Pressor responses to hyperventilation in elderly subjects differentiate essential from secondary hypertension

AbstractWe evaluated pressor responses to the hyperventilation test in elderly normotensive (n=43, mean age 82 ± 5 years) and elderly hypertensive subjects (n=45 with essential hypertension, mean age 82 ± 2 years, and n=49 with secondary hypertension, mean age 82 ± 3 years). Hyperventilation did not change blood pressure (BP) in normotensive and secondary hypertensive subjects, whereas it decreased BP in essential hypertensives. Hierarchical cluster analysis based on BP responses to hyperventilation disclosed three groups of subjects in each population: group 1 exhibited a reduction in BP (essential hypertensives: 76%), group 2 no change (normotensives: 70%, secondary hypertensives: 76%), and group 3 an increase (normotensives: 19%, essential hypertensives: 13%, secondary hypertensives: 14%). Ambulatory BP monitoring found significant differences in pressor daytime profiles of hypertensive patients according to pressor responses to hyperventilation showing wide fluctuations in group 1 and 3 patients. Interestingly, the peak ambulatory SBP values correlated to the pre-hyperventilation SBP values in group 1, and to the hyperventilation peak SBP values in group 3. In conclusion: 1) Aging decreases reactivity to respiratory alkalosis in elderly normotensives; 2) hyperventilation induces significant pressor changes frequently in essential hypertension, but rarely in secondary hypertension; 3) the significant pressor responses to hyperventilation reflect the daytime pressor profiles predicting the highest daily fluctuations of BP values

L-Acetylcarnitine causes analgesia in mice modeling Fabry disease by up-regulating type-2 metabotropic glutamate receptors

Fabry disease (FD) is a X-linked lysosomal storage disorder caused by deficient function of the alpha-galactosidase A (α-GalA) enzyme. α-GalA deficiency leads to multisystemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide (Gb3). A hallmark symptom of FD patients is neuropathic pain that appears in the early stage of the disease as a result of peripheral small fiber damage. Previous studies have shown that Acetyl-L-carnitine (ALC) has neuroprotective, neurotrophic, and analgesic activity in animal models of neuropathic pain. To study the action of ALC on neuropathic pain associated with FD, we treated α-GalA gene null mice (α-GalA(-/0)) with ALC for 30 days. In α-Gal KO mice ALC treatment induced acute and long-lasting analgesia, which persisted 1 month after drug withdrawal. This effect was antagonized by single administration of LY341495, an orthosteric antagonist of mGlu2/3 metabotropic glutamate receptors. We also found an up-regulation of mGlu2 receptors in cultured DRG neurons isolated from 30-day ALC treated α-GalA KO mice. However, the up-regulation of mGlu2 receptors was no longer present in DRG neurons isolated 30 days after the end of treatment. Taken together, these findings suggest that ALC induces analgesia in an animal model of FD by up-regulating mGlu2 receptors, and that analgesia is maintained by additional mechanisms after ALC withdrawal. ALC might represent a valuable pharmacological strategy to reduce pain in FD patients

Social withdrawal and neurocognitive correlates in schizophrenia

Poor neurocognitive performance has been associated with poor functional outcome in schizophrenia (SCZ) in past studies. Nonetheless, the likely association between neurocognition and social withdrawal has never been investigated. The aim of our study was to investigate in a large and heterogeneous sample of SCZ patient cross-sectional associations between neurocognitive domains and social withdrawal. The sample included 761 SCZ patients who completed the baseline visit in the CATIE study. Neurocognition was assessed by a comprehensive battery of tests resulting in five domain scores and a composite score. Social withdrawal was measured by a specific item of the Heinrichs-Carpenter Quality of Life Scale. Social withdrawal was associated with a lower score in the neurocognitive composite score and in 'Verbal memory,' 'Processing speed' and 'Working memory' scores. 'Verbal memory' score showed the strongest association with social withdrawal. Eight percent of the total variance of social withdrawal was explained by these three cognitive domains and additional clinical and sociodemographic factors (education years, PANSS positive symptoms score, and employment). Our results confirmed the wide heterogeneity and specificity of the correlation between neurocognitive domains and indicators of functional outcome in SCZ, underlining the role of certain neurocognitive abilities in social withdrawal

Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case-control collections.

Despite significant research efforts aimed at understanding the neurobiological underpinnings of psychiatric disorders, the diagnosis and the evaluation of treatment of these disorders are still based solely on relatively subjective assessment of symptoms. Therefore, biological markers which could improve the current classification of psychiatry disorders, and in perspective stratify patients on a biological basis into more homogeneous clinically distinct subgroups, are highly needed. In order to identify novel candidate biological markers for major depression and schizophrenia, we have applied a focused proteomic approach using plasma samples from a large case-control collection. Patients were diagnosed according to DSM criteria using structured interviews and a number of additional clinical variables and demographic information were assessed. Plasma samples from 245 depressed patients, 229 schizophrenic patients and 254 controls were submitted to multi analyte profiling allowing the evaluation of up to 79 proteins, including a series of cytokines, chemokines and neurotrophins previously suggested to be involved in the pathophysiology of depression and schizophrenia. Univariate data analysis showed more significant p-values than would be expected by chance and highlighted several proteins belonging to pathways or mechanisms previously suspected to be involved in the pathophysiology of major depression or schizophrenia, such as insulin and MMP-9 for depression, and BDNF, EGF and a number of chemokines for schizophrenia. Multivariate analysis was carried out to improve the differentiation of cases from controls and identify the most informative panel of markers. The results illustrate the potential of plasma biomarker profiling for psychiatric disorders, when conducted in large collections. The study highlighted a set of analytes as candidate biomarker signatures for depression and schizophrenia, warranting further investigation in independent collections

Velusetrag rescues GI dysfunction, gut inflammation and dysbiosis in a mouse model of Parkinson's disease

: In patients with Parkinson's disease (PD), constipation is common, and it appears in a prodromal stage before the hallmark motor symptoms. The present study aimed to investigate whether Velusetrag, a selective 5‑HT4 receptor agonist, may be a suitable candidate to improve intestinal motility in a mouse model of PD. Five months old PrP human A53T alpha-synuclein transgenic (Tg) mice, which display severe constipation along with decreased colonic cholinergic transmission already at 3 months, were treated daily with the drug for 4 weeks. Velusetrag treatment reduced constipation by significantly stimulating both the longitudinal and circular-driven contractions and improved inflammation by reducing the level of serum and colonic IL1β and TNF-α and by decreasing the number of GFAP-positive glia cells in the colon of treated mice. No significant downregulation of the 5-HT4 receptor was observed but instead Velusetrag seemed to improve axonal degeneration in Tgs as shown by an increase in NF-H and VAChT staining. Ultimately, Velusetrag restored a well-balanced intestinal microbial composition comparable to non-Tg mice. Based on these promising data, we are confident that Velusetrag is potentially eligible for clinical studies to treat constipation in PD patients

Wearable devices for assessing function in Alzheimer’s disease: a European public involvement activity about the features and preferences of patients and caregivers

Background: Alzheimer's Disease (AD) impairs the ability to carry out daily activities, reduces independence and quality of life and increases caregiver burden. Our understanding of functional decline has traditionally relied on reports by family and caregivers, which are subjective and vulnerable to recall bias. The Internet of Things (IoT) and wearable sensor technologies promise to provide objective, affordable, and reliable means for monitoring and understanding function. However, human factors for its acceptance are relatively unexplored. Objective: The Public Involvement (PI) activity presented in this paper aims to capture the preferences, priorities and concerns of people with AD and their caregivers for using monitoring wearables. Their feedback will drive device selection for clinical research, starting with the study of the RADAR-AD project. Method: The PI activity involved the Patient Advisory Board (PAB) of the RADAR-AD project, comprised of people with dementia across Europe and their caregivers (11 and 10, respectively). A set of four devices that optimally represent various combinations of aspects and features from the variety of currently available wearables (e.g., weight, size, comfort, battery life, screen types, water-resistance, and metrics) was presented and experienced hands-on. Afterwards, sets of cards were used to rate and rank devices and features and freely discuss preferences. Results: Overall, the PAB was willing to accept and incorporate devices into their daily lives. For the presented devices, the aspects most important to them included comfort, convenience and affordability. For devices in general, the features they prioritized were appearance/style, battery life and water resistance, followed by price, having an emergency button and a screen with metrics. The metrics valuable to them included activity levels and heart rate, followed by respiration rate, sleep quality and distance. Some concerns were the potential complexity, forgetting to charge the device, the potential stigma and data privacy. Conclusions: The PI activity explored the preferences, priorities and concerns of the PAB, a group of people with dementia and caregivers across Europe, regarding devices for monitoring function and decline, after a hands-on experience and explanation. They highlighted some expected aspects, metrics and features (e.g., comfort and convenience), but also some less expected (e.g., screen with metrics)

Cerebral blood flow predicts differential neurotransmitter activity

Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans

Neural response to the observable self in social anxiety disorder

Background: Distorted images of the observable self are considered crucial in the development and maintenance of social anxiety. We generated an experimental situation in which participants viewed themselves from an observer's perspective when exposed to scrutiny and evaluation by others. Method: Twenty patients with social anxiety disorder (SAD) and 20 control subjects were assessed using functional magnetic resonance imaging (fMRI) during the public exposure of pre-recorded videos in which they were each shown performing a verbal task. The examiners acted as the audience in the experiment and rated performance. Whole-brain functional maps were computed using Statistical Parametric Mapping. Results: Robust activation was observed in regions related to self-face recognition, emotional response and general arousal in both study groups. Patients showed significantly greater activation only in the primary visual cortex. By contrast, they showed significant deactivation or smaller activation in dorsal frontoparietal and anterior cingulate cortices relevant to the cognitive control of negative emotion. Task-related anxiety ratings revealed a pattern of negative correlation with activation in this frontoparietal/cingulate network. Importantly, the relationship between social anxiety scores and neural response showed an inverted-U function with positive correlations in the lower score range and negative correlations in the higher range. Conclusions: Our findings suggest that exposure to scrutiny and evaluation in SAD may be associated with changes in cortical systems mediating the cognitive components of anxiety. Disorder severity seems to be relevant in shaping the neural response pattern, which is distinctively characterized by a reduced cortical response in the most severe cases

Relating constructs of attention and working memory to social withdrawal in Alzheimer's disease and schizophrenia: issues regarding paradigm selection

Central nervous system diseases are not currently diagnosed based on knowledge of biological mechanisms underlying their symptoms. Greater understanding may be offered through an agnostic approach to traditional disease categories, where learning more about shared biological mechanisms across conditions could potentially reclassify sub-groups of patients to allow realisation of more effective treatments. This review represents the output of the collaborative group "PRISM", tasked with considering assay choices for assessment of attention and working memory in a transdiagnostic cohort of Alzheimer's disease and schizophrenia patients exhibiting symptomatic spectra of social withdrawal. A multidimensional analysis of this nature has not been previously attempted. Nominated assays (continuous performance test III, attention network test, digit symbol substitution, N-back, complex span, spatial navigation in a virtual environment) reflected a necessary compromise between the need for broad assessment of the neuropsychological constructs in question with several pragmatic criteria: patient burden, compatibility with neurophysiologic measures and availability of preclinical homologues