Redefining migraine prevention: early treatment with anti-CGRP monoclonal antibodies enhances response in the real world.

BACKGROUND: Anti-CGRP monoclonal antibodies (anti-CGRP MAbs) are approved and available treatments for migraine prevention. Patients do not respond alike and many countries have reimbursement policies, which hinder treatments to those who might respond. This study aimed to investigate clinical factors associated with good and excellent response to anti-CGRP MAbs at 6 months. METHODS: European multicentre, prospective, real-world study, including high-frequency episodic or chronic migraine (CM) patients treated since March 2018 with anti-CGRP MAbs. We defined good and excellent responses as ≥50% and ≥75% reduction in monthly headache days (MHD) at 6 months, respectively. Generalised mixed-effect regression models (GLMMs) were used to identify variables independently associated with treatment response. RESULTS: Of the 5818 included patients, 82.3% were females and the median age was 48.0 (40.0-55.0) years. At baseline, the median of MHD was 20.0 (14.0-28.0) days/months and 72.2% had a diagnosis of CM. At 6 months (n=4963), 56.5% (2804/4963) were good responders and 26.7% (1324/4963) were excellent responders. In the GLMM model, older age (1.08 (95% CI 1.02 to 1.15), p=0.016), the presence of unilateral pain (1.39 (95% CI 1.21 to 1.60), p<0.001), the absence of depression (0.840 (95% CI 0.731 to 0.966), p=0.014), less monthly migraine days (0.923 (95% CI 0.862 to 0.989), p=0.023) and lower Migraine Disability Assessment at baseline (0.874 (95% CI 0.819 to 0.932), p<0.001) were predictors of good response (AUC of 0.648 (95% CI 0.616 to 0.680)). These variables were also significant predictors of excellent response (AUC of 0.691 (95% CI 0.651 to 0.731)). Sex was not significant in the GLMM models. CONCLUSIONS: This is the largest real-world study of migraine patients treated with anti-CGRP MAbs. It provides evidence that higher migraine frequency and greater disability at baseline reduce the likelihood of responding to anti-CGRP MAbs, informing physicians and policy-makers on the need for an earlier treatment in order to offer the best chance of treatment success.

Do Acoustic Characteristics of Dysarthria in People With Parkinson's Disease Differ Across Languages?

PURPOSE: Cross-language studies suggest more similarities than differences in how dysarthria affects the speech of people with Parkinson's disease (PwPD) who speak different languages. In this study, we aimed to identify the relative contribution of acoustic variables to distinguish PwPD from controls who spoke varieties of two Romance languages, French and Portuguese. METHOD: This bi-national, cross-sectional, and case-controlled study included 129 PwPD and 124 healthy controls who spoke French or Portuguese. All participants underwent the same clinical examinations, voice/speech recordings, and self-assessment questionnaires. PwPD were evaluated off and on optimal medication. Inferential analyses included Disease (controls vs. PwPD) and Language (French vs. Portuguese) as factors, and random decision forest algorithms identified relevant acoustic variables able to distinguish participants: (a) by language (French vs. Portuguese) and (b) by clinical status (PwPD on and off medication vs. controls). RESULTS: French-speaking and Portuguese-speaking individuals were distinguished from each other with over 90% accuracy by five acoustic variables (the mean fundamental frequency and the shimmer of the sustained vowel /a/ production, the oral diadochokinesis performance index, the relative sound level pressure and the relative sound pressure level standard deviation of the text reading). A distinct set of parameters discriminated between controls and PwPD: for men, maximum phonation time and the oral diadochokinesis speech proportion were the most significant variables; for women, variables calculated from the oral diadochokinesis were the most discriminative. CONCLUSIONS: Acoustic variables related to phonation and voice quality distinguished between speakers of the two languages. Variables related to pneumophonic coordination and articulation rate were the more effective in distinguishing PwPD from controls. Thus, our research findings support that respiration and diadochokinesis tasks appear to be the most appropriate to pinpoint signs of dysarthria, which are largely homogeneous and language-universal. In contrast, identifying language-specific variables with the speech tasks and acoustic variables studied was less conclusive.

µ-Opioid Receptor Activation at the Dorsal Reticular Nucleus Shifts Diffuse Noxious Inhibitory Controls to Hyperalgesia in Chronic Joint Pain in Male Rats.

BACKGROUND: The dorsal reticular nucleus is a pain facilitatory area involved in diffuse noxious inhibitory control (DNIC) through opioidergic mechanisms that are poorly understood. The hypothesis was that signaling of µ-opioid receptors is altered in this area with prolonged chronic inflammatory pain and that this accounts for the loss of DNICs occurring in this condition. METHODS: Monoarthritis was induced in male Wistar rats (n = 5 to 9/group) by tibiotarsal injection of complete Freund's adjuvant. The immunolabeling of µ-opioid receptors and the phosphorylated forms of µ-opioid receptors and cAMP response element binding protein was quantified. Pharmacologic manipulation of µ-opioid receptors at the dorsal reticular nucleus was assessed in DNIC using the Randall-Selitto test. RESULTS: At 42 days of monoarthritis, µ-opioid receptor labeling decreased at the dorsal reticular nucleus, while its phosphorylated form and the phosphorylated cAMP response element binding protein increased. [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin acetate (DAMGO) enhanced DNIC analgesia in normal animals (means ± SD: pre-DNIC: 126.9 ± 7.0 g; DNIC - DAMGO: 147.5 ± 8.0 g vs. DNIC + DAMGO: 198.1 ± 19.3 g; P < 0.001), whereas it produced hyperalgesia in monoarthritis (pre-DNIC: 67.8 ± 7.5 g; DNIC - DAMGO: 70.6 ± 7.7 g vs. DNIC + DAMGO: 32.2 ± 2.6 g; P < 0.001). An ultra-low dose of naloxone, which prevents the excitatory signaling of the µ-opioid receptor, restored DNIC analgesia in monoarthritis (DNIC - naloxone: 60.0 ± 6.1 g vs. DNIC + naloxone: 98.0 ± 13.5 g; P < 0.001), compared to saline (DNIC - saline: 62.5 ± 5.2 g vs. DNIC + saline: 64.2 ± 3.8 g). When injected before DAMGO, it restored DNIC analgesia and decreased the phosphorylated cAMP response element binding protein in monoarthritis. CONCLUSIONS: The dorsal reticular nucleus is likely involved in a facilitatory pathway responsible for DNIC hyperalgesia. The shift of µ-opioid receptor signaling to excitatory in this pathway likely accounts for the loss of DNIC analgesia in monoarthritis.

Neglect scoring modifications in the National Institutes of Health Stroke Scale improve right hemisphere stroke lesion volume prediction.

BACKGROUND: The National Institutes of Health Stroke Scale (NIHSS) does not equitably assess stroke severity in the two cerebral hemispheres. By attributing a maximum of two points for neglect and seven for language, it undervalues right hemisphere deficits. We aimed to investigate if NIHSS equally predicts right hemisphere lesion volumes in patients with and without neglect, and if a modification of the neglect scoring rules could increase its predictive capacity. METHODS: We analyzed a prospective cohort of acute right middle cerebral artery ischemic stroke patients. First, we calculated the correlation between NIHSS scores and lesion volume and analyzed the partial correlation of neglect. Then, we applied different modifications in the neglect scoring rules and investigated how they interfered with lesion volume predictive capacity. RESULTS: A total of 162 ischemic stroke patients were included, 108 with neglect and 54 without. The correlation between lesion volume and NIHSS was lower in patients with neglect (r = 0.540 vs. r = 0.219, p = 0.004) and neglect was a statistically significant covariate in the partial correlation analysis between NIHSS and lesion volume (p = 0.017). With the neglect score tripled and with the duplication or triplication of all neglect modalities, the correlation was significantly higher than with the standard NIHSS (p = 0.043, p = 0.005, p = 0.001, respectively). With these modifications, neglect was no longer a significant covariable in the partial correlation between lesion volume and NIHSS. CONCLUSION: A modification of NIHSS neglect scoring might improve the scale's capacity to predict lesion volume.

How do opioids control pain circuits in the brainstem during opioid-induced disorders and in chronic pain? Implications for the treatment of chronic pain.

ABSTRACT: Brainstem areas involved in descending pain modulation are crucial for the analgesic actions of opioids. However, the role of opioids in these areas during tolerance, opioid-induced hyperalgesia (OIH), and in chronic pain settings remains underappreciated. We conducted a revision of the recent studies performed in the main brainstem areas devoted to descending pain modulation with a special focus on the medullary dorsal reticular nucleus (DRt), as a distinctive pain facilitatory area and a key player in the diffuse noxious inhibitory control paradigm. We show that maladaptive processes within the signaling of the µ-opioid receptor (MOR), which entail desensitization and a switch to excitatory signaling, occur in the brainstem, contributing to tolerance and OIH. In the context of chronic pain, the alterations found are complex and depend on the area and model of chronic pain. For example, the downregulation of MOR and δ-opioid receptor (DOR) in some areas, including the DRt, during neuropathic pain likely contributes to the inefficacy of opioids. However, the upregulation of MOR and DOR, at the rostral ventromedial medulla, in inflammatory pain models, suggests therapeutic avenues to explore. Mechanistically, the rationale for the diversity and complexity of alterations in the brainstem is likely provided by the alternative splicing of opioid receptors and the heteromerization of MOR. In conclusion, this review emphasizes how important it is to consider the effects of opioids at these circuits when using opioids for the treatment of chronic pain and for the development of safer and effective opioids.

Working memory during spontaneous migraine attacks: an fMRI study.

OBJECTIVE: To investigate the neural correlates of working memory during a spontaneous migraine attack compared to the interictal phase, using functional magnetic resonance imaging (fMRI). BACKGROUND: Cognitive disturbances are commonly observed during migraine attacks, particularly in the headache phase. However, the neural basis of these changes remains unknown. METHODS: In a fMRI within-subject test-retest design study, eleven women (32 years of age, average) with episodic migraine were evaluated twice, first during a spontaneous migraine attack, and again in a pain-free period. Each session consisted in a cognitive assessment and fMRI while performing a working memory task (N-back). RESULTS: Cognitive test scores were lower during the ictal session than in the pain-free session. Regions typically associated with working memory were activated during the N-back task in both sessions. A voxel wise between session comparison showed significantly greater activation in the left frontal pole and orbitofrontal cortex during the attack relative to the interictal phase. CONCLUSION: Migraine patients exhibited greater activation of the left frontal pole and orbitofrontal cortex while executing a verbal working memory task during a spontaneous migraine attack when compared to the interictal state. Given the association of these regions with pain processing and inhibitory control, these findings suggest that patients recruit inhibitory areas to accomplish the cognitive task during migraine attacks, a neural signature of their cognitive difficulties.

Rosin from Pinus pinaster Portuguese forests shows a regular profile of resin acids.

Pinus pinaster forestry occupies >20% of the forest ecosystem area in the continental territory of Portugal with a high impact on the national economy. This species' major derived non-wood product is oleoresin, the raw material for rosin production. Rosin comprises mainly a blend of resin acids and has broad industrial and pharmaceutical applications. Oleoresin production in Portugal has been progressively reduced due to low-cost producers in other countries; currently, it reaches only 2% of the existing P. pinaster trees. To support this value chain, the chemical fingerprint of rosin derived from the national forest requires focused analysis. In the present study, we collected oleoresin within seven geographically distinct pure P. pinaster forests in two consecutive collection years. A high-resolution nuclear magnetic resonance (NMR) method was used to quantify the diversity of resin acids in the corresponding rosin samples. Overall, the acquired data highlighted that the profile of resin acids in P. pinaster rosin produced in Portugal is highly regular, regardless of the forest location, having as the major constituents abietic acid and dehydroabietic acid. The diversity of resin acids is possibly influenced, to a minor extent, by some edaphoclimatic factors.

Real-world effectiveness of fremanezumab for the preventive treatment of migraine: Interim analysis of the pan-European, prospective, observational, phase 4 PEARL study.

BACKGROUND: The ongoing Pan-European Real Life (PEARL) phase 4 study is evaluating fremanezumab effectiveness and safety for the prevention of episodic and chronic migraine. This interim analysis reports primary, secondary and exploratory endpoints from when 500 participants completed at least six months of treatment. METHODS: Adults with episodic migraine or chronic migraine maintaining daily headache diaries were enrolled upon initiation of fremanezumab. Primary endpoint: proportion of participants with ≥50% reduction in monthly migraine days during the six-month period after fremanezumab initiation. Secondary endpoints: mean change from baseline across months 1-12 in monthly migraine days, acute migraine medication use, and headache-related disability. Exploratory endpoint: mean change in headache severity from baseline across months 1-12. Safety was assessed through adverse events reported. RESULTS: Overall, 897 participants were enrolled and 574 included in the effectiveness analyses (episodic migraine, 25.8%; chronic migraine, 74.2%). Of participants with data available, 175/313 (55.9%) achieved ≥50% monthly migraine days reduction during the six-month period post-initiation. Across months 1-12, there were sustained reductions in mean monthly migraine days, acute medication use, disability scores, and headache severity. Few adverse events were reported. CONCLUSION: PEARL interim results support the effectiveness and safety of fremanezumab for migraine prevention in a real-world population across several European countries.Trial registration: encepp.eu: EUPAS35111.

Altered functional connectivity in a sensorimotor-insular network during spontaneous migraine attacks: A resting-state FMRI study.

BACKGROUND: Previous functional magnetic resonance imaging studies have identified brain-connectivity alterations across multiple regions in people with migraine when compared to healthy controls. Few studies have focused on such changes throughout the different phases of the migraine cycle. We aimed to investigate functional connectivity during spontaneous occurring episodic migraine attacks, in comparison to interictal periods. METHODS: Eleven women with episodic migraine without aura underwent two sessions of resting-state fMRI, during and outside of a spontaneous migraine attack. Functional connectivity changes were assessed across canonical resting-state networks, identified by independent component analysis. Significantly altered connectivity was correlated with migraine attack symptoms. RESULTS: Decreased functional connectivity between subregions of the sensorimotor network (specifically, the primary somatosensory and motor cortices) and the posterior insula, bilaterally, was found during attacks. In both sessions, the functional connectivity between these regions was lower in patients who usually suffered longer attacks. DISCUSSION: The sensorimotor and insular regions are involved in nociceptive, autonomic, and somatosensory processing so the finding of reduced connectivity between these structures within a migraine attack is likely associated to the perception of pain and the heighten sensitivity to stimuli experienced in this disorder.

Diffuse noxious inhibitory controls in chronic joint inflammatory Pain: Study of the descending serotonergic modulation mediated through 5HT3 receptors.

The loss of diffuse noxious inhibitory controls (DNIC) is recognized as a predictor of chronic pain. Mechanistically, DNIC produces analgesia by a heterotopically applied conditioning-noxious stimulus (CS) and yet underexplored descending modulatory inputs. Here, we aimed at studying DNIC in monoarthritis (MA) by exploring the spinal component of the descending serotonergic system, specifically 5-hydroxytryptamine 3 receptors (5-HT3R). MA was induced in male Wistar rats by tibiotarsal injection of complete Freund's adjuvant. Mechanical hyperalgesia and DNIC were assessed weekly by the Randall-Selitto test. Immunohistochemistry was used to quantify spinal 5-HT3R, and tryptophan hydroxylase (TPH) colocalization with phosphorylated extracellular signal-regulated protein kinases 1/2 at the rostroventromedial medulla (RVM). Spinal serotonin (5-HT) was quantified by HPLC. The effects of intrathecal ondansetron, a 5-HT3R antagonist, were assessed on mechanical hyperalgesia and DNIC. MA resulted in a prolonged steady-state mechanical hyperalgesia. In contrast, DNIC peaked after 28 days, decreasing afterwards until extinction at 42 days. At this later timepoint, MA rats showed increased: (i) spinal 5-HT3R and 5-HT levels, (ii) neuronal serotonergic activation and TPH expression at the RVM. Ondansetron reversed mechanical hyperalgesia and restored DNIC, regardless of being administered before or after CS. However, data variability was higher upon administration before CS in MA-animals. Prolonged MA upregulates the descending serotonergic modulation, which simultaneously results in increased nociception and DNIC extinction, through 5-HT3R. Our data suggest a role for spinal 5-HT3R in the top-down modulation of DNIC. Additionally, these receptors may also be involved in the bottom-up circuitry implicated in the trigger of DNIC.

The potential of almonds, hazelnuts, and walnuts SFE-CO2 extracts as sources of bread flavouring ingredients.

Nuts have been part of the human diet since our early ancestors, and their use goes beyond nutritional purposes, for example, as aromatic sources for dairy products. This work explores the potential of almond (Prunus dulcis (Mill.) DA Webb), hazelnut (Corylus avellana L.), and walnut (Juglans regia L.) extracts as sources of food flavouring agents, suggesting a new added-value application for lower quality or excess production fruits. The extracts were obtained by supercritical fluid extraction with carbon dioxide and characterized by: quantification of the volatile fraction by HS-SPME GC-MS; sensory perception and description; and cytotoxicity against Vero cells. All extracts revealed potential as flavouring ingredients due to terpene abundance. No significant differences were observed for the minimal sensory perception, in which the odour threshold values ranged from 8.3 × 10-4 to 6.9 × 10-3 µg·mL-1 for walnuts and almonds extracts, respectively. In contrast, the cytotoxic potential differed significantly among the extracts, and P. dulcis extract presented lower cytotoxicity. Notes as woody, fresh, and green were identified in the volatile intensifiers obtained from the P. dulcis extract. Thus, almond extract was identified as the most promising ingredient to increase the sensory value of food products, namely bread. This potential was verified by an increase in the odour perception of bread after adding 4 µL of extract to each 100 g of bread dough. The quantified eucalyptol and d-limonene terpenes - found in the P. dulcis extract - have improved the release of the pleasant and natural volatile compounds from bread crust and crumb compared to the control bread chemical and sensory profiles.

Cranial Autonomic Symptoms and Neck Pain in Differential Diagnosis of Migraine.

Cranial autonomic symptoms and neck pain have been reported to be highly prevalent in migraine, although they are rarely considered in clinical evaluation. The aim of this review is to focus on the prevalence, pathophysiology, and clinical characteristics of these two symptoms, and their importance in the differential diagnosis between migraines and other headaches. The most common cranial autonomic symptoms are aural fullness, lacrimation, facial/forehead sweating, and conjunctival injection. Migraineurs experiencing cranial autonomic symptoms are more likely to have more severe, frequent, and longer attacks, as well as higher rates of photophobia, phonophobia, osmophobia, and allodynia. Cranial autonomic symptoms occur due to the activation of the trigeminal autonomic reflex, and the differential diagnosis with cluster headaches can be challenging. Neck pain can be part of the migraine prodromal symptoms or act as a trigger for a migraine attack. The prevalence of neck pain correlates with headache frequency and is associated with treatment resistance and greater disability. The convergence between upper cervical and trigeminal nociception via the trigeminal nucleus caudalis is the likely mechanism for neck pain in migraine. The recognition of cranial autonomic symptoms and neck pain as potential migraine features is important because they often contribute to the misdiagnosis of cervicogenic problems, tension-type headache, cluster headache, and rhinosinusitis in migraine patients, delaying appropriate attack and disease management.

Locations of objects are better remembered than their identities in naturalistic scenes: An eye-tracking experiment in mild cognitive impairment.

OBJECTIVE: Retaining the identity or location of decontextualized objects in visual short-term working memory (VWM) is impaired by healthy and pathological ageing, but research remains inconclusive on whether these two features are equally impacted by it. Moreover, it is unclear whether similar impairments would manifest in naturalistic visual contexts. METHOD: 30 people with mild cognitive impairment (MCI) and 32 age-matched control participants (CPs) were eye-tracked within a change detection paradigm. They viewed 120 naturalistic scenes, and after a retention interval (1 s) asked whether a critical object in the scene had (or not) changed on either: identity (became a different object), location (same object but changed location), or both (changed in location and identity). RESULTS: MCIs performed worse than CP but there was no interaction with the type of change. Changes in both were easiest while changes in identity alone were hardest. The latency to first fixation and first-pass duration to the critical object during successful recognition was not different between MCIs and CPs. Objects that changed in both features took longer to be fixated for the first time but required a shorter first pass compared to changes in identity alone which displayed the opposite pattern. CONCLUSIONS: Locations of objects are better remembered than their identities; memory for changes is best when involving both features. These mechanisms are spared by pathological ageing as indicated by the similarity between groups besides trivial differences in overall performance. These findings demonstrate that VWM mechanisms in the context of naturalistic scene information are preserved in people with MCI. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Clinical presentation and neural correlates of stroke-associated spatial delusions.

BACKGROUND AND PURPOSE: Incongruent beliefs about self-localization in space markedly disturb patients' behavior. Spatial delusions, or reduplicative paramnesias, are characterized by a firm conviction of place reduplication, transformation, or mislocation. Evidence suggests they are frequent after right hemisphere lesions, but comprehensive information about their clinical features is lacking. METHODS: We prospectively screened 504 acute right-hemisphere stroke patients for the presence of spatial delusions. Their behavioral and clinical features were systematically assessed. Then, we analyzed the correlation of their duration with the magnitude of structural disruption of belief-associated functional networks. Finally, we described the syndrome subtypes and evaluated whether the clinical categorization would be predicted by the structural disruption of familiarity-associated functional networks using an unsupervised k-means clustering algorithm. RESULTS: Sixty patients with spatial delusions were identified and fully characterized. Most (93%) localized the misidentified places closer to home than the hospital. The median time duration was 3 days (interquartile range = 1-7 days), and it was moderately correlated with the magnitude of structural-functional decoupling of belief-associated functional networks (r = 0.39, p = 0.02; beta coefficient regressing for lesion volume = 3.18, p = 0.04). Each clinical subtype had characteristic response patterns, which were reported, and representative examples were provided. Clustering based on structural disruption of familiarity- and unfamiliarity-associated functional networks poorly matched the clinical categorization (lesion: Rand index = 0.47; structural disconnection: Rand index = 0.51). CONCLUSIONS: The systematic characterization of the peculiar clinical features of stroke-associated spatial delusions may improve the syndrome diagnosis and clinical approaches. The novel evidence about their neural correlates fosters the clarification of the pathophysiology of delusional misidentifications.

Knowing the Enemy Is Halfway towards Victory: A Scoping Review on Opioid-Induced Hyperalgesia.

Opioid-induced hyperalgesia (OIH) is a paradoxical effect of opioids that is not consensually recognized in clinical settings. We conducted a revision of clinical and preclinical studies and discuss them side by side to provide an updated and renewed view on OIH. We critically analyze data on the human manifestations of OIH in the context of chronic and post-operative pain. We also discuss how, in the context of cancer pain, though there are no direct evidence of OIH, several inherent conditions to the tumor and chemotherapy provide a substrate for the development of OIH. The review of the clinical data, namely in what concerns the strategies to counter OIH, emphasizes how much OIH rely mechanistically on the existence of µ-opioid receptor (MOR) signaling through opposite, inhibitory/antinociceptive and excitatory/pronociceptive, pathways. The rationale for the maladaptive excitatory signaling of opioids is provided by the emerging growing information on the functional role of alternative splicing and heteromerization of MOR. The crossroads between opioids and neuroinflammation also play a major role in OIH. The latest pre-clinical data in this field brings new insights to new and promising therapeutic targets to address OIH. In conclusion, although OIH remains insufficiently recognized in clinical practice, the appropriate diagnosis can turn it into a treatable pain disorder. Therefore, in times of scarce alternatives to opioids to treat pain, mainly unmanageable chronic pain, increased knowledge and recognition of OIH, likely represent the first steps towards safer and efficient use of opioids as analgesics.

Cognitive testing in late-stage Parkinson's disease: A critical appraisal of available instruments.

OBJECTIVE: For patients with Parkinson's disease (PD), cognitive impairment is one of the most disabling non-motor symptoms, particularly in the late disease stages (LSPD). Without a common cognitive assessment battery, it is difficult to estimate its prevalence and limits comparisons across studies. In addition, some instruments traditionally used in PD may not be adequate for use in LSPD. We sought to identify instruments used to assess cognition in LSPD and to investigate their global characteristics and psychometric properties to recommend a cognitive battery for the LSPD population. METHOD: We conducted a literature search of EMBASE and MEDLINE for articles reporting the use of cognitive tests in LSPD. The global characteristics and psychometric properties of the four most used cognitive tests in each cognitive domain were verified to recommend a cognitive assessment battery. RESULTS: Of 60 included studies, 71.7% used screening scales to assess cognition. Of the 53 reported instruments, the Montreal Cognitive Assessment, the Digit Span, the Trail Making Test, the Semantic Fluency test, the Rey Auditory Verbal Learning Test, the Brief Visuospatial Memory Test-Revised, the Boston Naming Test, the Judgment of Line Orientation, and the Clock Drawing Test corresponded best overall to the requirements considered important for selecting instruments in LSPD. CONCLUSION: Screening scales are frequently used to assess cognition in LSPD. We recommend a cognitive assessment battery that considers the special characteristics of the LSPD population, including being quick and easy to use, with minimized motor demands, and covering all relevant cognitive domains.

Untargeted Metabolomics Sheds Light on the Secondary Metabolism of Fungi Triggered by Choline-Based Ionic Liquids.

Fungal secondary metabolites constitute a rich source of yet undiscovered bioactive compounds. Their production is often silent under standard laboratory conditions, but the production of some compounds can be triggered simply by altering the cultivation conditions. The usage of an organic salt - ionic liquid - as growth medium supplement can greatly impact the biosynthesis of secondary metabolites, leading to higher diversity of compounds accumulating extracellularly. This study examines if such supplements, specifically cholinium-based ionic liquids, can support the discovery of bioactive secondary metabolites across three model species: Neurospora crassa, Aspergillus nidulans, and Aspergillus fumigatus. Enriched organic extracts obtained from medium supernatant revealed high diversity in metabolites. The supplementation led apparently to increased levels of either 1-aminocyclopropane-1-carboxylate or α-aminoisobutyric acid. The extracts where bioactive against two major foodborne bacterial strains: Staphylococcus aureus and Escherichia coli. In particular, those retrieved from N. crassa cultures showed greater bactericidal potential compared to control extracts derived from non-supplemented cultures. An untargeted mass spectrometry analysis using the Global Natural Product Social Molecular Networking tool enabled to capture the chemical diversity driven by the ionic liquid stimuli. Diverse macrolides, among other compounds, were putatively associated with A. fumigatus; whereas an unexpected richness of cyclic (depsi)peptides with N. crassa. Further studies are required to understand if the identified peptides are the major players of the bioactivity of N. crassa extracts, and to decode their biosynthesis pathways as well.