GWAS identifies DPP6 as risk gene of cognitive decline in Parkinson's disease.

BACKGROUND: Cognitive decline is among the most common non-motor symptoms in Parkinson's disease (PD), while its physiological mechanisms remain poorly understood. Genetic factors constituted a fundamental determinant in the heterogeneity of cognitive decline among PD patients. However, the underlying genetic background was still less studied. METHODS: To explore the genetic determinants contributing to cognitive decline in PD, we performed genome-wide survival analysis using a Cox proportional hazards model in a longitudinal cohort of 450 Chinese patients with PD, and further explored the functional effect of the target variant. Additionally, we built a clinical-genetic model by incorporating clinical characteristics and polygenic risk score (PRS) to predict cognitive decline in PD. RESULTS: The cohort was followed up for an average of 5.25 (SE=2.46) years, with 95 incidents of cognitive impairment. We identified significant association between locus rs75819919 (DPP6) and accelerated cognitive decline (P=8.63E-09, beta=1.74, SE=0.30). Dual-luciferase reporter assay suggested this locus might be involved in the regulation of DPP6 expression. Using dataset from the UK Biobank, we identified rs75819919 was associated with cognitive performance in the general population. Incorporation of PRS increased the model predictability, achieving an average AUC of 75.6% through 5-fold cross-validation in 1,000 iterations. CONCLUSIONS: These findings improve the current understanding of the genetic etiology of cognitive impairment in PD, and provide a novel target DPP6 to explore therapeutic options. Our results also demonstrate the potential to develop clinical-genetic model to identify patients susceptible to cognitive impairment and thus provide personalized clinical guidance.

Peripheral immunity involvement in the cognitive impairment of sporadic amyotrophic lateral sclerosis.

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.

Clinical and genetic characteristics of ALS patients with variants in genes regulating DNA methylation.

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.

Amyotrophic lateral sclerosis patients with various gene mutations show diverse motor phenotypes and survival in China.

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.

Development and Validation of a Diagnostic Model for Identifying Clear Cell Renal Cell Carcinoma in Small Renal Masses Based on CT Radiological Features: A Multicenter Study.

RATIONALE AND OBJECTIVES: This study aimed to develop a diagnostic model based on clinical and CT features for identifying clear cell renal cell carcinoma (ccRCC) in small renal masses (SRMs). MATERIAL AND METHODS: This retrospective multi-centre study enroled patients with pathologically confirmed SRMs. Data from three centres were used as training set (n = 229), with data from one centre serving as an independent test set (n = 81). Univariate and multivariate logistic regression analyses were utilised to screen independent risk factors for ccRCC and build the classification and regression tree (CART) diagnostic model. The area under the curve (AUC) was used to evaluate the performance of the model. To demonstrate the clinical utility of the model, three radiologists were asked to diagnose the SRMs in the test set based on professional experience and re-evaluated with the aid of the CART model. RESULTS: There were 310 SRMs in 309 patients and 71% (220/310) were ccRCC. In the testing cohort, the AUC of the CART model was 0.90 (95% CI: 0.81, 0.97). For the radiologists' assessment, the AUC of the three radiologists based on the clinical experience were 0.78 (95% CI:0.66,0.89), 0.65 (95% CI:0.53,0.76), and 0.68 (95% CI:0.57,0.79). With the CART model support, the AUC of the three radiologists were 0.93 (95% CI:0.86,0.97), 0.87 (95% CI:0.78,0.95) and 0.87 (95% CI:0.78,0.95). Interobserver agreement was improved with the CART model aids (0.323 vs 0.654, P < 0.001). CONCLUSION: The CART model can identify ccRCC with better diagnostic efficacy than that of experienced radiologists and improve diagnostic performance, potentially reducing the number of unnecessary biopsies.

Homogentisic acid metabolism inhibits papillary thyroid carcinoma proliferation through ROS and p21-induced cell cycle arrest.

Thyroid cancer is one of the most common primary endocrine malignancies worldwide, and papillary thyroid carcinoma (PTC) is the predominant histological type observed therein. Although PTC has been studied extensively, our understanding of the altered metabolism and metabolic profile of PTC tumors is limited. We identified that the content of metabolite homogentisic acid (HGA) in PTC tissues was lower than that in adjacent non-cancerous tissues. We evaluated the potential of HGA as a novel molecular marker in the diagnosis of PTC tumors, as well as its ability to indicate the degree of malignancy. Studies have further shown that HGA contributes to reactive oxygen species (ROS) associated oxidative stress, leading to toxicity and inhibition of proliferation. In addition, HGA caused an increase in p21 expression levels in PTC cells and induced G1 arrest. Moreover, we found that the low HGA content in PTC tumors was due to the low expression levels of tyrosine aminotransferase (TAT) and p-hydroxyphenylpyruvate hydroxylase (HPD), which catalyze the conversion of tyrosine to HGA. The low expression levels of TAT and HPD are strongly associated with a higher probability of PTC tumor invasion and metastasis. Our study demonstrates that HGA could be used to diagnose PTC and provides mechanisms linking altered HGA levels to the biological behavior of PTC tumors.

Calcium channel blockers and Parkinson's disease: a systematic review and meta-analysis.

Background: The calcium channel has been considered to have great potential as a drug target for neuroprotective therapy in Parkinson's disease (PD), but previous studies yielded inconsistent results. Objectives: This study aimed to conduct a systematic review and meta-analysis to assess the relationship between using calcium channel blockers (CCBs) and the risk and progression of PD. Data sources and methods: The terms such as 'Parkinson's disease', 'PD', 'calcium channel blockers', and 'CCB' were used to search the literature published before 1 May 2023 in English databases, including PubMed, Embase, and Cochrane Library, for studies on CCB and PD. Data analysis was performed using Review Manager 5.3 software. Results: A total of 190 works of literature were preliminarily retrieved, and 177 works of literature were excluded by eliminating duplicates, reading abstracts, and reading full texts. A total of nine studies were finally included in the meta-analysis of the CCB and the risk of PD, and five studies were included in the systematic review of the CCB and the progression of PD. A total of 2,961,695 participants were included in the meta-analysis. The random-effects model was used for analysis due to significant heterogeneity. The main results of the meta-analysis showed that the use of CCB could reduce the risk of PD (relative risk 0.78, 95% confidence interval 0.62-0.99). Conclusion: CCB use was associated with a significantly reduced risk of PD. Whether CCB use has a disease-modifying effect on PD needs further study. Registration: PROSPERO: CRD42024508242.

Cognitive impairment, neuroimaging abnormalities, and their correlations in myotonic dystrophy: a comprehensive review.

Myotonic dystrophy (DM) encompasses a spectrum of neuromuscular diseases characterized by myotonia, muscle weakness, and wasting. Recent research has led to the recognition of DM as a neurological disorder. Cognitive impairment is a central nervous system condition that has been observed in various forms of DM. Neuroimaging studies have increasingly linked DM to alterations in white matter (WM) integrity and highlighted the relationship between cognitive impairment and abnormalities in WM structure. This review aims to summarize investigations into cognitive impairment and brain abnormalities in individuals with DM and to elucidate the correlation between these factors and the potential underlying mechanisms contributing to these abnormalities.

Longitudinal Evolution and Plasma Biomarkers for Excessive Daytime Sleepiness in Parkinson's Disease.

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], p = .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], p = .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.

Plasma GFAP as a prognostic biomarker of motor subtype in early Parkinson's disease.

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.

Genome-wide DNA methylation analysis related to ALS patient progression and survival.

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.

Systemic inflammation and risk of Parkinson's disease: A prospective cohort study and genetic analysis.

BACKGROUND: Multiple evidence has suggested the complex interplay between Parkinson's disease (PD) and systemic inflammation marked by C-reactive protein (CRP) and interleukin 6 (IL-6). Nevertheless, the findings across studies have shown inconsistency, and the direction of the effect remains controversial. Here, we aimed to explore the link between CRP and IL-6 and the risk of PD. METHODS: Based on data from the UK Biobank, we investigated the association between baseline CRP and IL-6 and the risk of incident PD with Cox proportional hazards regression analysis. We further performed extensive genetic analyses including genetic correlation, polygenic risk score (PRS), and pleiotropic enrichment based on summary statistics from previous genome-wide association studies. RESULTS: A higher level of CRP at baseline was associated with a lower risk of PD (HR = 0.85, 95 % CI: 0.79-0.90, P = 4.23E-07). The results remained consistent in the subgroup analyses stratified by sex, age and body mass index. From the genetic perspective, a significant negative genetic correlation was identified between CRP and PD risk (correlation: -0.14, P = 6.31E-05). Higher PRS of CRP was associated with a lower risk of PD (P = 0.015, beta = -0.04, SE = 0.017). Moreover, we observed significant pleiotropic enrichment for PD conditional on CRP, and identified 13 risk loci for PD, some of which are implicated in immune functionality and have been linked to PD, including CTSB, HNF4A, PPM1G, ACMSD, and NCOR1. In contrast, no significant association was identified between IL-6 and PD. CONCLUSIONS: Systemic inflammation at baseline measured by CRP level is associated with decreased future risk of PD. These discoveries contribute to a deeper comprehension of the role of inflammation in the risk of PD, and hold implications for the design of therapeutic interventions in clinical trials.

A novel microfluidic chip-based digital PCR method for enhanced sensitivity in the early diagnosis of colorectal cancer via mSEPT9.

BACKGROUND: To enhance the sensitivity of plasma methylated Septin9 gene (mSEPT9) detection in colorectal cancer (CRC) screening, we developed a microfluidic chip-based digital PCR (dPCR) method suitable for low-concentration samples, aiming to apply it for mSEPT9 detection in CRC diagnosis. METHODS: Our microfluidic chip-based dPCR method utilized specific primers and probes with locked nucleic acids (LNAs) modifications for mSEPT9 detection. We evaluated its performance, including detection limit, specificity, and linear range, comparing it with a commercial qPCR reagent kit using the same samples (95 CRC, 23 non-CRC). RESULTS: The LNAs-modified dPCR method showed a linear range of 100-104 copies/µL and a detection limit of 100 copies/µL. Clinical testing revealed that our dPCR method exhibited a sensitivity of 82.11 % and specificity of 95.65 % for CRC diagnosis, outperforming the commercial qPCR kit (sensitivity: 58.95 %, specificity: 91.30 %), particularly in Stage I with a diagnostic sensitivity of 90.91 %. Combining mSEPT9 and carcinoembryonic antigen (CEA) improved diagnostic sensitivity to 91.49 %. CONCLUSIONS: Our accurate microfluidic chip-based dPCR method, especially in combination with CEA, holds promise for effective CRC screening and timely interventions, offering enhanced mSEPT9 quantification over conventional qPCR.

Peripheral immunity relate to disease progression and prognosis in amyotrophic lateral sclerosis.

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.

Relationship between plasma NFL and disease progression in Parkinson's disease: a prospective cohort study.

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.

Rare DNAJC7 Variants May Play a Minor Role in Chinese Patients with ALS.

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.

Rare variant analysis of UQCRC1 in Chinese patients with early-onset Parkinson's disease.

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.

Freezing of gait in Parkinson's disease with glucocerebrosidase mutations: prevalence, clinical correlates and effect on quality of life.

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.

Orthostatic Hypotension in Multiple System Atrophy: Related Factors and Disease Prognosis.

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, p = 0.021). 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, p < 0.001; 77/64 vs. 29/59 vs. 32/183, p < 0.001). Factors related to the severity of OH included sex (OR, 0.65; p = 0.031), onset age (OR, 0.98; p = 0.029), and SH (OR, 0.21; p < 0.001). The median survival time of patients with severe OH was significantly lower than that of patients without OH (6.79 vs. 8.13 years, p = 0.001). 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; p < 0.001). CONCLUSION: Our large cohort study of MSA provides additional evidence for the negative impact of severe OH on survival.

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.