Cerebrospinal fluid P-tau(181P):biomarker for improved differential dementia diagnosis

The goal of this study is to investigate the value of tau phosphorylated at threonine 181 (P-tau(181p)) in the Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker panel for differential dementia diagnosis in autopsy confirmed AD and non-AD patients. The study population consisted of 140 autopsy confirmed AD and 77 autopsy confirmed non-AD dementia patients. CSF concentrations of amyloid-beta peptide of 42 amino acids (A(beta 1-42)), total tau protein (T-tau), and P-tau(181p) were determined with single analyte ELISA-kits (INNOTEST, Fujirebio, Ghent, Belgium). Diagnostic accuracy was assessed through receiver operating characteristic (ROC) curve analyses to obtain area under the curve (AUG) values and to define optimal cutoff values to discriminate AD from pooled and individual non-AD groups. ROC curve analyses were only performed on biomarkers and ratios that differed significantly between the groups. Pairwise comparison of AUG values was performed by means of DeLong tests. The A(beta 1-42)/P-tau(181p) ratio (AUG = 0.770) performed significantly better than A(beta 1-42) (AUG = 0.677, P = 0.004), T-tau (AUG = 0.592, P <0.001), and A beta(1-42)/T-tau (AUG = 0.678, P = 0.001), while Ptau(181p) (AUG = 0.720) performed significantly better than T-tau (AUG = 0.592, P <0.001) to discriminate between AD and the pooled non-AD group. When comparing AD and the individual non-AD diagnoses, A beta(1-42)/P-tau(181P) (AUG =0.894) discriminated AD from frontotemporal dementia significantly better than A(beta 1-42) (AUG = 0.776, P = 0.020) and T-tau (AUG = 0.746, P = 0.004), while P-tauisip/T-tau (AUG = 0.958) significantly improved the differentiation between AD and Creutzfeldt-Jakob disease as compared to A beta(1-42) (AUG = 0.688, P = 0.004), T-tau (AUG = 0.874, P = 0.040), and A beta(1-42)/P-tau(181P) (AUG = 0.760, P = 0.003). In conclusion, this study demonstrates P-tau(181P) P is an essential component of the AD CSF biomarker panel, and combined assessment of A beta(1-42), Ttau, and P-tau(181p) renders, to present date, the highest diagnostic power to discriminate between AD and non-AD dementias

Primary Human Testicular Cells Self-Organize into Organoids with Testicular Properties.

So far, successful de novo formation of testicular tissue followed by complete spermatogenesis in vitro has been achieved only in rodents. Our findings reveal that primary human testicular cells are able to self-organize into human testicular organoids (TOs), i.e., multi-cellular tissue surrogates, either with or without support of a biological scaffold. Despite lacking testis-specific topography, these mini-tissues harbored spermatogonia and their important niche cells, which retained specific functionalities during long-term culture. These observations indicate the posibility of in vitro re-engineering of a human testicular microenvironment from primary cells. Human TOs might help in the development of a biomimetic testicular model that would exert a tremendous impact on research and development, clinical treatment of infertility, and screening in connection with drug discovery and toxicology

Diagnostic impact of cerebrospinal fluid biomarker (pre-)analytical variability in Alzheimers disease

Intra- and inter-laboratory variability of cerebrospinal fluid (CSF) biomarker analyses remains an important issue. We investigated the clinical-diagnostic impact of CSF biomarker concentration shifts in mild cognitive impairment (MCI) and autopsy-confirmed Alzheimer’s disease (AD) dementia patients. MCI patients (n = 85), autopsy-confirmed AD dementia patients (n = 72), and cognitively healthy controls (n = 100) were included in this prospective, longitudinal study. AD dementia patients were followed up until death, and controls were included from 1992 until 2003. In-house validated cutoff values of biomarkers were applied: Aβ(1-42) <638.5 pg/mL, T-tau>296.5 pg/mL, P-tau(181P) >56.5 pg/mL. Both increments and decrements (from ± 5% to ± 40% ) were added to the true (=observed) CSF biomarker values, imitating the anticipated differences in biomarker concentrations. Within certain limits, the clinical diagnostic performance of AD CSF biomarkers remains largely unchanged and clinical diagnostic accuracy deviated less than 8.2% from the reference when concentration shifts ranging between –20% and +20% were added to one of the three CSF biomarkers in MCI and autopsy-confirmed AD patients. Notwithstanding the fact that (pre- and post-)analytical parameters can affect the clinical classification, the present exploratory study provides evidence that for a specific context of use, the impact on clinical accuracy of biomarker concentration shifts might be lower than originally expected. In conclusion, induced shifts of ±20% in only one of the three biomarkers has limited impact on the clinical accuracy of AD CSF biomarkers in MCI and autopsy-confirmed AD patients when using the IWG-2 criteria

TDP-43 as a possible biomarker for frontotemporal lobar degeneration : a systematic review of existing antibodies

Frontotemporal lobar degeneration (FTLD) is one of the leading causes of dementia after Alzheimer’s disease. A high-ranking candidate to become a diagnostic marker for a major pathological subtype of FTLD is the transactive response DNA binding protein of 43 kDa (TDP-43). The main objective is to elucidate which antibodies are specific for pathological TDP-43, with special interest in its modified isoforms. Indeed, TDP-43 has been shown to be hyperphosphorylated and truncated in disease. A secondary objective is to review existing immunoassays that quantify TDP-43 in biofluids. A systematic review of literature was performed by searching PubMed and Web of Science using predefined keywords. Of considered research papers the methods section was reviewed to select publications that enabled us to answer our learning objective. After quality assessment, antibody characteristics and related outcomes were extracted. We identified a series of well-characterized antibodies based on a scoring system that assessed the ability of each antibody to detect TDP-43 pathology. A selection of 29 unique antibodies was made comprising 10 high-ranking antibodies which were reported multiple times to detect TDP-43 pathology in both immunostaining and immunoblotting experiments and 19 additional antibodies which detected TDP-43 pathology but were only scored once. This systematic review provides an overview of antibodies that are reported to detect pathological TDP-43. These antibodies can be used in future studies of TDP-43 proteinopathies. Additionally, selected antibodies hold the potential to be used in the development of novel immunoassays for the quantification of TDP-43 in biofluids, as a possible biomarker for FTLD-TDP. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-015-0195-1) contains supplementary material, which is available to authorized users

TSPO PET upregulation predicts epileptic phenotype at disease onset independently from chronic TSPO expression in a rat model of temporal lobe epilepsy

Neuroinflammation is a key component of epileptogenesis, the process leading to acquired epilepsy. In recent years, with the development of non-invasive in vivo positron emission tomography (PET) imaging of translocator protein 18 kDa (TSPO), a marker of neuroinflammation, it has become possible to perform longitudinal studies to characterize neuroinflammation at different disease stages in animal models of epileptogenesis. This study aimed to utilize the prognostic capability of TSPO PET imaging at disease onset (2 weeks post-SE) to categorize epileptic rats with distinct seizure burden based on TSPO levels at disease onset and investigate their association to TSPO expression at the chronic epilepsy stage. Controls (n = 14) and kainic acid-induced status epilepticus (KASE) rats (n = 41) were scanned non-invasively with [18F]PBR111 PET imaging measuring TSPO expression. Animals were monitored using video-electroencephalography (vEEG) up to chronic disease (12 weeks post-SE), at which TSPO levels ([3H]PK11195) as well as other post-mortem abnormalities (namely synaptic density ([3H]UCB-J), neuronal loss (NeuN), and neurodegeneration (FjC)) were investigated. By applying multivariate analysis, TSPO PET imaging at disease onset identified three KASE groups with significantly different spontaneous recurrent seizures (SRS) burden (defined as rare SRS, sporadic SRS, and frequent SRS) (p = 0.003). Interestingly, TSPO levels were significantly different when comparing the three KASE groups (p < 0.0001), with the frequent SRS group characterized only by a limited focal TSPO increase at disease onset. On the contrary, TSPO measured during chronic epilepsy was found to be the highest in the frequent SRS group and correlated with seizure burden (r = 0.826, p < 0.0001). Importantly, early and chronic TSPO levels did not correlate (r = −0.05). Finally, significant pathological changes in neuronal loss, synaptic density, and neurodegeneration were found not only when compared to control animals (p < 0.01), but also between the three KASE rat categories in the hippocampus (p < 0.05). Early and chronic TSPO upregulation following epileptogenic insult appear to be driven by two superimposed dynamic processes. The former is associated with epileptogenesis as measured at disease onset, while the latter is related to seizure frequency as quantified during chronic epilepsy