BACKGROUND:The development of non-invasive diagnostic tools for Parkinson's disease (PD) remains an unmet clinical need. Given the contribution by peripheral metabolism and environmental factors toward PD pathogenesis, comprehensive profiling of the plasma phenome could enable early disease detection. Accordingly, this study aimed to develop a non-invasive diagnostic panel for PD, to comprehensively characterize potential environmental triggers of PD pathogenesis, and to delineate the relationship between peripheral metabolism and disease progression. METHODS:We performed quantitative plasma phenome profiling - including metabolomics, lipidomics and bile acid analysis - in two independent cohorts of early PD (n = 226, median disease duration <5 years) comprising predominantly treated and treatment-naive patients, respectively, and healthy controls (HCs; n = 122) to identify PD-associated metabolites. Longitudinal analyses were conducted in a patient subset over a two-year follow-up. Longitudinal analyses (2 years) and trans-omics integration were applied. RESULTS:Trans-omics integration showed glutathione metabolism dysregulation, with reduced plasma γ-glutamyl peptides and elevated sphingomyelin linked to motor dysfunction; higher baseline γ-glutamyl peptides predicted worse motor prognosis in PD. Reduced sphingosine-1-phosphates (S1Ps) and lysophosphatidic acids (LPAs) were correlated with abated tricarboxylic acid (TCA) cycle and motor deterioration. A three-metabolite panel (pyroglutamic acid, 2-methylbutyrylglycine, α-ketoisovaleric acid), selected via LASSO regression, robustly discriminated early PD from HCs, consistently outperforming clinical indices and lipid/bile acid panels (Discovery AUROC = 0.97 [0.96-0.99]; Validation AUROC = 0.83 [0.75-0.91]). CONCLUSION:Our findings demonstrate the clinical utility of plasma metabolites as robust, medication-independent biomarkers for early PD diagnosis, and delineate disease-associated metabolic deficits as potential targets for nutritional/metabolic intervention.

Dorsal nigral hyperintensity (DNH) abnormality associated with excessive iron deposition in the substantia nigra, is recognized as an imaging characteristic of Parkinson’s disease (PD) and can be effectively visualized using 7T MRI. This study was aimed to develop and validate the optimal DNH assessment method as a biomarker for PD, idiopathic rapid eye movement sleep behavior disorder (iRBD), and Parkinson-plus syndromes, and to explore the nigral iron deposition patterns in these diseases. Three-dimensional gradient-echo T2*-weighted images were acquired by 7T MRI from a total of 402 patients and 100 healthy controls (HCs) in two independent cohorts (development and validation cohorts). Seven methods, including four dichotomous methods and three DNH rating scales, were used to assess DNH and evaluate their diagnostic performance. R2* mapping and principal component analysis were performed to assess nigral iron deposition patterns. Bilateral DNH detection rates in the development cohort were 22.6

Background:Frailty, a clinically recognized geriatric syndrome marked by diminished physiological reserve and heightened vulnerability to adverse health outcomes stemming from multisystem dysregulation, represents a growing global health challenge. This investigation sought to examine the potential association between cephalalgia and incident frailty risk in aging populations. Methods: Leveraging longitudinal data from the China Health and Retirement Longitudinal Study (CHARLS) across 2011-2015 waves, we performed both cross-sectional and prospective cohort analyses involving 17,705 community-dwelling adults aged ≥45 years. Episodic headache was defined as reporting headache either at baseline (2011, Wave 1) or at the follow-up (2015, Wave 3).Chronic headache was defined as reporting headache at both baseline (2011, Wave 1) and at the follow-up endpoint (2015, Wave 3).. Frailty status was quantified using a validated 32-item frailty index (FI) encompassing functional, cognitive, and comorbid conditions. Results: At Wave 1, significant differences were observed between the headache group (n = 1,416) and non-headache group (n = 10,314). The headache group had a higher proportion of females (67.4% vs. 47.4%) and a higher prevalence of comorbidities, including frailty (30.2% vs. 7.8%). They also reported lower engagement in hobbies, smoking, and drinking, as well as shorter sleep duration (5.7 ± 2.1 vs. 6.5 ± 1.7 hours) (all P < 0.001). Logistic regression analysis indicated significantly higher odds of frailty for the headache group in the unadjusted model (OR 5.13, 95% CI 4.48–5.87) and after adjusting for sociodemographic factors (OR 5.39, 95% CI 4.60–6.32) and lifestyle factors (OR 4.22, 95% CI 3.52–5.06) (all P < 0.001). At Wave 3, individuals with chronic headache had markedly elevated odds of frailty (OR 8.30, 95% CI 5.91–11.66) compared to episodic headache (OR 3.71, 95% CI 3.04–4.53). Both chronic (OR 7.98, 95% CI 5.18–12.28) and episodic headaches (OR 3.49, 95% CI 2.73–4.45) remained significantly associated with frailty after adjustments. Subgroup analyses confirmed consistent associations across various demographics, including age and marital status (all P < 0.001). No significant interactions were noted across subgroups. Conclusion:Our study demonstrates that headache is significantly associated with an increased risk of frailty in middle-aged and older adults, with chronic headache showing a more pronounced effect. These results underscore the clinical imperative for optimized headache management strategies as a potential modifiable factor in frailty prevention. Implementing such strategies may concurrently improve geriatric quality of life and reduce the socioeconomic burdens linked to aging-related disability.

BACKGROUND:This study investigated the association between high-risk perioperative medications (HRPOMs) and postoperative cardiac complications in older adults undergoing spinal surgery. METHODS:This retrospective cohort study included patients aged 75 years and older who underwent elective spinal surgery under general anesthesia between January 2020 and December 2022. We collected data on demographic characteristics, comorbidities, preoperative hemoglobin level, intraoperative details and postoperative cardiac complications. Univariate and multivariate regression analyses were conducted to identify risk factors for postoperative cardiac complications. RESULTS:Of 427 patients who underwent spinal surgery included in the study, 301 were found to be using high-risk cardiac medications. Postoperatively, 28 patients experienced cardiac complications, an incidence rate of 6.6 %. Multivariate analysis identified several significant predictors of these complications: lower preoperative serum hemoglobin levels (adjusted odds ratio (AOR) = 0.969; p = 0.017), intraoperative blood loss (AOR = 1.124; p = 0.010) and preoperative long-term use of beta-blockers (AOR = 2.708; p = 0.026). In particular, a failure to resume the use of beta-blockers after surgery (AOR = 159.942; p<0.001) seems to be the most significant factor. CONCLUSION:In summary, our study highlights important risk factors for postoperative cardiac complications in older adults undergoing spinal surgery, especially the standardized use of HRPOMs in the perioperative period. Future research should aim to validate these findings through prospective studies and ensure the safety of perioperative medications for patients.

BACKGROUND:Repeat expansions have been reported as genetic causes/risk factors of Parkinson's disease (PD). As a novel repeat expansion locus, the FGF14-SCA27B (GAA)•(TTC) repeat locus is unexplored in PD. METHODS:Utilizing genetic sequencing and various polymerase chain reaction (PCR) methodologies, pure and complex repeat expansions in FGF14 were detected in Asian PD patients. Targeted long-read sequencing was performed to investigate the detailed sequence composition of these repeat expansions. Case-control studies were further performed. RESULTS:Pure (TTC)≥250 repeat expansion was detected in 2 of 1190 PD patients (0.17%). Additionally, a more common and complex (TTC)/(TGC)≥300 repeat expansion was detected as the main expanded genotype in our discovery cluster. Using targeted long-read sequencing, these complex (TTC)/(TGC) repeat expansions were characterized as (TTC)exp(TGCTTC)exp(TGCTTCTTCTTCTTC)n(TTC)n alleles with four segments (Seg 1-4), and further classified into four genotypic patterns. Pattern 1 was mainly characterized by a (CTC) interruption in the Seg 1-(TTC)exp. Patterns 2-4 were characterized by different repeat length of Seg 1-(TTC)exp and Seg 3-(TGCTTCTTCTTCTTC)n. Case-control analysis revealed a significant enrichment of Pattern 4 (TTC)/(TGC) repeat expansion in PD compared with controls (P = 0.024, OR: 2.60, 95% CI: 1.07-7.23) in the discovery cluster. This significant association between Pattern 4 (TTC)/(TGC) repeat expansion and PD was confirmed in one of two replication clusters (P = 0.035, OR: 2.18, 95% CI: 0.95-4.53) and the meta-analysis across all three clusters (P = 0.015, OR: 1.75, 95% CI: 1.10-2.79). INTERPRETATION:We identified a unique complex (TTC)/(TGC) repeat expansion in FGF14 as a novel genetic risk factor of PD in the Asian population. © 2025 International Parkinson and Movement Disorder Society.

INTRODUCTION:Pantothenate kinase-associated neurodegeneration (PKAN) is a rare neurodegenerative disorder marked by brain iron accumulation and mitochondrial dysfunction, with limited effective treatments. This study investigates cellular dysfunctions in PKAN fibroblasts with PANK2 mutations and evaluates the therapeutic potential of the antioxidant allantoin for protecting mitochondrial and autophagic functions. METHODS:We investigated oxidative stress, mitochondrial impairment, and autophagic dysfunction in skin fibroblasts derived from PKAN patients carrying mutations in the PANK2 gene and siR-pank2 treated fibroblasts, and evaluates the therapeutic potential of allantoin in mitigating these defects. RESULTS:Our results revealed significantly elevated levels of H2O2 and an increased mitochondrial labile iron pool (LIP), also reduced aconitase 2 (ACO2) activity and mitochondrial membrane potential, suggesting heightened oxidative stress and mitochondrial dysfunction. Autophagic flux was also impaired, as evidenced by the increased LC3-II and p62 accumulation. Allantoin treatment significantly reduced intracellular iron deposition and lipid peroxidation in PANK2-deficient fibroblasts. LIP levels were decreased, and ACO2 activity was elevated in allantoin-treated PANK2 mutant fibroblasts and siRNA-pank2 fibroblasts. Additionally, allantoin treatment promoted autophagic flux by reducing LC3-II and p62 levels. CONCLUSION:These findings highlight the key pathological effect of oxidative stress, mitochondrial dysfunction and impaired autophagy in PKAN and suggest a protective role of allantoin in iron deposition via dual regulation of mitochondrial dysfunction and compromised autophagy. The data provides a foundation for future in vivo studies and the potential clinical application of allantoin in PKAN and related neurodegenerative diseases.

BACKGROUND:The aim of this study was to develop and validate a functional ability index (FAI) that incorporates aspects of intrinsic capacity and environmental factors of older individuals based on the World Health Organization framework of healthy ageing. METHODS:Data of 7016 participants ≥60 years participating in the baseline survey of China Health and Retirement Longitudinal Study was used for the development and internal validation of the FAI. External validation was performed in a separate cohort of 1295 older individuals aged ≥60 years. Functional independency was considered the primary outcome and additional proxies of healthy ageing were considered as secondary outcomes. Cluster dendrogram was used to identify the distinct hierarchical clusters of all included variables for inclusion in the FAI. Backward elimination logistic regression model was implemented to identify the most significant variables associated with independency to be included in the FAI. RESULTS:The FAI score ranged from 0 to 19 and individuals having FAI ≥ 12 were more likely to be independent and at lower risk of negative outcomes. For each unit increase in the FAI the risk of having independency increased by 30%-58% cross-sectionally in the two cohorts, whilst the 2-year risk of independency increased by 20%. The FAI demonstrated a C-statistic of 0.73 (95% confidence interval, 0.72 and 0.75) for the primary outcome. CONCLUSIONS:The FAI we developed effectively measured the functional ability status of community dwelling older individuals. FAI could serve as a tool for evaluating older individual's functional ability in routine health assessment.

While numerous single nucleotide variants and small indels have been identified in Parkinson's disease (PD), the contribution of structural variants (SVs), copy number variants (CNVs), and short tandem repeats (STRs) remains poorly understood. Here we investigated the association using the high-depth whole-genome sequencing data from 466 Chinese PD patients and 513 controls. Totally, we identified 29,561 SVs, 32,153 CNVs, and 174,905 STRs, and found that CNV deletions were significantly enriched in the end-proportion of autosomal chromosomes in PD. After genome-wide association analysis and replication in an external cohort of 352 cases and 547 controls, we validated that the 1.6 kb-deletion neighboring MUC19, 12.4kb-deletion near RXFP1 and GGGAAA repeats in SLC2A13 were significantly associated with PD. Moreover, the MUC19 deletion and the SLC2A13 5-copy repeat reduced the penetrance of the LRRK2 G2385R variant. Moreover, genes with these variants were dosage-sensitive. These data provided novel insights into the genetic architecture of PD.

患儿 女，2岁，自1岁3月龄开始反复出现癫痫持续状态发作，合并发作性偏瘫，运动、语言发育落后，小头畸形，颅脑CT示特征性颅内钙化，病初颅脑磁共振成像未见明显异常，多次癫痫持续状态发作后可见脑萎缩。予丙戊酸钠、托吡酯联合抗癫痫发作治疗，随访至2岁6月龄患儿未再有癫痫发作，肢体肌力基本恢复基线水平。家系全外显子测序检出CLDN5基因变异：c.178G>A（p.Gly60Arg）（NM_001363066.2），为新发变异，线粒体环基因检测结果为阴性。

The brain of patients with Parkinson’s disease (PD) was characterized by increased phosphorylation and oligomerization of α-synuclein (α-syn) and altered activity of enzymes regulating α-syn phosphorylation and oligomerization. Whether increased α-syn phosphorylation and oligomerization as well as related enzyme changes can be detected in the plasma of PD patients remains unclear. Here, we showed that human α-syn proteins incubated in PD plasma formed more oligomerized α-syn (O-α-syn) and phosphorylated α-syn (pS-α-syn) than those in healthy control (HC) plasma. Receiver operating characteristic (ROC) curve indicated that α-syn oligomerization rate and phosphorylation rate discriminated PD patients well from HC subjects. Moreover, they were both positively correlated with Hoehn and Yahr staging and polo-like kinase 2 (PLK2, an enzyme promoting α-syn phosphorylation) levels, and negatively correlated with protein phosphatase 2A levels (PP2A, an enzyme dephosphorylating α-syn) and glucocerebrosidase (GCase, an enzyme whose deficiency causes α-syn oligomerization) activity and ceramide (a product of GCase and a natural PP2A activator) levels. The above results suggest that increased α-syn oligomerization and phosphorylation rates and related enzyme changes can be detected in PD plasma and used to discriminate PD patients from HC subjects and predict PD progression.

Objective To investigate the effect of perioperative individualized nutritional intervention on the changes of nutritional indicators and prognosis of elderly patients with nutritional risk after posterior lumbar interbody fusion. Methods From January 2018 to December 2019,a total of 181 elderly patients over 75 years old with posterior lumbar interbody fusion in Xuanwu Hospital Capital Medical University were included in this study.85 patients with≥3 points of NRS2002 were included in the intervention group,and 96 patients with<3 points of NRS2002 were included in the control group.The control group was given routine diet education,and the patients ordered meals according to their own dietary patterns and preferences.The intervention group was given further nutritional assessment and individualized nutritional treatment plan was developed.Nutritional indices(serum total protein,albumin,prealbumin and hemoglobin),potential risk factors for postoperative hypoproteinemia(whether diabetes mellitus,frailty,operative time and intraoperative blood loss) and postoperative infection were compared between the two groups. Results There were no significant differences in gender,course of disease,proportion of combined diabetes and frailty between the two groups(P>0.05).The age of the intervention group was higher than that of the control group,the body mass index,intraoperative blood loss,preoperative serum total protein,albumin,prealbumin and hemoglobin levels were lower than those of the control group,and the operation time was shorter than that of the control group,with statistical significance(P<0.05).The levels of serum total protein,albumin,prealbumin and hemoglobin in both groups were decreased after operation,but the levels of all indexes in the intervention group were lower than those in the control group,with statistical significance(P<0.05).There was no significant difference in length of hospital stay and postoperative infection between the two groups(P>0.05). Conclusion For elderly patients with nutritional risk,preoperative nutritional intervention can reduce the decline of postoperative nutritional indicators.

Introduction Multiple system atrophy (MSA) is a rapidly progressing neurodegenerative disorder. Although diverse biomarkers have been established for Parkinson's disease (PD), no widely accepted markers have been identified in MSA. Pyruvate and lactate are the end-product of glycolysis and crucial for brain metabolism. However, their correlation with MSA remains unclear. Moreover, it is elusive how lifestyles modify these metabolites. Methods To investigate the correlation and diagnostic value of plasma pyruvate and lactate levels in MSA and PD. Moreover, we explored how lifestyle-related metabolites interact with these metabolites in determining the disease risk. We assayed the 3 metabolites in pyruvate/lactate and 6 in the tea/coffee metabolic pathways by targeted mass spectrometry and evaluate their interactions and performance in diagnosis and differentiation between MSA and PD. Results We found that 7 metabolites were significantly different between MSA, PD and healthy controls (HCs). Particularly, pyruvate was increased in PD while significantly decreased in MSA patients. Moreover, the tea/coffee metabolites were negatively associated with the pyruvate level in HCs, but not in MSA and PD patients. Using machine-learning models, we showed that the combination of pyruvate and tea/coffee metabolites diagnosed MSA (AUC = 0.878) and PD (AUC = 0.833) with good performance. Additionally, pyruvate had good performance in distinguishing MSA from PD (AUC = 0.860), and the differentiation increased (AUC = 0.922) when combined with theanine and 1,3-dimethyluric acid. Conclusions This study demonstrates that pyruvate correlates reversely with MSA and PD, and may play distinct roles in their pathogenesis, which can be modified by lifestyle-related tea/coffee metabolites.

Autosomal recessive spinocerebellar ataxias (SCARs) are a heterogeneous group of neurodegenerative disorders. VPS13D gene is currently the only gene associated with autosomal recessive spinocerebellar ataxia type 4 (SCAR4), also known as VPS13D dyskinesia. SCAR4 is a rare inherited disease, with only 34 reported cases reported worldwide. In this study, we reported three independent SCAR4 cases with adolescent onsets caused by five novel variants of the VPS13D gene. Each patient carried one frameshift and one missense variant: Patient 1 with c.10474del and c.9734C > A (p.Leu3492Tyrfs*43 and p.Thr3245Asn), Patient 2 with c.6094_6107delGTTCTCTTGATCCC and c.9734C > A (p.Val2032Argfs*7 and p.Thr3245Asn), and Patient 3 with c.11954_11963del and c.9833 T > G (p.Phe3985Serfs*10 and p.Ile3278Ser). Two of the three patients shared nystagmus with an identical variant c.9734C > A. Magnetic resonance imaging indicated thoracic spinal atrophy in all three patients and corpus callosum atrophy in one patient, along with other typical manifestations of white matter degradation, cerebral atrophy, and cerebellar atrophy. These findings expanded the genetic, clinical, and neuroimaging spectrum of SCAR4, and provided new insights into the genetic counseling, molecular mechanisms, and differential diagnosis of the disease.

BackgroundPrevious genome-wide association studies investigating the relationship between the HLA-DRB1 and the risk of Parkinson’s disease (PD) have shown limited racial diversity and have not explored clinical heterogeneity extensively.MethodsThe study consisted of three parts: a case–control study, a cross-sectional study, and a longitudinal cohort study. The case–control study included 477 PD patients and 477 healthy controls to explore the relationship between rs660895 and PD susceptibility. The cross-sectional study utilized baseline data from 429 PD patients to examine the correlation between rs660895 and PD features. The longitudinal study included 388 PD patients who completed a 3-year follow-up to investigate the effects of rs660895 on PD progression.ResultsIn the case–control study, HLA-DRB1 rs660895-G allele was associated with a decreased risk of PD in allele model (adjusted OR=0.72, p = 0.003) and dominant model (AG + GG vs. AA: adjusted OR = 0.67, p = 0.003). In the cross-sectional analysis, there was no association between rs660895 and the onset age, motor phenotype, or initial motor symptoms. In the longitudinal analysis, PD patients with the G allele exhibited a slower progression of motor symptoms (MDS-UPDRS-III total score: β = −5.42, p < 0.001, interaction ptime × genotype < 0.001) and non-motor symptoms (NMSS score: β = −4.78, p = 0.030, interaction ptime × genotype < 0.001).ConclusionOur findings support HLA-DRB1 rs660895-G allele is a protective genetic factor for PD risk in Chinese population. Furthermore, we also provide new evidence for the protective effect of rs660895-G allele in PD progression.