Quantifying cerebral blood flow changes using arterial spin labeling: A comparative study of idiopathic rapid eye movement sleep behavior disorder and Parkinson's disease.

INTRODUCTION: Idiopathic rapid eye movement sleep behavior disorder (iRBD) and Parkinson's disease (PD) have been found to have changes in cerebral perfusion and overlap of some of the lesioned brain areas. However, a consensus regarding the specific location and diagnostic significance of these cerebral blood perfusion alternations remains elusive in both iRBD and PD. The present study evaluated the patterns of cerebral blood flow changes in iRBD and PD. MATERIAL AND METHODS: A total of 59 right-handed subjects were enrolled, including 15 patients with iRBD, 20 patients with PD, and 24 healthy controls (HC). They were randomly divided into groups at a ratio of 4 to 1 for training and testing. A PASL sequence was employed to obtain quantitative cerebral blood flow (CBF) maps. The CBF values were calculated from these acquired maps. In addition, AutoGluon was employed to construct a classifier for CBF features selection and classification. An independent t-test was performed for CBF variations, with age and sex as nuisance variables. The performance of the feature was evaluated using receiver operating characteristic (ROC) curves. A significance level of P < 0.05 was considered significant. CBF in several brain regions, including the left median cingulate and paracingulate gyri and the right middle occipital gyrus (MOG), showed significant differences between PD and HC, demonstrating good classification performance. The combined model that integrates all features achieved even higher performance with an AUC of 0.9380. Additionally, CBF values in multiple brain regions, including the right MOG and the left angular gyrus, displayed significant differences between PD and iRBD. Particularly, CBF values in the left angular gyrus exhibited good performance in classifying PD and iRBD. The combined model achieved improved performance, with an AUC of 0.8533. No significant differences were found in brain regions when comparing CBF values between iRBD and HC subjects. CONCLUSIONS: ASL-based quantitative CBF change features can offer reliable biomarkers to assist in the diagnosis of PD. Regarding the characteristic of CBF in the right MOG, it is anticipated to serve as an imaging biomarker for predicting the progression of iRBD to PD.

Unraveling the interplay between dyskinesia and overactive bladder symptoms in Parkinson's disease: a comprehensive cohort study based on the long-term follow-up database of Parkinson's disease.

OBJECTIVES: Overactive bladder (OAB) and dyskinesia are frequent complications in patients with Parkinson's disease (PD). However, the correlation between OAB and dyskinesia has been insufficiently explored. The purpose of this study was to examine the relationship between dyskinesia, OAB, and clinical characteristics among individuals with PD. METHODS: 1338 PD patients were included in the present study. Demographic features were compared between patients with or without dyskinesia and OAB symptoms. Logistic regression was conducted on dyskinesia to screen clinically relevant factors. Overactive Bladder Symptom Score (OABSS) was further used to stratify the association between the severity of OAB and the occurrence of dyskinesia. RESULTS: This study indicates that both dyskinesia and OAB are significantly related to disease severity and cognitive status. PD patients with dyskinesia and OAB having higher UPDRS scores (p < 0.001), H-Y scores (p < 0.001), NMSQ (p < 0.001) and MoCA scores (p < 0.001), and lower MMSE scores (p < 0.001) are identified. The multivariate logistic regression confirms that disease duration (p = 0.041), LEDD (p < 0.001), UPDRSII (p < 0.001), MoCA (p = 0.024), urgency (p < 0.001), frequency (p < 0.001), and nocturia (p = 0.002) are independent risk factors for dyskinesia. Trend analysis indicates that the risk of dyskinesia significantly increases when patients exhibit moderate to severe OAB symptoms (OABSS > 5) (p < 0.001). No significant interactions were found between OABSS and age, gender, disease duration, LEDD, and NMSQ scores in different subgroups, indicating that dyskinesia is more pronounced in patients with OABSS > 5. DISCUSSION: This study provides compelling evidence supporting the strong correlation between OAB and dyskinesia in PD patients, emphasizing the presence of shared pathogenic mechanisms between these two conditions. Our findings underscore the importance of considering both OAB and dyskinesia in the clinical management of PD, investigating the intricate connections between OAB and dyskinesia could unveil valuable insights into the complex pathophysiology of PD and potentially identify novel therapeutic targets for more effective PD treatment strategies.

Higher cortical excitability to negative emotions involved in musculoskeletal pain in Parkinson's disease.

OBJECTIVE: Changes in brain structure and neurotransmitter systems are involved in pain in Parkinson's disease (PD), and emotional factors are closely related to pain. Our study applied electroencephalography (EEG) to investigate the role of emotion in PD patients with chronic musculoskeletal pain. METHODS: Forty-two PD patients with chronic musculoskeletal pain and 38 without were enrolled. EEG data were recorded under resting conditions, and while viewing pictures with neutral, positive, and negative content. We compared spectrum power, functional connectivity, and late positive potential (LPP), an event-related potential (ERP), between the groups. RESULTS: PD patients with pain tended to have higher scores for the Hamilton Rating Scale for Depression (HRSD). In the resting EEG, mean ß-band amplitude was significantly higher in patients with pain than in those without. Logistic regression analysis showed that higher HRSD scores and higher mean ß-band amplitude were associated with pain. ERP analysis revealed that the amplitudes of LPP difference waves (the absolute difference between positive and negative condition LPP and neutral condition LPP) at the central-parietal region were significantly reduced in patients with pain (P = 0.029). Spearman correlation analysis showed that the amplitudes of late (700-1000 ms) negative versus neutral condition LPP difference waves were negatively correlated with pain intensity, assessed by visual analogue scale, (r = -0.393, P = 0.010) and HRSD scores (r = -0.366, P = 0.017). CONCLUSION: Dopaminergic and non-dopaminergic systems may be involved in musculoskeletal pain in PD by increasing ß-band activity and weakening the connection of the θ-band at the central-parietal region. PD patients with musculoskeletal pain have higher cortical excitability to negative emotions. The changes in pain-related EEG may be used as electrophysiological markers and therapeutic targets in PD patients with chronic pain.

Slow-wave sleep and REM sleep without atonia predict motor progression in Parkinson's disease.

BACKGROUND: Growing evidence supports the potential role of sleep in the motor progression of Parkinson's disease (PD). Slow-wave sleep (SWS) and rapid eye movement (REM) sleep without atonia (RWA) are important sleep parameters. The association between SWS and RWA with PD motor progression and their predictive value have not yet been elucidated. METHODS: We retro-prospectively analyzed clinical and polysomnographic data of 136 patients with PD. The motor symptoms were assessed using Unified Parkinson's Disease Rating Scale Part III (UPDRS III) at baseline and follow-up to determine its progression. Partial correlation analysis was used to explore the cross-sectional associations between slow-wave energy (SWE), RWA and clinical symptoms. Longitudinal analyses were performed using Cox regression and linear mixed-effects models. RESULTS: Among 136 PD participants, cross-sectional partial correlation analysis showed SWE decreased with the prolongation of the disease course (P = 0.046), RWA density was positively correlated with Hoehn & Yahr (H-Y) stage (tonic RWA, P < 0.001; phasic RWA, P = 0.002). Cox regression analysis confirmed that low SWE (HR = 1.739, 95% CI = 1.038-2.914; P = 0.036; FDR-P = 0.036) and high tonic RWA (HR = 0.575, 95% CI = 0.343-0.963; P = 0.032; FDR-P = 0.036) were predictors of motor symptom progression. Furthermore, we found that lower SWE predicted faster rate of axial motor progression (P < 0.001; FDR-P < 0.001) while higher tonic RWA density was associated with faster rate of rigidity progression (P = 0.006; FDR-P = 0.024) using linear mixed-effects models. CONCLUSIONS: These findings suggest that SWS and RWA might represent markers of different motor subtypes progression in PD.

The association between plasma GPNMB and Parkinson's disease and multiple system atrophy.

AIMS: Parkinson's disease (PD), as the second most common neurodegenerative disorder, often presents diagnostic challenges in differentiation from other forms of Parkinsonism. Recent studies have reported an association between plasma glycoprotein nonmetastatic melanoma protein B (pGPNMB) and PD. METHODS: A retrospective study was conducted, comprising 401 PD patients, 111 multiple system atrophy (MSA) patients, 13 progressive supranuclear palsy (PSP) patients and 461 healthy controls from the Chinese Han population, with an assessment of pGPNMB levels. RESULTS: The study revealed that pGPNMB concentrations were significantly lower in PD and MSA patients compared to controls (area under the receiver operating characteristics curve (AUC) 0.62 and 0.74, respectively, P < 0.0001 for both), but no difference was found in PSP patients compared to controls (P > 0.05). Interestingly, the level of pGPNMB was significantly higher in PD patients than in MSA patients (AUC = 0.63, P < 0.0001). Furthermore, the study explored the association between pGPNMB levels and disease severity in PD and MSA patients, revealing a positive correlation in PD patients but not in MSA patients with both disease severity and cognitive impairment. CONCLUSION: This study successfully replicated prior findings, demonstrating an association between pGPNMB levels and disease severity, and also identified a correlation with cognitive impairment in PD patients of the Chinese Han population. Additionally, this study is the first to identify a significant difference in pGPNMB levels between MSA, PD, and normal controls. The data provide new evidence supporting the potential role of pGPNMB in the diagnosis and differential diagnosis of Parkinsonism.

Safinamide alleviates hyperalgesia via inhibiting hyperexcitability of DRG neurons in a mouse model of Parkinson's disease.

Pain is a widespread non-motor symptom that presents significant treatment challenges in patients with Parkinson's disease (PD). Safinamide, a new drug recently introduced for PD treatment, has demonstrated analgesic effects on pain in PD patients, though the underlying mechanisms remain unclear. To investigate the analgesic and anti-PD effect of safinamide, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model was used, and rasagiline as positive control on motor symptoms. Notably, only safinamide alleviated hyperalgesia in MPTP mice. Whole-cell patch-clamp recordings of dorsal root ganglion (DRG) neurons revealed hyperexcitability in MPTP mice, which safinamide counteracted in a concentration-dependent manner. The voltage clamp further demonstrated that sodium current in DRG neurons of MPTP mice was enhanced and safinamide reduced sodium current density. RT-qPCR identified upregulated Nav1.7 and Nav1.8 transcripts (Scn9a and Scn10a) in DRG neurons of MPTP mice. Our results suggest that safinamide could relieve hyperalgesia by inhibiting DRG neuron hyperexcitability in MPTP mice.

The value of ultrasound measurement of muscle thickness at different sites and shear wave elastography in Parkinson's disease with sarcopenia: a pilot study.

Background: Patients with Parkinson's disease (PD) and sarcopenia often exhibit resilience, frailty, disability, and depression, highlighting the complex and interrelated nature of these conditions. Objective: Despite the presence of clinical manifestations of muscle atrophy in both PD and sarcopenia, accurately discerning the coexistence of sarcopenia in PD patients remains a challenging task with significant implications for treatment strategies and prognostic assessments. This study aims to elucidate the specific ultrasonic diagnostic parameters associated with PD accompanied by sarcopenia through a comparative analysis of muscle ultrasound parameters in patients with PD, thereby presenting a novel approach for rapid identification of this condition. Methods: A total of 110 participants were enrolled in this study, including patients with PD and control subjects. Demographic data, clinical characteristics, physical performance tests, appendicular skeletal muscle mass index (ASMI), bioelectrical impedance analysis and muscle ultrasound measurements were collected from all participants. The muscle ultrasound measurements encompassed assessments of muscle thickness, pennation angle and shear wave elastography at various anatomical sites. Results: Parkinson's disease patients exhibited decreased muscle strength and physical performance, and increased shear wave elastography value. In PD patients with sarcopenia, body circumference, including calf circumference, mid-arm circumference, Waist-to-Hip Ratio and body mass index (BMI) were all significantly decreased. Biceps brachii muscle thickness (MT) and gastrocnemius MT decreased in PD patients with sarcopenia and low ASMI. Binary logistic regression analysis revealed that male PD patients, BMI and gastrocnemius MT were predictive factors for ASMI in PD patients. Conclusion: Biceps brachii MT and gastrocnemius MT are important indicators for distinguishing whether PD patients have sarcopenia. Male patients, low BMI and gastrocnemius MT were identified as valid predictors of low ASMI in PD patients. The findings of this study provide important insights into the use of muscle ultrasound in the diagnosis of PD with sarcopenia.

How sleep quality affects activities of daily living in Parkinson's disease: the mediating role of disease severity and the moderating role of cognition.

Objective: The aim of this study was to explore the influential mechanism of the relationship between sleep quality and activities of daily living (ADL) in patients with Parkinson's disease (PD), we hypothesized disease severity as a mediator and assumed the mediating process was regulated by cognition. Methods: 194 individuals with PD (95 women and 99 men) were enrolled in study. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality of PD patients. Patients' ADL, disease severity and cognition were measured by the Unified Parkinson's Disease Rating Scale-II (UPDRSII), Hoehn-Yahr (H-Y) Scale, and Mini-Mental State Examination (MMSE). We investigated the mediating role of disease severity and the moderating effect of cognition on the association between sleep quality and ADL in PD patients. Results: The score of UPDRSII was positively correlated with the score of PSQI and H-Y stage, while the score of MMSE was negatively correlated with the score of H-Y stage and UPDRSII. Sleep quality predicts disease severity, and disease severity predicts ADL. Disease severity mediated the relationship between sleep quality and ADL, and the mediating effect was 0.179. Cognition alone did not affect ADL, but the interaction between disease severity and cognition was significantly affected ADL, confirming the moderating effect of cognition in PD patients. Conclusion: Disease severity mediated the association between sleep quality and ADL, good cognition significantly reduced disease severity's mediating influence on the relationship between sleep quality and ADL. Our study indicated a close relationship between ADL and sleep and cognition in PD, and also provided new insights into the overall management of PD and a better quality of life of PD patients.

Mass Spectrometric Analysis of Urinary N-Glycosylation Changes in Patients with Parkinson's Disease.

Urine is thought to provide earlier and more sensitive molecular changes for biomarker discovery than blood. Numerous glycoproteins, peptides, and free glycans are present in urine through glomerular filtration of plasma, cell shedding, apoptosis, proteolytic cleavage, and exosome secretion. Urine biomarkers have enormous diagnostic potential, and the use of these biomarkers is a long-standing practice. The discovery of non-urological disease biomarkers from urine is also gaining attention due to its non-invasive sample collection and ease of analysis. Abnormal protein glycosylation in plasma or cerebrospinal fluid has been associated with Parkinson's disease, however, whether urine with Parkinson's disease has characteristic glycosylation remains to be explored. Here, we use mass spectrometry-based glycomics and glycoproteomics approaches to analyze urine samples for glycans, glycosites, and intact glycopeptides of urine samples. Reduced abundance of N-glycans was detected at the level of total glycans as well as specific glycosites of glycopeptides. The most abundant N-glycan in urine is S(6)1H5N4F1; S(6)2H5N4 and N4H4F1 are highly present in serum and urine, and 10 biantennary galactosylated N-glycans in the urine of PD patients were significantly decreased. The downregulation of sialylation may be due to the reduction of ST3GAL2. Site-specific N-glycosylation analysis revealed that AMBP, UMOD, and RNase1 have PD-specific N-glycosylation sites. GO and KEGG analysis revealed that N-glycosylation changes may provide clues to identify disease-specific glycosylation biomarkers in Parkinson's disease.

Effects of Sleep Fragmentation on White Matter Pathology in a Rat Model of Cerebral Small Vessel Disease.

STUDY OBJECTIVES: Mounting evidence indicated the correlation between sleep and cerebral small vessel disease (CSVD). However, little is known about the exact causality between poor sleep and white matter injury, a typical signature of CSVD, as well as the underlying mechanisms. METHODS: Spontaneously hypertensive rats (SHR) and control Wistar Kyoto rats were subjected to sleep fragmentation for 16 weeks. The effects of chronic sleep disruption on the deep white matter and cognitive performance were observed. RESULTS: SHR were validated as a rat model for CSVD. Fragmented sleep induced strain-dependent white matter abnormalities, characterized by reduced myelin integrity, impaired oligodendrocytes precursor cells (OPC) maturation and pro-inflammatory microglial polarization. Partially reversible phenotypes of OPC and microglia were observed in parallel following sleep recovery. CONCLUSIONS: Long-term SF induced pathological effects on the deep white matter in a rat model of CSVD. The pro-inflammatory microglial activation and the block of OPC maturation may be involved in the mechanisms linking sleep to white matter injury.

Sarcopenia is associated with non-motor symptoms in Han Chinese patients with Parkinson's Disease: a cross-sectional study.

BACKGROUND: Sarcopenia is commonly seen in the older adults and increases in incidence with age, also in Parkinson's disease (PD). Although research has indicated that the development of sarcopenia in patients with PD may be related to both motor symptoms and non-motor symptoms (NMS), the precise relationship between the two conditions remains unclear. Therefore, we aimed to investigate the incidence of sarcopenia in patients with PD and its association with NMS. METHODS: The study included 123 patients with PD and 38 age- and sex-matched healthy controls (HC). All participants were evaluated for sarcopenia using the 2019 Asian Sarcopenia Diagnostic Criteria, and patients with PD underwent standard assessments of motor symptoms and NMS. Multiple logistic regression and receiver operating characteristic (ROC) curve analyses were used to examine the association between sarcopenia and NMS in patients with PD. RESULTS: The incidence of sarcopenia was significantly higher in patients with PD than in HC (26.8% vs. 10.4%, p = 0.046). Multiple logistic regression analysis revealed that poorer sleep quality (odds ratio [OR]: 1.245; 95% confidence interval [CI]: 1.011-1.533; p = 0.040) and fatigue (OR: 1.085, 95% CI: 1.006-1.170, p = 0.034) were independently associated with sarcopenia. ROC analysis indicated that the optimal cut-off value for Pittsburgh Sleep Quality Index (PSQI) scores was 10, with 72.7% sensitivity and 74.4% specificity (area under the curve [AUC] = 0.776, 95% CI: 0.683-0.868, p < 0.001). The optimal cut-off value for Fatigue Severity Scale (FSS) scores was 39, with 87% sensitivity and 50% specificity (AUC = 0.725, 95% CI: 0.629 -0.820, p < 0.001). Joint use of FSS and PSQI scores increased the predictive value for sarcopenia(AUC = 0.804, 95% CI: 0.724-0.885, p < 0.001). CONCLUSION: Patients with PD are more susceptible to sarcopenia than healthy older adults, and fatigue and poorer sleep are positively associated with sarcopenia. Further longitudinal studies are needed to clarify the causal relationships.

PACAP/PAC1-R activation contributes to hyperalgesia in 6-OHDA-induced Parkinson's disease model rats via promoting excitatory synaptic transmission of spinal dorsal horn neurons.

Pain is a common annoying non-motor symptom in Parkinson's disease (PD) that causes distress to patients. Treatment for PD pain remains a big challenge, as its underlying mechanisms are elusive. Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1-R play important roles in regulating a variety of pathophysiological processes. In this study, we investigated whether PACAP/PAC1-R signaling was involved in the mechanisms of PD pain. 6-hydroxydopamine (6-OHDA)-induced PD model was established in rats. Behavioral tests, electrophysiological and Western blotting analysis were conducted 3 weeks later. We found that 6-OHDA rats had significantly lower mechanical paw withdrawal 50% threshold in von Frey filament test and shorter tail flick latency, while mRNA levels of Pacap and Adcyap1r1 (gene encoding PAC1-R) in the spinal dorsal horn were significantly upregulated. Whole-cell recordings from coronal spinal cord slices at L4-L6 revealed that the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in dorsal horn neurons was significantly increased, which was reversed by application of a PAC1-R antagonist PACAP 6-38 (250 nM). Furthermore, we demonstrated that intrathecal microinjection of PACAP 6-38 (0.125, 0.5, 2 µg) dose-dependently ameliorated the mechanical and thermal hyperalgesia in 6-OHDA rats. Inhibition of PACAP/PAC1-R signaling significantly suppressed the activation of Ca2+/calmodulin-dependent protein kinase II and extracellular signal-regulated kinase (ERK) in spinal dorsal horn of 6-OHDA rats. Microinjection of pAAV-Adcyap1r1 into L4-L6 spinal dorsal horn alleviated hyperalgesia in 6-OHDA rats. Intrathecal microinjection of ERK antagonist PD98059 (10 µg) significantly alleviated hyperalgesia in 6-OHDA rats associated with the inhibition of sEPSCs in dorsal horn neurons. In addition, we found that serum PACAP-38 concentration was significantly increased in PD patients with pain, and positively correlated with numerical rating scale score. In conclusion, activation of PACAP/PAC1-R induces the development of PD pain and targeting PACAP/PAC1-R is an alternative strategy for treating PD pain.

Decreased serum BDNF contributes to the onset of REM sleep behavior disorder in Parkinson's disease patients.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) promotes neuroprotection and neuroregeneration. BDNF enhances the survival of dopaminergic neurons and improves dopaminergic neurotransmission and motor performance in patients with Parkinson's disease (PD). However, the association between BDNF levels and rapid eye movement (REM) sleep behavior disorder (RBD) in PD patients has received limited attention. METHODS: We employed the Rapid Eye Movement Sleep Behavior Disorder Questionnaire-Hong Kong version (RBDQ-HK) and the Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire (RBDSQ) for RBD diagnosis. Patients were categorized into three groups: healthy controls (n = 53), PD patients without RBD (PD-nRBD; n = 56), and PD patients with RBD (PD-RBD; n = 45). Serum BDNF concentrations, demographic information, medical history, and motor/non-motor manifestations were compared between the three groups. Logistic regression analysis was performed to identify independent factors associated with PD and RBD. P-trend analysis was used to assess the relationship between BDNF levels and the risk of PD and RBD onset. Interaction effects were analyzed between BDNF, patients' age, and gender on the risk of RBD onset in PD patients. RESULTS: Our findings indicate that serum BDNF levels were significantly lower in PD patients compared to healthy controls (p < 0.001). PD-RBD patients exhibited higher motor symptom scores (UPDRS III) than PD-nRBD patients (p = 0.021). Additionally, the PD-RBD group demonstrated lower cognitive function scores as measured by the Montreal Cognitive Assessment (MoCA) (p < 0.001) and Mini-Mental State Examination (MMSE) (p = 0.015). PD-RBD patients displayed significantly lower BDNF levels compared to both PD-nRBD and healthy control groups (p < 0.001). Univariate and multivariate logistic regression analyses showed that reduced BDNF levels were associated with an increased risk of RBD in PD patients (p = 0.005). P-trend analysis further confirmed the progressive relationship between decreased BDNF levels and the risk of PD and RBD onset. Furthermore, our interaction analysis highlighted the importance of monitoring younger PD patients with low serum BDNF levels for potential RBD onset. CONCLUSIONS: This study illustrates that decreased serum BDNF levels may be linked to the development of RBD in PD patients, highlighting the potential utility of BDNF as a biomarker in clinical practice.

Association of Cortical Gyrification With Imaging and Serum Biomarkers in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVES: Pathologic progression across the cortex is a key feature of Parkinson disease (PD). Cortical gyrification is a morphologic feature of human cerebral cortex that is tightly linked to the integrity of underlying axonal connectivity. Monitoring cortical gyrification reductions may provide a sensitive marker of progression through structural connectivity, preceding the progressive stages of PD pathology. We aimed to examine the progressive cortical gyrification reductions and their associations with overlying cortical thickness, white matter (WM) integrity, striatum dopamine availability, serum neurofilament light (NfL) chain, and CSF α-synuclein levels in PD. METHODS: This study included a longitudinal dataset with baseline (T0), 1-year (T1), and 4-year (T4) follow-ups and 2 cross-sectional datasets. Local gyrification index (LGI) was computed from T1-weighted MRI data to measure cortical gyrification. Fractional anisotropy (FA) was computed from diffusion-weighted MRI data to measure WM integrity. Striatal binding ratio (SBR) was measured from 123Ioflupane SPECT scans. Serum NfL and CSF α-synuclein levels were also measured. RESULTS: The longitudinal dataset included 113 patients with de novo PD and 55 healthy controls (HCs). The cross-sectional datasets included 116 patients with relatively more advanced PD and 85 HCs. Compared with HCs, patients with de novo PD showed accelerated LGI and FA reductions over 1-year period and a further decline at 4-year follow-up. Across the 3 time points, the LGI paralleled and correlated with FA (p = 0.002 at T0, p = 0.0214 at T1, and p = 0.0037 at T4) and SBR (p = 0.0095 at T0, p = 0.0035 at T1, and p = 0.0096 at T4) but not with overlying cortical thickness in patients with PD. Both LGI and FA correlated with serum NfL level (LGI: p < 0.0001 at T0, p = 0.0043 at T1; FA: p < 0.0001 at T0, p = 0.0001 at T1) but not with CSF α-synuclein level in patients with PD. In the 2 cross-sectional datasets, we revealed similar patterns of LGI and FA reductions and associations between LGI and FA in patients with more advanced PD. DISCUSSION: We demonstrated progressive reductions in cortical gyrification that were robustly associated with WM microstructure, striatum dopamine availability, and serum NfL level in PD. Our findings may contribute biomarkers for PD progression and potential pathways for early interventions of PD.

A systematic analysis of genotype-phenotype associations with PLA2G6.

BACKGROUND: PLA2G6-associated neurodegeneration (PLAN) can be categorized into infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (aNAD), neurodegeneration with brain iron accumulation (NBIA), and early-onset parkinsonism (EOP). OBJECTIVES: To determine the genotype-phenotype association in PLAN. METHODS: "PLA2G6" or "PARK14" or "phospholipase A2 group VI" or "iPLA2ß" were searched across MEDLINE from June 23, 1997, to March 1, 2023. A total of 391 patients were identified, and 340 patients of them were finally included in the assessment. RESULTS: The loss of function (LOF) mutation ratios were significantly different (p < 0.001), highest in INAD, followed by NBIA, aNAD, and EOP. Four ensemble scores (i.e., BayesDel, VARITY, ClinPred, and MetaRNN) were assessed to predict the deleteriousness of missense mutations and demonstrated significant differences (p < 0.001). Binary logistic regression analyses demonstrated that LOF mutations were independently associated with brain iron accumulation (p = 0.006) and ataxia (p = 0.025). CONCLUSIONS: LOF or more deleterious missense mutations are more likely to promote the development of serious phenotype of PLAN, and LOF mutations are independently associated with brain iron accumulation and ataxia.

Circadian disruption and sleep disorders in neurodegeneration.

Disruptions of circadian rhythms and sleep cycles are common among neurodegenerative diseases and can occur at multiple levels. Accumulating evidence reveals a bidirectional relationship between disruptions of circadian rhythms and sleep cycles and neurodegenerative diseases. Circadian disruption and sleep disorders aggravate neurodegeneration and neurodegenerative diseases can in turn disrupt circadian rhythms and sleep. Importantly, circadian disruption and various sleep disorders can increase the risk of neurodegenerative diseases. Thus, harnessing the circadian biology findings from preclinical and translational research in neurodegenerative diseases is of importance for reducing risk of neurodegeneration and improving symptoms and quality of life of individuals with neurodegenerative disorders via approaches that normalize circadian in the context of precision medicine. In this review, we discuss the implications of circadian disruption and sleep disorders in neurodegenerative diseases by summarizing evidence from both human and animal studies, focusing on the bidirectional links of sleep and circadian rhythms with prevalent forms of neurodegeneration. These findings provide valuable insights into the pathogenesis of neurodegenerative diseases and suggest a promising role of circadian-based interventions.

Associations between variants in levodopa metabolic pathway genes and levodopa-induced dyskinesia in Parkinson's disease.

INTRODUCTION: Levodopa-induced dyskinesia (LID) is a common motor complication in Parkinson's disease (PD). Several genes in the levodopa metabolic pathway, such as COMT, DRDx and MAO-B, were reported associated with LID. However, there has been no systematic analyses between common variants in levodopa metabolic pathway genes and LID in a large sample of the Chinese population. METHODS: Through the whole exome sequencing (WES) and target region sequencing, we aimed to explore the potential associations between common single nucleotide polymorphisms (SNPs) in the levodopa metabolic pathway and LID in Chinese PD individuals. Five hundred and two PD individuals were enrolled in our study, among them, 348 individuals underwent WES, and 154 individuals underwent target region sequencing. We acquired the genetic profile of 11 genes including COMT, DDC, DRD1-5, SLC6A3, TH and MAO-A/B. We established a stepwise strategy to filter SNPs, which finally included 34 SNPs in our analyses. And we used a two-stage study, with discovery (348 individuals with WES) and the replication (all 502 individuals) to confirm our findings. RESULTS: Among the 502 PD individuals, 104 (20.7%) were diagnosed with LID. In the discovery stage, we found that COMT rs6269, DRD2 rs6275 and DRD2 rs1076560 were associated with LID. In the replication stage, associations between the three above-mentioned SNPs and LID were still present in all 502 individuals. CONCLUSION: We demonstrated that in the Chinese population, COMT rs6269, DRD2 rs6275 and rs1076560 were significantly associated with LID. And rs6275 was reported associated with LID for the first time.

Pramipexole inhibits astrocytic NLRP3 inflammasome activation via Drd3-dependent autophagy in a mouse model of Parkinson's disease.

Inflammation is one of the pathogenic processes in Parkinson's disease (PD). Dopamine receptor agonist pramipexole (PPX) is extensively used for PD treatment in clinics. A number of studies show that PPX exerts neuroprotection on dopaminergic (DA) neurons, but the molecular mechanisms underlying the protective effects of PPX on DA neurons are not fully elucidated. In the present study, we investigated whether PPX modulated PD-related neuroinflammation and underlying mechanisms. PD model was established in mice by bilateral striatum injection of lipopolyssaccharide (LPS). The mice were administered PPX (0.5 mg·kg-1·d-1, i.p.) 3 days before LPS injection, and for 3 or 21 days after surgery, respectively, for biochemical and histological analyses. We showed that PPX administration significantly alleviated the loss of DA neurons, and suppressed the astrocyte activation and levels of proinflammatory cytokine IL-1ß in the substantia nigra of LPS-injected mice. Furthermore, PPX administration significantly decreased the expression of NLRP3 inflammasome-associated proteins, i.e., cleaved forms of caspase-1, IL-1ß, and apoptosis-associated speck-like protein containing a caspase recruit domain (ASC) in the striatum. These results were validated in LPS+ATP-stimulated primary mouse astrocytes in vitro. Remarkably, we showed that PPX (100-400 µM) dose-dependently enhanced the autophagy activity in the astrocytes evidenced by the elevations in LC3-II and BECN1 protein expression, as well as the increase of GFP-LC3 puncta formation. The opposite effects of PPX on astrocytic NLRP3 inflammasome and autophagy were eliminated by Drd3 depletion. Moreover, we demonstrated that both pretreatment of astrocytes with autophagy inhibitor chloroquine (40 µM) in vitro and astrocyte-specific Atg5 knockdown in vivo blocked PPX-caused inhibition on NLRP3 inflammasome and protection against DA neuron damage. Altogether, this study demonstrates an anti-neuroinflammatory activity of PPX via a Drd3-dependent enhancement of autophagy activity in astrocytes, and reveals a new mechanism for the beneficial effect of PPX in PD therapy.