Neuropathological diagnostic considerations in hyperkinetic movement disorders

Neuropathology of hyperkinetic movement disorders can be very challenging. This paper starts with basic functional anatomy of the basal ganglia in order to appreciate that focal lesions like for instance tumor or infarction can cause hyperkinetic movement disorders like (hemi)ballism. The neuropathology of different causes of chorea (amongst others Huntington’s disease, neuroacanthosis, and HLD-2) and dystonia (DYT1, PD, and Dopa-Responsive Dystonia) are described. Besides the functional anatomy of the basal ganglia a wider anatomical network view is provided. This forms the basis for the overview of the neuropathology of different forms of tremor

The Potential of Ferroptosis-Targeting Therapies for Alzheimer's Disease:From Mechanism to Transcriptomic Analysis

Alzheimer’s disease (AD), the most common form of dementia, currently affects 40–50 million people worldwide. Despite the extensive research into amyloid β (Aβ) deposition and tau protein hyperphosphorylation (p-tau), an effective treatment to stop or slow down the progression of neurodegeneration is missing. Emerging evidence suggests that ferroptosis, an iron-dependent and lipid peroxidation-driven type of programmed cell death, contributes to neurodegeneration in AD. Therefore, how to intervene against ferroptosis in the context of AD has become one of the questions addressed by studies aiming to develop novel therapeutic strategies. However, the underlying molecular mechanism of ferroptosis in AD, when ferroptosis occurs in the disease course, and which ferroptosis-related genes are differentially expressed in AD remains to be established. In this review, we summarize the current knowledge on cell mechanisms involved in ferroptosis, we discuss how these processes relate to AD, and we analyze which ferroptosis-related genes are differentially expressed in AD brain dependant on cell type, disease progression and gender. In addition, we point out the existing targets for therapeutic options to prevent ferroptosis in AD. Future studies should focus on developing new tools able to demonstrate where and when cells undergo ferroptosis in AD brain and build more translatable AD models for identifying anti-ferroptotic agents able to slow down neurodegeneration

Corrigendum:The Potential of Ferroptosis-Targeting Therapies for Alzheimer's Disease: From Mechanism to Transcriptomic Analysis

[This corrects the article DOI: 10.3389/fnagi.2021.745046.].</p

Recruitment of bone marrow derived cells during anti-angiogenic therapy in GBM:The potential of combination strategies

Glioblastoma (GBM) is a highly vascular tumor characterized by rapid and invasive tumor growth, followed by oxygen depletion, hypoxia and neovascularization, which generate a network of disorganized, tortuous and permeable vessels. Recruitment of bone marrow derived cells (BMDC) is crucial for vasculogenesis. These dells may act as vascular progenitors by integrating into the newly formed blood vessels or as vascular modulators by releasing pro-angiogenic factors. In patients with recurrent GBM, anti-vascular endothelial growth factor (VEGF) therapy has been evaluated in combination with chemotherapy, yielding improvements in progression-free survival (PFS). However, benefits are temporary as vascular tumors acquire angiogenic pathways independently of VEGF. Specifically, acute hypoxia following prolonged VEGF depletion induces the recruitment of certain myeloid cell subpopulations, which highly contribute to treatment refractoriness. Here we review the molecular mechanisms of neovascularization in relation to bevacizumab therapy with special emphasis on the recruitment of BMDCs and possible combination therapies for GBM patients. (C) 2014 Elsevier Ireland Ltd. All rights reserved

An aggressive poorly differentiated plurihormonal Pit-1-positive adenoma

In July 2017, a 35-year-old woman was referred to our care for treatment of a large pituitary mass with an unusually high growth rate. She presented with right-sided ptosis and diplopia (n. III palsy), increasing retrobulbar pain and vertigo. Although laboratory investigations were consistent with acromegaly, she exhibited no clear phenotypic traits. During transsphenoidal surgery aimed at biopsy, typical adenomatous tissue was encountered, upon which it was decided to proceed to debulking. Histopathological analysis demonstrated a poorly differentiated plurihormonal Pit-1-positive adenoma with focal growth hormone (GH) and prolactin positivity, positive SSTR2 staining and a Ki-67 of 20–30%. Postoperative magnetic resonance imaging (MRI) examination revealed a large tumour remnant within the sella invading the right cavernous sinus with total encasement of the internal carotid artery and displacement of the right temporal lobe. As a consequence, she was treated additionally with radiotherapy, and a long-acting first-generation somatostatin analogue was prescribed. Subsequently, the patient developed secondary hypocortisolism and diabetes mellitus despite adequate suppression of GH levels. In September 2019, her symptoms recurred. Laboratory evaluations indicated a notable loss of biochemical control, and MRI revealed tumour progression. Lanreotide was switched to pasireotide, and successful removal of the tumour remnant and decompression of the right optic nerve was performed. She received adjuvant treatment with temozolomide resulting in excellent biochemical and radiological response after three and six courses. Symptoms of right-sided ptosis and diplopia remained. Evidence for systemic therapy in case of tumour progression after temozolomide is currently limited, although various potential targets can be identified in tumour tissue

Primary Cauda Equina T-Cell Lymphoblastic Lymphoma

BACKGROUND: T-cell lymphoblastic lymphoma (T-LBL) is a rare and aggressive form of non-Hodgkin lymphoma. This report describes, to our knowledge, the first adult case of a primary cauda equina T-LBL. Treatment consists of multiagent chemotherapy, and surgical removal of T-LBL does not improve outcome. We discuss the workup of patients with an intradural spinal mass, together with a review of the literature on primary spinal lymphoma of the cauda equina. CASE DESCRIPTION: A 54-year-old woman with Crohn's disease, for which she was taking immunosuppressive medication, presented with progressive back pain radiating to both legs and deteriorating neurologic deficits caused by an intradural, contrast-enhancing lesion in the L1-5 region. During acute surgery, the tumor was partially resected. Immunohistochemical phenotyping revealed a T-LBL. No other lymphoma localizations were found after subsequent staging. Despite extensive treatment, the patient died of disseminated disease throughout the central nervous system, 6 weeks after the diagnosis. CONCLUSIONS: Pain and progressive neurologic complaints can be symptoms of a (malignant) intradural spinal tumor. Intradural lymphoma must be considered as a differential diagnosis by clinicians because it can mimic neoplasms that often require urgent surgery. The histopathologic diagnosis should preferably be obtained by way of cerebrospinal fluid analysis or tumor biopsy because tumor resection has no beneficial effect on the oncologic outcome

Novel insights into vascularization patterns and angiogenic factors in glioblastoma subclasses

Glioblastoma (GBM) is a highly vascularized and aggressive type of primary brain tumor in adults with dismal survival. Molecular subtypes of GBM have been identified that are related to clinical outcome and response to therapy. Although the mesenchymal type has been ascribed higher angiogenic activity, extensive characterization of the vascular component in GBM subtypes has not been performed. Therefore, we aimed to investigate the differential vascular status and angiogenic signaling levels in molecular subtypes. GBM tissue samples representing proneural IDH1 mutant, classical-like and mesenchymal-like subtypes were analyzed by morphometry for the number of vessels, vessel size and vessel maturity. Also the expression levels of factors from multiple angiogenic signaling pathways were determined. We found that necrotic and hypoxic areas were relatively larger in mesenchymal-like tumors and these tumors also had larger vessels. However, the number of vessels, basement membrane deposition and pericyte coverage did not vary between the subtypes. Regarding signaling patterns the majority of factors were expressed at similar levels in the subtypes, and only ANGPT2, MMP2, TIMP1, VEGFA and MMP9/TIMP2 were higher expressed in GBMs of the classical-like subtype. In conclusion, although morphological differences were observed between the subtypes, the angiogenic signaling status of GBM subtypes seemed to be rather similar. These results challenge the concept of mesenchymal GBMs being more angiogenic than other subclasses

Development of muscle ultrasound density in healthy fetuses and infants

Muscle ultrasound density (MUD) is a non-invasive parameter to indicate neuromuscular integrity in both children and adults. In healthy fetuses and infants, physiologic MUD values during development are still lacking. We therefore aimed to determine the physiologic, age-related MUD trend of biceps, quadriceps, tibialis anterior, hamstrings, gluteal and calf muscles, from pre- to the first year of postnatal life. To avoid a bias by pregnancy-related signal disturbances, we expressed fetal MUD as a ratio against bone ultrasound density. We used the full-term prenatal MUD ratio and the newborn postnatal MUD value as reference points, so that MUD development could be quantified from early pre- into postnatal life. Results: During the prenatal period, the total muscle group revealed a developmental MUD trend concerning a fetal increase in MUD-ratio from the 2nd trimester up to the end of the 3rd trimester [median increase: 27% (range 16-45), p < .001]. After birth, MUD-values increased up to the sixth month [median increase: 11% (range -7-27), p = 0.025] and stabilized thereafter. Additionally, there were also individual MUD characteristics per muscle group and developmental stage, such as relatively low MUD values of fetal hamstrings and high values of the paediatric gluteus muscles. These MUD trends are likely to concur with analogous developmentally, maturation-related alterations in the muscle water to peptide content ratios