Cortical proteins may provide motor resilience in older adults.
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ABSTRACT:
SUBMITTER: Buchman AS
PROVIDER: S-EPMC8163829 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
Publications
Cortical proteins may provide motor resilience in older adults.
Buchman Aron S AS Yu Lei L Oveisgharan Shahram S Petyuk Vladislav A VA Tasaki Shinya S Gaiteri Chris C Wilson Robert S RS Grodstein Francine F Schneider Julie A JA Klein Hans-Ulrich HU De Jager Philip L PL Bennett David A DA
Scientific reports 20210528 1
Motor resilience proteins may be a high value therapeutic target that offset the negative effects of pathologies on motor function. This study sought to identify cortical proteins associated with motor decline unexplained by brain pathologies that provide motor resilience. We studied 1226 older decedents with annual motor testing, postmortem brain pathologies and quantified 226 proteotypic peptides in prefrontal cortex. Twenty peptides remained associated with motor decline in models controlling ...[more]
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Project description:BackgroundMotor resilience proteins have not been identified. This proteome-wide discovery study sought to identify proteins that may provide motor resilience.MethodsWe studied the brains of older decedents with annual motor testing, postmortem brain pathologies, and proteome-wide data. Parkinsonism was assessed using 26 items of a modified United Parkinson Disease Rating Scale. We used linear mixed-effect models to isolate motor resilience, defined as the person-specific estimate of progressive parkinsonism after controlling for age, sex, and 10 brain pathologies. A total of 8 356 high-abundance proteins were quantified from dorsal lateral prefrontal cortex using tandem mass tag and liquid chromatography-mass spectrometry.ResultsThere were 391 older adults (70% female), mean age 80 years at baseline and 89 years at death. Five proteins were associated with motor resilience: A higher level of AP1B1 (Estimate -0.504, SE 0.121, p = 3.12 × 10-5) and GNG3 (Estimate -0.276, SE 0.068, p = 4.82 × 10-5) was associated with slower progressive parkinsonism. By contrast, a higher level of TTC38 (Estimate 0.140, SE 0.029, p = 1.87 × 10-6), CARKD (Estimate 0.413, SE 0.100, p = 3.50 × 10-5), and ABHD14B (Estimate 0.175, SE 0.044, p = 6.48 × 10-5) was associated with faster progressive parkinsonism. Together, these 5 proteins accounted for almost 25% of the variance of progressive parkinsonism above the 17% accounted for by 10 indices of brain pathologies.DiscussionCortical proteins may provide more or less motor resilience in older adults. These proteins are high-value therapeutic targets for drug discovery that may lead to interventions that maintain motor function despite the accumulation of as yet untreatable brain pathologies.
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Project description:ImportanceIdentifying genes and proteins for cognitive resilience (ie, targets that may be associated with slowing or preventing cognitive decline regardless of the presence, number, or combination of common neuropathologic conditions) provides a complementary approach to developing novel therapeutics for the treatment and prevention of Alzheimer disease and related dementias.ObjectiveTo identify proteins associated with cognitive resilience via a proteome-wide association study of the human dorsolateral prefrontal cortex.Design, setting, and participantsThis study used data from 391 community-dwelling older persons who participated in the Religious Orders Study and the Rush Memory and Aging Project. The Religious Orders Study began enrollment January 1, 1994, and the Rush Memory and Aging Project began enrollment September 1, 1997, and data were collected and analyzed through October 23, 2019.ExposuresParticipants had undergone annual detailed clinical examinations, postmortem evaluations, and tandem mass tag proteomics analyses.Main outcomes and measuresThe outcome of cognitive resilience was defined as a longitudinal change in cognition over time after controlling for common age-related neuropathologic indices, including Alzheimer disease, Lewy bodies, transactive response DNA-binding protein 43, hippocampal sclerosis, infarcts, and vessel diseases. More than 8000 high abundance proteins were quantified from frozen dorsolateral prefrontal cortex tissue using tandem mass tag and liquid chromatography-mass spectrometry.ResultsThere were 391 participants (273 women); their mean (SD) age was 79.7 (6.7) years at baseline and 89.2 (6.5) years at death. Eight cortical proteins were identified in association with cognitive resilience: a higher level of NRN1 (estimate, 0.140; SE, 0.024; P = 7.35 × 10-9), ACTN4 (estimate, 0.321; SE, 0.065; P = 9.94 × 10-7), EPHX4 (estimate, 0.198; SE, 0.042; P = 2.13 × 10-6), RPH3A (estimate, 0.148; SE, 0.031; P = 2.58 × 10-6), SGTB (estimate, 0.211; SE, 0.045; P = 3.28 × 10-6), CPLX1 (estimate, 0.136; SE, 0.029; P = 4.06 × 10-6), and SH3GL1 (estimate, 0.179; SE, 0.039; P = 4.21 × 10-6) and a lower level of UBA1 (estimate, -0.366; SE, 0.076; P = 1.43 × 10-6) were associated with greater resilience.Conclusions and relevanceThese protein signals may represent novel targets for the maintenance of cognition in old age.
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Project description:Alzheimer's disease and related disorders (ADRD) may manifest cognitive and non-cognitive phenotypes including motor impairment, suggesting a shared underlying biology. We tested the hypothesis that five cortical proteins identified from a gene network that drives AD and cognitive phenotypes are also related to motor function in the same individuals. We examined 1208 brains of older adults with motor and cognitive assessments prior to death. Cortical proteins were quantified with SRM proteomics and we collected indices of AD and other related pathologies. A higher level of IGFBP5 was associated with poorer motor function proximate to death but AK4, HSPB2, ITPK1 and PLXNB1 were unrelated to motor function. The association of IGFBP5 with motor function was unrelated to the presence of indices of brain pathologies. In contrast, the addition of a term for cognition attenuated the association of IGFBP5 with motor function by about 90% and they were no longer related. These data lend support for the idea that unidentified cortical proteins like IGFBP5, which may not manifest a known pathologic footprint, may contribute to motor and cognitive function in older adults.
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Project description:BackgroundAs the global population ages and life expectancy increases, older adults encounter challenges like chronic illnesses and losing loved ones; resilience is crucial for adapting to these difficulties. This study aims to culturally and linguistically adapt the psychological resilience scale designed for older adults to the Turkish context.MethodsThis methodological study included 566 individuals aged 65 and older. All participants completed the Resilience Scale for Older Adults, the Perceived Stress Scale, the Geriatric Depression Scale, and the Quality of Life in Older Adults Scale-Short Form. Construct validity was assessed through confirmatory and exploratory factor analyses, while convergent and discriminant validity were evaluated through the correlation of the scales. Reliability was determined using internal consistency and the split-half method.ResultsThe scale retains its original structure with 33 items and four sub-dimensions (Intrapersonal, Interpersonal, Spiritual, and Experiential). The content validity index of the scale is 0.98, with item loadings ranging from 0.406 to 0.947, according to exploratory factor analysis. Confirmatory factor analysis indicates good fit indices. Convergent validity is supported by a strong positive correlation (r = 0.657, p < 0.001) between the Resilience Scale for Older Adults and the Quality of Life in Older Adults Scale-Short Form. Reliability measures include a Cronbach's alpha internal consistency coefficient of 0.93 and a Guttman split-half reliability coefficient of 0.723.ConclusionThe results show that the Turkish version of the Resilience Scale for Older Adults is a valid and reliable measurement tool.
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Project description:Improving deteriorated sensorimotor functions in older individuals is a social necessity in a super-aging society. Previous studies suggested that the declined interhemispheric sensorimotor inhibition observed in older adults is associated with their deteriorated hand/finger dexterity. Here, we examined whether bimanual digit exercises, which can train the interhemispheric inhibitory system, improve deteriorated hand/finger dexterity in older adults. Forty-eight healthy, right-handed, older adults (65-78 years old) were divided into two groups, i.e., the bimanual (BM) digit training and right-hand (RH) training groups, and intensive daily training was performed for 2 months. Before and after the training, we evaluated individual right hand/finger dexterity using a peg task, and the individual state of interhemispheric sensorimotor inhibition by analyzing ipsilateral sensorimotor deactivation via functional magnetic resonance imaging when participants experienced a kinesthetic illusory movement of the right-hand without performing any motor tasks. Before training, the degree of reduction/loss of ipsilateral motor-cortical deactivation was associated with dexterity deterioration. After training, the dexterity improved only in the BM group, and the dexterity improvement was correlated with reduction in ipsilateral motor-cortical activity. The capability of the brain to inhibit ipsilateral motor-cortical activity during a simple right-hand sensory-motor task is tightly related to right-hand dexterity in older adults.
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Project description:This study examined the relation between lumbar spinal motor neuron (SMN) indices and motor function proximate to death in community-dwelling older adults. Older adults (N = 145) participating in the Rush Memory and Aging Project underwent structured clinical testing proximate to death and brain and spinal cord autopsy at time of death. Ten motor performances were summarized by a composite global motor score. Choline acetyltransferase immunostaining was used to identify spinal motor neurons of the L4/5 segment. SMN counts and area and ventral horn area were collected. Linear regression modeling showed that the association of SMN counts and density with global motor scores proximate to death varied with sex. Separate models in men and women showed that this significant interaction was due to the association of higher SMN counts and density with higher global motor scores proximate to death in men but not women. These associations were unchanged when we controlled for indices of brain pathologies or chronic health conditions. In 38 cases with counts of activated microglia available, higher counts of activated microglia were associated with lower SMN counts. Activated spinal microglia and loss of spinal motor neurons may contribute to motor impairments in older men.
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Project description:BackgroundThe network approach may provide a framework for understanding intrinsic capacity (IC) as a system's underlying functioning. The system's resilience to resist functional decline may arise from the interrelationships among system components, that is, body functions or capacities. We applied network analysis to investigate whether the interplay between different intrinsic capacities differs according to age and self-rated health (SRH) in older adults.MethodsThe study sample consisted of a population-based cohort of community-dwelling older adults aged 75, 80, and 85 years (men n = 356 and women n = 469). We quantified 5 IC domains: vitality, locomotion, cognition, psychology, and sensory, using performance-based measurements and questionnaires, and estimated IC networks for 2 age (75 vs 80 and 85 years) and SRH (higher vs lower) groups separately for sexes. Differences in global network properties (eg, density, overall connectivity) and centrality indices were compared between the groups.ResultsIntrinsic capacity network density (ie, the number of edges) was higher in the 80- and 85-year-olds compared to the 75-year-olds, and in the worse compared to the better SRH group in both sexes. However, the differences in edge weights and global strength of the networks were statistically nonsignificant. Walking speed was the most central node in the estimated networks.ConclusionsWith increasing age and health decline, the IC network seems to become denser, which may indicate a loss of system resilience. Walking is a more complex activity than the others requiring the functioning of many subsystems, which may explain why it connects multiple domains in the IC network.
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Project description:BackgroundPrevious studies suggest that low emotional resilience may correspond with increased or over-active amygdala function. Complementary studies suggest that emotional resilience increases with age; older adults tend to have decreased attentional bias to negative stimuli compared to younger adults. Amygdala nuclei and related brain circuits have been linked to negative affect, and depressed patients have been demonstrated to have abnormal amygdala function.MethodsIn the current study, we correlated psychological resilience measures with amygdala function measured with resting-state arterial spin-labelled (ASL) and blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in older adults with and without depression. Specifically, we targeted the basolateral, centromedial, and superficial nuclei groups of the amygdala, which have different functions and brain connections.ResultsHigh levels of psychological resilience correlated with lower basal levels of amygdala activity measured with ASL fMRI. High resilience also correlated with decreased connectivity between amygdala nuclei and the ventral default-mode network independent of depression status. Instead, lower depression symptoms were associated with higher connectivity between the amygdalae and dorsal frontal networks.LimitationsFuture multi-site studies with larger sample size and improved neuroimaging technologies are needed. Longitudinal studies that target resilience to naturalistic stressors will also be a powerful contribution to the field.ConclusionsOur results suggest that resilience in older adults is more closely related to function in ventral amygdala networks, while late-life depression is related to reduced connectivity between the amygdala and dorsal frontal regions.
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Project description:ObjectivesThe goal of this paper was to examine associations between personality traits and resilience to neuropathologic burden.MethodUsing data from the Religious Orders Study and the Rush Memory and Aging Project, we identified a total of 1,375 participants with personality, cognitive, and post-mortem neuropathology data. We regressed cognition onto pathology and extracted the residuals as an indicator of cognitive resilience. We then modeled the effect of Big Five personality traits on cognitive resilience, adjusting for demographics, APOE status, medical comorbidities, and cognitive activity. The analytic plan was preregistered prior to data access or analysis, and all scripts and outputs are available online.ResultsHigher neuroticism was associated with greater vulnerability to pathology. Results from exploratory analyses suggest that higher conscientiousness was associated with less cognitive decline relative to the amount of pathology, or greater resilience. Education and cognitive activity did not moderate these associations.DiscussionPersonality may have a pathoplastic effect on neuropathology, as low neuroticism and high conscientiousness are associated with better function despite neuropathologic burden.
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