Human peripheral monocytes capture elements of the state of microglial activation in the brain

Despite a growing focus on neuroimmune mechanisms of Alzheimer’s disease (AD), the role of peripheral monocytes remains largely unknown. Circulating monocytes communicate with the brain’s resident myeloid cells, microglia, via chemical signaling and can directly infiltrate the brain parenchyma.1 Thus, molecular signatures of monocytes may serve as indicators of neuropathological events unfolding in the CNS.2–5 However, no studies have yet directly tested the association of monocyte gene expression on longitudinal cognitive decline or postmortem neuropathology and brain gene expression in aging. Here we present a resource of RNA sequencing of purified CD14+ human monocytes - including an eQTL map - from over 200 elderly individuals, most with accompanying bulk brain RNA sequencing profiles, longitudinal cognitive assessments, and detailed postmortem neuropathological examinations. We tested the direct correlation of gene expression between monocytes and bulk brain tissue, finding very few significant signals driven largely by genetic variation. However, we did identify sets of monocyte-expressed genes that were highly predictive of postmortem microglial activation, diffuse amyloid plaque deposition, and cerebrovascular disease. Our findings prioritize potential blood-based molecular biomarkers for AD; they also reveal the previously unknown architecture of shared gene expression between the CNS and peripheral immune system in aging.

INTRACEREBRAL HEMORRHAGE (ICH) INCIDENCE PROFILE IN JEMURSARI ISLAMIC HOSPITAL DURING THE PERIOD 2017-2019

Background: Intracerebral hemorrhage or ICH or hemorrhagic stroke is caused by bleeding within brain parenchyma. Riskesdas reported that stroke patients in Indonesia experienced an increase from 7 permil in 2013 to 10.9 permil in 2018. Mortality rate for ICH is estimated 40% in 1 month and 54% in 1 year. Rumah sakit Islam Jemursari (RSI) is the only type B hospital in Wonocolo sub-district, Surabaya city. This study aimed to analyze the pattern of incidents and variations of ICH at RSI Jemursari Surabaya.Method: This was a descriptive observational study. Medical record data is collected from 2017-2019. The data were obtained from medical records section of total number of ICH, gender, age and outcome of patients. Furthermore, data is analyzed and illustrated through a bar chart and the frequency of mortality is calculated.Results: Total ICH patients at Jemursari Hospital were 310 with 192 male patients and 118 female patients over 3 years. Meanwhile, the most groups experienced ICH were 45-64 years, followed by +65 age group. This is consistent with several epidemiological studies related to ICH, where the incidence of ICH increases with increasing age. The mortality rate for ICH patients, in the 2017-2019 periode, was around 23-30%.Conclusion: It can be concluded that male more susceptible to ICH than female subjects. Meanwhile, the mortality rate for ICH patients ranged from 23-30% in the 2017-2019 period. It is necessary to carry out further evaluation related to other data from the patient. So it could describe incidence rate as well as an overview of the ICH profile at RSI Jemursari.

Unilateral absence of internal carotid artery: A rare case report

Unilateral absence of internal carotid artery (ICA) is a rare congenital anomaly. We present the case of a 35-year-old man with episodes of recurrent strokes in the past and now presenting with right-sided upper limb weakness. Radiological diagnostic workup revealed a thin left ICA in the neck with non-visualization beyond petrous bone in the intracranial course. The ipsilateral brain parenchyma is supplied by vessels from the contralateral side of the Circle of Willis. As the patient had no evidence of a cerebrovascular accident on radiological evaluation and no neurological signs and symptoms, he was discharged with anticoagulant medications with the advice of follow-up. This is the first report to describe a case of ICA agenesis with a pattern of collateral circulation that doesn’t fit any of the six types described by Lie.

Multiple Myeloma Involving Left Hemicranium

Multiple myeloma (MM) is a malignant neoplasm of bone marrow affecting plasma cells. It is commonly seen as multiple punched-out lesions in the skull bone as a characteristic feature. Its presentation as hemicranial involvement with intracranial extension is rare. A 46-year-old male presented with left side scalp swelling, prominent over parietal region. X-ray showed multiple punched out lesions involving left hemicranium. CT and MRI brain showed intracranial extension of lesion without brain parenchyma invasion. He was treated with biopsy of lesion followed by chemotherapy.

A red herring CVA with unexpected outcome: illustrative case

BACKGROUND Disruptions to the integrity of the inner table and trabeculae of the calvaria are rare phenomena. Increasingly rare is the phenomenon of herniation of brain parenchyma through the defects in the skull causing neurological deficit. Surgical intervention is commonly performed but is fraught with risk of brain tissue loss. OBSERVATIONS The authors present a case of a 78-year-old White male presenting with strokelike symptoms who was found to have an intradiploic encephalocele that was successfully treated with surgical intervention and neuroplastic reconstruction of the anatomical deficit. The patient had a marked recovery and had near-complete resolution of symptoms. LESSONS This notably rare phenomenon resolved with neurosurgical intervention, sparing the parenchyma, and provided the patient with perceivably normal contour of the head using a collaborative approach with neuroplastic intervention.

Pathological α-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brain

Background Leucine rich repeat kinase 2 (LRRK2) and SNCA are genetically linked to late-onset Parkinson’s disease (PD). Aggregated α-synuclein pathologically defines PD. Recent studies identified elevated LRRK2 expression in pro-inflammatory CD16+ monocytes in idiopathic PD, as well as increased phosphorylation of the LRRK2 kinase substrate Rab10 in monocytes in some LRRK2 mutation carriers. Brain-engrafting pro-inflammatory monocytes have been implicated in dopaminergic neurodegeneration in PD models. Here we examine how α-synuclein and LRRK2 interact in monocytes and subsequent neuroinflammatory responses. Methods Human and mouse monocytes were differentiated to distinct transcriptional states resembling macrophages, dendritic cells, or microglia, and exposed to well-characterized human or mouse α-synuclein fibrils. LRRK2 expression and LRRK2-dependent Rab10 phosphorylation were measured with monoclonal antibodies, and myeloid cell responses to α-synuclein fibrils in R1441C-Lrrk2 knock-in mice or G2019S-Lrrk2 BAC mice were evaluated by flow cytometry. Chemotaxis assays were performed with monocyte-derived macrophages stimulated with α-synuclein fibrils and microglia in Boyden chambers. Results α-synuclein fibrils robustly stimulate LRRK2 and Rab10 phosphorylation in human and mouse macrophages and dendritic-like cells. In these cells, α-synuclein fibrils stimulate LRRK2 through JAK-STAT activation and intrinsic LRRK2 kinase activity in a feed-forward pathway that upregulates phosphorylated Rab10. In contrast, LRRK2 expression and Rab10 phosphorylation are both suppressed in microglia-like cells that are otherwise highly responsive to α-synuclein fibrils. Corroborating these results, LRRK2 expression in the brain parenchyma occurs in pro-inflammatory monocytes infiltrating from the periphery, distinct from brain-resident microglia. Mice expressing pathogenic LRRK2 mutations G2019S or R1441C have increased numbers of infiltrating pro-inflammatory monocytes in acute response to α-synuclein fibrils. In primary cultured macrophages, LRRK2 kinase inhibition dampens α-synuclein fibril and microglia-stimulated chemotaxis. Conclusions Pathologic α-synuclein activates LRRK2 expression and kinase activity in monocytes and induces their recruitment to the brain. These results predict that LRRK2 kinase inhibition may attenuate damaging pro-inflammatory monocyte responses in the brain.

GFAP splice variants fine-tune glioma cell invasion and tumour dynamics by modulating migration persistence

Glioma is the most common form of malignant primary brain tumours in adults. Their highly invasive nature makes the disease incurable to date, emphasizing the importance of better understanding the mechanisms driving glioma invasion. Glial fibrillary acidic protein (GFAP) is an intermediate filament protein that is characteristic for astrocyte- and neural stem cell-derived gliomas. Glioma malignancy is associated with changes in GFAP alternative splicing, as the canonical isoform GFAPα is downregulated in higher-grade tumours, leading to increased dominance of the GFAPδ isoform in the network. In this study, we used intravital imaging and an ex vivo brain slice invasion model. We show that the GFAPδ and GFAPα isoforms differentially regulate the tumour dynamics of glioma cells. Depletion of either isoform increases the migratory capacity of glioma cells. Remarkably, GFAPδ-depleted cells migrate randomly through the brain tissue, whereas GFAPα-depleted cells show a directionally persistent invasion into the brain parenchyma. This study shows that distinct compositions of the GFAPnetwork lead to specific migratory dynamics and behaviours of gliomas.

Heparin-derived theranostic nanoprobes overcome the blood-brain barrier and target glioma in murine model

The poor permeability of theranostic agents across the blood-brain-barrier (BBB) significantly hampers the development of new treatment modalities for neurological diseases. We have discovered a new biomimetic nanocarrier using heparin (HP) that effectively passes the BBB and targets glioblastoma. Specifically, we designed HP coated gold nanoparticles (HP-AuNPs) that were labeled with three different imaging modalities namely, fluorescein (FITC-HP-AuNP), radioisotope 68Gallium (68Ga-HP-AuNPs), and MRI active gadolinium (Gd-HP-AuNPs). The systemic infusion of FITC-HP-AuNPs in three different mouse strains (C57BL/6JRj, FVB, and NMRI-nude) displayed excellent penetration and revealed uniform distribution of fluorescent particles in the brain parenchyma (69-86%) with some accumulation in neurons (8-18%) and microglia (4-10%). Tail-vein administration of radiolabeled 68Ga-HP-AuNPs in healthy rats also showed 68Ga-HP-AuNP inside the brain parenchyma and in areas containing cerebrospinal fluid, such as the lateral ventricles, the cerebellum, and brain stem. Finally, tail-vein administration of Gd-HP-AuNPs (that display ~3 fold higher relaxivity than that of commercial Gd-DTPA) in an orthotopic glioblastoma (U87MG xenograft) model in nude mice demonstrated enrichment of T1-contrast at the intracranial tumor with a gradual increase in the contrast in the tumor region between 1h-3h. We believe, our finding offers the untapped potential of HP-derived-NPs to deliver cargo molecules for treating neurological disorders.

In-utero Diagnosis of Double Encephalocele - Imaging Features and Review of Literature

Encephalocele is protrusion of brain parenchyma through a defect in the cranium. It is classified into various types based on the defect location: sincipital (fronto-ethmoidal), basal (trans-sphenoidal, spheno-ethmoidal, trans-ethmoidal, and spheno-orbital), occipital and parietal. Double encephaloceles are very rare with only a handful of cases reported in the literature and most of these cases involved either occipital or sub-occipital region. All, except one, cases of double encephaloceles were diagnosed postnatally. We present a case of double encephalocele with parietal and occipital components diagnosed in utero. To the best of our knowledge, this is the first case of double encephalocele involving the parietal and occipital skull bones diagnosed in-utero.