Neurovascular coupling alteration in drug-naïve Parkinson's disease: The underlying molecular mechanisms and levodopa's restoration effects.

BACKGROUND: Parkinson's disease (PD) patients exhibit an imbalance between neuronal activity and perfusion, referred to as abnormal neurovascular coupling (NVC). Nevertheless, the underlying molecular mechanism and how levodopa, the standard treatment in PD, regulates NVC is largely unknown. MATERIAL AND METHODS: A total of 52 drug-naïve PD patients and 49 normal controls (NCs) were enrolled. NVC was characterized in vivo by relating cerebral blood flow (CBF) and amplitude of low-frequency fluctuations (ALFF). Motor assessments and MRI scanning were conducted on drug-naïve patients before and after levodopa therapy (OFF/ON state). Regional NVC differences between patients and NCs were identified, followed by an assessment of the associated receptors/transporters. The influence of levodopa on NVC, CBF, and ALFF within these abnormal regions was analyzed. RESULTS: Compared to NCs, OFF-state patients showed NVC dysfunction in significantly lower NVC in left precentral, postcentral, superior parietal cortex, and precuneus, along with higher NVC in left anterior cingulate cortex, right olfactory cortex, thalamus, caudate, and putamen (P-value <0.0006). The distribution of NVC differences correlated with the density of dopaminergic, serotonin, MU-opioid, and cholinergic receptors/transporters. Additionally, levodopa ameliorated abnormal NVC in most of these regions, where there were primarily ALFF changes with limited CBF modifications. CONCLUSION: Patients exhibited NVC dysfunction primarily in the striato-thalamo-cortical circuit and motor control regions, which could be driven by dopaminergic and nondopaminergic systems, and levodopa therapy mainly restored abnormal NVC by modulating neuronal activity.

Microstructural alterations of the hypothalamus in Parkinson's disease and probable REM sleep behavior disorder.

BACKGROUND: Whether there is hypothalamic degeneration in Parkinson's disease (PD) and its association with clinical symptoms and pathophysiological changes remains controversial. OBJECTIVES: We aimed to quantify microstructural changes in hypothalamus using a novel deep learning-based tool in patients with PD and those with probable rapid-eye-movement sleep behavior disorder (pRBD). We further assessed whether these microstructural changes associated with clinical symptoms and free thyroxine (FT4) levels. METHODS: This study included 186 PD, 67 pRBD, and 179 healthy controls. Multi-shell diffusion MRI were scanned and mean kurtosis (MK) in hypothalamic subunits were calculated. Participants were assessed using Unified Parkinson's Disease Rating Scale (UPDRS), RBD Questionnaire-Hong Kong (RBDQ-HK), Hamilton Depression Rating Scale (HAMD), and Activity of Daily Living (ADL) Scale. Additionally, a subgroup of PD (n = 31) underwent assessment of FT4. RESULTS: PD showed significant decreases of MK in anterior-superior (a-sHyp), anterior-inferior (a-iHyp), superior tubular (supTub), and inferior tubular hypothalamus when compared with healthy controls. Similarly, pRBD exhibited decreases of MK in a-iHyp and supTub. In PD group, MK in above four subunits were significantly correlated with UPDRS-I, HAMD, and ADL. Moreover, MK in a-iHyp and a-sHyp were significantly correlated with FT4 level. In pRBD group, correlations were observed between MK in a-iHyp and UPDRS-I. CONCLUSIONS: Our study reveals that microstructural changes in the hypothalamus are already significant at the early neurodegenerative stage. These changes are associated with emotional alterations, daily activity levels, and thyroid hormone levels.

Cholinergic basal forebrain system degeneration underlies postural instability/gait difficulty and attention impairment in Parkinson's disease.

BACKGROUND AND PURPOSE: The specific pathophysiological mechanisms underlying postural instability/gait difficulty (PIGD) and cognitive function in Parkinson's disease (PD) remain unclear. Both postural and gait control, as well as cognitive function, are associated with the cholinergic basal forebrain (cBF) system. METHODS: A total of 84 PD patients and 82 normal controls were enrolled. Each participant underwent motor and cognitive assessments. Diffusion tensor imaging was used to detect structural abnormalities in the cBF system. The cBF was segmented using FreeSurfer, and its fiber tract was traced using probabilistic tractography. To provide information on extracellular water accumulation, free-water fraction (FWf) was quantified. FWf in the cBF and its fiber tract, as well as cortical projection density, were extracted for statistical analyses. RESULTS: Patients had significantly higher FWf in the cBF (p < 0.001) and fiber tract (p = 0.021) than normal controls, as well as significantly lower cBF projection in the occipital (p < 0.001), parietal (p < 0.001) and prefrontal cortex (p = 0.005). In patients, a higher FWf in the cBF correlated with worse PIGD score (r = 0.306, p = 0.006) and longer Trail Making Test A time (r = 0.303, p = 0.007). Attentional function (Trail Making Test A) partially mediated the association between FWf in the cBF and PIGD score (indirect effect, a*b = 0.071; total effect, c = 0.256; p = 0.006). CONCLUSIONS: Our findings suggest that degeneration of the cBF system in PD, from the cBF to its fiber tract and cortical projection, plays an important role in cognitive-motor interaction.

Fibroblast growth factor-21 alleviates proteasome injury via activation of autophagy flux in Parkinson's disease.

Parkinson's disease (PD) is one of the most common and complex Neurodegeneration, with an inherited metabolic disorder. Fibroblast growth factor 21 (FGF21), an endocrine hormone that belongs to the fibroblast growth factor superfamily, plays an extensive role in metabolic regulation. However, our understandings of the specific function and mechanisms of FGF21 on PD are still quite limited. Here, we aimed to elucidate the actions and the underlying mechanisms of FGF21 on dopaminergic neurodegeneration using cellular models of parkinsonism. To investigate the effects of FGF21 on dopaminergic neurodegeneration in vitro, proteasome impairment models of PD were utilized. Human dopaminergic neuroblastoma SH-SY5Y cells were treated with the proteasome inhibitor lactacystin (5 µmol/L) for 12 h, then with 50 ng/ml FGF-21 with or without 5 mmol/L of 3-methyladenine.The cells were dissected to assess alterations in autophagy using immunofluorescence, immunoblotting and electron microscopy assays. Our data indicate that FGF21 prevents dopaminergic neuron loss and shows beneficial effects against proteasome impairment induced PD syndrome, indicating it might be a potent candidate for developing novel drugs to deal with PD.

Early-onset familial essential tremor is associated with nucleotide expansions of spinocerebellar ataxia in China.

BACKGROUND: Essential tremor (ET) is a neurological disease characterized by action tremor in upper arms. Although its high heritability and prevalence worldwide, its etiology and association with other diseases are still unknown. METHOD: We investigated 10 common spinocerebellar ataxias (SCAs), including SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, SCA36, dentatorubral-pallidoluysian atrophy (DRPLA) in 92 early-onset familial ET pedigrees in China collected from 2016 to 2022. RESULT: We found one SCA12 proband carried 51 CAG repeats within PPP2R2B gene and one SCA3 proband with intermediate CAG repeats (55) with ATXN3 gene. The other 90 ET probands all had normal repeat expansions. CONCLUSION: Tremor can be the initial phenotype of certain SCA. For early-onset, familial ET patients, careful physical examinations are needed before genetic SCA screening.

A novel and independent survival prognostic model for OSCC: the functions and prognostic values of RNA-binding proteins.

BACKGROUND: Oral squamous cell carcinoma (OSCC), exhibiting high morbidity and malignancy, is the most common type of oral cancer. The abnormal expression of RNA-binding proteins (RBPs) plays important roles in the occurrence and progression of cancer. The objective of the present study was to establish a prognostic assessment model of RBPs and to evaluate the prognosis of OSCC patients. METHODS: Gene expression data in The Cancer Genome Atlas (TCGA) were analyzed by univariate Cox regression analysis model that established a novel nine RBPs, which were used to build a prognostic risk model. A multivariate Cox proportional regression model and the survival analysis were used to evaluate the prognostic risk model. Moreover, the receive operator curve (ROC) analysis was tested further the efficiency of prognostic risk model based on data from TCGA database and Gene Expression Omnibus (GEO). RESULTS: Nine RBPs' signatures (ACO1, G3BP1, NMD3, RNGTT, ZNF385A, SARS, CARS2, YARS and SMAD6) with prognostic value were identified in OSCC patients. Subsequently, the patients were further categorized into high-risk group and low-risk in the overall survival (OS) and disease-free survival (DFS), and external validation dataset. ROC analysis was significant for both the TCGA and GEO. Moreover, GSEA revealed that patients in the high-risk group significantly enriched in many critical pathways correlated with tumorigenesis than the low, including cell cycle, adheres junctions, oocyte meiosis, spliceosome, ERBB signaling pathway and ubiquitin-mediated proteolysis. CONCLUSIONS: Collectively, we developed and validated a novel robust nine RBPs for OSCC prognosis prediction. The nine RBPs could serve as an independent and reliable prognostic biomarker and guiding clinical therapy for OSCC patients.

Functional connectome predicting individual gait function and its relationship with molecular architecture in Parkinson's disease.

Gait impairment is a common symptom of Parkinson's disease (PD), but its neural signature remains unclear due to the interindividual variability of gait performance. Identifying a robust gait-brain correlation at the individual level would provide insight into a generalizable neural basis of gait impairment. In this context, this study aimed to detect connectome that can predict individual gait function of PD, and follow-up analyses assess the molecular architecture underlying the connectome by relating it to the neurotransmitter-receptor/transporter density maps. Resting-state functional magnetic resonance imaging was used to detect the functional connectome, and gait function was assessed via a 10 m-walking test. The functional connectome was first detected within drug-naive patients (N = 48) by using connectome-based predictive modeling following cross-validation and then successfully validated within drug-managed patients (N = 30). The results showed that the motor, subcortical, and visual networks played an important role in predicting gait function. The connectome generated from patients failed to predict the gait function of 33 normal controls (NCs) and had distinct connection patterns compared to NCs. The negative connections (connection negatively correlated with 10 m-walking-time) pattern of the PD connectome was associated with the density of the D2 receptor and VAChT transporter. These findings suggested that gait-associated functional alteration induced by PD pathology differed from that induced by aging degeneration. The brain dysfunction related to gait impairment was more commonly found in regions expressing more dopaminergic and cholinergic neurotransmitters, which may aid in developing targeted treatments.

Presence but not the timing of onset of REM sleep behavior disorder distinguishes evolution patterns in Parkinson's disease.

BACKGROUND: Rapid eye movement (REM) sleep behavior disorder (RBD) could develop preceding or come after motor symptoms during Parkinson's disease (PD). It remains unknown that whether PD with different timing of RBD onset relative to motor symptoms suggests different spatiotemporal sequence of neurodegeneration. This study aimed to explore the sequence of disease progression in crucially involved brain regions in PD with different timing of RBD onset. METHOD: We recruited 157 PD, 16 isolated RBD (iRBD), and 78 healthy controls. PD patients were identified as (1) PD with RBD preceding motor symptoms (PD-preRBD, n = 50), (2) PD with RBD posterior to motor symptoms (PD-postRBD, n = 31), (3) PD without RBD (PD-nonRBD, n = 75). The volumes of crucial brain regions, including the basal ganglia and limbic structures in T1-weighted imaging, and the contrast-noise-ratios of locus coeruleus (LC) and substantia nigra (SN) in neuromelanin-sensitive magnetic resonance imaging, were extracted. To simulate the sequence of disease progression for cross-sectional data, an event-based model was introduced to estimate the maximum likelihood sequence of regions' involvement for each group. Then, a statistical parameter, the Bhattacharya coefficient (BC), was used to evaluate the similarity of the sequence. RESULTS: The model predicted that SN occupied the highest likelihood in the maximum likelihood sequence of disease progression in the all PD subgroups, while LC was specifically positioned earlier to SN in iRBD, a prodromal phase of PD. Subsequent early involvement of LC was observed in the both PD-preRBD and PD-postRBD. In contrast, atrophy in the para-hippocampal gyrus but relatively intact LC in the early stage was demonstrated in PD-nonRBD. Then, the similarity comparisons indicated higher BC between PD-postRBD and PD-preRBD (BC = 0.76) but lower BC between PD-postRBD and PD-nonRBD group (BC = 0.41). iRBD had higher BC against PD-preRBD (BC = 0.66) and PD-postRBD (BC = 0.63) but lower BC against PD- nonRBD (BC = 0.48). CONCLUSION: The spatiotemporal sequence of neurodegeneration between PD-pre and PD-post were similar but distinct from PD-nonRBD. The presence of RBD may be the essential factor for differentiating the degeneration patterns of PD, but the timing of RBD onset has currently proved to be not.

Normalization effect of dopamine replacement therapy on brain functional connectome in Parkinson's disease.

Dopamine replacement therapy (DRT) represents the standard treatment for Parkinson's disease (PD), however, instant and long-term medication influence on patients' brain function have not been delineated. Here, a total of 97 drug-naïve patients, 43 patients under long-term DRT, and 94 normal control (NC) were, retrospectively, enrolled. Resting-state functional magnetic resonance imaging data and motor symptom assessments were conducted before and after levodopa challenge test. Whole-brain functional connectivity (FC) matrices were constructed. Network-based statistics were performed to assess FC difference between drug-naïve patients and NC, and these significant FCs were defined as disease-related connectomes, which were used for further statistical analyses. Patients showed better motor performances after both long-term DRT and levodopa challenge test. Two disease-related connectomes were observed with distinct patterns. The FC of the increased connectome, which mainly consisted of the motor, visual, subcortical, and cerebellum networks, was higher in drug-naïve patients than that in NC and was normalized after long-term DRT (p-value <.050). The decreased connectome was mainly composed of the motor, medial frontal, and salience networks and showed significantly lower FC in all patients than NC (p-value <.050). The global FC of both increased and decreased connectome was significantly enhanced after levodopa challenge test (q-value <0.050, false discovery rate-corrected). The global FC of increased connectome in ON-state was negatively associated with levodopa equivalency dose (r = -.496, q-value = 0.007). Higher global FC of the decreased connectome was related to better motor performances (r = -.310, q-value = 0.022). Our findings provided insights into brain functional alterations under dopaminergic medication and its benefit on motor symptoms.

ASC specks exacerbate α­synuclein pathology via amplifying NLRP3 inflammasome activities.

BACKGROUND: Inflammasome activation has a pathogenic role in Parkinson's disease (PD). Up-regulated expressions of inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and assembly of ASC specks have been observed in postmortems of human PD brains and experimental PD models. Extracellular ASC specks behave like danger signals and sustain prolonged inflammasome activation. However, the contribution of ASC specks in propagation of inflammasome activation and pathological progression in PD has not been fully established. METHODS: Herein, we used human A53T mutant α-synuclein preformed fibrils (PFFs)-stimulated microglia in vitro and unilateral striatal stereotaxic injection of PFFs-induced mice model of PD in vivo, to investigate the significance of ASC specks in PD pathological progression. Rotarod and open-field tests were performed to measure motor behaviors of indicated mice. Changes in the molecular expression were evaluated by immunofluorescence and immunoblotting (IB). Intracellular knockdown of the ASC in BV2 cells was performed using si-RNA. Microglial and neuronal cells were co-cultured in a trans-well system to determine the effects of ASC knockdown on cytoprotection. RESULTS: We observed a direct relationship between levels of ASC protein and misfolded α­synuclein aggregates in PD mice brains. ASC specks amplified NLRP3 inflammasome activation driven by α-synuclein PFFs stimulation, which aggravated reactive microgliosis and accelerated α­synuclein pathology, dopaminergic neurodegeneration and motor deficits. Endogenous ASC knockdown suppressed microglial inflammasome activation and neuronal α­synuclein aggregation. CONCLUSIONS: In conclusion, our study elucidated that ASC specks contribute to the propagation of inflammasome activation-associated α­synuclein pathology in PD, which forms the basis for targeting ASC as a potential therapy for PD.