Atypical chemokine receptor ACKR2-V41A has decreased CCL2 binding, scavenging, and activation, supporting sustained inflammation and increased Alzheimer’s disease risk

Josue D. Gonzalez Murcia, Allen Weinert, Claudia M. Tellez Freitas, Daniel K. Arens, Meganne N. Ferrel, Julianne H. Grose, Perry G. Ridge, Eric Wilson, John S. K. Kauwe, K. Scott Weber, 2020

Abstract

A recent genome-wide association study (GWAS) of 59 cerebrospinal fluid (CSF) proteins with a connection to Alzheimer’s disease (AD) demonstrated an association between increased levels of chemokine ligand 2 (CCL2) with an atypical chemokine receptor chemokine-binding protein 2 variant V41A (ACKR2-V41A; rs2228467). High levels of CCL2 are associated with increased risk of AD development as well as other inflammatory diseases. In this study we characterized the biological function of the ACKR2-V41A receptor compared to the wild type allele by measuring its ligand binding affinity, CCL2 scavenging efficiency, and cell activation sensitivity. We transfected Chinese hamster ovary cells with plasmids carrying wild type ACKR2 (ACKR2-WT) or the mutant ACKR2-V41A receptor. Binding affinity assays showed that ACKR2-V41A has a lower binding affinity for CCL2 and CCL4 than ACKR2-WT. CCL2 scavenging results aligned with binding affinity assays, with ACKR2-V41A cells scavenging CCL2 with a lower efficiency than ACKR2-WT. Cell activation assays also showed that ACKR2-V41A cells had significantly lower receptor upregulation (β-Arrestin-dependent signaling pathway) upon stimulation compared to ACKR2-WT cells. These findings provide molecular and biological mechanistic insights into the GWAS association of ACKR2-V41A with increased levels of CCL2 in CSF and possibly other chemokine ligands. Increased CCL2 levels are associated with accelerated cognitive decline and increased risk of AD. Understanding how this atypical chemokine receptor allele increases serum markers of inflammation could lead to novel therapeutic solutions for AD.

Automated Speech Recognition in Adult Stroke Survivors: Comparing Human and Computer Transcriptions

Adam Jacks, K.L. Haley, G. Bishop, Tyson Harmon, 2019

Abstract

Objective: Speech sound errors are common in people with a variety of communication disorders and can result in impaired message transmission to listeners. Valid and reliable metrics exist to quantify this problem, but they are rarely used in clinical settings due to the time-intensive nature of speech transcription by humans. Automated speech recognition (ASR) technologies have advanced substantially in recent years, enabling them to serve as realistic proxies for human listeners. This study aimed to determine how closely transcription scores from human listeners correspond to scores from an ASR system. Patients and Methods: Sentence recordings from 10 stroke survivors with aphasia and apraxia of speech were transcribed orthographically by 3 listeners and a web-based ASR service. Adjusted transcription scores were calculated for all samples based on accuracy of transcribed content words. Results: As expected, transcription scores were significantly higher for the humans than for ASR. However, intraclass correlations revealed excellent agreement among the humans and ASR systems, and the systematically lower scores for computer speech recognition were effectively equalized simply by adding the regression intercept. Conclusions: The results suggest the clinical feasibility of supplementing or substituting human transcriptions with computer-generated scores, though extension to other speech disorders requires further research.

Conducting Research With Older Adults With Vision Impairment: Lessons Learned and Recommended Best Practices

Corinna Trujillo Tanner, Michael S. Caserta, Julia J. Kleinschmidt, Margaret S. Clayton,Paul S. Bernstein, and Jia Wen Guo, 2018

Abstract

Older adults are underrepresented in research, and a potential barrier to their participation may be the increasing prevalence of vision loss and lack of accommodation for this challenge. Although vision loss may initially pose a challenge to research participation, its effects can be mitigated with early, in-depth planning. For example, recruitment is more inclusive when best practices identified in the literature are used in the preparation of written materials to reduce glare and improve readability and legibility. Alternatives to obtaining written consent may be used. Interviews are made accessible when done verbally and the author uses cueing and good diction. Remaining vision can be optimized through seating arrangement, lighting, and magnification. Challenges encountered and resolved in a recent study with severely visually impaired older adults are offered here as exemplars. Methodology for identifying and recruiting a sample comprised exclusively of visually impaired older adults is also offered herein.

Teacher, group, self: Music teaching and learning in two New Horizons ensembles

Samuel Tsugawa, 2018

Abstract

This article presents a study investigating music teaching and learning among members of two senior adult music ensembles. This study employed a qualitative multiple case-study design in which members of a New Horizons band and orchestra located in two different cities were observed and interviewed over a period of several months. Video recordings of embedded observations, verbatim interview transcripts of sixteen participants and personal journal entries of two members served as primary data sources. Analysis of the data revealed members’ preferred attributes of effective conductor-teachers, their motivation to participate in group music making and how members engaged in music making and learning as individuals. Findings of this study suggest implications for research and practice that deal with: (1) understanding effective and appropriate strategies on how to teach senior adult musicians; (2) providing increased opportunities for music learning and participation among senior adults; (3) expanding the current music teacher education curriculum to include teaching adult musicians; and (4) the growth and future of the New Horizons movement.

Sleep disturbances and depression severity in patients with Parkinson's disease

Daniel Kay, Jared J. Tanner, Dawn Bowers, 2018

Abstract

Parkinson's disease (PD) is a multisystem movement disorder associated with sleep disturbance and depression. Sleep disturbances and depression severity share a bidirectional association. This association may be greater in individuals who are more vulnerable to the deleterious consequences of sleep disturbance and depression severity. We investigated whether the association between sleep disturbances and depression severity is greater in patients with PD than in matched controls (MC).

A method for characterizing essential tremor from the shoulder to the wrist

D. W. Geiger, D. L. Eggett, and S. K. Charles, 2018

Abstract

Background: Despite the pervasive and devastating effect of Essential Tremor (ET), the distribution of ET throughout the upper limb is unknown. We developed a method for characterizing the distribution of ET and performed a preliminary characterization in a small number of subjects with ET. Methods: Using orientation sensors and inverse kinematics, we measured tremor in each of the seven major degrees of freedom (DOF) from the shoulder to the wrist while ten patients with mild ET assumed 16 different postures. We described the tremor in each DOF in terms of power spectral density measures and investigated how tremor varied between DOF, postures, gravitational torques, and repetitions. Findings: Our method successfully resulted in tremor measures in each DOF, allowing one to compare tremor between DOF and determine the distribution of tremor throughout the upper limb, including how the distribution changes with posture. In our small number of subjects, we found that the amount of power in the frequency band associated with ET (4–12 Hz) was lowest in the shoulder and greatest in the wrist. Similarly, the existence and amplitude of peaks in this band increased from proximal to distal. Although the amount of tremor differed significantly between postures, we did not find any clear patterns with changes in posture or gravitational torque. Interpretation: This method can be used to characterize the distribution of tremor throughout the upper limb. Our preliminary characterization suggests that the amount of tremor increases in a proximal-distal manner.

Mechanisms of In Vivo Ribosome Maintenance Change in Response to Nutrient Signals

Andrew D. Mathis, Bradley C. Naylor, Richard H. Carson, Eric Evans, Justin Harwell, Jared Knecht, Eric Hexem, Fredrick F. Peelor III, Benjamin F. Miller, Karyn L. Hamilton, Mark K. Transtrum, Benjamin T. Bikman, and John C. Price, 2018

Abstract

Control of protein homeostasis is fundamental to the health and longevity of all organisms. Because the rate of protein synthesis by ribosomes is a central control point in this process, regulation, and maintenance of ribosome function could have amplified importance in the overall regulatory circuit. Indeed, ribosomal defects are commonly associated with loss of protein homeostasis, aging, and disease (1⇓⇓–4), whereas improved protein homeostasis, implying optimal ribosomal function, is associated with disease resistance and increased lifespan (5⇓–7). To maintain a high-quality ribosome population within the cell, dysfunctional ribosomes are targeted for autophagic degradation. It is not known if complete degradation is the only mechanism for eukaryotic ribosome maintenance or if they might also be repaired by replacement of defective components. We used stable-isotope feeding and protein mass spectrometry to measure the kinetics of turnover of ribosomal RNA (rRNA) and 71 ribosomal proteins (r-proteins) in mice. The results indicate that exchange of individual proteins and whole ribosome degradation both contribute to ribosome maintenance in vivo. In general, peripheral r-proteins and those with more direct roles in peptide-bond formation are replaced multiple times during the lifespan of the assembled structure, presumably by exchange with a free cytoplasmic pool, whereas the majority of r-proteins are stably incorporated for the lifetime of the ribosome. Dietary signals impact the rates of both new ribosome assembly and component exchange. Signal-specific modulation of ribosomal repair and degradation could provide a mechanistic link in the frequently observed associations among diminished rates of protein synthesis, increased autophagy, and greater longevity.

Acute extracellular matrix, inflammatory and MAPK response to lengthening contractions in elderly human skeletal muscle

JR Sorensen , C Skousen, A Holland, K Williams, RD Hyldahl, 2018

Abstract

To uncover potential factors that may be involved in the impaired regenerative capacity of aged skeletal muscle, we comprehensively assessed the molecular stress response following muscle damage in old and young individuals. 10 young (22.7 ± 2.25 yrs) and 8 physically active old (70.9 ± 7.5 yrs) subjects completed a bout of 300 lengthening contractions (LC), and muscle biopsies were taken pre-exercise and at 3, 24, and 72 h post-LC. Both age groups performed the same amount of work during LC, with the old group displaying a resistance to LC-induced fatigue during the exercise. Muscle damage was evident by soreness and losses in isokinetic force and power production, though older subjects experienced reduced force and power losses relative to the young group. The acute extracellular matrix (ECM) response was characterized by substantial increases in the glycoproteins tenascin C and fibronectin in the young, which were blunted in the old muscle following damage. Old muscle displayed a generally heightened and asynchronous inflammatory response compared to young muscle, with higher expression of MCP-1 that appeared at later time points, and increased NF-κb activity. Expression of the stress-related MAPKs P38 and JNK increased only in the old groups following muscle damage. In summary, aberrations appear in the inflammatory, ECM and MAPK responses of aged skeletal muscle following damaging LC, each of which may individually or collectively contribute to the deterioration of muscle repair mechanisms that accompanies aging.

The Mediating Effects of Resilience, Morale, and Sense of Coherence Between Physical Activity and Perceived Physical/Mental Health Among Japanese Community-Dwelling Older Adults: A Cross-Sectional Study

Hiroko Kukihara, Niwako Yamawaki, Michiyo Ando, Yoshiko Tamura, Kumi Arita, Emiko Nakashima, 2017

Abstract

The aim of this study was to examine the mediating effects of resilience, morale, and sense of coherence (SOC) on the relationship between physical activity and respondents’ perceived physical/mental health and depression among community-dwelling older adults in Japan. There were a total of 369 participants with an average age of 74 from Kasuishimohara District in Fukuoka prefecture, Japan. They completed a survey that included the Resilience Scale, the Sense of Coherence Scale, the Medical Outcomes Short Form 8, Philadelphia Geriatric Center Morale Scale, Geriatric Depression Scale (Short Form), and a demographic questionnaire. The results of the path mediation analyses revealed that resilience and morale fully mediated the relationship between physical activity and perceived physical/mental health and depression. However, SOC was not a significant mediator. Some intervention programs are suggested to maximize the effects of physical activity on one’s well-being. At-risk populations who need such programs are also discussed.

Long-Term Cognitive Decline After Newly Diagnosed Heart Failure

Christa A. Hammond, Natalie J. Blades, Sarwat I. Chaudhry, John A. Dodson, W.T. Longstreth, Susan R. Heckbert, Bruce M. Psaty, Alice M. Arnold, Sascha Dublin, Colleen M. Sitlani, Julius M. Gardin, Stephen M. Thielke, Michael G. Nanna, Rebecca F. Gottesman, Anne B. Newman, Evan L. Thacker, 2018

Abstract

Heart failure (HF) is associated with cognitive impairment. However, we know little about the time course of cognitive change after HF diagnosis, the importance of comorbid atrial fibrillation, or the role of ejection fraction. We sought to determine the associations of incident HF with rates of cognitive decline and whether these differed by atrial fibrillation status or reduced versus preserved ejection fraction.Heart failure (HF) is associated with cognitive impairment. However, we know little about the time course of cognitive change after HF diagnosis, the importance of comorbid atrial fibrillation, or the role of ejection fraction. We sought to determine the associations of incident HF with rates of cognitive decline and whether these differed by atrial fibrillation status or reduced versus preserved ejection fraction.

Biological, Psychological, and Social Predictors of Longevity Among Utah Centenarians

Jeremy B. Yorgason, Thomas W. Draper, Haley Bronson, Makayla Nielson, Kate Babcock, Karolina Jones, Melanie S. Hill, Myranda Howard, 2018

Abstract

Studies of longevity among centenarians examine biological, psychological, and social factors, yet few consider these components concurrently. This study explores such factors individually and collectively, as they are related to days lived past the age of 100 years. Data from 268 family members of centenarians identified in the State of Utah between 2008 and 2015 were used in negative binomial models predicting number of days lived among the centenarians. Findings suggested that sleep latency (biological), life satisfaction (psychological), and attachment closeness (social) were predictive factors of more days lived within individual models. When considered together, sleep latency and life satisfaction remained significant predictors of days lived. Although biological factors are commonly considered in relation to longevity, this study further indicates that psychological and social factors may play important roles in life expectancy. Further examination is needed to explore how these factors link additionally to active life expectancy.

The Potential Public Health Relevance of Social Isolation and Loneliness: Prevalence, Epidemiology, and Risk Factors

Julianne Holt-Lunstad, 2018

Abstract

Our social relationships are widely considered crucial to emotional well-being; however, the possibility that social connection may be a biological need, vital to physical well-being and even survival, is commonly unrecognized. Still, extreme examples clearly illustrate infants in custodial care who lack human contact fail to thrive and often die (UNICEF, 1997), and social isolation is so distressing that solitary confinement has been used as a form of punishment and even torture. Yet an increasing portion of the U.S. population now experiences isolation regularly. News headlines from many nations, including the United States, Germany, Australia, and the United Kingdom, suggest that we are facing a loneliness epidemic (http://www.campaigntoendloneliness.org/loneliness-research, http://www.spiegel.de/international/germany/germany-faces-epidemic-of-lonely-and-isolated-seniors-a-876635.html, https://startsat60.com/health/new-survey-reveals-australias-loneliness-epidemic, http://www.huffingtonpost.com.au/tania-de-jong/loneliness-is-the-global-epidemic-of-our-times), leading to the important question of whether there is evidence to support such a claim and, if so, whether we are facing a public health crisis. Recently my work has systematically examined and summarized the available evidence supporting the public health prioritization of social connections (Holt-Lunstad, Robles, & Sbarra, 2017). Here I will summarize data on prevalence rates, epidemiological evidence of risk, and potential risk factors.

Assembly of 809 whole mitochondrial genomes with clinical, imaging, and fluid biomarker phenotyping

Perry G. Ridge, M.E. Wadsworth, J.B. Miller, A.J. Saykin, R.C. Green, John S. Kauwe, 2018

Abstract

Introduction: Mitochondrial genetics are an important but largely neglected area of research in Alzheimer’s disease. A major impediment is the lack of data sets. Methods: We used an innovative, rigorous approach, combining several existing tools with our own, to accurately assemble and call variants in 809 whole mitochondrial genomes. Results: To help address this impediment, we prepared a data set that consists of 809 complete and annotated mitochondrial genomes with samples from the Alzheimer’s Disease Neuroimaging Initiative. These whole mitochondrial genomes include rich phenotyping, such as clinical, fluid biomarker, and imaging data, all of which is available through the Alzheimer’s Disease Neuroimaging Initiative website. Genomes are cleaned, annotated, and prepared for analysis. Discussion: These data provide an important resource for investigating the impact of mitochondrial genetic variation on risk for Alzheimer’s disease and other phenotypes that have been measured in the Alzheimer’s Disease Neuroimaging Initiative samples.

Implementing reverse mentoring to address social isolation among older adults

Bethany M. Breck, Cory B. Dennis & Skye N. Leedahl, 2018

Abstract

Reverse mentoring is a means to address the social work Grand Challenge of social isolation. Among older adults, reverse mentoring can improve social connection by increasing the digital competence of older adults so they can use technology for social benefit, and by facilitating intergenerational connections with young adult mentors. In this paper, reverse mentoring is examined within an intergenerational program that serves older adults and utilizes the native technological knowledge and skills of young adults who mentor older adult participants. Qualitative data were collected through young adult mentor logs of each session, and through open-ended questions on the post-surveys collected from older adults and young adult mentors. Qualitative analysis revealed three themes related to social connection: (1) an increased sense of self-efficacy for older adults as they build confidence in technological use, and for young adults as they develop leadership skills through mentoring, (2) the breaking down of age-related stereotypes, and (3) intergenerational engagement and connection. The findings demonstrate that reverse mentoring can be used in various settings to decrease the social isolation of older adults by developing intergenerational connections and increasing older adult usage of technology.

Age-related differences in the response of the L5-S1 intervertebral disc to spinal traction

Ulrike H. Mitchell, P.F. Beattie, J. Bowden, R. Larson, H. Wang, 2017

Abstract

BACKGROUND: Lumbar traction is a common treatment for low back pain; however its mechanisms of action are poorly understood. It has been hypothesized that a key effect of lumbar traction is its capacity to influence fluid movement within the intervertebral disc (IVD). OBJECTIVES: To determine differences in the apparent diffusion coefficient (ADC) obtained with lumbar diffusion-weighted imaging (DWI) of the L5-S1 IVD before, and during, the application of lumbar traction. DESIGN: Case series, repeated measures. METHODS: A static traction load of ∼50% of body-weight was applied to the low back using a novel "MRI-safe" apparatus. DWI of the lumbar spine was performed prior to, and during the application of the traction load. RESULTS: Participants were currently asymptomatic and included a young adult group (n = 18) and a middle-aged group (n = 15). The young adult group had a non-significant 2.2% increase in ADC (mean change = 0.03 × 10-3 mm2/s, SD = 0.24, 95% CI = -0.09, 0.15). The ADC for the middle-aged group significantly increased by 20% (mean change of 0.18 × 10-3 mm2/s, SD = 0.19; 95% CI = 0.07, 0.28; p = 0.003; effect size = 0.95). There was an inverse relationship between the ADC obtained before traction and the percent increase in ADC that was measured during traction. CONCLUSION: Static traction was associated with an increase in diffusion of water within the L5-S1 IVDs of middle-age individuals, but not in young adults, suggesting age-related differences in the diffusion response. Further study is needed to assess the relationship between these findings and the symptoms of back pain.

Envejecer con éxito: Roles y potenciales de adultos mayores (Successful aging: Roles and potential for older adults)

Jeremy B. Yorgason, Tyler K. Anderson, E. Jeffrey Hill, 2018

Abstract

This article examines ways in which older adults can be seen and can see themselves in order to maintain a positive perception of aging. We begin by exploring ways that older adults can be seen in Argentina. Next we review models that outline successful aging, aging well and active aging, along with a critique and research examples of these approaches. We discuss an example of successful aging seen in grandparents. Research and personal examples of grandparents are shared, along with the ways in which grandparents can be served. This article demonstrates that grandparents have a potential role in which they continue to be included in their families and communities.

The BMP2 nuclear variant, nBMP2, is expressed in mouse hippocampus and impacts memory

Ryan D. Cordner, Lindsey N. Friend, Jaime L. Mayo, Corinne Badgley, AndrewWallmann, Conrad N. Stallings, Peter L.Young, Darla R. Miles, JeffreyG. Edwards & Laura C. Bridgewater, 2017

Abstract

The novel nuclear protein nBMP2 is synthesized from the BMP2 gene by translational initiation at an alternative start codon. We generated a targeted mutant mouse, nBmp2NLStm, in which the nuclear localization signal (NLS) was inactivated to prevent nuclear translocation of nBMP2 while still allowing the normal synthesis and secretion of the BMP2 growth factor. These mice exhibit abnormal muscle function due to defective Ca2+ transport in skeletal muscle. We hypothesized that neurological function, which also depends on intracellular Ca2+ transport, could be affected by the loss of nBMP2. Agematched nBmp2NLStm and wild type mice were analyzed by immunohistochemistry, behavioral tests, and electrophysiology to assess nBMP2 expression and neurological function. Immunohistochemical staining of the hippocampus detected nBMP2 in the nuclei of CA1 neurons in wild type but not mutant mice, consistent with nBMP2 playing a role in the hippocampus. Mutant mice showed deficits in the novel object recognition task, suggesting hippocampal dysfunction. Electrophysiology experiments showed that long-term potentiation (LTP) in the hippocampus, which is dependent on intracellular Ca2+ transport and is thought to be the cellular equivalent of learning and memory, was impaired. Together, these results suggest that nBMP2 in the hippocampus impacts memory formation.

Running exercise mitigates the negative consequences of chronic stress on dorsal hippocampal long-term potentiation in male mice

Roxanne M.Miller, David Marriott, Jacob Trotter, Tyler Hammond, Dane Lyman, Timothy Call, Bethany Walker, Nathanael Christensen, Deson Haynie, Zoie Badura, Morgan Homan, Jeffrey G. Edwards, 2018

Abstract

In the hippocampus, learning and memory are likely mediated by synaptic plasticity, known as long-term potentiation (LTP). While chronic intermittent stress is negatively correlated, and exercise positively correlated to LTP induction, we examined whether exercise could mitigate the negative consequences of stress on LTP when co-occurring with stress. Mice were divided into four groups: sedentary no stress, exercise no stress, exercise with stress, and sedentary with stress. Field electrophysiology performed on brain slices confirmed that stress alone significantly reduced dorsal CA1 hippocampal LTP and exercise alone increased LTP compared to controls. Exercise with stress mice exhibited LTP that was significantly greater than mice undergoing stress alone but were not different from sedentary no stress mice. An ELISA illustrated increased corticosterone in stressed mice compared to no stress mice. In addition, a radial arm maze was used to examine behavioral changes in memory during 6 weeks of stress and/or exercise. Exercised mice groups made fewer errors in week 2. RT-qPCR was used to examine the mRNA expression of components in the stress and exercise pathways in the four groups. Significant changes in the expression of the following targets were detected: BDNF, TrkB, glucocorticoid, mineralocorticoid, and dopamine 5 receptors. Collectively, exercise can mitigate some of the negative impact stress has on hippocampal function when both occur concurrently.