Gestational diabetes mellitus is associated with greater incidence of dementia during long-term post-partum follow-up.

BACKGROUND: The impact of gestational diabetes mellitus (GDM) on incident dementia is unknown. Our aim was to evaluate the relationship between GDM and all-cause dementia and the mediating effects of chronic diseases on this relationship. METHODS: This prospective cohort study included women from the UK Biobank who were grouped based on GDM history. Multivariate Cox proportional hazard models were used to explore the associations between GDM and dementia. We further analysed the mediating effects of chronic diseases on this relationship and the interactions of covariates. RESULTS: A total of 1292 women with and 204,171 women without a history of GDM were included. During a median follow-up period of 45 years after first birth, 2921 women were diagnosed with dementia. Women with a GDM history had a 67% increased risk of incident dementia (hazard ratio 1.67, 95% confidence interval: 1.03-2.69) compared with those without a GDM history. According to mediation analyses, type 2 diabetes, coronary heart disease, chronic kidney disease and comorbidities (diagnosed with any two of the three diseases) explained 34.5%, 8.4%, 5.2% and 18.8% of the mediating effect on the relationship. Subgroup analyses revealed that physical activity modified the association between GDM history and dementia (p for interaction = 0.030). Among physically inactive women, GDM was significantly associated with incident dementia; however, this association was not observed among physically active women. CONCLUSIONS: A history of GDM was associated with a greater risk of incident dementia. Type 2 diabetes partially mediated this relationship. Strategies for dementia prevention might be considered for women with a history of GDM.

Association of Cardiovascular Health With Risk of Incident Depression and Anxiety.

OBJECTIVE: To investigate the association between cardiovascular health (CVH), defined by the American Heart Association's Life's Essential 8 (LE8) score, and incident depression and anxiety. DESIGN: A prospective cohort study using data from UK Biobank. SETTING: Participants were enrolled from March 2006 to October 2010. PARTICIPANTS: Participants without cardiovascular diseases and common mental disorders at baseline and having complete data on metrics of LE8 were included. MEASUREMENTS: CVH was assessed by LE8 score including eight components. The overall CVH was categorized as low (LE8 score <50), moderate (50≤ LE8 score <80), and high (LE8 score ≥80). RESULTS: We included 115,855 participants (mean age: 55.7 years; female: 52.6%). During a median follow-up of 12.4 years, 3,194 (2.8%) and 4,005 (3.5%) participants had incident depression and anxiety, respectively. Compared with participants having low CVH, those having moderate and high CVH had 37% (HR = 0.63, 95% CI: 0.57-0.70) and 52% (HR = 0.48, 95% CI: 0.41-0.55) lower risk of incident depression. Similarly, moderate and high CVH were related to a lower risk of incident anxiety (HR = 0.81, 95% CI: 0.73-0.89 and HR = 0.68, 95% CI: 0.60-0.78). Restricted cubic spline showed that LE8 score was inversely related to incident depression and anxiety in a linear manner, and the risk of incident depression and anxiety decreased by 17% (HR = 0.83, 95% CI: 0.80-0.85) and 10% (HR = 0.90, 95% CI: 0.88-0.92) for 10-point increment in LE8 score, respectively. CONCLUSIONS: Higher CVH, evaluated by LE8 score, is strongly associated with a lower risk of incident depression and anxiety, suggesting the significance of optimizing CVH by adopting LE8.

Reduced grid-like theta modulation in schizophrenia.

The hippocampal formation has been implicated in the pathophysiology of schizophrenia, with patients showing impairments in spatial and relational cognition, structural changes in entorhinal cortex and reduced theta coherence with medial prefrontal cortex. Both the entorhinal cortex and medial prefrontal cortex exhibit a 6-fold (or 'hexadirectional') modulation of neural activity during virtual navigation that is indicative of grid cell populations and associated with accurate spatial navigation. Here, we examined whether these grid-like patterns are disrupted in schizophrenia. We asked 17 participants with diagnoses of schizophrenia and 23 controls (matched for age, sex and IQ) to perform a virtual reality spatial navigation task during magnetoencephalography. The control group showed stronger 4-10 Hz theta power during movement onset, as well as hexadirectional modulation of theta band oscillatory activity in the right entorhinal cortex whose directional stability across trials correlated with navigational accuracy. This hexadirectional modulation was absent in schizophrenia patients, with a significant difference between groups. These results suggest that impairments in spatial and relational cognition associated with schizophrenia may arise from disrupted grid firing patterns in entorhinal cortex.

Sex differences in changes of depressive symptoms among older adults before and during the COVID-19 pandemic: evidence from two longitudinal cohorts.

BACKGROUND: Major concerns about the adverse mental health impact of the rapidly spread COVID-19 pandemic have been raised. Previous studies on changes of depressive symptoms during the COVID-19 pandemic have yielded inconsistent results regarding the sex differences. Since women have higher depressive symptoms even without the pandemic, it is essential to consider the pre-existing change of depressive symptoms of a similar period to discern the effect of the pandemic on depression. This study aimed to evaluate sex differences in depressive symptoms before and during the pandemic. METHODS: Data from the Health and Retirement Study (HRS; waves 13 to 15) and the English Longitudinal Study of Ageing (ELSA; wave 8 to COVID-19 wave 2) were analyzed. Depressive symptoms were assessed by the 8-item Center for Epidemiological Studies Depression (CES-D) scale. According to the time of COVID-19 outbreak in the US and the UK, the intervals from waves 13 to 14 surveys of the HRS and from waves 8 to 9 surveys of the ELSA were employed as pre-pandemic periods to control for the pre-existing depressive symptoms, respectively. Changes of CES-D scores during the pre-pandemic and pandemic periods were assessed by linear mixed models. RESULTS: Nine thousand, seven hundred thirty-seven participants (mean age: 66.7 ± 10.7 years) from the HRS and 5,098 participants (mean age: 68.7 ± 10.0 years) from the ELSA were included. CES-D scores among women were significantly higher than those among men at all waves in both cohorts. During the pre-pandemic period, no significant sex difference on changes of CES-D scores was detected in either the HRS or the ELSA. During the pandemic period, CES-D scores were increased in both men and women and the sex differences in CES-D increments of the two cohorts were both significant. Enlarged sex differences were demonstrated in increments of CES-D scores during the pandemic period. CONCLUSIONS: Our results suggest women suffered from worse depressive symptoms in response to the pandemic, although the changes of depression were similar between men and women before the pandemic. These findings underscore the necessity to support the vulnerable populations, especially women, to manage the distress brought by the pandemic and maintain optimal mental health status.

Targeting Mitochondrial Oxidative Stress: Potential Neuroprotective Therapy for Spinal Cord Injury.

Spinal cord injury (SCI) is a serious central nervous system (CNS) injury disease related to hypoxia-ischemia and inflammation. It is characterized by excessive reactive oxygen species (ROS) production, oxidative damage to nerve cells, and mitochondrial dysfunction. Mitochondria serve as the primary cellular origin of ROS, wherein the electron transfer chain complexes within oxidative phosphorylation frequently encounter electron leakage. These leaked electrons react with molecular oxygen, engendering the production of ROS, which culminates in the occurrence of oxidative stress. Oxidative stress is one of the common forms of secondary injury after SCI. Mitochondrial oxidative stress can lead to impaired mitochondrial function and disrupt cellular signal transduction pathways. Hence, restoring mitochondrial electron transport chain (ETC), reducing ROS production and enhancing mitochondrial function may be potential strategies for the treatment of SCI. This article focuses on the pathophysiological role of mitochondrial oxidative stress in SCI and evaluates in detail the neuroprotective effects of various mitochondrial-targeted antioxidant therapies in SCI, including both drug and non-drug therapy. The objective is to provide valuable insights and serve as a valuable reference for future research in the field of SCI.

Long-term physical activity participation trajectories were associated with subsequent cognitive decline, risk of dementia and all-cause mortality among adults aged ≥50 years: a population-based cohort study.

AIM: to evaluate self-reported physical activity (PA) participation trajectories over a 6-year span and to assess associations with subsequent cognitive decline, incident dementia and all-cause mortality. METHODS: population-based cohort of 8,842 community-dwelling adults aged ≥50 years in England. Group-based trajectory modelling was used to identify 6-year trajectories of PA participation. Cognitive decline, incident dementia and all-cause mortality were outcomes. RESULTS: five trajectories were identified, including persistently low (N = 2,511), initially low then improving (1,651), initially high then declining (249), persistently moderate (2,422) and persistently high (2,009). Compared with persistently low, participants of initially low then improving and persistently high PA participation experienced decelerated global cognitive decline of 0.012 standard deviation (SD)/year (95% confidence interval [CI]: 0.004-0.021, P = 0.004) and 0.021 SD/year (95% CI: 0.013-0.029, P < 0.001). They were also associated with lower dementia risk, with multivariate-adjusted hazard ratios (HRs) of 0.43 (95% CI: 0.31-0.60) and 0.35 (95% CI: 0.27-0.45). A similar pattern was observed for all-cause mortality, with HRs of 0.31 (95% CI: 0.13-0.74) and 0.25 (95% CI: 0.14-0.45). No significant differences were observed between persistently low and initially high then declining trajectories. CONCLUSION: for middle-aged and older adults, both gradually improved and persistently active PA participation were associated with decelerated cognitive decline, lower risk of dementia and all-cause mortality. Strategies focusing on improving and maintaining PA participation could be of significance by attaining considerable neurocognitive and longevity benefits.

Impaired theta phase coupling underlies frontotemporal dysconnectivity in schizophrenia.

Frontotemporal dysconnectivity is a key pathology in schizophrenia. The specific nature of this dysconnectivity is unknown, but animal models imply dysfunctional theta phase coupling between hippocampus and medial prefrontal cortex (mPFC). We tested this hypothesis by examining neural dynamics in 18 participants with a schizophrenia diagnosis, both medicated and unmedicated; and 26 age, sex and IQ matched control subjects. All participants completed two tasks known to elicit hippocampal-prefrontal theta coupling: a spatial memory task (during magnetoencephalography) and a memory integration task. In addition, an overlapping group of 33 schizophrenia and 29 control subjects underwent PET to measure the availability of GABAARs expressing the α5 subunit (concentrated on hippocampal somatostatin interneurons). We demonstrate-in the spatial memory task, during memory recall-that theta power increases in left medial temporal lobe (mTL) are impaired in schizophrenia, as is theta phase coupling between mPFC and mTL. Importantly, the latter cannot be explained by theta power changes, head movement, antipsychotics, cannabis use, or IQ, and is not found in other frequency bands. Moreover, mPFC-mTL theta coupling correlated strongly with performance in controls, but not in subjects with schizophrenia, who were mildly impaired at the spatial memory task and no better than chance on the memory integration task. Finally, mTL regions showing reduced phase coupling in schizophrenia magnetoencephalography participants overlapped substantially with areas of diminished α5-GABAAR availability in the wider schizophrenia PET sample. These results indicate that mPFC-mTL dysconnectivity in schizophrenia is due to a loss of theta phase coupling, and imply α5-GABAARs (and the cells that express them) have a role in this process.

Chiral Phosphoric Acids in Metal-Organic Frameworks with Enhanced Acidity and Tunable Catalytic Selectivity.

Chiral phosphoric acids are incorporated into indium-based metal-organic frameworks (In-MOFs) by sterically preventing them from coordination. This concept leads to the synthesis of three chiral porous 3D In-MOFs with different network topologies constructed from three enantiopure 1,1'-biphenol-phosphoric acid derived tetracarboxylate linkers. More importantly, all the uncoordinated phosphoric acid groups are periodically aligned within the channels and display significantly enhanced acidity compared to the non-immobilized acids. This facilitates the Brønsted acid catalysis of asymmetric condensation/amine addition and imine reduction. The enantioselectivities can be tuned (up to >99 % ee) by varying the substituents to achieve a nearly linear correlation with the concentrations of steric bulky groups in the MOFs. DFT calculations suggest that the framework provides a chiral confined microenvironment that dictates both selectivity and reactivity of chiral MOFs.

HbA1c, diabetes and cognitive decline: the English Longitudinal Study of Ageing.

AIMS/HYPOTHESIS: The aim of the study was to evaluate longitudinal associations between HbA1c levels, diabetes status and subsequent cognitive decline over a 10 year follow-up period. METHODS: Data from wave 2 (2004-2005) to wave 7 (2014-2015) of the English Longitudinal Study of Ageing (ELSA) were analysed. Cognitive function was assessed at baseline (wave 2) and reassessed every 2 years at waves 3-7. Linear mixed models were used to evaluate longitudinal associations. RESULTS: The study comprised 5189 participants (55.1% women, mean age 65.6 ± 9.4 years) with baseline HbA1c levels ranging from 15.9 to 126.3 mmol/mol (3.6-13.7%). The mean follow-up duration was 8.1 ± 2.8 years and the mean number of cognitive assessments was 4.9 ± 1.5. A 1 mmol/mol increment in HbA1c was significantly associated with an increased rate of decline in global cognitive z scores (-0.0009 SD/year, 95% CI -0.0014, -0.0003), memory z scores (-0.0005 SD/year, 95% CI -0.0009, -0.0001) and executive function z scores (-0.0008 SD/year, 95% CI -0.0013, -0.0004) after adjustment for baseline age, sex, total cholesterol, HDL-cholesterol, triacylglycerol, high-sensitivity C-reactive protein, BMI, education, marital status, depressive symptoms, current smoking, alcohol consumption, hypertension, CHD, stroke, chronic lung disease and cancer. Compared with participants with normoglycaemia, the multivariable-adjusted rate of global cognitive decline associated with prediabetes and diabetes was increased by -0.012 SD/year (95% CI -0.022, -0.002) and -0.031 SD/year (95% CI -0.046, -0.015), respectively (p for trend <0.001). Similarly, memory, executive function and orientation z scores showed an increased rate of cognitive decline with diabetes. CONCLUSIONS/INTERPRETATION: Significant longitudinal associations between HbA1c levels, diabetes status and long-term cognitive decline were observed in this study. Future studies are required to determine the effects of maintaining optimal glucose control on the rate of cognitive decline in people with diabetes.

Persistent depressive symptoms and cognitive decline in older adults.

BACKGROUND: Little is known about the effect of persistent depressive symptoms on the trajectory of cognitive decline.AimsWe aimed to investigate the longitudinal association between the duration of depressive symptoms and subsequent cognitive decline over a 10-year follow-up period. METHOD: The English Longitudinal Study of Ageing cohort is a prospective and nationally representative cohort of men and women living in England aged ≥50 years. We examined 7610 participants with two assessments of depressive symptoms at wave 1 (2002-2003) and wave 2 (2004-2005), cognitive data at wave 2 and at least one reassessment of cognitive function (wave 3 to wave 7, 2006-2007 to 2014-2015). RESULTS: The mean age of the 7610 participants was 65.2 ± 10.1 years, and 57.0% were women. Of these, 1157 (15.2%) participants had episodic depressive symptoms and 525 participants (6.9%) had persistent depressive symptoms. Compared with participants without depressive symptoms at wave 1 and wave 2, the multivariable-adjusted rates of global cognitive decline associated with episodic depressive symptoms and persistent depressive symptoms were faster by -0.065 points/year (95% CI -0.129 to -0.000) and -0.141 points/year (95% CI -0.236 to -0.046), respectively (P for trend < 0.001). Similarly, memory, executive and orientation function also declined faster with increasing duration of depressive symptoms (all P for trend < 0.05). CONCLUSIONS: Our results demonstrated that depressive symptoms were significantly associated with subsequent cognitive decline over a 10-year follow-up period. Cumulative exposure of long-term depressive symptoms in elderly individuals could predict accelerated subsequent cognitive decline in a dose-response pattern.Declaration of interestNone.

High-sensitivity C-reactive protein and cognitive decline: the English Longitudinal Study of Ageing.

BACKGROUND: High-sensitivity C-reactive protein (hs-CRP) has been suggested to be involved in the process of cognitive decline. However, the results from previous studies exploring the relationship between hs-CRP concentration and cognitive decline are inconsistent. METHOD: We employed data from wave 2 (2004-2005) to wave 7 (2014-2015) of the English Longitudinal Study of Ageing. Cognitive function was assessed at baseline (wave 2) and reassessed biennially at waves 3-7. RESULTS: A total of 5257 participants (54.9% women, mean age 65.4 ± 9.4 years) with baseline hs-CRP levels ranged from 0.2 to 210.0 mg/L (median: 2.0 mg/L, interquartile range: 0.9-4.1 mg/L) were studied. The mean follow-up duration was 8.1 ± 2.8 years, and the mean number of cognitive assessment was 4.9 ± 1.5. Linear mixed models show that a one-unit increment in natural log-transformed hs-CRP was associated with faster declines in global cognitive scores [-0.048 points/year, 95% confidence interval (CI) -0.072 to -0.023], memory scores (-0.022 points/year, 95% CI -0.031 to -0.013), and executive function scores (-0.025 points/year, 95% CI -0.043 to -0.006), after multivariable adjustment. Compared with the lowest quartile of hs-CRP, the multivariable-adjusted rate of global cognitive decline associated with the second, third, and highest quartile was faster by -0.043 points/year (95% CI -0.116 to 0.029), -0.090 points/year (95% CI -0.166 to -0.015), -0.145 (95% CI -0.221 to -0.069), respectively (p for trend <0.001). Similarly, memory and executive function also declined faster with increasing quartiles of hs-CRP. CONCLUSIONS: A significant association between hs-CRP concentration and long-term cognitive decline was observed in this study. Hs-CRP might serve as a biomarker for cognitive decline.

ALDH2 Glu504Lys Confers Susceptibility to Schizophrenia and Impacts Hippocampal-Prefrontal Functional Connectivity.

Although previous evidence suggested that ALDH2 is a candidate gene for schizophrenia, the association and underlying mechanisms have never been investigated. Therefore, we investigated ALDH2 as a susceptibility gene for schizophrenia and explored the effect of its polymorphisms on brain functions. In the discovery stage, we detected a positive association between a dominant-negative mutant, Glu504Lys, and schizophrenia (P= 8.01E-5, OR = 1.34, 95% CI = 1.16-1.55). This association was confirmed in the validation stage (P= 3.48E-6, OR = 1.28, 95% CI = 1.15-1.42). The combined P reached a genome-wide significance (Pcombined= 1.32E-9, OR = 1.30, 95% CI = 1.20-1.42). To investigate the neural mechanism linking Glu504Lys to schizophrenia, we calculated the functional connectivity (FC) and applied an imaging genetics strategy using resting-state fMRI data. The imaging analysis revealed a significant interaction of diagnostic group by genotype for FC between the left hippocampus and the prefrontal cortex. In the Glu homozygotes, hippocampal-prefrontal FC correlated inversely with memory performance in the healthy controls and with the PANSS negative score in the schizophrenia patients. Our results supported a role for ALDH2 in the pathophysiology of schizophrenia. Moreover, variation at Glu504Lys disrupts hippocampal-prefrontal FC, which might be the neural mechanism linking it to the disease.

Genetic Effects on Fine-Grained Human Cortical Regionalization.

Various brain structural and functional features such as cytoarchitecture, topographic mapping, gyral/sulcal anatomy, and anatomical and functional connectivity have been used in human brain parcellation. However, the fine-grained intrinsic genetic architecture of the cortex remains unknown. In the present study, we parcellated specific regions of the cortex into subregions based on genetic correlations (i.e., shared genetic influences) between the surface area of each pair of cortical locations within the seed region. The genetic correlations were estimated by comparing the correlations of the surface area between monozygotic and dizygotic twins using bivariate twin models. Our genetic subdivisions of diverse brain regions were reproducible across 2 independent datasets and corresponded closely to fine-grained functional specializations. Furthermore, subregional genetic correlation profiles were generally consistent with functional connectivity patterns. Our findings indicate that the magnitude of the genetic covariance in brain anatomy could be used to delineate the boundaries of functional subregions of the brain and may be of value in the next generation human brain atlas.

Time in target range of systolic blood pressure and cognitive outcomes in patients with hypertension.

BACKGROUND: Blood pressure (BP) is a dynamic measure that fluctuates over time. However, conventional BP control indicators may not adequately reflect the variability of BP during a period of time. METHODS: We performed a secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), which compared systolic blood pressure (SBP) targets of <120 mmHg (intensive) and <140 mmHg (standard) among patients with hypertension and high cardiac risks. The target ranges were defined as 110 to 130 mmHg in intensive treatment arm and 120 to 140 mmHg in standard treatment arm, respectively. Time in target range (TTR) was calculated based on SBP measurements recorded during the first 3-month follow-up using linear interpolation method. The Fine-Gray competing risk regression models were used to evaluate the association between TTR and cognitive outcomes. RESULTS: A total of 7965 patients with the mean (SD) age of 68.0 (9.2) years were included, and 35% were female. Patients with higher TTR were younger, more likely to be male and take <3 BP-lowering agents. Compared to the last quartile, the first quartile of TTR was significantly associated with a higher risk of probable dementia (HR: 1.74; 95% CI: 1.22-2.46; p = 0.002) and the composite of probable dementia or mild cognitive impairment (HR: 1.26; 95% CI: 1.03-1.55; p = 0.025). The risk of probable dementia and the composite outcome increased with per quartile decrease of TTR (HR: 1.18; 95% CI: 1.06-1.30; p = 0.002 and HR: 1.07; 95% CI: 1.00-1.14; p = 0.036). Sensitivity analyses showed similar results after adjusting mean SBP during the first 3-month follow-up. CONCLUSIONS: In this secondary analysis of SPRINT data, TTR was independently associated with probable dementia among patients with hypertension, suggesting that TTR could be used as a practical metric of BP control to evaluate the risk of dementia in older adults. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Identifier: NCT01206062.

Association between Age at Diagnosis of Hyperlipidemia and Subsequent Risk of Dementia.

OBJECTIVES: The relationship between age at diagnosis of hyperlipidemia and dementia remains unclear. We examined whether younger age at diagnosis of hyperlipidemia is associated with higher risk of subsequent dementia. DESIGN: A longitudinal population-based study with a median follow-up of 12.8 years. SETTING AND PARTICIPANTS: We analyzed data on a sample of 489,642 participants in the United Kingdom. METHODS: This study was based on the UK Biobank. Information on hyperlipidemia and dementia diagnoses was collected at baseline (2006-2010) and follow-up [median = 12.8 years, interquartile range (IQR): 12.1-13.6 years]. Propensity score matching method and Cox proportional hazards models were used to assess the association between age at diagnosis of hyperlipidemia and dementia. RESULTS: Among 489,642 participants (mean age: 56.9 ± 8.1 years; female: 54.7%), 114,112 (23.3%) were diagnosed with hyperlipidemia. Younger age at diagnosis of hyperlipidemia (per 10-year decrease) was significantly associated with higher risks of all-cause dementia [hazard ratio (HR), 1.12; 95% CI, 1.07-1.18; P < .001], Alzheimer's disease (AD) (HR, 1.22; 95% CI, 1.14-1.31; P < .001), and vascular dementia (VD) (HR, 1.16; 95% CI, 1.05-1.27; P < .001). After propensity score matching, patients with hyperlipidemia diagnosed before 50 years had the highest HR for all-cause dementia (HR, 1.46; 95% CI, 1.15-1.86; P = .002), followed by patients diagnosed between 50 and 69 years (HR, 1.21; 95% CI, 1.12-1.31; P < .001) and then patients diagnosed aged 70 years and older (HR, 0.94; 95% CI, 0.84-1.06; P = .302). Similar results were observed for AD and VD. CONCLUSIONS AND IMPLICATIONS: A dose-response relationship between age at hyperlipidemia diagnosis and risk of dementia was found in the longitudinal cohort study, with younger age at diagnosis of hyperlipidemia being associated with higher subsequent risk.

Associations Between Onset Age of Orthostatic Hypotension and Incident Myocardial Infarction, Stroke, and Dementia: A Prospective Cohort Study.

BACKGROUND: The associations of age at orthostatic hypotension onset with incident myocardial infarction (MI), stroke, and dementia remain unknown. This study aimed to examine whether younger onset age of orthostatic hypotension was associated with higher risks of incident MI, stroke, and dementia. METHODS: Data were obtained from the UK Biobank. Information on the diagnosis of orthostatic hypotension, MI, stroke, and dementia was collected at baseline (2006-2010) and follow-ups (median = 13 years). The propensity score matching method and the Cox proportional hazard models were employed. RESULTS: A total of 448 374 adults (mean age: 56.8 ±â€…8.1 years), of whom 3 795 had orthostatic hypotension, were included. orthostatic hypotension patients exhibited higher risks of developing MI, stroke, and dementia than non-orthostatic hypotension participants. Importantly, among orthostatic hypotension patients, younger onset age (per 10-year decrement) was significantly associated with high risks of MI (HR = 3.15, 95% CI: 2.54-3.90, p < .001), stroke (HR = 1.72, 95% CI: 1.33-2.23, p < .001), and dementia (HR = 1.26, 95% CI: 1.02-1.57, p = .034). After propensity score matching, orthostatic hypotension patients had significantly higher risks of MI, stroke, and dementia than matched controls among all onset age groups, and the HRs gradually increased with descending onset age. CONCLUSIONS: Younger onset age of orthostatic hypotension was associated with higher risks of incident MI, stroke, and dementia, underscoring the necessity to pay additional attention to the cardiovascular health and neurocognitive status of individuals diagnosed with orthostatic hypotension at younger ages to attenuate subsequent risks of incident cardiovascular diseases and dementia.

Prediction Abilities of SCORE2 Risk Algorithms for Incident Dementia and All-Cause Mortality: Results From the UK Biobank Cohort Study.

BACKGROUND: Whether the updated Systematic COronary Risk Evaluation (SCORE2) risk algorithm is suitable for the prediction of incident dementia and all-cause mortality and whether its discrimination abilities for these outcomes are higher than those of the SCORE and Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) risk algorithms are unclear. METHODS: The present study included 429 033 participants (mean age: 57.1 ± 8.1 years; male: 46.2%; White: 94.1%) free of dementia from the UK Biobank at baseline, with a median follow-up of 12.8 years. Cox regression models were adopted to investigate the longitudinal relationships of SCORE2 risk categories with outcomes, and receiver operating characteristic curve analyses were used to compare the discrimination abilities of the 3 algorithms. RESULTS: During 5 376 778 person-years of follow-up, 6 477 all-cause dementia, 2 726 Alzheimer's disease (AD), 1 439 vascular disease (VD), and 31 981 all-cause deaths were identified. We found that higher SCORE2 risk was associated with higher risks of all-cause dementia, AD, VD, and all-cause mortality. The C-indices of SCORE2 risk for discriminating incident all-cause dementia, AD, VD, and all-cause death were 0.750 (95% confidence interval [CI]: 0.745 to 0.755), 0.750 (95% CI: 0.743 to 0.757), 0.800 (95% CI: 0.791 to 0.809), and 0.721 (95% CI: 0.718 to 0.724), respectively, which were significantly improved in comparison to those of the SCORE and CAIDE risk algorithms. CONCLUSION: The SCORE2 risk algorithm is applicable in predicting incident all-cause dementia, AD, VD, and all-cause mortality in European populations, and its discrimination abilities for dementia and death are significantly higher than those of the SCORE and CAIDE risk algorithms. Further validations in other populations are warranted.

Altered functional connectivity in anterior cingulate cortex subregions in treatment-resistant schizophrenia patients.

BACKGROUND: The anterior cingulate cortex (ACC) plays a key role in motor control, attention, and cognitive control. It is well established that schizophrenia is associated with impaired functional connectivity (FC) of the ACC pathway. So far, however, there has been little discussion about the ACC subregions function in patients with treatment-resistant schizophrenia (TRS). AIM: This study aims to characterize resting-state functional connectivity (rs-FC) profiles of ACC subregions in patients with TRS. The association between these FC and clinical symptoms, neurocognitive function, and grey matter volume (GMV) was studied as well. METHODS: A total of 81 patients with schizophrenia (40 patients with TRS = 40, 41 patients with non-treatment-resistant schizophrenia (NTRS)) and 39 age- and gender-matched healthy controls (HC) were enrolled, and underwent structural magnetic resonance imaging (MRI), resting-state functional MRI (rs-fMRI), clinical evaluation. The ACC subregions, including subgenual ACC (sgACC), pregenual ACC (pgACC), and dorsal ACC (dACC), were selected as seed regions from the automated anatomical labelling atlas 3 (AAL3). The GMV of the ACC subregions were calculated and seed-based FC maps for all ACC subregions were generated and compared between the TRS and NTRS, HC group. Additionally, correlations between altered FC and clinical symptoms, GMV, and neurocognitive functions in the TRS patients were explored. RESULT: Compared with HC, increased FC was observed in TRS and NTRS groups between bilateral sgACC and left cuneus, right cuneus, and left lingual gyrus, while decreased FC was found between bilateral dACC and thalamic. Additionally, compared with NTRS, the TRS group showed increased FC between bilateral dACC and right cuneus and decreased FC between bilateral dACC and thalamic. The TRS group showed decreased GMV in all ACC subregions than the HC group, and there is no significant difference between the TRS group and the NTRS group. CONCLUSION: The findings in this study suggest that disrupted FC of subregional ACC has the potential as a marker for TRS. The dysconnectivity of bilateral dACC- right cuneus and bilateral dACC-thalamus, are likely to be the unique FC profiles of TRS. These findings further our understanding of the neurobiological impairments in TRS.

Utility of SCORE2 risk algorithm for predicting life course accelerated frailty and physical function decline.

BACKGROUND: Frailty is a dynamic process that increases with ageing, while it remains unclear whether cardiovascular disease (CVD) risk algorithm could predict life course dynamic frailty trajectories, for example, the longitudinal patterns of how frailty evolves with time. We intended to examine the predictive utility of the Systemic Coronary Risk Estimation 2 (SCORE2) algorithm for life course accelerated frailty and physical function decline, in comparison with the precedent SCORE algorithm. METHODS: Longitudinal data regarding accumulation of deficits frailty index (FI) and physical function (grip strength, gait speed, peak expiratory flow and timed chair rises) were drawn from the English Longitudinal Study of Ageing (ELSA) and Health and Retirement Study (HRS), two nationally representative cohorts with community-dwelling adults aged ≥50 years. SCORE and SCORE2 were calculated at baselines following European Society of Cardiology guidelines. A group-based trajectory modelling approach was used for identifying potential life course frailty trajectories, based on 14- and 12-year FI data in the ELSA and HRS. Modified Poisson regression and linear mixed model were applied for analysing associations between SCORE2 with accelerated frailty trajectory and physical function decline, respectively. Receiver operating characteristic curve (ROC) analysis was conducted to evaluate predictive utility for accelerated frailty increase trajectory of SCORE and SCORE2, with the area under the curve (AUC) compared using the paired DeLong's test. RESULTS: A total of 4834 participants from the ELSA and 7815 participants from the HRS were included (mean age: 64.0 ± 9.2 and 65.4 ± 9.9 years; men: 44.3% and 41.4%, respectively). Three frailty trajectories were consistently identified in both cohorts: (1) stable frailty increase (n = 3026 in ELSA and 4004 in HRS); (2) moderate frailty increase (n = 1325 in ELSA and 2955 in HRS); (3) accelerated frailty increase (n = 483 in ELSA and 856 in HRS). Each 10% increment in SCORE2 risk was associated with the higher risk of accelerated frailty increase (risk ratio [RR]: 3.58, 95% confidence interval [CI] [3.22, 3.98], P < 0.001 in ELSA; RR: 1.61, 95% CI [1.56, 1.67], P < 0.001 in HRS) and faster declines in all physical function measurements. SCORE2 algorithm showed good accuracy for predicting accelerated frailty increase (area under the curve [AUC] in ELSA: 0.759; HRS: 0.744), with better performance than the SCORE (AUC in ELSA: 0.729; HRS: 0.700) in both cohorts (P < 0.001 for comparison). CONCLUSIONS: SCORE2 algorithm could serve good utility for predicting life course accelerated frailty increase and physical function decline among community-dwelling non-frail adults aged ≥50 years.

Progression of depressive symptoms after early exposure to famine: The China Health and Retirement Longitudinal Study.

BACKGROUND: The effect of early exposure to famine on progression of depressive symptoms has not been studied and the Chinese Famine offers a unique opportunity to explore this association with its long duration and widespread influence. OBJECTIVE: To investigate the longitudinal association of early famine exposure with subsequent depressive symptoms and whether there existed a critical exposure period. METHODS: Data from the China Health and Retirement Longitudinal Study (CHARLS) were analysed. Famine exposure was evaluated retrospectively in 2014 and severe famine exposure was defined as starvation to death of family members. Depressive symptoms were assessed prospectively from wave 1 (2011-2012) to wave 4 (2018) using the 10-item Center for Epidemiological Studies Depression Scale (CES-D). Linear mixed model and Cox proportional hazards model were applied to evaluate associations of famine exposure with progression or occurrence of depressive symptoms. RESULTS: A total of 7053 participants were included. Compared with no famine exposure, severe famine exposure was associated with a faster growth in CES-D score (0.169 point/year, 95 % CI 0.035 to 0.304, P = 0.013) and an elevated risk of occurrence of depressive symptoms (HR 1.360, 95 % CI 1.069 to 1.729, P = 0.012). Further analysis revealed that famine exposure during middle childhood was associated with a faster growth in CES-D score (0.404 point/year, 95 % CI 0.164 to 0.644, P = 0.001). LIMITATIONS: This is an observational study therefore causal relationship cannot be concluded. CONCLUSIONS: Early exposure to severe famine was associated with aggravation of depressive symptoms. Middle childhood might be a critical time window for depression prevention.