RESUMO
A 76-year-old woman was diagnosed with invasive bladder cancer and underwent cystectomy, bilateral external iliac, internal iliac and obturator lymph node dissection, and bilateral cutaneous ureterostomy. Pathological findings showed no lymph node metastasis ; however, the patient had lower abdominal pain and fever from the 14th postoperative day, and computed tomography (CT) revealed fluid retention in the pelvis. Retrograde pyelography showed no leakage from the urinary tract, and a drain was placed after percutaneous puncture of the pelvic cavity. There was copious drainage fluid and its nature and composition suggested lymphorrhea. Ultrasound-guided intranodal lymphangiography revealed contrast material leakage from the bilateral lymph node dissection sites. After lymphangiography, drainage from the drain decreased. Despite the drainage being minimal yet persistent, sclerotherapy was performed, the drain was removed and the patient was discharged. After discharge, there was leakage from the site of urethral extraction, and CT revealed recurrent lymph leakage. The patient was readmitted, and a second lymphangiography was performed. The leakage from the site of urethral extraction gradually decreased, and the patient was discharged on the 59th postoperative day. CT after discharge confirmed that the lymphorrhea had shrunk in size, and there has been no recurrence since then. Lymphangiography is a promising treatment option for lymphorrhea after pelvic surgery.
Assuntos
Cistectomia , Linfografia , Neoplasias da Bexiga Urinária , Humanos , Feminino , Idoso , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Ultrassonografia , Complicações Pós-Operatórias/diagnóstico por imagem , Doenças Linfáticas/diagnóstico por imagem , Doenças Linfáticas/etiologia , Doenças Linfáticas/terapia , Excisão de Linfonodo/efeitos adversos , Tomografia Computadorizada por Raios XRESUMO
Since the identification of vacuolar protein sorting (VPS) 35, as a causative molecule for familial Parkinson's disease (PD), retromer-mediated endosomal machinery has been a rising factor in the pathogenesis of the disease. The retromer complex cooperates with sorting nexin (SNX) dimer and DNAJC13, another causal molecule in PD, to transport cargoes from endosomes to the trans-Golgi network, and is also involved in mitochondrial dynamics and autophagy. Retromer dysfunction may induce neuronal death leading to PD via several biological cascades, including misfolded, insoluble α-synuclein (aS) accumulation and mitochondrial dysfunction; however, the detailed mechanisms remain poorly understood. In this study, we showed that the stagnation of retromer-mediated retrograde transport consistently occurs in different PD-mimetic conditions, i.e., overexpression of PD-linked mutant DNAJC13, excess aS induction, or toxin-induced mitochondrial dysfunction. Mechanistically, DNAJC13 was found to be involved in clathrin-dependent retromer transport as a functional modulator of SNX1 together with heat shock cognate 70 kDa protein (Hsc70), which was controlled by the binding and dissociation of DNAJC13 and SNX1 in an Hsc70 activity-dependent manner. In addition, excess amount of aS decreased the interaction between SNX1 and VPS35, the core component of retromer. Furthermore, R33, a pharmacological retromer chaperone, reduced insoluble aS and mitigated rotenone-induced neuronal apoptosis. These findings suggest that retrograde transport regulated by SNX1-retromer may be profoundly involved in the pathogenesis of PD and is a potential target for disease-modifying therapy for the disease.
RESUMO
Transient expression and induction of RNA silencing by agroinfiltration is a fundamental method in plant RNA biology. Here, we introduce a new reporter assay using RUBY, which encodes three key enzymes of the betalain biosynthesis pathway, as a polycistronic mRNA. The red pigmentation conferred by betalains allows visual confirmation of gene expression or silencing levels without tissue disruption, and the silencing levels can be quantitatively measured by absorbance in as little as a few minutes. Infiltration of RUBY in combination with p19, a well-known RNA silencing suppressor, induced a fivefold higher accumulation of betalains at 7 days post infiltration compared to infiltration of RUBY alone. We demonstrated that co-infiltration of RUBY with two RNA silencing inducers, targeting either CYP76AD1 or glycosyltransferase within the RUBY construct, effectively reduces RUBY mRNA and betalain levels, indicating successful RNA silencing. Therefore, compared to conventional reporter assays for RNA silencing, the RUBY-based assay provides a simple and rapid method for quantitative analysis without the need for specialized equipment, making it useful for a wide range of RNA silencing studies.
Assuntos
Betalaínas , Nicotiana , Interferência de RNA , Betalaínas/metabolismo , Nicotiana/genética , Nicotiana/metabolismo , Plantas Geneticamente Modificadas , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA de Plantas/genética , RNA de Plantas/metabolismoRESUMO
We detected enzymatic activity that generates 20-nucleotide (nt) RNA from double-stranded RNAs (dsRNAs) in crude extracts prepared from various silkworm (Bombyx mori) organs. The result using knocked-down cultured cells indicated that this dicing activity originated from B. mori Dicer-2 (BmDcr2). Biochemical analyses revealed that BmDcr2 preferentially cleaves 5'-phosphorylated dsRNAs at the 20-nt site-counted from the 5'-phosphorylated end-and required ATP and magnesium ions for the dicing reaction. This is the first report of the biochemical characterization of Dicer-2 in lepidopteran insects. This enzymatic property of BmDcr2 in vitro is consistent with the in vivo small interfering RNA profile in virus-infected silkworm cells.
Assuntos
Bombyx , RNA de Cadeia Dupla , Ribonuclease III , Animais , Bombyx/genética , Bombyx/metabolismo , Proteínas de Insetos/metabolismo , Proteínas de Insetos/genética , Larva/metabolismo , Larva/genética , Larva/crescimento & desenvolvimento , Magnésio/metabolismo , Ribonuclease III/metabolismo , Ribonuclease III/genética , RNA de Cadeia Dupla/metabolismo , RNA Interferente Pequeno/metabolismoRESUMO
Dehydroeffusol, a major phenanthrene in Juncus effusus, protects neurodegeneration induced by intracellular Zn2+ ferried by extracellular amyloid ß1-42 (Aß1-42). Here we focused on adrenaline ß receptor activation and the induction of metallothioneins (MTs), intracellular Zn2+-binding proteins to test the protective mechanism of dehydroeffusol. Isoproterenol, an agonist of adrenergic ß receptors elevated the level of MTs in the dentate granule cell layer 1 day after intracerebroventricular (ICV) injection. When Aß1-42 was injected 1 day after isoproterenol injection, pre-injection of isoproterenol protected Aß1-42 toxicity via reducing the increase in intracellular Zn2+ after ICV injection of Aß1-42. On the basis of the effect of increased MTs by isoproterenol, dehydroeffusol (15 mg/kg body weight) was orally administered to mice once a day for 2 days. On day later, dehydroeffusol elevated the level of MTs and prevented Aß1-42 toxicity via reducing Aß1-42-mediated increase in intracellular Zn2+. In contrast, propranolol, an antagonist of adrenergic ß receptors reduced the level of MTs increased by dehydroeffusol, resulting in invalidating the preventive effect of dehydroeffusol on Aß1-42 toxicity. The present study indicates that blockage of MT synthesis via adrenaline ß receptor activation invalidates dehydroeffusol-mediated prevention of Aß1-42 toxicity. It is likely that MT synthesis via adrenaline ß receptor activation is beneficial to neuroprotection and that oral intake of dehydroeffusol preventively serves against the Aß1-42 toxicity.
Assuntos
Peptídeos beta-Amiloides , Metalotioneína , Fenantrenos , Camundongos , Animais , Peptídeos beta-Amiloides/toxicidade , Peptídeos beta-Amiloides/metabolismo , Epinefrina , Isoproterenol , Receptores Adrenérgicos beta , Fragmentos de Peptídeos/toxicidade , Fragmentos de Peptídeos/metabolismoRESUMO
BACKGROUND: Recently, the hypothesis that pathological α-Synuclein propagates from the gut to the brain has gained attention. Although results from animal studies support this hypothesis, the specific mechanism remains unclear. This study focused on the intestinal fatty acid-binding protein (FABP2), which is one of the subtypes of fatty acid binding proteins localizing in the gut, with the hypothesis that FABP2 is involved in the gut-to-brain propagation of α-synuclein. The aim of this study was to clarify the pathological significance of FABP2 in the pathogenesis and progression of synucleinopathy. METHODS: We examined the relationship between FABP2 and α-Synuclein in the uptake of α-Synuclein into enteric neurons using primary cultured neurons derived from mouse small intestinal myenteric plexus. We also quantified disease-related protein concentrations in the plasma of patients with synucleinopathy and related diseases, and analyzed the relationship between plasma FABP2 level and progression of the disease. RESULTS: Experiments on α-Synuclein uptake in primary cultured enteric neurons showed that following uptake, α-Synuclein was concentrated in areas where FABP2 was localized. Moreover, analysis of the plasma protein levels of patients with Parkinson's disease revealed that the plasma FABP2 and α-Synuclein levels fluctuate with disease duration. The FABP2/α-Synuclein ratio fluctuated more markedly than either FABP2 or α-Synuclein alone, depending on the duration of disease, indicating a higher discriminant ability of early Parkinson's disease patients from healthy patients. CONCLUSIONS: These results suggest that FABP2 potentially contributes to the pathogenesis and progression of α-synucleinopathies. Thus, FABP2 is an important molecule that has the potential to elucidate the consistent mechanisms that lead from the prodromal phase to the onset and subsequent progression of synucleinopathies.
Assuntos
Doença de Parkinson , Sinucleinopatias , Animais , Humanos , Camundongos , alfa-Sinucleína/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Neurônios/metabolismo , Doença de Parkinson/metabolismo , Sinucleinopatias/metabolismo , Sinucleinopatias/patologiaRESUMO
The advent of a super-aged society poses urgent challenges in overcoming age-related neurological disorders and extending a healthy lifespan. Neurodegenerative diseases such as Alzheimer's disease, dementia with Lewy bodies, and Parkinson's disease are characterized by the accumulation of pathogenic proteins in the brain, leading to the formation of intracellular aggregates known as pathological hallmarks. In the early stages of protein accumulation, before the onset of clinical symptoms such as cognitive impairment or motor dysfunction, brain inflammation begins to occur. Subsequently, neuronal death progresses, and clinical symptoms manifest as dementia or Parkinson's disease. Therefore, there is a need for early prediction of neurodegeneration and the development of disease-modifying drugs for pre-symptomatic prevention. To address this issue, we have focused on enhancing the degradation of amyloid-ß protein by targeting Ca2+/calmodulin-dependent kinase II (CaMKII)/proteasome system and on suppressing the propagation and uptake mechanisms of α-synuclein by targeting fatty acid-binding proteins (FABPs) coupled with the long isoform of dopamine D2 (D2L) receptor. Additionally, our analysis of FABP knockout mice has revealed an increased expression of FABPs in the neurodegenerative process, suggesting their involvement in mitochondrial dysfunction and neuronal death. Based on these findings, this article highlights the physiological significance of FABP family proteins in neurodegeneration and discusses the analysis of plasma biomarkers for predicting neurodegenerative disorders and the discriminatory methods for distinguishing between Alzheimer's disease, dementia with Lewy bodies, and Parkinson's disease. Furthermore, we explore the potential of ultra-early prediction of neurodegenerative disorders.
Assuntos
Doença de Alzheimer , Doença por Corpos de Lewy , Doenças Neurodegenerativas , Doença de Parkinson , Animais , Camundongos , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/patologia , Doença de Parkinson/diagnóstico , Doença de Alzheimer/metabolismo , Corpos de Lewy/metabolismo , Corpos de Lewy/patologia , alfa-SinucleínaRESUMO
Parkinson's disease (PD), which has characteristic motor symptoms such as tremor, muscle rigidity, and akinesia, and as the disease progresses, Lewy bodies spread throughout the brain, eventually causing Parkinson disease dementia (PDD). The clinical picture of PDD is similar to Dementia with Lewy bodies (DLB) and their pathological features are indistinguishable from each other. More than 80% of PD cases will eventually develop dementia and their prognosis are generally 3 to 4 years from the onset of dementia, regardless of disease duration or age of onset. We found that patients with severe olfactory impairment had lower cognitive function scores, more frequent onset of dementia, brain atrophy, and prominent cerebral metabolic abnormalities in a 3-year longitudinal study (Brain 135:161-169, 2012). This study demonstrated for the first time in the world that olfaction tests are useful in predicting dementia in PD, and similar results have been followed up worldwide. Based on these results, a randomized, double-blind, multicenter comparative study of donepezil in PD with severe olfactory dysfunction (DASH-PD study) was conducted and completed a 4-year follow-up period. The results were recently published showing the efficacy and safety of cholinesterase inhibitors for PD without dementia (eClinicalMedicine 51: 101571, 2022).
Assuntos
Demência , Doença por Corpos de Lewy , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/tratamento farmacológico , Doença por Corpos de Lewy/patologia , Demência/etiologia , Demência/patologia , Demência/psicologia , Estudos Longitudinais , Donepezila/uso terapêuticoRESUMO
A 74-year-old man with no overt symptoms was referred for a chest computed tomography (CT) that revealed multiple bilaterally pulmonary ground-glass nodules (GGNs) with subtle changes in size over eight months. Surgical lung biopsies were performed in the left upper lobe. A pathologic study confirmed the intravascular large B-cell lymphoma (IVLBCL). This lesion was a nodule-like cluster of atypical cells, meaning that it had been localized for several months. Pulmonary IVLBCL may form focal lesions presenting as GGN on chest CT and progress slowly without apparent symptoms.
Assuntos
Neoplasias Pulmonares , Linfoma Difuso de Grandes Células B , Nódulos Pulmonares Múltiplos , Nódulo Pulmonar Solitário , Masculino , Humanos , Idoso , Neoplasias Pulmonares/patologia , Nódulo Pulmonar Solitário/patologia , Nódulo Pulmonar Solitário/cirurgia , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Pulmão/patologia , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/patologiaRESUMO
OBJECTIVE: The aim of this study was to clarify the roles of the cerebellum and basal ganglia for temporal integration. METHODS: We studied 39 patients with spinocerebellar degeneration (SCD), comprising spinocerebellar atrophy 6 (SCA6), SCA31, Machado-Joseph disease (MJD, also called SCA3), and multiple system atrophy (MSA). Thirteen normal subjects participated as controls. Participants were instructed to tap on a button in synchrony with isochronous tones. We analyzed the inter-tap interval (ITI), synchronizing tapping error (STE), negative asynchrony, and proportion of delayed tapping as indicators of tapping performance. RESULTS: The ITI coefficient of variation was increased only in MSA patients. The standard variation of STE was larger in SCD patients than in normal subjects, especially for MSA. Negative asynchrony, which is a tendency to tap the button before the tones, was prominent in SCA6 and MSA patients, with possible basal ganglia involvement. SCA31 patients exhibited normal to supranormal performance in terms of the variability of STE, which was surprising. CONCLUSIONS: Cerebellar patients generally showed greater STE variability, except for SCA31. The pace of tapping was affected in patients with possible basal ganglia pathology. SIGNIFICANCE: Our results suggest that interaction between the cerebellum and the basal ganglia is essential for temporal processing. The cerebellum and basal ganglia and their interaction regulate synchronized tapping, resulting in distinct tapping pattern abnormalities among different SCD subtypes.
Assuntos
Atrofia de Múltiplos Sistemas , Ataxias Espinocerebelares , Degenerações Espinocerebelares , Humanos , Cerebelo , Ataxias Espinocerebelares/patologia , Gânglios da Base/patologiaRESUMO
α-Synuclein (αS) is a key molecule in the pathomechanism of Parkinson's disease. Most studies on αS to date have focused on its function in the neuronal cytosol, but its action in the nucleus has also been postulated. Indeed, several lines of evidence indicate that overexpressed αS leads to epigenomic alterations. To clarify the functional role of αS in the nucleus and its pathological significance, HEK293 cells constitutively expressing αS were used to screen for nuclear proteins that interact with αS by nanoscale liquid chromatography/tandem mass spectrometry. Interactome analysis of the 229 identified nuclear proteins revealed that αS interacts with the BRG1-associated factor (BAF) complex, a family of multi-subunit chromatin remodelers important for neurodevelopment, and protein arginine methyltransferase 5 (PRMT5). Subsequent transcriptomic analysis also suggested a functional link between αS and the BAF complex. Based on these results, we analyzed the effect of αS overexpression on the BAF complex in neuronally differentiated SH-SY5Y cells and found that induction of αS disturbed the BAF maturation process, leading to a global increase in symmetric demethylation of histone H4 on arginine 3 (H4R3me2s) via enhanced BAF-PRMT5 interaction. Chromatin immunoprecipitation sequencing confirmed accumulated H4R3me2s methylation near the transcription start site of the neuronal cell adhesion molecule (NRCAM) gene, which has roles during neuronal differentiation. Transcriptional analyses confirmed the negative regulation of NRCAM by αS and PRMT5, which was reconfirmed by multiple datasets in the Gene Expression Omnibus (GEO) database. Taken together, these findings suggest that the enhanced binding of αS to the BAF complex and PRMT5 may cooperatively affect the neuronal differentiation process.
Assuntos
Histonas , Proteína-Arginina N-Metiltransferases , alfa-Sinucleína , Humanos , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Histonas/metabolismo , Histonas/genética , Metilação , Células HEK293 , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , DNA Helicases/metabolismo , DNA Helicases/genética , Arginina/metabolismo , Neurônios/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/patologiaRESUMO
Prescription doses of levodopa in patients with advanced Parkinson's disease (PD) are generally lower in Japan than in the United States or Europe, although Japanese guidelines for the management of PD recommend increasing the dosage as the disease progresses. However, data regarding levodopa prescription practices in patients with advanced PD in the clinical setting are limited. This retrospective observational study analyzed patterns of drug use for patients with advanced PD in Japan using claims data from hospitalized patients in the Medical Data Vision Co. database. Eligible patients had at least two PD-associated claims in two different quarters between April 1, 2008, and November 30, 2018, and a 10-item activities of daily living score <60 upon hospital discharge (as a proxy for advanced PD). The primary endpoint was the prescribed dosage of levodopa at the index hospitalization. Dosages of other PD drugs (medications with an on-label indication for PD) and non-PD drugs were also assessed. Overall, 4029 patients met the inclusion criteria (mean age, 76.9 years; 83.3% aged ≥70 years). At the index date, 74.0% were receiving levodopa. Patients received a median of one PD drug in addition to levodopa, and 27.4% and 20.2% received one or two concomitant PD drugs, respectively. Patients received a median of two non-PD drugs. The median levodopa dosage and total levodopa equivalent dosage (LED) at the index hospitalization were 418.2 and 634.8 mg/day (adjusted for body weight, 9.0 and 13.7 mg/kg/day), respectively. The median levodopa and total LED dosage in each 6-month increment during the 5 years before and after the index date ranged between 263.9 and 330.2 mg/day (5.0 and 6.5 mg/kg/day) and 402.0 and 504.9 mg/day (8.3 and 10.1 mg/kg/day), respectively. This study suggests that many Japanese patients with advanced PD could receive more intensive treatment with higher doses of levodopa.
RESUMO
An increase in the global aging population is leading to an increase in age-related conditions such as dementia and movement disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB). The accurate prediction of risk factors associated with these disorders is crucial for early diagnosis and prevention. Biomarkers play a significant role in diagnosing and monitoring diseases. In neurodegenerative disorders like α-synucleinopathies, specific biomarkers can indicate the presence and progression of disease. We previously demonstrated the pathogenic impact of fatty acid-binding proteins (FABPs) in α-synucleinopathies. Therefore, this study investigated FABPs as potential biomarkers for Lewy body diseases. Plasma FABP levels were measured in patients with AD, PD, DLB, and mild cognitive impairment (MCI) and healthy controls. Plasma FABP3 was increased in all groups, while the levels of FABP5 and FABP7 tended to decrease in the AD group. Additionally, FABP2 levels were elevated in PD. A correlation analysis showed that higher FABP3 levels were associated with decreased cognitive function. The plasma concentrations of Tau, GFAP, NF-L, and UCHL1 correlated with cognitive decline. A scoring method was applied to discriminate between diseases, demonstrating high accuracy in distinguishing MCI vs. CN, AD vs. DLB, PD vs. DLB, and AD vs. PD. The study suggests that FABPs could serve as potential biomarkers for Lewy body diseases and aid in early disease detection and differentiation.
Assuntos
Doença de Alzheimer , Doença por Corpos de Lewy , Doença de Parkinson , Sinucleinopatias , Humanos , Idoso , Doença de Parkinson/diagnóstico , Corpos de Lewy , Doença por Corpos de Lewy/diagnóstico , Proteínas de Ligação a Ácido Graxo , Doença de Alzheimer/diagnóstico , BiomarcadoresRESUMO
Disaster preparation is an important issue for patients with amyotrophic lateral sclerosis (ALS). However, to the best of our knowledge, no studies have investigated disaster preparedness among patients with ALS. In this study, we aimed to investigate disaster preparation in patients with ALS and their caregivers, including their families, in Japan. We conducted a nationwide webinar in September 2022 titled "ALS Café" and distributed a self-report questionnaire to participants with questions about awareness of disaster preparedness, social countermeasures, stockpiles, and electricity demand. Forty-eight patients with ALS (27 male; average age 60.0 ± 9.3 years) and 23 caregivers (8 male; 55.7 ± 9.9 years) responded. The median revised ALS Functional Rating Scale score was 30.5, and 25% of the patients with ALS were on a ventilator. More than 70% of the respondents answered that they were not prepared for disasters, increasing to 89% in patients not using ventilators. In the event of their phones being down, 86% of the respondents had no plans for alternative means of communication. <30% of the respondents, including ventilator users, had secured human resources for transportation. Twenty-five percent of the respondents did not stockpile food and beverages, and 12% of the ventilator users had no government-recommended ventilator preparation equipment. Thus, although patients with ALS and their families with ventilators have a high awareness of disaster preparedness, their awareness remains insufficient. Furthermore, patients with ALS and their families without ventilators have a low awareness of disaster preparedness. Therefore, better education regarding disaster preparedness is necessary for these groups.
Assuntos
Esclerose Lateral Amiotrófica , Desastres , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Esclerose Lateral Amiotrófica/terapia , Comunicação , Escolaridade , JapãoRESUMO
BACKGROUND: Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder characterized by motor and nonmotor symptoms. Several features have prognostic importance and have been used as key indicators for identifying clinical subtypes. However, the symptom-based classification approach has limitations with respect to the stability of the obtained subtypes. OBJECTIVES: The purpose of this study was to identify subtypes of PD using nuclear imaging biomarkers targeting the cardiac sympathetic nervous and nigro-striatal systems and to compare patterns of cortical morphological change among obtained subtypes. METHODS: We performed unbiased hierarchical cluster analysis using 123 I-metaiodobenzylguanidine cardiac scintigraphy and 123 I-N-(3-fluoropropyl)-2ß-carbomethoxy-3ß-(4-iodophenyl) nortropane single photon emission computed tomography data for 56 patients with PD. We compared clinical characteristics and the patterns of cortical atrophy in the obtained clusters. RESULTS: Three clusters were identified and showed distinct characteristics in onset ages and dopamine-replacement therapy and deep brain stimulation requirements. According to the characteristics, clusters were classified into two subtypes, namely, "cardio-cortical impairment (CC)" and "dopaminergic-dominant dysfunction (DD)" subtype. The three clusters were named according to subtype and time since onset in which 14 patients were classified as "early DD," 25 as "advanced DD," and 17 as "early CC." Compared with the early DD subtype, the early CC subtype showed parietal-dominant diffuse cortical atrophy and the advanced DD subtype showed left-side predominant mild cortical atrophy. CONCLUSIONS: Nuclear imaging biomarker-based classification can be used to identify clinically and pathologically relevant PD subtypes with distinct disease trajectories. © 2023 International Parkinson and Movement Disorder Society.
Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico , Cintilografia , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Corpo Estriado/metabolismo , Atrofia , Tropanos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismoRESUMO
Corticobasal syndrome is a clinical entity characterized by asymmetric akinetic rigidity and a variety of higher cortical dysfunction. Predicting background pathology of corticobasal syndrome is rather challenging; however, clinical and neuroimaging findings may provide a clue to its etiopathological origin. Visuospatial dysfunction of posterior cortical atrophy and logopenic-type language impairment indicate the presence of Alzheimer's disease-related pathology, and they provide useful information in distinguishing Alzheimer's disease from other types of corticobasal syndrome. Here we describe a case of corticobasal syndrome who showed characteristic visuospatial symptoms with imaging evidence of Alzheimer's disease supported by amyloid-PET and tau/astrogliosis-PET. Early, accurate diagnosis based on clinical features and predictable biomarkers is mandatory to the success of early intervention in corticobasal syndrome associated with Alzheimer's disease.
Assuntos
Doença de Alzheimer , Degeneração Corticobasal , Humanos , Doença de Alzheimer/patologia , Proteínas tau , Tomografia por Emissão de Pósitrons , Biomarcadores , Atrofia/complicaçõesRESUMO
Olfactory dysfunction is closely associated with cognitive dysfunction, and it is a known risk factor for the development of dementia. However, pathological studies revealed it to be more closely associated with the degree of Lewy body pathology than with the severity of pathological changes in Alzheimer's. Notably, more than half the patients with clinically diagnosed Alzheimer's dementia have accompanying Lewy body pathology, and olfactory loss may serve as an important symptom for suggesting its presence and enabling its detection.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença por Corpos de Lewy , Humanos , Doença de Alzheimer/patologia , Doença por Corpos de Lewy/patologia , Corpos de Lewy/patologia , Disfunção Cognitiva/etiologia , Diagnóstico DiferencialRESUMO
Cell-to-cell spreading of misfolded α-synuclein (αSYN) is supposed to play a key role in the pathological progression of Parkinson's disease (PD) and other synucleinopathies. Receptor-mediated endocytosis has been shown to contributes to the uptake of αSYN in both neuronal and glial cells. To determine the receptor involved in αSYN endocytosis on the cell surface, we performed unbiased, and comprehensive screening using a membrane protein library of the mouse whole brain combined with affinity chromatography and mass spectrometry. The candidate molecules hit in the initial screening were validated by co-immunoprecipitation using cultured cells; sortilin, a vacuolar protein sorting 10 protein family sorting receptor, exhibited the strongest binding to αSYN fibrils. Notably, the intracellular uptake of fibrillar αSYN was slightly but significantly altered, depending on the expression level of sortilin on the cell surface, and time-lapse image analyses revealed the concomitant internalization and endosomal sorting of αSYN fibrils and sortilin. Domain deletion in the extracellular portion of sortilin revealed that the ten conserved cysteines (10CC) segment of sortilin was involved in the binding and endocytosis of fibrillar αSYN; importantly, pretreatment with a 10CC domain-specific antibody significantly hindered αSYN fibril uptake. The presence of sortilin in the core structure of Lewy bodies and glial cytoplasmic inclusions in the brain of synucleinopathy patients was confirmed via immunohistochemistry, and the expression level of sortilin in mesencephalic dopaminergic neurons may be altered with disease progression. These results provide compelling evidence that sortilin acts as an endocytic receptor for pathogenic form of αSYN, and yields important insight for the development of disease-modifying targets for synucleinopathies.