Pathogenesis of Alzheimer's disease: Involvement of the choroid plexus.

The choroid plexus (ChP) produces and is bathed in the cerebrospinal fluid (CSF), which in aging and Alzheimer's disease (AD) shows extensive proteomic alterations including evidence of inflammation. Considering inflammation hampers functions of the involved tissues, the CSF abnormalities reported in these conditions are suggestive of ChP injury. Indeed, several studies document ChP damage in aging and AD, which nevertheless remains to be systematically characterized. We here report that the changes elicited in the CSF by AD are consistent with a perturbed aging process and accompanied by aberrant accumulation of inflammatory signals and metabolically active proteins in the ChP. Magnetic resonance imaging (MRI) imaging shows that these molecular aberrancies correspond to significant remodeling of ChP in AD, which correlates with aging and cognitive decline. Collectively, our preliminary post-mortem and in vivo findings reveal a repertoire of ChP pathologies indicative of its dysfunction and involvement in the pathogenesis of AD. HIGHLIGHTS: Cerebrospinal fluid changes associated with aging are perturbed in Alzheimer's disease Paradoxically, in Alzheimer's disease, the choroid plexus exhibits increased cytokine levels without evidence of inflammatory activation or infiltrates In Alzheimer's disease, increased choroid plexus volumes correlate with age and cognitive performance.

COVID-19-free workplace: Measuring the level of antibodies against coronavirus as a basis for testing strategy in companies.

The Czech Republic is one of the countries most affected by the coronavirus pandemic - approximately 16% of the population had a positive PCR test, 2-3 times more people underwent infection without undergoing this examination. It is particularly useful for employers to know how many employees have already contracted the infection and for how many people are still at risk of the coronavirus infection. For this purpose, it is appropriate to examine IgG antibodies. However, the testing strategy is different at present - antigen testing is mandatory to look for infectious individuals, regardless of human immunity. The aim of the pilot study was to determine the number of immune individuals after infection at three clinics of GENNET s.r.o. At the same time, unvaccinated individuals who had not had COVID-19 or had undergone it more than three months ago were tested with antigen tests. The cohort included 297 subjects, of whom 182 were not vaccinated (61.3 %) and 115 subjects (38.7 %) were after the vaccination. Of the unvaccinated, 71 people had in the past a positive PCR test (39 %), another 18 people had positive IgG antibodies without infection (9.9 %) and 38 people (20.9 %) had negative IgG antibodies. So far, 55 persons (30.2 %) have not been examined. If we add people vaccinated and people with antibodies, then 74.3 % of employees of the GENNET Archa clinic, 68 % of employees from the GENNET Kostelní clinic and 58.1 % from the GENNET Liberec clinic were immune to infection. 153 individuals on average (60 of whom had antibodies) were tested for the antigen test in four rounds. The infection was detected in two people. Both belonged to the group without tested antibodies. No person with antibodies was tested positive for antigen. People who have antibodies after vaccination or infection are substantially less prone to infection and have a low risk of continuing to spread the virus. By examining antibodies, employers will gain a better overview of the situation in the workplace. Based on our study, we recommend including antibody testing into antiepidemic measures and limit antigen testing to seronegative individuals.

Association between genetic variability of neuronal nitric oxide synthase and sensorimotor gating in humans.

Research increasingly suggests that nitric oxide (NO) plays a role in the pathogenesis of schizophrenia. One important line of evidence comes from genetic studies, which have repeatedly detected an association between the neuronal isoform of nitric oxide synthase (nNOS or NOS1) and schizophrenia. However, the pathogenetic pathways linking nNOS, NO, and the disorder remain poorly understood. A deficit in sensorimotor gating is considered to importantly contribute to core schizophrenia symptoms such as psychotic disorganization and thought disturbance. We selected three candidate nNOS polymorphisms (Ex1f-VNTR, rs6490121 and rs41279104), associated with schizophrenia and cognition in previous studies, and tested their association with the efficiency of sensorimotor gating in healthy human adults. We found that risk variants of Ex1f-VNTR and rs6490121 (but not rs41279104) were associated with a weaker prepulse inhibition (PPI) of the acoustic startle reflex, a standard measure of sensorimotor gating. Furthermore, the effect of presence of risk variants in Ex1f-VNTR and rs6490121 was additive: PPI linearly decreased with increasing number of risk alleles, being highest in participants with no risk allele, while lowest in individuals who carry three risk alleles. Our findings indicate that NO is involved in the regulation of sensorimotor gating, and highlight one possible pathogenetic mechanism for NO playing a role in the development of schizophrenia psychosis.

The definitions of three-dimensional landmarks on the human face: an interdisciplinary view.

The analysis of shape is a key part of anatomical research and in the large majority of cases landmarks provide a standard starting point. However, while the technology of image capture has developed rapidly and in particular three-dimensional imaging is widely available, the definitions of anatomical landmarks remain rooted in their two-dimensional origins. In the important case of the human face, standard definitions often require careful orientation of the subject. This paper considers the definitions of facial landmarks from an interdisciplinary perspective, including biological and clinical motivations, issues associated with imaging and subsequent analysis, and the mathematical definition of surface shape using differential geometry. This last perspective provides a route to definitions of landmarks based on surface curvature, often making use of ridge and valley curves, which is genuinely three-dimensional and is independent of orientation. Specific definitions based on curvature are proposed. These are evaluated, along with traditional definitions, in a study that uses a hierarchical (random effects) model to estimate the error variation that is present at several different levels within the image capture process. The estimates of variation at these different levels are of interest in their own right but, in addition, evidence is provided that variation is reduced at the observer level when the new landmark definitions are used.

Craniofacial dysmorphology in 22q11.2 deletion syndrome by 3D laser surface imaging and geometric morphometrics: illuminating the developmental relationship to risk for psychosis.

Persons with 22q11.2 deletion syndrome (22q11.2DS) are characterized inter alia by facial dysmorphology and greatly increased risk for psychotic illness. Recent studies indicate facial dysmorphology in adults with schizophrenia. This study evaluates the extent to which the facial dysmorphology of 22q11.2DS is similar to or different from that evident in schizophrenia. Twenty-one 22q11.2DS-sibling control pairs were assessed using 3D laser surface imaging. Geometric morphometrics was applied to 30 anatomical landmarks, 480 geometrically homologous semi-landmarks on curves and 1720 semi-landmarks interpolated on each 3D facial surface. Principal component (PC) analysis of overall shape space indicated PC2 to strongly distinguish 22q11.2DS from controls. Visualization of PC2 indicated 22q11.2DS and schizophrenia to be similar in terms of overall widening of the upper face, lateral displacement of the eyes/orbits, prominence of the cheeks, narrowing of the lower face, narrowing of nasal prominences and posterior displacement of the chin; they differed in terms of facial length (increased in 22q11.2DS, decreased in schizophrenia), mid-face and nasal prominences (displaced upwards and outwards in 22q11.2DS, less prominent in schizophrenia); lips (more prominent in 22q11.2DS; less prominent in schizophrenia) and mouth (open mouth posture in 22q11.2DS; closed mouth posture in schizophrenia). These findings directly implicate dysmorphogenesis in a cerebral-craniofacial domain that is common to 22q11.2DS and schizophrenia and which may repay further clinical and genetic interrogation in relation to the developmental origins of psychotic illness.

Anatomical curve identification.

Methods for capturing images in three dimensions are now widely available, with stereo-photogrammetry and laser scanning being two common approaches. In anatomical studies, a number of landmarks are usually identified manually from each of these images and these form the basis of subsequent statistical analysis. However, landmarks express only a very small proportion of the information available from the images. Anatomically defined curves have the advantage of providing a much richer expression of shape. This is explored in the context of identifying the boundary of breasts from an image of the female torso and the boundary of the lips from a facial image. The curves of interest are characterised by ridges or valleys. Key issues in estimation are the ability to navigate across the anatomical surface in three-dimensions, the ability to recognise the relevant boundary and the need to assess the evidence for the presence of the surface feature of interest. The first issue is addressed by the use of principal curves, as an extension of principal components, the second by suitable assessment of curvature and the third by change-point detection. P-spline smoothing is used as an integral part of the methods but adaptations are made to the specific anatomical features of interest. After estimation of the boundary curves, the intermediate surfaces of the anatomical feature of interest can be characterised by surface interpolation. This allows shape variation to be explored using standard methods such as principal components. These tools are applied to a collection of images of women where one breast has been reconstructed after mastectomy and where interest lies in shape differences between the reconstructed and unreconstructed breasts. They are also applied to a collection of lip images where possible differences in shape between males and females are of interest.

Visual image retention does not contribute to modulation of event-related potentials by mental rotation.

Rotation of a visual image in mind is associated with a slow posterior negative deflection of the event-related potential (ERP), termed rotation-related negativity (RRN). Retention of a visual image in short-term memory is also associated with a slow posterior negative ERP, termed negative slow wave (NSW). We tested whether short-term memory retention, indexed by the NSW, contributes to the RRN. ERPs were recorded in the same subjects in two tasks, a mental rotation task, eliciting the RRN, and a visual short-term memory task, eliciting the NSW. Over both right and left parietal scalp, no association was found between the NSW and the RRN amplitudes. Furthermore, adjusting for the effect of the NSW had no influence on a significant association between the RRN amplitude and response time, an index of mental rotation performance. Our data indicate that the RRN reflects manipulation of a visual image but not its retention in short-term memory.

Sensitivity of Individual and Composite Test Scores from the Cogstate Brief Battery to Mild Cognitive Impairment and Dementia Due to Alzheimer's Disease.

BACKGROUND: The Cogstate Brief Battery (CBB) is a computerized cognitive test battery used commonly to identify cognitive deficits related to Alzheimer's disease (AD). However, AD and normative samples used to understand the sensitivity of the CBB to AD in the clinic have been limited, as have the outcome measures studied. OBJECTIVE: This study investigated the sensitivity of CBB outcomes, including potential composite scores, to cognitive impairment in mild cognitive impairment (MCI) and dementia due to AD, in carefully selected samples. METHODS: Samples consisted of 4,871 cognitively unimpaired adults and 184 adults who met clinical criteria for MCI (Clinical Dementia Rating (CDR) = 0.5) or dementia (CDR > 0.5) due to AD and CBB naive. Speed and accuracy measures from each test were examined, and theoretically- and statistically-derived composites were created. Sensitivity and specificity of classification of cognitive impairment were compared between outcomes. RESULTS: Individual CBB measures of learning and working memory showed high discriminability for AD-related cognitive impairment for CDR 0.5 (AUCs ∼ 0.79-0.88), and CDR > 0.5 (AUCs ∼ 0.89-0.96) groups. Discrimination ability for theoretically derived CBB composite measures was high, particularly for the Learning and Working Memory (LWM) composite (CDR 0.5 AUC = 0.90, CDR > 0.5 AUC = 0.97). As expected, statistically optimized linear composite measures showed strong discrimination abilities albeit similar to the LWM composite. CONCLUSIONS: In older adults, the CBB is effective for discriminating cognitive impairment due to MCI or AD-dementia from unimpaired cognition with the LWM composite providing the strongest sensitivity.

Technical note: a novel geometric morphometric approach to the study of long bone shape variation.

Procrustes-based geometric morphometrics (GM) is most often applied to problems of craniofacial shape variation. Here, we demonstrate a novel application of GM to the analysis of whole postcranial elements in a study of 77 hominoid tibiae. We focus on two novel methodological improvements to standard GM approaches: 1) landmark configurations of tibiae including 15 epiphyseal landmarks and 483 semilandmarks along articular surfaces and muscle insertions along the tibial shaft and 2) an artificial affine transformation that sets moments along the shaft equal to the sum of the moments estimated in the other two anatomical directions. Diagrams of the principal components of tibial shapes support most differences between human and non-human primates reported previously. The artificial affine transformation proposed here results in an improved clustering of the great apes that may prove useful in future discriminant or clustering studies. Since the shape variations observed may be related to different locomotor behaviors, posture, or activity patterns, we suggest that this method be used in functional analyses of tibiae or other long bones in modern populations or fossil specimens.

Enriched environment ameliorates propagation of tau pathology and improves cognition in rat model of tauopathy.

Introduction: The typical symptoms of Alzheimer's disease (AD) are cognitive impairment, disrupted spatial orientation, behavioral and psychiatric abnormalities, and later motor deficits. Neuropathologically, AD is characterized by deposits of pathological forms of endogenous proteins - amyloid-ß, and neurofibrillary tau protein pathology. The latter closely correlates with brain atrophy and clinical impairment. Pharmacological therapies for these pathologies are largely absent, raising the question whether non-pharmacological interventions could be efficacious. Environmental factors can play a role in the manifestation of AD. It is unknown whether enriched environment (EE) can ameliorate the propagation of protein aggregates or their toxic components. Methods: We injected insoluble tau extracts from human brains with AD (600 or 900 ng per animal) into hippocampi of SHR72 transgenic rats that express non-mutated truncated human tau 151-391/4R, but usually do not develop hippocampal tangles. The rats had either standard housing, or could access an EE 5×/week for 3 months. Behavioral analysis included the Morris Water Maze (MWM). Histological analysis was used to assess the propagation of tau pathology. Results: Animals exposed to EE performed better in the MWM (spatial acquisition duration and total distance, probe test); unexposed animals improved over the course of acquisition trials, but their mean performance remained below that of the EE group. Enriched environment abrogated tau propagation and hippocampal tangle formation in the 600 ng group; in the 900 ng group, tangle formation was ∼10-fold of the 600 ng group, and unaffected by EE. Conclusion: Even a small difference in the amount of injected human AD tau can cause a pronounced difference in the number of resulting tangles. EE leads to a noticeably better spatial navigation performance of tau-injected animals. Furthermore, EE seems to be able to slow down tau pathology progression, indicating the possible utility of similar interventions in early stages of AD where tangle loads are still low.

Quantitative assessment of interproximal wear facet outlines for the association of isolated molars.

The determination of the minimum number of individuals can be very challenging, especially in an assemblage of fragmentary bones and isolated teeth. Similarities in tooth morphology, degree of wear, and interproximal wear facets (IPWF) are generally used to associate isolated teeth qualitatively. However, no quantitative method has yet been established for an objective identification and matching of isolated tooth crowns. In this study, we analyze the IPWF morphology of adjacent mandibular molars (17 M(1)/M(2) pairs), applying both qualitative and quantitative methods to test a reproducible approach for crown association. The surfaces of distal (for M(1)) and mesial (for M(2)) IPWF were surface-scanned and digitally selected. Three-dimensional (3D) and two-dimensional (2D) outlines of IPWF were analyzed using elliptic Fourier analysis (EFA) and geometric morphometrics methods (GMM). Additionally, teeth were qualitatively associated by visual evaluation of the IPWF outline and by physical matching. Unsatisfactory results with less than 50% of tooth pairs correctly associated were obtained by using both methods, shape analysis (digital approach) and the visual evaluation (qualitative assessment) of the IPWF outline. The physical matching of the crowns showed highly variable accuracy ranging between 53% and 77%. The quantitative form-space analysis of 2D IPWF outlines provided the best results (82% of correctly associated teeth), but no statistically significant differences were recorded when compared with the manual matching. Since three tooth pairs out of 17 could not be quantitatively associated, we suggest that the quantitative analysis of IPWF should be used only in addition with other approaches.

Comparison of dental measurement systems for taxonomic assignment of first molars.

Morphometrics of the molar crown is based traditionally on diameter measurements but is nowadays more often based on 2D image analysis of crown outlines. An alternative approach involves measurements at the level of the cervical line. We compare the information content of the two options in a three-dimensional (3D) digital sample of lower and upper first molars (M(1) and M(1) ) of modern human and Neanderthal teeth. The cervical outline for each tooth was created by digitizing the cervical line and then sectioning the tooth with a best fit plane. The crown outline was projected onto this same plane. The curves were analyzed by direct extraction of diameters, diagonals, and area and also by principal component analysis either of the residuals obtained by regressing out these measurements from the radii (shape information) or directly by the radii (size and shape information). For M(1) , the crown and cervical outline radii allow us to discriminate between Neanderthals and modern humans with 90% and 95% accuracy, respectively. Fairly good discrimination between the groups (80-82.5%) was also obtained using cervical measurements. With respect to M(1) , general overlap of the two groups was obtained by both crown and cervical measurements; however, the two taxa were differentiable by crown outline residuals (90-97%). Accordingly, while crown diameters or crown radii should be used for taxonomic analysis of unworn or slightly worn M(1) s, the crown outline, after regressing out size information, could be promising for taxonomic assignment of lower M1s.

Functional data analysis and visualisation of three-dimensional surface shape.

The advent of high-resolution imaging has made data on surface shape widespread. Methods for the analysis of shape based on landmarks are well established but high-resolution data require a functional approach. The starting point is a systematic and consistent description of each surface shape and a method for creating this is described. Three innovative forms of analysis are then introduced. The first uses surface integration to address issues of registration, principal component analysis and the measurement of asymmetry, all in functional form. Computational issues are handled through discrete approximations to integrals, based in this case on appropriate surface area weighted sums. The second innovation is to focus on sub-spaces where interesting behaviour such as group differences are exhibited, rather than on individual principal components. The third innovation concerns the comparison of individual shapes with a relevant control set, where the concept of a normal range is extended to the highly multivariate setting of surface shape. This has particularly strong applications to medical contexts where the assessment of individual patients is very important. All of these ideas are developed and illustrated in the important context of human facial shape, with a strong emphasis on the effective visual communication of effects of interest.

ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1, an active immunotherapy against pathological tau in Alzheimer's disease.

Alzheimer's disease (AD) pathology is partly characterized by accumulation of aberrant forms of tau protein. Here we report the results of ADAMANT, a 24-month double-blinded, parallel-arm, randomized phase 2 multicenter placebo-controlled trial of AADvac1, an active peptide vaccine designed to target pathological tau in AD (EudraCT 2015-000630-30). Eleven doses of AADvac1 were administered to patients with mild AD dementia at 40 µg per dose over the course of the trial. The primary objective was to evaluate the safety and tolerability of long-term AADvac1 treatment. The secondary objectives were to evaluate immunogenicity and efficacy of AADvac1 treatment in slowing cognitive and functional decline. A total of 196 patients were randomized 3:2 between AADvac1 and placebo. AADvac1 was safe and well tolerated (AADvac1 n = 117, placebo n = 79; serious adverse events observed in 17.1% of AADvac1-treated individuals and 24.1% of placebo-treated individuals; adverse events observed in 84.6% of AADvac1-treated individuals and 81.0% of placebo-treated individuals). The vaccine induced high levels of IgG antibodies. No significant effects were found in cognitive and functional tests on the whole study sample (Clinical Dementia Rating-Sum of the Boxes scale adjusted mean point difference -0.360 (95% CI -1.306, 0.589)), custom cognitive battery adjusted mean z-score difference of 0.0008 (95% CI -0.169, 0.172). We also present results from exploratory and post hoc analyses looking at relevant biomarkers and clinical outcomes in specific subgroups. Our results show that AADvac1 is safe and immunogenic, but larger stratified studies are needed to better evaluate its potential clinical efficacy and impact on disease biomarkers.

A Novel UHPLC-MS Method Targeting Urinary Metabolomic Markers for Autism Spectrum Disorder.

Autism spectrum disorder is a heterogeneous neurodevelopmental disease. Currently, no biomarker of this disease is known. Diagnosis is performed through observation, standardized behavioral scales, and interviews with parents. In practice, diagnosis is often delayed to the average age of four years or even more which adversely affects a child's perspective. A laboratory method allowing to detect the disorder at earlier stages is of a great need, as this could help the patients to start with treatment at a younger age, even prior to the clinical diagnosis. Recent evidence indicates that metabolomic markers should be considered as diagnostic markers, also serving for further differentiation and characterization of different subgroups of the autism spectrum. In this study, we developed an ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometry method for the simultaneous determination of six metabolites in human urine. These metabolites, namely methylguanidine, N-acetyl arginine, inosine, indole-3-acetic acid, indoxyl sulfate and xanthurenic acid were selected as potential biomarkers according to prior metabolomic studies. The analysis was carried out by means of reversed-phase liquid chromatography with gradient elution. Separation of the metabolites was performed on a Phenomenex Luna® Omega Polar C18 (100 × 1.0 mm, 1.6 µm) column at a flow rate of 0.15 mL/min with acetonitrile/water 0.1% formic acid aqueous as the mobile phase. The analysis was performed on a group of children with autism spectrum disorder and age-matched controls. In school children, we have detected disturbances in the levels of oxidative stress markers connected to arginine and purine metabolism, namely methylguanidine and N-acetylargine. Also, products of gut bacteria metabolism, namely indoxyl sulfate and indole-3-acetic acid, were found to be elevated in the patients' group. We can conclude that this newly developed method is fast, sensitive, reliable, and well suited for the quantification of proposed markers.

Refining the resolution of craniofacial dysmorphology in bipolar disorder as an index of brain dysmorphogenesis.

As understanding of the genetics of bipolar disorder increases, controversy endures regarding whether the origins of this illness include early maldevelopment. Clarification would be facilitated by a 'hard' biological index of fetal developmental abnormality, among which craniofacial dysmorphology bears the closest embryological relationship to brain dysmorphogenesis. Therefore, 3D laser surface imaging was used to capture the facial surface of 21 patients with bipolar disorder and 45 control subjects; 21 patients with schizophrenia were also studied. Surface images were subjected to geometric morphometric analysis in non-affine space for more incisive resolution of subtle, localised dysmorphologies that might distinguish patients from controls. Complex and more biologically informative, non-linear changes distinguished bipolar patients from control subjects. On a background of minor dysmorphology of the upper face, maxilla, midface and periorbital regions, bipolar disorder was characterised primarily by the following dysmorphologies: (a) retrusion and shortening of the premaxilla, nose, philtrum, lips and mouth (the frontonasal prominences), with (b) some protrusion and widening of the mandible-chin. The topography of facial dysmorphology in bipolar disorder indicates disruption to early development in the frontonasal process and, on embryological grounds, cerebral dysmorphogenesis in the forebrain, most likely between the 10th and 15th week of fetal life.

Evaluation of a novel immunoassay to detect p-tau Thr217 in the CSF to distinguish Alzheimer disease from other dementias.

OBJECTIVE: To investigate whether tau phosphorylated at Thr217 (p-tau T217) assay in CSF can distinguish patients with Alzheimer disease (AD) from patients with other dementias and healthy controls. METHODS: We developed and validated a novel Simoa immunoassay to detect p-tau T217 in CSF. There was a total of 190 participants from 3 cohorts with AD (n = 77) and other neurodegenerative diseases (n = 69) as well as healthy participants (n = 44). RESULTS: The p-tau T217 assay (cutoff 242 pg/mL) identified patients with AD with accuracy of 90%, with 78% positive predictive value (PPV), 97% negative predictive value (NPV), 93% sensitivity, and 88% specificity, compared favorably with p-tau T181 ELISA (52 pg/mL), showing 78% accuracy, 58% PPV, 98% NPV, 71% specificity, and 97% sensitivity. The assay distinguished patients with AD from age-matched healthy controls (cutoff 163 pg/mL, 98% sensitivity, 93% specificity), similarly to p-tau T181 ELISA (cutoff 60 pg/mL, 96% sensitivity, 86% specificity). In patients with AD, we found a strong correlation between p-tau T217 and p-tau T181, total tau and ß-amyloid 40, but not ß-amyloid 42. CONCLUSIONS: This study demonstrates that p-tau T217 displayed better diagnostic accuracy than p-tau T181. The data suggest that the new p-tau T217 assay has potential as an AD diagnostic test in clinical evaluation. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a CSF immunoassay for p-tau T217 distinguishes patients with AD from patients with other dementias and healthy controls.

A Hierarchical Curve-Based Approach to the Analysis of Manifold Data.

One of the data structures generated by medical imaging technology is high resolution point clouds representing anatomical surfaces. Stereophotogrammetry and laser scanning are two widely available sources of this kind of data. A standardised surface representation is required to provide a meaningful correspondence across different images as a basis for statistical analysis. Point locations with anatomical definitions, referred to as landmarks, have been the traditional approach. Landmarks can also be taken as the starting point for more general surface representations, often using templates which are warped on to an observed surface by matching landmark positions and subsequent local adjustment of the surface. The aim of the present paper is to provide a new approach which places anatomical curves at the heart of the surface representation and its analysis. Curves provide intermediate structures which capture the principal features of the manifold (surface) of interest through its ridges and valleys. As landmarks are often available these are used as anchoring points, but surface curvature information is the principal guide in estimating the curve locations. The surface patches between these curves are relatively flat and can be represented in a standardised manner by appropriate surface transects to give a complete surface model. This new approach does not require the use of a template, reference sample or any external information to guide the method and, when compared with a surface based approach, the estimation of curves is shown to have improved performance. In addition, examples involving applications to mussel shells and human faces show that the analysis of curve information can deliver more targeted and effective insight than the use of full surface information.

A novel liquid chromatography/mass spectrometry method for determination of neurotransmitters in brain tissue: Application to human tauopathies.

Neurotransmitters, small molecules widely distributed in the central nervous system are essential in transmitting electrical signals across neurons via chemical communication. Dysregulation of these chemical signaling molecules is linked to numerous neurological diseases including tauopathies. In this study, a precise and reliable liquid chromatography method was established with tandem mass spectrometry detection for the simultaneous determination of aspartic acid, asparagine, glutamic acid, glutamine, γ-aminobutyric acid, N-acetyl-l-aspartic acid, pyroglutamic acid, acetylcholine and choline in human brain tissue. The method was successfully applied to the analysis of human brain tissues from three different tauopathies; corticobasal degeneration, progressive supranuclear palsy and parkinsonism-dementia complex of Guam. Neurotransmitters were analyzed on ultra-high performance chromatography (UHPLC) using an ethylene bridged hybrid amide column coupled with tandem mass spectrometry (MS/MS). Identification and quantification of neurotransmitters was carried out by ESI+ mass spectrometry detection. We optimized sample preparation to achieve simple and fast extraction of all nine analytes. Our method exhibited an excellent linearity for all analytes (all coefficients of determination >0.99), with inter-day and intra-day precision yielding relative standard deviations 3.2%-11.2% and an accuracy was in range of 92.6%-104.3%. The present study, using the above method, is the first to demonstrate significant alterations of brain neurotransmitters caused by pathological processes in the brain tissues of patient with three different tauopathies.

FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer's disease.

BACKGROUND: Neurofibrillary pathology composed of tau protein is closely correlated with severity and phenotype of cognitive impairment in patients with Alzheimer's disease and non-Alzheimer's tauopathies. Targeting pathological tau proteins via immunotherapy is a promising strategy for disease-modifying treatment of Alzheimer's disease. Previously, we reported a 24-week phase 1 trial on the active vaccine AADvac1 against pathological tau protein; here, we present the results of a further 72 weeks of follow-up on those patients. METHODS: We did a phase 1, 72-week, open-label study of AADvac1 in patients with mild to moderate Alzheimer's disease who had completed the preceding phase 1 study. Patients who were previously treated with six doses of AADvac1 at monthly intervals received two booster doses at 24-week intervals. Patients who were previously treated with only three doses received another three doses at monthly intervals, and subsequently two boosters at 24-week intervals. The primary objective was the assessment of long-term safety of AADvac1 treatment. Secondary objectives included assessment of antibody titres, antibody isotype profile, capacity of the antibodies to bind to AD tau and AADvac1, development of titres of AADvac1-induced antibodies over time, and effect of booster doses; cognitive assessment via 11-item Alzheimer's Disease Assessment Scale cognitive assessment (ADAS-Cog), Category Fluency Test and Controlled Oral Word Association Test; assessment of brain atrophy via magnetic resonance imaging (MRI) volumetry; and assessment of lymphocyte populations via flow cytometry. RESULTS: The study was conducted between 18 March 2014 and 10 August 2016. Twenty-six patients who completed the previous study were enrolled. Five patients withdrew because of adverse events. One patient was withdrawn owing to noncompliance. The most common adverse events were injection site reactions (reported in 13 [50%] of vaccinated patients). No cases of meningoencephalitis or vasogenic oedema were observed. New micro-haemorrhages were observed only in one ApoE4 homozygote. All responders retained an immunoglobulin G (IgG) antibody response against the tau peptide component of AADvac1 over 6 months without administration, with titres regressing to a median 15.8% of titres attained after the initial six-dose vaccination regimen. Booster doses restored previous IgG levels. Hippocampal atrophy rate was lower in patients with high IgG levels; a similar relationship was observed in cognitive assessment. CONCLUSIONS: AADvac1 displayed a benign safety profile. The evolution of IgG titres over vaccination-free periods warrants a more frequent booster dose regimen. The tendency towards slower atrophy in MRI evaluation and less of a decline in cognitive assessment in patients with high titres is encouraging. Further trials are required to expand the safety database and to establish proof of clinical efficacy of AADvac1. TRIAL REGISTRATION: The studies are registered with the EU Clinical Trials Register and ClinicalTrials.gov : the preceding first-in-human study under EudraCT 2012-003916-29 and NCT01850238 (registered on 9 May 2013) and the follow-up study under EudraCT 2013-004499-36 and NCT02031198 (registered 9 Jan 2014), respectively.