Pyramidal system involvement in progressive supranuclear palsy - a clinicopathological correlation.

BACKGROUND: We aimed to produce a detailed neuropathological analysis of pyramidal motor system pathology and provide its clinical pathological correlation in cases with definite progressive supranuclear palsy (PSP). METHODS: Pyramidal motor system pathologies were analyzed in 18 cases with neuropathologically confirmed PSP. Based on a retrospective clinical analysis, cases were subtyped according to Movement Disorder Society criteria for clinical diagnosis of PSP as probable, possible or suggestive of PSP with Richardson's syndrome (n = 10), PSP with predominant corticobasal syndrome (n = 3), PSP with predominant parkinsonism (n = 3), PSP with predominant speech/language disorder (n = 1), and PSP with progressive gait freezing (n = 1). Clinical manifestations of motor neuron involvement (pseudobulbar or bulbar signs and spasticity) were retrospectively assessed semiquantitatively. Neuropathologically, hyperphosphorylated tau-related pyramidal motor system neuronal, neuritic, and glial pathology using anti-tau AT8 clone immunohistochemistry, was also evaluated. RESULTS: Clinical manifestations of pyramidal motor system involvement were found in patients with different PSP subtypes. A statistically significant higher load of tau pathology was found in the pyramidal system in PSP-Richardson's syndrome compared to other PSP subtypes (p = 0.016); however, there was no significant correlation between pyramidal system tau pathology and related motor clinical symptoms. CONCLUSIONS: Tau pathology in the spinal cord and pyramidal motor system structures is very common in progressive supranuclear palsy and may neuropathologically supplement the distinction between classic Richardson's syndrome from other progressive supranuclear palsy subtypes.

[Molecular pathology of lung cancer in routine diagnostic practice: 2017 update]. / Molekulární patologie plicních karcinomu pro rutinní praxi - update 2017.

The group of non-small cell lung carcinomas includes tumors that are variable at the clinical, histopathological and molecular levels. Advances in the understanding of molecular pathology of lung adenocarcinomas in particular led to changes in their histopathological classification and treatment. Patients diagnosed with lung adenocarcinoma harboring specific mutations benefit from the administration of specific targeted therapy. Analysis of EGFR gene mutations and ALK rearrangement in lung adenocarcinomas are already routinely performed and are closely related to the indication for the administration of tyrosinkinase inhibitors. Besides EGFR mutations and ALK rearrangement there are also available other potential markers for analyzing, e.g. b-raf - BRAF, ROS1. Moreover, immunotherapy needs standardization of detection of crucial molecules, namely PD-L1. The aim of this review is to summarize the role of the most relevant molecules that could also serve as the therapeutic target for practicing pathologists.

Multisite Assessment of Aging-Related Tau Astrogliopathy (ARTAG).

Aging-related tau astrogliopathy (ARTAG) is a recently introduced terminology. To facilitate the consistent identification of ARTAG and to distinguish it from astroglial tau pathologies observed in the primary frontotemporal lobar degeneration tauopathies we evaluated how consistently neuropathologists recognize (1) different astroglial tau immunoreactivities, including those of ARTAG and those associated with primary tauopathies (Study 1); (2) ARTAG types (Study 2A); and (3) ARTAG severity (Study 2B). Microphotographs and scanned sections immunostained for phosphorylated tau (AT8) were made available for download and preview. Percentage of agreement and kappa values with 95% confidence interval (CI) were calculated for each evaluation. The overall agreement for Study 1 was >60% with a kappa value of 0.55 (95% CI 0.433-0.645). Moderate agreement (>90%, kappa 0.48, 95% CI 0.457-0.900) was reached in Study 2A for the identification of ARTAG pathology for each ARTAG subtype (kappa 0.37-0.72), whereas fair agreement (kappa 0.40, 95% CI 0.341-0.445) was reached for the evaluation of ARTAG severity. The overall assessment of ARTAG showed moderate agreement (kappa 0.60, 95% CI 0.534-0.653) among raters. Our study supports the application of the current harmonized evaluation strategy for ARTAG with a slight modification of the evaluation of its severity.

Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer's disease.

Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD.

FTLD-TDP and progressive supranuclear palsy in comorbidity-a report of two cases with different clinical presentations.

Frontotemporal lobar degeneration with transactive response DNA-binding protein 43 (FTLD-TDP) and progressive supranuclear palsy (PSP) are distinct neurodegenerations with different clinical presentations. We report two cases with FTLD-TDP and PSP in comorbidity: a patient with amnestic dementia developing frontal lobe dementia, Parkinsonism and supranuclear gaze palsy and a patient with cerebellar ataxia and nystagmus developing akinesia, rigidity, and subcortical dementia. Neuropathological examination revealed neuronal and glial tau pathology together with ubiquitin, and phospho-TDP-43-immunoreactivities in the hippocampus, striatum, mesencephalon, and frontal and temporal cortices. Clinical and neuropathological correlations in atypical neurodegenerations are crucial to describe new entities of overlapping syndromes.

Shared and Distinct Patterns of Oligodendroglial Response in α-Synucleinopathies and Tauopathies.

Pathological protein deposits in oligodendroglia are common but variable features of various neurodegenerative conditions. To evaluate oligodendrocyte response in neurodegenerative diseases (NDDs) with different extents of oligodendroglial protein deposition we performed immunostaining for tubulin polymerization-promoting protein p25α (TPPP/p25α), α-synuclein (α-syn), phospho-tau, ubiquitin, myelin basic protein, and the microglial marker HLA-DR. We investigated cases of multiple system atrophy ([MSA] n = 10), Lewy body disease ([LBD] n = 10), globular glial tauopathy ([GGT] n = 7) and progressive supranuclear palsy ([PSP] n = 10). Loss of nuclear TPPP/p25α immunoreactivity correlated significantly with the degree of microglial reaction and loss of myelin basic prtein density as a marker of tract degeneration. This was more prominent in MSA and GGT, which, together with enlarged cytoplasmic TPPP/p25α immunoreactivity and inclusion burden allowed these disorders to be grouped as predominant oligodendroglial proteinopathies. However, distinct features, ie more colocalization of α-syn than tau with TPPP/p25α, more obvious loss of oligodendrocyte density in MSA, but more prominent association of tau protein inclusions in GGT to loss of nuclear TPPP/p25α immunoreactivity, were also recognized. In addition, we observed previously underappreciated oligodendroglial α-synuclein pathology in the pallidothalamic tract in LBD. Our study demonstrates common and distinct aspects of oligodendroglial involvement in the pathogenesis of diverse NDDs.

[The autopsy of the brain and spinal cord in the diagnosis of neurodegenerative diseases - a practical approach to optimize the examination]. / Pitva mozku a míchy pri diagnóze neurodegenerativního onemocnení - praktický postup pro optimalizaci vysetrení.

Brain and spinal cord autopsies aimed at neuropathological diagnosis of the causes of dementia and motor abnormalities are of increasing importance. Neuropathological brain examination is often the only diagnostic modality capable of definitive diagnosis of a neurodegenerative disease and thus serves as invaluable feedback for clinicians and biochemical and imaging diagnostics. The brain and spinal cord autopsy is performed following a standardized protocol and its goal is to sample all diagnostically relevant structures. Subsequent diagnostics are then done using standard and special histologic stainings, however state-of-the-art diagnostics can be achieved only using immunohistochemical methods. The purpose of the article is to provide the pathologists with a brief and practical guideline for brain and spinal cord autopsy when diagnosis of a neurodegenerative disease is suspected.

Rare Variants in PLD3 Do Not Affect Risk for Early-Onset Alzheimer Disease in a European Consortium Cohort.

Rare variants in the phospholipase D3 gene (PLD3) were associated with increased risk for late-onset Alzheimer disease (LOAD). We identified a missense mutation in PLD3 in whole-genome sequence data of a patient with autopsy confirmed Alzheimer disease (AD) and onset age of 50 years. Subsequently, we sequenced PLD3 in a Belgian early-onset Alzheimer disease (EOAD) patient (N = 261) and control (N = 319) cohort, as well as in European EOAD patients (N = 946) and control individuals (N = 1,209) ascertained in different European countries. Overall, we identified 22 rare variants with a minor allele frequency <1%, 20 missense and two splicing mutations. Burden analysis did not provide significant evidence for an enrichment of rare PLD3 variants in EOAD patients in any of the patient/control cohorts. Also, meta-analysis of the PLD3 data, including a published dataset of a German EOAD cohort, was not significant (P = 0.43; OR = 1.53, 95% CI 0.60-3.31). Consequently, our data do not support a role for PLD3 rare variants in the genetic etiology of EOAD in European EOAD patients. Our data corroborate the negative replication data obtained in LOAD studies and therefore a genetic role of PLD3 in AD remains to be demonstrated.

Proteinase-activated receptor 2 and disease biomarkers in cerebrospinal fluid in cases with autopsy-confirmed prion diseases and other neurodegenerative diseases.

BACKGROUND: Proteinase-activated receptor 2 (PAR-2) has been shown to promote both neurotoxic and neuroprotective effects. Similarly, other routinely used nonspecific markers of neuronal damage can be found in cerebrospinal fluid (CSF) and can be used as biomarkers for different neurodegenerative disorders. METHODS: Using enzyme-linked immunosorbent assays and western blotting we assessed PAR-2, total-tau, phospho-tau, beta-amyloid levels, and protein 14-3-3 in the CSF of former patients who had undergone a neuropathological autopsy after death and who had been definitively diagnosed with a prion or other neurodegenerative disease. RESULTS: We did not find any significant correlation between levels of PAR-2 and other biomarkers, nor did we find any differences in PAR-2 levels between prion diseases and other neurodegenerative conditions. However, we confirmed that very high total-tau levels were significantly associated with definitive prion diagnoses and exhibited greater sensitivity and specificity than protein 14-3-3, which is routinely used as a marker. CONCLUSIONS: Our study showed that PAR-2, in CSF, was not specifically altered in prion diseases compared to other neurodegenerative conditions. Our results also confirmed that very high total-tau protein CSF levels were significantly associated with a definitive Creutzfeldt-Jakob disease (CJD) diagnosis and should be routinely tested as a diagnostic marker. Observed individual variability in CSF biomarkers provide invaluable feedback from neuropathological examinations even in "clinically certain" cases.

Genetic variability in SQSTM1 and risk of early-onset Alzheimer dementia: a European early-onset dementia consortium study.

Meta-analysis of existing genome-wide association studies on Alzheimer's disease (AD) showed subgenome-wide association of an intronic variant in the sequestosome 1 (SQSTM1) gene with AD. We performed targeted resequencing of SQSTM1 in Flanders-Belgian AD patients selected to be enriched for a genetic background (n = 435) and geographically matched nonaffected individuals (n = 872) to investigate the role of both common and rare SQSTM1 variants. Results were extended to the European early-onset dementia cohorts (926 early-onset Alzheimer's disease [EOAD] patients and 1476 nonaffected individuals). Of the 61 detected exonic variants in SQSTM1, the majority were rare (n = 57). Rare variant (minor allele frequency <0.01) burden analysis did not reveal an increased frequency of rare variants in EOAD patients in any of the separate study populations nor when meta-analyzing all cohorts. Common variants p.D292= and p.R312= showed nominal association with AD (odds ratiop.D292= = 1.11 [95% confidence interval = 1-1.22], p = 0.04), only when including the Flanders-Belgian cohort in the meta-analysis. We cannot exclude a role of SQSTM1 genetic variability in late-onset AD, but our data indicate that SQSTM1 does not play a major role in the etiology of EOAD.

The contribution of proteinase-activated receptors to intracellular signaling, transcellular transport and autophagy in Alzheimer's disease.

The etiopathogenesis of Alzheimer´s disease is characterized by beta amyloid Aß(1-42) toxic fragment aggregation and its association with impaired autophagy. In mitochondria, chronic damage due to transport and enzymatic processes together with the production of reactive oxygen species (ROS) are followed by the subsequent accumulation of Aß in the form of senile plaques and the accumulation of hyperphosphorylated tau protein in intracellular deposits called tangles. Proteinase-activated receptors (PARs), members of the G protein-coupled receptor (GPCR) family, facilitate and modulate the transcellular transport and distribution of a variety of subcellular molecular components to the lysosomal system and, thus, influence their degradation. A review of the data shows that the activation or inhibition of PARs leads to changes in the process of autophagy, which may influence ROS production and Aß (1-42) degradation in lysosomes and result in AD pathogenesis.

Oligodendroglial response in the spinal cord in TDP-43 proteinopathy with motor neuron involvement.

BACKGROUND: TDP-43 proteinopathies represent a spectrum of neurodegenerative disorders. Variable clinical presentations including frontotemporal dementia, amyotrophic lateral sclerosis (ALS) and mixed forms are associated with the spatial heterogeneity of the TDP-43 pathology. Recent studies have emphasized the role of oligodendrocytes in the pathogenesis of ALS. OBJECTIVE: To evaluate whether TDP-43 proteinopathies are associated with an oligodendroglial response. METHODS: We performed a study on 7 controls and 10 diseased patients with spinal cord involvement. Using the oligodendroglia-specific antibody TPPP/p25, we assessed oligodendrocyte density in the lateral corticospinal tracts (LCSs) along with the presence of perineuronal oligodendrocytes (PNOGs) in the anterior horns. We performed a densitometry of myelin basic protein (MBP) immunoreactivity. The numbers of TDP-43 and p62 immunoreactive inclusions were counted in both the LCSs and the anterior horns. RESULTS: Double immunolabeling confirmed that oligodendrocytes harbor TDP-43 inclusions. In the LCSs, MBP density, but not the number of oligodendrocytes, was decreased in the diseased group. However, oligodendrocyte counts in the LCS correlated positively, and the density of MBP inversely, with the number of neuronal inclusions in the anterior horn, suggestive of a compensatory response of oligodendrocytes. The number of neurons with PNOGs correlated with the amount of inclusions. CONCLUSION: Our study further emphasizes the importance of oligodendroglia in the pathogenesis of TDP-43 proteinopathies with spinal cord involvement.

[Molecular pathology of pulmonary carcinomas]. / Molekulární patologie plicních karcinomu

The group of non-small cell lung carcinomas includes tumors that are variable at the clinical, histopathological and molecular levels. Advances in the understanding of molecular pathology of lung adenocarcinomas in particular has led to changes in their histopathological classification and treatment. Patients diagnosed with lung adenocarcinoma harboring specific mutations benefit from the administration of specific targeted therapy. Therefore, pathologists closely involved in the diagnostics of lung tumors significantly contribute to the diagnostic-therapeutical algorithm. Analysis of EGFR gene mutations in lung adenocarcinomas is already routinely performed and the presence of activating mutations in EGFR is the main indication for the administration of tyrosinkinase inhibitors. Besides EGFR mutations, EML4-ALK rearrangement is also being analysed and there is potential in analysing BRAF mutations as well. The aim of this review is to summarize the role of the most relevant molecules that also serve as the therapeutic target for practicing pathologists.

Current concepts in the classification and diagnosis of frontotemporal lobar degenerations: a practical approach.

Frontotemporal lobar degenerations are clinically, genetically, and molecularly heterogeneous diseases characterized by mainly frontal and temporal atrophy and affecting behavioral, language, cognitive, and motor functions. The term frontotemporal dementia incorporates 3 distinct clinical syndromes seen in frontotemporal degenerations: behavioral variant of frontotemporal dementia, progressive nonfluent aphasia, and semantic dementia. Progressive supranuclear palsy syndrome, corticobasal syndrome, and motor neuron disease syndrome are also associated with frontotemporal lobar degenerations. The neuropathologic hallmark of frontotemporal lobar degenerations is accumulation of abnormal proteins in the cytoplasm and nuclei of neurons and glial cells. Proteins involved in pathologic processes that represent the basis for frontotemporal lobar degeneration classification are tau protein, transactive response DNA-binding protein of 43 kDa, and "fused in sarcoma" protein. The aim of this review is to provide a summary of practical approaches for neuropathologic diagnostics of the rapidly evolving classifications of frontotemporal lobar degenerations.

Corticotropin-releasing hormone affects short immobilization stress-induced changes in lung cytosolic and membrane glucocorticoid binding sites.

Glucocorticoids act via glucocorticoid receptors (GR), typically localized in the cytosol (cGR). Rapid action is probably mediated via membrane receptors (mGR). In corticotropin-releasing hormone knockouts (CRH-KO), basal plasma glucocorticoid levels do differ from wild type levels (WT), but are approximately ten times lower during exposure to immobilization stress (IMMO) in comparison to WT. We tested the following hypotheses: (1) the mice lung tissue GR basal numbers would not be changed in CRH-KO (because of similar glucocorticoid levels), (2) the number of GR would be changed in WT but not in KO during short (30, 90, and 120 min) IMMO (because of higher increase of glucocorticoid levels in WT). The basal levels of cGR were not changed in CRH-KO (compared to WT), while mGR were significantly lower (62 %) in CRH-KO. In WT, there was the only decrease (to 32 %) in cGR after 120 min when we also found an increase in mGR in WT (to 201 %). In CRH-KO, IMMO caused gradual decrease in cGR (to 52 % after 30 min, to 46 % after 90 min, and to 32 % after 120 min). In CRH-KO, the only increase in mGR appeared already at 30 min of IMMO. These data suggest, on the contrary to our hypotheses, that CRH-KO are more susceptible to GR changes in early phases of stress.