Cerebral Amyloid Angiopathy-Related Inflammation (CAA-rI): Three Heterogeneous Case Reports and a Focused Literature Review

Cerebral amyloid angiopathy-related inflammation (CAA-rI) is a largely reversible, subacute encephalopathy, which is considered as a rare variant of cerebral amyloid angiopathy (CAA). Although the diagnosis of this inflammatory vasculopathy is generally clinico-pathologic, a probable or possible diagnosis can often be established based on current clinico-radiological diagnostic criteria. This is important since CAA-rI is considered as a treatable disorder, which most commonly occurs in the elderly population. Behavioral changes and cognitive deterioration are highlighted as the most common clinical signs of CAA-rI, followed by a heterogeneous spectrum of typical and atypical clinical presentations. However, despite the well-established clinical and radiological features incorporated in the current diagnostic criteria for this CAA variant, this rare disorder is still insufficiently recognized and treated. Here, we have shown three patients diagnosed with probable CAA-rI, with significant heterogeneity in the clinical and neuroradiological presentations, followed by different disease courses and outcomes after the introduction of immunosuppressive treatment. Moreover, we have also summarized up-to-date literature data about this rare, yet underdiagnosed, immune-mediated vasculopathy

Relationship Between Regional Distributions of Cytochrome C Oxidase and Copper-Delivering Chaperones in Sclerotic Hippocampi of Epilepsy Patients

Aims: A drop in copper level and the loss of energy homeostasis are both portrayed in mesial temporal lobe epilepsy (mTLE) with hippocampal sclerosis (HS) patients. Cytochrome c oxidase (COX) represents a crossroad of energy and copper metabolism; it is a key component of mitochondrial machinery and contains two copper centers. Our aim here was to examine the link between COX activity and the copper transporting system in HS. COX activity and the levels of mRNA of selected chaperones - COX11, COX17, Sco1 and Sco2 were determined in 13 anatomically distinct hippocampal regions. Methods: Study was performed on seven hippocampal samples, four of which had been acquired during the course of amygdalohippocampectomy treatment of medically intractable epilepsy and three control postmortem samples. Adjacent slices were used for Nissl staining, COX activity assay and mRNA in situ hybridization with autoradiography. Densitometry was performed using ImageJ. Results: Overall COX activity was decreased in HS compared to controls (P = 0.0003). However, 5 regions showed significantly lower COX activity in HS and 8 did not. Subiculum showed slightly higher activity in HS. The levels of mRNA levels were lowered in HS in 6 regions for COX11, 10 regions for COX17, two regions for Sco1 and 11 regions for Sco2. Conclusions: Our findings suggest the loss of energy homeostasis in HS may be related to pathological changes in specific components of copper delivery to COX, and that the impact may vary between different hippocampal regions

Odabir endogene kontrole za imunoblot analizu proteina u sklerotičnim hipokampusima pacijenata sa epilepsijom temporalnog režnja

Skleroza hipokampusa je najčešći neuropatološki nalaz kod epilepsije temporalnog režnja. Pored morfoloških promena odlikuju ga i promene nivoa različitih proteina u ćeliji. Imunoblot je nezamenjiva metoda za određivanje nivoa proteina i podrazumeva normalizaciju u odnosu na endogenu kontrolu (kontrolu jednakog nanošenja uzorka). Za tu svrhu se koriste proteini za koje se smatra da imaju stabilnu ekspresiju koja najmanje varira u ispitivanim uslovima, tretmanima i patofiziološkim stanjima. Ipak u nekim patofiziološkim stanjima se i ekspresija tradicionalno korišćenih endogenih kontrola menja, 1 što može dovesti do prikupljanja netačnih podataka i pogrešnog tumačenja rezultata. Cilj ovog rada je bio da se ispita stabilnost najčešće korišćenih endogenih kontrola i izabere najstabilnija koja će se koristiti za normalizaciju pri poređenju nivoa ciljnih proteina hipokampusa obolelih od epilepsije i neurološki intaktnih kontrola. Imunoblotom su detektovani β-aktin, α-tubulin, TATA-vezujući protein i gliceraldehid3-fosfat dehidrogenaza u tkivnim ekstraktima hipokampusa 9 pacijenata i 7 kontrola, i NormFinder softverom2 određene unutargrupna i međugrupna varijabilnost. Pokazano je da nivo strukturnih proteina β-aktina i α-tubulina najmanje varira u ispitivanim uslovima te se mogu koristiti za poređenje nivoa proteina u sklerotičnim i intaktnim hipokampusima. Rezultati upućuju da je odabir endogenih kontrola važan preduslov za dobijanje tačnih i pouzdanih podataka imunoblot metodom

Imaging and regional distribution of copper, zinc, manganese and iron in sclerotic hippocampi of patients with mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy (mTLE) represents the most common subtype of human focal epilepsies and perhaps the best-characterized disorder of this type 1 . Hippocampal sclerosis (HS) is the most common histopathologic abnormality found in adults with drugresistant mTLE 2 . The histopathologic hallmark of HS is segmental pyramidal cell loss, which can affect any field of the cornu Ammonis (CA1-4). Hippocampal neuronal cell loss is always associated with a severe pattern of astrogliosis 3 . Therewithal, disturbed homeostasis of metals is implicated in the pathology of mTLE-HS. Zinc has been considered to play a major role in epileptogenesis in relation to its involvement in the modulation of excitability and synaptic plasticity 4,5. Further, it has been shown that epileptogenic hippocampi are exposed to oxidative stress and that the development of prooxidative conditions in the CNS usually involves the loss of homeostasis of iron 6,7. Low brain levels of copper and manganese have been reported in patients with Menkes disease and in animal models of epilepsy, and linked to seizure development 8,9. Ristić et al. were the first to conduct a case-control study of total concentration of metals in tissue of human HS, and report lower concentrations of copper and manganese 10

The importance of copper in pathology of mesial temporal lobe epilepsy

More and more studies are identifying the regulation of metal homeostasis as one of the key points of central nervous system’s well-being. Epilepsy is a particularly interesting neurological condition when viewed in terms of the correlation between the amount of metals and the development of a seizure. This lecture will present contribution of our group to the field of metal biology in epilepsy by mapping brain metals in sclerotic hippocampus resected from drug resistant mesial temporal lobe epilepsy (mTLE) patients as surgical therapeutic approach. Direct insight into this epileptogenic area, by two powerful techniques, optical emission and mass spectrometry, has led us to investigation of copper turnover. Namely, among the examined metals, we found the deficiency of copper in sclerotic hippocampus on two levels: (i) in whole structure (ii) and locally in the areas of neuronal loss, with significant correlation between copper concentration and neuron density. Furthermore, analysis of copper metalloproteins showed: (i) significant increase or decrease in levels of protein that is participating in copper transport into the cell (CTR1) depending on the degree of hippocampal neuronal loss; (ii) and lower activity of an enzyme in which copper is part of the active site, cytochrome c oxidase, in sclerotic hippocampi of patients compared to control tissue. In our further investigations it remained to be determined whether changes in copper concentrations and copper metalloproteins are causal to pathology of mTLE or they represent epiphenomenon

Cortical thickness, surface area and folding in patients with psychogenic nonepileptic seizures

OBJECTIVE: To determine cortical thickness (CTh), cortical surface area (CSA), curvature and sulcal depth (SD) in patients with psychogenic nonepileptic seizures (PNES). METHODS: Freesurfer software was used to identify differences between active and control group in Cth, CSA, curvature, and SD. Neuropsychological tests intending to document possible frontal lobe deficit were applied. RESULTS: We included 37 patients with PNES (age 37.3±13.8; female/male 31/6; age of disease onset 26.1±10.6; age of disease duration 11.1±11.1), and 37 healthy controls (age 38.4; ±12.7; female/male 26/11). No difference in CSA and curvature was detected between groups. Patients with PNES had increased CTh in the left insula, left and right medial-orbitofrontal, and left lateral-orbitofrontal, and decreased CTh in the left and right precentral, right enthorinal, and right lateral-occipital region than healthy controls. SD was increased at the level of the left and right insula, right rostral anterior cingulate, right posterior cingulate, and left cuneus, and reduced at the level of the right and left medial-orbitofrontal sulci in patients with PNES compared to healthy controls. CONCLUSION: Individuals with PNES display a distinct profile of changes in CTh, in association with increase in SD in both insula as compared to controls. Our results may contribute to the understanding of the neurobiological background of PNES. Further research, to include replication of the findings and directed to understand the role of insula is needed

Hippocampal antioxidative system in mesial temporal lobe epilepsy

ObjectiveTo examine antioxidative system in hippocampi of patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis (mTLE-HS). MethodsActivity and levels of antioxidative enzymescatalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), manganese superoxide dismutase (MnSOD), and copper-zinc superoxide dismutase (CuZnSOD)were assessed in hippocampi of nine pharmacoresistant mTLE-HS patients (mean age 37.7{[}standard deviation] 6.6years) who underwent amygdalohippocampectomy, and in 10 hippocampi obtained via autopsy from five neurologically intact controls (mean age 34.49.0years). Subfield and cellular (neuron/astrocyte) distribution of CAT, GPx, and MnSOD was analyzed in detail using immunohistochemical staining. ResultsSclerotic hippocampi showed drastically increased activity of hydrogen peroxide-removing enzymes, CAT (p<0.001), GPx (p<0.001), and GR (p<0.001), and significantly higher protein levels of CAT (p=0.006), GPx (p=0.040), GR (p=0.024), and MnSOD (p=0.004), compared to controls. CAT immunofluorescence was located mainly in neurons in both controls and HS. Control hippocampi showed GPx staining in blood vessels and CA neurons. In HS, GPx-rich loci, representing bundles of astrocytes, emerged in different hippocampal regions, whereas the number of GPx-positive vessels was drastically decreased. Neurons with abnormal morphology and strong MnSOD immunofluorescence were present in all neuronal layers in HS. Small autofluorescent deposits, most likely lipofuscin, were observed, along with astrogliosis, in CA1 in HS. SignificanceAntioxidative system is upregulated in HS. This documents, for the first time, that epileptogenic hippocampi are exposed to oxidative stress. Our findings provide a basis for understanding the potential involvement of redox alterations in the pathology of epilepsy, and may open new pharmacologic perspectives for mTLE-HS treatment.Ministry of Education, Science and Technological Development of the Republic of Serbia {[}III41014, OI173014