FABP2 is Involved in Intestinal α-Synuclein Pathologies.

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.

Using Fatty Acid-Binding Proteins as Potential Biomarkers to Discriminate between Parkinson's Disease and Dementia with Lewy Bodies: Exploration of a Novel Technique.

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.

Nuclear Imaging Data-Driven Classification of Parkinson's Disease.

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.

Bedside evaluation of swallowing function to predict aspiration pneumonia in Duchenne muscular dystrophy.

OBJECTIVE: Aspiration pneumonia is one of the leading causes of death in patients with muscular dystrophy; therefore, it is important to predict its occurrence in the clincal setting. We aimed to examine the usefulness of repeated saliva swallowing test (RSST), modified water swallowing test (MWST), and flexible endoscopic evaluation of swallowing (FEES) for evaluating the Hyodo score at the bedside, to predict the risk of aspiration pneumonia in patients with Duchenne muscular dystrophy (DMD). METHODS: In this retrospective cohort study involving 43 patients, we evaluated the swallowing function using the RSST, MWST, and FEES, and predicted the likelihood of aspiration pneumonia within 2 years after the assessment. The Hyodo score, a scoring system for evaluating the swallowing function determined by the FEES, was used. RESULTS: Pneumonia was observed in 14 patients (32.6%). The RSST was not significantly useful for predicting the onset of pneumonia. The MWST was reported to have a cutoff value of < 4 points. Significantly more patients in the pneumonia group had an MWST score of < 4 points. The results revealed that the occurrence of pneumonia could be predicted based on a Hyodo cutoff score of ≥ 6. Significantly more patients in the pneumonia group had an MWST score of < 4 or a Hyodo score of ≥ 6. CONCLUSIONS: Combining MWST and FEES is useful for evaluating the bedside swallowing function and predicting the onset of pneumonia.

Plasma sphingolipid abnormalities in neurodegenerative diseases.

BACKGROUND: In recent years, there has been increasing evidence that several lipid metabolism abnormalities play an important role in the pathogenesis of neurodegenerative diseases. However, it is still unclear which lipid metabolism abnormalities play the most important role in neurodegenerative diseases. Plasma lipid metabolomics (lipidomics) has been shown to be an unbiased method that can be used to explore lipid metabolism abnormalities in neurodegenerative diseases. Plasma lipidomics in neurodegenerative diseases has been performed only in idiopathic Parkinson's disease (IPD) and Alzheimer's disease (AD), and comprehensive studies are needed to clarify the pathogenesis. METHODS: In this study, we investigated plasma lipids using lipidomics in individuals with neurodegenerative diseases and healthy controls (CNs). Plasma lipidomics was evaluated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in those with IPD, dementia with Lewy bodies (DLB), multiple system atrophy (MSA), AD, and progressive supranuclear palsy (PSP) and CNs. RESULTS: The results showed that (1) plasma sphingosine-1-phosphate (S1P) was significantly lower in all neurodegenerative disease groups (IPD, DLB, MSA, AD, and PSP) than in the CN group. (2) Plasma monohexylceramide (MonCer) and lactosylceramide (LacCer) were significantly higher in all neurodegenerative disease groups (IPD, DLB, MSA, AD, and PSP) than in the CN group. (3) Plasma MonCer levels were significantly positively correlated with plasma LacCer levels in all enrolled groups. CONCLUSION: S1P, Glucosylceramide (GlcCer), the main component of MonCer, and LacCer are sphingolipids that are biosynthesized from ceramide. Recent studies have suggested that elevated GlcCer and decreased S1P levels in neurons are related to neuronal cell death and that elevated LacCer levels induce neurodegeneration by neuroinflammation. In the present study, we found decreased plasma S1P levels and elevated plasma MonCer and LacCer levels in those with neurodegenerative diseases, which is a new finding indicating the importance of abnormal sphingolipid metabolism in neurodegeneration.

Phosphorylated alpha-synuclein in Iba1-positive macrophages in the skin of patients with Parkinson's disease.

BACKGROUND: Increasing evidence suggests that alpha-synuclein (αSyn) accumulation in cholinergic and adrenergic fibers in the skin is a useful biomarker to diagnose idiopathic Parkinson's disease (IPD). It has been widely reported that phosphorylated αSyn (p-αSyn) deposits in autonomic fibers in IPD are a biomarker in the skin, but other tissue localizations have not been fully investigated. OBJECTIVE: It has been previously suggested that αSyn aggregates activate peripheral macrophages and that peripheral macrophages ingest pathological αsyn aggregates in aged rats or IPD patients. However, it remains to be elucidated whether peripheral macrophages in the skin of IPD patients accumulate αSyn. We evaluated whether (1) p-αSyn deposits in dermal macrophages might represent a useful biomarker for IPD and (2) dermal macrophages play a role in the underlying pathogenesis of IPD. METHODS: We performed an immunohistological analysis of skin biopsy specimens from IPD patients and controls. RESULTS: We found that (1) p-αSyn accumulation is present in dermal macrophages in skin biopsy specimens from patients with IPD, (2) not only dermal adrenergic fibers with p-αSyn deposits but also dermal macrophages with p-αSyn deposits are useful biomarkers for IPD patients and (3) the number of macrophages was significantly positively correlated with the number of macrophages with p-αSyn deposits in the dermis of IPD patients. INTERPRETATION: Our results suggest that dermal macrophages, which are innate immune cells, play an important role in IPD patients and are a novel biomarker for IPD.

The characteristics of dysphagia and the incidence of pneumonia in Myotonic dystrophy type 1 patients especially concerning swallowing function evaluated by endoscopy.

OBJECTIVE: The objectives of the study were to clarify the characteristics of dysphagia and the incidence of pneumonia in Myotonic dystrophy type 1 (DM1) patients, and to investigate the relationship between the development of pneumonia and the DM1 patient's background, especially concerning swallowing function evaluated by endoscopy. METHODS: The subjects were 88 DM1 patients who underwent swallowing function evaluation. The severity of disease in DM1patients was assessed based on the muscular impairment rating scale (MIRS), and the number of CTG repeats. Patients were divided into two groups; those who developed aspiration pneumonia within two years after swallowing assessment and those who did not develop aspiration pneumonia. Swallowing function was assessed using the food intake level scale (FILS), repetitive saliva swallowing test (RSST), the modified water swallowing test (MWST), and the Hyodo score. RESULTS: Onset of pneumonia within two years of assessment was observed in 22 cases (25%). Age, FILS, and Hyodo score were significantly different between pneumonia and non-pneumonia groups. There was a significant difference in swallowing function tests such as FILS, RSST, and Hyodo score between males and females. The Hyodo score cutoff value for predicting pneumonia within two years was determined by ROC analysis. A cutoff value of 6 was found to have a sensitivity of 0.545 and a specificity of 0.833 (area under the curve=0.722). CONCLUSION: It is important to evaluate the swallowing function of DM1 patients by endoscopy to prevent aspiration pneumonia. In addition, male patients are more likely to deteriorate in swallowing function and should be carefully monitored.

Fatty Acid-Binding Protein 3 Expression in the Brain and Skin in Human Synucleinopathies.

Parkinson's disease (PD) and multiple system atrophy are types of adult-onset neurodegenerative disorders named synucleinopathies, which are characterized by prominent intracellular α-synuclein (αSyn) aggregates. We have previously found that αSyn aggregates and the vulnerability of dopaminergic neurons in the mouse brain are partly associated with the expression of fatty acid-binding protein 3 (FABP3, heart FABP). However, it remains to be elucidated whether FABP3 accumulation is associated with αSyn aggregates in human tissues. Here, we histologically studied FABP3 expression in human tissues obtained from patients with synucleinopathies, patients with Alzheimer disease (AD) and controls. We found that (1) a variety of neurons expressed the FABP3 protein in human brain tissues, (2) FABP3 was colocalized with αSyn aggregates in the brains of individuals with synucleinopathies but not with amyloid ß or p-tau aggregates in the brains of individuals with AD, and (3) FABP3 was not present in p-αSyn deposits in biopsied skin tissues from individuals with PD. These findings suggest that FABP3 expression is associated with αSyn aggregation in synucleinopathies and provide new insights into the involvement of FABP3 in synucleinopathies.

Predominant vasogenic edema in a patient with fatal cerebral air embolism.

Cerebral air embolism (CAE) is a rare neurologic complication that can occur in patients undergoing various medical procedures or trauma. CAE can sometimes result in death caused by severe brain edema. In spite of these implications, the pathophysiologic mechanisms and radiologic features of fatal CAE remain to be elucidated. In this case report, a patient with carcinomatous pleuritis lost consciousness and developed quadriplegia and had generalized seizures during intrathoracic lavage. Serial computed tomography (CT) revealed the presence of air in intracranial blood vessels following severe brain edema; these are typically observed on the CT scans of patients with fatal CAE. Diffusion-weighted imaging (DWI) of the brain obtained at 24 hours after the onset of CAE revealed scattered cortical gyriform high signal intensity often observed in CAE cases, whereas the apparent diffusion coefficient and T2-weighted imaging revealed diffuse hyperintensity in the subcortical deep white matter, indicating vasogenic edema. Our case showed predominant vasogenic edema rather than cortical ischemic changes in the subcortical deep white matter area. These findings indicate that diffuse subcortical vasogenic edema could be the main cause of mortality in fatal CAE.

A case of cerebral embolism with metastatic chondrosarcoma in the left atrium.

Cardiac tumor is a rare, but clinically important source of cerebral embolism. We report a case of metastatic chondrosarcoma in the left atrium with multiple cerebral emboli. A computed tomography scan of the chest revealed a large mass in the left atrium and pulmonary vein. The patient underwent heart surgery to remove the metastatic chondrosarcoma in the left atrium, to prevent the formation of further systemic emboli and possible sudden death. The cardiac tumor resection was successful, and the patient was discharged from the hospital without any handicap. This is a rare case of metastatic cardiac tumor that was a source of emboli into the brain and was eradicated.

Chondrosarcoma with atypical clinical presentation treated by gamma knife radiosurgery for multiple brain metastases--case report.

A 60-year-old male was first treated for World Health Organization (WHO) grade II chondrosarcoma arising from the ring finger manifesting as painful swelling. Four years later, the patient presented with cerebral infarction. Echocardiography revealed a tumor occupying the left atrium. He underwent open heart surgery and the tumor was identified as metastatic chondrosarcoma with malignant transformation to WHO grade III lesion. Five months following the cardiac surgery, the patient suffered generalized seizure. Cerebral magnetic resonance imaging revealed multiple parenchymal lesions. Surgical tumor extirpation confirmed the histological diagnosis as metastatic grade III chondrosarcoma. Gamma knife radiosurgery (GKS) performed postoperatively controlled the parenchymal lesions for more than 10 months without relapse. GKS may be effective for the treatment of brain metastasis from high grade chondrosarcoma.

Successful treatment with Yokukansan for behavioral and psychological symptoms of Parkinsonian dementia.

OBJECTIVE: To evaluate the efficacy and safety of Yokukansan, a traditional Chinese herbal medicine, for treating behavioral and psychological symptoms of dementia (BPSD) in patients with Parkinson disease (PD; n=7) and those with PD with dementia (PDD; n=7). BACKGROUND: BPSD are often seen in patients with senile dementia and have serious deleterious effects on the lives of patients and caregivers. Recent studies indicate that the traditional Chinese herbal medicine Yokukansan may be safe and beneficial for the treatment of BPSD patients. METHODS: We treated 7 PD and 7 PDD patients for 4 weeks with Yokukansan and observed them without Yokukansan for 4 weeks. Changes in behavioral and psychological symptoms were evaluated every 4 weeks according to the Neuropsychiatric Inventory (NPI) scale. RESULTS: Significant improvements in behavioral and psychological symptoms, particularly in the incidence and duration of hallucinations, were observed in most PD and PDD patients after 4 weeks of Yokukansan treatment. No significant changes were observed in the laboratory tests, cognitive function, activities of daily living, or parkinsonism. CONCLUSION: Our results suggest that Yokukansan improves BPSD in both PD and PDD patients without worsening their cognitive function, ability to perform activities of daily living, or parkinsonism.

Alteration in the differentiation-related molecular expression in the subventricular zone in a mouse model of Parkinson's disease.

Enhancement of neurogenesis could be a suitable treatment approach to up-regulate dopaminergic neurons in Parkinson's disease (PD). In the present study, we focused on the kinetics of the subventricular zone (SVZ) in a mouse model of PD induced by MPTP injection. We showed recently the proliferation potential of neuronal stem cells (NSCs) prepared from the olfactory bulb of an animal model of PD [Hayakawa, H., Hayashita-Kinoh, H., Nihira, T., Seki, T., Mizuno, Y., Mochizuki, H., 2007. The isolation of neural stem cells from the OB of Parkinson's disease model. Neurosci. Res.]. In this study, we examined the relationship between proliferation and differentiation of NSCs in SVZ of both acute and chronic PD models. Only acute MPTP treatment significantly increased the areas of glial fibrillary acidic protein (GFAP)-expressing cells and decreased the areas of polysialylated neural cell adhesion molecule (PSA-NCAM)-expressing cells in the SVZ. In the case of caspase-11 knockout mice, MPTP did not induce alteration in the areas of GFAP-expressing cells and PSA-NCAM-expressing cells. Our results suggest that neuroinflammation related to the caspase-11 cascade in the striatum regulates differentiation of neural stem cells in the SVZ of our mouse model of PD.

Recombinant human granulocyte colony-stimulating factor protects against MPTP-induced dopaminergic cell death in mice by altering Bcl-2/Bax expression levels.

Granulocyte colony-stimulating factor (G-CSF) has been used for the treatment of neutropenia in hematologic disorders. The neuroprotective effects of G-CSF were reported in neurological disease models. In the present study, we examined whether G-CSF can protect dopaminergic neurons against MPTP-induced cell death in a mouse model of Parkinson's disease. Mice of one group were injected intraperitoneally with MPTP for five consecutive days, those of another group with MPTP and intraperitoneal G-CSF at 2 days and 1 day before the first MPTP injection, and 30 min before each MPTP injection, while control mice received saline injections. Immunohistochemistry, western blotting analysis, and HPLC were performed to evaluate damage of substantia nigra dopaminergic neurons and expression of Bcl-2 and Bax protein. MPTP induced dopaminergic cell death in the substantia nigra. G-CSF significantly prevented MPTP-induced loss of tyrosine hydroxylase-positive neurons (p < 0.05), increased Bcl-2 protein and decreased Bax protein expression. Our findings indicate that G-CSF provides neuroprotection against MPTP-induced cell death and this effect is mediated by increasing Bcl-2 expression levels and decreasing Bax expression levels in C57BL/6 mice.

Expression levels of vascular endothelial growth factor and its receptors in Parkinson's disease.

Recently, we confirmed the presence of enhanced neural reconstruction in Parkinson's disease and in an animal model of Parkinson's disease based on increased polysialic acid-like immunoreactivity. Changes in neurogenesis often appear parallel to changes in angiogenesis. Moreover, both these processes share similar modulating factors, like vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1). Using immunohistochemistry, we identified in this study upregulation of VEGF in the substantia nigra but not in the striatum of patients with Parkinson's disease by enzyme-linked immunosorbent assay. Such overexpression may participate in vascular remodeling and neurogenesis in the substantia nigra of Parkinson's disease.