Development and validation of cognitive ageing risk score (CARS) for early detection of subtle cognitive deficits in older people.

BACKGROUND: Early cognitive deficits commonly seen in older people have not been well defined and managed in primary care. The objectives are (1) to develop and validate a new risk score to estimate the risk of dementia in Chinese older population; and (2) to evaluate the use of risk score in conjunction with cognitive screening in detecting early cognitive deficits in community older people. METHODS: A development cohort of 306 cognitive healthy older adults aged 60 or above were followed for 6 years. A CARS was constructed using the estimated coefficients of risk factors associated with dementia at follow up. Validation was carried out in another five-year cohort of 383 older adults. The usefulness of CARS in detecting early cognitive deficits was evaluated. RESULTS: Risk factors include older age, male gender, low level of education, poorly controlled diabetes, prolonged sleep latency, fewer mind body or light exercise, loneliness, and being apolipoprotein e4 carriers. A cutoff of CARS at -1.3 had a sensitivity of 83.9% and a specificity of 75.4% to predict dementia. The area under curve was 82.5% in the development cohort. Early cognitive deficits were characterized by impaired retention (p <.001, 95% CI 0.2-0.9) and attention (p =.012, 95% CI 0.1-0.8). CONCLUSION: The CARS can be used as a standard risk assessment of dementia or in conjunction with a computerized cognitive screening to evaluate a full cognitive profile for detecting early cognitive deficits. The result put forward the integration of risk algorithm into smart healthcare system to provide personalized lifestyle interventions.

Effect of increasing cognitive activity participation on default mode network in older adults with subjective cognitive decline: a randomised controlled trial.

BACKGROUND: Having more cognitive activities may prevent dementia, but its evidence of modulating the functional brain network is limited. This randomised controlled trial (RCT) investigated the effect of increased cognitive activity participation on the default mode network (DMN) in older adults who had already been having regular cognitive activity participation and experiencing subjective cognitive decline (SCD). METHODS: Community-living Chinese individuals aged 55-75 years with regular practice of Chinese calligraphy and screened positive for SCD (but negative for mild cognitive impairment or dementia) were randomly allocated to either the intervention or control group. Over 6 months, the intervention group doubled their weekly calligraphy practice time, while the control group maintained their usual amount of practice. The primary outcome was functional connectivities (FCs) of DMN, with pre-specified regions of interest including medial prefrontal cortex (mPFC), inferior parietal lobe (IPL), hippocampal formation (HF), posterior cingulate cortex (PCC), and lateral temporal cortex (LTC). FC changes were compared using repeated measures multivariate analysis of variance (MANOVA). This study is registered at the Chinese Clinical Trial Registry, ChiCTR1900024433. FINDINGS: Between 15 January 2020 and 31 December 2021, 112 individuals consented and completed the baseline assessment. The participants, who had a mean age of 66.3 (SD 4.3) years, with 83 (74%) being women, had been practising calligraphy for an average duration of 9.7 years before enrolment and, in the preceding six months, for an average of 3.1 hours per week. 96 (86%) completed the post-intervention fMRI scan. Significant between-group differences were observed in the FCs between mPFC and right LTC (group difference = 0.25 [95% CI = 0.06-0.44], p = 0.009), mPFC and right IPL (0.23 [0.06-0.39]; p = 0.007), left HF and right LTC (0.28 [0.002-0.57]; p = 0.04), and left HF and right IPL (0.34 [0.09-0.60]; p = 0.009). INTERPRETATION: Our findings, which reveal positive neuromodulatory effects with increased calligraphy practice, highlight the importance of engaging more in cognitive activities in late life for better brain health. FUNDING: Research Grants Council, Hong Kong (grant number 24114519).

Effect of computerized cognitive training on mood, cognition, and serum brain-derived neurotrophic factor level in late-life depression - a pilot randomized controlled trial.

Background: The aim of this pilot randomized controlled trial was to test the feasibility of a computerized cognitive training targeting executive dysfunction in late-life depression and to investigate its impact on mood, cognition, and brain-derived neurotrophic factor (BDNF) levels. Methods: A total of 28 community-living Chinese individuals aged 55-75 with moderate-to-severe depression and cognitive symptoms (but without mild cognitive impairment or dementia) were recruited from a community centre in Hong Kong. Participants were randomly allocated to either the experimental (receiving computerized cognitive training) or the control group (receiving computer-based health education). Both programs lasted for one hour and were conducted twice a week for 6 weeks at the community centre. We assessed mood using the Hamilton Rating Scale for Depression (HAM-D) and Patient Health Questionaire-9 (PHQ-9), cognition using the Montreal Cognitive Assessment (MoCA), and serum BDNF levels at baseline and follow-up. We performed repeated measures analysis of variance to compare the differences in outcome changes between groups and correlation analysis to test if changes in mood and cognition correlated with changes in BDNF level. Results: Our sample had a mean age of 66.8 (SD = 5.3) years, a mean HAM-D score of 19.4 (SD = 7.5), and a mean PHQ-9 score of 18.0 (SD = 6.3). No adverse effects were reported. Significant differences were observed between the experimental and control groups in changes in HAM-D (-8.4 vs. -2.9; group difference = -5.5; p = 0.01), PHQ-9 (-6.6 vs. -0.6; -6.0; p < 0.001), MoCA (1.4 vs. -1.3; 2.7; p = 0.001), and serum BDNF levels (in pg/ml; 2088.3 vs. -3277.4; 5365.6; p = 0.02). Additionally, changes in HAM-D, PHQ-9, and MoCA scores correlated significantly with changes in BDNF level. Conclusion: With computerized cognitive training improving mood and cognition and increasing serum BDNF levels in 6 weeks, it may serve as a safe and effective evidence-based alternative or adjuvant treatment for late-life depression. Clinical trial registration: https://www.chictr.org.cn/indexEN.html, identifier ChiCTR1900027029.

Anxiety symptoms predicted decline in episodic memory in cognitively healthy older adults: A 3-year prospective study.

OBJECTIVE: Prospective studies on late-life anxiety disorders suggested that history of anxiety symptoms may be predictive of cognitive decline in old age. However, the relationship between anxiety and cognitive decline is still inconclusive due to heterogeneity in sample and methodology. This study was to explore how baseline anxiety symptoms associated with the change of memory in older people without cognitive impairment over a 3-year period. METHODS: This was a 3-year prospective study on 91 cognitively normal older adults with anxiety symptoms. They were matched with 91 controls based on age, gender, and education. Anxiety symptoms were assessed with Revised Clinical Interview Schedule (CIS-R). Physical health was assessed with Chronic Illness Rating Scale (CIRS). Cognitive performance was measured using Cantonese version of the mini-mental state examination (CMMSE); 10-minute delay recall; Category verbal fluency test (CVFT); Trail making tests (TMT); and digit and visual span tests. Outcomes were determined as the change of cognitive performance over a 3-year period. RESULTS: As expected, anxiety group had higher score in CIRS score (t = 4.45, P < .001) and CIS-R score (t = 9.24, P < .001) than control group. Linear regression showed that baseline anxiety symptoms were associated with change in delayed recall (B = 0.77, P = 0.027, 95% CI = 0.09-1.46), after adjusting for cognitive performance, physical, and mental health statuses. CONCLUSIONS: Anxious healthy older adults showed specific decline in episodic memory over a 3-year interval. Our result suggested that anxiety symptoms are predictive of episodic memory decline in cognitively healthy older adults and may be an early sign of neurodegenerative disorders.

Lifetime Prevalence and Correlates of Schizophrenia-Spectrum, Affective, and Other Non-affective Psychotic Disorders in the Chinese Adult Population.

Lifetime prevalence of psychotic disorders varies widely across studies. Epidemiological surveys have rarely examined prevalences of specific psychotic disorders other than schizophrenia, and the majority used a single-phase design without employing clinical reappraisal interview for diagnostic verification. The current study investigated lifetime prevalence, correlates and service utilization of schizophrenia-spectrum, affective, and other non-affective psychotic disorders in a representative sample of community-dwelling Chinese adult population aged 16-75 years (N = 5719) based on a territory-wide, population-based household survey for mental disorders in Hong Kong. The survey adopted a 2-phase design comprising first-phase psychosis screening and second-phase diagnostic verification incorporating clinical information from psychiatrist-administered semi-structured interview and medical record review to ascertain DSM-IV lifetime diagnosis for psychotic disorders. Data on sociodemographics, psychosocial characteristics and service utilization were collected. Our results showed that lifetime prevalence was 2.47% for psychotic disorder overall, 1.25% for schizophrenia, 0.15% for delusional disorder, 0.38% for psychotic disorder not otherwise specified, 0.31% for bipolar disorder with psychosis, and 0.33% for depressive disorder with psychosis. Schizophrenia-spectrum disorder was associated with family history of psychosis, cigarette smoking and variables indicating socioeconomic disadvantage. Victimization experiences were significantly related to affective psychoses and other non-affective psychoses. Around 80% of participants with any psychotic disorder sought some kind of professional help for mental health problems in the past year. Using comprehensive diagnostic assessment involving interview and record data, our results indicate that approximately 2.5% of Chinese adult population had lifetime psychotic disorder which represents a major public health concern.

Widened pulse pressure is a potential risk factor for significant cognitive impairment among community-dwelling Chinese younger old people.

Hypertension is a risk factor for dementia, but its exact role in contributing to dementia remains unknown. We conducted a community-based retrospective cohort study to examine the association of hypertension and widened pulse pressure (PP) with incident significant cognitive impairment (SCI) in Chinese older people in Hong Kong. A total of 1,925 subjects who were 65 years and older, ethnic Chinese, and community-living, with no history of cerebrovascular accidents or dementia, were recruited. Demographics, medical history, and physical parameters recorded at baseline were retrieved for analysis. Primary outcome was SCI developed in 6 years, which was defined by the presence of clinical dementia, scoring below the cutoff point on the Cantonese version of the Mini-Mental State Examination, and/or a global Clinical Dementia Rating of 1 to 3. Our data showed no difference in the point prevalence of pre-existing hypertension between subjects who remained cognitively stable and those who developed SCI (64.2% versus 65.8%; χ2 test, p = 0.68). However, subjects with incident SCI had a higher baseline PP (70 mmHg versus 66 mmHg; Mann-Whitney U-test, p = 0.03) and a decreasing trend in PP with time. Multiple logistic regression analysis showed that PP had a small but significant effect on the risk of SCI among the younger old subjects (OR = 1.02, p = 0.03). Our findings suggested that widened PP might be a risk factor for SCI among the younger old people. Further studies are needed to ascertain the association between hypertension and SCI in the Chinese older population and how widened PP contributes to SCI.

DNA-based subtyping of glycogen storage disease type III: mutation and haplotype analysis of the AGL gene in Chinese.

Glycogen storage disease type III (GSD III) is an inborn error of glycogen metabolism caused by a deficiency of glycogen debranching enzyme (AGL). Here, we investigate two unrelated Hong Kong Chinese GSD III patients and identify a novel 5-base pair deletional mutation, 2715_2719delTCAGAin exon 22, in one patient and a nonsense mutation, 1222C>T (R408X) in exon 11, in another patient. Since GSD IIIb is only caused by mutation in exon 3 of the AGL gene, we diagnose our patients to have GSD IIIa, which is consistent with the clinical diagnosis. Until now, R408X has only been reported in Faroe Islands GSDIII patients and was thought to demonstrate a founder effect. In this study, haplotyping of the disease-bearing chromosomes in the AGL locus by 19 intragenic single nucleotide polymorphisms shows that R408X is linked with IVS16+8T and IVS23-21T in our patient while R408X is linked with IVS16+8C and IVS23-21A in the Faroe Islands. The different haplotypes of R408X in Chinese and Faroese indicated that R408X is a recurrent mutation.

Activation of iberiotoxin-sensitive, Ca2+-activated K+ channels of porcine isolated left anterior descending coronary artery by diosgenin.

The objective of this study was to determine the vasodilating effect of 3beta-hydroxy-5-spirostene (diosgenin), a phytoestrogen found in wild yams, using porcine resistance left anterior descending coronary artery. In 5-hydroxytryptamine (3 microM) pre-contracted preparation, diosgenin caused a concentration-dependent (0.01 to 1 microM), endothelium-independent relaxation, with a maximum relaxation of approximately 72% at 1 microM. No apparent effect was observed with 17beta-oestradiol and progesterone with concentrations < or =0.3 microM, and a relaxation of approximately 15% and approximately 23% caused by 17beta-oestradiol (1 microM) and progesterone (1 microM), respectively. Diosgenin-elicited relaxation was not altered by 7alpha,17beta-[9[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol (ICI 182,780), mifepristone, (+)-bicuculline, cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine (MDL 12330A), glibenclamide and scavengers of reactive oxygen species. The iberiotoxin-sensitive, Ca2+-activated K+ (BK(Ca)) current of single vascular myocytes recorded, using patch-clamp techniques, was markedly enhanced by diosgenin, 17beta-oestradiol and progesterone. Application of (9S, 10R, 12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT 5823, 300 nM) eradicated the enhancement of BK(Ca) amplitude. Diosgenin, 17beta-oestradiol and progesterone did not affect whereas phloretin, biochanin A and zearalanone (1 microM each) significantly suppressed [Ca2+]o-induced contraction. In oestrogen competition essay using human breast cancer cell (MCF-7 cells), diosgenin (0.001 nM to 10 microM) did not interact with oestrogen receptor-alpha, and no displacement of [3H]17beta-oestradiol was observed. In oestrogen receptor alpha- and beta-fluorescence polarization competitor assay, diosgenin (100 microM) demonstrated a greater competition with the beta-isoform of oestrogen receptor. These results suggest that diosgenin caused an acute, endothelium-independent coronary artery relaxation via protein kinase G signalling cascade and an activation of BK(Ca) channel of arterial smooth muscle cells. The oestrogen receptor (alpha and beta-isoforms) and progesterone receptor are probably not involved.