Association between the blood pressure variability and cognitive decline in Parkinson's disease.

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.

Prediction of early-wheelchair dependence in multiple system atrophy based on machine learning algorithm: A prospective cohort study.

Objective: The predictive factors for wheelchair dependence in patients with multiple system atrophy (MSA) are unclear. We aimed to explore the predictive factors for early-wheelchair dependence in patients with MSA focusing on clinical features and blood biomarkers. Methods: This is a prospective cohort study. This study included patients diagnosed with MSA between January 2014 and December 2019. At the deadline of October 2021, patients met the diagnosis of probable MSA were included in the analysis. Random forest (RF) was used to establish a predictive model for early-wheelchair dependence. Accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were used to evaluate the performance of the model. Results: Altogether, 100 patients with MSA including 49 with wheelchair dependence and 51 without wheelchair dependence were enrolled in the RF model. Baseline plasma neurofilament light chain (NFL) levels were higher in patients with wheelchair dependence than in those without (P = 0.037). According to the Gini index, the five major predictive factors were disease duration, age of onset, Unified MSA Rating Scale (UMSARS)-II score, NFL, and UMSARS-I score, followed by C-reactive protein (CRP) levels, neutrophil-to-lymphocyte ratio (NLR), UMSARS-IV score, symptom onset, orthostatic hypotension, sex, urinary incontinence, and diagnosis subtype. The sensitivity, specificity, accuracy, and AUC of the RF model were 70.82 %, 74.55 %, 72.29 %, and 0.72, respectively. Conclusion: Besides clinical features, baseline features including NFL, CRP, and NLR were potential predictive biomarkers of early-wheelchair dependence in MSA. These findings provide new insights into the trials regarding early intervention in MSA.

Association between vascular risk factors and cognitive impairment in amyotrophic lateral sclerosis: a case-control study.

OBJECTIVE: The disease-modifying effects of type 2 diabetes mellitus (T2DM), and hyperlipidemia on the risk and prognosis of amyotrophic lateral sclerosis (ALS) have gained significant attention. We aim to evaluate the association between common vascular risk factors and cognitive impairment in patients with ALS. METHODS: Patients with ALS were consecutively recruited between June 2012 and November 2019 from a tertiary referral center for ALS at the West China Hospital. Vascular risk factors (hypertension, T2DM, hyperlipidemia, overweight, and smoking) were confirmed based on clinical data. Cognitive function was evaluated by the Chinese version of Addenbrooke's Cognitive Examination-revised. With careful confounder adjustment, multivariable logistic regression analysis was performed separately and accumulatively to determine the association between cognitive impairment and vascular risk factors in ALS. RESULTS: Of 870 patients, 266 (30.6%) had cognitive impairment. No cognitive burden from vascular risk factors was found in patients with ALS. On the contrary, we first observed that T2DM (odds ratio [OR], 0.50; 95% confidence interval [CI], 0.25-0.98; p = 0.04) and hyperlipidemia (OR, 0.50; 95% CI, 0.26-0.97; p = 0.04) showed protective effects against cognitive decline in ALS, adjusted for age, sex, educational level, site of onset, Revised-ALS Functional Rating Scale score, predominant upper motor neuron phenotype, family history of ALS, and the remaining vascular risk factors. Sensitivity analyses of sex did not substantially reverse the risk estimates. CONCLUSIONS: T2DM and hyperlipidemia decrease the risk of cognitive impairment in patients with ALS. The fitness hypothesis in ALS has been tested and expanded in our work.

Cystatin C is associated with poor survival in amyotrophic lateral sclerosis patients.

Background: Cystatin C (CysC) levels in amyotrophic lateral sclerosis (ALS) have been found changes, however, the associations between serum CysC levels and the progression and survival of ALS remain largely unknown. Methods: A total of 1,086 ALS patients and 1,026 sex-age matched healthy controls (HCs) were enrolled in this study. Serum CysC, other renal function, and metabolic parameters were measured. Correlation analysis and binary logistic regression were used to explore the factors related to serum CysC. Kaplan-Meier curve and Cox regression model were used for survival analysis. Results: CysC levels were significantly higher in ALS patients compared to HCs (0.94 vs. 0.85 mg/L, p < 0.001). Compared with ALS patients with lower CysC levels, those with higher CysC levels had an older age of onset, significantly lower ALSFRS-R scores (40.1 vs. 41.3, p < 0.001), a faster disease progression rate (0.75 vs. 0.67, p = 0.011), and lower frontal lobe function scores (15.8 vs. 16.1, p = 0.020). In the correlation analysis, CysC levels were significantly negatively correlated with ALSFRS-R scores (r = -0.16, p < 0.001). Additionally, ALS patients with higher CysC levels had significantly shorter survival time (40.0 vs. 51.8, p < 0.001) compared to patients with lower CysC levels. Higher CysC levels were associated with a higher risk of death in Cox analysis (HR: 1.204, 95% CI: 1.012-1.433). However, when treatment was included in the model, the result was no longer significant. Conclusion: CysC levels in ALS patients were higher compared to HCs. Higher CysC levels were associated with greater disease severity, faster progression rate and shorter survival, needing early intervention.

Cystatin C predicts cognitive decline in multiple system atrophy: A 1-year prospective cohort study.

Background: Accumulating evidence has suggested that cystatin C is associated with cognitive impairment in patients with neurodegenerative diseases. However, the association between cystatin C and cognitive decline in patients with multiple system atrophy (MSA) remains largely unknown. Objectives: The objective was to determine whether cystatin C was independently associated with cognitive decline in patients with early-stage MSA. Methods: Patients with MSA underwent evaluation at baseline and the 1-year follow-up. Cognitive function was evaluated with Montreal cognitive assessment (MoCA). Changes in the MoCA score and the absolute MoCA score at the 1-year assessment were considered the main cognitive outcome. The cystatin C concentrations in patients with MSA and age, sex, and body mass index matched-healthy controls (HCs) were measured. A multiple linear regression model was used to test the association between cystatin C and cognitive decline. Results: A total of 117 patients with MSA and 416 HCs were enrolled in the study. The cystatin C levels were significantly higher in patients with MSA than in HCs (p < 0.001). Cystatin C levels were negatively correlated with MoCA score at baseline and at 1-year follow-up. Multiple linear regression model adjusted for potential confounders showed that baseline cystatin C levels were significantly associated with the MoCA score (p = 0.004) or change in the MoCA score (p = 0.008) at 1-year follow-up. Conclusion: Our results suggested that cystatin C may serve as a potential biomarker of cognitive decline in patients with early-stage MSA.

Stability of motor-nonmotor subtype in early-stage Parkinson's disease.

Background: The different clinical characteristics and prognostic values of the motor-nonmotor subtypes of Parkinson's disease (PD) have been established by previous studies. However, the consistency of motor-nonmotor subtypes in patients with early-stage Parkinson's disease required further investigation. The present study aimed to evaluate the consistency of motor-nonmotor subtypes across five years of follow-up in a longitudinal cohort. Materials and methods: Patients were classified into different subtypes (mild-motor-predominant, intermediate, diffuse malignant; or tremor-dominant, indeterminate, postural instability and gait difficulty) according to previously verified motor-nonmotor and motor subtyping methods at baseline and at every year of follow-up. The agreement between subtypes was examined using Cohen's kappa and total agreement. The determinants of having the diffuse malignant subtype as of the fifth-year visit were explored using logistic regression. Results: A total of 421 patients were included. There was a fair degree of agreement between the baseline motor-nonmotor subtype and the subtype recorded at the one-year follow-up visit (κ = 0.30 ± 0.09; total agreement, 60.6%) and at following years' visits. The motor-nonmotor subtype had a lower agreement between baseline and follow-up than did the motor subtype. The baseline motor-nonmotor subtype was the determinant of diffuse malignant subtype at the fifth-year visit. Conclusion: Many patients experienced a change in their motor-nonmotor subtype during follow-up. Further studies of consistency in PD subtyping methods should be conducted in the future.

A case of juvenile-onset amyotrophic lateral sclerosis with a de novo frameshift FUS gene mutation presenting with bilateral abducens palsy.

Fused in sarcoma (FUS) is the most common causative gene in juvenile-onset amyotrophic lateral sclerosis (jALS). We presented a case of a 15-year-old Chinese girl with atypical and extremely rare bilateral abducens palsy was caused by a heterozygous c.1520del (p.Gly507Alafs*22) pathogenic frameshift mutation in the FUS gene revealed by whole-exome sequencing. This is the first jALS case presenting with bilateral abducens palsy and carrying de novo FUS genetic variant.

Vascular Risk Factors and Cognition in Multiple System Atrophy.

Objective: Vascular risk factors have been reported to be associated with cognitive impairment (CI) in the general population, but their role on CI in multiple system atrophy (MSA) is unclear. This study aimed to explore the relationship between vascular risk factors and CI in patients with MSA. Methods: The clinical data and vascular risk factors were collected. The Montreal Cognitive Assessment tool was used to test the cognitive function of patients with MSA. Binary logistic regression was used to analyze the correlation between vascular risk factors and CI. Results: A total of 658 patients with MSA with a mean disease duration of 2.55 ± 1.47 years were enrolled. In MSA patients, hypertension was recorded in 20.2%, diabetes mellitus in 10.3%, hyperlipidemia in 10.2%, smoking in 41.2%, drinking in 34.8%, and obesity in 9.6%. The prevalence of CI in patients with MSA, MSA with predominant parkinsonism (MSA-P), and MSA with predominant cerebellar ataxia (MSA-C) was 45.0, 45.1, and 44.9%, respectively. In the binary logistic regression model, patients with more than one vascular risk factors were significantly more likely to have CI in MSA (OR = 4.298, 95% CI 1.456-12.691, P = 0.008) and MSA-P (OR = 6.952, 95% CI 1.390-34.774, P = 0.018), after adjusting for age, sex, educational years, disease duration, and total Unified multiple system atrophy rating scale scores. Conclusion: Multiple vascular risk factors had a cumulative impact on CI in MSA. Therefore, the comprehensive management of vascular risk factors in MSA should not be neglected.