Fukushimura Hospital

BackgroundIt has become evident that various different neuropathologies including Alzheimer's disease neuropathologic change, limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC), and argyrophilic grain disease (AGD) coexist in patients with Lewy body disease (LBD). However, the effect of these comorbidities on brain atrophy remains understudied.ObjectiveThis study aimed to explore the morphological impacts of comorbidities using voxel-based morphometry (VBM).MethodsThirty-four individuals with a neuropathological diagnosis of LBD were included. Antemortem whole-brain 3D-T1-weighted images were preprocessed using Computational Anatomy Toolbox 12. Associations between gray matter (GM) atrophy and specific comorbid neuropathology, as well as interactions among them, were analyzed using VBM.ResultsNeurofibrillary tangle (NFT) pathology exhibited inverse correlations with GM volumes of the right temporal, bilateral frontal lobes, and left posterior cingulate gyrus. Neuritic plaque (NP) pathology-related GM atrophy was localized to the left posterior cingulate gyrus and parts of the parietal lobes. LATE-NC exhibited inverse correlations mainly in the left temporal lobe and left-dominant limbic lobes including the hippocampi. AGD pathology-related GM atrophy was predominant in the left-dominant limbic lobes and left temporal pole. Small vessel disease (SVD) scores were inversely correlated with GM volumes in the left frontal lobe and bilateral cerebellar hemispheres. Interactions between NFT and LATE-NC were limited to limbic and temporal lobes, while interactions between NFT and NP, SVD and NFT or LATE-NC showed more posterior-dominant distributions.ConclusionsVBM analyses revealed distinct atrophy patterns reflective of isolated neuropathologies. Furthermore, the study suggests that interactions between neuropathologies may influence brain atrophy patterns.

Regaining independence in gait is a major goal of stroke rehabilitation. Although gait ability is significantly affected by age and motor paresis, independent walking can be achieved even in patients with advanced age and/or severe paresis. Brain imaging provides valuable prognostic information regarding gait independence. However, the characteristics of the brain lesions that contribute to the recovery of gait ability, even in cases of severe paresis, remain unclear. This study aimed to identify brain lesion areas associated with gait independence using support vector regression lesion symptom mapping (SVR-LSM), excluding the effects of age and motor paresis. We conducted an SVR-LSM analysis in 132 patients with first-time strokes using age and Fugl-Meyer motor assessment scores for the lower extremities as covariates. Gait independence at admission was associated with the corticospinal tract (CST), putamen, and pallidus when adjusted for age, whereas no significant association with lesion location was observed after adjusting for motor function. Gait independence at discharge was correlated with the CST, sensory tracts, putamen, pallidus, thalamus, and supplementary motor area (SMA). These findings suggest that, at admission, strong motor impairments overshadowed the association of motor paresis with specific lesion locations when motor paresis was controlled. By the time of discharge, regions such as the CST, putamen, and SMA were highlighted even after controlling for motor impairments. This indicates that factors other than motor deficits, such as motor learning, play a significant role in achieving gait independence. Identifying lesion locations may be crucial for enhancing the skills required for independent walking despite persistent paresis.

PurposeVoxel-based morphometry (VBM) is widely used to investigate white matter (WM) atrophy in patients with progressive supranuclear palsy (PSP). In contrast to high-resolution 3D T1-weighted imaging such as magnetization-prepared rapid acquisition with gradient echo (MPRAGE) sequences, the utility of other 3D sequences has not been sufficiently evaluated. This study aimed to assess the feasibility of using a 3D fast low-angle shot sequence captured as a localizer image (L3DFLASH) for VBM analysis of WM atrophy patterns in patients with PSP.MethodsThis retrospective study included 12 patients with pathologically or clinically confirmed PSP, and 18 age- and sex-matched healthy controls scanned with both L3DFLASH and MPRAGE sequences. Image processing was conducted with the Computational Anatomy Toolbox 12 in statistical parametric mapping 12. In addition to the atrophic WM pattern of PSP on VBM, we assessed the WM volume agreement between the two sequences using simple linear regression and Bland–Altman plots.ResultsDespite the slightly larger clusters on MPRAGE, VBM using both sequences showed similar characteristics of PSP-related WM atrophy, including in the midbrain, pons, thalamus, and precentral gyrus. In contrast, VBM showed gray matter (GM) atrophy of the precuneus and right superior parietal lobule exclusively on L3DFLASH. Unlike the measured values of total intracranial volume, GM, and cerebrospinal fluid on MPRAGE, the value of WM was larger on L3DFLASH. In contrast to the total intracranial volume, brainstem, and frontal and occipital lobes, the correlation with WM volume in other regions was relatively low. However, the Bland–Altman plots demonstrated strong agreement, with over 90% of the values falling within the agreement limits.ConclusionBoth MPRAGE and L3DFLASH are useful for detecting PSP-related WM atrophy using VBM.

Due to clinicoradiological similarities, including amnestic cognitive impairment and limbic atrophy, differentiation of argyrophilic grain disease (AGD) from Alzheimer's disease (AD) is often challenging. Minimally invasive biomarkers, especially magnetic resonance imaging (MRI), are valuable in routine clinical practice. Although it is necessary to explore radiological clues, morphometry analyses using new automated analytical methods, including whole-brain voxel-based morphometry (VBM) and surface-based morphometry (SBM), have not been sufficiently investigated in patients with pathologically confirmed AGD and AD. This study aimed to determine the volumetric differences in VBM and SBM analyses between patients with pathologically confirmed AGD and AD. Eight patients with pathologically confirmed AGD with a lower Braak neurofibrillary tangle stage (<III), 11 patients with pathologically confirmed AD without comorbid AGD, and 10 healthy controls (HC) were investigated. Gray matter volumetric changes in VBM and cortical thickness changes in SBM were compared between the two patient groups (i.e., AGD and AD) and the HC group. In contrast to widespread gray matter volume or cortical thickness loss in the bilateral limbic, temporoparietal, and frontal lobes of the AD group, these were limited, especially in the limbic lobes, in the AGD group, compared with that of the HC group. Although bilateral posterior dominant gray matter volume loss was identified in the AD group compared with the AGD group on VBM, there was no significant cluster between these patient groups on SBM. VBM and SBM analyses both showed a different distribution of atrophic changes between AGD and AD.

Echinocandin antifungal drugs, including micafungin, anidulafungin, and caspofungin, have been recently reported to exhibit antiviral effects against various viruses such as flavivirus, alphavirus, and coronavirus. In this study, we focused on micafungin and its derivatives and analyzed their antiviral activities against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The micafungin derivatives Mi-2 and Mi-5 showed higher antiviral activity than micafungin, with 50% maximal inhibitory concentration (IC50) of 5.25 and 6.51 µM, respectively (3.8 to 4.7-fold stronger than micafungin) and 50% cytotoxic concentration (CC50) of >64 µM in VeroE6/TMPRSS2 cells. This high anti-SARS-CoV-2 activity was also conserved in human lung epithelial cell-derived Calu-3 cells. Micafungin, Mi-2, and Mi-5 were suggested to inhibit the intracellular virus replication process; additionally, these compounds were active against SARS-CoV-2 variants, including Delta (AY.122, hCoV-19/Japan/TY11-927/2021), Omicron (BA.1.18, hCoV-19/Japan/TY38-873/2021), a variant resistant to remdesivir (R10/E796G C799F), and a variant resistant to casirivimab/imdevimab antibody cocktail (E406W); thus, our results provide basic evidence for the potential use of micafungin derivatives for developing antiviral agents.

Characterization of amyloid β (Aβ) oligomers, the transition species present prior to the formation of Aβ fibrils and that have cytotoxicity, has become one of the major topics in the investigations of Alzheimer's disease (AD) pathogenesis. However, studying pathophysiological properties of Aβ oligomers is challenging due to the instability of these protein complexes in vitro. Here, we report that conformation-restricted Aβ42 with an intramolecular disulfide bond at positions 17 and 28 (SS-Aβ42) formed stable Aβ oligomers in vitro. Thioflavin T binding assays, nondenaturing gel electrophoresis, and morphological analyses revealed that SS-Aβ42 maintained oligomeric structure, whereas wild-type Aβ42 and the highly aggregative Aβ42 mutant with E22P substitution (E22P-Aβ42) formed Aβ fibrils. In agreement with these observations, SS-Aβ42 was more cytotoxic compared to the wild-type and E22P-Aβ42 in cell cultures. Furthermore, we developed a monoclonal antibody, designated TxCo-1, using the toxic conformation of SS-Aβ42 as immunogen. X-ray crystallography of the TxCo-1/SS-Aβ42 complex, enzyme immunoassay, and immunohistochemical studies confirmed the recognition site and specificity of TxCo-1 to SS-Aβ42. Immunohistochemistry with TxCo-1 antibody identified structures resembling senile plaques and vascular Aβ in brain samples of AD subjects. However, TxCo-1 immunoreactivity did not colocalize extensively with Aβ plaques identified with conventional Aβ antibodies. Together, these findings indicate that Aβ with a turn at positions 22 and 23, which is prone to form Aβ oligomers, could show strong cytotoxicity and accumulated in brains of AD subjects. The SS-Aβ42 and TxCo-1 antibody should facilitate understanding of the pathological role of Aβ with toxic conformation in AD.

The differentiation of Alzheimer's disease (AD) from age-related limbic tauopathies (LT), including argyrophilic grain disease (AGD) and senile dementia of the neurofibrillary tangle type (SD-NFT), is often challenging because specific clinical diagnostic criteria have not yet been established. Despite the utility of specific biomarkers evaluating amyloid and tau to detect the AD-related pathophysiological changes, the expense and associated invasiveness preclude their use as first-line diagnostic tools for all demented patients. Therefore, less invasive and costly biomarkers would be valuable in routine clinical practice for the differentiation of AD and LT. The purpose of this study is to develop a simple reproducible method on magnetic resonance imaging (MRI) that could be adopted in daily clinical practice for the differentiation of AD and other forms of LT. Our newly proposed three quantitative indices and well-known medial temporal atrophy (MTA) score were evaluated using MRI of pathologically-proven advanced-stage 21 AD, 10 AGD, and 2 SD-NFT patients. Contrary to MTA score, hippocampal angle (HPA), inferior horn area (IHA), and ratio between HPA and IHA (i.e., IHPA index) demonstrated higher diagnostic performance and reproducibility, especially to differentiate advanced-stage AD patients with Braak neurofibrillary tangle stage V/VI from LT patients (the area under the receiver-operating-characteristic curve of 0.83, 089, and 0.91; intraclass correlation coefficients of 0.930, 0.998, and 0.995, respectively). Quantitative indices reflecting hippocampal deformation with ventricular enlargement are useful to differentiate advanced-stage AD from LT. This simple and convenient method could be useful in daily clinical practice.

Even with postmortem pathological examination, only limited information is provided of the foci of in vivo clinical information. Cerebral small vessel disease, which is associated with ageing, dementia and stroke, highlights the difficulty in arriving at a definitive diagnosis of the lesions detected on in vivo radiological examination. We performed a radiological−pathological comparative study using ex vivo MRI to examine small cerebral lesions. Four patients with small vessel disease lesions detected on in vivo MRI were studied. Exact pathological findings of in vivo MRI-detected lesions were revealed. The ischaemic lesion after 17 days from onset showed positivity for peroxiredoxin, cluster of differentiation 204 and glial fibrillary acidic protein, indicating sterile inflammation and neuroprotective reaction. Cortical microinfarcts beneath the cortical superficial siderosis were associated with inflammation from the superficial layer in a patient with cerebral amyloid angiopathy; in this patient, a bilinear track-like appearance of the cortical superficial siderosis on the ex vivo MRI was compatible with iron deposition on the pia matter and within cortical layers II–III. An in vivo MRI-detected cerebral microbleed was revealed to be heterogeneous. An in vivo MRI-detected cerebral microbleed was revealed to be a venous angioma. Furthermore, a neuropathologically confirmed embolic cerebral microbleed was firstly detected using this method. Our results suggest that in vivo MRI-detected lobar cerebral microbleeds can be caused by non-cerebral amyloid angiopathy aetiologies, such as microembolism and venous angioma. Venous angioma and embolic microbleeds may mimic cerebral amyloid angiopathy markers on in vivo MRI. To clarify the clinical importance of these lesions, we should investigate their rate and frequency in a large cohort of healthy individuals and patients with cardiac risk factors. Thus, we provide evidence that ex vivo micro-MRI improves the clinical diagnosis of small vessel diseases.

Abstract Background: Ankle sprains are one of the most common musculoskeletal injuries. However, they may be more serious than commonly believed since many patients reportedly experience chronic problems afterwards. It is necessary to improve the treatment, such as the method and duration of fixation, of sprained ankles.Methods: Magnetic resonance imaging of 70 patients with acute moderate or advanced ankle sprains presenting consecutively between November 2014 and December 2019 were reviewed for analysis of bone bruising associated with ankle sprains. The patients were treated conservatively with a solid splint or cast until walking pain could be resolved without external fixation. In cases with pain at the time of weight bearing after solid fixation, crutches were prescribed for pain relief. The fixation period ranged from 8 days to 72 days (mean: 29.5 days). Afterwards, 54.0% of patients had walking pain and required the use of crutches. The ankle joint pain disappeared after conservative treatment in all patients.Results: The incidence of bone bruises detected by magnetic resonance imaging in the ankle and midfoot associated with ankle sprain was 81.4%. Bone bruises of the midfoot, including the tarsal bone and Chopart joint, were found in 34.3% of ankle sprains. Bone bruises of the talus were the most common, being present in 60% of ankle sprains. Bone bruises were also evident in the tibia (44.3%), the calcaneus (21.4%), and the tarsal bone (25.7%). There was a significant association between bone bruises of the talocrural joint surface and use of the crutches after fixation (P=0.041). Multiple regression analysis adjusted for age and gender revealed that bone bruises of the talocrural joint surface of the talus was a significant independent predictor of crutch use (P=0.045), with an odds ratio (95% confidence interval) of 3.03 (1.03-8.94).Conclusion: Bone bruises of the ankle and midfoot are often present in ankle sprains. In moderate or advanced cases of ankle sprain, external solid fixation of both the ankle and midfoot should be performed. In cases with pain at weight bearing following solid fixation, crutches are advised for pain relief and proper ligament and bone healing.