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1.
Brain Imaging Behav ; 16(3): 1234-1245, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34973120

RESUMO

Tremor in Parkinson's disease (PD) has distinct responsiveness to dopamine, which is supposed not be exclusively related to dopamine deficiency but has a close relationship with cholinergic system. This phenomenon indicates that cholinergic system may be an important regulatory for distinct dopamine responsiveness of parkinsonian tremor. Through investigating the alterations of cholinergic and dopaminergic network during levodopa administration, we aimed at exploring the mechanisms of differed dopamine responsiveness of parkinsonian tremor. Fifty-two PD patients with tremor were enrolled. MRI scanning, UPDRS III and its sub-symptom scores were collected in OFF and ON status (dopaminergic challenge test). Then, patients were divided into two groups (dopamine-resistant tremor and dopamine-responsive tremor) according to the tremor change rate median score. Dopaminergic and cholinergic network were obtained. LASSO regression was conducted to identify functional connectivity with distinct reactivity during levodopa administration between groups. Afterwards, detailed group comparisons, interaction and correlation analyses were performed. The reactivity of cholinergic connectivity showed the highest possibility to distinguish two groups, especially connectivity of right basal forebrain 123 to right parietal operculum cortex (R.BF123-R.PO). After levodopa administration, connectivity of R.BF123-R.PO was decreased for dopamine-responsive tremor while which remained unchanged for dopamine-resistant tremor. The reactivity of R.BF123-R.PO was negatively correlated with tremor change rate. Reduced cholinergic connectivity to parietal operculum may be an underlying mechanism for the responsive tremor in PD and the distinct cholinergic reactivity of parietal operculum to levodopa may be a core pathophysiology for the differed DA responsiveness of tremor in PD.

2.
Eur J Neurol ; 29(4): 1000-1010, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34882309

RESUMO

BACKGROUND AND PURPOSE: This study was undertaken to investigate the effect of genetic risk on whole brain white matter (WM) integrity in patients with Parkinson disease (PD). METHODS: Data were acquired from the Parkinson's Progression Markers Initiative (PPMI) database. Polygenic load was estimated by calculating weighted polygenic risk scores (PRS) using (i) all available 26 PD-risk single nucleotide polymorphisms (SNPs) (PRS1) and (ii) 23 SNPs with minor allele frequency (MAF) > 0.05 (PRS2). According to the PRS2, and combined with clinical and diffusion tensor imaging (DTI) data over 3-year follow-up, 60 PD patients were screened and assigned to the low-PRS group (n = 30) and high-PRS group (n = 30) to investigate intergroup differences in clinical profiles and WM microstructure measured by DTI cross-sectionally and longitudinally. RESULTS: PRS were associated with younger age at onset in patients with PD (PRS1, Spearman ρ = -0.190, p = 0.003; PRS2, Spearman ρ = -0.189, p = 0.003). The high-PRS group showed more extensive WM microstructural degeneration compared with the low-PRS group, mainly involving the anterior thalamic radiation (AThR) and inferior fronto-occipital fasciculus (IFOF) (p < 0.05). Furthermore, WM microstructural changes in AThR correlated with declining cognitive function (r = -0.401, p = 0.028) and increasing dopaminergic deficits in caudate (r = -0.405, p = 0.030). CONCLUSIONS: These findings suggest that PD-associated polygenic load aggravates the WM microstructural degeneration and these changes may lead to poor cognition with continuous dopamine depletion. This study provides advanced evidence that combined with a cumulative PRS and DTI methods may predict disease progression in PD patients.


Assuntos
Doença de Parkinson , Substância Branca , Encéfalo/diagnóstico por imagem , Cognição , Imagem de Tensor de Difusão/métodos , Humanos , Estudos Longitudinais , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/genética , Substância Branca/diagnóstico por imagem
3.
Eur Neurol ; 85(1): 24-30, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34689144

RESUMO

BACKGROUND: Growing evidence suggests important effects of body mass index (BMI) and metabolic status on neurodegenerative diseases. However, the roles of BMI and metabolic status on cognitive outcomes in Parkinson's disease (PD) may vary and are yet to be determined. METHODS: In total, 139 PD patients from the whole PD cohort in Parkinson's Progression Markers Initiative database underwent complete laboratory measurements, demographic and anthropometric parameters at baseline, and were enrolled in this study. Further, they were categorized into 4 different BMI-metabolic status phenotypes using Adult Treatment Panel-III criteria. Motor and cognition scales at baseline and longitudinal changes after a 48-month follow-up were compared among the 4 groups. Repeated-measure linear mixed models were performed to compare PD-related biomarkers among BMI-metabolic status phenotypes across time. RESULTS: We found that PD patients in the metabolically unhealthy normal weight group showed more cognitive decline in global cognition and visuospatial perception after a 48-month follow-up than those in the other 3 groups (p < 0.05). No difference was found in motor scales among different BMI-metabolic status phenotypes. Finally, compared to the metabolically healthy normal weight group, the metabolically healthy obesity group had lower CSF Aß42 and serum neurofilament levels in repeated-measure linear mixed models adjusting for age, gender, APOE e4 carrier status, and years of education (p = 0.031 and 0.046, respectively). CONCLUSION: The MUNW phenotype was associated with a rapid cognitive decline in PD.


Assuntos
Disfunção Cognitiva , Doença de Parkinson , Biomarcadores , Índice de Massa Corporal , Disfunção Cognitiva/complicações , Progressão da Doença , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/genética , Fenótipo
4.
Hum Brain Mapp ; 43(6): 1984-1996, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-34970835

RESUMO

Identifying a whole-brain connectome-based predictive model in drug-naïve patients with Parkinson's disease and verifying its predictions on drug-managed patients would be useful in determining the intrinsic functional underpinnings of motor impairment and establishing general brain-behavior associations. In this study, we constructed a predictive model from the resting-state functional data of 47 drug-naïve patients by using a connectome-based approach. This model was subsequently validated in 115 drug-managed patients. The severity of motor impairment was assessed by calculating Unified Parkinson's Disease Rating Scale Part III scores. The predictive performance of model was evaluated using the correlation coefficient (rtrue ) between predicted and observed scores. As a result, a connectome-based model for predicting individual motor impairment in drug-naïve patients was identified with significant performance (rtrue  = .845, p < .001, ppermu  = .002). Two patterns of connection were identified according to correlations between connection strength and the severity of motor impairment. The negative motor-impairment-related network contained more within-network connections in the motor, visual-related, and default mode networks, whereas the positive motor-impairment-related network was constructed mostly with between-network connections coupling the motor-visual, motor-limbic, and motor-basal ganglia networks. Finally, this predictive model constructed around drug-naïve patients was confirmed with significant predictive efficacy on drug-managed patients (r = .209, p = .025), suggesting a generalizability in Parkinson's disease patients under long-term drug influence. In conclusion, this study identified a whole-brain connectome-based model that could predict the severity of motor impairment in Parkinson's patients and furthers our understanding of the functional underpinnings of the disease.


Assuntos
Conectoma , Transtornos Motores , Doença de Parkinson , Encéfalo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Doença de Parkinson/diagnóstico por imagem
5.
NPJ Parkinsons Dis ; 8(1): 54, 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35487930

RESUMO

Alpha-synucleinopathy is postulated to be central to both idiopathic rapid eye movement sleep behaviour disorder (iRBD) and Parkinson's disease (PD). Growing evidence suggests an association between the diminished clearance of α-synuclein and glymphatic system dysfunction. However, evidence accumulating primarily based on clinical data to support glymphatic system dysfunction in patients with iRBD and PD is currently insufficient. This study aimed to use diffusion tensor image analysis along the perivascular space (DTI-ALPS) to evaluate glymphatic system activity and its relationship to clinical scores of disease severity in patients with possible iRBD (piRBDs) and those with PD. Further, we validated the correlation between the ALPS index and the prognosis of PD longitudinally. Overall, 168 patients with PD, 119 piRBDs, and 129 healthy controls were enroled. Among them, 50 patients with PD had been longitudinally reexamined. Patients with PD exhibited a lower ALPS index than those with piRBDs (P = 0.036), and both patient groups showed a lower ALPS index than healthy controls (P < 0.001 and P = 0.001). The ALPS index and elevated disease severity were negatively correlated in the piRBD and PD subgroups. Moreover, the ALPS index was correlated with cognitive decline in patients with PD in the longitudinal analyses. In conclusion, DTI-ALPS provided neuroimaging evidence of glymphatic system dysfunction in piRBDs and patients with PD; however, the potential of assessing the pathological progress of α-synucleinopathies as an indicator is worth verifying. Further development of imaging methods for glymphatic system function is also warranted.

6.
World J Clin Cases ; 9(31): 9645-9651, 2021 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-34877302

RESUMO

BACKGROUND: Tuberculous myelitis is a rare manifestation of tuberculosis (TB) that is usually caused by hematogenous spread of Mycobacterium tuberculosis (MTB). Neurosyphilis is a neurological disease that occurs when Treponema pallidum invades the brain or the spinal cord. Individually, these two diseases involving the spinal cord are rare and cases of concurrent tuberculous transverse myelitis and asymptomatic neurosyphilis have seldom been reported. CASE SUMMARY: A 56-year-old man presented with numbness and pain of both lower limbs for 2 wk and dysuria for 1 wk. Syphilis serology and cerebrospinal fluid (CSF) analysis supported the diagnosis of neurosyphilis and the patient was treated with intravenous ceftriaxone at first, but symptoms still progressed. Then, magnetic resonance images revealed multiple lesions along the cervicothoracic junction, and chest computed tomography showed a typical TB lesion. MTB DNA was detected in the CSF sample by metagenomic next-generation sequencing. Eventually the patient was diagnosed with tuberculous myelitis combined with asymptomatic neurosyphilis. Subsequently, quadruple anti-TB drug standardized therapy was empirically used and his neurological symptoms improved gradually. CONCLUSION: Patients can have coinfection with tuberculous transverse myelitis and asymptomatic neurosyphilis. Patients with neurosyphilis should be examined for other pathogens.

7.
Neuroimage Clin ; 32: 102873, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34749290

RESUMO

Degeneration of the locus coeruleus (LC) is recognized as a critical hallmark of Parkinson's disease (PD). Recent studies have reported that noradrenaline produced from the LC has critical effects on brain functional organization. However, it is unknown if LC degeneration in PD contributes to cognitive/motor manifestations through modulating brain functional organization. This study enrolled 94 PD patients and 68 healthy controls, and LC integrity was measured using the contrast-to-noise ratio of the LC (CNRLC) calculated from T1-weighted magnetic resonance imaging. We used graph-theory-based network analysis to characterize brain functional organization. The relationships among LC degeneration, network disruption, and cognitive/motor manifestations in PD were assessed. Whether network disruption was a mediator between LC degeneration and cognitive/motor impairments was assessed further. In addition, an independent PD subgroup (n = 35) having functional magnetic resonance scanning before and after levodopa administration was enrolled to evaluate whether LC degeneration-related network deficiencies were independent of dopamine deficiency. We demonstrated that PD patients have significant LC degeneration compared to healthy controls. CNRLC was positively correlated with Montreal Cognitive Assessment score and the nodal efficiency (NE) of several cognitive-related regions. Lower NE of the superior temporal gyrus was a mediator between LC degeneration and cognitive impairment in PD. However, levodopa treatment could not normalize the reduced NE of the superior temporal gyrus (mediator). In conclusion, we provided evidence for the relationship between LC degeneration and extensive network disruption in PD, and highlight the role of network disorganization in LC degeneration-related cognitive impairment.


Assuntos
Doença de Parkinson , Encéfalo , Humanos , Levodopa , Locus Cerúleo , Imageamento por Ressonância Magnética
8.
J Parkinsons Dis ; 11(4): 1631-1640, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34366373

RESUMO

BACKGROUND: The widely divergent responsiveness of Parkinson's disease (PD) patients to levodopa is an important clinical issue because of its relationship with quality of life and disease prognosis. Preliminary animal experiments have suggested that degeneration of the locus coeruleus (LC) attenuates the efficacy of levodopa treatment. OBJECTIVE: To explore the relationship between LC degeneration and levodopa responsiveness in PD patients in vivo. METHODS: Neuromelanin-sensitive magnetic resonance imaging (NM-MRI), a good indicator of LC and substantia nigra (SN) degeneration, and levodopa challenge tests were conducted in 57 PD patients. Responsiveness to levodopa was evaluated by the rates of change of the Unified Parkinson's Disease Rating Scale Part III score and somatomotor network synchronization calculated from resting-state functional MRI before and after levodopa administration. Next, we assessed the relationship between the contrast-to-noise ratio of LC (CNRLC) and levodopa responsiveness. Multiple linear regression analysis was conducted to rule out the potential influence of SN degeneration on levodopa responsiveness. RESULTS: A significant positive correlation was found between CNRLC and the motor improvement after levodopa administration (R = 0.421, p = 0.004). CNRLC also correlated with improvement in somatomotor network synchronization (R = -0.323, p = 0.029). Furthermore, the relationship between CNRLC and levodopa responsiveness was independent of SN degeneration. CONCLUSION: LC degeneration might be an essential factor for levodopa resistance. LC evaluation using NM-MRI might be an alternative tool for predicting levodopa responsiveness and for helping to stratify patients into clinical trials aimed at improving the efficacy of levodopa.


Assuntos
Levodopa , Doença de Parkinson , Animais , Humanos , Levodopa/uso terapêutico , Locus Cerúleo , Imageamento por Ressonância Magnética , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/tratamento farmacológico , Qualidade de Vida , Estudos Retrospectivos
9.
Neurosci Lett ; 762: 136150, 2021 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-34352340

RESUMO

OBJECTIVE: Recently, a meta-analysis of genome-wide association studies (GWASs) has identified 38 novel independent loci associated with risk of Parkinson's disease (PD) in European populations. We sought to investigate whether these genetic susceptibility variants could be replicated in the Chinese Han population. METHODS: We genotyped 38 independent loci in 495 Chinese sporadic PD patients and 470 unrelated controls and performed allelic and genotypic association test using chi-square tests or Armitage test for trend. Polygenic risk score (PRS) models were built to evaluate the cumulative effects of the selected SNPs. RESULTS: We found that the rs11610045 of FBRSL1 (p = 0.02, OR = 0.63, allele model), rs76116224 of KCNS3 (p < 0.01, OR = 0.09, allele model), and the rs2248244 of DYRK1A (p = 0.02, OR = 1.35, allele model) were significantly associated with PD. The PRS model of cumulative effects of the SNPs associated with PD in our study had the area under the curve (AUC) of 0.61. CONCLUSIONS: Our study revealed that rs11610045 of FBRSL1, rs76116224 of KCNS3 and rs2248244 of DYRK1A showed an impact on the risk of PD, and the GWAS-derived PRS models we built had predictive value for PD risk in the Chinese population. Further studies are needed to explore the pathogenesis of these potentially risk-associated variants.


Assuntos
Predisposição Genética para Doença/genética , Doença de Parkinson/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Proteínas Tirosina Quinases/genética , Idoso , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
10.
Brain Struct Funct ; 226(8): 2665-2673, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34373950

RESUMO

Increasing evidence suggests that genetic factors play a key role in the development of Parkinson's disease (PD). The variant rs11240572 in the PARK16 gene locus is strongly associated with PD. However, its effect on the pathogenesis of PD is yet to be clarified. The objective of the study was to explore the effect of the PARK16 rs11240572 variant on brain structure in PD patients. A total of 51 PD patients were enrolled in the study and genotyped for the rs11240572 variant. Clinical assessments and MRI scans were conducted across all participants. Voxel-based morphometry (VBM) was used to investigate gray matter volume (GMV) of the whole brain between these two groups. Correlation analysis was performed to identify the relationships between GMV and clinical features. There were 17 rs11240572-A variant carriers and 34 non-carriers, with no significant demographic differences between these two groups. Compared with non-carriers, rs11240572-A carriers showed increased GMV in the left caudate nucleus and putamen, but decreased GMV in the left superior temporal gyrus and supramarginal gyrus. In non-carriers, left basal ganglia GMV was positively correlated with UPDRS III (r = 0.365, p = 0.034) and bradykinesia (r = 0.352, p = 0.042), but negatively correlated with MMSE (r = - 0.344, p = 0.047), while in carriers negative correlation between basal ganglia GMV and MMSE was also observed (r = - 0.666, p = 0.004). Moreover, the GMV of left temporoparietal cortex was positively associated with cognitive function in both groups (carriers, r = 0.692, p = 0.002; non-carriers, r = 0.879, p < 0.001). When reducing the sample size of non-carriers to the level of the carrier sample, similar correlations were observed in both groups. Our study showed that the PARK16 rs11240572 variant affects the brain structure of patients with PD, especially in the basal ganglia and temporoparietal cortex. This indicated that this variant might play an important role in the pathogenesis of PD.


Assuntos
Encéfalo/anatomia & histologia , Doença de Parkinson , Encéfalo/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/genética
11.
Parkinsonism Relat Disord ; 88: 82-89, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34147950

RESUMO

OBJECTIVES: To explore the microstructural alterations in subcortical nuclei in Parkinson's disease (PD) at different stages with diffusion kurtosis imaging (DKI) and tensor imaging and to test the performance of diffusion metrics in identifying PD. METHODS: 108 PD patients (64 patients in early-stage PD group (EPD) and 44 patients in moderate-late-stage PD group (MLPD)) and 64 healthy controls (HC) were included. Tensor and kurtosis metrics in the subcortical nuclei were compared. Partial correlation was used to correlate the diffusion metrics and Unified Parkinson's Disease Rating Scale part-III (UPDRS-III) score. Logistic regression and receiver operating characteristic analysis were applied to test the diagnostic performance of the diffusion metrics. RESULTS: Compared with HC, both EPD and MLPD patients showed higher fractional anisotropy and axial diffusivity, lower mean kurtosis (MK) and axial kurtosis in substantia nigra, lower MK and radial kurtosis (RK) in globus pallidus (GP) and thalamus (all p < 0.05). Compared with EPD, MLPD patients showed lower MK and RK in GP and thalamus (all p < 0.05). MK and RK in GP and thalamus were negatively correlated with UPDRS-III score (all p < 0.01). The logistic regression model combining kurtosis and tensor metrics showed the best performance in diagnosing PD, EPD, and MLPD (areas under curve were 0.817, 0.769, and 0.914, respectively). CONCLUSIONS: PD has progressive microstructural alterations in the subcortical nuclei. DKI is sensitive to detect microstructural alterations in GP and thalamus during PD progression. Combining kurtosis and tensor metrics can achieve a good performance in diagnosing PD.


Assuntos
Imagem de Difusão por Ressonância Magnética/normas , Globo Pálido/patologia , Doença de Parkinson/patologia , Tálamo/patologia , Idoso , Imagem de Tensor de Difusão/normas , Progressão da Doença , Feminino , Globo Pálido/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Tálamo/diagnóstico por imagem
12.
J Magn Reson Imaging ; 54(4): 1098-1106, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33949744

RESUMO

BACKGROUND: Excessive iron accumulation is one of the main pathogeneses of Parkinson's disease (PD). Ceruloplasmin plays an important role in keeping the iron homoeostasis. PURPOSE: To explore the association between serum ceruloplasmin depletion and subcortical iron distribution in PD. STUDY TYPE: Prospective. POPULATION: One hundred and twenty-one normal controls, 34 PD patients with low serum ceruloplasmin (PD-LC), and 28 patients with normal serum ceruloplasmin (PD-NC). SEQUENCE: Enhanced susceptibility-weighted angiography (ESWAN) on a 3 T scanner. ASSESSMENT: Quantitative susceptibility mapping was employed to quantify the regional iron content by using a semi-automatic method. Serum ceruloplasmin concentration was measured from peripheral blood sample. Clinical assessments were conducted by a neurologist. STATISTICAL TESTS: General linear model was used to compare the intergroup difference of region iron distribution among groups, and the statistics was adjusted by Bonferroni method (P < 0.01). Partial correlation analysis was used to detect the association between regional iron distribution and serum ceruloplasmin concentration (P < 0.05). RESULTS: Compared with normal controls, significant iron accumulation in substantia nigra, putamen, and red nucleus was observed in PD-LC, while the only region showing significant iron accumulation was SN in PD-NC. Between PD-NC and PD-LC, the iron accumulation in putamen remained significantly different, which had a negative correlation with serum ceruloplasmin in whole PD patients (r = -0.338, P = 0.008). DATA CONCLUSION: Nigral iron accumulation characterizes PD patients without significant association with serum ceruloplasmin. Differentially, when PD patients appear with reduced serum ceruloplasmin, more widespread iron accumulation would be expected with additionally involving putamen and red nucleus. All these findings provide insightful evidence for the abnormal iron metabolism behind the ceruloplasmin depletion in PD. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: 2.


Assuntos
Ceruloplasmina , Doença de Parkinson , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Ceruloplasmina/metabolismo , Humanos , Ferro/metabolismo , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Doença de Parkinson/diagnóstico por imagem , Estudos Prospectivos , Substância Negra
13.
Exp Neurol ; 336: 113525, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33161049

RESUMO

A pivotal neuropathological manifestation of synucleinopathies, like Parkinson's disease (PD), is the aggregation of α-synuclein. In a recent cell-to-cell transmission model of α-synuclein, α-synuclein propagation was demonstrated to resemble that of prion proteins in the central nervous system. Furthermore, exosomes, as biomolecule carriers, have been shown to transmit α-synuclein from neuron to neuron. However, the mechanisms underlying exosomal α-synuclein transmission have not been well understood. The NLR family pyrin domain containing 3 protein (NLRP3) inflammasome activation in microglia, and the subsequent release of proinflammatory cytokines, are two crucial pathological events involved in neuroinflammation and PD progression. Research has revealed that the NLRP3 inflammasome may facilitate the secretion of extracellular vesicles, as well as exosomal transmission of proteins like aggregated α-synuclein. However, only a few reports have evaluated these pathogenic mechanisms. Herein we evaluate for the first time the current evidence for the involvement of the NLRP3 inflammasome in microvesicle generation by microglial cells, and the various mechanisms regarding the production, shedding, and content of exosomes in relation to α-synuclein transmission from neuron to neuron. Furthermore, we propose a model of microglial NLRP3 inflammasome-dependent exosome secretion and exosomal α-synuclein transmission in PD. This knowledge may lead to the identification of novel potential targets for drug development and stimulate further research in PD.


Assuntos
Exossomos/genética , Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Doença de Parkinson/genética , alfa-Sinucleína/genética , Animais , Humanos , Microglia/metabolismo , Neurônios
15.
Front Aging Neurosci ; 13: 740491, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35356146

RESUMO

Objective: Aquaporin-4 (AQP4) facilitates a sleep-enhanced interstitial brain waste clearance system. This study was conducted to determine the clinical implication of AQP4 polymorphisms in Parkinson's disease (PD). Methods: Three-hundred and eighty-two patients with PD and 180 healthy controls with a mean follow-up time of 66.1 months from the Parkinson's Progression Marker Initiative study were analyzed. We examined whether AQP4 SNPs were associated with an altered rate of motor or cognitive decline using linear mixed model and Cox regression. We then investigated whether AQP4 SNPs were associated with Aß burden as measured by 18F Florbetapir standard uptake values. Furthermore, we examined if AQP4 SNPs moderated the association between REM sleep behavior disorder (RBD) and CSF biomarkers. Results: In patients with PD, AQP4 rs162009 (AA/AG vs. GG) was associated with slower dementia conversion, better performance in letter-number sequencing and symbol digit modalities, lower Aß deposition in the putamen, anterior cingulum, and frontotemporal areas. In the subgroup of high RBD screening questionnaire score, rs162009 AA/AG had a higher CSF Aß42 level. rs162009 AA/AG also had better performance in semantic fluency in healthy controls. Besides, rs68006382 (GG/GA vs. AA) was associated with faster progression to mild cognitive impairment, worse performance in letter-number sequencing, semantic fluency, and symbol digit modalities in patients with PD. Interpretation: Genetic variations of AQP4 and subsequent alterations of glymphatic efficacy might contribute to an altered rate of cognitive decline in PD. AQP4 rs162009 is likely a novel genetic prognostic marker of glymphatic function and cognitive decline in PD.

16.
Front Aging Neurosci ; 12: 580853, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33250763

RESUMO

BACKGROUND: Excessive aggregation of α-synuclein is the key pathophysiological feature of Parkinson's disease (PD). Rapid eye movement sleep behavior disorder (RBD) is also associated with synucleinopathies and considered as a powerful predictor of PD. Growing evidence suggests the diminished clearance of α-synuclein may be partly attributable to poor interstitial fluid drainage, which can be reflected by magnetic resonance imaging (MRI)-visible enlarged perivascular space (EPVS). However, the effect of MRI-visible EPVS on iRBD and PD, and their correlation with clinical characteristics remain unclear. OBJECTIVE: To evaluate the clinical and neuroimaging significance of MRI-visible EPVS in iRBD and PD patients. METHODS: We enrolled 33 iRBD patients, 82 PD (with and without RBD) patients, and 35 healthy controls (HCs), who underwent clinical evaluation and 3.0 Tesla MRI. Two neurologists assessed MRI-visible EPVS in centrum semiovale (CSO), basal ganglia (BG), substantia nigra (SN), and brainstem (BS). Independent risk factors for iRBD and PD were investigated using multivariable logistic regression analysis. Spearman analysis was used to test the correlation of MRI-visible EPVS with clinical characteristics of patients. RESULTS: iRBD patients had significantly higher EPVS burdens (CSO, BG, SN, and BS) than PD patients. Higher CSO-EPVS and BS-EPVS burdens were independent risk factors for iRBD. Furthermore, higher CSO-EPVS and SN-EPVS burdens were positively correlated with the severity of clinical symptom in iRBD patients, and higher BG-EPVS burden was positively correlated with the severity of cognitive impairment in PD patients. CONCLUSION: iRBD and PD patients have different MRI-visible EPVS burdens, which may be related with a compensatory mechanism in glymphatic system. Lower MRI-visible EPVS burden in PD patients may be a manifestation of severe brain waste drainage dysfunction. These findings shed light on the pathophysiologic relationship between iRBD and PD with respect to neuroimaging marker of PD.

17.
Aging (Albany NY) ; 12(24): 25805-25818, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33234732

RESUMO

Perivascular spaces in the brain have been known to communicate with cerebrospinal fluid and contribute to waste clearance in animal models. In this study, we sought to determine the association between MRI-visible enlarged perivascular spaces (EPVS) and disease markers in Parkinson's disease (PD). We obtained longitudinal data from 245 patients with PD and 98 healthy controls from the Parkinson's Progression Marker Initiative. Two trained neurologists performed visual ratings on T2-weighted images to characterize EPVS in the centrum semiovale (CSO), the basal ganglia (BG) and the midbrain. We found that a greater proportion of patients with PD had low grade BG-EPVS relative to healthy controls. In patients with PD, lower grade of BG-EPVS and CSO-EPVS predicted lower CSF α-synuclein and t-tau. Lower grade of BG-EPVS were also associated with accelerated Hoehn &Yahr stage progression in patients with baseline stage 1. BG-EPVS might be a valuable predictor of disease progression.


Assuntos
Sistema Glinfático/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , alfa-Sinucleína/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Gânglios da Base/diagnóstico por imagem , Estudos de Casos e Controles , Líquido Cefalorraquidiano , Progressão da Doença , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Mesencéfalo/diagnóstico por imagem , Pessoa de Meia-Idade , Doença de Parkinson/líquido cefalorraquidiano , Doença de Parkinson/fisiopatologia
18.
Chem Commun (Camb) ; 56(64): 9067-9078, 2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32613958

RESUMO

Fluorescent probes find widespread applications in chemical analysis, biosensing, and disease diagnosis and are also the cornerstones of many cutting-edge biotechnologies. Yet, the numerous probes developed thus far are actually based on a handful of probe design principles. In this article, we wish to summarize the recent progress of the field toward the use of a novel "covalent-assembly" principle for probe design.


Assuntos
Desenho de Fármacos , Corantes Fluorescentes/química , Linhagem Celular Tumoral , Humanos , Estrutura Molecular
19.
CNS Neurosci Ther ; 26(8): 837-841, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32196977

RESUMO

INTRODUCTION: Essential tremor (ET) is one of the most prevalent movement disorders. The genetic etiology of ET has not been well defined although a significant proportion (≥50%) are familial cases. Linkage analysis and genome-wide association studies (GWASs) have identified several risk variants. In recent years, whole-exome sequencing of ET has revealed several specific causal variants in FUS (p.Q290X), HTRA2 (p.G399S), and TENM4 (c.4324 G>A, c.4100C>A, and c.3412G>A) genes. OBJECTIVE: To investigate the genetic contribution of these three genes to ET, the protein-coding sequences of FUS, HTRA2, and TENM4 were analyzed in a total of 238 ET patients and 272 controls from eastern China using direct Sanger sequencing. RESULTS: We identified two synonymous coding single nucleotide polymorphisms (SNPs), rs741810 and rs1052352 in FUS, and three previously reported synonymous SNPs, rs11237621, rs689369, and rs2277277 in TENM4. No nonsynonymous exonic variants were identified in these subjects. We found that the frequency of the rs1052352C allele was significantly higher (P = .001) in the ET group than in the control group. CONCLUSION: Overall, our findings suggest that rs1052352 of FUS might contribute to ET risk in Chinese population.


Assuntos
/genética , Tremor Essencial/genética , Testes Genéticos/métodos , Serina Peptidase 2 de Requerimento de Alta Temperatura A/genética , Glicoproteínas de Membrana/genética , Proteína FUS de Ligação a RNA/genética , Adolescente , Adulto , Idoso , Criança , Tremor Essencial/diagnóstico , Tremor Essencial/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
20.
Angew Chem Int Ed Engl ; 58(47): 16826-16830, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31532051

RESUMO

NIR light responsive nanoplatforms hold great promise for on-demand drug release in precision cancer medicine. However, currently available systems utilize "always-on" photothermal transducers that lack target specificity, and thus inaccurately differentiate tumors from normal tissues. Developed here is a theranostic nanoplatform featuring H2 S-mediated in situ production of NIR photothermal agents for imaging-guided and photocontrolled drug release. The system targets H2 S-rich cancers. This nanoplatform shows H2 S-activatable NIR-II emission and NIR light controllable release of the drug Camptothecin-11. Upon administering the system to HCT116 tumor-bearing mice, the tumor is greatly suppressed with minimal side effects, arising from the synergy of the cancer-specific and NIR light activated therapy. This theranostic nanoplatform thus sheds light on precision medicine with guidance through NIR-II imaging.


Assuntos
Neoplasias do Colo/terapia , Liberação Controlada de Fármacos , Sulfeto de Hidrogênio/química , Irinotecano/farmacologia , Nanopartículas/administração & dosagem , Fototerapia , Nanomedicina Teranóstica , Animais , Apoptose , Proliferação de Células , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/patologia , Humanos , Camundongos , Nanopartículas/química , Inibidores da Topoisomerase I/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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