Erythrocytes' surface properties and stiffness predict survival and functional decline in ALS patients.

Erythrocytes play a fundamental role in oxygen delivery to tissues and binding to inflammatory mediators. Evidences suggest that dysregulated erythrocyte function could contribute to the pathophysiology of several neurodegenerative diseases. We aimed to evaluate changes in morphological, biomechanical, and biophysical properties of erythrocytes from amyotrophic lateral sclerosis (ALS) patients, as new areas of study in this disease. Blood samples were collected from ALS patients, comparing with healthy volunteers. Erythrocytes were assessed using atomic force microscopy (AFM) and zeta potential analysis. The patients' motor and respiratory functions were evaluated using the revised ALS Functional Rating Scale (ALSFRS-R) and percentage of forced vital capacity (%FVC). Patient survival was also assessed. Erythrocyte surface roughness was significantly smoother in ALS patients, and this parameter was a predictor of faster decline in ALSFRS-R scores. ALS patients exhibited higher erythrocyte stiffness, as indicated by reduced AFM tip penetration depth, which predicted a faster ALSFRS-R score and respiratory subscore decay. A lower negative charge on the erythrocyte membrane was predictor of a faster ALSFRS-R and FVC decline. Additionally, a larger erythrocyte surface area was an independent predictor of lower survival. These changes in morphological and biophysical membrane properties of ALS patients' erythrocytes, lead to increased cell stiffness and morphological variations. We speculate that these changes might precipitate motoneurons dysfunction and accelerate disease progression. Further studies should explore the molecular alterations related to these observations. Our findings may contribute to dissect the complex interplay between respiratory function, tissue hypoxia, progression rate, and survival in ALS.

Sphingolipid and Phospholipid Levels Are Altered in Human Brain in Chorea-Acanthocytosis.

BACKGROUND: Chorea-acanthocytosis (ChAc) is associated with mutations of VPS13A, which encodes for chorein, a protein implicated in lipid transport at intracellular membrane contact sites. OBJECTIVES: The goal of this study was to establish the lipidomic profile of patients with ChAc. METHODS: We analyzed 593 lipid species in the caudate nucleus (CN), putamen, and dorsolateral prefrontal cortex (DLPFC) from postmortem tissues of four patients with ChAc and six patients without ChAc. RESULTS: We found increased levels of bis(monoacylglycerol)phosphate, sulfatide, lysophosphatidylserine, and phosphatidylcholine ether in the CN and putamen, but not in the DLPFC, of patients with ChAc. Phosphatidylserine and monoacylglycerol were increased in the CN and N-acyl phosphatidylserine in the putamen. N-acyl serine was decreased in the CN and DLPFC, whereas lysophosphatidylinositol was decreased in the DLPFC. CONCLUSIONS: We present the first evidence of altered sphingolipid and phospholipid levels in the brains of patients with ChAc. Our observations are congruent with recent findings in cellular and animal models, and implicate defects of lipid processing in VPS13A disease pathophysiology. © 2023 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Serum Phospholipid Profile Changes in Gaucher Disease and Parkinson's Disease.

Alterations in the levels of serum sphingolipids and phospholipids have been reported in Gaucher disease and in Parkinson's disease, suggesting a potential role of these lipids as biomarkers. This project's objective is to detect novel associations and novel candidate biomarkers in the largest Spanish Gaucher and Parkinson diseases of the Iberian Peninsula. For that, 278 participants were included: 100 sporadic Parkinson's patients, 70 Gaucher patients, 15 GBA1-mutation-carrier Parkinson's patients and 93 controls. A serum lipidomics array including 10 phospholipid groups, 368 species, was performed using high-performance liquid chromatography-mass spectrometry. Lipid levels were compared between groups via multiple-regression analyses controlling for clinical and demographic parameters. Additionally, lipid levels were compared within the Gaucher and Parkinson's groups controlling for medication and/or disease severity. Results were controlled for robustness by filtering of non-detectable lipid values. There was an increase in the levels of phosphatidylcholine, with a simultaneous decrease in lyso-phosphatidylcholine, in the Gaucher, Parkinson's and GBA1-mutation-carrier Parkinson's patients vs. controls. Phosphatidylethanolamine, lyso- and plasmalogen-phosphatidylethanolamine were also increased in Gaucher and Parkinson's. Gaucher patients also showed an increase in lyso-phosphatidylserine and phosphatidylglycerol. While in the Gaucher and Parkinson's groups, velaglucerase alpha and dopamine agonists, respectively, showed positive associations with the lipid changes, miglustat treatment in Gaucher patients normalized the altered phosphatidylcholine/lyso-phosphatidylcholine ratio. In conclusion, Gaucher and Parkinson's patients showed changes in various serum phospholipid levels when compared with healthy controls, further supporting the role of such lipids in disease development and, possibly, as putative biomarkers. This hypothesis was reinforced by the normalizing effect of miglustat, and by controlling for data robustness, even though the limited number of participants, especially in the sub-distribution by treatment groups in GD requires validation in a larger number of patients.

Convergent neural correlates of prenatal exposure to air pollution and behavioral phenotypes of risk for internalizing and externalizing problems: Potential biological and cognitive pathways.

Humans are ubiquitously exposed to neurotoxicants in air pollution, causing increased risk for psychiatric outcomes. Effects of prenatal exposure to air pollution on early emerging behavioral phenotypes that increase risk of psychopathology remain understudied. We review animal models that represent analogues of human behavioral phenotypes that are risk markers for internalizing and externalizing problems (behavioral inhibition, behavioral exuberance, irritability), and identify commonalities among the neural mechanisms underlying these behavioral phenotypes and the neural targets of three types of air pollutants (polycyclic aromatic hydrocarbons, traffic-related air pollutants, fine particulate matter < 2.5 µm). We conclude that prenatal exposure to air pollutants increases risk for behavioral inhibition and irritability through distinct mechanisms, including altered dopaminergic signaling and hippocampal morphology, neuroinflammation, and decreased brain-derived neurotrophic factor expression. Future studies should investigate these effects in human longitudinal studies incorporating complex exposure measurement methods, neuroimaging, and behavioral characterization of temperament phenotypes and neurocognitive processing to facilitate efforts aimed at improving long-lasting developmental benefits for children, particularly those living in areas with high levels of exposure.

Psychopathic traits and reinforcement learning under acute stress.

OBJECTIVE: Individuals with high levels of psychopathic traits are often characterized by aberrant reinforcement learning. This type of learning, which implicates making choices that maximize rewards and minimize punishments, may be affected by acute stress. However, how acute stress affects reinforcement learning in individuals with different levels of psychopathic traits is not well-understood. Here, we investigated whether and how individual differences in psychopathic traits modulated the impact of acute stress on reward and punishment learning. METHOD: Sixty-two male participants from a university sample completed the Self-Report Psychopathy-Short Form scale and performed a reinforcement-learning task involving monetary gains and losses whilst under acute stress and control conditions. RESULTS: Individual differences in psychopathic traits modulated the impact of acute stress on behavioral performance toward obtaining gains, but not toward avoiding losses. As levels of psychopathic traits increased, the impairing effect of acute stress on reward learning decreased. Specifically, acute stress impaired performance toward seeking gains to a larger extent in individuals with lower levels of psychopathic traits than in individuals with higher levels of these traits. CONCLUSIONS: Our study indicates that psychopathic traits modulate the impact of acute stress on reward learning.

Corrigendum: γ' Fibrinogen as a Predictor of Survival in Amyotrophic Lateral Sclerosis.

[This corrects the article DOI: 10.3389/fcvm.2021.715842.].

Acute stress blunts prediction error signals in the dorsal striatum during reinforcement learning.

Acute stress is pervasive in everyday modern life and is thought to affect how people make choices and learn from them. Reinforcement learning, which implicates learning from the unexpected rewarding and punishing outcomes of our choices (i.e., prediction errors), is critical for adjusted behaviour and seems to be affected by acute stress. However, the neural mechanisms by which acute stress disrupts this type of learning are still poorly understood. Here, we investigate whether and how acute stress blunts neural signalling of prediction errors during reinforcement learning using model-based functional magnetic resonance imaging. Male participants completed a well-established reinforcement-learning task involving monetary gains and losses whilst under stress and control conditions. Acute stress impaired participants' (n = 23) behavioural performance towards obtaining monetary gains (p < 0.001), but not towards avoiding losses (p = 0.57). Importantly, acute stress blunted signalling of prediction errors during gain and loss trials in the dorsal striatum (p = 0.040) - with subsidiary analyses suggesting that acute stress preferentially blunted signalling of positive prediction errors. Our results thus reveal a neurocomputational mechanism by which acute stress may impair reward learning.

γ' Fibrinogen as a Predictor of Survival in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is an aggressive neurodegenerative disorder related to neuroinflammation that is associated with increased risk of thrombosis. We aimed to evaluate γ' fibrinogen plasma level (an in vivo variant of fibrinogen) as a biomarker in ALS, and to test its role as a predictor of disease progression and survival. Sixty-seven consecutive patients with ALS were followed and the results were compared with those from 82 healthy blood donors. Patients were clinically evaluated at the time of blood sampling and on follow-up (every 3 months for the beginning of the follow-up until death) by applying the revised ALS Functional Rating Scale. Human plasma γ' fibrinogen concentration was quantified using a specific two-site sandwich kit enzyme-linked immunosorbent assay. We found, for the first time, a positive association between γ' fibrinogen concentration and survival in ALS patients: patients with higher γ' fibrinogen plasma levels survived longer, and this finding was not influenced by confounders such as age, gender, respiratory impairment, or functionality (ALSFRS-R score). Since increased levels have a positive impact on outcome, this novel biomarker should be further investigated in ALS.

Plasma Creatinine Level Does Not Predict Respiratory Function in Amyotrophic Lateral Sclerosis.

In amyotrophic lateral sclerosis (ALS) lower plasma creatinine level has been associated with shorter survival and faster functional decline. It has not been clear if creatinine is associated with respiratory outcome. We analyzed retrospectively a population of unselected ALS patients. Multiple-regression and Cox-regression analyses were performed. We included 233 patients, mean age 62.8, mean disease duration of 18.6 months. At baseline, creatinine was significantly associated with ALSFRS-R, but not with its decline rate. No predictive value was disclosed for FVC, its decline rate, or with survival. We did not confirm that creatinine is a marker of respiratory outcome.

Acute stress impairs reward learning in men.

Acute stress is ubiquitous in everyday life, but the extent to which acute stress affects how people learn from the outcomes of their choices is still poorly understood. Here, we investigate how acute stress impacts reward and punishment learning in men using a reinforcement-learning task. Sixty-two male participants performed the task whilst under stress and control conditions. We observed that acute stress impaired participants' choice performance towards monetary gains, but not losses. To unravel the mechanism(s) underlying such impairment, we fitted a reinforcement-learning model to participants' trial-by-trial choices. Computational modeling indicated that under acute stress participants learned more slowly from positive prediction errors - when the outcomes were better than expected - consistent with stress-induced dopamine disruptions. Such mechanistic understanding of how acute stress impairs reward learning is particularly important given the pervasiveness of stress in our daily life and the impact that stress can have on our wellbeing and mental health.

Increased monohexosylceramide levels in the serum of established rheumatoid arthritis patients.

OBJECTIVES: To identify serum sphingolipids that could act as candidate biomarkers in RA. METHODS: We performed lipidomic analyses in the serum of 82 participants: 19 established RA patients, 18 untreated early RA patients, 13 untreated early arthritis patients not fulfilling the classification criteria for RA, 12 established SpA patients and 20 controls. We compared the lipid levels from the different patient groups with the control group through multiple-regression analyses controlling for age at diagnosis, gender and medication (cDMARDs and corticoids). RESULTS: Established RA patients had significantly increased levels of sphingosine, monohexosylceramide and ceramide compared with controls, when controlling for age and gender. Monohexosylceramide levels remained significantly increased when additionally controlling for medication. On the contrary, SpA patients had significantly decreased levels of ceramide, in both analyses. CONCLUSION: We observed a detectable increase in the levels of certain sphingolipids in the serum of established RA patients when compared with controls, in line with previous observations in the synovial fluid. Such findings provide further evidence that sphingolipids may play a key role in the pathophysiology of RA.

Dopaminergic Disturbances in Tourette Syndrome: An Integrative Account.

Tourette syndrome (TS) is thought to involve dopaminergic disturbances, but the nature of those disturbances remains controversial. Existing hypotheses suggest that TS involves 1) supersensitive dopamine receptors, 2) overactive dopamine transporters that cause low tonic but high phasic dopamine, 3) presynaptic dysfunction in dopamine neurons, or 4) dopaminergic hyperinnervation. We review evidence that contradicts the first two hypotheses; we also note that the last two hypotheses have traditionally been considered too narrowly, explaining only small subsets of findings. We review all studies that have used positron emission tomography and single-photon emission computerized tomography to investigate the dopaminergic system in TS. The seemingly diverse findings from those studies have typically been interpreted as pointing to distinct mechanisms, as evidenced by the various hypotheses concerning the nature of dopaminergic disturbances in TS. We show, however, that the hyperinnervation hypothesis provides a simple, parsimonious explanation for all such seemingly diverse findings. Dopaminergic hyperinnervation likely causes increased tonic and phasic dopamine. We have previously shown, using a computational model of the role of dopamine in basal ganglia, that increased tonic dopamine and increased phasic dopamine likely increase the propensities to express and learn tics, respectively. There is therefore a plausible mechanistic link between dopaminergic hyperinnervation and TS via increased tonic and phasic dopamine. To further bolster this argument, we review evidence showing that all medications that are effective for TS reduce signaling by tonic dopamine, phasic dopamine, or both.

Premonitory urges and tics in Tourette syndrome: computational mechanisms and neural correlates.

Tourette syndrome is characterized by open motor behaviors - tics - but another crucial aspect of the disorder is the presence of premonitory urges: uncomfortable sensations that typically precede tics and are temporarily alleviated by tics. We review the evidence implicating the somatosensory cortices and the insula in premonitory urges and the motor cortico-basal ganglia-thalamo-cortical loop in tics. We consider how these regions interact during tic execution, suggesting that the insula plays an important role as a nexus linking the sensory and emotional character of premonitory urges with their translation into tics. We also consider how these regions interact during tic learning, integrating the neural evidence with a computational perspective on how premonitory-urge alleviation reinforces tics.

Serum lipid alterations in GBA-associated Parkinson's disease.

INTRODUCTION: Mutations in the GBA gene, encoding for the lysosomal enzyme glucocerebrosidase, are associated with Gaucher disease. Alterations in plasma sphingolipids have been reported in Gaucher, and similarly in brain extracts in Lewy body disease. As GBA mutations are prevalent risk factors for Parkinson's disease and overlap of molecular pathways are presumable, here we assessed the lipid profiles in Parkinson's patients with and without GBA mutations. METHODS: We sequenced all GBA exons in 415 Parkinson's patients, previously genotyped for LRRK2. 64 patients (29 GBA positive vs. 35 non-GBA-carriers including 18 LRRK2 positive and 17 non-mutated) were analyzed for chitotriosidase activity and for the concentration of 40 lipid classes using HPLC-MS. RESULTS: 29/415 patients (6.9%) carried 8 different GBA mutations associated with Gaucher or Parkinson's, including one novel mutation. Chitotriosidase activity was similar across the genetic groups, while the levels of key lipids were altered in GBA mutation carriers: Monohexosylceramide, Ceramide and Sphingomyelin were elevated; while Phosphatidic acid (PA), Phosphatidylethanolamine (PE), Plasmalogen phosphatidylethanolamine (PEp) and Acyl Phosphatidylglycerol (AcylPG) were decreased. CONCLUSION: The results suggest an important role for these lipids in GBA mediated Parkinson's disease and assist in the identification of common pathways between Gaucher and Parkinson's. Ultimately, our findings may lead to the identification of novel biomarkers for individuals at increased risk of developing Parkinson's disease.

The Roles of Phasic and Tonic Dopamine in Tic Learning and Expression.

Tourette syndrome (TS) prominently involves dopaminergic disturbances, but the precise nature of those disturbances has remained elusive. A substantial body of empirical work and recent computational models have characterized the specific roles of phasic and tonic dopamine (DA) in action learning and selection, respectively. Using insights from this work and models, we suggest that TS involves increases in both phasic and tonic DA, which produce increased propensities for tic learning and expression, respectively. We review the evidence from reinforcement-learning and habit-learning studies in TS, which supports the idea that TS involves increased phasic DA responses; we also review the evidence that tics engage the habit-learning circuitry. On the basis of these findings, we suggest that tics are exaggerated, maladaptive, and persistent motor habits reinforced by aberrant, increased phasic DA responses. Increased tonic DA amplifies the tendency to execute learned tics and also provides a fertile ground of motor hyperactivity for tic learning. We review evidence suggesting that antipsychotics may counter both the increased propensity for tic expression, by increasing excitability in the indirect pathway, and the increased propensity for tic learning, by shifting plasticity in the indirect pathway toward long-term potentiation (and possibly also through more complex mechanisms). Finally, we review evidence suggesting that low doses of DA agonists that effectively treat TS decrease both phasic and tonic DA, thereby also reducing the propensity for both tic learning and tic expression, respectively.