Association study of COMT gene Val158Met polymorphism with auditory P300 and performance on neurocognitive tests in patients with schizophrenia and their relatives.

A number of studies have reported an association between catechol-O-methyltransferase (COMT) gene Val158Met polymorphism and neuropsychological traits in patients with schizophrenia, their relatives and healthy controls, with the Met allele carriers performing better on neurocognitive tasks than those with the Val allele. But the association was not confirmed in all studies. The present paper was aimed at further investigation of the COMT gene relationship with some neurocognitive traits, assessing mainly working and verbal memory, and to P300 event-related potentials (auditory oddball). A total sample of 319 individuals, including schizophrenic patients, their relatives and controls, was studied. No significant differences in performance of neurocognitive tasks were found by Val158Met genotypes. An association was observed between the Met/Met genotype and higher amplitude in centro-parietal area in relatives. Factors that could explain the non-replication of previous studies on the COMT gene polymorphism and neurocognitive traits are discussed. We suggest here that (1) Val158Met polymorphism rather exerts a modifying influence on brain activation in general than impacts directly on performance of the particular neurocognitive test, and (2) P300 amplitude seems to be a correlate of this activation reflecting, along with information processing, the subject's affective and personality features.     

“Do you have mowing the lawn?” – improvements in word retrieval and grammar following constraint-induced language therapy in primary progressive aphasia

Background: Much recent progress has been made in developing speech–language therapy in primary progressive aphasia (PPA). Several treatment approaches that have shown significant effects with people with aphasia have been adapted and re-evaluated for PPA. Constraint-induced aphasia therapy (CIAT) is a well-evaluated method that has yielded significant language improvements in people with post-stroke aphasia but has not yet been evaluated with people with PPA. Nevertheless, the combination of CIAT features like massed practice and a motivating communicative setting seem likely to make it a suitable tool for improving the speech and language performance of individuals with PPA as well.

Aims: This study investigates the effectiveness of a modified CIAT protocol on word retrieval, grammatical structure and connected speech in two individuals with non-fluent variant PPA (nfvPPA).

Methods and procedures: Two participants with nfvPPA took part in a 9-day intensive CIAT-based group therapy with additional computer-based home training. Stimuli were 120 photos of people performing daily life activities, which could be described using a simple (e.g., “The man is mowing the lawn”) or reduced (e.g., “mowing the lawn”) sentence structure. During the treatment phase, the participants were required to request picture cards from other group members using spoken language only. The task difficulty was increased hierarchically (shaped) in accordance to each participant’s performance level.

Outcomes and results: Directly after therapy, both participants achieved significant improvements in their noun and verb naming accuracy and their grammatical structure for trained items. Training effects were maintained 2 months after therapy. Moreover, generalisation to different pictures of the same item was found for both participants and one participant also showed improved grammatical structure when describing untrained pictures. No significant generalisation to untrained connected speech samples was observed for either participant.

Conclusion: This study illustrates that CIAT can be effective in people with PPA. However, further modifications of CIAT should be considered to facilitate generalisation and in order to determine which aspects of the treatment are most important.     

Enlarged hyperechogenic substantia nigra is related to motor performance and olfaction in the elderly

Enlarged substantia nigra hyperechogenicity (SN+) assessed by transcranial sonography (TCS) may be associated with Parkinson's disease (PD) risk markers such as impaired motor performance and hyposmia. The aim of this multicenter cross‐sectional study was to define the association between SN+ and these risk markers in a large population older than 50 years without the diagnosis of PD. In three centers (Tuebingen, Homburg, and Innsbruck), 1,839 individuals were examined. The echostatus of the SN was assessed by TCS, motor performance by the Unified Parkinson's Disease Rating Scale (UPDRS) motor score, and olfactory function with Sniffin' Sticks. From the 1,603 subjects included in the analysis, 16.2% were SN+, 23.0% scored above zero in the UPDRS motor section, and 28.0% were hyposmic as defined by less than 75% correctly classified Sniffin' Sticks. SN+ was associated with a UPDRS motor score above zero (OR 1.45, 95% CI 1.08–1.96) and with a lower odor identification capability (OR 1.48, 95% CI 1.12–1.96). The combination of these two features (OR 1.98, 95% CI 1.25–3.15) and UPDRS motor scores ≥3 lead to higher OR. It is concluded that SN+, impaired motor performance, and hyposmia are frequently observed in the elderly and in isolation are unspecific and of limited use to predict a subject's risk for PD. Whether the association of SN+ with both impaired motor performance and hyposmia as seen in this study predicts an increased risk for the development of PD needs to be evaluated in the follow‐up investigations. © 2010 Movement Disorder Society     

Histologic and Manometric Studies on the Esophagus Following Endoscopic Sclerotherapy

Objective The aim of this work was to study the histologic and manometric changes in the distal esophagus beyond 2 years following endoscopic sclerotherapy (EST) and/or surgical intervention, and to try to understand the etiological factors associated with these changes. Patients and interventions Forty patients, with an average age of 61.5 years, were studied for 2–12 years following sclerotherapy and/or surgical intervention. The causes of liver disease were alcoholic cirrhosis (78.6%), primary biliary cirrhosis (14.3%), and chronic aggressive hepatitis (7.1%). A predominant number of cases (65%) had a mesocaval interposition shunt due to the failure of EST, 32.5% EST alone, and 2.5% esophageal devascularization. All patients had esophageal manometry following mucosal biopsies taken in duplicate endoscopically from three levels of the distal esophagus. Results In the EST and shunt groups, 88.5% had manometric abnormalities, esophagitis, and chronic inflammatory changes. In the EST group, all but two patients had manometric abnormalities and chronic inflammatory changes. Analysis of the patient groups on the basis of the number of EST sessions and the amount of sclerosant injected showed that both histologic changes and dysmotility were more profound in those treated over five times with EST. The differences were significant. Conclusion It appears that EST causes persistent manometric abnormalities and chronic inflammatory changes in the distal esophagus, the severity of which seems to vary directly with the frequency of sclerotherapy and not amount of sclerosant injected.     

Role of rhodopsin and arrestin phosphorylation in retinal degeneration of Drosophila

Arrestins belong to a family of multifunctional adaptor proteins that regulate internalization of diverse receptors including G-protein-coupled receptors (GPCRs). Defects associated with endocytosis of GPCRs have been linked to human diseases. We used enhanced green fluorescent protein-tagged arrestin 2 (Arr2) to monitor the turnover of the major rhodopsin (Rh1) in live Drosophila. We demonstrate that during degeneration of norpA(P24) photoreceptors the loss of Rh1 is parallel to the disappearance of rhabdomeres, the specialized visual organelle that houses Rh1. The cause of degeneration in norpA(P24) is the failure to activate CaMKII (Ca(2+)/calmodulin-dependent protein kinase II) and retinal degeneration C (RDGC) because of a loss of light-dependent Ca(2+) entry. A lack of activation in CaMKII, which phosphorylates Arr2, leads to hypophosphorylated Arr2, while a lack of activation of RDGC, which dephosphorylates Rh1, results in hyperphosphorylated Rh1. We investigated how reversible phosphorylation of Rh1 and Arr2 contributes to photoreceptor degeneration. To uncover the consequence underlying a lack of CaMKII activation, we characterized ala(1) flies in which CaMKII was suppressed by an inhibitory peptide, and showed that morphology of rhabdomeres was not affected. In contrast, we found that expression of phosphorylation-deficient Rh1s, which either lack the C terminus or contain Ala substitution in the phosphorylation sites, was able to prevent degeneration of norpA(P24) photoreceptors. This suppression is not due to a loss of Arr2 interaction. Importantly, co-expression of these modified Rh1s offered protective effects, which greatly delayed photoreceptor degeneration. Together, we conclude that phosphorylation of Rh1 is the major determinant that orchestrates its internalization leading to retinal degeneration.     

Polygenic load: Earlier disease onset but similar longitudinal progression in Parkinson's disease

Objectives: In order to evaluate the influence of the genetic load of 49 genetic variants known to be associated with PD on the age at onset as well as on clinical outcome parameters. Background: PD patients show a large variability in phenotype and progression reflecting interindividual heterogeneity. This might be influenced by a diverse genetic architecture. Methods: Six hundred seventeen PD patients were included in this study and stratified by their “genetic load,” which is based on the weighted odds ratios of 49 genetic variants known to be associated with PD from genome‐wide association studies. Clinical parameters (H & Y, UPDRS‐III, MMSE, and Beck's Depression Inventory) were evaluated cross‐sectionally and in a subgroup longitudinally over 8 years. Results: PD patients with the highest genetic load were younger at disease onset, whereas severity of clinical parameters were similar compared to patients with the lowest genetic load. These findings could be confirmed regarding progression to clinical endpoints in the longitudinal analysis. Conclusion: A high genetic load is associated with a younger age at onset, which, in turn, might possibly promote more effective compensatory mechanisms resulting in a similar rate of disease progression. © 2018 International Parkinson and Movement Disorder Society     

Cerebrospinal fluid biomarkers in human genetic transmissible spongiform encephalopathies

The 14-3-3 protein test has been shown to support the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) when associated with an adequate clinical context, and a high differential potential for the diagnosis of sporadic CJD has been attributed to other cerebrospinal fluid (CSF) proteins such as tau protein, S100b and neuron specific enolase (NSE). So far there has been only limited information available about biochemical markers in genetic transmissible spongiform encephalopathies (gTSE), although they represent 10–15% of human TSEs. In this study, we analyzed CSF of 174 patients with gTSEs for 14-3-3 (n = 166), tau protein (n = 78), S100b (n = 46) and NSE (n = 50). Levels of brain-derived proteins in CSF varied in different forms of gTSE. Biomarkers were found positive in the majority of gCJD (81%) and insert gTSE (69%), while they were negative in most cases of fatal familial insomnia (13%) and Gerstmann-Sträussler-Scheinker syndrome (10%). Disease duration and codon 129 genotype influence the findings in a different way than in sporadic CJD.     

GDF15 promotes simultaneous astrocyte remodeling and tight junction strengthening at the blood–brain barrier

Perivascular astrocyte processes (PAP) surround cerebral endothelial cells (ECs) and modulate the strengthening of tight junctions to influence blood–brain barrier (BBB) permeability. Morphologically altered astrocytes may affect barrier properties and trigger the onset of brain pathologies. However, astrocyte-dependent mediators of these events remain poorly studied. Here, we show a pharmacologically driven elevated expression and release of growth/differentiation factor 15 (GDF15) in rat primary astrocytes and cerebral PAP. GDF15 has been shown to possess trophic properties for motor neurons, prompting us to hypothesize similar effects on astrocytes. Indeed, its increased expression and release occurred simultaneously to morphological changes of astrocytes in vitro and PAP, suggesting modulatory effects of GDF15 on these cells, but also neighboring EC. Administration of recombinant GDF15 was sufficient to promote astrocyte remodeling and enhance barrier properties between ECs in vitro, whereas its pharmacogenetic abrogation prevented these effects. We validated our findings in male high anxiety-related behavior rats, an animal model of depressive-like behavior, with shrunk PAP associated with reduced expression of the junctional protein claudin-5, which were both restored by a pharmacologically induced increase in GDF15 expression. Thus, we identified GDF15 as an astrocyte-derived trigger of astrocyte process remodeling linked to enhanced tight junction strengthening at the BBB.     

REPIMPACT - a prospective longitudinal multisite study on the effects of repetitive head impacts in youth soccer

Brain Imaging and Behavior - Repetitive head impacts (RHI) are common in youth athletes participating in contact sports. RHI differ from concussions; they are considered hits to the head that...