Human brain tissues obtained from autopsies, as well as muscle and nerve samples derived from biopsies, constitute indispensable resources for translational research investigating the pathomechanisms of neuropsychiatric disorders. In this study, we introduce the Nervous System Tissue Bank of University of Debrecen, which contains formalin-preserved and formalin-fixed paraffin-embedded (FFPE) brain samples, as well as frozen nerve and muscle biopsy specimens. Database was established containing clinical and pathological parameters. For autopsy cases, the following variables were recorded: sex, age, number of hospitalization days, admission diagnosis, comorbidities, cause of death, post-mortem interval, general autopsy findings, and macro- and microscopic brain pathology diagnoses. For biopsy samples, we recorded: sex, age, biopsy site, and microscopic and molecular genetic diagnoses. Based on the recorded parameters and their temporal changes, retrospective statistical analyses were performed. Formalin-fixed brain samples and FFPE blocks were available from 2425 deceased individuals, and nerve/muscle samples from 257 patients. The brain samples originate from the period between 1990 and 2012. The most frequent admission diagnoses included ischemic stroke (n = 1070), hemorrhagic stroke (n = 462), subarachnoid hemorrhage (n = 102), epilepsy (n = 103), brain metastasis (n = 70), primary brain tumor (n = 60), parkinsonism (n = 28), dementia (n = 21), and amyotrophic lateral sclerosis (n = 21). Prevalence of hypertension (67.6

Spontaneous Gram-negative bacillary meningitis in adults is rare and carries high mortality, particularly in elderly patients with significant comorbidities. Although multiplex meningitis-encephalitis (ME) panels have improved diagnostic turnaround time, their limited pathogen spectrum may reduce sensitivity for certain clinically relevant Gram-negative organisms. We report a 78-year-old man presenting with acute meningoencephalitis, septic deterioration, and cerebrospinal fluid (CSF) findings strongly suggestive of bacterial infection. Despite marked neutrophilic pleocytosis and elevated protein levels, the multiplex ME panel was negative. Blood cultures subsequently yielded Proteus mirabilis. Given the discordance between inflammatory CSF findings and routine molecular testing, following interdisciplinary consultation, an off-label BioFire® Joint Infection multiplex PCR panel was performed directly on CSF. The assay identified Proteus mirabilis harboring a cefotaximase-Munich (CTX-M)-type extended-spectrum β-lactamase (ESBL) resistance determinant. Based on this result, antimicrobial therapy was escalated from ceftriaxone-based empiric treatment to meropenem prior to availability of phenotypic susceptibility data. Despite early pathogen identification and targeted antimicrobial therapy, the patient died due to multiorgan dysfunction secondary to severe sepsis. This case suggests a potential diagnostic limitation of standard ME panels in selected high-risk scenarios and indicates that selective off-label use of broader multiplex PCR platforms may provide additional clinically relevant information in carefully selected patients. In the setting of high clinical suspicion and negative routine multiplex testing, rapid resistance-gene detection may provide actionable information within a decisive therapeutic window and support timely antimicrobial optimization in severe Gram-negative central nervous system infections. Further studies are required to evaluate the diagnostic performance and clinical impact of such approaches. Written informed consent for publication was obtained from the patient’s next of kin, and the study was conducted in accordance with institutional and ethical standards. Clinical trial number Not applicable.

Background: Idiopathic inflammatory myopathies (IIMs), also known as myositis, are systemic autoimmune diseases characterized by chronic inflammation affecting the skin, muscles, and internal organs. Besides traditional risk factors and immune-mediated myocarditis, continuous activity of the immune system increases cardiovascular disease (CVD) risk, meaning that cardiovascular events are the leading causes of mortality in IIM patients. Statins are the most widely used lipid-lowering therapies, which reduce cardiovascular risk, but the fear of adverse muscular events inhibits the frequency of use. Methods: Our aim was to assess the CVD risk in a myositis cohort using the SCORE2 prediction system, carotid artery Doppler ultrasound measurement, and biomarkers; recommend individual lipid-lowering treatment; and follow the efficacy and adverse events of therapy in a 6-month treatment period. Results: The study population (80 IIM patients) was a middle-aged, female-dominant myositis cohort with an average disease duration of 9 years and low median global disease activity. Based on the SCORE2 evaluation, 78.8% of patients had medium/high CVD risk, while 73.13% had asymptomatic carotid plaque. After 6 months of adequate lipid-lowering therapy, 37.5% of patients reached a lower CVD risk category, the biomarker levels of atherosclerosis significantly decreased, and no progression in carotid plaques was detected. None of the patients reported an adverse muscular event or IIM relapse. Conclusions: Our findings proved that the CVD risk of patients with myositis is high, but carefully applied lipid-lowering treatment is the key to effective risk reduction. Risk stratification and the recommendation of preventive treatment are the responsibility of the treating physician.

Background: Ischemic stroke is a leading cause of mortality worldwide, and intravenous thrombolysis, while improving functional outcomes, still leaves a significant mortality rate. This study aimed to investigate the clinical and pathological data of thrombolysed stroke patients who subsequently died and underwent autopsy, focusing on hemorrhagic transformation (HT). Methods: Over a 10-year period, 1426 acute ischemic stroke patients received thrombolysis at our center, with an in-hospital mortality rate of 11.7%. Autopsies were performed on 98 of the 167 deceased patients. Results: HT was found in 47% of these cases, only less than half occurring within a day of thrombolysis. Significant independent predictors of HT included higher lactate dehydrogenase (LD) levels and higher INR values at admission. HT directly caused death in 30% of cases, often through herniation, while other complications (pulmonary embolism, pneumonia) were also common. Conclusions: These findings highlight the importance of postmortem investigations to accurately determine the incidence of HT and contributing factors. Our data indicate that in the vast majority of HT cases, the role of contributing factors other than rt-PA may be important. Of the routinely assessed clinical and laboratory parameters at admission, only LD and INR were found to be independent predictors of HT in the autopsied studied cohort.

Ischemic stroke, resulting from insufficient blood supply to the brain, is among the leading causes of death and disability worldwide. A potentially severe complication of the disease itself or its treatment aiming to restore optimal blood flow is hemorrhagic transformation (HT) increasing morbidity and mortality. Detailed summaries can be found in the literature on the pathophysiological background of hemorrhagic transformation, the potential clinical risk factors increasing its chance, and the different biomarkers expected to help in its prediction and clinical outcome. Clinicopathological studies also contribute to the improvement in our knowledge of hemorrhagic transformation. We summarized the clinical risk factors of the hemorrhagic transformation of ischemic strokes in terms of risk reduction and collected the most promising biomarkers in the field. Also, auxiliary treatment options in reperfusion therapies have been reviewed and collected. We highlighted that the optimal timing of revascularization treatment for carefully selected patients and the individualized management of underlying diseases and comorbidities are pivotal. Another important conclusion is that a more intense clinical follow-up including serial cranial CTs for selected patients can be recommended, as clinicopathological investigations have shown HT to be much more common than clinically suspected.

Semi-quantitative scoring is a method that is widely used to estimate the quantity of proteins on chromogen-labelled immunohistochemical (IHC) tissue sections. However, it suffers from several disadvantages, including its lack of objectivity and the fact that it is a time-consuming process. Our aim was to test a recently established artificial intelligence (AI)-aided digital image analysis platform, Pathronus, and to compare it to conventional scoring by five observers on chromogenic IHC-stained slides belonging to three experimental groups. Because Pathronus operates on grayscale 0-255 values, we transformed the data to a seven-point scale for use by pathologists and scientists. The accuracy of these methods was evaluated by comparing statistical significance among groups with quantitative fluorescent IHC reference data on subsequent tissue sections. The pairwise inter-rater reliability of the scoring and converted Pathronus data varied from poor to moderate with Cohen’s kappa, and overall agreement was poor within every experimental group using Fleiss’ kappa. Only the original and converted that were obtained from Pathronus original were able to reproduce the statistical significance among the groups that were determined by the reference method. In this study, we present an AI-aided software that can identify cells of interest, differentiate among organelles, protein specific chromogenic labelling, and nuclear counterstaining after an initial training period, providing a feasible and more accurate alternative to semi-quantitative scoring.

A Lewy-testes demencia (DLB) és a Parkinson-kórhoz társuló demencia (PDD) számos klinikai, patofiziológiai és morfológiai átfedést mutató neurodegeneratív kórkép. Neuropatológiai szempontból meghatározó a kóros α -szinuklein-aggregátumokat tartalmazó Lewy-testek (LB) jelenléte. DLB-ben nagyszámú LB található a corticalis régiókban, míg PDD-ben elsősorban cerebrospinal fluid biomarkers shows higher oligomeric α -synuclein burden in PDD. Levodopa is less effective in DLB than in PDD and may increase the risk of psychosis. In this review, we comprehensively analyse the pathological, radiological and clinical features of DLB and PDD, highlighting the overlaps and differences.

Alzheimer’s disease (AD) is the most common neurodegenerative dementia. Mapping the pathomechanism and providing novel therapeutic options have paramount significance. Recent studies have proposed the role of LMTK2 in AD. However, its expression pattern and association with the pathognomonic neurofibrillary tangles (NFTs) in different brain regions and neuropathological stages of AD is not clear. We performed chromogenic (CHR) LMTK2 and fluorescent phospho-tau/LMTK2 double-labelling (FDL) immunohistochemistry (IHC) on 10–10 postmortem middle frontal gyrus (MFG) and anterior hippocampus (aHPC) samples with early and late neuropathological Braak tau stages of AD. MFG in early stage was our ‘endogenous control’ region as it is not affected by NFTs. Semiquantitative CHR-IHC intensity scoring revealed significantly higher (p < 0.001) LMTK2 values in this group compared to NFT-affected regions. FDL-IHC demonstrated LMTK2 predominance in the endogenous control region, while phospho-tau overburden and decreased LMTK2 immunolabelling were detected in NFT-affected groups (aHPC in early and both regions in late stage). Spearman’s correlation coefficient showed strong negative correlation between phospho-tau/LMTK2 signals within each group. According to our results, LMTK2 expression is inversely proportionate to the extent of NFT pathology, and decreased LMTK2 level is not a general feature in AD brain, rather it is characteristic of the NFT-affected regions.

Absztrakt: A Lewy-testes demencia (DLB) és a Parkinson-kórhoz társuló demencia (PDD) számos klinikai, patofiziológiai és morfológiai átfedést mutató neurodegeneratív kórkép. Neuropatológiai szempontból meghatározó a kóros α-szinuklein-aggregátumokat tartalmazó Lewy-testek (LB) jelenléte. DLB-ben nagyszámú LB található a corticalis régiókban, míg PDD-ben elsősorban a subcorticalis területek érintettek. Továbbá, DLB-ben gyakoribb az Alzheimer-kórra (AD) jellegzetes β-amyloid-plakkok és neurofibrillaris kötegek megjelenése. A mai napig vitatott, hogy valóban két külön betegségről vagy egyazon kórkép különböző megnyilvánulásairól van-e szó. A klinikai diagnózis alapja a motoros és a kognitív tünetek megjelenése között eltelt idő: DLB-ben a demencia gyakran a parkinsonizmus előtt jelentkezik, míg PDD-ben a motoros tünetek alakulnak ki korábban. Az egyre pontosabb képalkotó módszerek alapján DLB-ben nagyobb mértékű a corticalis károsodás, a kolinerg deficit, valamint a társuló AD-patológia, mint PDD-ben. Terápiás szempontból a PDD-ben gyakran használt levodopa DLB-ben kevésbé hatékony, sőt növelheti a pszichózis kialakulásának kockázatát, a betegség magtüneteihez tartozó hallucinációk és viselkedési tünetek kezelése pedig a jelentős antipszichotikum-hiperszenzitivitás miatt ütközik nehézségekbe. Összefoglalónkban részletesen tárgyaljuk a kórképek jellegzetességeit a patológia, a radiológia és a klinikai tünetek vonatkozásában, külön figyelmet fordítva az átfedések, valamint a különbségek bemutatására. Orv Hetil. 2020; 161(18): 727–737.

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are two major neurodegenerative diseases sharing common clinical, pathophysiological and morphologic features. The pathological hallmark of both diseases is the presence of Lewy-bodies (LB). The main constituent of these inclusions is the pathologically aggregated oc-synuclein protein. In DLB, LBs are predominantly located in the cortex, whereas in PDD, the subcortical regions are predominantly affected. Furthermore, in DLB, coexisting Alzheimer's disease (AD), pathology with (3-amyloid plaques and neurofibrillary tangles are more common. It is still debated whether DLB and PDD are two distinct entities or different phenotypes of the same disease. Clinical diagnosis is based on the temporal sequence of motor and cognitive symptoms. Dementia often precedes parkinsonism in DLB, while in PDD, cognitive decline generally appears after the onset of motor symptoms. Also, fluctuation of cognitive functions and neuroleptic sensitivity is more severe in DLB than PDD. The recent advancements of imaging techniques revealed that cortical damage, cholinergic deficit and concomitant AD pathology are more severe in DLB compared to PDD. The analysis of cerebrospinal fluid biomarkers shows higher oligomeric a-smuclein burden in PDD. Levodopa is less effective in DLB than in PDD and may increase the risk of psychosis. In this review, we comprehensively analyse the pathological, radiological and clinical features of DLB and PDD, highlighting the overlaps and differences.

Alzheimer's disease (AD) and neocortical Lewy body disease (LBD) are the most common neurodegenerative dementias, with no available curative treatment. Elucidating pathomechanism and identifying novel therapeutic targets are of paramount importance. Lemur tyrosine kinase 2 (LMTK2) is involved in several physiological and pathological cellular processes. Herewith a neuropathological characterization is presented in AD and neocortical LBD samples using chromogenic and fluorescent LMTK2 immunohistochemistry on post-mortem brain tissues and compared them to age-matched controls (CNTs). LMTK2 immunopositivity was limited to the neuronal cytoplasm. Neurons, including tau-positive tangle-bearing ones, showed decreased chromogenic and immunofluorescent labelling in AD in every cortical layer compared to CNT and neocortical LBD. Digital image analysis was performed to measure the average immunopositivity of groups. Mean grey values were calculated for each group after measuring the grey scale LMTK2 signal intensity of each individual neuron. There was significant difference between the mean grey values of CNT vs. AD and neocortical LBD vs. AD. The moderate decrease in neocortical LBD suggests the effect of coexisting AD pathology. We provide neuropathological evidence on decreased neuronal LMTK2 immunolabelling in AD, with implications for pathogenesis.

Neurodegenerative disorders are frequent, incurable diseases characterised by abnormal protein accumulation and progressive neuronal loss. Despite their growing prevalence, the underlying pathomechanism remains unclear. Lemur tyrosine kinase 2 (LMTK2) is a member of a transmembrane serine/threonine-protein kinase family. Although it was described more than a decade ago, our knowledge on LMTK2's biological functions is still insufficient. Recent evidence has suggested that LMTK2 is implicated in neurodegeneration. After reviewing the literature, we identified three LMTK2-mediated mechanisms which may contribute to neurodegenerative processes: disrupted axonal transport, tau hyperphosphorylation and enhanced apoptosis. Moreover, LMTK2 gene expression is decreased in an Alzheimer's disease mouse model. According to these features, LMTK2 might be a promising therapeutic target in near future. However, further investigations are required to clarify the exact biological functions of this unique protein.