Effect modification by aging on the associations of nicotine exposure with cognitive impairment among Chinese elderly.

Active and passive exposure to tobacco smoke may increase risk of cognitive decline. However, effects of enhanced the aging process on the association of urinary nicotine metabolites with cognitive impairment remain unclear. In this study, 6657 Chinese older adults completed the physical examinations and cognitive tests. We measured urinary nicotine metabolite levels, mitochondrial DNA copy number (mtDNA-CN), and relative telomere length (RTL) and analyzed effects of urinary nicotine metabolites and their interaction with mtDNA-CN or RTL on cognitive impairment by generalized linear models and qg-computation, respectively. Each 1-unit increase in urinary 3-OHCot, 3-OHCotGluc, CotGluc, or NicGluc levels corresponded to a 1.05-, 1.09-, 1.04-, and 0.90-fold increased risk of cognitive impairment. Each 1-quantile increment in the mixture level of 8 nicotine metabolites corresponded to an increment of 1.40- and 1.34-fold risk of cognitive impairment in individuals with longer RTL or low mtDNA-CN. Urinary 3-OHCotGluc and RTL or mtDNA-CN exhibited an additive effect on cognitive impairment in addition to the mixture of 8 nicotine metabolites and mtDNA-CN. The findings suggested that aging process may increase the risk of tobacco-related cognitive impairment.

Non-linear dose-response relation between urinary levels of nicotine and its metabolites and cognitive impairment among an elderly population in China.

BACKGROUND: Active smoking and exposure to environmental tobacco smoke may be related to cognitive function decline. We assessed the associations of urinary levels of nicotine and its metabolites with cognitive function. METHODS: A total of 553 elder adults at high risk of cognitive impairment and 2212 gender- and age-matched individuals at low risk of cognitive impairment were selected at a ratio of 1: 4 from the remained individuals (n = 6771) who completed the baseline survey of the Shenzhen Ageing-Related Disorder Cohort, after excluding those with either Alzheimer's disease, Parkinson's syndrome or stroke as well as those with missing data on variables (including active and passive smoking status, Mini-Cog score). Urinary levels of nicotine and its metabolites and cognitive function for all individuals were measured by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) and assessed using the Mini-Cog test, respectively. Associations of urinary levels of nicotine and its metabolites with cognitive function were analyzed by conditional logistic regression models. RESULTS: Individuals in the highest tertile of urinary OHCotGluc (OR: 1.52, 95%CI: 1.19-1.93) or NNO (OR: 1.50, 95%CI: 1.16-1.93) levels as well as in the second tertile of urinary ∑Nic level (OR: 1.43, 95%CI: 1.13-1.82) were at higher risk of cognitive impairment compared with those in the corresponding lowest tertile. Restricted cubic spline models revealed the non-linear dose-response relationships between urinary levels of OHCotGluc, NNO or ∑Nic and the risk of cognitive impairment. CONCLUSIONS: Urinary levels of OHCotGluc, NNO or ∑Nic exhibited a non-linear dose-response relationship with cognitive function in the urban elderly.

Identification of two pathogenic mutations in SORL1 in early-onset Alzheimer's disease.

The sortilin-related receptor 1 (SORL1) gene has been the subject of many studies focusing on frequent polymorphisms, which is associated with increased risk for Alzheimer's Disease (AD). By whole-exome sequencing (WES), we identified two pathogenic missense mutations c.579C > G (p.F193L) and c.1397A > G (p.N466S) in SORL1. The two mutations were located in the same protein domain, and the two unrelated probands both had an onset of memory problems at less than 65 years of age, but their clinical manifestations and cranial imaging are different. The protein structure and function affected by these mutations were predicted using bioinformatics analysis, which suggested they were pathogenic. 3D protein structural analysis revealed that these amino acid substitutions might result in instability of protein structure and adverse intramolecular interactions. These findings suggest that both F193L and N466S should be thought as potential causative mutations in early-onset Alzheimer's disease (EOAD) patients. Further functional studies are warranted to evaluate their roles in the pathogenesis of AD.

SORL1 mutations are associated with parkinsonian and psychiatric features in Alzheimer disease: Case reports.

RATIONALE: The sortilin-related receptor 1 gene (SORL1) encodes a key protein (SORLA) involved in the pathophysiology of Alzheimer disease (AD). SORLA also mediates a trophic pathway that acts through glial cell line-derived neurotrophic factor (GDNF), a critical survival factor for the midbrain dopaminergic (DA) neurons. PATIENT CONCERNS: Four patients presented to our hospital with complaints of progressive memory decline, who developed extrapyramidal signs (EPS) and psychiatric symptoms. DIAGNOSES: All 4 patients were diagnosed with AD based on their symptoms, findings from cranial magnetic resonance imaging, and cerebrospinal fluid analysis. INTERVENTIONS: We also performed whole-exome sequencing (WES) and found 4 novel mutations in SORL1. Donepezil, rivastigmine, memantine, madopar, quetiapine, and risperidone were administrated as therapy. OUTCOMES: The four mutations would change the thermal stability of SORLA domain. This could be associated with parkinsonian and psychiatric features in AD. These patients showed improvements in parkinsonian and psychiatric features. LESSONS: These cases suggest that SORL1 mutations might result in aggregation of a-synuclein through altered function of GDNF and further lead to appearance of core dementia with Lewy bodies features.

Berberine Protects Secondary Injury in Mice with Traumatic Brain Injury Through Anti-oxidative and Anti-inflammatory Modulation.

Traumatic brain injury (TBI) is one of the major causes of death and disability worldwide. Novel and effective therapy is needed to prevent the secondary spread of damage beyond the initial injury. The aim of this study was to investigate whether berberine has a neuroprotective effect on secondary injury post-TBI, and to explore its potential mechanism in this protection. The mice were randomly divided into Sham-saline, TBI-saline and TBI-Berberine (50 mg/kg). TBI was induced by Feeney's weight-drop technique. Saline or berberine was administered via oral gavage starting 1 h post-TBI and continuously for 21 days. Motor coordination, spatial learning and memory were assessed using beam-walking test and Morris water maze test, respectively. Brain sections were processed for lesion volume assessment, and expression of neuronal nuclei (NeuN), cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS), 8-hydroxy-2-deoxyguanosine (8-OHdG), ionized calcium-binding adapter molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) were detected via immunohistochemistry and immunofluorescence. There were statistically significant improvement in motor coordination, spatial learning and memory in the TBI-Berberine group, compared to the TBI-saline group. Treatment with berberine significantly reduced cortical lesion volume, neuronal loss, COX-2, iNOS and 8-OHdG expression in both the cortical lesion border zone (LBZ) and ipsilateral hippocampal CA1 region (CA1), compared to TBI-saline. Berberine treatment also significantly decreased Iba1- and GFAP-positive cell number in both the cortical LBZ and ipsilateral CA1, relative to saline controls. These results indicated that berberine exerted neuroprotective effects on secondary injury in mice with TBI probably through anti-oxidative and anti-inflammatory properties.

[A historic cohort study on the survival rate and the correlated risk factors regarding 174 patients with subarachnoid hemorrhage].

OBJECTIVE: To describe the survival state and to investigate the risk factors of death on patients with subarachnoid hemorrhage (SAH). METHODS: Age, past history, number of encephalic region suffering SAH, laboratory examination indexes, therapeutic measures, complications and prognosis of 174 patients with SAH were followed-up and investigated. The survival states and risk factors of death of the patients with SAH were identified by both Kaplan-Meier survival analysis and Cox proportional risk model. RESULTS: There were 10 patients (5.75%) losing follow-up investigation and 164 patients with SAH completed the follow-up investigation. 66 patients died and the longest follow-up investigation time was 5.64 years. The survival rates of 28 days, 1 year and 3-5 years were 70.60%, 63.40% and 57.20% respectively. The treatment of nimotop, aneurysm occlusion treatment and aneurysm embolotherapy could decrease the death of SAH. At the same time, advanced age, the long time smoking, hyponatremia, the rising of leucocyte in acute stage, repeated hemorrhage and cerebral angio spasm were the independent risk factors to the death of patients. CONCLUSION: Prognosis of patients with advanced age, the rising of leucocyte in acute stage, gastrointestinal blooding, hyponatremia, repeated hemorrhage and cerebral angio spasm were unfavorable. When giving patients with aneurysm, the aneurysm occlusion and embolotherapy and nimotop treatment, the death risk could be reduced.