The effects of sensorial and mobility frailty on the overall and domain-specific cognition performance of Chinese community-dwelling older adults.

This study aimed to investigate the different impacts of sensorial and mobility frailty on overall and domain-specific cognitive function. Further, the independent associations between other intricate capacity (IC) dimensions, including vitality and psychological dimensions, and overall and domain-specific cognitive function were investigated. A total of 429 participants (mean age, 72.91 ±â€…7.014 years; 57.30% female) underwent IC capacity assessment. Other covariates, such as demographics, health-related variables were also assessed. Overall or domain-specific cognitive impairment was used as a dependent variable in logistic regression analyses adjusted for demographic, health-related, and psychosocial confounders. After adjustment for demographic, health-related, and psychosocial confounders, individuals with sensorial frailty (odds ratio [OR] = 0.435; 95% confidence interval [CI] = 0.236-0.801; P = .008) had a significantly lower risk of mild cognitive impairment (MCI), marginally low delayed memory impairment (OR = 0.601, 95% CI = 0.347-1.040; P = .069), and language impairment (OR = 0.534, 95% CI = 0.305-0.936; OR = 0.318, P = .029; OR = 0.318,95% CI = 0.173-0.586; P < .001) by Boston naming and animal fluency tests than did those with both sensorial and mobility frailty or mobility frailty only. Depressive symptoms had a significant negative influence on executive function. Cardiovascular disease and non-skin malignancy were independent determinants of MCI, and diabetes mellitus was independently associated with processing speed, attention, and executive function. Sensorial and mobility frailty were independent risk factors for cognitive impairment. Mobility frailty had a greater negative influence on the overall cognitive function and memory and language function than did sensorial frailty. The reserve decline in the psychological dimension of IC and chronic diseases also had a significant adverse influence on overall and domain-specific cognition function.

Mutations in the NUP93, NUP107 and NUP160 genes cause steroid-resistant nephrotic syndrome in Chinese children.

BACKGROUND: The variants of nucleoporins are extremely rare in hereditary steroid-resistant nephrotic syndrome (SRNS). Most of the patients carrying such variants progress to end stage kidney disease (ESKD) in their childhood. More clinical and genetic data from these patients are needed to characterize their genotype-phenotype relationships and elucidate the role of nucleoporins in SRNS. METHODS: Four patients of SRNS carrying biallelic variants in the NUP93, NUP107 and NUP160 genes were presented. The clinical and molecular genetic characteristics of these patients were summarized, and relevant literature was reviewed. RESULTS: All four patients in this study were female and initially presented with SRNS. The median age at the onset of the disease was 5.08 years, ranging from 1 to 10.5 years. Among the four patients, three progressed to ESKD at a median age of 7 years, ranging from 1.5 to 10.5 years, while one patient reached stage 3 chronic kidney disease (CKD3). Kidney biopsies revealed focal segmental glomerulosclerosis in three patients. Biallelic variants were detected in NUP93 in one patient, NUP107 in two patients, as well as NUP160 in one patient respectively. Among these variants, five yielded single amino acid substitutions, one led to nonsense mutation causing premature termination of NUP107 translation, one caused a single nucleotide deletion resulting in frameshift and truncation of NUP107. Furthermore, one splicing donor mutation was observed in NUP160. None of these variants had been reported previously. CONCLUSION: This report indicates that biallelic variants in NUP93, NUP107 and NUP160 can cause severe early-onset SRNS, which rapidly progresses to ESKD. Moreover, these findings expand the spectrum of phenotypes and genotypes and highlight the importance of next-generation sequencing in elucidating the molecular basis of SRNS and allowing rational treatment for affected individuals.

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.

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.

Combining electrochemical nitrate reduction and anammox for treatment of nitrate-rich wastewater: A short review.

Treatment of nitrate-rich wastewater is important but challenging for the conventional biological denitrification process. Here, we propose combining the electrochemical reduction and anaerobic ammonium oxidation (anammox) processes together for treatment of nitrate-rich wastewater. This article reviews the mechanism and current research status of electrochemical reduction of nitrate to ammonium as well as the mechanism and applicability of the anammox process. This article discusses the principles, superiorities and challenges of this combined process. The feasibility of the combined process depends on the efficiency of electrochemical nitrate reduction to ammonium and the conditions in the anammox process to use the reduced ammonium as the substrate to achieve deep nitrogen removal. The article provides a feasible strategy for using the electrochemical reduction and anammox combined process to treat nitrate-rich wastewater.

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.

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.

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.

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.

Emerging biomarkers and screening for cognitive frailty.

Physical frailty and cognitive frailty are two important targets of secondary intervention in aging research to narrow the gap between life and health span. The objective of the present narrative review was to examine clinical and epidemiological studies investigating the recently proposed construct of cognitive frailty and its subtypes, with a focus on operational definitions, clinical criteria, and emerging biomarkers potentially useful for the screening of this novel entity. Both physical frailty and frailty indexes with a multidimensional nature were associated with late-life cognitive impairment/decline, incident dementia, Alzheimer's disease (AD), mild cognitive impairment, vascular dementia, non-AD dementias, and AD pathology proposing cognitive frailty as a clinical entity with cognitive impairment related to physical causes with a potential reversibility. The new clinical and research AD criteria established by the National Institute on Aging-Alzheimer's Association and the American Psychiatric Association could improve the differential diagnosis of cognitive impairment within the cognitive frailty construct. The emerging biomarkers of sarcopenia, physical frailty, and cognitive impairment will provide the basis to establish more reliable clinical and research criteria for cognitive frailty, using different operational definitions for frailty and cognitive impairment and useful clinical, biological, and imaging markers for this novel clinical construct.

Phytochemicals in the Treatment of Alzheimer's Disease: A Systematic Review.

BACKGROUND: Alzheimer's disease (AD) is the most widespread age-related neurodegenerative disease. Recently, a growing body of evidence suggested the phytochemical use to slow down AD onset and progression. OBJECTIVE: To review the phytochemical role potentially involved in AD treatment. METHOD: A systematic review from existing literature on phytochemicals used in the treatment of AD patients was conducted. Selection criteria included: 1) age≥60 years; 2) AD diagnosis in agreement with the criteria of National Institute on Aging-Alzheimer's Association (NIAAA), and 3) suitable measures to asses cognitive, functional and clinical status. RESULTS: Ninety-seven articles were involved in the present study. Several phytochemicals seem to slow down AD onset, delay disease progression and let recovery through targeting multiple pathological causes by anti-cholinergic, antioxidant and anti-inflammatory features. CONCLUSION: Deeper knowledge on phytochemicals and their specific molecular targets is essential to guarantee safe use of these compounds as an option for AD treatment.

Chronic kidney disease-related physical frailty and cognitive impairment: a systemic review.

AIM: The objective of this review was to assess chronic kidney disease-related frailty and cognitive impairment, as well as their probable causes, mechanisms and the interventions. METHODS: Studies from 1990 to 2015 were reviewed to evaluate the relationship between chronic kidney disease and physical frailty and cognitive impairment. Of the 1694 studies from the initial search, longitudinal studies (n = 22) with the keywords "Cognitive and CKD" and longitudinal or cross-sectional studies (n = 5) with the keywords "Frailty and CKD" were included in final analysis. RESULTS: By pooling current research, we show clear evidence for a relationship between chronic kidney disease and frailty and cognitive impairment in major studies. Vascular disease is likely an important mediator, particularly for cognitive impairment. However, non-vascular factors also play an important role. Many of the other mechanisms that contribute to impaired cognitive function and increased frailty in CKD remain to be elucidated. In limited studies, medication therapy did not obtain the ideal effect. There are limited data on treatment strategies, but addressing the vascular disease risk factors earlier in life might decrease the subsequent burden of frailty and cognitive impairment in this population. Multidimensional interventions, which address both microvascular health and other factors, may have substantial benefits for both the cognitive impairments and physical frailty in this vulnerable population. CONCLUSIONS: Chronic kidney disease is a potential cause of frailty and cognitive impairment. Vascular and non-vascular factors are the possible causes. The mechanism of chronic kidney disease-induced physical frailty and cognitive impairment suggests that multidimensional interventions may be effective therapeutic strategies in the early stage of chronic kidney disease. Geriatr Gerontol Int 2017; 17: 529-544.

Potential fluid biomarkers for pathological brain changes in Alzheimer's disease: Implication for the screening of cognitive frailty.

Cognitive frailty (CF) overlaps with early neuropathological alterations associated with aging­related major neurocognitive disorders, including Alzheimer's disease (AD). Fluid biomarkers for these pathological brain alterations allow for early diagnosis in the preclinical stages of AD, and for objective prognostic assessments in clinical intervention trials. These biomarkers may also be helpful in the screening of CF. The present study reviewed the literature and identified systematic reviews of cohort studies and other authoritative reports. The selection criteria for potentially suitable fluid biomarkers included: i) Frequent use in studies of fluid­derived markers and ii) evidence of novel measurement techniques for fluid­derived markers. The present study focused on studies that assessed these biomarkers in AD, mild cognitive impairment and non­AD demented subjects. At present, widely used fluid biomarkers include cerebrospinal fluid (CSF), total tau, phosphorylated tau and amyloid­ß levels. With the development of novel measurement techniques and improvements in understanding regarding the mechanisms underlying aging­related major neurocognitive disorders, numerous novel biomarkers associated with various aspects of AD neuropathology are being explored. These include specific measurements of Aß oligomer or monomer forms, tau proteins in the peripheral plasma and CSF, and novel markers of synaptic dysfunction, neuronal damage and apoptosis, neuronal activity alteration, neuroinflammation, blood brain barrier dysfunction, oxidative stress, metabolites, mitochondrial function and aberrant lipid metabolism. The proposed panels of fluid biomarkers may be useful in the early diagnosis of AD, prediction of the progression of AD from preclinical stages to the dementia stage, and the differentiation of AD from non­AD dementia. In combination with physical frailty, the present study surmised that these biomarkers may also be used as biomarkers for CF, thus contribute to discovering causes and informing interventions for cognitive impairment in individuals with CF.