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Parkinsonism has heterogeneous nature, showing distinctive patterns of disease progression and prognosis. We aimed to find clusters of parkinsonism based on 18 F-fluoropropyl-carbomethoxyiodophenylnortropane (FP-CIT) PET as a data-driven approach to evaluate heterogenous dopaminergic neurodegeneration patterns. Two different cohorts of patients who received FP-CIT PET were collected. A labeled cohort (n = 94) included patients with parkinsonism who underwent a clinical follow-up of at least 3 years (mean 59.0 ± 14.6 months). An unlabeled cohort (n = 813) included all FP-CIT PET data of a single-center. All PET data were clustered by a dimension reduction method followed by hierarchical clustering. Four distinct clusters were defined according to the imaging patterns. When the diagnosis of the labeled cohort of 94 patients was compared with the corresponding cluster, parkinsonism patients were mostly included in two clusters, cluster "0" and "2." Specifically, patients with progressive supranuclear palsy were significantly more included in cluster 0. The two distinct clusters showed significantly different clinical features. Furthermore, even in PD patients, two clusters showed a trend of different clinical features. We found distinctive clusters of parkinsonism based on FP-CIT PET-derived heterogeneous neurodegeneration patterns, which were associated with different clinical features. Our results support a biological underpinning for the heterogeneity of neurodegeneration in parkinsonism.
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Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Trastornos Parkinsonianos/clasificación , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Análisis por Conglomerados , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Parálisis Supranuclear Progresiva/clasificación , Parálisis Supranuclear Progresiva/diagnóstico por imagen , Parálisis Supranuclear Progresiva/metabolismo , Tropanos/farmacocinéticaRESUMEN
BACKGROUND: Multiple system atrophy (MSA) patients pre-sent a variety of symptoms other than autonomic dysfunctions, parkinsonism, and cerebellar ataxia. The aim of this study was to evaluate the frequency of various motor and non-motor symptoms including so-called "red flags" in patients with early MSA and to determine whether the frequency of these symptoms was different between the parkinsonian (MSA-P) and cerebellar (MSA-C) subtypes. METHODS: Sixty-one probable or possible MSA patients with disease duration of 3 years or less were included. Patients were classified into MSA-P, MSA-C, and MSA-PC. The frequency of 13 features including various motor and non-motor symptoms that commonly occur in MSA was assessed. RESULTS: Dysarthria was the most prevalent feature (98.4%) followed by sexual dysfunction (95.1%). Probable REM sleep behavior disorder was present in 90.2%. The frequency of constipation (82.0%), dysphagia (68.9%), and snoring (70.5%) was also high. Stridor was present in 42.6% and more common in MSA-C than in MSA-P. CONCLUSIONS: Increasing awareness of various motor and non-motor symptoms may assist clinicians to make an early, accurate diagnosis and to improve management of patients with MSA. We suggest that the diagnostic accuracy can be improved if these features are appropriately reflected in the new diagnostic criteria for MSA.
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Atrofia de Múltiples Sistemas/diagnóstico , Atrofia de Múltiples Sistemas/fisiopatología , Estudios Transversales , Diagnóstico Diferencial , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: A major obstacle to targeted cancer therapy is identifying suitable targets that are specifically and abundantly expressed by solid tumors. Certain bacterial strains selectively colonize solid tumors and can deliver genetically encoded cargo molecules to the tumor cells. Here, we engineered bacteria to express monomeric streptavidin (mSA) in tumors, and developed a novel tumor pre-targeting system by visualizing the presence of tumor-associated mSA using a biotinylated imaging probe. PROCEDURES: We constructed a plasmid expressing mSA fused to maltose-binding protein and optimized the ribosome binding site sequence to increase solubility and expression levels. E. coli MG1655 was transformed with the recombinant plasmid, expression of which is driven by the pBAD promotor. Expression of mSA was induced by L-arabinose 4 days after injection of bacteria into mice bearing CT26 mouse colon carcinoma cells. Selective accumulation of mSA in tumor tissues was visualized by optical imaging after administration of a biotinylated fluorescent dye. Counting of viable bacterial cells was also performed. RESULTS: Compared with a conventional system, the novel expression system resulted in significantly higher expression of mSA and sustained binding to biotin. Imaging signals in tumor tissues were significantly stronger in the mSA-expressing group than in non-expressing group (P = 0.0005). Furthermore, the fluorescent signal in tumor tissues became detectable again after multiple inductions with L-arabinose. The bacterial counts in tumor tissues showed no significant differences between conditions with and without L-arabinose (P = 0.45). Western blot analysis of tumor tissues confirmed expression and binding of mSA to biotin. CONCLUSIONS: We successfully engineered tumor-targeting bacteria carrying a recombinant plasmid expressing mSA, which was targeted to, and expressed in, tumor tissues. These data demonstrate the potential of this novel tumor pre-targeting system when combined with biotinylated imaging probes or therapeutic agents.
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Estreptavidina , Estreptavidina/química , Animales , Ratones , Línea Celular Tumoral , Escherichia coli/genética , Escherichia coli/metabolismo , Ratones Endogámicos BALB C , Neoplasias/diagnóstico por imagen , Neoplasias/patología , Plásmidos/metabolismo , Femenino , Biotina , Arabinosa/metabolismoRESUMEN
Early and accurate detection of colorectal cancer (CRC) is critical for improving patient outcomes. Existing diagnostic techniques are often invasive and carry risks of complications. Herein, we introduce a plasmonic gold nanopolyhedron (AuNH)-coated needle-based surface-enhanced Raman scattering (SERS) sensor, integrated with endoscopy, for direct mucus sampling and label-free detection of CRC. The thin and flexible stainless-steel needle is coated with polymerized dopamine, which serves as an adhesive layer and simultaneously initiates the nucleation of gold nanoparticle (AuNP) seeds on the needle surface. The AuNP seeds are further grown through a surface-directed reduction using Au ions-hydroxylamine hydrochloride solution, resulting in the formation of dense AuNHs. The formation mechanism of AuNHs and the layered structure of the plasmonic needle-based SERS (PNS) sensor are thoroughly analyzed. Furthermore, a strong field enhancement of the PNS sensor is observed, amplified around the edges of the polyhedral shapes and at nanogap sites between AuNHs. The feasibility of the PNS sensor combined with endoscopy system is further investigated using mouse models for direct colonic mucus sampling and verifying noninvasive label-free classification of CRC from normal controls. A logistic regression-based machine learning method is employed and successfully differentiates CRC and normal mice, achieving 100% sensitivity, 93.33% specificity, and 96.67% accuracy. Moreover, Raman profiling of metabolites and their correlations with Raman signals of mucus samples are analyzed using the Pearson correlation coefficient, offering insights for identifying potential cancer biomarkers. The developed PNS-assisted endoscopy technology is expected to advance the early screening and diagnosis approach of CRC in the future.
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In this study, we developed an endoscopic hyperspectral imaging (eHSI) system and evaluated its performance in analyzing tissues within tissue phantoms and orthotopic mouse pancreatic tumor models. Our custom-built eHSI system incorporated a liquid crystal tunable filter. To assess its tissue discrimination capabilities, we acquired images of tissue phantoms, distinguishing between fat and muscle regions. The system underwent supervised training using labeled samples, and this classification model was then applied to other tissue phantom images for evaluation. In the tissue phantom experiment, the eHSI effectively differentiated muscle from fat and background tissues. The precision scores regarding fat tissue classification were 98.3% for the support vector machine, 97.7% for the neural network, and 96.0% with a light gradient-boosting machine algorithm, respectively. Furthermore, we applied the eHSI system to identify tumors within an orthotopic mouse pancreatic tumor model. The F-score of each pancreatic tumor-bearing model reached 73.1% for the KPC tumor model and 63.1% for the Pan02 tumor models. The refined imaging conditions and optimization of the fine-tuning of classification algorithms enhance the versatility and diagnostic efficacy of eHSI in biomedical applications.
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INTRODUCTION: Patients with multiple system atrophy (MSA) are conventionally identified as having MSA-P (prominent parkinsonism) or MSA-C (prominent cerebellar ataxia) based on their predominant motor manifestations. The objective of the present study was to conduct latent class analysis (LCA) of various motor and nonmotor symptoms in early MSA to characterize data-driven subgroups. METHODS: Sixty-one probable or possible MSA patients with disease durations of 3 years or less were included prospectively. LCAs were performed to identify similar clinical subgroups giving even weights to a wide range of MSA motor and nonmotor features. We ran latent models of up to 6 class solutions; the overall model fit was evaluated based on the parsimony of the derived classes, the fit indices, and clinical interpretability. RESULTS: The LCA outcome supported categorization of at least three subgroups of patients with early MSA: the largest class 1, labeled "moderate parkinsonism + extensive dysautonomia", included approximately half of our study patients and showed marked autonomic dysfunction with a burden of parkinsonism. The two other classes, class 2 "predominant parkinsonism + limited dysautonomia" and class 3 "predominant cerebellar symptoms + limited dysautonomia", showed marked core motor features (parkinsonism or cerebellar symptoms) with generally mild dysautonomia. CONCLUSIONS: To our knowledge, this is the first data-driven identification of disease subtypes covering various symptom constellations in early MSA (<3 years from motor symptom onset). The present LCA result did not replicate the conventional motor classification and supported the heterogeneity within MSA-P and MSA-C subtypes.
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Enfermedades del Sistema Nervioso Autónomo , Ataxia Cerebelosa , Atrofia de Múltiples Sistemas , Trastornos Parkinsonianos , Cerebelo , Humanos , Trastornos Parkinsonianos/diagnósticoRESUMEN
OBJECTIVE: To assess nocturnal hypokinesia using the Korean version of the Nocturnal Hypokinesia Questionnaire (NHQ-K) in Parkinson's disease (PD) patients across disease stages. METHODS: We developed the NHQ-K and performed questionnaire-based interviews with 108 PD patients from three referral hospitals. Clinical associations of nocturnal hypokinesia and its impact on health-related quality of life (HRQoL) were also analyzed. RESULTS: The NHQ-K showed acceptable internal consistency (0.83) and interrater reliability (0.95). Nocturnal hypokinesia significantly affected HRQoL in PD patients at both the early and advanced stages (adjusted p < 0.001). Increased severity of nocturnal hypokinesia was associated with dyskinesias, off-period disability, apathy, and anxious mood in PD patients (adjusted p < 0.01) after controlling for disease severity and medication dose. CONCLUSION: The NHQ-K is useful for screening nocturnal hypokinesia in PD patients. Given the high impact of nocturnal hypokinesia on HRQoL, comprehensive management of nocturnal disability is needed for PD patients.
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F-box only protein 7 (FBXO7) is a rare monogenic cause of hereditary Parkinson's disease (PD) with an autosomal recessive mode of inheritance and a broad spectrum of clinical manifestations. Here, we report a de novo PD patient with onset at the age of 28 with novel compound heterozygous variants in the FBXO7 gene (c.1162C>T, p.Gln388X; c.80G>A, p.Arg27His). The clinical features of the patient were problematic impulse control disorder behaviors and pyromania, and pyramidal signs were negative. We describe the novel pathogenic variants of the FBXO7 gene with detailed clinical pictures to report the expanding genotypes and phenotypes of FBXO7-associated parkinsonism.
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OBJECTIVE: To determine whether non-motor symptoms predict the development of functional dependency in Parkinson's disease (PD). METHODS: This study using the PPMI data included 405 patients with newly diagnosed PD without functional dependency at baseline visit. We collected baseline demographic and clinical data. Non-motor symptoms were measured using well-validated instruments covering neuropsychiatric, sleep-related, olfactory, and autonomic symptoms. The development of dependency was defined to be present if a Schwab and England (S&E) score of less than 80% at any time point remained during the rest of the follow-up. Cox proportional-hazards regression analyses were performed to identify predictors of dependency. To further validate our findings, additional analysis was performed using an S&E cut-off of 60%. RESULTS: Over a 5-year follow-up period, 61 patients became functionally dependent. The cumulative incidence of dependency was 17% at the 5-year follow-up. Among the non-motor variables, only the REM sleep behavior disorder (RBD) screening questionnaire (RBDSQ) score was associated with the development of dependency. The bradykinesia subscore also predicted dependency. However, when using a cut-off score of 60% or below, the RBDSQ score but not the bradykinesia subscore increased the risk of dependency. The RBDSQ score was further inserted as a dichotomous variable in the multivariable Cox model. The presence of RBD was a significant predictor of dependency for both S&E cut-off scores. CONCLUSION: The presence of RBD in early PD patients was associated with an increased risk of functional dependency. This finding supports the notion that RBD portends poor prognosis in PD.
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Actividades Cotidianas , Progresión de la Enfermedad , Enfermedad de Parkinson/fisiopatología , Trastorno de la Conducta del Sueño REM/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico , Pronóstico , Trastorno de la Conducta del Sueño REM/etiologíaRESUMEN
OBJECTIVES: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been reported to have a positive effect on sleep-wake disturbance in Parkinson's disease (PD). We aimed to investigate the long-term effects of STN DBS on sleep in patients with PD. METHODS: Sixty-one patients with PD who had undergone bilateral STN DBS were followed for 3 years with assessments including the Parkinson's disease sleep scale (PDSS), Epworth sleepiness scale (ESS), total sleep hours per day, Unified PD Rating Scale part I-III, Hoehn & Yahr stage, levodopa equivalent dose, quality of life measure, and depression scale measured preoperatively and at 6 months after postoperatively, and annually thereafter. RESULTS: Among the 61 patients at baseline, 46 patients completed the last follow-up assessment. The total PDSS score significantly improved after STN DBS from baseline up to 3 years after STN DBS (79.0±30, 100.0±23.3, 98.8±23.0, 97.1±29.6, and 93.3±28.0 at baseline, 6, 12, 24, and 36 months, respectively, p = 0.006 for the change over time). Among the eight PDSS domains, the domains for overall quality of a night's sleep, sleep onset and maintenance insomnia, and nocturnal motor symptoms showed significant improvement after STN DBS (p = 0.036, 0.029, and < 0.001, respectively, for the change over time). The total sleep hours per day were increased, but the total ESS score did not show significant change after STN DBS (p = 0.001 and 0.055, respectively, for the change over time). Changes in the total PDSS were associated with changes in the depression and motivation items in the Unified PD Rating Scale part I, depression scale, and quality of life measure, but those variables at baseline were not predictive of changes in the total PDSS after STN DBS. CONCLUSION: In the largest systematic long-term follow-up study, the improvement in subjective sleep quality after bilateral STN DBS was sustained in PD patients. Improved nocturnal sleep and nocturnal motor symptoms were correlated with an improved mood and quality of life. However, STN DBS did not reduce excessive daytime sleepiness despite reductions in antiparkinsonian medications.
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Estimulación Encefálica Profunda , Enfermedad de Parkinson/cirugía , Trastornos del Sueño-Vigilia/cirugía , Sueño/fisiología , Núcleo Subtalámico/cirugía , Actividades Cotidianas , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/fisiopatología , Periodo Posoperatorio , Escalas de Valoración Psiquiátrica , Calidad de Vida , Trastornos del Sueño-Vigilia/complicaciones , Trastornos del Sueño-Vigilia/fisiopatología , Núcleo Subtalámico/fisiopatología , Resultado del TratamientoRESUMEN
The aim of this study was to characterize peripheral inflammatory markers in patients with early Parkinson's disease (PD) and to explore whether these markers contribute to motor and non-motor symptoms. We collected serum from patients with early PD (nâ¯=â¯58) and from healthy control subjects (nâ¯=â¯20). The following inflammatory markers were measured: interleukin (IL)-1ß, IL-2, IL-6, IL-10, tumor necrosis factor-α, and high-sensitivity C-reactive protein. The Movement Disorders Society Unified Parkinson's Disease Rating Scale part 3 and Hoehn and Yahr stage were used to assess motor symptoms, and the Non-motor Symptoms Scale, the Cross-Cultural Smell Identification Test, the Montreal Cognitive Assessment, and the Composite Autonomic Symptom Score 31 (COMPASS-31) were used to assess non-motor symptoms. The levels of IL-1ß, IL-2, and IL-6 were higher in the PD group than in the control group. However, only IL-1ß among those markers remained significant after Bonferroni correction (Pâ¯=â¯0.024). In the PD group, the anti-inflammatory cytokine IL-10 levels correlated positively with the COMPASS-31 score (râ¯=â¯0.277, Pâ¯=â¯0.035), whereas no correlation was found between the other inflammatory marker levels and motor or non-motor symptoms. Among the domains of the COMPASS-31, the IL-10 levels correlated only with the gastrointestinal domain (râ¯=â¯0.358, Pâ¯=â¯0.006). Our results suggest increased peripheral inflammation in the early stage of PD, but the role of inflammation in motor and non-motor symptoms is unclear. Although we found a correlation between IL-10 levels and gastrointestinal symptoms, this finding may simply reflect a protective response against inflammatory processes associated with the disease.
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Mediadores de Inflamación/sangre , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/diagnóstico , Anciano , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Citocinas/sangre , Diagnóstico Precoz , Femenino , Humanos , Interleucina-10/sangre , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/sangreRESUMEN
BACKGROUND AND PURPOSE: Recent studies have shown that several nonmotor symptoms differ between Parkinson's disease (PD) and drug-induced parkinsonism (DIP). However, there have been no reports on cardiovascular autonomic function in DIP, and so this study investigated whether cardiovascular autonomic function differs between PD and DIP patients. METHODS: This study consecutively enrolled 20 DIP patients, 99 drug-naïve PD patients, and 25 age-matched healthy controls who underwent head-up tilt-table testing and 24-h ambulatory blood pressure monitoring. RESULTS: Orthostatic hypotension was more frequent in patients with PD or DIP than in healthy controls. In DIP, orthostatic hypotension was associated with the underlying psychiatric diseases and neuroleptics use, whereas prokinetics were not related to orthostatic hypotension. The supine blood pressure, nighttime blood pressure, and nocturnal blood pressure dipping did not differ significantly between the DIP and control groups. Supine hypertension and nocturnal hypertension were more frequent in PD patients than in controls. CONCLUSIONS: The included DIP patients frequently exhibited orthostatic hypotension that was associated with the underlying diseases as well as the nature of and exposure time to the offending drugs. Clinicians should individualize the manifestations of DIP according to underlying diseases as well as the action mechanism of and exposure time to each offending drug.
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BACKGROUND AND PURPOSE: We investigated the relationship between transcranial Doppler (TCD) pulsatility index (PI) and central aortic pressure by measurement of the aortic augmentation index (AIx). METHODS: We enrolled 148 consecutive patients with a diagnosis of acute ischemic stroke. Patients were eligible for the study if they experienced their first ischemic stroke within the preceding 7 days and were 45 years of age or older. At Day 7 (±2) after stroke onset, TCD studies were performed and AIx was measured by applanation tonometry on the same days. RESULTS: The mean age was 66.3 (47-90) years and 37.8% were women. The mean middle cerebral artery (MCA) PI was significantly related with age (r =.361), hypertension (r = .184), peripheral systolic blood pressure (SBP; r = .211), peripheral pulse pressure (PP; r = .396), aortic SBP (r = .184), aortic DBP (r = -.181), and aortic PP (r = .371). The basilar artery (BA) PI was significantly related with age (r = .311), peripheral DBP (r = -.267), peripheral PP (r = .358), aortic DBP (r = -.266), and aortic PP (r = .347). CONCLUSIONS: TCD PI was significantly related with central aortic pressure, especially PP. The PI in the MCA and BA is closely associated with the pulsatile component of BP in the systemic circulation.