Opportunities, barriers, and recommendations in down syndrome research

Recent advances in medical care have increased life expectancy and improved the quality of life for people with Down syndrome (DS). These advances are the result of both pre-clinical and clinical research but much about DS is still poorly understood. In 2020, the NIH announced their plan to update their DS research plan and requested input from the scientific and advocacy community. The National Down Syndrome Society (NDSS) and the LuMind IDSC Foundation worked together with scientific and medical experts to develop recommendations for the NIH research plan. NDSS and LuMind IDSC assembled over 50 experts across multiple disciplines and organized them in eleven working groups focused on specific issues for people with DS. This review article summarizes the research gaps and recommendations that have the potential to improve the health and quality of life for people with DS within the next decade. This review highlights many of the scientific gaps that exist in DS research. Based on these gaps, a multidisciplinary group of DS experts has made recommendations to advance DS research. This paper may also aid policymakers and the DS community to build a comprehensive national DS research strategy

Oxidant production and SOD1 protein expression in single skeletal myofibers from Down syndrome mice

Down syndrome (DS) is a genetic condition caused by the triplication of chromosome 21. Persons with DS exhibit pronounced muscle weakness, which also occurs in the Ts65Dn mouse model of DS. Oxidative stress is thought to be an underlying factor in the development of DS-related pathologies including muscle dysfunction. High-levels of oxidative stress have been attributed to triplication and elevated expression of superoxide dismutase 1 (SOD1); a gene located on chromosome 21. The elevated expression of SOD1 is postulated to increase production of hydrogen peroxide and cause oxidative injury and cell death. However, it is unknown whether SOD1 protein expression is associated with greater oxidant production in skeletal muscle from Ts65Dn mice. Thus, our objective was to assess levels of SOD1 expression and oxidant production in skeletal myofibers from the flexor digitorum brevis obtained from Ts65Dn and control mice. Measurements of oxidant production were obtained from myofibers loaded with 2′,7′-dichlorodihydrofluorescein diacetate (DCFH2-DA) in the basal state and following 15 min of stimulated unloaded contraction. Ts65Dn myofibers exhibited a significant decrease in basal DCF emissions (p 0.05). Myofibers from Ts65Dn mice tended to be smaller and myonuclear domain was lower (p < 0.05). In summary, myofibers from Ts65Dn mice exhibited decreased basal DCF emissions that were coupled with elevated protein expression of SOD1. Stimulated contraction in isolated myofibers did not affect DCF emissions in either group. These findings suggest the skeletal muscle dysfunction in the adult Ts65Dn mouse is not associated with skeletal muscle oxidative stress

Young and middle‐aged mouse breathing behavior during the light and dark cycles

Abstract Unrestrained barometric plethysmography is a common method used for characterizing breathing patterns in small animals. One source of variation between unrestrained barometric plethysmography studies is the segment of baseline. Baseline may be analyzed as a predetermined time‐point, or using tailored segments when each animal is visually calm. We compared a quiet, minimally active (no sniffing/grooming) breathing segment to a predetermined time‐point at 1 h for baseline measurements in young and middle‐aged mice during the dark and light cycles. Additionally, we evaluated the magnitude of change for gas challenges based on these two baseline segments. C57BL/6JEiJ x C3Sn.BliA‐Pde6b+/DnJ male mice underwent unrestrained barometric plethysmography with the following baselines used to determine breathing frequency, tidal volume (VT) and minute ventilation (VE): (1) 30‐sec of quiet breathing and (2) a 10‐min period from 50 to 60 min. Animals were also exposed to 10 min of hypoxic (10% O2, balanced N2), hypercapnic (5% CO2, balanced air) and hypoxic hypercapnic (10% O2, 5% CO2, balanced N2) gas. Both frequency and VE were higher during the predetermined 10‐min baseline versus the 30‐sec baseline, while VT was lower (P  0.05) in an analysis of one cohort. During baseline, dark cycle testing had increased VT values versus those in the light (P < 0.05). For gas challenges, both frequency and VE showed higher percent change from the 30‐sec baseline compared to the predetermined 10‐min baseline (P < 0.05), while VT showed a greater change from the 10‐min baseline (P < 0.05). Dark cycle hypoxic exposure resulted in larger percent change in breathing frequency versus the light cycle (P < 0.05). Overall, light and dark cycle pattern of breathing differences emerged along with differences between the 30‐sec behavior observational method versus a predetermined time segment for baseline

Metallothionein deficiency leads to soleus muscle contractile dysfunction following acute spinal cord injury in mice

Metallothionein (MT) is a small molecular weight protein possessing metal binding and free radical scavenging properties. We hypothesized that MT-1/MT-2 null (MT−/−) mice would display exacerbated soleus muscle atrophy, oxidative injury, and contractile dysfunction compared with the response of wild-type (WT) mice following acute spinal cord transection (SCT). Four groups of mice were studied: WT laminectomy, WT transection, MT−/− laminectomy (MT−/− lami), and MT−/− transection (MT−/− trans). Laminectomy animals served as surgical controls. Mice in SCT groups experienced similar percent body mass (BM) losses at 7 days postinjury. Soleus muscle mass (MM) and MM-to-BM ratio were lower at 7 days postinjury in SCT vs. laminectomy mice, with no differences observed between strains. However, soleus muscles from MT−/− trans mice showed reduced maximal specific tension compared with MT−/− lami animals. Mean cross-sectional area (μm2) of type I and type IIa fibers decreased similarly in SCT groups compared with laminectomy controls, and no difference in fiber distribution was observed. Lipid peroxidation (4-hydroxynoneal) was greater in MT−/− trans vs. MT−/− lami mice, but protein oxidation (protein carbonyls) was not altered by MT deficiency or SCT. Expression of key antioxidant proteins (catalase, manganese, and copper-zinc superoxide dismutase) was similar between the groups. In summary, MT deficiency did not impact soleus MM loss, but resulted in contractile dysfunction and increased lipid peroxidation following acute SCT. These findings suggest a role of MT in mediating protective adaptations in skeletal muscle following disuse mediated by spinal cord injury

Iron status of young males and females performing weight-training exercise

OBJECTIVES: Burdensome symptoms frequently develop as part of the dementia trajectory and influence quality of life. We explore the course of symptoms and their treatment during nursing home stay to help target adequate symptom management. DESIGN: Data were collected as part of the Dutch End of Life in Dementia study, a longitudinal observational study with up to 3.5 years of follow-up. Physicians performed assessments at baseline, semiannually, and shortly after death of pain, agitation, shortness of breath, and treatment provided for these symptoms. SETTING: Long-term care facilities (28) in the Netherlands. PARTICIPANTS: Newly admitted nursing home residents (372) in variable stages of dementia. MEASUREMENTS: We described prevalence and course of symptoms, and treatment provided for these symptoms. We used generalized estimating equations to evaluate the longitudinal change in symptoms and their treatment, and the associations between the symptoms of pain and agitation, as well as between stage of dementia and symptoms. RESULTS: Pain was common (varying from 47% to 68% across the semiannual assessments) and frequently persistent (36%-41% of all residents); it increased to 78% in the last week of life. Agitation was the most common symptom (57%-71%), and also frequently persistent (39%-53%), yet it decreased to 35% in the last week of life. Shortness of breath was less common (16%-26%), but it increased to 52% at the end of life. Pain was not significantly associated with agitation. Advanced dementia was associated with more pain only. Treatment changed in particular at the end of life. Pain was treated mostly with acetaminophen (34%-52%), and at the end of life with parenteral opioids (44%). Agitation was mostly treated nonpharmacologically (78%-92%), and at the end of life anxiolytics were the most frequently prescribed treatment (62%). Overall, aerosolized bronchodilators were the most frequently prescribed treatment for shortness of breath (29%-67%), but at the end of life, this was morphine (69%). CONCLUSION: Pain and agitation were common and frequently persisted in residents with dementia during nursing home stay, but symptom management intensified only at the end of life. Symptom control may be suboptimal from admission, and a stronger focus on symptom control is needed at an earlier stage than the end of life