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2.
BMC Geriatr ; 21(1): 692, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34911470

RESUMO

BACKGROUND: Sarcopenia, an age-related disease, has been implicated as both a cause and consequence of type 2 diabetes mellitus (T2DM) and a symbol of poor prognosis in older adults with T2DM. Therefore, early detection and effective treatment of sarcopenia are particularly important in older adults with T2DM. We aimed to investigate the prevalence of sarcopenia in Chinese older T2DM patients and explore whether homocysteine and inflammatory indexes could serve as biomarkers and participate in the development process of sarcopenia. METHODS: T2DM patients aged over 60 years were consecutively recruited from the ward of department of Endocrinology, Xuanwu Hospital between April 2017 and April 2019. Sarcopenia was defined based on the standard of the Asian Working Group of Sarcopenia, including muscle mass, grip strength and gait speed. Logistic regression was used to explore the association between biochemical indicators and sarcopenia. Receiver operating characteristic (ROC) curves were applied to determine the diagnostic effect of these clinical indicators. RESULTS: Totally 582 older adults with T2DM were characterized and analyzed in the study. Approximately 8.9% of the older T2DM patients had sarcopenia. After adjusting for age, sex, body mass index (BMI) and hemoglobin A1c (HbA1c), increased concentrations of homocysteine [odds ratio (OR): 2.829; 95% confidence interval (CI), 1.064-7.525] and high-sensitive C-reactive protein (hs-CRP) (OR: 1.021; 95% CI, 1.001-1.042) were independent predictors of sarcopenia; but not interleukin-6. The combination of age, sex, BMI and HbA1c provided a discriminatory effect of sarcopenia with an area under the curve (AUC) of 0.856, when homocysteine was added to the model, the value of the ROC curve was further improved, with an AUC of 0.861. CONCLUSION: In the current study, we demonstrated a positive correlation of homocysteine, hs-CRP with sarcopenia in older adults with T2DM and the relationship remained significant even after adjustment for HbA1c. These biomarkers (homocysteine and hs-CRP) may play important roles in the pathological process of sarcopenia.


Assuntos
Diabetes Mellitus Tipo 2 , Sarcopenia , Idoso , China , Estudos Transversais , Citocinas , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Força da Mão , Homocisteína , Humanos , Sarcopenia/diagnóstico , Sarcopenia/epidemiologia
3.
J Alzheimers Dis ; 2021 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-34958039

RESUMO

BACKGROUND: Subjective cognitive decline (SCD), an at-risk condition of Alzheimer's disease (AD), can involve various cognitive domains, such as memory, language, planning, and attention. OBJECTIVE: We aims to explore the differences in amyloid load between the single memory domain SCD (sd-SCD) and the multidomain SCD (md-SCD) and assess the relationship of amyloid pathology with quantitative SCD scores and objective cognition. METHODS: A total of 63 SCD participants from the SILCODE study underwent the clinical evaluation, neuropsychological assessment, and 18F-florbetapir PET scan. Global amyloid standard uptake value ratio (SUVr) was calculated. Additionally, regional amyloid SUVr was quantified in 12 brain regions of interests. A nonparametric rank ANCOVA was used to compare the global and regional amyloid SUVr between the md-SCD (n = 34) and sd-SCD (n = 29) groups. A multiple linear regression analysis was conducted to test the relationship of amyloid SUVr with quantitative SCD scores and objective cognition. RESULTS: Compared with individuals with sd-SCD, individuals with md-SCD had increased global amyloid SUVr (F = 5.033, p = 0.029) and regional amyloid SUVr in the left middle temporal gyrus (F = 12.309, p = 0.001; Bonferroni corrected), after controlling for the effects of age, sex, and education. When pooling all SCD participants together, the increased global amyloid SUVr was related with higher SCD-plus sum scores and lower Auditory Verbal Learning Test-delayed recall scores. CONCLUSION: According to our findings, individuals with md-SCD showed higher amyloid accumulation than individuals with sd-SCD, suggesting that md-SCD may experience a more advanced stage of SCD. Additionally, increased global amyloid load was predictive of a poorer episodic memory function in SCD individuals.

4.
Front Neurol ; 12: 720293, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34764927

RESUMO

Multiple studies have identified segregated functional territories in the basal ganglia for the control of goal-directed and habitual actions. It has been suggested that in PD, preferential loss of dopamine in the posterior putamen may cause a major deficit in habitual control (mediated by the sensorimotor cortical-striatal loop), and the patients may therefore be forced into a progressive reliance on the goal-directed behavior (regulated by the associative cortical-striatal loop). Functional evidence supporting this point is scarce at present. This study aims to verify the functional connectivity changes within the sensorimotor, associative, and limbic cortical-striatal loops in PD. Resting-state fMRI of 70 PD patients and 30 controls were collected. Bilateral tripartite functional territories of basal ganglia and their associated cortical structures were chosen as regions of interest, including ventral striatum and ventromedial prefrontal cortex for limbic loop; dorsomedial striatum and dorsolateral prefrontal cortex for associative loop; dorsolateral striatum and sensorimotor cortex for sensorimotor loop. Pearson's correlation coefficients for each seed pair were calculated to obtain the functional connectivity. The relationships between functional connectivity and disease severity were further investigated. Functional connectivity between dorsolateral striatum and sensorimotor cortex is decreased in PD patients, and negatively correlated with disease duration; whereas functional connectivity between dorsomedial striatum and dorsolateral prefrontal cortex is also decreased but postitively correlated with disease duration. The functional connectivity within the sensorimotor loop is pathologically decreased in PD, while the altered connectivity within the associative loop may indicate a failed attempt to compensate for the loss of connectivity within the sensorimotor loop.

5.
Front Aging Neurosci ; 13: 734807, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34759813

RESUMO

Selective depletion of dopaminergic neurotransmission in the caudal sensorimotor striatum, a subdivision implicated in habitual control, is a major pathological feature in Parkinson's disease (PD). Here, we evaluated the effects of PD on the formation of goal-directed and habitual control during learning, and for the first time investigated the conflict between these two strategies in the expression of acquired learning. Twenty PD patients and 20 healthy individuals participated in a set of tasks designed to assess relative goal-directed versus habitual behavioral control. In the instrumental training phase, participants first learned by trial and error to respond to different pictured stimuli in order to gain rewarding outcomes. Three associations were trained, with standard and congruent associations mediated predominantly by goal-directed action, and incongruent association regulated predominantly by habitual control. In a subsequent "slips-of-action" test, participants were assessed to determine whether they can flexibly adjust their behavior to changes in the desirability of the outcomes. A baseline test was then administered to rule out the possibility of general inhibitory deficit, and a questionnaire was finally adopted to test the explicit knowledge of the relationships between stimuli, responses, and outcomes. Our results showed that during the instrumental training phase, PD patients had impaired learning not only of the standard and congruent associations (mediated by goal-directed system), but also the incongruent association (mediated by habitual control system). In the slips-of-action test, PD patients responded less for valuable outcomes and more often to stimuli that were associated with devalued outcomes, with poor performance predicted by symptom severity. No significant difference was found between PD and healthy subjects for the baseline test and questionnaire performance. These results collectively demonstrate that the formation of both goal-directed and habitual control are impaired in PD patients. Furthermore, PD patients are more prone to slips of action, suggesting PD patients exhibit an impairment in engaging the goal-directed system with a relatively excessive reliance on habitual control in the expression of acquired learning.

6.
Front Med (Lausanne) ; 8: 753295, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34651003

RESUMO

Objective: This study aimed to assess the status of intrinsic capacity (IC)-a novel function-centered construct proposed by the WHO and examine whether impairment in IC predicts subsequent 1-year activities of daily living (ADL) disability better than a disease-based approach, i. e., multimorbidity status. Methods: This study included data of community-dwelling older adults from the Beijing Longitudinal Study on Aging II aged 65 years or older who were followed up at 1 year. Multivariate logistic regressions were performed to estimate the odds of ADL disability at baseline and 1-year follow-up. Results: A total of 7,298 older participants aged 65 years or older were included in the current study. About 4,742 older adults were followed up at 1 year. At baseline, subjects with a higher impairment in IC domains showed higher odds of ADL disability [adj. odds ratio (OR) = 9.51 for impairment in ≥3 domains, area under the curve (AUC) = 0.751] compared to much lower odds of ADL disability in subjects with a higher number (≥3) of chronic diseases (adj. OR 3.92, AUC = 0.712). At 1-year follow-up, the overall incidence of ADL disability increased with the impairment in IC domains higher than the increase in multimorbidity status. A higher impairment in IC domains showed higher odds of incidence ADL disability for impairment in 2 or ≥3 IC domains (adj. OR 2.32 for impairment in ≥3 domains, adj. OR 1.43 for impairment in two domains, AUC = 0.685). Only subjects who had ≥3 chronic diseases had higher odds of 1-year incident ADL disability (adj. OR 1.73, AUC = 0.681) that was statistically significant. Conclusion: Our results imply that a function-centered construct could have higher predictability of disability compared to the multimorbidity status in community older people. Our results need to be confirmed by studies with longer follow-up.

7.
Natl Sci Rev ; 8(2): nwaa127, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34691567

RESUMO

Aging-related degeneration of pancreatic islet cells contributes to impaired glucose tolerance and diabetes. Endocrine cells age heterogeneously, complicating the efforts to unravel the molecular drivers underlying endocrine aging. To overcome these obstacles, we undertook single-cell RNA sequencing of pancreatic islet cells obtained from young and aged non-diabetic cynomolgus monkeys. Despite sex differences and increased transcriptional variations, aged ß-cells showed increased unfolded protein response (UPR) along with the accumulation of protein aggregates. We observed transcriptomic dysregulation of UPR components linked to canonical ATF6 and IRE1 signaling pathways, comprising adaptive UPR during pancreatic aging. Notably, we found aging-related ß-cell-specific upregulation of HSP90B1, an endoplasmic reticulum-located chaperone, impeded high glucose-induced insulin secretion. Our work decodes aging-associated transcriptomic changes that underlie pancreatic islet functional decay at single-cell resolution and indicates that targeting UPR components may prevent loss of proteostasis, suggesting an avenue to delaying ß-cell aging and preventing aging-related diabetes.

8.
BMC Geriatr ; 21(1): 606, 2021 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-34702166

RESUMO

BACKGROUND: The objective was to investigate the individual effect and potential interactions of probable rapid eye movement sleep behavior disorder (pRBD) and sleep insufficiency on fall risk among a Chinese elderly population. METHODS: Community-dwelling population aged 55 years or above were recruited from the Beijing Longitudinal Study on Aging II cohort from 2010 to 2011. Odds ratio (ORs) and 95% confidence intervals (CIs) were estimated using multivariate logistic regression models. Multiplicative and additive interactions between pRBD and sleep insufficiency were examined using likelihood ratio tests and relative excess risk due to interaction (RERI), respectively. RESULTS: Among 6891 included participants, 479 experienced at least once fall. pRBD and sleep insufficiency were both independently associated with elevated fall risk. Compared to the elderly without pRBD or sleep insufficiency, pRBD and sleep insufficiency was each associated with a 2.57-fold (OR = 2.57, 95%CI: 1.46-4.31) and 1.45-fold (OR = 1.45, 95%CI: 1.11-1.88) risk of falls individually, while their coexistence was associated with a less-than-additive 17% (OR = 1.17, 95%CI: 0.43-2.63) increased risk of falls. The combination of these two factors demonstrated evidence of a negative interaction on both multiplicative (ratio of ORs = 0.31, 95%CI: 0.10, 0.86) and additive (RERI = - 1.85, 95%CI: - 3.61, - 0.09) scale. CONCLUSIONS: Our study has provided robust evidence for the adverse effect of pRBD and sleep insufficiency, as well as their negative interaction on increasing fall risk in a Chinese elderly population.


Assuntos
Transtorno do Comportamento do Sono REM , Idoso , Humanos , Vida Independente , Estudos Longitudinais , Transtorno do Comportamento do Sono REM/diagnóstico , Transtorno do Comportamento do Sono REM/epidemiologia , Risco , Privação do Sono
9.
Front Neurol ; 12: 678013, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512503

RESUMO

Background: Cognitive impairment is one of the most prominent non-motor symptoms in Parkinson's disease (PD), due in part to known cerebellar dysfunctions. Furthermore, previous studies have reported altered cerebellar functional connectivity (FC) in PD patients. Yet whether these changes are also due to the cognitive deficits in PD remain unclear. Methods: A total of 122 non-dementia participants, including 64 patients with early PD and 58 age- and gender-matched elderly controls were stratified into four groups based on their cognitive status (normal cognition vs. cognitive impairment). Cerebellar volumetry and FC were investigated by analyzing, respectively, structural and resting-state functional MRI data among groups using quality control and quantitative measures. Correlation analysis between MRI metrics and clinical features (motor and cognitive scores) were performed. Results: Compared to healthy control subjects with no cognitive deficits, altered cerebellar FC were observed in early PD participants with both motor and cognitive deficits, but not in PD patients with normal cognition, nor elderly subjects showing signs of a cognitive impairment. Moreover, connectivity between the "motor" cerebellum and SMA was positively correlated with motor scores, while intracerebellar connectivity was positively correlated with cognitive scores in PD patients with cognitive impairment. No cerebellar volumetric difference was observed between groups. Conclusions: These findings show that altered cerebellar FC during resting state in early PD patients may be driven not solely by the motor deficits, but by cognitive deficits as well, hence highlighting the interplay between motor and cognitive functioning, and possibly reflecting compensatory mechanisms, in the early PD.

11.
Brain Inform ; 8(1): 18, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34585306

RESUMO

OBJECTIVES: The literature regarding the use of diffusion-tensor imaging-derived metrics in the evaluation of Parkinson's disease (PD) is controversial. This study attempted to assess the feasibility of a deep-learning-based method for detecting alterations in diffusion kurtosis measurements associated with PD. METHODS: A total of 68 patients with PD and 77 healthy controls were scanned using scanner-A (3 T Skyra) (DATASET-1). Meanwhile, an additional five healthy volunteers were scanned with both scanner-A and an additional scanner-B (3 T Prisma) (DATASET-2). Diffusion kurtosis imaging (DKI) of DATASET-2 had an extra b shell compared to DATASET-1. In addition, a 3D-convolutional neural network (CNN) was trained from DATASET-2 to harmonize the quality of scalar measures of scanner-A to a similar level as scanner-B. Whole-brain unpaired t test and Tract-Based Spatial Statistics (TBSS) were performed to validate the differences between the PD and control groups using the model-fitting method and CNN-based method, respectively. We further clarified the correlation between clinical assessments and DKI results. RESULTS: An increase in mean diffusivity (MD) was found in the left substantia nigra (SN) in the PD group. In the right SN, fractional anisotropy (FA) and mean kurtosis (MK) values were negatively correlated with Hoehn and Yahr (H&Y) scales. In the putamen (Put), FA values were positively correlated with the H&Y scales. It is worth noting that these findings were only observed with the deep learning method. There was neither a group difference nor a correlation with clinical assessments in the SN or striatum exceeding the significance level using the conventional model-fitting method. CONCLUSIONS: The CNN-based method improves the robustness of DKI and can help to explore PD-associated imaging features.

12.
Mov Disord ; 2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34390510

RESUMO

BACKGROUND: China's socioeconomic and population structures have evolved markedly during the past few decades, and consequently, monitoring the prevalence of Parkinson's disease (PD) is crucial. OBJECTIVE: This study aimed to investigate the prevalence of PD within Chinese communities, particularly in older people. METHODS: A nationwide study of 24,117 participants, aged 60 years or older, was carried out in 2015 using multistage clustered sampling. All participants were initially screened using a nine-item questionnaire, from which those suspected of having PD were examined by neurologists and a diagnosis was given, according to the 2015 Movement Disorder Society Clinical Diagnostic Criteria. RESULTS: The prevalence of PD was 1.37% (95% confidence interval 1.02%-1.73%) in people aged over 60 years. Thus, the estimated total number of people in China with PD could be as high as 3.62 million. CONCLUSIONS: Although the PD population prevalence percentage did not change significantly, the total number of PD sufferers has increased with the increased population, which poses a significant challenge in a rapidly aging population. © 2021 International Parkinson and Movement Disorder Society.

13.
Int J Med Sci ; 18(14): 3309-3317, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34400900

RESUMO

Background: Frailty is known to be highly prevalent in older hemodialysis (HD) patients. We studied the prevalence of frailty and its associated factors in Chinese HD patients. We further studied if frailty could predict survival in HD patients. Methods: This is a prospective study involving patients receiving maintenance HD in the dialysis center of Xuanwu Hospital, Beijing. Study subjects were enrolled from October to December, 2017 and followed up for two years. Demographic data, comorbidities and biological parameters were collected. Frailty was assessed using the Fried frailty phenotype at baseline. Cox regression analysis was performed to identify the relationship between frailty and mortality in HD patients. Kaplan-Meier was plotted using the cutoff value obtained by ROC curve to evaluate survival rates in different frailty status. Results: Total of 208 HD patients were enrolled with a mean age of 60.5±12.7 years. According to the frailty criteria, at baseline the prevalence of robust, pre-frail and frail in HD patients was 28.7%, 45.9%, and 25.4%, respectively. The two-year all-cause mortality was 18.8% (39/207) and underlying causes of death included coronary artery disease (CAD), cerebrovascular disease (CVD), hyperkalemia, severe infection, malignant tumor and others. Survival curve showed the patients with frailty score ≥4 to have significantly shorter survival time as compared to patients with frailty score ≤ 3. Frailty predicted two-year mortality when frailty score ≥4 with a sensitivity of 70% and a specificity of 83.67% with an AUC of 0.819. Frailty score was positively associated with age and ratio of ultrafiltration volume to dry weight, while negatively associated with levels of serum albumin, uric acid and diastolic blood pressure after HD. Conclusions: Our results confirm frailty to be very common among HD patients and severity of frailty was a significant predictor of mortality for HD patients. Factors such as age, malnutrition and low blood pressure are the factors to be associated with frailty. Interdialytic weight gain inducing excessive ultrafiltration volume is an important risk factor.

14.
IEEE J Biomed Health Inform ; 25(9): 3564-3575, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34038373

RESUMO

Recent fMRI connectivity-based parcellation (CBP) methods have been developed to obtain homogeneous and functionally coherent brain parcels. However, most of these studies utilize traditional clustering methods that neglect hidden nonlinear features. To enhance parcellation performance, here we propose a deep embedded connectivity-based parcellation (DECBP) framework and apply it to determine functional subdivisions of the striatum in public resting state fMRI data sets. This framework integrates fMRI connectivity features into deep embedded clustering (DEC), a deep neural network based on a stacked autoencoder. Compared to three prevalent clustering methods and their combinations with principal component analysis (PCA), the DECBP exhibited a significantly higher similarity between scans, individuals, and groups, indicating enhanced reproducibility. The generated reliable parcellations were also largely consistent with other public atlases. We further explored the functional subunits in the striatum in a data set from 23 Parkinson's disease (PD) subjects and 27 age-matched healthy controls (HC). All putaminal subregions of PD demonstrated lower interhemispheric connectivity than those of HC, which might reflect imbalance in the pathological progression of PD. Such hypo-connectivity was also observed between putaminal subregions and other brain regions, reflecting neuroimaging manifestations of the altered cortico-striato-thalamo-cortical circuit. These observed weaker couplings were associated with PD severity and duration. Our results support the utilization of the DECBP framework and suggest that abnormal connectivity in putaminal subregions may be a potential indicator of PD.


Assuntos
Doença de Parkinson , Mapeamento Encefálico , Análise por Conglomerados , Humanos , Imageamento por Ressonância Magnética , Vias Neurais , Doença de Parkinson/diagnóstico por imagem , Reprodutibilidade dos Testes
15.
Protein Cell ; 12(9): 695-716, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34052996

RESUMO

The hippocampus plays a crucial role in learning and memory, and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases. Yet a systematic profiling of the aging effects on various hippocampal cell types in primates is still missing. Here, we reported a variety of new aging-associated phenotypic changes of the primate hippocampus. These include, in particular, increased DNA damage and heterochromatin erosion with time, alongside loss of proteostasis and elevated inflammation. To understand their cellular and molecular causes, we established the first single-nucleus transcriptomic atlas of primate hippocampal aging. Among the 12 identified cell types, neural transiently amplifying progenitor cell (TAPC) and microglia were most affected by aging. In-depth dissection of gene-expression dynamics revealed impaired TAPC division and compromised neuronal function along the neurogenesis trajectory; additionally elevated pro-inflammatory responses in the aged microglia and oligodendrocyte, as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for neurogenesis. This rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases.

16.
Front Bioeng Biotechnol ; 9: 627481, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33937213

RESUMO

Patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) are at high risk for conversion to synucleinopathy and Parkinson disease (PD). This can potentially be monitored by measuring gait characteristics of iRBD patients, although quantitative data are scarce and previous studies have reported inconsistent findings. This study investigated subclinical gait changes in polysomnography-proven iRBD patients compared to healthy controls (HCs) during 3 different walking conditions using wearable motor sensors in order to determine whether gait changes can be detected in iRBD patients that could reflect early symptoms of movement disorder. A total 31 iRBD patients and 20 HCs were asked to walk in a 10-m corridor at their usual pace, their fastest pace, and a normal pace while performing an arithmetic operation (dual-task condition) for 1 min each while using a wearable gait analysis system. General gait measurements including stride length, stride velocity, stride time, gait length asymmetry, and gait variability did not differ between iRBD patients and HCs; however, the patients showed decreases in range of motion (P = 0.004) and peak angular velocity of the trunk (P = 0.001) that were significant in all 3 walking conditions. iRBD patients also had a longer step time before turning compared to HCs (P = 0.035), and the difference between groups remained significant after adjusting for age, sex, and height. The decreased trunk motion while walking and increased step time before turning observed in iRBD may be early manifestations of body rigidity and freezing of gait and are possible prodromal symptoms of PD.

17.
Front Psychol ; 12: 631672, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679559

RESUMO

The ability to sequence thoughts and actions is impaired in Parkinson's disease (PD). In PD, a distinct error pattern has been found in the offline performance of sequential working memory. This study examined how PD's performance of sequential working memory unfolds over time using mouse tracking techniques. Non-demented patients with mild PD (N = 40) and healthy controls (N = 40) completed a computerized digit ordering task with a computer mouse. We measured response dynamics in terms of the initiation time, ordering time, movement time, and area under the movement trajectory curve. This approach allowed us to distinguish between the cognitive processes related to sequence processing before the actual movement (initiation time and ordering time) and the execution processes of the actual movement (movement time and area under the curve). PD patients showed longer initiation times, longer movement times, and more constrained movement trajectories than healthy controls. The initiation time and ordering time negatively correlated with the daily exposure to levodopa and D2/3 receptor agonists, respectively. The movement time positively correlated with the severity of motor symptoms. We demonstrated an altered temporal profile of sequential working memory in PD. Stimulating D1 and D2/3 receptors might speed up the maintenance and manipulation of sequences, respectively.

18.
Alzheimers Res Ther ; 13(1): 62, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731209

RESUMO

BACKGROUND: New therapies are urgently needed for Alzheimer's disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide with a novel proposed mechanism of action. The first phase 3 clinical trial of GV-971 has been completed in China. METHODS: We conducted a phase 3, double-blind, placebo-controlled trial in participants with mild-to-moderate AD to assess GV-971 efficacy and safety. Participants were randomized to placebo or GV-971 (900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, and Neuropsychiatric Inventory (NPI). Safety and tolerability were monitored. RESULTS: A total of 818 participants were randomized: 408 to GV-971 and 410 to placebo. A significant drug-placebo difference on the ADAS-Cog12 favoring GV-971 was present at each measurement time point, measurable at the week 4 visit and continuing throughout the trial. The difference between the groups in change from baseline was - 2.15 points (95% confidence interval, - 3.07 to - 1.23; p < 0.0001; effect size 0.531) after 36 weeks of treatment. Treatment-emergent adverse event incidence was comparable between active treatment and placebo (73.9%, 75.4%). Two deaths determined to be unrelated to drug effects occurred in the GV-971 group. CONCLUSIONS: GV-971 demonstrated significant efficacy in improving cognition with sustained improvement across all observation periods of a 36-week trial. GV-971 was safe and well-tolerated. TRIAL REGISTRATION: ClinicalTrials.gov, NCT0229391 5. Registered on November 19, 2014.


Assuntos
Doença de Alzheimer , Preparações Farmacêuticas , Atividades Cotidianas , Doença de Alzheimer/tratamento farmacológico , China , Inibidores da Colinesterase , Método Duplo-Cego , Humanos , Manose/análogos & derivados , Oligossacarídeos , Sódio , Resultado do Tratamento
19.
Cell Death Dis ; 12(1): 81, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441545

RESUMO

Iron deposition is present in main lesion areas in the brains of patients with Parkinson's disease (PD) and an abnormal iron content may be associated with dopaminergic neuronal cytotoxicity and degeneration in the substantia nigra of the midbrain. However, the cause of iron deposition and its role in the pathological process of PD are unclear. In the present study, we investigated the effects of the nasal mucosal delivery of synthetic human α-synuclein (α-syn) preformed fibrils (PFFs) on the pathogenesis of PD in Macaca fascicularis. We detected that iron deposition was clearly increased in a time-dependent manner from 1 to 17 months in the substantia nigra and globus pallidus, highly contrasting to other brain regions after treatments with α-syn PFFs. At the cellular level, the iron deposits were specifically localized in microglia but not in dopaminergic neurons, nor in other types of glial cells in the substantia nigra, whereas the expression of transferrin (TF), TF receptor 1 (TFR1), TF receptor 2 (TFR2), and ferroportin (FPn) was increased in dopaminergic neurons. Furthermore, no clear dopaminergic neuron loss was observed in the substantia nigra, but with decreased immunoreactivity of tyrosine hydroxylase (TH) and appearance of axonal swelling in the putamen. The brain region-enriched and cell-type-dependent iron localizations indicate that the intranasal α-syn PFFs treatment-induced iron depositions in microglia in the substantia nigra may appear as an early cellular response that may initiate neuroinflammation in the dopaminergic system before cell death occurs. Our data suggest that the inhibition of iron deposition may be a potential approach for the early prevention and treatment of PD.


Assuntos
Microglia/metabolismo , Substância Negra/metabolismo , alfa-Sinucleína/administração & dosagem , Administração Intranasal , Animais , Humanos , Macaca fascicularis , Masculino , Microglia/efeitos dos fármacos , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/terapia , Substância Negra/efeitos dos fármacos
20.
BMC Geriatr ; 21(1): 14, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407187

RESUMO

BACKGROUND: With the extended life expectancy of the Chinese population and improvements in surgery and anesthesia techniques, the number of aged patients undergoing surgery has been increasing annually. However, safety, effectiveness, and quality of life of aged patients undergoing surgery are facing major challenges. In order to standardize the perioperative assessment and procedures, we have developed a perioperative evaluation and auxiliary decision-making system named "Aged Patient Perioperative Longitudinal Evaluation-Multidisciplinary Trial (APPLE-MDT)". METHODS: We will conduct a perioperative risk evaluation and targeted intervention, with follow-ups at 1, 3, and 6 months after surgery. The primary objective of the study is to evaluate the effectiveness of the "Aged Patient Perioperative Longitudinal Evaluation-Multiple Disciplinary Trial Path" (hereinafter referred to as the APPLE-MDT path) in surgical decision-making for aged patients (≥75 years) undergoing elective surgery under non-local anesthesia in the operating room. The secondary objectives of the study are to evaluate the postoperative outcome and health economics of the APPLE-MDT path applied to the surgical decision-making of aged patients (≥75 years) undergoing elective surgery under non-local anesthesia and to optimize intervention strategies for aged patients undergoing surgery to reduce the occurrence of postoperative complications and improve the quality of life after surgery. DISCUSSION: It is necessary to formulate a reliable, effective, and concise evaluation tool, which can effectively predict the perioperative complications and mortality of aged patients, support targeted intervention strategies, and allow for a more comprehensive risk and benefit analysis, thereby forming an effective senile perioperative surgery management path. It is expected that the implementation of this protocol can reduce the occurrence of postoperative complications, improve the postoperative quality of life, shorten hospital stay, reduce hospitalization expenses, reduce social burden, and allow the elderly to have a good quality of life after surgery. TRIAL REGISTRATION: ChiCTR, ChiCTR1800020363 , Registered 15 December 2018.


Assuntos
Procedimentos Cirúrgicos Eletivos , Qualidade de Vida , Idoso , Humanos , Tempo de Internação , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Projetos de Pesquisa
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