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BACKGROUND: Most cases of dementia with Lewy bodies (DLB) show Alzheimer's disease pathology-like senile plaques and neurofibrillary tangles. Several studies have also revealed a high prevalence of positive amyloid imaging with positron emission tomography (PET) in DLB and moderate prevalence in Parkinson's disease (PD) with dementia. However, it remains unclear in PD without dementia as to when the brain ß amyloid (Aß) burden begins and progresses. Our study aimed to determine the prevalence of Aß deposition in PD without dementia using amyloid PET. METHODS: This was a cross-sectional study on 33 patients with PD without dementia, of whom 21 had normal cognition and 12 met the criteria for PD-mild cognitive impairment. All subjects underwent neuropsychological assessment and [18F] florbetaben (FBB) PET. RESULTS: All subjects had Lewy body-related disorders, displaying a significantly reduced myocardial [123I] metaiodobenzylguanidine uptake. The cortical FBB-binding pattern in all subjects, including APOE e4 carriers, suggested negative Aß deposition. CONCLUSION: Patients with PD without dementia exhibit an extremely low prevalence of Aß positivity compared with those reported in cognitively normal elderly controls. Further longitudinal imaging studies and long-term follow-up are needed; however, our findings provide novel insights for understanding Aß metabolism in PD.
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Amiloide/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Anciano , Estudios Transversales , Femenino , Humanos , Masculino , Enfermedad de Parkinson/diagnóstico por imagen , Tomografía de Emisión de Positrones , PrevalenciaRESUMEN
BACKGROUND: Extracellular vesicles (EVs) hold the potential for elucidating the pathogenesis of amyotrophic lateral sclerosis (ALS) and serve as biomarkers. Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and cerebrospinal fluid (CSF; cEVs) of sporadic ALS (SALS) patients remain uncharted. Ropinirole hydrochloride (ROPI; dopamine D2 receptor [D2R] agonist), a new anti-ALS drug candidate identified through induced pluripotent stem cell (iPSC)-based drug discovery, has been suggested to inhibit ALS disease progression in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial, but its mechanism of action is not well understood. Therefore, we tried to reveal longitudinal changes with disease progression and the effects of ROPI on protein profiles of EVs. METHODS: We collected serum and CSF at fixed intervals from ten controls and from 20 SALS patients participating in the ROPALS trial. Comprehensive proteomic analysis of EVs, extracted from these samples, was conducted using liquid chromatography/mass spectrometer (LC/MS). Furthermore, we generated iPSC-derived astrocytes (iPasts) and performed RNA sequencing on astrocytes with or without ROPI treatment. RESULTS: The findings revealed notable disparities yet high congruity in sEVs and cEVs protein profiles concerning disease status, time and ROPI administration. In SALS, both sEVs and cEVs presented elevated levels of inflammation-related proteins but reduced levels associated with unfolded protein response (UPR). These results mirrored the longitudinal changes after disease onset and correlated with the revised ALS Functional Rating Scale (ALSFRS-R) at sampling time, suggesting a link to the onset and progression of SALS. ROPI appeared to counteract these changes, attenuating inflammation-related protein levels and boosting those tied to UPR in SALS, proposing an anti-ALS impact on EV protein profiles. Reverse translational research using iPasts indicated that these changes may partly reflect the DRD2-dependent neuroinflammatory inhibitory effects of ROPI. We have also identified biomarkers that predict diagnosis and disease progression by machine learning-driven biomarker search. CONCLUSIONS: Despite the limited sample size, this study pioneers in reporting time-series proteomic alterations in serum and CSF EVs from SALS patients, offering comprehensive insights into SALS pathogenesis, ROPI-induced changes, and potential prognostic and diagnostic biomarkers.
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iPSC-based drug discovery led to a phase 1/2a trial of ropinirole in ALS. 20 participants with sporadic ALS received ropinirole or placebo for 24 weeks in the double-blind period to evaluate safety, tolerability, and therapeutic effects. Adverse events were similar in both groups. During the double-blind period, muscle strength and daily activity were maintained, but a decline in the ALSFRS-R, which assesses the functional status of ALS patients, was not different from that in the placebo group. However, in the open-label extension period, the ropinirole group showed significant suppression of ALSFRS-R decline and an additional 27.9 weeks of disease-progression-free survival. iPSC-derived motor neurons from participants showed dopamine D2 receptor expression and a potential involvement of the SREBP2-cholesterol pathway in therapeutic effects. Lipid peroxide represents a clinical surrogate marker to assess disease progression and drug efficacy. Limitations include small sample sizes and high attrition rates in the open-label extension period, requiring further validation.
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Esclerosis Amiotrófica Lateral , Células Madre Pluripotentes Inducidas , Humanos , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Indoles/efectos adversos , Indoles/farmacología , Neuronas MotorasRESUMEN
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable neurological disease, and patients diagnosed with ALS have a survival time of 2-5 years without life-sustaining therapy. Decision-making processes for the acceptance or decline of percutaneous endoscopic gastrostomy (PEG) and tracheostomy with invasive ventilation (TIV) therapy are complex and multifaceted. In this study, we examined whether participation or no participation in clinical trials of ALS had an influence on the decision-making processes of ALS patients. METHODS: Fifty-seven consecutive ALS participants were recruited. Two participants did not wish to participate in any clinical trials, and Twenty-two participants were enrolled in clinical trials. Twenty-three participants wished to participate but could not be enrolled in any of the clinical trials because they exceeded the number of participants in these trials or they met the exclusion criteria. RESULT: At baseline, there was no significant difference in the preference rates for PEG and TIV between the participant and non-participant groups, but after the double-blind period/6 months, both preference rates were significantly higher in the non-participant group than in the participant group. Notably, the rate of preferred TIV in the participant group drastically decreased after the double-blind period. A single regression analysis revealed that participation in clinical trials had a strong influence on the change of TIV preference for 6 months. CONCLUSION: Participation in a clinical trial decreases the willingness to prolong life after the clinical trial. The present results are meaningful when designing clinical trials and discussing life-sustaining treatments with ALS patients.
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Esclerosis Amiotrófica Lateral , Ensayos Clínicos como Asunto , Toma de Decisiones , Esclerosis Amiotrófica Lateral/terapia , Humanos , TraqueostomíaRESUMEN
Locally advanced cervical cancer occasionally induces pyometra, but there have been no reports of meningitis where pyometra is the cause of infection. Here, we report a case of Listeria monocytogenes meningitis related to pyometra during concurrent chemoradiotherapy (CCRT) in a cervical cancer patient. The patient, a 77-year-old woman, was diagnosed with Stage IIB (FIGO 2018) cervical adenocarcinoma, and CCRT was initiated. Pyometra was exacerbated during CCRT, and after her first brachytherapy, she presented at our hospital with fever and decreased consciousness level. After admission to the Intensive Care Unit, the patient lost consciousness and experienced frequent seizures; tracheal intubation was required. Whole-body computed tomography revealed pyometra; therefore, transvaginal removal of the abscess was performed. Laboratory tests and vital signs indicated septic shock, and meropenem was administered. L. monocytogenes was detected in the abscess from the uterine cavity and the blood cultures on the third day of hospitalization. A lumbar puncture was performed on the same day to investigate whether the patient had meningitis. A FilmArray meningitis/encephalitis panel test of the spinal fluid revealed L. monocytogenes. After the diagnosis of meningitis with L. monocytogenes, ampicillin and gentamicin were started, and the blood test results gradually improved. Five months after the initial episode, her consciousness recovered, however she still received mechanical ventilatory support. L. monocytogenes infections can occur in patients undergoing chemotherapy, even without the use of steroids or immunosuppressive agents. In cases with pyometra, intrauterine manipulation can increase the risk of severe infection.
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OBJECTIVES: As the population of patients with cognitive decline grows, physicians and caregivers need brief screening tools. Comprehensive neurocognitive batteries require special training and time for evaluation. We focused on accessibility and compared the diagnostic power of several easy questions. DESIGN: "Attended With" (AW) and "Head-Turning Sign" (HTS) factors and participants' replies to following questions were recorded: "Do you feel that you have more difficulties in your daily life than you used to?", [no consciousness (C-) or consciousness+ (C+)], "Could you tell me about your daily pleasures or pastimes?" [no pleasure (P-) or pleasure + (P+)], "What are notable current/recent news/topics?" [no news (N-) or news+ (N+)]. SETTING: This took place in our Memory Clinic between May 2016 and July 2019. PARTICIPANTS: We enrolled 162 consecutive cases (44 cognitive normal (CN), 55 amnestic mild cognitive impairment (aMCI), and 48 Alzheimer's disease (AD)). MEASUREMENTS: The sensitivity and specificity of each battery were calculated, and on account of those numbers, the population attributable risk percent % (PAR%) of (AW and HTS+), (C- and P-), (C- and N-), (P- and N-) as analysis of combination of questions, respectively, were calculated. RESULTS: AW had high sensitivity, 87.4, 95.8% (CN vs aMCI + AD, CN + aMCI vs AD) but the sensitivity of HTS was only 46.4, 57.7%, and HTS showed high specificity, 100.0, 71.8%. C- had high sensitivity, 80.6, 87.5%, whereas P- and N- had high specificity, both 83.9% in CN vs aMCI + AD, 88.1% and 75.9% in CN + aMCI vs AD, respectively. In combination analysis, the PAR% of (C- and N-) were as high as (AW and HTS+). CONCLUSIONS: The combination of (C- and N-) is as powerful as (AW and HTS+) in screening AD. Our findings provide novel insights for screening utility of brief questions "Consciousness of Impairment" and "Recent News."
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Disfunción Cognitiva/diagnóstico , Actividades Cotidianas , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Comunicación , Femenino , Humanos , Masculino , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Estudios Retrospectivos , Sensibilidad y Especificidad , HablaRESUMEN
Extracorporeal adsorption therapy has been carried out clinically in cases of myasthenia gravis (MG) since the 1980s without any major complications. Despite a lack of clinical evidence, it has been accepted as a potential therapy for steroid-resistant patients in many institutes. Recently, we experienced a case of MG with an anaphylactoid reaction during extracorporeal immunoadsorption therapy. A 64 year old women with MG showed an anaphylactoid reaction immediately after the initiation of adsorption therapy using a polyvinylalcohol gel column. It is therefore important to bear in mind that extracorporeal adsorption therapy could trigger an anaphylactoid reaction, which may induce a MG crisis.