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OBJECTIVES: To investigate the relationship among patients' apathy, cognitive impairment, depression, anxiety, and caregiver burden in amyotrophic lateral sclerosis (ALS). DESIGN: A cross-sectional study design was used. SETTING: The study was conducted at a tertiary hospital in Wuhan, Hubei, China. PARTICIPANTS: A total of 109 patients with ALS and their caregivers were included. OUTCOME MEASURES: Patients with ALS were screened using the Edinburgh Cognitive and Behavioural Screen, Beck Depression Inventory-II, Generalised Anxiety Disorder-7 and Apathy Scale to assess their cognition, depression, anxiety and apathy, respectively. The primary caregivers completed the Zarit Burden Interview. The association between apathy, cognitive impairment, depression, anxiety and caregiver burden was analysed using logistic regression. Mediation models were employed to investigate the mediating effect of patients' apathy on the relationship between depression/anxiety and caregiver burden. RESULTS: Patients in the high caregiver burden group exhibited significantly higher levels of depression, anxiety and apathy compared with those in the low caregiver burden group (p<0.05). There was a positive association observed between caregiver burden and disease course (rs=0.198, p<0.05), depression (rs=0.189, p<0.05), anxiety (rs=0.257, p<0.05) and apathy (rs=0.388, p<0.05). There was a negative association between caregiver burden and the Revised ALS Functional Rating Scale (rs=-0.275, p<0.05). Apathy was an independent risk factor for higher caregiver burden (OR 1.121, 95% CI 1.041 to 1.206, p<0.05). Apathy fully mediated the relationship between depression and caregiver burden (ß=0.35, 95% CI 0.16 to 0.54, p<0.05) while partially mediating the relationship between anxiety and caregiver burden (ß=0.34, 95% CI 0.16 to 0.52, p<0.05). CONCLUSIONS: Apathy, depression and anxiety exerted a detrimental impact on caregiver burden in individuals with ALS. Apathy played a mediating role in the relationship between depression and caregiver burden and between anxiety and caregiver burden. These findings underscore the importance of identifying apathy and developing interventions for its management within the context of ALS.
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Esclerosis Amiotrófica Lateral , Ansiedad , Apatía , Carga del Cuidador , Depresión , Humanos , Esclerosis Amiotrófica Lateral/psicología , Masculino , Femenino , Estudios Transversales , Persona de Mediana Edad , Ansiedad/psicología , Ansiedad/etiología , Depresión/psicología , Depresión/etiología , China/epidemiología , Carga del Cuidador/psicología , Anciano , Cuidadores/psicología , Adulto , Disfunción Cognitiva/etiología , Disfunción Cognitiva/psicología , Escalas de Valoración Psiquiátrica , Modelos Logísticos , Costo de EnfermedadRESUMEN
BACKGROUND: Recent evidence highlights the potential of axonal degeneration as a biomarker for amyotrophic lateral sclerosis (ALS) detection. However, the diagnostic potential of peripheral nerve axon changes in ALS remains unclear. PURPOSE: To evaluate the diagnostic performance of quantitative MRI of the brachial plexus and limb-girdle muscles (LGMs) in patients with upper extremity onset of ALS. STUDY TYPE: Retrospective. POPULATION: 47 patients with upper extremity onset of ALS and 20 healthy volunteers. FIELD STRENGTH/SEQUENCE: 3-T, three-dimensional sampling perfection with application-optimized contrasts using different flip angle evolutions with short-tau inversion recovery sequences, T2-weighted turbo spin-echo Dixon sequence. ASSESSMENT: The cross-sectional area (CSA) and nerve-muscle T2 signal intensity ratio (nT2) of the bilateral brachial plexus as well as the CSA and fat fraction (FF) of the bilateral LGMs were assessed by two radiologists. Disease severity and clinical stage of ALS patients were assessed by two neurologists. STATISTICAL TESTS: Student's t-test, Wilcoxon rank-sum test, binary logistic regression, interclass correlation coefficient, receiver operating characteristic analysis, and correlation analysis were performed for MRI quantitative metrics and clinical variables. Significance level: P < 0.05. RESULTS: In the affected limbs of patients with ALS, the CSA of the brachial plexus roots, trunks, and cords and the nT2 values of the brachial plexus trunks were significantly smaller than in the healthy controls. In the LGMs, the affected limbs of ALS showed significantly smaller CSA and higher FF than controls. The model containing parameters such as brachial plexus trunk CSA, subscapularis CSA, infraspinatus CSA, and subscapularis FF had excellent diagnostic efficacy for ALS. Additionally, increased subscapularis FF and supraspinatus FF were correlated with disease severity, and subscapularis CSA was negatively correlated with the clinical stage. DATA CONCLUSION: Brachial plexus thinning, LGM atrophy, and fatty infiltration might serve as MRI-derived biomarkers for ALS with upper extremity onset. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 2.
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A growing body of evidence suggests immune involvement in the pathology of multiple system atrophy (MSA). Research on detailed peripheral immune indices, however, is relatively sparse, and is one of the intriguing aspects of MSA yet to be elucidated. A total of 26 MSA patients and 56 age-and sex-matched healthy controls (HC) were enrolled in the current case-control study to delineate the peripheral immune traits of MSA patients. The ratio of CD4+/CD8+ T cells, natural killer cells, CD28 expression on both CD4+ T cells and CD8+ T cells increased in MSA patients compared to HC, but CD8+ T cells and active marker (HLA-DR) expression on total T cells decreased (p < 0.05). This study sheds light on the dysregulation of cellular immunity in MSA, pointing to future mechanistic research.
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Background: Observational studies have suggested that peripheral immune disorders are associated with amyotrophic lateral sclerosis (ALS). Previous studies predominantly focused on changes in adaptive immunity. However, emerging evidence showed natural killer (NK) cells, an essential component of innate immunity, were involved in the degeneration of motor neurons. However, the causal relationship between dysregulated NK cells-related immune traits and ALS remains unclear. Objective: This study aimed to explore the causal relationship between NK cells-related immune traits and the risk of ALS. Materials and methods: Single nucleotide polymorphisms (SNPs) significantly associated with NK cells-related immune traits were selected as instrumental variables to estimate their causal effects on ALS. SNPs from a genome-wide association study (GWAS) on NK cells-related immune traits were used as exposure instruments, including an absolute NK-cells count, absolute HLA-DR+ NK-cells count, NK cells/lymphocytes, NK cells/CD3- lymphocytes, HLA DR+ NK cells/NK cells, HLA DR+ NK cells/CD3- lymphocytes, and the median fluorescence intensities of CD16-CD56+ on NK cells and HLA-DR+ NK cells. Summary-level GWAS statistics of ALS were used as the outcome data. Exposure and outcome data were analyzed using the two-sample Mendelian randomization (MR) method. Results: Each one standard deviation increase in the expression levels of CD16-CD56+ on NK cells and HLA-DR+ NK cells were associated with a lower risk of ALS in both the MR-Egger and inverse variance weighted methods (P < 0.05). The results proved robust under all sensitivity analyses. Neither instrumental outliers nor heterogeneity were detected. Conclusion: Our results suggest that higher expression levels of CD16-CD56+ on NK cells and HLA-DR+ NK cells are associated with a lower risk of ALS.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by irreversible deterioration of upper and lower motor neurons (MNs). Previously, studies on the involvement of glial cells in the pathogenic process of ALS have mainly revolved around astrocytes and microglia. And oligodendrocytes (OLs) have only recently been highlighted. Grey matter demyelination within the motor cortex and proliferation of the oligodendrocyte precursor cells (OPCs) was observed in ALS patients. The selective ablation of mutant SOD1 (the dysfunctional superoxide dismutase) from the oligodendrocyte progenitors after birth significantly delayed disease onset and prolonged the overall survival in ALS mice model (SOD1 G37R). In this study, we review the several mechanisms of oligodendrocyte dysfunction involved in the pathological process of myelin damage and MNs death during ALS. Particularly, we examined the insufficient local energy supply from OLs to axons, impaired differentiation from OPCs into OLs mediated by oxidative stress damage, and inflammatory injury to the OLs. Since increasing evidence depicted that ALS is not a disease limited to MNs damage, exploring the mechanisms by which oligodendrocyte dysfunction is involved in MNs death would contribute to a more comprehensive understanding of ALS and identifying potential drug targets.
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Recently, cognitive impairments (CI) and behavioral abnormalities in patients with amyotrophic lateral sclerosis (ALS) have been reported. However, the underlying mechanisms have been poorly understood. In the current study, we explored the role of gut microbiota in CI of ALS patients. We collected fecal samples from 35 ALS patients and 35 healthy controls. The cognitive function of the ALS patients was evaluated using the Edinburgh Cognitive and Behavioral ALS Screen. We analyzed these samples by using 16S rRNA gene sequencing as well as both untargeted and targeted (bile acids) metabolite mapping between patients with CI and patients with normal cognition (CN). We found altered gut microbial communities and a lower ratio of Firmicutes/ Bacteroidetes in the CI group, compared with the CN group. In addition, the untargeted metabolite mapping revealed that 26 and 17 metabolites significantly increased and decreased, respectively, in the CI group, compared with the CN group. These metabolites were mapped to the metabolic pathways associated with bile acids. We further found that cholic acid and chenodeoxycholic acid were significantly lower in the CI group than in the CN group. In conclusion, we found that the gut microbiota and its metabolome profile differed between ALS patients with and without CI and that the altered bile acid profile in fecal samples was significantly associated with CI in ALS patients. These results need to be replicated in larger studies in the future.
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Objective: Uric acid as an antioxidant plays an important role in neurodegenerative disease. Our objective is to investigate the relationship between plasma uric acid and cognitive impairment in patients with amyotrophic lateral sclerosis (ALS). Methods: In this cross-sectional study, 124 ALS patients were screened by the Edinburgh Cognitive and Behavioral Screen (ECAS) and classified according to the revised Strong's criteria. Additionally, based on total ECAS cut-off score patients were categorized into those with cognitive impairment (ALS-cie) and those without cognitive impairment (ALS-ncie), and clinical data and uric acid level were compared between the two groups. Parameters with significant differences were further included in a multivariate linear regression analysis with ECAS score as a dependent variable. Hold-out validation was performed to evaluate the fitness of regression model. Results: Up to 60% of ALS patients showed cognitive or/and behavioral impairment. The ALS-cie group had lower education level (p < 0.001), older age at symptom onset (p = 0.001), older age at testing (p = 0.001), and lower plasma uric acid (p = 0.01). Multivariate analysis showed increased uric acid (ß = 0.214, p = 0.01), lower age at testing (ß = -0.378, p < 0.001), and higher education level (ß = 0.424, p < 0.001) could predict higher ECAS score (F = 19.104, R 2 = 0.381, p < 0.0001). Validation analysis showed that predicted ECAS score was significantly correlated with raw ECAS score in both the training set (rs = 0.621, p < 0.001) and the testing set (rs = 0.666, p < 0.001). Conclusions: Cognitive impairment was a common feature in our Chinese ALS patients. Plasma uric acid might help evaluate the risk of cognitive impairment in ALS patients when combined with education level and age at testing.
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BACKGROUND: ALS patients have changed peripheral immunity. It is unknown whether peripheral immunity is related to cognitive dysfunction in ALS patients. OBJECTIVE: To explore the relationship between the peripheral blood lymphocyte subsets and the cognitive status in ALS patients. METHODS: Among 81 ALS patients, we compared the demographic, clinical, and peripheral levels of total T lymphocyte, CD4+ T lymphocyte, CD8+ T lymphocyte, B lymphocyte, and NK cell between those with cognitive impairment (ALS-ci) and those without (ALS-nci). The cognitive status was evaluated via the Chinese version of the Edinburgh cognitive and behavioral screen (ECAS). Significant predictors of cognitive impairment in univariate logistic regression analysis were further examined using multivariate logistic regression analysis. RESULTS: 39.5% of all ALS patients had cognitive impairment. The ALS-ci group had shorter education time, older age at both symptom onset and testing, longer disease duration, and lower levels of peripheral total, CD4+, and CD8+ T lymphocyte and B lymphocyte than the ALS-nci group. Frequency of behavioral impairment did not differ between the two groups. While parameters with significant differences identified by group comparison were also significant predictors of cognitive impairment in univariate logistic regression analysis except the level of B lymphocyte, only older age at testing, education time less than 9 years, and lower level of CD4+ T lymphocyte remained significant in multivariate logistic regression analysis. The predictive model combining these three parameters had an area under the receiver operating characteristic curve value of 0.842 with a sensitivity of 90.6% and a specificity of 67.3%. CONCLUSION: In Chinese ALS patients, blood CD4+ T lymphocyte might help evaluate cognitive impairment along with age and education level.