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BACKGROUND: Several variants of sequestosome 1 (SQSTM1) were screened in patients with amyotrophic lateral sclerosis (ALS), while the pathogenicity and genotype-phenotype correlation remains unclear. METHODS: We screened variants of SQSTM1 gene in 2011 Chinese patients with ALS and performed a burden analysis focusing on the rare variants. Furthermore, we conducted a comprehensive analysis of patients with variants of SQSTM1 gene in patients with ALS from our cohort and published studies. RESULTS: In our cohort, we identified 32 patients with 25 different SQSTM1 variants with a mutant frequency of 1.6%. Notably, 26% (5/19) of the patients with ALS with SQSTM1 variant in our cohort had comorbid cognitive impairment and 43% (3/7) of them had behavioural variant frontotemporal dementia (FTD). Our meta-analysis found a total frequency of SQSTM1 variants in 7183 patients with ALS was 2.4%; burden analysis indicated that patients with ALS had enrichment of ultra-rare (minor allele frequency<0.01%) probably pathogenic variants in SQSTM1. Most variants were missense variants and distributed in various domains of p62 protein, some of which might be related to comorbidities of Paget's disease of bone and FTD. CONCLUSION: Our study established the largest cohort of patients with ALS with SQSTM1 variants, expanded the mutation spectrum and investigated the genotype-phenotype correlations of SQSTM1 variants.
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BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by progressive degeneration of motor neurons. Genetic factors have a substantial impact on ALS. Therefore, this study aimed to explore the correlation between genotype (SOD1, TARDBP, FUS, C9orf72) and phenotype in ALS. METHODS: Genetic analysis was performed on 2038 patients with ALS, among which 1696 patients with sporadic ALS (SALS) as controls for genotype-phenotype analysis, and 1602 SALS as controls for survival analysis. Logistic regression and Cox proportional hazards models were used for statistical analysis. RESULTS: A total of 172 patients with ALS with the gene mutations were included in the statistical analysis (SOD1, n=65; FUS, n=43; TARDBP, n=27; C9orf72, n=37). SOD1 mutations were more frequent in flail leg phenotype (OR 7.317, p=0.001) and less in bulbar phenotype (OR 0.222, p=0.038). C9orf72 expansions exhibited higher frequency in bulbar phenotype (OR 2.770, p=0.008). SOD1 and FUS mutations were significantly associated with earlier age of onset (HR 2.039, p<0.001; HR 1.762, p=0.001). The patients with SOD1 mutations, C9orf72 expansions and those carrying pathogenic FUS mutations had significantly increased death risk (HR 2.217, p<0.001; HR 1.694, p=0.008; HR 1.652, p=0.036). The increased risk of death in ALS with C9orf72 expansions was significant in females (HR 2.419, p=0.014) but not in males (HR 1.442, p=0.128). CONCLUSION: Our study revealed distinct motor phenotypic tendencies in patients with ALS with different genotypes, indicating variations in the vulnerability of motor neurons during the disease's progression. Furthermore, we made novel discoveries regarding survival of different gene mutations, warranting further investigation.
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Esclerose Lateral Amiotrófica , Proteína C9orf72 , Estudos de Associação Genética , Mutação , Fenótipo , Superóxido Dismutase-1 , Humanos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/mortalidade , Esclerose Lateral Amiotrófica/patologia , Masculino , Feminino , Proteína C9orf72/genética , Pessoa de Meia-Idade , China/epidemiologia , Superóxido Dismutase-1/genética , Adulto , Estudos de Associação Genética/métodos , Proteína FUS de Ligação a RNA/genética , Proteínas de Ligação a DNA/genética , Idoso , Genótipo , Idade de Início , Predisposição Genética para Doença , Proteínas/genéticaRESUMO
BACKGROUND: Aberrant DNA methylation alterations are implicated in amyotrophic lateral sclerosis (ALS). Nevertheless, the influence of genetic variants in genes regulating DNA methylation on ALS patients is not well understood. Therefore, we aim to provide a comprehensive variant profile of genes related to DNA methylation (DNMT1, DNMT3A, DNMT3B, DNMT3L) and demethylation (TET1, TET2, TET3, TDG) and to investigate the association of these variants with ALS. METHODS: Variants were screened in a cohort of 2240 ALS patients from Southwest China, using controls from the Genome Aggregation Database (n = 9976) and the China Metabolic Analytics Project (n = 10,588). The over-representation of rare variants and their association with ALS risk were evaluated using Fisher's exact test with Bonferroni correction at both allele and gene levels. Kaplan-Meier analysis and Cox regression analysis were employed to explore the relationship between variants and survival. RESULTS: A total of 210 variants meeting the criteria were identified. Gene-based burden analysis identified a significant increase in ALS risk associated with rare variants in the TET2 gene (OR = 1.95, 95% CI = 1.29-2.88, P = 0.001). Survival analysis demonstrated that patients carrying variants in demethylation-related genes had a higher risk of death compared to those with methylation-related gene variants (HR = 1.29, 95% CI = 1.03-1.86, P = 0.039). CONCLUSIONS: This study provides a genetic variant profile of genes involved in DNA methylation and demethylation regulation, along with the clinical characteristics of ALS patients carrying these variants. The findings offer genetic evidence implicating disrupted DNA methylation dynamics in ALS.
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Esclerose Lateral Amiotrófica , Metilação de DNA , Humanos , Esclerose Lateral Amiotrófica/genética , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , China , Predisposição Genética para Doença/genética , Proteínas de Ligação a DNA/genética , Estudos de Coortes , Adulto , Dioxigenases , Variação GenéticaRESUMO
Background: Recent research has indicated the significance of immune activation in amyotrophic lateral sclerosis (ALS). However, the impact of peripheral immunity on cognitive impairment in sporadic ALS remains poorly characterized. Therefore, we aim to assess the relationship between peripheral immune parameters and cognitive impairment in patients with sporadic ALS. Methods: A case-control study involving 289 patients with sporadic ALS was conducted. All participants underwent cognitive assessment and measurements of blood immune parameters. The main outcomes included adjusted odds ratios (ORs) in multivariate logistic regression analysis and adjusted coefficients in a multivariate linear regression model. Sensitivity analysis was performed with stratification by the King's clinical stage. Results: Cognitive impairment was observed in 98 (33.9%) patients. Higher counts of leukocyte (OR, 0.53; 95% CI, 0.29 to 0.95; p = 0.03), neutrophil (OR, 0.48; 95% CI, 0.26 to 0.88; p = 0.02), and monocyte (OR, 0.33; 95% CI, 0.18 to 0.60; p < 0.001) were significantly associated with better cognitive preformence in sporadic ALS, particularly among patients in King's clinical stages 1 and 2. Conversely, a higher percentage of CD4+ T cells was linked to an increased risk of cognitive impairment (OR, 2.79; 95% CI, 1.52 to 5.09; p = 0.001), particularly evident in patients in King's clinical stage 3. Conclusion: These results highlight the involvement of peripheral immunity in the cognitive impairment of sporadic ALS and suggest dynamic and intricate roles that vary across disease stages. Elucidating the links between immunity and ALS sheds light on the pathophysiological mechanisms underlying this fatal neurodegenerative disorder and informs potential immunotherapeutic strategies.
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Objectives: This study aims to elucidate the role of peripheral inflammation in Huntington's disease (HD) by examining the correlation of peripheral inflammatory markers with clinical manifestations and disease prognosis. Methods: This investigation involved 92 HD patients and 92 matched healthy controls (HCs). We quantified various peripheral inflammatory markers and calculated their derived metrics including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII). Clinical assessments spanning cognitive, motor, and disease severity were administered. Comparative analysis of inflammatory markers and clinical correlations between HD and controls was performed. Kaplan-Meier survival analysis and Cox regression model were used to assess the effect of inflammatory markers on survival. Results: The study revealed that HD patients had significantly reduced lymphocyte counts, and LMR. Conversely, NLR, PLR, and SII were elevated compared to HCs. Lymphocyte levels inversely correlated with the age of onset and monocyte levels inversely correlated with the UHDRS-total functional capacity (TFC) scores. After adjusting for age, sex, and CAG repeat length, lymphocyte count, NLR, PLR, and SII were significantly correlated with the progression rate of TFC scores. Elevated levels of white blood cells and monocytes were associated with an increased risk of disability and mortality in the HD cohort. Conclusion: Our findings indicate that HD patients display a distinct peripheral inflammatory profile with increased NLR, PLR, and SII levels compared to HCs. The peripheral inflammation appears to be linked with accelerated disease progression and decreased survival in HD.
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BACKGROUND: Excessive daytime sleepiness (EDS) is one of the most frequent nonmotor symptoms in Parkinson's disease (PD); however, the pathogenesis of EDS is unclear, and there is a lack of information on plasma biomarkers for EDS in PD. We aimed to investigate the plasma biomarkers of EDS in a large PD cohort. METHODS: A total of 159 PD patients were included in the prospective cohort study and followed up annually for 3 years. Plasma biomarkers including glial fibrillary acidic protein, amyloid-beta, p-tau181, and neurofilament light chain (NfL), were measured using an ultrasensitive single-molecule array (Simoa) technology at each visit. EDS was evaluated using the Epworth Sleepiness Scale (ESS). RESULTS: The frequency of EDS in PD increased from 15.1% at baseline to 25.0% after 3 years. The mean ESS scores increased from 5.1 (standard deviation [SD]: 4.8) at baseline to 6.1 (SD: 5.5) at the third year of follow-up. At baseline, compared with patients with PD without EDS, those with EDS were more likely to be male, had poorer cognitive performance, and more severe motor and nonmotor symptoms. The adjusted generalized estimating equations models showed that higher plasma NfL levels (OR: 1.047 [1.002-1.094], pâ =â .042) were associated with EDS during follow-ups. The adjusted linear mixed-effects model showed that higher plasma NfL levels (ß 0.097 [0.012-0.183], pâ =â .026) were associated with ESS scores during follow-ups. CONCLUSIONS: Higher plasma NfL levels were associated with EDS in PD, indicating an association between neuro-axonal degeneration and EDS in PD.
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Biomarcadores , Distúrbios do Sono por Sonolência Excessiva , Doença de Parkinson , Humanos , Doença de Parkinson/sangue , Doença de Parkinson/complicações , Masculino , Feminino , Biomarcadores/sangue , Idoso , Estudos Prospectivos , Distúrbios do Sono por Sonolência Excessiva/sangue , Distúrbios do Sono por Sonolência Excessiva/etiologia , Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Proteínas de Neurofilamentos/sangue , Pessoa de Meia-Idade , Peptídeos beta-Amiloides/sangue , Proteínas tau/sangue , Estudos LongitudinaisRESUMO
Parkinson's disease (PD) is a heterogeneous movement disorder with different motor subtypes including tremor dominant (TD), indeterminate and postural instability, and gait disturbance (PIGD) motor subtypes. Plasma glial fibrillary acidic protein (GFAP) was elevated in PD patients and may be regarded as a biomarker for motor and cognitive progression. Here we explore if there was an association between plasma GFAP and different motor subtypes and whether baseline plasma GFAP level can predict motor subtype conversion. Patients with PD classified as TD, PIGD or indeterminate subtypes underwent neurological evaluation at baseline and 2 years follow-up. Plasma GFAP in PD patients and controls were measured using an ultrasensitive single molecule array. The study enrolled 184 PD patients and 95 control subjects. Plasma GFAP levels were significantly higher in the PIGD group compared to the TD group at 2-year follow-up. Finally, 45% of TD patients at baseline had a subtype shift and 85% of PIGD patients at baseline remained as PIGD subtypes at 2 years follow-up. Baseline plasma GFAP levels were significantly higher in TD patients converted to PIGD than non-converters in the baseline TD group. Higher baseline plasma GFAP levels were significantly associated with the TD motor subtype conversion (OR = 1.283, P = 0.033) and lower baseline plasma GFAP levels in PIGD patients were likely to shift to TD and indeterminate subtype (OR = 0.551, P = 0.021) after adjusting for confounders. Plasma GFAP may serve as a clinical utility biomarker in differentiating motor subtypes and predicting baseline motor subtypes conversion in PD patients.
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BACKGROUND: Epigenetics contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS). We aimed to characterize the DNA methylation profiles associated with clinical heterogeneity in disease progression and survival among patients. METHODS: We included a cohort of 41 patients with sporadic ALS, with a median follow-up of 86.9 months, and 27 rigorously matched healthy controls. Blood-based genome-wide DNA methylation analysis was conducted. RESULTS: A total of 948 progression rate-associated differentially methylated positions, 298 progression rate-associated differentially methylated regions (R-DMRs), 590 survival time-associated DMPs, and 197 survival time-associated DMRs (S-DMRs) were identified, using complementary grouping strategies. Enrichment analysis of differentially methylated genes highlighted the involvement of synapses and axons in ALS progression and survival. Clinical analysis revealed a positive correlation between the average methylation levels of the R-DMR in PRDM8 and disease progression rate (r = 0.479, p = 0.002). Conversely, there was an inverse correlation between the average methylation levels of the R-DMR in ANKRD33 and disease progression rate (r = - 0.476, p = 0.002). In addition, patients with higher methylation levels within the S-DMR of ZNF696 experienced longer survival (p = 0.016), while those with elevated methylation levels in the S-DMR of RAI1 had shorter survival (p = 0.006). CONCLUSION: DNA methylation holds promise as a potential biomarker for tracking disease progression and predicting survival outcome and also offers targets for precision medicine.
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Esclerose Lateral Amiotrófica , Metilação de DNA , Progressão da Doença , Humanos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Epigênese Genética , Estudo de Associação Genômica Ampla , SeguimentosRESUMO
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Abnormalities in the peripheral immune system in ALS have been paid attention; however, the results of changes in peripheral immune parameters were inconsistent. METHODS: A total of 1109 ALS patients were enrolled in the study. All patients received clinical evaluation and peripheral immune parameters measurement. The outcomes were analyzed by correlation analysis, multiple linear regression and cox survival analysis. RESULTS: We found that ALS patients had significantly higher percentage of CD4+ T cells (39.3 vs. 37.1%, p < 0.001) and CD4+/CD8+ ratio (1.88 vs. 1.72, p = 0.011), significantly lower IgG (11.73 vs.12.82, p < 0.001) and IgA (2130.70 vs. 2284.8, p = 0.013) compared with the health controls. In the multivariate linear model, we found that each increase of 1.262, 0.278, and 4.44E-4 in ALSFRS-R scores were significantly associated with each increment of lymphocyte count, IgG, and IgA, respectively. However, each decrease of 0.341, 0.068, and 0.682 in ALSFRS-R score was associated with each increment in neutrophils, CD4+ T cells, and CD4+/CD8+ ratio, respectively. Cox survival regression analysis showed that the death risk of ALS patients was related to the levels of C3 (HR 0.592, 95% CI 0.361-0.973). CONCLUSION: We found that there were differences in peripheral immune parameters of ALS patients with the severity of the disease, especially neutrophil, lymphocyte, CD4+ T, and IgG; C3 is an independent predictor of survival in ALS patients. More studies are needed to elucidate the mechanisms associated with altered immune parameters in ALS.
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Esclerose Lateral Amiotrófica , Progressão da Doença , Humanos , Esclerose Lateral Amiotrófica/imunologia , Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Prognóstico , Adulto , Linfócitos T CD4-Positivos/imunologia , Imunoglobulina G/sangueRESUMO
DnaJ heat shock protein family member C7 gene (DNAJC7) has been identified as a genetic risk factor for amyotrophic lateral sclerosis (ALS). In our study, we aimed to screen for rare variants in DNAJC7 in a large cohort of Chinese ALS patients, and investigate the genotype-phenotype correlation of DNAJC7 in ALS. Four (0.19%) variants of DNAJC7 with minor allele frequency (MAF) < 0.1% among 2124 patients were identified, including 1 protein-truncating variant and 3 missense variants, all of which were predicted to be damaging. The patients carrying variants of DNAJC7 in our cohort tented to have a limb onset and a relatively slow disease progression. However, burden analysis did not show an enrichment of rare damaging variants in ALS patients compared to controls. Further analysis involving diverse regions and larger sample size is necessary to elucidate the role of DNAJC7 in the pathogenicity of ALS.
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Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/genética , Estudos de Associação Genética , Mutação de Sentido Incorreto , Frequência do Gene , China , Proteínas de Choque Térmico/genética , Chaperonas MolecularesRESUMO
Mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene has been identified as a causative gene for autosomal dominant Parkinson's disease (PD), with the p.Y314S variant potentially associated with polyneuropathy in PD patients. The objectives of our study were to screen for UQCRC1 variants in Chinese patients with early-onset PD (EOPD) and explore the role of UQCRC1 in EOPD. We investigated the rare variants in 913 EOPD patients in our cohort using whole-exome sequencing, assessing their link to PD at both allele and gene levels. A total of 7 rare variants (minor allele frequency < 0.1%) of UQCRC1 were identified. However, no excessive burden of rare UQCRC1 variants was suggested in the EOPD patients. Further analysis with larger sample size and diverse regions is needed to determine the role of UQCRC1 in PD.
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Complexo III da Cadeia de Transporte de Elétrons , Doença de Parkinson , Humanos , Idade de Início , China , Sequenciamento do Exoma , Doença de Parkinson/genética , Complexo III da Cadeia de Transporte de Elétrons/genéticaRESUMO
OBJECTIVE: We aimed to examine the longitudinal change of plasma neurofilament light chain (NFL) level and explore its diagnostic and prognostic implications in Parkinson's disease (PD). METHODS: A total of 184 patients with early PD who completed 5-year annually repeated clinical assessments were included. Plasma NFL at baseline, 1 year, and 2 year were examined, which were quantified using the ultrasensitive Simoa technology. At baseline, blood from 86 sex- and age-matched healthy controls (HC) were obtained for comparison. RESULTS: Plasma NFL in PD patients at baseline was significantly higher than those in HC (P = 0.046), and significantly increased after 2 years (P = 0.046). Receiver operating characteristic curve indicated that a plasma NFL cut-off value of 10.79 pg/mL resulted in 39.7% sensitivity and 84.0% specificity, with an area under the curve of 0.635, to distinguish PD from HC (P < 0.001). Linear mixed-effect models indicated that baseline plasma NFL (> 9.24 pg/mL) correlated with a greater increase in the Unified Parkinson's Disease Rating Scale III (estimate = 0.651, P = 0.001) and Hoehn & Yahr stage (estimate = 0.072, P < 0.001), and also correlated with a greater decrease in the Montreal Cognitive Assessment (estimate = - 0.387, P < 0.001) during follow-up visits. CONCLUSIONS: Plasma NFL exhibits a tendency to increase with disease progression, and elevated baseline plasma NFL can serve as a predictor for accelerated motor deterioration and cognitive decline in PD. However, plasma NFL does not have high accuracy to distinguish individuals with early-stage PD from HC.
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Disfunção Cognitiva , Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico , Estudos Prospectivos , Proteínas de Neurofilamentos , Testes de Estado Mental e Demência , Progressão da Doença , BiomarcadoresRESUMO
Background: Malnutrition is associated with poor survival in some diseases. However, the nutritional status in multiple system atrophy (MSA) is unknown, and the significance of malnutrition for the prediction of mortality in MSA has not been well established. Objective: We aimed to determine the prevalence of malnutrition and the prognostic value of malnutrition in patients with early-stage MSA. Methods: Patients diagnosed with early phase MSA (disease duration<3 years) were recruited, and they were followed every year until May 2023. The nutritional status of patients with MSA was assessed using the Controlling Nutritional Status (CONUT) score and Geriatric Nutritional Risk Index (GNRI). Kaplan-Meier survival analysis and Cox regression model were used to assess the prognostic value of malnutrition in MSA. Results: A total of 224 patients with probable MSA (106 MSA died and 118 were still alive) and 213 matched healthy controls (HCs) were enrolled. According to COUNT score and GNRI, patients with MSA had higher prevalence of malnutrition than HCs (44.6% vs. 14.1 and 17.9% vs. 0.9%, respectively). The median survival from symptom onset in patients with MSA in the malnutrition group was shorter than those in the normal-nutrition group (5.98 vs. 7.06 years, p = 0.012) by COUNT score. Additionally, malnutrition increased the risk of mortality in patients with MSA (HR = 1.556, p = 0.030) and MSA-P (HR = 1.973, p = 0.042) by COUNT score. Interpretation: Malnutrition was common in patients with early-stage MSA. Malnutrition increased the risk of mortality in patients with MSA, and early nutritional supplementation should be taken into consideration.
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Objectives: Mutations in glucocerebrosidase (GBA1) can change the clinical phenotype of Parkinson's disease (PD). This study aimed to explore the clinical characteristics of freezing of gait (FOG) in PD patients with GBA1 mutations. Methods: A whole-exome sequencing analysis was used to identify the GBA1 mutations (pathogenic or likely pathogenic) and exclude other PD-related gene mutations. A forward binary logistic regression model was conducted to identify the associated factors of FOG. The stepwise multiple linear regression analysis models were used to explore the effect of FOG on quality of life. Results: The prevalence of FOG in patients with GBA1 mutations (30/95, 31.6%) was significantly higher than those in patients without GBA1 mutations (152/760, 20%) (p = 0.009). A higher (i.e., worse) Unified PD Rating Scale part III score (OR = 1.126, 95%CI = 1.061-1.194, p < 0.001) and a lower (i.e., worse) Montreal Cognitive Assessment score (OR = 0.830, 95%CI = 0.713-0.967, p = 0.017) were significantly associated with FOG in PD patients with GBA1 mutations. The presence of FOG was significantly associated with the decreased (i.e., worse) score of PD Questionnaire 39 after adjustment for sex, age, disease duration, motor score, and non-motor score (B = 14.981, p = 0.001). Conclusion: FOG is a relatively common disabling symptom in PD patients with GBA1 mutations, which is affected by motor disability and cognitive decline. Quality of life is reduced in patients with FOG and GBA1 mutations.
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BACKGROUND: Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by Parkinsonism, ataxia, and autonomic nervous failure. Orthostatic hypotension (OH) is the main feature of central vascular autonomic failure in MSA. OBJECTIVE: The study aimed elucidate the effects of OH on cognitive function, disease milestones, and survival. METHODS: A total of 444 patients with clinically established MSA were enrolled. Mild and severe OH were defined as a decrease in systolic blood pressure (SBP)/diastolic blood pressure (DBP) >20/10 mmHg and SBP/DBP ≥30/15 mmHg, respectively. RESULTS: In this study, 215 MSA patients presented without OH, 88 had mild OH, and 141 had severe OH. The proportion of MSA-C in the severe OH subgroup was significantly higher than that in the subgroup without OH (95/46 vs. 113/102, pâ=â0.021). The UMSARS I score and the frequency of supine hypertension (SH) in patients with OH were significantly higher than those in patients without OH (16.22 vs. 16.89 vs. 14.60, pâ<â0.001; 77/64 vs. 29/59 vs. 32/183, pâ<â0.001). Factors related to the severity of OH included sex (OR, 0.65; pâ=â0.031), onset age (OR, 0.98; pâ=â0.029), and SH (OR, 0.21; pâ<â0.001). The median survival time of patients with severe OH was significantly lower than that of patients without OH (6.79 vs. 8.13 years, pâ=â0.001). Consistently, Cox survival analysis found that compared with patients without OH, patients with severe OH had a significantly increased risk of death (OR, 2.22; pâ<â0.001). CONCLUSION: Our large cohort study of MSA provides additional evidence for the negative impact of severe OH on survival.
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Hipertensão , Hipotensão Ortostática , Atrofia de Múltiplos Sistemas , Doença de Parkinson , Humanos , Atrofia de Múltiplos Sistemas/complicações , Estudos de Coortes , Doença de Parkinson/complicações , Hipertensão/complicações , Hipertensão/epidemiologia , PrognósticoRESUMO
BACKGROUND: Reactive astrogliosis has been demonstrated to have a role in Parkinson's disease (PD); however, astrocyte-specific plasma glial fibrillary acidic protein (GFAP)'s correlation with PD progression remains unknown. We aimed to determine whether plasma GFAP can monitor and predict PD progression. METHODS: A total of 184 patients with PD and 95 healthy controls (HCs) were included in this prospective cohort study and followed-up for 5 years. Plasma GFAP, amyloid-beta (Aß), p-tau181, and neurofilament light chain (NfL) were measured at baseline and at 1- and 2-year follow-ups. Motor and non-motor symptoms, activities of daily living, global cognitive function, executive function, and disease stage were evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) part III, UPDRS-I, UPDRS-II, Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), and Hoehn and Yahr (H&Y) scales at each visit, respectively. RESULTS: Plasma GFAP levels were higher in patients with PD (mean [SD]: 69.80 [36.18], pg/mL) compared to HCs (mean [SD]: 57.89 [23.54], pg/mL). Higher levels of GFAP were observed in female and older PD patients. The adjusted linear mixed-effects models showed that plasma GFAP levels were significantly associated with UPDRS-I scores (ß: 0.006, 95% CI [0.001-0.011], p = 0.027). Higher baseline plasma GFAP correlated with faster increase in UPDRS-I (ß: 0.237, 95% CI [0.055-0.419], p = 0.011) and UPDRS-III (ß: 0.676, 95% CI [0.023-1.330], p = 0.043) scores and H&Y stage (ß: 0.098, 95% CI [0.047-0.149], p < 0.001) and faster decrease in MoCA (ß: - 0.501, 95% CI [- 0.768 to - 0.234], p < 0.001) and FAB scores (ß: - 0.358, 95% CI [- 0.587 to - 0.129], p = 0.002). Higher baseline plasma GFAP predicted a more rapid progression to postural instability (hazard ratio: 1.009, 95% CI [1.001-1.017], p = 0.033). CONCLUSIONS: Plasma GFAP might be a potential biomarker for monitoring and predicting disease progression in PD.
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Doença de Parkinson , Humanos , Atividades Cotidianas , Biomarcadores , Progressão da Doença , Proteína Glial Fibrilar Ácida , Filamentos Intermediários , Doença de Parkinson/complicações , Estudos ProspectivosRESUMO
OBJECTIVES: High visit-to-visit blood pressure variability (BPV) was found to be associated with cognitive decline in the elderly. This study aimed to investigate the impact of visit-to-visit BPV on cognition in patients with early-stage Parkinson's disease (PD). DESIGN: This is a retrospective analysis of a prospective cohort. SETTING AND PARTICIPANTS: A total of 297 patients with early-stage PD (103 mild cognitive impairments [PD-MCI] and 194 normal cognitions [PD-NC] at baseline) were included from the Parkinson's Progression Markers Initiative study. METHODS: Variation independent of mean (VIM) of the first year was used as the indicator of BPV. The Montreal Cognitive Assessment (MoCA) was used to assess global cognition. Patients were divided into PD-MCI and PD-NC according to the MoCA score at baseline. Longitudinal cerebrospinal fluid (Aß-42, Aß, α-synuclein, neurofilament light protein, tau phosphorylated at the threonine 181 position, total tau, glial fibrillary acidic protein) and serum (neurofilament light protein) biomarkers were assessed. The Bayesian linear growth model was used to evaluate the relationship between baseline BPV and the rate of change in cognition and biomarkers. RESULTS: Higher systolic VIM of the first year was related to a greater rate of decline in MoCA score in the following years in PD-MCI (ß = -.15 [95% CI -.29, -.01]). No association was found between BPV and biomarkers. CONCLUSION AND IMPLICATIONS: Higher systolic VIM predicted a steeper decline in cognitive tests in PD-MCI independently from the mean value of blood pressure, orthostatic hypotension, and supine hypertension.
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Disfunção Cognitiva , Doença de Parkinson , Humanos , Idoso , Doença de Parkinson/complicações , Estudos Prospectivos , Pressão Sanguínea , Estudos Retrospectivos , Teorema de Bayes , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Disfunção Cognitiva/complicações , Biomarcadores/líquido cefalorraquidiano , Proteínas de NeurofilamentosRESUMO
BACKGROUND: The progression of sleep disturbances remains unclear in patients with early multiple system atrophy (MSA). We aimed to explore the frequency, severity, and coexistence of 2-year longitudinal changes of sleep disturbances including REM sleep behavior disorder (RBD), excessive daytime sleepiness (EDS), and Parkinson's disease-related sleep problems (PD-SP) in early MSA. METHODS: MSA patients with a disease duration < 3 years were enrolled to complete a 2-year follow-up visit. Sleep disturbances including RBD, EDS, and PD-SP were assessed using the RBD Screening Questionnaire, Epworth sleepiness scale, and PD sleep scale-2, respectively. RESULTS: A total of 220 patients with MSA enrolled in the study and 90 patients completed the 2-year follow-up visit. The score of all three sleep disturbances significantly increased over the 2-year follow-up in MSA and MSA with the predominant parkinsonism group (all p < 0.05). The frequency of PD-SP (from 14.5 to 26.7%) and EDS (from 17.7 to 37.8%) was progressively increased (all p < 0.05) except for RBD (from 51.8 to 65.6%, p = 0.152) over the 2-year follow-up in MSA. The frequency of coexistence of two or three sleep disturbances also increased over time. The most common sleep disturbance was RBD, followed by EDS and PD-SP over the 2-year follow-up. CONCLUSIONS: The present study demonstrated that the frequency of different types of sleep disturbances progressively increased except for RBD and the coexistence of two or three sleep disturbances became more common over time in early MSA. Our study suggested that the assessment and management of sleep disturbances should begin early in MSA.
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Distúrbios do Sono por Sonolência Excessiva , Atrofia de Múltiplos Sistemas , Doença de Parkinson , Transtorno do Comportamento do Sono REM , Transtornos do Sono-Vigília , Humanos , Atrofia de Múltiplos Sistemas/complicações , Atrofia de Múltiplos Sistemas/epidemiologia , Atrofia de Múltiplos Sistemas/diagnóstico , Estudos Prospectivos , Doença de Parkinson/complicações , Doença de Parkinson/epidemiologia , Doença de Parkinson/diagnóstico , Transtorno do Comportamento do Sono REM/complicações , Transtorno do Comportamento do Sono REM/diagnóstico , Transtornos do Sono-Vigília/epidemiologia , SonoRESUMO
BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) demonstrate great heterogeneity in the age at onset (AAO), which is closely related to the course of disease. However, most genetic studies focused on the risk of ALS, while the genetic background underlying AAO of ALS is still unknown. METHODS: To identify genetic determinants influencing AAO of ALS, we performed genome-wide association analysis using a Cox proportional hazards model in 2,841 patients with ALS (Ndiscovery = 2,272, Nreplication = 569) in the Chinese population. We further conducted colocalization analysis using public cis-eQTL dataset, and Mendelian randomization analysis to identify risk factors for AAO of ALS. Finally, functional experiments including dual-luciferase reporter assay and RT-qPCR were performed to explore the regulatory effect of the target variant. RESULTS: The total heritability of AAO of ALS was ~ 0.24. One novel locus rs10128627 (FRMD8) was significantly associated with earlier AAO by ~ 3.15 years (P = 1.54E-08, beta = 0.31, SE = 0.05). This locus was cis-eQTL of NEAT1 in multiple brain tissues and blood. Colocalization analysis detected association signals at this locus between AAO of ALS and expression of NEAT1. Furthermore, functional exploration supported the variant rs10128627 was associated with upregulated expression of NEAT1 in cell models and patients with ALS. Causal inference suggested higher total cholesterol, low-density lipoprotein, and eosinophil were nominally associated with earlier AAO of ALS, while monocyte might delay the AAO. CONCLUSIONS: Collective evidence from genetic, bioinformatic, and functional results suggested NEAT1 as a key player in the disease progression of ALS. These findings improve the current understanding of the genetic role in AAO of ALS, and provide a novel target for further research on the pathogenesis and therapeutic options to delay the disease onset.
Assuntos
Esclerose Lateral Amiotrófica , Humanos , Idade de Início , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Povo Asiático , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
We modified the original Unified Multiple System Atrophy Rating Scale (UMSARS) for remote video-based visits by excluding ocular motor dysfunction, increased tone, and body sway, resulting in a 23-item UMSARS (mUMSARS-23). The mUMSARS-23 demonstrated excellent reliability and strong validity when compared to the original scale, making it a promising tool for conducting video-based virtual assessments in patients with multiple system atrophy.