Switched Aβ43 generation in familial Alzheimer’s disease with presenilin 1 mutation

Presenilin (PS) with a genetic mutation generates abundant β-amyloid protein (Aβ) 43. Senile plaques are formed by Aβ43 in the cerebral parenchyma together with Aβ42 at middle ages. These brains cause the early onset of Alzheimer’s disease (AD), which is known as familial Alzheimer’s disease (FAD). Based on the stepwise processing model of Aβ generation by γ-secretase, we reassessed the levels of Aβs in the cerebrospinal fluid (CSF) of FAD participants. While low levels of Aβ38, Aβ40, and Aβ42 were generated in the CSF of FAD participants, the levels of Aβ43 were unchanged in some of them compared with other participants. We sought to investigate why the level of Aβ43 was unchanged in FAD participants. These characteristics of Aβ generation were observed in the γ-secretase assay in vitro using cells, which express FAD mutations in PS1. Aβ38 and Aβ40 generation from their precursors, Aβ42 and Aβ43, was decreased in PS1 mutants compared with wild-type (WT) PS1, as observed in the CSF. Both the ratios of Aβ38/Aβ42 and Aβ40/Aβ43 in PS1 mutants were lower than those in the WT. However, the ratio of Aβ43/amyloid precursor protein intracellular domain (AICD) increased in the PS1 mutants in an onset age dependency, while other Aβ/AICD ratios were decreased or unchanged. Importantly, liquid chromatography–mass spectrometry found that the generation of Aβ43 was stimulated from Aβ48 in PS1 mutants. This result indicates that PS1 mutants switched the Aβ43 generating line, which reflects the level of Aβ43 in the CSF and forming senile plaques.

A case of transpetrosal penetrating head injury near the sigmoid sinus

Background: Penetrating brain injury is relatively rare, which occurs in 0.4% of all head trauma. In past reports, the orbit, nasal cavity, and oral cavity are the most common routes of entry of foreign substances into the skull. In this case report, we experienced a rare case of head trauma who injury through the petrosal bone. To the best of our knowledge, there is no similar literature. Case Description: A 69-year-old man accidentally fell from a stepladder with a height of 3 m. There was a sprinkler on the ground, and it went through his posterior part of the right auricle at the collision. He was alert on admission. However, neurological examination showed right trigeminal, abducens, and facial nerve palsy. Computed tomography was performed, and it revealed that the objects penetrated the petrosal bone. Furthermore, it caused traumatic subarachnoid hemorrhage and acute subdural hemorrhage. Fortunately, it did not reach any cerebral artery and cerebral parenchyma. Immediately it was surgically removed with a good outcome. Conclusion: When suspected sigmoid sinus injury in head penetrating injury, craniotomy should be considered with bleeding from the sigmoid sinus during surgery.

Neuropathology and Inflammatory Cell Characterization in 10 Autoptic COVID-19 Brains

COVID-19 presents with a wide range of clinical neurological manifestations. It has been recognized that SARS-CoV-2 infection affects both the central and peripheral nervous system, leading to smell and taste disturbances; acute ischemic and hemorrhagic cerebrovascular disease; encephalopathies and seizures; and causes most surviving patients to have long lasting neurological symptoms. Despite this, typical neuropathological features associated with the infection have still not been identified. Studies of post-mortem examinations of the cerebral cortex are obtained with difficulty due to laboratory safety concerns. In addition, they represent cases with different neurological symptoms, age or comorbidities, thus a larger number of brain autoptic data from multiple institutions would be crucial. Histopathological findings described here are aimed to increase the current knowledge on neuropathology of COVID-19 patients. We report post-mortem neuropathological findings of ten COVID-19 patients. A wide range of neuropathological lesions were seen. The cerebral cortex of all patients showed vascular changes, hyperemia of the meninges and perivascular inflammation in the cerebral parenchyma with hypoxic neuronal injury. Perivascular lymphocytic inflammation of predominantly CD8-positive T cells mixed with CD68-positive macrophages, targeting the disrupted vascular wall in the cerebral cortex, cerebellum and pons were seen. Our findings support recent reports highlighting a role of microvascular injury in COVID-19 neurological manifestations.

Mortality in Parenchymal and Subarachnoid Neurocysticercosis

Neurocysticercosis (NCC) is endemic in many parts of the world, carrying significant neurological morbidity that varies according to whether lesions are located inside the cerebral parenchyma or in extraparenchymal spaces. The latter, in particular subarachnoid NCC, is assumed to be more severe, but no controlled studies comparing mortality between types of NCC exist. The aim of this study was to compare all-cause mortality between patients with intraparenchymal NCC and those with subarachnoid NCC. Vital status and sociodemographic characteristics were evaluated in patients with intraparenchymal viable, intraparenchymal calcified, and subarachnoid NCC attending a neurological referral hospital in Lima, Perú. Survival analyses using Kaplan–Meier curves and Cox proportional regression models were carried out to compare mortality rates between groups. From 840 NCC patients followed by a median time of 82.3 months, 42 (5.0%) died, six (1.8%) in the intraparenchymal viable group, four (1.3%) in the calcified group, and 32 (16.6%) in the subarachnoid group (P < 0.001). Older age and lower education were significantly associated with mortality. The age-adjusted hazard ratio for death in the subarachnoid group was 13.6 (95% CI: 5.6–33.0, P < 0.001) compared with the intraparenchymal viable group and 10.7 (95% CI: 3.7–30.8, P < 0.001) when compared with the calcified group. We concluded that subarachnoid disease is associated with a much higher mortality in NCC.

Co-Therapy of Albendazole and Dexamethasone Reduces Pathological Changes in the Cerebral Parenchyma of Th-1 and Th-2 Dominant Mice Heavily Infected with Angiostrongylus cantonensis: Histopathological and RNA-seq Analyses

Administration of albendazole alone was not very suitable for the treatment of cerebral angiostrongyliasis. This study was designed to evaluate the effects of the co-therapy of this drug and dexamethasone in Th-1 and Th-2 dominant mice infected with Angiostrongylus cantonensis. Each of BALB/c and C57BL/6 mice infected with 50 A. cantonensis third-stage larvae were administered albendazole (10 mg/kg/day) alone, dexamethasone (0.5 mg/kg/day) alone, or co-therapy of the two drugs from day 7 or 14 post-infection for 7 or 14 days. After sacrifice, coronal slices were prepared from five brain regions and stained with hematoxylin and eosin. Eight pathological changes were employed to determine the therapeutic effectiveness using a scoring system. RNA-seq analysis was performed to confirm the histopathological findings. The infected BALB/c and C57BL/6 mice had similar patterns in the pathological changes. Meningitis, hemorrhage, size of worms, and encephalitis in the cerebral parenchyma were slighter in the mice treated with co-therapy than the remaining groups. Mice treated from day 14 had more severe changes than those from day 7. The histopathological findings were found to be consistent to immune responses determined by RNA-seq analysis. Co-therapy was determined to reduce pathological changes after administration to mice infected with A. cantonensis.

Multiple Brain Abscesses Secondary to Odontogenic Infection: A Clinical Case Report

Introduction Cerebral abscess is a suppurative infection of the cerebral parenchyma, which may occur due to contiguity, hematogenous dissemination of distant foci, secondary to open traumatic brain injuries, or be idiopathic. Clinical Case A 63-year-old male patient sought assistance due to a severe headache in the frontal region associated with chills and lack of appetite that started four days before. Clinical examination of the patient showed no significant changes. Imaging and laboratory tests on admission showed only nonspecific changes, such as leukocytes 18,540, platelets 517,000, and c-reactive protein 2,0. In such case, magnetic resonance imaging (MRI) of the skull was performed with contrast, showing the presence of expansive lesions compatible with multiple brain abscesses in the right parieto-occipital region. Discussion After excluding the main focus of hematogenous dissemination and in view of the identification of the agent Streptococcus intermedius by means of secretion culture collected through a surgical method, the hypothesis of abscess due to contiguous dental pyogenic foci was pointed out. Conclusion Dental evaluation showed multiple foci of infection with periodontitis and dental abscess, which were treated along with the use of antibiotics directed to the etiologic agent.

Minute changes of cerebral parenchymal non-contrast computed tomography attenuation reflect cerebral volume alterations of blood

Aims Non-infarcted acute cerebral ischaemic areas appear hypo-attenuated on non-contrast narrow-window computed tomography images. We aimed to determine the mechanism underlying minute computed tomography hypo-attenuation and visualise these attenuation changes on non-contrast computed tomography images. Methods The cerebral parenchyma was defined by pixels with attenuation of 20–50 Hounsfield units. We calculated the mean cerebral parenchymal attenuation in non-contrast computed tomography images. We analysed the correlation of complete blood counts with corresponding mean cerebral parenchymal attenuation values using linear regression analysis. Moreover, we developed an image processing method that involved pixel colorisation based on the noise-reduced attenuation value for minute cerebral parenchymal attenuation visualisation. Results Haemoglobin, haematocrit and red blood cell counts positively correlated with mean cerebral parenchymal attenuation values. The cerebral haematocrit is correlated with the blood haematocrit; therefore, cerebral parenchymal attenuation correlated linearly with cerebral haemoglobin concentration. Haemoglobin contents in a pixel partially determine the X-ray absorption dose and attenuation value. Pixel haemoglobin contents are determined by the cerebral volume of blood in a pixel. Image processed computed tomography images reflected cerebral volume of blood and showed the same alterations with regional cerebral blood volume maps of perfusion computed tomography. Conclusions Cerebral parenchymal attenuation correlated with cerebral haemoglobin concentration and cerebral volume of blood. Infarcted cerebral parenchyma shows about 5 Hounsfield units gray matter attenuation decrease. Attenuation decrease by less than 5 Hounsfield units means decreased cerebral volume of blood, indicating a reversible functional change. One cannot recognise minute hypo-attenuation (<5 Hounsfield units) in routine computed tomography images. However, it can be visualised through an image processing method on non-contrast computed tomography images. It may detect pre-infarction cerebral volume of blood and regional cerebral blood volume alterations.

Abstract 10: Radiomic Signature of the White Matter Hyperintensity Burden Correlates With Clinical Phenotypes

Introduction: Structural integrity of cerebral parenchyma is an essential radiographic equivalent of brain health; but its assessment usually requires dedicated advanced image acquisitions. Radiomics analyses bear the potential to describe radiophenotypes beyond what meets the naked eye. We sought to: 1) evaluate this novel approach to predict white matter hyperintensity (WMH) burden and 2) uncover latent clinico-radiological associations. Methods: An international, multi-site cohort of 4,164 acute ischemic stroke (AIS) patients with FLAIR MRI (MRI-GENIE study) underwent total brain and WMH lesion segmentation using convolutional neural networks. Radiomic features (n=1905) were extracted from clinical FLAIR images outside of the WMH (brain mask - WMH mask). Prediction of the WMH burden using radiomics was done using LASSO regression. Radiomic signature of WMH was built with the most stable selected features, then compared to the clinical variables using canonical correlation analysis. Results: In this cohort, (mean age=62.8±15.0, median WMH volume=4.2cc IQR 1.4-11.2), radiomic features were highly predictive of WMH burden (R2=0.8±0.012). Radiomic signature of WMH included 68 features. All 7 pairs of extracted canonical variates (CV) were statistically significant with respective canonical correlations of 0.79, 0.64, 0.44, 0.21, 0.16, 0.15 (Bonferroni corrected p-values CV1-6 <.001, p-value CV7 =.003). Upon examination, CV1 was mainly influenced by age, CV2 by sex, CV3 by history of smoking and diabetes mellitus (DM), CV4 by hypertension, CV5 by atrial fibrillation (AF) and DM, CV6 by coronary artery disease (CAD) and CV7 by CAD and DM. Conclusion: Radiomics extracted from clinical grade FLAIR images of AIS patients seem able to capture structural integrity of the cerebral parenchyma and to correlate with clinical phenotypes. Further research could evaluate radiomics to predict the progression of cerebral small vessel disease on longitudinal data.