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.

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.

The effect of dopamine replacement therapy on cortical structure in Parkinson's disease.

AIMS: To explore the cortical structural reorganization in Parkinson's disease (PD) patients under chronic dopamine replacement therapy (DRT) in cross-sectional and longitudinal data and determine whether these changes were associated with clinical alterations. METHODS: A total of 61 DRT-treated, 60 untreated PD patients, and 61 normal controls (NC) were retrospectively included. Structural MRI scans and neuropsychological tests were conducted. Cortical thickness and volume were extracted based on FreeSurfer and were analyzed using general linear model to find statistically significant differences among three groups. Correlation analyses were performed among significant cortical areas, medication treatment (duration and dosage), and neuropsychological tests. Longitudinal cortical structural changes of patients who initiated DRT were analyzed using linear mixed-effect model. RESULTS: Significant cortical atrophy was primarily observed in the prefrontal cortex in treated patients, including the cortical thickness of right pars opercularis and the volume of bilateral superior frontal cortex (SFC), left rostral anterior cingulate cortex (rACC), right lateral orbital frontal cortex, right pars orbitalis, and right rostral middle frontal cortex. A negative correlation was detected between the left SFC volume and levodopa equivalent dose (LED) (r = -0.316, p = 0.016), as well as the left rACC volume and medication duration (r = -0.329, p = 0.013). In the patient group, the left SFC volume was positively associated with digit span forward score (r = 0.335, p = 0.017). The left SFC volume reduction was longitudinally correlated with increased LED (standardized coefficient = -0.077, p = 0.001). CONCLUSION: This finding provided insights into the influence of DRT on cortical structure and highlighted the importance of drug dose titration in DRT.

Assessing the Role of Locus Coeruleus Degeneration in Essential Tremor and Parkinson's Disease with Sleep Disorders.

Background: Previous studies have demonstrated the importance of the locus coeruleus (LC) in sleep-wake regulation. Both essential tremor (ET) and Parkinson's disease (PD) share common sleep disorders, such as poor quality of sleep (QoS). LC pathology is a feature of both diseases. A question arises regarding the contribution of LC degeneration to the occurrence of poor QoS. Objective: To evaluate the association between LC impairment and sleep disorders in ET and PD patients. Methods: A total of 83 patients with ET, 124 with PD, and 83 healthy individuals were recruited and divided into ET/PD with/without poor QoS (Sle/NorET and Sle/NorPD) subgroups according to individual Pittsburgh Sleep Quality Index (PSQI) score. Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) and free-water imaging derived from diffusion MRI were performed. Subsequently, we evaluated the association between contrast-to-noise ratio of LC (CNRLC) and free-water value of LC (FWLC) with PSQI scores in ET and PD groups. Results: CNRLC was significantly lower in ET (p = 0.047) and PD (p = 0.018) than in healthy individuals, whereas no significant difference was found in FWLC among the groups. No significant differences were observed in CNR/FWLC between patients with/without sleep disorders after multiple comparison correction. No correlation was identified between CNR/FWLC and PSQI in ET and PD patients. Conclusions: LC degeneration was observed in both ET and PD patients, implicating its involvement in the pathophysiology of both diseases. Additionally, no significant association was observed between LC integrity and PSQI, suggesting that LC impairment might not directly relate to overall QoS.

Differential influences of rest tremor on brain fiber architecture in essential tremor and Parkinson's disease.

BACKGROUND: Rest tremor is a movement disorder commonly found in diseases like Parkinson's disease (PD) and essential tremor (ET). Rest tremor typically shows slower progression in PD, but more severe progression in ET. However, the underlying white matter organization of rest tremor behind PD and ET remains unclear. METHODS: This study included 57 ET patients (40 without rest tremor (ETWR), 17 with rest tremor (ETRT)), 68 PD patients (34 without rest tremor (PDWR), 34 with rest tremor (PDRT)), and 62 normal controls (NC). Fixel-based analysis was used to evaluate the structural changes of white matter in rest tremor in these different diseases. RESULTS: The fiber-bundle cross-section (FC) of the right non-decussating dentato-rubro-thalamic tract and several fibers outside the dentato-rubro-thalamic pathway in ETWR were significantly higher than that in NC. The fiber density and cross-section of the left nigro-pallidal in PDWR is significantly lower than that in NC, while the FC of bilateral nigro-pallidal in PDRT is significantly lower than that in NC. CONCLUSION: ET patients with pure action tremor showed over-activation of fiber tracts. However, when superimposed with rest tremor, ET patients no longer exhibited over-activation of fiber tracts, but rather showed a trend of fiber tract damage. Except for the nigro-pallidal degeneration in all PD, PDRT will not experience further deterioration in fiber organization. These results provide important insights into the unique effects of rest tremor on brain fiber architecture in ET and PD.

Cotransport of different electrically charged microplastics with PFOA in saturated porous media.

The fate and transport behavior of microplastics (MPs), emerging colloidal contaminant ubiquitous in natural environments, would be greatly affected by other copresent pollutants. PFOA (emerging surfactant pollutant) would interact with MPs after encounter with them in natural environments, which could alter the transport behavior of both pollutants. Relevant knowledge is still lacking, affecting accurate prediction the fate and distribution of these two emerging contaminants in natural porous media. The cotransport behavior of different surface charged MPs (negatively/positively charged, CMPs/AMPs) with PFOA (three concentrations ranging from 0.1 to 10 mg/L) in porous media in both 10 and 50 mM NaCl solutions thus was investigated in the present study. We found PFOA inhibited CMPs transport in porous media, while enhanced AMPs transport. The mechanisms leading to the altered transport of CMPs/AMPs caused by PFOA were found to be different. The decreased electrostatic repulsion between CMPs-sand induced by the decreased CMPs negative zeta potentials via the adsorption of PFOA led to the inhibited transport of CMPs in CMPs-PFOA suspension. The enhanced electrostatic repulsion between AMPs-sand due to the decreased positive charge of AMPs via the adsorption of PFOA together with steric repulsion induced by suspended PFOA resulted in the increased transport of AMPs in AMPs-PFOA suspension. Meanwhile, we found that the adsorption onto MPs surfaces also impacted the transport of PFOA. Due to the lower mobility of MPs than PFOA, the presence of MPs despite their surface charge decreased the transport of PFOA of all examined concentrations in quartz sand columns. This study demonstrates that when MPs and PFOA are co-existing in environments, their interaction with each other will alter the fate and transport behavior of both pollutants in porous media and the alteration is highly correlated with the amount of PFOA adsorbed onto MPs and original surface properties of MPs.

Influence of flagella and their property on the initial attachment behaviors of bacteria onto plastics.

Flagella and their property would influence the initial attachment of bacteria onto plastics, yet their impacts have not been investigated. In present study, four types of E. coli with or without flagella as well as with normal or sticky flagella were utilized to investigate the effects of flagella and their property on the initial attachment behaviors of bacteria onto six types of plastics in freshwater systems. We found that E. coli with flagella exhibited better initial attachment performance onto all six types of plastics than strain without flagella. Flagella could help bacteria swim near to plastics, pierce the energy barrier, and subsequently attach onto plastics. With stronger adhesive force, sticky flagella could further facilitate bacterial attachment onto plastics. Moreover, flagella especially sticky flagella could help bacteria form more rigid attachment layer on plastics. Even with humic acid in suspensions or in river water, flagellar E. coli showed greater attachment onto plastics than E. coli without flagella. Humic acid might adsorb onto sticky flagella and thus decreased the attachment of bacteria with sticky flagella onto plastics. Obviously, flagella as well as their property would impact the initial attachment of bacteria onto plastics and the subsequent formation of plastisphere in freshwater.

Freeze-thaw treatment of bacteria significantly affects bacterial transport behaviors in both saturated and unsaturated porous media: Deep investigation the roles of flagella and extracellular polymeric substances.

The effects of freeze-thaw (FT) treatment and mechanisms on bacteria transport/retention in porous media with different moisture contents remain unclear. The transport/retention behaviors of bacteria with different FT treatment cycles (0, 1, and 3) in sand columns with different moisture contents (100 %, 90 %, 60 %, and 30 %) in NaCl solutions (10 and 100 mM) thus were investigated. Regardless of moisture content and solution chemistry, FT treatment increased bacteria deposition in sand columns, consistent with the results of QCM-D and visible parallel plate flow chamber (PPFC) systems. Via deep investigation of the contribution of flagella through using genetic-modified bacteria strain without flagella and that of extracellular polymeric substances (EPS) through analyzing its overall quantity, composition as well as the secondary structure of its two major components (proteins and polysaccharides), the mechanisms of FT treatment controlling bacterial transport/deposition were revealed. Although FT treatment induced flagella loss, it was not the major contributor to driving to the enhanced FT-treated cell deposition. Instead, FT treatment stimulated EPS secretion and increased its hydrophobicity (via increasing hydrophobicity of both proteins and polysaccharides), mainly contributing to the enhanced bacterial deposition. Even with copresent humic acid, FT treatment still enhanced bacterial deposition in sand columns with different moisture contents.

Aberrant dentato-rubro-thalamic pathway in action tremor but not rest tremor: A multi-modality magnetic resonance imaging study.

AIMS: The purpose of this study was to clarify the dentato-rubro-thalamic (DRT) pathway in action tremor in comparison to normal controls (NC) and disease controls (i.e., rest tremor) by using multi-modality magnetic resonance imaging (MRI). METHODS: This study included 40 essential tremor (ET) patients, 57 Parkinson's disease (PD) patients (29 with rest tremor, 28 without rest tremor), and 41 NC. We used multi-modality MRI to comprehensively assess major nuclei and fiber tracts of the DRT pathway, which included decussating DRT tract (d-DRTT) and non-decussating DRT tract (nd-DRTT), and compared the differences in DRT pathway components between action and rest tremor. RESULTS: Bilateral dentate nucleus (DN) in the ET group had excessive iron deposition compared with the NC group. Compared with the NC group, significantly decreased mean diffusivity and radial diffusivity were observed in the left nd-DRTT in the ET group, which were negatively correlated with tremor severity. No significant difference in each component of the DRT pathway was observed between the PD subgroup or the PD and NC. CONCLUSION: Aberrant changes in the DRT pathway may be specific to action tremor and were indicating that action tremor may be related to pathological overactivation of the DRT pathway.

Regional white matter hyperintensity volume in Parkinson's disease and associations with the motor signs.

OBJECTIVE: To determine whether white matter hyperintensity (WMH) volumes in specific regions are associated with Parkinson's disease (PD) compared to non-PD controls, and to assess their impact on motor signs through cross-sectional and longitudinal analyses. METHODS: A total of 50 PD participants and 47 age- and gender-matched controls were enrolled. All PD participants were followed up for at least 2 years. To detect regions of greater WMH in the PD, the WMH volume of each region was compared with the corresponding region in the control group. Linear regression and linear mixed effects models were respectively used for cross-sectional and longitudinal analyses of the impact of increases in WMH volume on motor signs. RESULTS: The PD group had greater WMH volume in the occipital region compared with the control group. Cross-sectional analyses only detected a significant correlation between occipital WMH volume and motor function in PD. Occipital WMH volume positively correlated with the severity of tremor, and gait and posture impairments, in the PD group. During the follow-up period, the participants' motor signs progressed and the WMH volumes remained stable, no longitudinal association was detected between them. The baseline occipital WMH volume cannot predict the progression of signs after adjustment for baseline disease duration and the presence of vascular risk factors. INTERPRETATION: PD participants in this study were characterized by greater WMH at the occipital region, and greater occipital WMH volume had cross-sectional associations with worse motor signs, while its longitudinal impact on motor signs progression was limited.

Terminal functionalized thiourea-containing dipeptides as multidrug-resistance reversers that target 20S proteasome and cell proliferation.

A series of inhibitors of 20S proteasome based on terminal functionalized dipeptide derivatives containing the thiourea moiety were synthesized and evaluated for inhibition of 20S proteasome and the effects of multidrug-resistance reversers. These compounds exhibited significant selectivity to the ß5-subunit of the human 20S proteasome with IC50 values at submicromolar concentrations. A docking study of the most active compound 6i revealed key interactions between 6i and the active site of the 20S proteasome in which the thiourea moiety and a nitro group were important for improving activity. In particular, compound 6i appeared to be the most potent compound against the NCI-H460 cell line, and displayed similar efficiency in drug-sensitive versus drug-resistant cancer cell lines, at least partly, by inhibition of the activity of 20S proteasome and induce apoptosis. In addition, 6i-induced apoptosis was significantly facilitated in NCI-H460/DOX cells that had been pretreated with inhibitors of P-gp. Mechanistically, compound 6i might trigger apoptotic signalling pathway. Thus, we conclude that dipeptide derivatives containing the thiourea moiety may be the potential inhibitors of proteasome with the ability to reverse multidrug resistance.

4-Methylumbelliferones Analogues as Anticancer Agents: Synthesis and in Cell Pharmacological Studies.

BACKGROUND: Cancer is one of the most serious clinical problems worldwide, and considerable efforts have been devoted to discovering therapeutic agents with novel modes of action. Natural and synthetic coumarin derivatives have attracted intense research interest due to their diverse structural features and remarkable array of biological properties. OBJECTIVE: In the present study, we synthesized a series of 4-MU derivatives containing urea-piperazine and thioureapiperazine moieties and evaluated their antitumor activities to find efficacy antitumor drugs. METHOD: Cell proliferation, apoptosis, cell cycle, the generation of reactive oxygen species and calcium were measured using MTT assay and flow cytometry, respectively. The expression of apoptosis- and proliferation-related proteins was determined by western blotting. The effect of 4l on apoptosis-related mRNA expression in NCI-H460 cells was detected by RT-PCR. RESULTS: Most of the target compounds exhibited potential anticancer activities against tested cancer cells but had low cytotoxicity to normal cells. Compound 4l inhibited the growth and proliferation of NCI-H460 cells and resulted in apoptosis. Successive studies conducted with 4l in NCI-H460 cells demonstrated that this compound induced the intracellular reactive oxygen species generation and calcium overload, suppressed nuclear factor-κB (NF-κB) activity and regulated anti- and pro-apoptotic proteins. In addition, compound 4l effectively arrested NCI-H460 cells in G2 phase and altered the cell cycle regulatory proteins especially cyclin B1. CONCLUSION: Compound 4l exerts significant anticancer effects on NCI-H460 cells in vitro through targeting of mitochondria-dependent apoptotic pathway. These results indicate that the strategy for rational design of 4-MU derivatives may identify potential anticancer agents.