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.

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.

Associations of Dental Health With the Progression of Hippocampal Atrophy in Community-Dwelling Individuals: The Ohasama Study.

BACKGROUND AND OBJECTIVES: Although tooth loss and periodontitis have been considered risk factors of Alzheimer disease, recent longitudinal researches have not found a significant association with hippocampal atrophy. Therefore, this study aimed to clarify a longitudinal association between the number of teeth present (NTP) and hippocampal atrophy dependent on the severity of periodontitis in a late middle-aged and older adult population. METHODS: This study included community-dwelling individuals aged 55 years or older who had no cognitive decline and had undergone brain MRI and oral and systemic data collection twice at 4-year intervals. Hippocampal volumes were obtained from MRIs by automated region-of-interest analysis. The mean periodontal probing depth (PD) was used as a measure of periodontitis. Multiple regression analysis was performed with the annual symmetric percentage change (SPC) of the hippocampal volume as the dependent variable and including an interaction term between NTP and mean PD as the independent variable. The interaction details were examined using the Johnson-Neyman technique and simple slope analysis. The 3-way interaction of NTP, mean PD, and time on hippocampal volume was analyzed using a linear mixed-effects model, and the interaction of NTP and time was examined in subgroups divided by the median mean PD. In all models, dropout bias was adjusted by inverse probability weighting. RESULTS: Data of 172 participants were analyzed. The qualitative interaction between NTP and the mean PD was significant for the annual SPC in the left hippocampus. The regression coefficient of the NTP on the annual SPC in the left hippocampus was positive (B = 0.038, p = 0.026) at the low-level mean PD (mean -1 SD) and negative (B = -0.054, p = 0.001) at the high-level mean PD (mean +1 SD). Similar results were obtained in the linear mixed-effects model; the interaction of NTP and time was significant in the higher mean PD group. DISCUSSION: In a late middle-aged and older cohort, fewer teeth were associated with a faster rate of left hippocampal atrophy in patients with mild periodontitis, whereas having more teeth was associated with a faster rate of atrophy in those with severe periodontitis. The importance of keeping teeth healthy is suggested.

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.

Female Reproductive Events and Subclinical Atherosclerosis of the Brain and Carotid Arteriopathy: the Ohasama Study.

AIMS: Few studies have investigated the subclinical atherosclerotic changes in the brain and carotid artery, and in East Asian populations. We sought to investigate whether gravidity, delivery, the age at menarche and menopause and estrogen exposure period are associated with subclinical atherosclerosis of the brain and carotid arteriopathy. METHODS: This cross-sectional study formed part of a cohort study of Ohasama residents initiated in 1986. Brain atherosclerosis and carotid arteriopathy were diagnosed as white matter hyperintensity (WMH) and lacunae evident on brain magnetic resonance imaging (MRI) and carotid intimal media thickness (IMT) or plaque revealed by ultrasound, respectively. The effect of the reproductive events on brain atherosclerosis and carotid arteriopathy was investigated using logistic regression and general linear regression models after adjusting for covariates. RESULTS: Among 966 women aged ≥ 55 years in 1998, we identified 622 and 711 women (mean age: 69.2 and 69.7 years, respectively) who underwent either MRI or carotid ultrasound between 1992-2008 or 1993-2018, respectively. The highest quartile of gravidity (≥ 5 vs. 3) and delivery (≥ 4 vs. 2), and the highest and second highest (3 vs. 2) quartiles of delivery were associated with an increased risk of WMH and carotid artery plaque, respectively. Neither of age at menarche, menopause, and estrogen exposure period estimated by subtracting age at menarche from age at menopause was associated with atherosclerotic changes of brain and carotid arteries. CONCLUSIONS: Higher gravidity and delivery are associated with subclinical atherosclerosis of the brain and carotid plaque.

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.

Impact of Catheter Ablation on Brain Microstructure and Blood Flow Alterations for Cognitive Improvements in Patients with Atrial Fibrillation: A Pilot Longitudinal Study.

Atrial fibrillation (AF) predisposes patients to develop cognitive decline and dementia. Clinical and epidemiological data propose that catheter ablation may provide further benefit to improve neurocognitive function in patients with AF, but the underlying mechanism is poorly available. Here, we conducted a pilot prospective study to investigate whether AF ablation can alter regional cerebral blood flow (rCBF) and brain microstructures, using multimodal magnetic resonance imaging (MRI) technique. Eight patients (63 ± 7 years) with persistent AF underwent arterial-spin labeling (ASL) perfusion, 3D T1-structural images and cognitive test batteries before and 6 months after intervention. ASL and structural MR images were spatially normalized, and the rCBF and cortical thickness of different brain areas were compared between pre- and 6-month post-treatment. Cognitive-psychological function was improved, and rCBF was significantly increased in the left posterior cingulate cortex (PCC) (p = 0.013), whereas decreased cortical thickness was found in the left posterior insular cortex (p = 0.023). Given that the PCC is a strategic site in the limbic system, while the insular cortex is known to play an important part in the central autonomic nervous system, our findings extend the hypothesis that autonomic system alterations are an important mechanism explaining the positive effect of AF ablation on cognitive function.

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.

Neuroimaging-pathological correlations of [18F]THK5351 PET in progressive supranuclear palsy.

Recent positron emission tomography (PET) studies have demonstrated the accumulation of tau PET tracer in the affected region of progressive supranuclear palsy (PSP) cases. To confirm the binding target of radiotracer in PSP, we performed an imaging-pathology correlation study in two autopsy-confirmed PSP patients who underwent [18F]THK5351 PET before death. One patient with PSP Richardson syndrome showed elevated tracer retention in the globus pallidus and midbrain. In a patient with PSP-progressive nonfluent aphasia, [18F]THK5351 retention also was observed in the cortical areas, particularly the temporal cortex. Neuropathological examination confirmed PSP in both patients. Regional [18F]THK5351 standardized uptake value ratio (SUVR) in antemortem PET was significantly correlated with monoamine oxidase-B (MAO-B) level, reactive astrocytes density, and tau pathology at postmortem examination. In in vitro autoradiography, specific THK5351 binding was detected in the area of antemortem [18F]THK5351 retention, and binding was blocked completely by a reversible selective MAO-B inhibitor, lazabemide, in brain samples from these patients. In conclusion, [18F]THK5351 PET signals reflect MAO-B expressing reactive astrocytes, which may be associated with tau accumulation in PSP.

A Case of Low-Grade Primary Cardiac Lymphoma with Pericardial Effusion Diagnosed by Combined 18F-Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography (FDG-PET/CT) Imaging and Effusion Cytology.

BACKGROUND Primary cardiac lymphoma is rare and can be an aggressive disease, depending on the grade. A case is reported of low-grade primary cardiac lymphoma associated with a pericardial effusion. 18F-fluorodeoxyglucose positron emission tomography and computed tomography (FDG-PET/CT) imaging was useful in the diagnosis and in evaluating the disease activity in this case. CASE REPORT A 72-year-old Japanese woman visited a general practitioner, complaining of dyspnea associated with cardiac tamponade. Pericardiocentesis was performed, and Group V malignant cells were identified by cytology, suspicious for malignant lymphoma. Whole-body FDG-PET/CT scans showed no pleural effusion or lymph node metastasis supporting the diagnosis of primary cardiac lymphoma diagnosed on pericardial effusion. The laboratory investigations showed that levels of serum soluble interleukin-2 (IL-2) receptor (sIL-2R), a diagnostic and prognostic marker for malignant lymphoma, were not elevated (258 U/ml). A six-month follow-up FDG-PET/CT scan showed an increased volume of the pericardial effusion and mild but abnormal uptake diffusely in the pericardial space, and the sIL-2R was slightly elevated (860 U/ml). No abnormal FDG accumulation outside the retained pericardial effusion was noted, which was compatible with a clinical picture of low-grade primary cardiac lymphoma, and in a period of watchful waiting during the first two years later, the sIL-2R had reduced to 195 U/ml. CONCLUSIONS This is a rare case of low-grade primary cardiac lymphoma detected in a pericardial effusion, and highlights the utility of the FDG-PET/CT scan as a valuable diagnostic and follow-up modality.

Posterior Associative and Cingulate Cortex Involvement of Brain Single-Photon Emission Computed Tomography (SPECT) Imaging in Semantic Dementia with Probable Alzheimer Disease Pathology: A Case Report.

BACKGROUND Semantic dementia (SD) is a type of primary progressive aphasia with prominent language dysfunction, mostly within the spectrum of frontotemporal lobar degeneration (FTLD). Although there is an overlap in clinical manifestations of SD attributable to FTLD and neuropathologically proven Alzheimer disease (AD), clinical diagnostic clues are not readily available. We present a characteristic finding based on a single-photon emission computed tomography (SPECT)-based regional cerebral blood flow study and its statistical imaging analysis for a rare case of SD with AD-like pathology. CASE REPORT A 61-year-old male was referred to our hospital due to difficulties in self-management and impaired comprehension of word meaning suggestive of SD. Although his brain MRI revealed mild frontal lobe atrophy, his SPECT with three-dimensional stereotactic surface projections (3D-SSP) analysis showed left-sided hypo-perfusion that was more prominent in the inferior temporal gyrus and the inferior parietal lobule, with bilateral frontal lobe hypo-perfusion. The SPECT scan also showed involvement of the right inferior parietal area and, in medial aspects, the posterior cingulate cortex and adjacent precuneus; these finding were compatible with early hypo-perfused areas seen in AD. The lumbar cerebrospinal fluid biomarker findings seemed to fit SD in association with probable AD pathology. CONCLUSIONS This is the first reported case to use SPECT with 3D-SSP statistical analysis as a potential, useful imaging modality for the diagnosis of SD with probable AD pathology.

Reduced CBF recovery detected by longitudinal 3D-SSP SPECT analyses predicts outcome of postoperative patients after subarachnoid haemorrhage.

The aim of this study was to evaluate the impact of cerebral blood flow (CBF) recovery obtained from brain single-photon emission computed tomography (SPECT) images on postoperative outcome after aneurysmal subarachnoid haemorrhage (SAH). Twenty-nine patients who had undergone surgical clipping for ruptured anterior communicating artery aneurysms were analyzed prospectively. Routine measurements of CBF were performed using technetium-99 m hexamethyl propyleneamine oxine SPECT on days 4 and 14 after SAH. Regional voxel data analyzed by three dimensional stereotactic surface projection (3D-SSP) were compared between patients and age-matched normal database (NDB). In 3D-SSP analysis of all patients, cortical hypoperfusion around the surgical site in bilateral frontal lobes was evident on day 4 (P < .05 vs NDB), which was improved significantly on day 14. However, the recovery was less complete in patients with poor clinical grades (P < .05) and presenting symptoms attributable to delayed cerebral ischaemia (DCI) (P < .05) than those without. Multivariate analysis showed that patients with mild to moderate CBF recovery (relative Z-score differences of <4) (P = .014; odds ratio, 2.5; 95% confidence interval, 1.93-3.31) was independently associated with poor functional outcome at 3 months. We conclude that reduced CBF recovery detected by serial 3D-SSP SPECT image analyses can be a potential predictor of poor prognosis in postoperative patients after SAH.

Neuro-Myelomatosis of the Brachial Plexus - An Unusual Site of Disease Visualized by FDG-PET/CT: A Case Report.

BACKGROUND Peripheral or cranial nerve root dysfunction secondary to invasion of the CNS in multiple myeloma is a rare clinical event that is frequently mistaken for other diagnoses. We describe the clinical utility of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scanning for diagnosing neuro-myelomatosis. CASE REPORT A 63-year-old woman whose chief complaints were right shoulder and upper extremity pain underwent MRI and 18F-FDG PET/CT scan. MRI revealed a non-specific brachial plexus tumor. 18F-FDG PET/CT demonstrated intense FDG uptake in multiple intramedullary lesions and in the adjacent right brachial plexus, indicating extramedullary neural involvement associated with multiple myeloma, which was confirmed later by a bone marrow biopsy. CONCLUSIONS This is the first reported case of neuro-myelomatosis of the brachial plexus. It highlights the utility of the 18F-FDG PET/CT scan as a valuable diagnostic modality.

Asymptomatic Mild Hyperperfusion for the Prediction of Clinical Outcome in Postoperative Patients After Subarachnoid Hemorrhage.

BACKGROUND Delayed cerebral ischemia (DCI) is one of the main causes of poor outcomes after subarachnoid hemorrhage (SAH). The early identification of DCI by noninvasive imaging modalities would provide valuable information of therapeutic intervention for improving the patient outcomes. We aimed to describe the clinical features of cerebral blood flow (CBF) data obtained from the single-photon emission computed tomography (SPECT) during the risk period for DCI after SAH. MATERIAL AND METHODS Clinical data from 94 SAH patients who underwent surgical clipping of anterior circulation aneurysms were reviewed retrospectively. 99mTc-HMPAO SPECT images were visually and semiquantitatively analyzed on days 7 and 14 after SAH. RESULTS In all cases, the areas of hypoperfusion were found in the middle cerebral artery territories. By contrast, the areas of mild hyperperfusion were always detected on the surgical side, the prevalence which increased from days 7 (n=28; 30%) to 14 (n=48; 51%) without neurological defects. Univariate analysis revealed that the hyperperfusion on day 14 had a significant relationship with functional outcome at 3 months (P=0.04). Multivariate analysis including age, clinical SAH grade, DCI, and hyperperfusion on day 14 showed that DCI (P=0.004; odds ratio [OR], 0.10; 95% confidence interval [CI], 0.02-0.48) and hyperperfusion on day 14 (P=0.002; OR, 2.44; 95% CI, 1.40-4.29) were independently associated with functional outcome at 3 months. CONCLUSIONS Delayed mild hyperperfusion around the surgical site can predict good prognosis after SAH, although it may hinder the CBF diagnosis of focal ischemia attributable to DCI.

Introduction and overview of the special issue "Brain imaging and aging": The new era of neuroimaging in aging research.

It is well known that the brain is one of the organs particularly affected by aging in terms of function, relative to the gastrointestinal tract and liver, which exhibit less functional decline. There is also a wide range of age-related neurological disorders such as stroke, Alzheimer's disease, and Parkinson's disease. Therefore, it is very important to understand the relationship between functional age-related change and neurological dysfunction. Neuroimaging techniques including magnetic resonance imaging and positron emission tomography have been significantly improved over recent years. Many physicians and researchers have investigated various mechanisms of age-related cerebral change and associated neurological disorders using neuroimaging techniques. In this special issue of Ageing Research Reviews, we focus on cerebral- and neuro-imaging, which are a range of tools used to visualize structure, functions, and pathogenic molecules in the nervous system. In addition, we summarize several review articles about the history, present values, and future perspectives of neuroimaging modalities.