We have previously determined that these aggregates represent condensed residue derived from degenerated pallidal neurons. However, the protein content, other than ubiquitin, of these aggregates remains unknown. In the present study, we performed biochemical and immunohistochemical studies to characterize these aggregates and found them to be enriched in apolipoprotein E that is poorly soluble in detergent solutions. However, did not determine a significant association between APOE genotype and the clinical phenotype of disease in our database of 81 cases. Rather, we frequently identified similar ubiquitin- and apolipoprotein E-enriched lesions in these neurons in non-PKAN patients in the penumbrae of remote infarcts that involve the globuspallidus, and occasionally in other brain sites that contain large γ-aminobutyric acid (GABA)ergic neurons. Our findings, taken together, suggest that tissue or cellular hypoxic/ischemic injury within the globuspallidus may underlie the pathogenesis of PKAN.

Purpose of review : Sarcopenia, defined as decreased muscle mass or function, is prevalent in chronic kidney disease (CKD) increasing the risk of mobility impairment and frailty. CKD leads to metabolic acidosis (MA) and retention of uremic toxins contributing to insulin resistance and impaired muscle mitochondrial energetics. Here we focus on the central role of muscle mitochondrial metabolism in muscle function. Recent findings : Mitochondrial dysfunction underlies muscle wasting and poor physical endurance in CKD. Uremic toxins accumulate in muscle disrupting mitochondrial respiration and enzymes. Changes in mitochondrial quantity, quality, and oxidative capacity contribute to mobility impairment in CKD. Major determinants of muscle mitochondrial function are kidney function, inflammation, and oxidative stress. In CKD, MA is the major determinant of muscle mitochondrial function. Metabolomics reveals defects in pathways linked to mitochondrial energy metabolism and acid-base homeostasis underlying insulin resistance in CKD. Summary : Decreased mitochondrial capacity and quality control can impair muscle function contributing to decreased physical endurance. MA augments insulin resistance perpetuating the catabolic state underlying muscle wasting in CKD. Further studies are needed to investigate if targeting of MA improves muscle mitochondrial function and insulin resistance translating into meaningful improvements in physical endurance.

Central hypoventilation, also known as Ondine’s curse, results from an impairment of the autonomic respiratory drive. It is characterized by an attenuated or absent respiratory response to hypoxemia and hypercapnia with preservation of volitional respiratory function. RJ was a 75-year-old woman with a diagnosis of probably PSP who developed central hypoventilation approximately four years after her initial onset of symptoms. Brain MRI showed no evidence of medullary lesions, one of the more common causes of adult onset central hypoventilation. The respiratory centers in the medulla, especially the ventral respiratory group (VRG) containing Botzinger and pre-Botzinger complex of neurons, appear critical for normal respiratory rhythm generation. RJ was maintained on a portable ventilator after her diagnosis of Central Hypoventilation. Ten month after being placed on ventilation she passed of unclear cause. RJ showed pathological features consistent with a diagnosis of PSP, specifically loss of neurons, secondary demyelination, and tau-positive inclusions in both astrocytes and neurons, chiefly in the globus pallidus, midbrain, and brainstem. RJ showed significant tauopathy in the region of the VRG in particular. We also examined this region in sixteen other cases of PSP and found similar tauopathy in all but one case, which had significantly less involvement of this area. We had limited clinical data on these cases but one had two episodes of unexplained hypoxia shortly before being placed on hospice. Central hypoventilation associated with tauopathy involving the VRG may be more common than often appreciated.

Remote patient monitoring allows monitoring high-risk patients through implementation of an expanding number of technologies in coordination with a healthcare team to augment care, with the potential to provide early detection of exacerbation, prompt access to therapy and clinical services, and ultimately improved patient outcomes and decreased healthcare utilization.In this review, we describe the application of remote patient monitoring in chronic obstructive pulmonary disease including the potential benefits and possible barriers to implementation both for the individual and the healthcare system.