Prevalence and risk factors for subjective cognitive decline and the correlation with objective cognition among community-dwelling older adults in China: Results from the Hubei memory and aging cohort study.

INTRODUCTION: The prevalence and risk factors for subjective cognitive decline (SCD) and its correlation with objective cognition decline (OCD) among community-dwelling older adults is inconsistent. METHODS: Older adults underwent neuropsychological and clinical evaluations to reach a consensus on diagnoses. RESULTS: This study included 7486 adults without mild cognitive impairment and dementia (mean age: 71.35 years [standard deviation = 5.40]). The sex-, age-, and residence-adjusted SCD prevalence was 58.33% overall (95% confidence interval: 58.29% to 58.37%), with higher rates of 61.25% and 59.87% in rural and female subgroups, respectively. SCD global and OCD language, SCD memory and OCD global, SCD and OCD memory, and SCD and OCD language were negatively correlated in fully adjusted models. Seven health and lifestyle factors were associated with an increased risk for SCD. DISCUSSION: SCD affected 58.33% of older adults and may indicate concurrent OCD, which should prompt the initiation of preventative intervention for dementia. HIGHLIGHTS: SCD affects 58.33% of older adults in China. SCD may indicate concurrent objective cognitive decline. Difficulty finding words and memory impairments may indicate a risk for AD. The presence of SCD may prompt preventative treatment initiation of MCI or dementia. Social network factors may be initial targets for the early prevention of SCD.

Degradation of FA reduces Aß neurotoxicity and Alzheimer-related phenotypes.

Dysregulation of formaldehyde (FA) has been implicated in the development of Alzheimer's Disease (AD). Elevated FA levels in Alzheimer's patients and animal models are associated with impaired cognitive functions. However, the exact role of FA in AD remains unknown. We now identified that oxidative demethylation at serine8/26 of amyloid-beta protein (Aß) induced FA generation and FA cross-linked with the lysine28 residue in the ß-turn of Aß monomer to form Aß dimers, and then accelerated Aß oligomerization and fibrillogenesis in vitro. However, Aß42 mutation in serine8/26, lysine28 abolished Aß self-aggregation. Furthermore, Aß inhibited the activity of formaldehyde dehydrogenase (FDH), the enzyme for FA degradation, resulting in FA accumulation. In turn, excess of FA stimulated Aß aggregation both in vitro and in vivo by increasing the formation of Aß oligomers and fibrils. We found that degradation of FA by formaldehyde scavenger-NaHSO3 or coenzyme Q10 reduced Aß aggregation and ameliorated the neurotoxicity, and improved the cognitive performance in APP/PS1 mice. Our study provides evidence that endogenous FA is essential for Aß self-aggregation and scavenging FA could be an effective strategy for treating AD.

5-Demethoxy-10'-ethoxyexotimarin F, a New Coumarin with MAO-B Inhibitory Potential from Murraya exotica L.

Rutaceae plants are known for being a rich source of coumarins. Preliminary molecular docking showed that there was no significant difference for coumarins in Clausena and Murraya, both of which had high scoring values and showed good potential inhibitory activity to the MAO-B enzyme. Overall, 32 coumarins were isolated from Murraya exotica L., including a new coumarin 5-demethoxy-10'-ethoxyexotimarin F (1). Their structures were elucidated on the basis of a comprehensive analysis of 1D and 2D NMR and HRMS spectroscopic data, and the absolute configurations were assigned via a comparison of the specific rotations and the ECD exciton coupling method. The potential of new coumarin (1) as a selective inhibitor of MAO-B was initially evaluated through molecular docking and pharmacophore studies. Compound (1) showed selectivity for the MAO-B isoenzyme and inhibitory activity in the sub-micromolar range with an IC50 value of 153.25 ± 1.58 nM (MAO-B selectivity index > 172).

Effect of Health-Related Uncertainty and Natural Variability on Health Impacts and Cobenefits of Climate Policy.

Climate policy can mitigate health risks attributed to intensifying air pollution under climate change. However, few studies quantify risks of illness and death, examine their contribution to climate policy benefits, or assess their robustness in light of natural climate variability. We employ an integrated modeling framework of the economy, climate, air quality, and human health to quantify the effect of natural variability on U.S. air pollution impacts under future climate and two global policies (2 and 2.5 °C stabilization scenarios) using 150 year ensemble simulations for each scenario in 2050 and 2100. Climate change yields annual premature deaths related to fine particulate matter and ozone (95CI: 25 000-120 000), heart attacks (900-9400), and lost work days (3.6M-4.9M) in 2100. It raises air pollution health risks by 20%, while policies avert these outcomes by 40-50% in 2050 and 70-88% in 2100. Natural variability introduces "climate noise", yielding some annual estimates with negative cobenefits, and others that reach 100% of annual policy costs. This "noise" is three times the magnitude of uncertainty (95CI) in health and economic responses in 2050. Averaging five annual simulations reduces this factor to two, which is still substantially larger than health-related uncertainty. This study quantifies the potential for inaccuracy in climate impacts projected using too few annual simulations.

Ablating ErbB4 in PV neurons attenuates synaptic and cognitive deficits in an animal model of Alzheimer's disease.

Accumulation of amyloid ß (Aß) induces neuronal, synaptic, and cognitive deficits in patients and animal models of Alzheimer's disease (AD). The underlying mechanisms, however, remain to be fully elucidated. In the present study, we found that Aß interacted with ErbB4, a member of the receptor tyrosine kinase family and mainly expressed in GABAergic interneurons. Deleting ErbB4 in parvalbumin-expressing neurons (PV neurons) significantly attenuated oligomeric Aß-induced suppression of long term potentiation (LTP). Furthermore, specific ablation of ErbB4 in PV neurons via Cre/loxP system greatly improved spatial memory and synaptic plasticity in the hippocampus of hAPP-J20 mice. The deposition of Aß detected by 3D6 and Thioflavin S staining and the proteolytic processing of hAPP analyzed by western blotting were not affected in the hippocampus of hAPP-J20 mice by deleting ErbB4 in PV neurons. Our data suggested that ErbB4 in PV neurons mediated Aß-induced synaptic and cognitive dysfunctions without affecting Aß levels.

[Toxic effect of formaldehyde on mouse different brain regions].

The aim of this study was to explore the mechanism of the nervous system lesions induced by formaldehyde (FA). Male Balb/c mice were exposed to gaseous formaldehyde for 7 days (8 h/d) with three different concentrations (0, 0.5 and 3.0 mg/m(3)). A group of animals injected with the nitric oxide synthase inhibitor L-NMMA (0.01 mL/g) was also set and exposed to 3.0 mg/m(3) FA. The concentrations of cAMP, cGMP, NO and the activity of NOS in cerebral cortex, hippocampus and brain stem were determined by corresponding assay kits. The results showed that, compared with the control (0 mg/m(3) FA) group, the cAMP contents in cerebral cortex and brain stem were significantly increased in 0.5 mg/m(3) FA group (P < 0.05), but decreased in 3.0 mg/m(3) FA group (P < 0.05); The concentration of cAMP in hippocampus was significantly decreased in 3.0 mg/m(3) FA group (P < 0.05). In comparison with the control group, L-NMMA group showed unchanged cAMP contents and NOS activities in different brain regions, but showed increased cGMP contents in hippocampus and NO contents in cerebral cortex (P < 0.05). In addition, compared with 3.0 mg/m(3) FA group, L-NMMA group showed increased contents of cAMP and reduced NOS activities in different brain regions, as well as significantly decreased cGMP contents in cerebral cortex and brain stem and NO content in brain stem. These results suggest that the toxicity of FA on mouse nervous system is related to NO/cGMP and cAMP signaling pathways.

Association Between Long-Term Exposure to Ambient Air Pollution and the Risk of Mild Cognitive Impairment in a Chinese Urban Area: A Case-Control Study.

Background: As a prodromal stage of dementia, significant emphasis has been placed on the identification of modifiable risks of mild cognitive impairment (MCI). Research has indicated a correlation between exposure to air pollution and cognitive function in older adults. However, few studies have examined such an association among the MCI population inChina. Objective: We aimed to explore the association between air pollution exposure and MCI risk from the Hubei Memory and Aging Cohort Study. Methods: We measured four pollutants from 2015 to 2018, 3 years before the cognitive assessment of the participants. Logistic regression models were employed to calculate odds ratios (ORs) to assess the relationship between air pollutants and MCI risk. Results: Among 4,205 older participants, the adjusted ORs of MCI risk for the highest quartile of PM2.5, PM10, O3, and SO2 were 1.90 (1.39, 2.62), 1.77 (1.28, 2.47), 0.56 (0.42, 0.75), and 1.18 (0.87, 1.61) respectively, compared with the lowest quartile. Stratified analyses indicated that such associations were found in both males and females, but were more significant in older participants. Conclusions: Our findings are consistent with the growing evidence suggesting that air pollution increases the risk of mild cognitive decline, which has considerable guiding significance for early intervention of dementia in the older population. Further studies in other populations and broader geographical areas are warranted to validate these findings.

Aberrant serotonergic signaling contributes to the hyperexcitability of CA1 pyramidal neurons in a mouse model of Alzheimer's disease.

Hyperactivity of pyramidal neurons (PNs) in CA1 is an early event in Alzheimer's disease. However, factors accounting for the hyperactivity of CA1 PNs remain to be completely investigated. In the present study, we report that the serotonergic signaling is abnormal in the hippocampus of hAPP-J20 mice. Interestingly, chemogenetic activation of serotonin (5-hydroxytryptamine; 5-HT) neurons in the median raphe nucleus (MRN) attenuates the activity of CA1 PNs in hAPP-J20 mice by regulating the intrinsic properties or inhibitory synaptic transmission of CA1 PNs through 5-HT3aR and/or 5-HT1aR. Furthermore, activating MRN 5-HT neurons improves memory in hAPP-J20 mice, and this effect is mediated by 5-HT3aR and 5-HT1aR. Direct activation of 5-HT3aR and 5-HT1aR with their selective agonists also improves the memory of hAPP-J20 mice. Together, we identify the impaired 5-HT/5-HT3aR and/or 5-HT/5-HT1aR signaling as pathways contributing to the hyperexcitability of CA1 PNs and the impaired cognition in hAPP-J20 mice.

Modulating adult neurogenesis affects synaptic plasticity and cognitive functions in mouse models of Alzheimer's disease.

New neurons are abnormal in the adult hippocampus of Alzheimer's disease (AD) mouse models. The effects of modulating adult neurogenesis on AD pathogenesis differ from study to study. We reported recently that ablation of adult neural stem cells (aNSCs) was associated with improved memory in AD models. Here, we found that long-term potentiation (LTP) was improved in the hippocampus of APP/PS1 mice after ablation of aNSCs. This effect was confirmed in hAPP-J20 mice, a second AD mouse model. On the other hand, we found that exposure to enriched environment (EE) dramatically increased the number of DCX+ neurons, promoted dendritic growth, and affected the location of newborn neurons in the dentate gyrus of APP/PS1 mice, and EE exposure significantly ameliorated memory deficits in APP/PS1 mice. Together, our data suggest that both inhibiting abnormal adult neurogenesis and enhancing healthy adult neurogenesis could be beneficial for AD, and they are not mutually exclusive.

Ablating Adult Neural Stem Cells Improves Synaptic and Cognitive Functions in Alzheimer Models.

Adult neurogenesis is impaired in the hippocampus of patients with Alzheimer disease (AD) as well as AD models. However, it is far from clear how modulating adult neurogenesis affects AD neuropathology. We confirm that adult hippocampal neurogenesis is impaired in two AD models. Surprisingly, however, cognitive functions are improved in AD models after ablating adult neural stem cells (aNSCs). Ablation of aNSCs does not affect the levels of amyloid ß but restores the normal synaptic transmission in the dentate gyrus (DG) granule cells of AD models. Furthermore, calbindin depletion in the DG of AD mice is ameliorated after aNSC ablation, and knocking down calbindin abolishes the effects of aNSC ablation on synaptic and cognitive functions of AD mice. Together, our data suggest that cognitive functions of AD mice are improved after aNSC ablation, which is associated with the restoration of synaptic transmission in the DG granule cells with calbindin as an important mediator.

Accumulation of formaldehyde causes motor deficits in an in vivo model of hindlimb unloading.

During duration spaceflight, or after their return to earth, astronauts have often suffered from gait instability and cerebellar ataxia. Here, we use a mouse model of hindlimb unloading (HU) to explore a mechanism of how reduced hindlimb burden may contribute to motor deficits. The results showed that these mice which have experienced HU for 2 weeks exhibit a rapid accumulation of formaldehyde in the gastrocnemius muscle and fastigial nucleus of cerebellum. The activation of semicarbazide-sensitive amine oxidase and sarcosine dehydrogenase induced by HU-stress contributed to formaldehyde generation and loss of the abilities to maintain balance and coordinate motor activities. Further, knockout of formaldehyde dehydrogenase (FDH-/-) in mice caused formaldehyde accumulation in the muscle and cerebellum that was associated with motor deficits. Remarkably, formaldehyde injection into the gastrocnemius muscle led to gait instability; especially, microinfusion of formaldehyde into the fastigial nucleus directly induced the same symptoms as HU-induced acute ataxia. Hence, excessive formaldehyde damages motor functions of the muscle and cerebellum.

Illumination with 630 nm Red Light Reduces Oxidative Stress and Restores Memory by Photo-Activating Catalase and Formaldehyde Dehydrogenase in SAMP8 Mice.

AIMS: Pharmacological treatments for Alzheimer's disease (AD) have not resulted in desirable clinical efficacy over 100 years. Hydrogen peroxide (H2O2), a reactive and the most stable compound of reactive oxygen species, contributes to oxidative stress in AD patients. In this study, we designed a medical device to emit red light at 630 ± 15 nm from a light-emitting diode (LED-RL) and investigated whether the LED-RL reduces brain H2O2 levels and improves memory in senescence-accelerated prone 8 mouse (SAMP8) model of age-related dementia. RESULTS: We found that age-associated H2O2 directly inhibited formaldehyde dehydrogenase (FDH). FDH inactivity and semicarbazide-sensitive amine oxidase (SSAO) disorder resulted in endogenous formaldehyde (FA) accumulation. Unexpectedly, excess FA, in turn, caused acetylcholine (Ach) deficiency by inhibiting choline acetyltransferase (ChAT) activity in vitro and in vivo. Interestingly, the 630 nm red light can penetrate the skull and the abdomen with light penetration rates of ∼49% and ∼43%, respectively. Illumination with LED-RL markedly activated both catalase and FDH in the brains, cultured cells, and purified protein solutions, all reduced brain H2O2 and FA levels and restored brain Ach contents. Consequently, LED-RL not only prevented early-stage memory decline but also rescued late-stage memory deficits in SAMP8 mice. INNOVATION: We developed a phototherapeutic device with 630 nm red light, and this LED-RL reduced brain H2O2 levels and reversed age-related memory disorders. CONCLUSIONS: The phototherapy of LED-RL has low photo toxicity and high rate of tissue penetration and noninvasively reverses aging-associated cognitive decline. This finding opens a promising opportunity to translate LED-RL into clinical treatment for patients with dementia. Antioxid. Redox Signal. 00, 000-000.

New insight into Alzheimer's disease: Light reverses Aß-obstructed interstitial fluid flow and ameliorates memory decline in APP/PS1 mice.

INTRODUCTION: Pharmacological therapies to treat Alzheimer's disease (AD) targeting "Aß" have failed for over 100 years. Low levels of laser light can disassemble Aß. In this study, we investigated the mechanisms that Aß-blocked extracellular space (ECS) induces memory disorders in APP/PS1 transgenic mice and addressed whether red light (RL) at 630 nm rescues cognitive decline by reducing Aß-disturbed flow of interstitial fluid (ISF). METHODS: We compared the heating effects on the brains of rats illuminated with laser light at 630, 680, and 810 nm for 40 minutes, respectively. Then, a light-emitting diode with red light at 630 nm (LED-RL) was selected to illuminate AD mice. The changes in the structure of ECS in the cortex were examined by fluorescent double labeling. The volumes of ECS and flow speed of ISF were quantified by magnetic resonance imaging. Spatial memory behaviors in mice were evaluated by the Morris water maze. Then, the brains were sampled for biochemical analysis. RESULTS: RL at 630 nm had the least heating effects than other wavelengths associated with ~49% penetration ratio into the brains. For the molecular mechanisms, Aß could induce formaldehyde (FA) accumulation by inactivating FA dehydrogenase. Unexpectedly, in turn, FA accelerated Aß deposition in the ECS. However, LED-RL treatment not only directly destroyed Aß assembly in vitro and in vivo but also activated FA dehydrogenase to degrade FA and attenuated FA-facilitated Aß aggregation. Subsequently, LED-RL markedly smashed Aß deposition in the ECS, recovered the flow of ISF, and rescued cognitive functions in AD mice. DISCUSSION: Aß-obstructed ISF flow is the direct reason for the failure of the developed medicine delivery from superficial into the deep brain in the treatment of AD. The phototherapy of LED-RL improves memory by reducing Aß-blocked ECS and suggests that it is a promising noninvasive approach to treat AD.

Ablation of ErbB4 in parvalbumin-positive interneurons inhibits adult hippocampal neurogenesis through down-regulating BDNF/TrkB expression.

Parvalbumin (PV) positive interneurons in the subgranular zone (SGZ) can regulate adult hippocampal neurogenesis. ErbB4 is mainly expressed in PV neurons in the hippocampus and is crucial for keeping normal function of PV neurons. However, whether ErbB4 in PV interneurons affects the adult hippocampal neurogenesis remains unknown. In the present study, we deleted ErbB4 specifically in PV neurons by crossing PV-Cre mice with ErbB4f/f mice. Results of BrdU labeling and NeuN staining revealed that the proliferation of neural progenitors was increased but the survival and maturation of newborn neurons were decreased in the hippocampus of mice after deleting ErbB4 in PV neurons, suggesting that ErbB4 in PV neurons is closely associated with the process of adult hippocampal neurogenesis. Interestingly, the expression of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), was significantly decreased in the hippocampus of ErbB4-deleted mice. Together, our data suggested that ErbB4 in PV neurons might modulate adult hippocampal neurogenesis by affecting BDNF-TrkB signaling pathway.

Reduction of Endogenous Melatonin Accelerates Cognitive Decline in Mice in a Simulated Occupational Formaldehyde Exposure Environment.

Individuals afflicted with occupational formaldehyde (FA) exposure often suffer from abnormal behaviors such as aggression, depression, anxiety, sleep disorders, and in particular, cognitive impairments. Coincidentally, clinical patients with melatonin (MT) deficiency also complain of cognitive problems associated with the above mental disorders. Whether and how FA affects endogenous MT metabolism and induces cognitive decline need to be elucidated. To mimic occupational FA exposure environment, 16 healthy adult male mice were exposed to gaseous FA (3 mg/m³) for 7 consecutive days. Results showed that FA exposure impaired spatial memory associated with hippocampal neuronal death. Biochemical analysis revealed that FA exposure elicited an intensive oxidative stress by reducing systemic glutathione levels, in particular, decreasing brain MT concentrations. Inversely, intraperitoneal injection of MT markedly attenuated FA-induced hippocampal neuronal death, restored brain MT levels, and reversed memory decline. At tissue levels, injection of FA into the hippocampus distinctly reduced brain MT concentrations. Furthermore, at cellular and molecular levels, we found that FA directly inactivated MT in vitro and in vivo. These findings suggest that MT supplementation contributes to the rescue of cognitive decline, and may alleviate mental disorders in the occupational FA-exposed human populations.

Aging-associated formaldehyde-induced norepinephrine deficiency contributes to age-related memory decline.

A norepinephrine (NE) deficiency has been observed in aged rats and in patients with Alzheimer's disease and is thought to cause cognitive disorder. Which endogenous factor induces NE depletion, however, is largely unknown. In this study, we investigated the effects of aging-associated formaldehyde (FA) on the inactivation of NE in vitro and in vivo, and on memory behaviors in rodents. The results showed that age-related DNA demethylation led to hippocampal FA accumulation, and when this occurred, the hippocampal NE content was reduced in healthy male rats of different ages. Furthermore, biochemical analysis revealed that FA rapidly inactivated NE in vitro and that an intrahippocampal injection of FA markedly reduced hippocampal NE levels in healthy adult rats. Unexpectedly, an injection of FA (at a pathological level) or 6-hydroxydopamine (6-OHDA, a NE depletor) can mimic age-related NE deficiency, long-term potentiation (LTP) impairments, and spatial memory deficits in healthy adult rats. Conversely, an injection of NE reversed age-related deficits in both LTP and memory in aged rats. In agreement with the above results, the senescence-accelerated prone 8 (SAMP8) mice also exhibited a severe deficit in LTP and memory associated with a more severe NE deficiency and FA accumulation, when compared with the age-matched, senescence-resistant 1 (SAMR1) mice. Injection of resveratrol (a natural FA scavenger) or NE into SAMP8 mice reversed FA accumulation and NE deficiency and restored the magnitude of LTP and memory. Collectively, these findings suggest that accumulated FA is a critical endogenous factor for aging-associated NE depletion and cognitive decline.