IMMU-24. IMPROVING OUTCOMES IN OLDER ADULTS WITH GLIOBLASTOMA BY REVERSING AGE-RELATED CHANGES

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi97-vi97
Author(s):  
Erik Ladomersky ◽  
Lijie Zhai ◽  
Lakshmi Bollu ◽  
April Bell ◽  
Kristen Lauing ◽  
...  
Keyword(s):  
Older Adults ◽  
T Cell ◽  
Brain Tumors ◽  
Older Adult ◽  
Nk Cell ◽  
Enzyme Inhibitor ◽  
Age Of Onset ◽  
Adult Mice ◽  
Age Related ◽  
The Brain

Abstract Wild-type IDH glioblastoma (wtGBM) represents ≥90% of human GBM patient diagnoses with a median age of onset at 68-70 years of age. We previously found a decline of GBM patient survival with progressive age and that subjects ≥65 years of age had the poorest prognosis. We also showed an age-dependent enhancement of immune suppression in the brain that negatively affected immunotherapeutic efficacy in older adult mice with syngeneic brain tumors. Here, we extended those observations while studying C57BL/6 mice with intracranial CT-2A or GL261 between 80-110 weeks old - analogous to the age of a wtIDH GBM patient diagnosis. Overall survival of older adult mice with CT-2A or GL261 was significantly decreased when subjects were lymphopenic for CD4+ T cells as compared to an IgG Ab treatment group (n=12/group; p< 0.01). CD8+ T cell or NK cell leukopenia had no effect on survival outcomes. The negative effect of CD4+ T cell lymphopenia in older adults was not observed in younger mice with brain tumors. We also investigated the increased immunosuppression in the brain and its relationship to the accumulation of senescent cells and the treatment with standard of care radiation/temozolomide (RT/TMZ). p16INK4A, a marker for senescent cells, was increased in non-tumor cells of the brain during advanced age and its expression was increased after treatment with RT/TMZ. Older adult mice with brain tumors and treated with senolytics showed decreased p16INK4A levels after treatment with RT/TMZ. Senolytic treatment also improved the efficacy of combination therapy with RT, anti-PD-1 mAb, and IDO enzyme inhibitor in older adults as compared to senolytics alone or the triple immunotherapeutic cocktail alone (n=12-15/group; p< 0.01). Collectively, the results suggest that strategies aimed at reversing the effects of the aging combined with tumor eradication therapies may be particularly beneficial for older adult human patients with GBM.

scholarly journals IMMU-40. IMPROVING OUTCOMES IN OLDER ADULTS WITH GLIOBLASTOMA BY REVERSING AGE-RELATED CHANGES OF THE CENTRAL NERVOUS SYSTEM

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii113-ii113
Author(s):  
Erik Ladomersky ◽  
Lijie Zhai ◽  
Lakshmi Bollu ◽  
April Bell ◽  
Kristen Lauing ◽  
...  
Keyword(s):  
Older Adults ◽  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
De Novo ◽  
Enzyme Inhibitor ◽  
T Cell Subsets ◽  
Advanced Age ◽  
Term Survival ◽  
Age Related

Abstract De novo glioblastoma (GBM) represents ≥ 90% of all GBM diagnoses and has a median age of onset at 65 years old. Because of its preponderance during advanced age, we investigated the mortality rate of older adult C57BL/6 (WT) mice with CT-2A glioma. Strikingly, we discovered a significant decrease of overall survival among animal subjects depleted for both CD4+ and CD8+ T cells as compared to the group treated with IgG control antibodies. This negative effect of lymphopenia only applied to older adults. We next questioned which of the major T cell subsets contribute to this effect and determined that the depletion of CD4+ T cells significantly decreased overall survival as compared to IgG control or CD8+ T cell-depleting antibodies (n=12/group; p< 0.01). We previously found increased immunosuppressive IDO levels in the mouse and human brain during advanced age. Although 78–86 week old WT mice have no survival benefit after triple combination immunotherapy, age-matched IDOKO mice have an impressive increase in median and overall survival – despite both groups being treated with a pharmacologic IDO enzyme inhibitor. Since IDO is potently-induced by proinflammatory cytokines, we hypothesized that a potential mechanism for the increased IDO during advanced age is associated with an accumulation of senescent cells in the brain with a proinflammatory secretory phenotype. To investigate this, 80 week old mice with intracranial GL261 were treated with (i) vehicle with IgG antibodies, (ii) the senolytic drugs dasatanib and quercetin, (iii) whole brain radiation, anti-PD-1 mAb, and IDO enzyme inhibitor, or (iv) the 5 agent combination. Only animal subjects treated with the 5 agent cocktail showed a significant increase in long-term survival in a subset of mice (n=12–15/group; p< 0.01). These results suggest that optimization of senescent cell eradication treatment may be particularly beneficial to older patients with GBM treated with immunotherapy.

CTIM-21. AN AGE-SPECIFIC BIOMARKER IN NEWLY-DIAGNOSED GLIOBLASTOMA PATIENTS TREATED WITH RADIATION, NIVOLUMAB AND BMS-986205

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi54-vi54
Author(s):  
Miri Kim ◽  
Erik Ladomersky ◽  
Lijie Zhai ◽  
Lakshmi Bollu ◽  
April Bell ◽  
...  
Keyword(s):  
Older Adults ◽  
Older Adult ◽  
Enzyme Inhibitor ◽  
Flow Cytometric Analysis ◽  
Advanced Age ◽  
Clinical Approach ◽  
Newly Diagnosed ◽  
Color Flow ◽  
Flow Cytometric ◽  
Age Related

Abstract INTRODUCTION We previously determined that advanced age plays a negative role in the survival outcome of human recurrent glioblastoma (GBM) patients treated with immune checkpoint blockade. Here we investigate the immunologic “signature” of younger patients who are < 65 years of age and older adult GBM patients who are ≥ 65 years of age that undergo simultaneous treatment with standard radiation, nivolumab (anti-PD-1 mAb), and BMS-986205 (a potent IDO enzyme inhibitor) and are newly diagnosed with O6-methylguanine-DNA methyl-transferase (MGMT) unmethylated GBM. Our objective was to identify age-dependent immunologic changes before and after treatment with immunotherapy. METHODS Patients ≥ 18 years old with newly diagnosed MGMT unmethylated GBM, KPS ≥ 70, and minimal steroid use were eligible for enrollment in this phase 1 trial. PBMCs and serum were drawn at baseline and routine post-treatment time points followed by mass spec analysis of kynurenine (Kyn) and tryptophan (Trp) metabolites, RNAseq, and 18-color flow cytometric analysis. RESULTS 8 younger adults with a median age of 50 years old and 4 older adults with a median age of 68.5 years old were studied. The median overall survival of younger and older adults was 368 and 108.5 days, respectively (p=0.032, HR 4.8 for age). BMS-986205 treatment decreased the Kyn/Trp ratio of all patients irrespective of age. RNAseq analysis found significant age-related changes using Gene Ontology pathway analysis of T cell related immunity, lymphocyte activation, and NK cell mediated immunity. Flow cytometric analysis is ongoing. CONCLUSIONS Similar to what was reported in older adult mice treated with simultaneous RT, anti-PD-1 mAb, and IDO enzyme inhibitor, advanced age negatively affected the survival in older adult human GBM patients treated with an analogous clinical approach. Future determination of whether the age-related biomarker profile can be used diagnostically and therapeutically is now under investigation.

scholarly journals Age influences susceptibility of brain capillary endothelial cells to La Crosse virus infection and cell death

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Rahul Basu ◽  
Vinod Nair ◽  
Clayton W. Winkler ◽  
Tyson A. Woods ◽  
Iain D. C. Fraser ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Virus Infection ◽  
La Crosse Virus ◽  
Brain Capillary ◽  
Adult Mice ◽  
Age Related ◽  
Capillary Endothelial Cells ◽  
The Brain

Abstract Background A key factor in the development of viral encephalitis is a virus crossing the blood-brain barrier (BBB). We have previously shown that age-related susceptibility of mice to the La Crosse virus (LACV), the leading cause of pediatric arbovirus encephalitis in the USA, was associated with the ability of the virus to cross the BBB. LACV infection in weanling mice (aged around 3 weeks) results in vascular leakage in the olfactory bulb/tract (OB/OT) region of the brain, which is not observed in adult mice aged > 6–8 weeks. Thus, we studied age-specific differences in the response of brain capillary endothelial cells (BCECs) to LACV infection. Methods To examine mechanisms of LACV-induced BBB breakdown and infection of the CNS, we analyzed BCECs directly isolated from weanling and adult mice as well as established a model where these cells were infected in vitro and cultured for a short period to determine susceptibility to virus infection and cell death. Additionally, we utilized correlative light electron microscopy (CLEM) to examine whether changes in cell morphology and function were also observed in BCECs in vivo. Results BCECs from weanling, but not adult mice, had detectable infection after several days in culture when taken ex vivo from infected mice suggesting that these cells could be infected in vitro. Further analysis of BCECs from uninfected mice, infected in vitro, showed that weanling BCECs were more susceptible to virus infection than adult BCECs, with higher levels of infected cells, released virus as well as cytopathic effects (CPE) and cell death. Although direct LACV infection is not detected in the weanling BCECs, CLEM analysis of brain tissue from weanling mice indicated that LACV infection induced significant cerebrovascular damage which allowed virus-sized particles to enter the brain parenchyma. Conclusions These findings indicate that BCECs isolated from adult and weanling mice have differential viral load, infectivity, and susceptibility to LACV. These age-related differences in susceptibility may strongly influence LACV-induced BBB leakage and neurovascular damage allowing virus invasion of the CNS and the development of neurological disease.

Exercise Impacts Age-Related Changes in Cognitive Function and Neural Complexity

2016 ◽  
Vol 5 (1) ◽  
pp. 30-38 ◽  
Author(s):  
Jennifer J. Heisz ◽  
Ana Kovacevic
Keyword(s):  
Older Adults ◽  
Cognitive Function ◽  
Executive Functions ◽  
Cognitive Outcomes ◽  
Physically Active ◽  
Age Related ◽  
The Neural Network ◽  
Future Work ◽  
The Brain ◽  
Age Related Changes

Age-related changes in the brain can compromise cognitive function. However, in some cases, the brain is able to functionally reorganize to compensate for some of this loss. The present paper reviews the benefits of exercise on executive functions in older adults and discusses a potential mechanism through which exercise may change the way the brain processes information for better cognitive outcomes. Specifically, older adults who are more physically active demonstrate a shift toward local neural processing that is associated with better executive functions. We discuss the use of neural complexity as a sensitive measure of the neural network plasticity that is enhanced through exercise. We conclude by highlighting the future work needed to improve exercise prescriptions that help older adults maintain their cognitive and physical functions for longer into their lifespan.

Age-related susceptibility to muscle damage following mechanotherapy in rats recovering from disuse atrophy

2021 ◽  
Author(s):  
Zachary R Hettinger ◽  
Kyoko Hamagata ◽  
Amy L Confides ◽  
Marcus M Lawrence ◽  
Benjamin F Miller ◽  
...  
Keyword(s):  
Older Adults ◽  
Muscle Mass ◽  
Older Adult ◽  
Recovery Period ◽  
Male Rats ◽  
Hindlimb Suspension ◽  
Disuse Atrophy ◽  
Adult Rats ◽  
Transverse Stiffness ◽  
Age Related

Abstract The inability to fully recover lost muscle mass following periods of disuse atrophy predisposes older adults to lost independence and poor quality of life. We have previously shown that mechanotherapy at a moderate load (4.5 N) enhances muscle mass recovery following atrophy in adult, but not older adult rats. We propose that elevated transverse stiffness in aged muscle inhibits the growth response to mechanotherapy and hypothesize that a higher load (7.6 N) will overcome this resistance to mechanical stimuli. F344/BN adult and older adult male rats underwent 14-days of hindlimb suspension, followed by 7-days of recovery with (RE+M) or without (RE) mechanotherapy at 7.6 N on gastrocnemius muscle. The 7.6 N load was determined by measuring transverse passive stiffness and linearly scaling up from 4.5 N. No differences in protein turnover or mean fiber cross sectional area were observed between RE and RE+M for older adult rats or adult rats at 7.6 N. However, there was a higher number of small muscle fibers present in older adult, but not adult rats, which was explained by a 16-fold increase in the frequency of small fibers expressing embryonic myosin heavy chain. Elevated central nucleation, satellite cell abundance, and dystrophin -/laminin + fibers were present in older adult rats only following 7.6 N, while 4.5 N did not induce damage at either age. We conclude that age is an important variable when considering load used during mechanotherapy and age-related transverse stiffness may predispose older adults to damage during the recovery period following disuse atrophy.

Increasing the Propulsive Demands of Walking to Their Maximum Elucidates Functionally Limiting Impairments in Older Adult Gait

2020 ◽  
Vol 28 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Katie A. Conway ◽  
Jason R. Franz
Keyword(s):  
Older Adults ◽  
Older Adult ◽  
Functional Limitations ◽  
Reaction Force ◽  
Ankle Moment ◽  
Effective Interventions ◽  
Age Related ◽  
Walking Performance ◽  
Biomechanical Changes ◽  
Hip Extension

The authors elucidated functional limitations in older adult gait by increasing horizontal impeding forces and walking speed to their maximums compared with dynamometry and with data from their young counterparts. Specifically, the authors investigated which determinants of push-off intensity represent genuine functionally limiting impairments in older adult gait versus biomechanical changes that do not directly limit walking performance. They found that older adults walked at their preferred speed with hallmark deficits in push-off intensity. These subjects were fully capable of overcoming deficits in propulsive ground reaction force, trailing limb positive work, trailing leg and hip extension, and ankle power generation when the propulsive demands of walking were increased to maximum. Of the outcomes tested, age-related deficits in ankle moment emerged as the lone genuine functionally limiting impairment in older adults. Distinguishing genuine functional limitations from age-related differences masquerading as limitations represents a critical step toward the development and prescription of effective interventions.

scholarly journals Dynapaenic obesity and its association with health outcomes in older adult populations: protocol for a systematic review

BMJ Open ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. e027728 ◽  
Author(s):  
Siobhan Leahy ◽  
Marica Cassarino ◽  
Matthew DL O' Connell ◽  
Liam Glynn ◽  
Rose Galvin
Keyword(s):  
Systematic Review ◽  
Older Adults ◽  
Health Outcomes ◽  
Older Adult ◽  
Observational Studies ◽  
Functional Disability ◽  
Age Groups ◽  
Ageing Population ◽  
Cross Sectional ◽  
Age Related

IntroductionTwo major global health challenges are the rapidly ageing population and the high prevalence of obesity in all age groups. Older adults are also susceptible to age-related loss of muscle strength, termed dynapaenia. The co-occurrence of both obesity and dynapaenia, termed dynapaenic obesity (DO), has been associated with poorer health outcomes and increased healthcare usage compared with either state alone. The purpose of this systematic review is to quantify the prevalence and incidence of DO in older adult populations, and to explore the association between DO and health outcomes, specifically chronic disease and multimorbidity, functional disability and healthcare usage.Methods and analysisUsing the Meta-analyses Of Observational Studies in Epidemiology guidelines, we will conduct a systematic review of cross-sectional and longitudinal observational studies of older adults, which include measures of DO and specified outcomes. Detailed literature searches of will be conducted using six electronic databases: Excerpta Medica dataBASE (EMBASE), PubMed, MEDLINE, SCOPUS, ScienceDirect and Cumulative Index of Nursing and Allied Health Complete (CINAHL), including articles published from database inception until Febuary 2019. The reference lists of included articles will also be searched. Two independent reviewers will undertake a three-step screening and review process using the Population, Risk Factor, Outcome framework to define eligibility. The Newcastle Ottawa Scale for non-randomised studies will be used to assess risk of bias and to rate study quality. The findings will be synthesised in a narrative summary, and a meta-analysis will be conducted where appropriate.Ethics and disseminationEthical approval is not required for this systematic review. Findings from this research will be submitted for peer-reviewed publication in academic journals, and presented at relevant academic conferences.PROSPERO registration numberCRD42018112471.

scholarly journals COVID-19, Telehealth and Access to Care

2021 ◽  
Author(s):  
Charles M. Lepkowsky
Keyword(s):  
Older Adults ◽  
Health Care ◽  
Information Technology ◽  
Access To Care ◽  
Older Adult ◽  
Patient Communication ◽  
It Use ◽  
Age Related

Telehealth has become increasingly prominent during the COVID-19 pandemic, highlighting limitations in access to care for older adults less fluent in information technology (IT). Although the 20 percent disparity in IT use between younger and older adult cohorts remains unchanged over several decades, insurers, institutional and independent providers of health care have made increasing use of IT for patient communication. Data demonstrate an age-related decline in the frequency of IT use for accessing health care. Restrictions on reimbursement for the use of the telephone for accessing health care during the COVID-19 pandemic are discussed as a barrier to access to care. Recommendations are made for assessment of media most available to older adults for accessing health care, as well as providing funding to support increased access to care.

scholarly journals Neural pattern similarity differentially affects memory performance of younger and older adults: Age differences in neural similarity and memory

2019 ◽  
Author(s):  
Verena R. Sommer ◽  
Yana Fandakova ◽  
Thomas H. Grandy ◽  
Yee Lee Shing ◽  
Markus Werkle-Bergner ◽  
...  
Keyword(s):  
Older Adults ◽  
Young Adults ◽  
Memory Performance ◽  
Activity Patterns ◽  
Quality Of Information ◽  
Neural Representations ◽  
Age Related ◽  
Pattern Similarity ◽  
The Brain

AbstractAge-related memory decline is associated with changes in neural functioning but little is known about how aging affects the quality of information representation in the brain. Whereas a long-standing hypothesis of the aging literature links cognitive impairments to less distinct neural representations in old age, memory studies have shown that high similarity between activity patterns benefits memory performance for the respective stimuli. Here, we addressed this apparent conflict by investigating between-item representational similarity in 50 younger (19–27 years old) and 63 older (63–75 years old) human adults (male and female) who studied scene-word associations using a mnemonic imagery strategy while electroencephalography was recorded. We compared the similarity of spatiotemporal frequency patterns elicited during encoding of items with different subsequent memory fate. Compared to younger adults, older adults’ memory representations were more similar to each other but items that elicited the most similar activity patterns early in the encoding trial were those that were best remembered by older adults. In contrast, young adults’ memory performance benefited from decreased similarity between earlier and later periods in the encoding trials, which might reflect their better success in forming unique memorable mental images of the joint picture–word pair. Our results advance the understanding of the representational properties that give rise to memory quality as well as how these properties change in the course of aging.Significance statementDeclining memory abilities are one of the most evident limitations for humans when growing older. Despite recent advances of our understanding of how the brain represents and stores information in distributed activation patterns, little is known about how the quality of information representation changes during aging and thus affects memory performance. We investigated how the similarity between neural representations relates to subsequent memory quality in younger and older adults. We present novel evidence that the interaction of pattern similarity and memory performance differs between age groups: Older adults benefited from increased similarity during early encoding whereas young adults benefited from decreased similarity between early and later encoding. These results provide insights into the nature of memory and age-related memory deficits.

scholarly journals Behavioral and fMRI evidence that arousal enhances bottom-up attention and memory selectivity in young but not older adults

2021 ◽  
Author(s):  
Sara N Gallant ◽  
Briana L Kennedy ◽  
Shelby L Bachman ◽  
Ringo Huang ◽  
Tae-Ho Lee ◽  
...  
Keyword(s):  
Older Adults ◽  
Young Adults ◽  
Age Differences ◽  
Emotional Experience ◽  
Noradrenergic System ◽  
Attention And Memory ◽  
Bottom Up ◽  
Age Related ◽  
Selective Processing ◽  
The Brain

During a challenge or emotional experience, increases in arousal help us focus on the most salient or relevant details and ignore distracting stimuli. The noradrenergic system integrates signals about arousal states throughout the brain and helps coordinate this adaptive attentional selectivity. However, age-related changes in the noradrenergic system and attention networks in the brain may reduce the efficiency of arousal to modulate selective processing in older adults. In the current neuroimaging study, we examined age differences in how arousal affects bottom-up attention to category-selective stimuli differing in perceptual salience. We found a dissociation in how arousal modulates selective processing in the young and older brain. In young adults, emotionally arousing sounds enhanced selective incidental memory and brain activity in the extrastriate body area for salient versus non-salient images of bodies. Older adults showed no such advantage in selective processing under arousal. These age differences could not be attributed to changes in the arousal response or less neural distinctiveness in old age. Rather, our results suggest that, relative to young adults, older adults become less effective at focusing on salient over non-salient details during increases in emotional arousal.

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