The overall and domain-specific quality of life of Chinese community-dwelling older adults: the role of intrinsic capacity and disease burden.

Objective: This study aimed to investigate the impact of the different domains of intrinsic capacity (IC) and chronic disease burden on health-related quality of life (HRQoL) and domain-specific HRQoL in Chinese community-dwelling older adults. Design: A cross-sectional observational study of a community-based cohort. Participants: We evaluated Chinese older adults (n = 429, mean age, 72.91 ± 7.014 years; female proportion, 57.30%). Measurements: IC contains five domains, namely locomotion, vitality, cognition, psychological, and sensory capacity. Locomotion dysfunction was defined as grip and/or gait decline. Vitality decline was defined if two of the following three parameters were present: fatigue, physical inactivity, and weight loss or overweight. Cognition was classified into normal cognition, pre-mild cognitive impairment (pre-MCI), and MCI according to the normative z-scores of the neuropsychological test battery. Psychological dysfunction was diagnosed based on depressive symptoms. Sensory dysfunction was defined as hearing and/or vision impairment. HRQoL was assessed using the AQoL-8D scale, which comprised physical (including independent living, senses, and pain) and psychosocial (including mental health, happiness, self-worth, coping, and relationships) dimensions. Low HRQoL (HRQoL score or subscores in the highest quintile) was used as a dependent variable in logistic regression analyses adjusted for demographic, health-related, and psychological confounders. Results: Sensory impairment was an independent determinant of senses, and locomotion impairment was significantly associated with overall HRQoL, independent living, and pain in the physical dimension of HRQoL. Cognition was an independent determinant of the senses. Vitality was independently associated with overall HRQoL, senses, and pain in the physical dimension and mental health and relationships in the psychological dimension of HRQoL. The psychological domain of IC was independently associated with overall and domain-specific HRQoL apart from senses after adjustment for all confounders. The number of multimorbidities mainly had a significant impact on independent living after adjustment for all confounders. Conclusion: IC domains and chronic disease burden had heterogeneous influences on overall and domain-specific HRQoL. The impairment of sensory and locomotion domains had a synergistic impact on the overall and physical dimensions of HRQoL. The vitality and psychological domains of IC had more profound effects on HRQoL. Older people with high morbidity might have a higher risk of poor independent living.

Which Came First, Age-Related Hearing Loss with Tinnitus or Cognitive Impairment? What are the Potential Pathways?

Research on the causal relationship between age-related hearing loss (ARHL) and/or tinnitus and dementia is an important and fast-moving field. In this opinion paper, the up-to-date evidence and potential mechanisms for the bidirectional relationship are reviewed. We also present several critical factors that increase the challenges of understanding the causal relationship. These factors include common causes (such as aging, frailty, vascular impairment, and chronic inflammation), auditory and cognitive reserves, and the difficulty in distinguishing central auditory processing disorder (CAPD) from cognitive impairment. Finally, based on cumulative evidence, we propose an integrated mechanism in which the central auditory system might be the common target of both peripheral auditory impairment and dementia or its precursor. There is a bidirectional interaction between the peripheral and central auditory systems and between the central auditory systems and the cognitive brain. CAPD causes the depletion of auditory and cognitive reserves, and indirectly affects the peripheral auditory system via the auditory efferent system. According to the proposal, multimodal intervention might be beneficial for patients with ARHL and/or tinnitus and cognitive impairment, apart from hearing restoration by hearing aids or cochlear implants.

Depressive and Biopsychosocial Frailty Phenotypes: Impact on Late-life Cognitive Disorders.

In older age, frailty is a detrimental transitional status of the aging process featuring an increased susceptibility to stressors defined by a clinical reduction of homoeostatic reserves. Multidimensional frailty phenotypes have been associated with all-cause dementia, mild cognitive impairment (MCI), Alzheimer's disease (AD), AD neuropathology, vascular dementia, and non-AD dementias. In the present article, we reviewed current evidence on the existing links among depressive and biopsychosocial frailty phenotypes and late-life cognitive disorders, also examining common pathways and mechanisms underlying these links. The depressive frailty phenotype suggested by the construct of late-life depression (LLD) plus physical frailty is poorly operationalized. The biopsychosocial frailty phenotype, with its coexistent biological/physical and psychosocial dimensions, defines a biological aging status and includes motivational, emotional, and socioeconomic domains. Shared biological pathways/substrates among depressive and biopsychosocial frailty phenotypes and late-life cognitive disorders are hypothesized to be inflammatory and cardiometabolic processes, together with multimorbidity, loneliness, mitochondrial dysfunction, dopaminergic neurotransmission, specific personality traits, lack of subjective/objective social support, and neuroendocrine dysregulation. The cognitive frailty phenotype, combining frailty and cognitive impairment, may be a risk factor for LLD and vice versa, and a construct of depressive frailty linking physical frailty and LLD may be a good dementia predictor. Frailty assessment may enable clinicians to better target the pharmacological and psychological treatment of LLD. Given the epidemiological links of biopsychosocial frailty with dementia and MCI, multidomain interventions might contribute to delay the onset of late-life cognitive disorders and other adverse health-related outcomes, such as institutionalization, more frequent hospitalization, disability, and mortality.

Association between age-related hearing loss with tinnitus and cognitive performance in older community-dwelling Chinese adults.

AIM: To examine how the severity of age-related hearing loss (ARHL) and tinnitus or the presentation of ARHL with tinnitus is associated with overall cognition, in terms of specific cognitive domains in older community-dwelling Chinese adults. METHODS: The study recruited 429 participants aged ≥58 years (mean age, 72.91 ± 7.014 years; female proportion, 57.30%), excluding those with dementia, disability, and severe mental illness. Patients were classified into normal cognition, pre-mild cognitive impairment (pre-MCI), and MCI according to the normative z-scores of neuropsychological test battery. The severity of ARHL and tinnitus was measured by pure-tone audiometry and the Tinnitus Handicap Inventory. Cognitive impairment and low functions in specific cognitive domains were used as dependent variables in multiple regression analyses adjusted for covariates. RESULTS: ARHL severity was positively associated with MCI and low executive function, delayed memory, and language function. Only individuals with mild (odds ratio (OR) 1.791; CI, 0.952-3.373; P = 0.071), and moderate and the disaster tinnitus (OR, 2.493; CI, 0.982-6.328; P = 0.055) were marginally associated with increased odds of MCI in model 1. Individuals with ARHL and tinnitus (OR, 3.888, CI = 1.481-10.205; OR, 4.471, CI = 1.636-12.219) were independently associated with high risk for MCI in models 1 and 2. CONCLUSIONS: ARHL severity and the presentation of ARHL or ARHL with tinnitus were associated with overall cognition. ARHL severity was independently associated with executive function, delayed memory, and language function. The association between tinnitus severity and cognition is not clear. But the group with ARHL and tinnitus is a high-risk group with cognitive impairment. CLINICALTRIALS: gov identifier: NCT2017K020.

Vulnerability to chronic stress and the phenotypic heterogeneity of presbycusis with subjective tinnitus.

Age-related functional reserve decline and vulnerability of multiple physiological systems and organs, as well as at the cellular and molecular levels, result in different frailty phenotypes, such as physical, cognitive, and psychosocial frailty, and multiple comorbidities, including age-related hearing loss (ARHL) and/or tinnitus due to the decline in auditory reserve. However, the contributions of chronic non-audiogenic cumulative exposure, and chronic audiogenic stress to phenotypic heterogeneity of presbycusis and/or tinnitus remain elusive. Because of the cumulative environmental stressors throughout life, allostasis systems, the hypothalamus-pituitary-adrenal (HPA) and the sympathetic adrenal-medullary (SAM) axes become dysregulated and less able to maintain homeostasis, which leads to allostatic load and maladaptation. Brain-body communication via the neuroendocrine system promotes systemic chronic inflammation, overmobilization of energetic substances (glucose and lipids), and neuroplastic changes via the non-genomic and genomic actions of glucocorticoids, catecholamines, and their receptors. These systemic maladaptive alterations might lead to different frailty phenotypes and physical, cognitive, and psychological comorbidities, which, in turn, cause and exacerbate ARHL and/or tinnitus with phenotypic heterogeneity. Chronic audiogenic stressors, including aging accompanying ontological diseases, cumulative noise exposure, and ototoxic drugs as well as tinnitus, activate the HPA axis and SAM directly and indirectly by the amygdala, promoting allostatic load and maladaptive neuroplasticity in the auditory system and other vulnerable brain regions, such as the hippocampus, amygdala, and medial prefrontal cortex (mPFC). In the auditory system, peripheral deafferentation, central disinhibition, and tonotopic map reorganization may trigger tinnitus. Cross-modal maladaptive neuroplasticity between the auditory and other sensory systems is involved in tinnitus modulation. Persistent dendritic growth and formation, reduction in GABAergic inhibitory synaptic inputs induced by chronic audiogenic stresses in the amygdala, and increased dendritic atrophy in the hippocampus and mPFC, might involve the enhancement of attentional processing and long-term memory storage of chronic subjective tinnitus, accompanied by cognitive impairments and emotional comorbidities. Therefore, presbycusis and tinnitus are multisystem disorders with phenotypic heterogeneity. Stressors play a critical role in the phenotypic heterogeneity of presbycusis. Differential diagnosis based on biomarkers of metabonomics study, and interventions tailored to different ARHL phenotypes and/or tinnitus will contribute to healthy aging and improvement in the quality of life.

Age-Related Hearing Loss With Tinnitus and Physical Frailty Influence the Overall and Domain-Specific Quality of Life of Chinese Community-Dwelling Older Adults.

Objective: To investigate the impact of the severity of age-related hearing loss (ARHL) and tinnitus, presence of ARHL and/or tinnitus, and physical frailty on the health-related quality of life (HRQoL) and domain-specific HRQoL in Chinese community-dwelling older adults. Design: This was a cross-sectional study of a community-based cohort. Participants: We evaluated Chinese older adults (n = 429, 183 men and 246 women) aged ≥ 58years. Measurements: The severity of HL and tinnitus were measured using pure-tone audiometry and the Tinnitus Handicap Inventory (THI), respectively. Physical frailty was measured using the five-item Fried scale. HRQoL was assessed using the Assessment of Quality of Life-8-Dimension (AQoL-8D) multi-attribute utility instrument (35 HRQoL items and eight domain-specific HRQoL subcategories). Low HRQoL (HRQoL score or subscores in the highest quintile) was used as a dependent variable in logistic regression analyses adjusted for demographic (Model 1) and health-related (Model 2) and psychosocial (Model 3) confounders. Results: Age-related hearing loss severity was an independent determinant of senses in the physical dimension of HRQoL after adjusting for all covariates. Tinnitus severity was significantly associated with HRQoL and with independent living, senses, and pain in the physical dimension after adjusting for demographic and health-related covariates and was still associated with independent living and senses after adjusting for all covariates. The presence of ARHL and/or tinnitus was significantly associated with independent living and senses in the physical dimension after adjusting for all the covariates. Physical frailty was an independent determinant of HRQoL, independent living, and pain in the physical dimension and with mental health, happiness, and coping in the psychosocial dimension after adjusting for demographic and health-related covariates. The association with HRQoL, independent living, and pain in the physical dimension, and with happiness and coping in the psychosocial dimension remained significant after adjusting for the covariates. Depressive symptoms, social dysfunction, and a number of comorbidities were critical determinants of psychosocial HRQoL. Conclusion: Physical frailty has a stronger and more profound effect on HRQoL, particularly on independent living and pain in the physical dimension and on happiness and coping in the psychosocial dimension. Domain-specific HRQoL should be considered in the management of patients with ARHL with tinnitus and physical frailty. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT2017K020.

Clinical and Objective Cognitive Measures for the Diagnosis of Cognitive Frailty Subtypes: A Comparative Study.

BACKGROUND: Cognitive frailty (CF) includes reversible and potentially reversible subtypes; the former is known as concurrent physical frailty (PF) and pre-mild cognitive impairment subjective cognitive decline (pre-MCI SCD), whereas the latter is known as concurrent PF and MCI. The diagnoses of pre-MCI SCD and MCI are based on clinical criteria and various subjective cognitive decline questionnaires. Heterogeneous assessment of cognitive impairment (CI) results in significant variability of CI, CF, and their subtype prevalence in various population-based studies. OBJECTIVE: This study aimed to compare the classification differences in CI and CF subtypes from PF and normal cognition by applying clinical and objective cognitive criteria. Clinical criteria comprised Fried PF and clinical MCI criteria combined with the SCD questionnaire, whereas objective criteria comprised Fried PF and objective cognitive criteria based on the norm-adjusted six neuropsychological test scores. METHODS: Of the 335 volunteers (age ≥ 60 years) in this study, 191 were diagnosed with CI based on clinical cognitive diagnosis criteria, and 144 were identified as robust normal based on objective cognitive assessment from the community-dwelling older adult cohort. Individuals with clinical CI, including 94 with MCI and 97 with pre-MCI SCD, were reclassified into different z-score-derived MCI, pre-MCI SCD, and normal subgroups based on objective cognitive criteria. The classification diagnostic accuracy of normal cognition, PF, pre-MCI, MCI, CF, and CF subtypes based on clinical and objective criteria was compared before and after adjusting for age, sex, and education level. RESULTS: The reclassification of objective assessments indicated better performance than that of clinical assessments in terms of discerning CI severity among different subgroups before adjusting for demographic factors. After covariate adjustment, clinical assessments significantly improved the ability to cognitively discriminate normal individuals from those with pre-MCI SCD and MCI but not the z-score-derived pre-MCI SCD and MCI groups from the robust normal group. Furthermore, the adjustment did not improve the ability to discriminate among individuals with reversible CF from those with potentially reversible CF and pre-MCI only SCD from MCI only SCD. CONCLUSIONS: Objective criteria showed better performance than clinical criteria in the diagnosis of individuals with CI or CF subtypes. Rapid clinical cognitive screening in combination with normative z-scores criteria is cost effective and sustainable in clinical practice.

Are need for affect and cognition culture dependent? Implications for global public health campaigns: a cross-sectional study.

BACKGROUND: Cultural differences in affective and cognitive intrinsic motivation could pose challenges for global public health campaigns, which use cognitive or affective goals to evoke desired attitudes and proactive health-promoting actions. This study aimed to identify cross-cultural differences in affective and cognitive intrinsic motivation and discuss the potential value of this information for public health promotion. METHODS: A cross-sectional survey using cross-culturally validated need for affect (NFA) and need for cognition (NFC) scales was carried out among 1166 Chinese participants, and the results were compared with published data from 980 American participants. Additionally, we assessed a highly prevalent symbolic geriatric health condition, hearing loss, in 500 Chinese community-dwelling seniors. The Chinese NFA scale was developed following the translation-back translation procedure, and the psychometric evaluation was performed by applying confirmatory factor analysis (CFA), exploratory structural equation modeling (ESEM), correlation analysis and multigroup invariance test. MANOVA and Hedge's g statistic were employed to compare the NFA and NFC levels between individuals from different countries and between Chinese seniors with and without hearing loss. The relation of early hearing intervention intention to NFA and NFC was also explored in the Chinese sample. RESULTS: A basic two-factor model of NFA adequately fit the sample data from Chinese and American cultures. The questionnaire demonstrated reasonable invariance of the factor structure and factor loadings across the groups. Those in the primary Chinese sample had lower NFA and NFC than their American peers. This difference held in the senior sample. Moreover, Chinese seniors with hearing loss had even lower NFA and NFC than those without hearing loss. Their early hearing intervention intention was low but was associated with intrinsic motivation. CONCLUSIONS: The Need for Affect (NFA) construct may be generalized beyond its Western origins. There was a general lack of affective and cognitive intrinsic motivation in Chinese individuals, particularly in seniors with hearing loss, compared with their American peers. These differences point to a potential challenge in framing effective messages for some cultures in the geriatric public health domain. Ideally, recognizing and understanding this challenge will inspire the consideration of novel persuasive strategies for these audiences.

Demographically Corrected Normative Z Scores on the Neuropsychological Test Battery in Cognitively Normal Older Chinese Adults.

BACKGROUND: Subjective questionnaires used for the diagnosis of pre-mild cognitive impairment (pre-MCI) and conventional criteria for MCI might mainly result in false-positive diagnostic errors. The integrated criteria based on demographically adjusted total and process Z scores on neuropsychological tests have been validated to be sensitive for measuring pre-MCI, MCI, and MCI subtypes. However, the underrepresentativity of Chinese populations and the complexity in some tests limit the use of the established Z scores in the elderly Chinese population. OBJECTIVE: The aim of this study was to develop a useful Z score calculator to assess individual cognitive performance after adjustment of the scores on each of the neuropsychological tests according to sex, age, and education and to establish preliminary norms for the objective assessment of cognition function in elderly Chinese individuals. METHODS: The neuropsychological test battery consists of measures of performance on different cognitive domains, including episodic memory, language, executive function, processing speed, and attention. Data were obtained from 220 clinically cognitively normal Chinese volunteers aged 60 years or older from the cohort of the Shanghai study of health promotion among frail elderly individuals. Regression models were used to investigate the impact of age, education, and sex on test scores. Z scores were estimated for the different scores by subtracting the predicted mean from the raw score and dividing it by the root mean square error term for any given linear regression model. RESULTS: Preliminary analyses indicated that age, sex, or level of education significantly affected test scores. A series of linear regression models was constructed for all instruments, i.e.: the Trail-Making Test A and B, to assess executive function or attention; the Boston Naming Test and animal list generation, to assess language; delayed free correct responses and the Hopkins Verbal Learning Test-Revised (HVLT-R) recognition, as well as three process scores, i.e., intrusion errors, learning slope, and retroactive interference, from the HVLT-R, to assess memory, by adjusting for the covariates of age, sex, and level of education concurrently. The Z scores on all neuropsychological tests were estimated based on the corresponding regression coefficients. CONCLUSIONS: We constructed a multivariable regression-based normative Z score method for the measurement of cognition among older Chinese individuals in the community. The normative score will be useful for the accurate diagnosis of different subtypes of pre-MCI and MCI after preliminary rapid screening in the community.

Identification and study of differentially expressed miRNAs in aged NAFLD rats based on high-throughput sequencing.

INTRODUCTION AND OBJECTIVES: Hepatic microRNA (miR) expression profiles were explored in aged rats with NAFLD, in order to clarify the molecular mechanisms underlying the pathophysiological processes of aging-related NAFLD. PATIENTS OR MATERIALS AND METHODS: 24 aged rats (18-month-old) and 24 young rats (2-month-old) were randomly divided into two subgroups according to diet, control group and NAFLD group. After 8 weeks of administering 45% high-fat diet or normal diet, total hepatic RNA was extracted from liver tissues of the aged rats. Differentially expressed microRNAs (DE-miRs) in aged NAFLD group were detected and screened out using high-throughput sequencing technology. The data were subjected to Gene Ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses using a bioinformatics approach. The sequencing results were further verified by RT-qPCR. RESULTS: Compared with the aged control liver tissues, 6 significantly upregulated miRs (miR-881-3p, miR-871-3p, miR-335, miR-223-3p, miR-155-5p, miR-146b-5p) and 4 significantly downregulated miRs (miR-182, miR-193-3p, miR-31a-5p and miR-96-5p) were identified in the aged NAFLD liver tissues. These DE-miRs were found to be involved in the regulation of cell signaling transduction and metabolism processes, probably affecting signaling pathways relevant to insulin secretion and some senile diseases. RT-qPCR results corroborated the sequencing results and demonstrated that 6 significantly upregulated miRs were not identified in the young group. CONCLUSIONS: A total of 10 DE-miRs identified in the aged NAFLD rats were involved in some certain insulin secretion and age-related functional pathways, which may serve as novel candidate targets for the diagnosis and treatment of aging-associated NAFLD.

Heterogeneous Influence of Frailty Phenotypes in Age-Related Hearing Loss and Tinnitus in Chinese Older Adults: An Explorative Study.

BACKGROUND: Fried physical frailty, with mobility frailty and non-motor frailty phenotypes, is a heterogeneous syndrome. The coexistence of the two phenotypes and cognitive impairment is referred to as cognitive frailty (CF). It remains unknown whether frailty phenotype has a different association with hearing loss (HL) and tinnitus. METHODS: Of the 5,328 community-dwelling older adults, 429 participants aged ≥58 years were enrolled in the study. The participants were divided into robust, mobility, and non-mobility frailty, mobility and non-mobility CF (subdivided into reversible and potentially reversible CF, RCF, and PRCF), and cognitive decline [subdivided into mild cognitive impairment (MCI) and pre-MCI] groups. The severity and presentations of HL and/or tinnitus were used as dependent variables in the multivariate logistic or nominal regression analyses with forward elimination adjusted for frailty phenotype stratifications and other covariates. RESULTS: Patients with physical frailty (mobility frailty) or who are robust were found to have lower probability of developing severe HL and tinnitus, and presented HL and/or tinnitus than those with only cognitive decline, or CF. Patients with RCF and non-mobility RCF had higher probability with less HL and tinnitus, and the presentation of HL and/or tinnitus than those with PRCF and mobility RCF. Other confounders, age, cognitive and social function, cardiovascular disease, depression, and body mass index, independently mediated the severity of HL and tinnitus, and presented HL and/or tinnitus. CONCLUSION: Frailty phenotypes have divergent association with HL and tinnitus. Further research is required to understand the differential mechanisms and the personalized intervention of HL and tinnitus. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT2017K020.

A parsimonious approach for screening moderate-to-profound hearing loss in a community-dwelling geriatric population based on a decision tree analysis.

BACKGROUND: Hearing loss is one of the most common modifiable factors associated with cognitive and functional decline in geriatric populations. An accurate, easy-to-apply, and inexpensive hearing screening method is needed to detect hearing loss in community-dwelling elderly people, intervene early and reduce the negative consequences and burden of untreated hearing loss on individuals, families and society. However, available hearing screening tools do not adequately meet the need for large-scale geriatric hearing detection due to several barriers, including time, personnel training and equipment costs. This study aimed to propose an efficient method that could potentially satisfy this need. METHODS: In total, 1793 participants (≥60 years) were recruited to undertake a standard audiometric air conduction pure tone test at 4 frequencies (0.5-4 kHz). Audiometric data from one community were used to train the decision tree model and generate a pure tone screening rule to classify people with or without moderate or more serious hearing impairment. Audiometric data from another community were used to validate the tree model. RESULTS: In the decision tree analysis, 2 kHz and 0.5 kHz were found to be the most important frequencies for hearing severity classification. The tree model suggested a simple two-step screening procedure in which a 42 dB HL tone at 2 kHz is presented first, followed by a 47 dB HL tone at 0.5 kHz, depending on the individual's response to the first tone. This approach achieved an accuracy of 91.20% (91.92%), a sensitivity of 95.35% (93.50%) and a specificity of 86.85% (90.56%) in the training dataset (testing dataset). CONCLUSIONS: A simple two-step screening procedure using the two tones (2 kHz and 0.5 kHz) selected by the decision tree analysis can be applied to screen moderate-to-profound hearing loss in a community-based geriatric population in Shanghai. The decision tree analysis is useful in determining the optimal hearing screening criteria for local elderly populations. Implanting the pair of tones into a well-calibrated sound generator may create a simple, practical and time-efficient screening tool with high accuracy that is readily available at healthcare centers of all levels, thereby facilitating the initiation of extensive nationwide hearing screening in older adults.

The effects of both age and sex on irisin levels in paired plasma and cerebrospinal fluid in healthy humans.

BACKGROUND: Adipo-myokine irisin has important effects on the metabolism and functioning of multiple tissues and organs. However, the effects of aging and sex on irisin levels in cerebrospinal fluid (CSF) and on circulation have not been comprehensively studied. OBJECTIVE: To investigate whether aging and sex can affect irisin levels in both CSF and plasma; to determine whether CSF irisin uptake involves a saturable transport mechanism. DESIGN AND METHODS: In the present study, the irisin levels in paired CSF and plasma samples drawn from 71 healthy individuals were used to investigate effects by using commercial ELISA kits and mass spectrometry. RESULTS: Multiple linear regression analysis results showed that CSF irisin levels are positively correlated with the CSF/plasma irisin ratio and age and that these levels present a reverse correlation with BMI. Age-related increases in CSF levels are validated by using ELISA and mass spectrometry. Higher plasma irisin levels are observed in men than women. CSF and plasma irisin levels are nonlinearly associated with the CSF/plasma irisin ratio, BMI, age and F scores. The CSF/plasma irisin ratio is U-shaped and associated with age. CONCLUSIONS: There might be an age-related increase in irisin levels in the cerebrospinal fluid of healthy humans. Circulating irisin levels are higher in males than in females in the healthy population. A saturable mechanism might be involved in mediating the transport of circulating irisin across the blood-brain barrier. Factors shaping irisin levels for both circulation and the CSF of healthy humans must be further defined in future experiments.

Cholinergic Hypofunction in Presbycusis-Related Tinnitus With Cognitive Function Impairment: Emerging Hypotheses.

Presbycusis (age-related hearing loss) is a potential risk factor for tinnitus and cognitive deterioration, which result in poor life quality. Presbycusis-related tinnitus with cognitive impairment is a common phenotype in the elderly population. In these individuals, the central auditory system shows similar pathophysiological alterations as those observed in Alzheimer's disease (AD), including cholinergic hypofunction, epileptiform-like network synchronization, chronic inflammation, and reduced GABAergic inhibition and neural plasticity. Observations from experimental rodent models indicate that recovery of cholinergic function can improve memory and other cognitive functions via acetylcholine-mediated GABAergic inhibition enhancement, nicotinic acetylcholine receptor (nAChR)-mediated anti-inflammation, glial activation inhibition and neurovascular protection. The loss of cholinergic innervation of various brain structures may provide a common link between tinnitus seen in presbycusis-related tinnitus and age-related cognitive impairment. We hypothesize a key component of the condition is the withdrawal of cholinergic input to a subtype of GABAergic inhibitory interneuron, neuropeptide Y (NPY) neurogliaform cells. Cholinergic denervation might not only cause the degeneration of NPY neurogliaform cells, but may also result in decreased AChR activation in GABAergic inhibitory interneurons. This, in turn, would lead to reduced GABA release and inhibitory regulation of neural networks. Reduced nAChR-mediated anti-inflammation due to the loss of nicotinic innervation might lead to the transformation of glial cells and release of inflammatory mediators, lowering the buffering of extracellular potassium and glutamate metabolism. Further research will provide evidence for the recovery of cholinergic function with the use of cholinergic input enhancement alone or in combination with other rehabilitative interventions to reestablish inhibitory regulation mechanisms of involved neural networks for presbycusis-related tinnitus with cognitive impairment.

Detection and quantitation of irisin in human cerebrospinal fluid by tandem mass spectrometry.

The myokine irisin can cross the blood brain barrier and act as a neurokine to protect brain function during endurance exercise. However, the mechanism of transport from the blood to cerebrospinal fluid is unknown. Irisin has been detected in rodent and human brain and human cerebrospinal fluid by using commercial antibodies and enzyme linked immunosorbent assay kits. However, as human FNDC5 has an atypical translation start codon, some studies have questioned the specificity of commercial antibodies. Recently, human irisin was identified and quantitated in plasma by using mass spectrometry. We investigated whether there was irisin in human cerebrospinal fluid and an irisin concentration gradient between in human cerebrospinal fluid and paired plasma. An irisin peptide was identified and quantitated by using mass spectrometry with control peptides enriched with heavy stable isotopes as internal standards. Quantitative mass spectrometry identified the presence of irisin in human cerebrospinal fluid. The internal irisin peptides were modified to the deamidated asparagine form after deglycosylation. The unmodified internal irisin peptides were not found in CSF and irisin concentration was approximately 0.26-1.86 ng/ml in men over 80 years of age with various diseases. However, the parallel reaction monitoring (PRM) elution profiles of both modified and unmodified internal irisin peptides were not found in paired plasma samples. These data unequivocally demonstrated the presence of the glycosylated form of irisin in human cerebrospinal fluid. There were significant individual differences in men over 80 years of age with diseases. However, irisin was not detected in plasma samples by using mass spectrometry.

Targeting NAD+ degradation: The therapeutic potential of flavonoids for Alzheimer's disease and cognitive frailty.

Flavonoids are efficacious candidates as pharmaceuticals or nutraceuticals in the treatment of Alzheimer's disease (AD), aging and other age-related chronic inflammatory diseases. Natural flavonoids reduce pathological hallmarks, extracellular amyloid deposits and neurofibrillary tangles by mediating amyloid precursor protein (APP) processing, Aß accumulation and tau pathology. The antioxidant and anti-inflammatory actions as well as modulation of sirtuins and telomeres are also involved in the amelioration of aging, neurodegeneration and other age-related diseases. Recently, some flavonoids were shown to inhibit poly (ADP-ribose) polymerases (PARPs) and cyclic ADP-ribose (cADP) synthases (CD38 and CD157), elevate intracellular nicotinamide adenine dinucleotide+ (NAD+) levels and activate NAD+ dependent sirtuin -mediated signaling pathways. We summarized how flavonoids reduce the degradation of NAD+ with an emphasis on the mechanisms through which flavonoids affect the NAD+-sirtuin axis to protect against AD. Aging and age-related diseases as well as a decline in the physiological reserve are the risk factors for cognitive frailty. Flavonoids with multiple therapeutic targets may also be potential candidates for the prevention and treatment of cognitive frailty.

Sexual dimorphism of frailty and cognitive impairment: Potential underlying mechanisms (Review).

The aim of the present study was to assess systematically gender differences in susceptibility to frailty and cognitive performance decline, and the underlying mechanisms. A systematic assessment was performed of the identified reviews of cohort, mechanistic and epidemiological studies. The selection criteria of the present study included: i) Sexual dimorphism of frailty, ii) sexual dimorphism of subjective memory decline (impairment) and atrophy of hippocampus during early life, iii) sexual dimorphism of late­onset Alzheimer's disease and iv) sexual dimorphism mechanisms underlying frailty and cognitive impairment. Males exhibit a susceptibility to poor memory performance and a severe atrophy of the hippocampus during early life and females demonstrate a higher prevalence for frailty and late­life dementia. The different alterations within the hypothalamic­pituitary­gonadal/adrenal axis, particularly with regard to gonadal hormones, cortisol and dehydroepiandrosterone/sulfate­bound dehydroepiandrosterone prior to and following andropause in males and menopause in females, serve important roles in sexual dimorphism of frailty and cognitive impairment. These endocrine changes may accelerate immunosenescence, weaken neuroprotective and neurotrophic effects, and promote muscle catabolism. The present study suggested that these age­associated endocrine alterations interact with gender­specific genetic and epigenetic factors, together with immunosenescence and iron accumulation. Environment factors, including psychological factors, are additional potential causes of the sexual dimorphism of frailty and cognitive impairment.

SOD2 Facilitates the Antiviral Innate Immune Response by Scavenging Reactive Oxygen Species.

Superoxide dismutase 2 (SOD2) is essential in radical scavenging, which balances the intracellular level of reactive oxygen species (ROS). The dysfunction of SOD2 is associated with increasing incidence of various human diseases, including cancer, neuron diseases, and myocardial defects. However, the connections between SOD2-mediated oxidative homeostasis and innate immune response remain unclear. In this study, we report that SOD2 is a crucial regulator of antiviral signaling. Depletion of SOD2 impairs RNA virus-induced type I interferon (IFN) and proinflammatory cytokine production, resulting in enhanced viral replication. Type I IFN production is highly sensitive to cellular level of ROS. SOD2 deficiency-mediated ROS accumulation potently inhibits RIG-I-like receptor (RLR)-induced innate immune responses through the regulation of nuclear factor-kappa B (NF-κB) and interferon regulatory factor-3 activation. These findings uncover a novel role for SOD2 in regulating RLR-mediated antiviral innate immune signaling.