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Objective: In this pilot prospective cohort study, we aimed to evaluate, using high‐density electroencephalography (HD‐EEG), the longitudinal changes in functional connectivity (FC) in patients with chronic migraine (CM) treated with onabotulinumtoxinA (OBTA). Background: OBTA is a treatment for CM. Several studies have shown the modulatory action of OBTA on the central nervous system; however, research on migraine is limited. Methods: This study was conducted at the Neurology Unit of "Policlinico Tor Vergata," Rome, Italy, and included 12 adult patients with CM treated with OBTA and 15 healthy controls (HC). Patients underwent clinical scales at enrollment (T0) and 3 months (T1) from the start of treatment. HD‐EEG was recorded using a 64‐channel system in patients with CM at T0 and T1. A source reconstruction method was used to identify brain activity. FC in δ‐θ‐α‐β‐low‐γ bands was analyzed using the weighted phase‐lag index. FC changes between HCs and CM at T0 and T1 were assessed using cross‐validation methods to estimate the results' reliability. Results: Compared to HCs at T0, patients with CM showed hyperconnected networks in δ (p = 0.046, area under the receiver operating characteristic curve [AUC: 0.76‐0.98], Cohen's κ [0.65‐0.93]) and β (p = 0.031, AUC [0.68‐0.95], Cohen's κ [0.51‐0.84]), mainly involving orbitofrontal, occipital, temporal pole and orbitofrontal, superior temporal, occipital, cingulate areas, and hypoconnected networks in α band (p = 0.029, AUC [0.80‐0.99], Cohen's κ [0.42‐0.77]), predominantly involving cingulate, temporal pole, and precuneus. Patients with CM at T1, compared to T0, showed hypoconnected networks in δ band (p = 0.032, AUC [0.73‐0.99], Cohen's κ [0.53‐0.90]) and hyperconnected networks in α band (p = 0.048, AUC [0.58‐0.93], Cohen's κ [0.37‐0.78]), involving the sensorimotor, orbitofrontal, cingulate, and temporal cortex. Conclusion: These preliminary results showed that patients with CM presented disrupted EEG‐FC compared to controls restored by a single session of OBTA treatment, suggesting a primary central modulatory action of OBTA. Plain Language Summary: Chronic migraine, a disabling neurological condition, can be treated with onabotulinumtoxin A (OBTA) which works by blocking the release of pain‐related substances from a major nerve of the head. This study aimed to learn how OBTA affects the message pathways in the brain by comparing the electrical activity in the brains of patients with migraine who were treated with OBTA and the electrical activity in the brains of healthy people. We found that patients with migraine had significant changes in several brain areas that were restored after just one session of OBTA treatment, confirming a primary action of OBTA on the brain's electrical activity. [ABSTRACT FROM AUTHOR]

Background and purpose: Idiopathic normal pressure hydrocephalus (iNPH) pathogenesis is multifactorial. Systemic inflammation might have a role in gathering clinical–pathological trajectories. We aimed to shape the peripheral immune profile of iNPH and establish correlations with cerebrospinal fluid (CSF) markers, ventricular enlargement, and clinical outcomes. Methods: We conducted a single‐center retrospective–longitudinal study, including 38 iNPH patients and 38 controls. Baseline iNPH Grading Scale and modified Rankin Scale (mRS) scores were collected with peripheral blood cell count, CSF amyloid‐β42 (Aβ42), total tau (t‐tau), phosphorylated‐181‐tau, and Evans index. Depending on 5‐year outcome, iNPH patients were grouped into "poor outcome" (PO; mRS ≥ 5) and "favorable outcome" (FO; mRS < 5). Biomarkers were compared and correlated with each other. Receiver operating characteristic analysis was performed. Results: iNPH patients compared to controls had higher neutrophil‐to‐lymphocyte ratio (NLR; 2.43 ± 1.04 vs. 1.61 ± 0.47, p < 0.001), higher neutrophils (4.22 ± 0.86 1000/mL vs. 3.48 ± 1.34, p = 0.033), and lower lymphocytes (1.45 ± 0.55 1000/mL vs. 2.07 ± 0.86, p = 0.038), with the expected CSF biomarkers signature. In the patients' cohort, NLR was associated directly with t‐tau and inversely with Aβ42. NLR directly correlated with Evans index. PO patients compared to those with FO had higher NLR (3.25 ± 1.40 vs. 2.01 ± 0.77, p = 0.035) and higher t‐tau (274.76 ± 114.39 pg/mL vs. 150.28 ± 72.62, p = 0.017), with an area under the curve of 0.786 and 0.793, respectively. Conclusions: iNPH patients present a proinflammatory state associated with neurodegeneration and predicting poor clinical outcome. Systemic inflammation represents a factor in the clinical–pathological progression of iNPH, and the NLR emerges as a potential prognostic index. [ABSTRACT FROM AUTHOR]

Introduction: Inflammation is an important player in Alzheimer's disease (AD), whose effects can be influenced by the blood–brain barrier (BBB). Here, we investigated the relationship between BBB permeability, indicated by cerebrospinal fluid (CSF)/plasma albumin quotient (Qalb), and CSF indexes of neuroinflammation in a cohort of biologically defined AD patients. Methods: Fifty‐nine consecutive patients with mild cognitive impairment (MCI) or early AD (Mini‐Mental State Examination [MMSE] >22) underwent CSF analysis for inflammatory cytokines (interleukin [IL]‐1β, IL‐2, IL‐4, IL‐5, IL‐6, IL‐7, IL‐8, Il‐10, IL‐12, IL‐13, IL‐17, tumor necrosis factor‐α [TNF‐α], interferon‐γ [IFN‐γ], granulocyte‐monocyte colony‐stimulating factor [GM‐CSF], granulocyte colony‐stimulating factor [G‐CSF]). Using backward stepwise linear regression analysis, we explored the potential influence of each cytokine CSF level on Qalb considering age, sex, and apolipoprotein E (APOE) as covariates. Results: Higher levels of IL‐4 (β = 0.356, 0.005) and IL‐8 (β = 0.249, 0.05) were associated with higher Qalb values, while macrophage inflammatory protein‐1α (MIP‐1β) (β = −0.274; p = 0.032) and TNF‐α (β = −0.248; p = 0.031) showed a significant negative association with BBB permeability. Age was also positively associated with Qalb (β = 0.283; p = 0.016). Conclusions: Despite the overall integrity of the BBB, its permeability could either influence or be influenced by central neuroinflammation, reflected by CSF cytokine levels. This is in line with previous studies that showed that patients with a more intact barrier are those with more prominent neurodegeneration. Our findings suggest that different neuroinflammatory profiles can be associated with different levels of BBB permeability in AD. [ABSTRACT FROM AUTHOR]

Background: Functional connectivity (FC) has shown promising results in assessing the pathophysiology and identifying early biomarkers of neurodegenerative disorders, such as Parkinson's disease (PD). Objectives: In this study, we aimed to assess possible resting‐state FC abnormalities in early‐stage PD patients using high‐density electroencephalography (EEG) and to detect their clinical relationship with motor and non‐motor PD symptoms. Methods: We enrolled 26 early‐stage levodopa naïve PD patients and a group of 20 healthy controls (HC). Data were recorded with 64‐channels EEG system and a source‐reconstruction method was used to identify brain‐region activity. FC was calculated using the weighted phase‐lag index in θ, α, and β bands. Additionally, we quantified the unbalancing between β and lower frequencies through a novel index (β‐functional ratio [FR]). Statistical analysis was conducted using a network‐based statistical approach. Results: PD patients showed hypoconnected networks in θ and α band, involving prefrontal‐limbic‐temporal and frontoparietal areas, respectively, and a hyperconnected network in the β frequency band, involving sensorimotor‐frontal areas. The θ FC network was negatively related to Non‐Motor Symptoms Scale scores and α FC to the Movement Disorder Society‐Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III gait subscore, whereas β FC and β‐FR network were positively linked to the bradykinesia subscore. Changes in θ FC and β‐FR showed substantial reliability and high accuracy, precision, sensitivity, and specificity in discriminating PD and HC. Conclusions: Frequency‐specific FC changes in PD likely reflect the dysfunction of distinct cortical networks, which occur from the early stage of the disease. These abnormalities are involved in the pathophysiology of specific motor and non‐motor PD symptoms, including gait, bradykinesia, mood, and cognition. © 2023 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background and purpose: Parkinson disease (PD) presents relevant sex‐related differences in epidemiology, pathophysiology, and clinical features, with males being more vulnerable to the disease. Sex hormones might have a role, as the experimental models suggest; however, human‐based evidence is scarce. Here, we integrated multimodal biomarkers to investigate the relationships between circulating sex hormones and clinical–pathological features in male PD patients. Methods: A cohort of 63 male PD patients underwent comprehensive clinical evaluation of motor and nonmotor disturbances; measurement of estradiol, testosterone, follicle‐stimulating hormone (FSH), and luteinizing hormone (LH) blood levels; and cerebrospinal fluid (CSF) assay of total α‐synuclein, amyloid‐β‐42, amyloid‐β‐40, total tau, and phosphorylated‐181 tau levels. A subgroup of 47 PD patients underwent brain volumetry by 3‐T magnetic resonance imaging for further correlations. A control group of 56 age‐matched individuals was enrolled for comparative analyses. Results: Male PD patients had higher estradiol and testosterone levels than controls. Estradiol had independent inverse associations with Movement Disorder Society–Unified Parkinson's Disease Rating Scale Part 3 score and disease duration; it was also lower in nonfluctuating patients. Testosterone had inverse independent correlations with CSF α‐synuclein and right globus pallidus volume. FSH and LH had age‐dependent correlations with cognitive impairment and CSF amyloid‐β‐42/amyloid‐β‐40 ratio. Conclusions: The study suggested that sex hormones could differentially contribute to clinical–pathological features of PD in male patients. Whereas estradiol might have a protective role in motor impairment, testosterone might be involved in male vulnerability to PD neuropathology. Gonadotropins instead might mediate age‐dependent phenomena of amyloidopathy and cognitive decline. [ABSTRACT FROM AUTHOR]

Background and Purpose: The locus coeruleus (LC) provides dopamine/noradrenaline (DA/NA) innervation throughout the brain and undergoes early degeneration in Alzheimer's disease (AD). We evaluated catecholaminergic enzyme levels in the cerebrospinal fluid (CSF) of a group of patients biologically defined as within the AD continuum (ADc) and explored their relationship with AD biomarkers and cytokine/growth factor levels to investigate their interplay with neurodegenerative and neuroinflammatory processes. Methods: The CSF concentration of DA transporter (DAT), tyrosine‐hydroxylase (TH), DOPA‐decarboxylase (DDC), and dopamine‐β‐hydroxylase (DβH), as well as cytokine/growth factor levels, were analyzed in 41 ADc patients stratified according to CSF beta‐amyloid (Aβ)1‐42 (A) and p‐tau (T) in AD pathological changes (A+ T‐) and AD (A+ T+) subgroups, as well as in 15 control subjects (A‐ T‐). Results: The ADc group had lower CSF levels of DAT and TH but increased DβH levels to compensate for NA synthesis. DDC levels were higher in the A+ T+ subgroup but comparable with controls in the A+ T– subgroup, probably because the DA system is resilient to the degeneration of LC neurons in the absence of tau pathology. Adjusting for age, sex, APOE genotype, and cognitive status, a significant association was found between TH and Aβ1‐42 (R2 = 0.25) and between DDC and p‐tau (R2 = 0.33). Finally, TH correlated with interleukin (IL)‐10 levels (p = 0.0008) and DβH with IL‐1β (p = 0.03), IL‐4 (p = 0.02), granulocyte colony‐stimulating factor (p = 0.007), and IL‐17 (p = 0.01). Conclusions: Taken together, these findings suggest that catecholaminergic enzymes, functional markers of the catecholaminergic system, are closely linked to the neurodegenerative and neuroinflammatory processes in AD pathology. [ABSTRACT FROM AUTHOR]

Objective: Sleep impairment is one of the most common comorbidities affecting people with epilepsy (PWE). The bidirectional relation between epilepsy and sleep has been widely established. Several studies investigated subjective sleep quality and daytime vigilance in PWE, highlighting frequent complaints of sleep fragmentation, difficulties in falling asleep, and daytime sleepiness. The present study aimed to evaluate sleep structure in drug‐naive PWE, distributed on the basis of epilepsy type, and compared with controls. Methods: This observational study included adult patients newly diagnosed with epilepsy and drug‐naive as well as a control group of healthy subjects. All PWE and controls underwent a dynamic 24‐h EEG with signals for sleep recording to evaluate sleep architecture, structure, continuity, and fragmentation. Results: Twenty‐four PWE were included and distributed in two groups based on epilepsy type. Eleven patients were included in the generalized epilepsy group (63.6% male; 34.91 ± 9.80 years) and 13 patients in the focal epilepsy group (53.8% male; 38.69 ± 12.74 years). The control group included 16 subjects (56.3% male; 32.75 ± 12.19 years). Patients with generalized or focal epilepsy had a significantly lower sleep efficiency than controls. Moreover, both patient groups presented the alteration of markers of sleep fragmentation and loss of continuity, with higher indices of sleep stage transitions and arousal. Finally, the two patient groups presented less REM sleep than controls. Significance: This study highlighted the alteration of sleep quality, continuity, and stability in both patients with focal or generalized epilepsy compared with controls, also in the absence of ictal events. This sleep impairment resulted in the reduction of REM sleep. Therefore, these findings may be explained by the increase in awakenings and sleep stage shifts, which may be attributed to both sleep networks impairment and neurotransmission dysfunction in PWE, and also possibly triggered by paroxysmal interictal abnormalities. [ABSTRACT FROM AUTHOR]

Background: The accumulation of α‐synuclein (α‐syn) fibrils in intraneuronal inclusions called Lewy bodies and Lewy neurites is a pathological signature of Parkinson's disease (PD). Although several aspects linked to α‐syn–dependent pathology (concerning its spreading, aggregation, and activation of inflammatory and neurodegenerative processes) have been under intense investigation, less attention has been devoted to the real impact of α‐syn overexpression on structural and functional properties of substantia nigra pars compacta (SNpc) dopamine (DA) neurons, particularly at tardive stages of α‐syn buildup, despite this has obvious relevance to comprehending mechanisms beyond PD progression. Objectives: We aimed to determine the consequences of a prolonged α‐syn overexpression on somatodendritic morphology and functions of SNpc DA neurons. Methods: We performed immunohistochemistry, stereological DA cell counts, analyses of dendritic arborization, ex vivo patch‐clamp recordings, and in vivo DA microdialysis measurements in a 12‐ to 13‐month‐old transgenic rat model overexpressing the full‐length human α‐syn (Snca+/+) and age‐matched wild‐type rats. Results: Aged Snca+/+ rats have mild loss of SNpc DA neurons and decreased basal DA levels in the SN. Residual nigral DA neurons display smaller soma and compromised dendritic arborization and, in parallel, increased firing activity, switch in firing mode, and hyperexcitability associated with hypofunction of fast activating/inactivating voltage‐gated K+ channels and Ca2+‐ and voltage‐activated large conductance K+ channels. These intrinsic currents underlie the repolarization/afterhyperpolarization phase of action potentials, thus affecting neuronal excitability. Conclusions: Besides clarifying α‐syn–induced pathological landmarks, such evidence reveals compensatory functional mechanisms that nigral DA neurons could adopt during PD progression to counteract neurodegeneration. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Epilepsy is increasing, being more common in older adults, with more than 20% of late‐onset cases with unknown aetiology (LOEU). Although epilepsy was associated with cognitive impairment, few studies evaluated the trajectories of cognitive decline in patients with LOEU. The present study aimed at assessing biomarkers of Alzheimer's disease (AD) in patients with LOEU and evaluating their cognitive performance for 12 months. For this study, 55 patients diagnosed with LOEU and 21 controls were included. Participants underwent cognitive evaluation and cerebrospinal fluid (CSF) biomarker analysis (ß‐amyloid42, tau proteins) before starting anti‐seizure medication and then repeated the cognitive evaluation at the 12‐month follow‐up. A subgroup of LOEU patients and controls also performed 18F‐fluoro‐2‐deoxy‐D‐glucose positron emission tomography (18F‐FDG PET) before starting anti‐seizure medication. At baseline, LOEU patients showed lower Mini‐Mental State Examination (MMSE) score, worse cognitive performance in several domains, lower β‐amyloid42 and higher tau proteins CSF levels than controls. Significantly reduced glucose consumption was observed in the right posterior cingulate cortex and left praecuneus areas in LOEU patients than controls, and this finding correlated with memory impairment. In the longitudinal analysis, a significant decrease in MMSE and an increase in verbal fluency scores were found in LOEU patients. These findings evidence that LOEU patients have a significant cognitive impairment, and alteration of cerebral glucose consumption and CSF AD biomarkers than controls. Moreover, they showed a progressive global cognitive decline at follow‐up, although verbal fluency was preserved. Further studies are needed to better understand the pathophysiological aspects of LOEU and its association with AD. [ABSTRACT FROM AUTHOR]

Background: Lenabasum is a synthetic cannabinoid receptor type‐2 (CB2) agonist able to exert potent anti‐inflammatory effects, but its role on T cells remains unknown. Objectives: The present study was undertaken to investigate anti‐inflammatory mechanisms of lenabasum in T lymphocyte subsets and its in vivo therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE). Methods: Mononuclear cells from 17 healthy subjects (HS) and 25 relapsing–remitting multiple sclerosis (RRMS) patients were activated in presence or absence of lenabasum and analysed by flow cytometry and qRT‐PCR. EAE mice were treated with lenabasum, and clinical score and neuroinflammation were evaluated. Results: Lenabasum significantly reduced TNF‐a production from CD4+ T cells and CD8+ T cells in a dose‐dependent manner in both HS and RRMS patients. In MS patients, lenabasum also reduced activation marker CD25 and inhibited IL‐2 production from both T cell subsets and IFN‐γ and IL‐17 from committed Th1 and Th17 cells, respectively. These effects were blocked by the pretreatment with selective CB2 inverse agonist SR144528. In vivo treatment of EAE mice with lenabasum significantly ameliorated disease severity, reduced neuroinflammation and demyelination in spinal cord. Conclusion: Lenabasum exerts potent T cell‐mediated immunomodulatory effects, suggesting CB2 as a promising pharmacological target to counteract neuroinflammation in MS. [ABSTRACT FROM AUTHOR]

Background and purpose: Diabetes mellitus (DM) is considered a risk factor for Alzheimer's disease (AD) and shares some pathological pathways, such as activation of amyloid cascade and tau phosphorylation. The aim of the present study was to investigate to what extent DM could impact on neurodegeneration within the AD continuum, using β amyloid (A: Aβ1‐42) and phosphorylated tau (T: p‐tau) biomarkers to discriminate patients by Alzheimer's pathological change (A+/T–) and AD (A+/T+), according to the National Institute on Aging and Alzheimer's Association classification. In addition, we aimed to evaluate whether APOE genotype interacts with tau protein and glucose metabolism dysfunction to affect the pathological process. Methods: For this retrospective observational study, 1350 patients were recruited. The patients underwent a complete clinical investigation, neuropsychological assessment, lumbar puncture for cerebrospinal fluid (CSF) biomarkers analysis and APOE genotyping. Results: A total of 607 patients fulfilled the clinical criteria of mild cognitive impairment or early dementia. In A+T– patients (n = 350), DM did not influence CSF biomarker levels, while among A+T+ patients (n = 257) those with DM showed increased total tau (t‐tau) levels compared to non‐DM patients (DM: 919.4 ± 444 vs. non‐DM: 773.1 ± 348.2; p = 0.04), but similar p‐tau (p = 0.72) and Aβ1‐42 levels (p = 0.83). Furthermore, multivariable regression analyses showed a significant association between DM and t‐tau CSF levels, adjusting for age and sex, in APOE E4+ carriers (coefficient 222.83, 95% confidence interval 47.49–398.1; p = 0.01), but not in APOE E4‐ (p = 0.53). Conclusions: The present study shows a clear dependency of CSF t‐tau levels on DM for APOE E4+ AD patients, suggesting important differences between APOE E4‐related and non‐related disease, with key implications for AD pathophysiology and treatment. [ABSTRACT FROM AUTHOR]

Background: COVID‐19 outbreak profoundly affected health systems and people's daily life worldwide. Parkinson's disease (PD) patients lost their normal routine and interrupted regular physical activity, either as physiotherapy or sport, with inevitable consequence on their daily‐life and well‐being. Objectives: To evaluate the changes in physical activity due to COVID‐19 emergency, including self‐management strategies or technology‐assisted activities, and the subsequent clinical implications in PD patients. Methods: Seventy‐four patients from an Italian center have been remotely examined during the lockdown (April–May 2020) by an e‐mail structured survey, including self‐administered scales. We collected and analyzed data on changes, modalities and amount of physical active practice, on the use of technology‐based tools, and on self‐perceived clinical condition. Results: Sixty percent of patients reported a significant worsening of their general conditions during the lockdown, the reduction of physical activity being the main risk factor for such change. However, patients found ways to practice physical activity, using satisfactorily technology assistance in 50% of cases (mostly women). Conclusions: The COVID‐19 emergency has been an ordeal for PD patients. Nevertheless, patients adapted their habits to continue practicing physical activity that resulted a main determinant of their well‐being; as well, they successfully approached technology‐based assistance. Education, communication, and networking emerge as critical for a constructive reaction to the emergency's challenges. [ABSTRACT FROM AUTHOR]

Introduction. Pisa syndrome (PS) is a postural complication of Parkinson’s disease (PD). Yet, its pathophysiology remains unclear, although a multifactorial component is probable. Cervical vestibular evoked myogenic potentials (cVEMPs) explore vestibulospinal pathway, but they have not been measured yet in PD patients with PS (PDPS) to assess a potential vestibular impairment. Materials and Methods. We enrolled 15 PD patients, 15 PDPS patients, and 30 healthy controls (HCs). They underwent neurological examination and were examined with Unified Parkinson’s Disease Rating Scale II-III (UPDRSII-III), audiovestibular workup, and cVEMP recordings. Data were analysed with Chi-square, one-way ANOVA, multinomial regression, nonparametric, and Spearman’s tests. Results. cVEMPs were significantly impaired in both PD and PDPS compared with HCs. PDPS exhibited more severe cVEMP abnormalities with prevalent bilateral loss of potentials, compared with the PD group, in which a prevalent unilateral loss was instead observed. No clinical-neurophysiological correlations emerged. Conclusions. Differently from HC, cVEMPs are altered in PD. Severity of cVEMPs alterations increases from PD without PS to PDPS, suggesting an involvement of vestibulospinal pathway in the pathophysiology of PS. Our results provide evidence for a significant impairment of cVEMPs in PDPS patients and encourage further studies to test validity of cVEMPs as diagnostic and prognostic biomarkers of PD progression. [ABSTRACT FROM AUTHOR]

Background and Purpose: One of the hallmarks of ventral midbrain dopamine-releasing neurons is membrane hyperpolarization in response to stimulation of somato-dendritic D2 receptors. At early postnatal age, under sustained dopamine, this inhibitory response is followed by a slow recovery, resulting in dopamine inhibition reversal (DIR). In the present investigation, we aimed to get a better insight into the cellular mechanisms underlying DIR.Experimental Approach: We performed single-unit extracellular recordings with a multi-electrode array device and conventional patch-clamp recordings on midbrain mouse slices.Key Results: While continuous dopamine (100 μM) perfusion gave rise to firing inhibition that recovered in 10 to 15 min, the same effect was not obtained with the D2 receptor agonist quinpirole (100 nM). Moreover, firing inhibition caused by the GABAB receptor agonist baclofen (300 nM) was reversed by dopamine (100 μM), albeit D2 receptors had been blocked by sulpiride (10 μM). Conversely, the block of the dopamine transporter (DAT) with cocaine (30 μM) prevented firing recovery by dopamine under GABAB receptor stimulation. Accordingly, in whole-cell recordings from single cells, the baclofen-induced outward current was counteracted by dopamine (100 μM) in the presence of sulpiride (10 μM), and this effect was prevented by the DAT antagonists cocaine (30 μM) and GBR12909 (2 μM).Conclusions and Implications: Our results indicate that the DAT plays a major role in DIR, mediating it under conditions of sustained dopamine exposure, and point to DAT as an important target for pharmacological therapies leading to prolonged enhancement of the dopaminergic signal. [ABSTRACT FROM AUTHOR]

Background: Mu opioid receptor activation modulates acetylcholine release in the dorsal striatum, an area deeply involved in motor function, habit formation, and reinforcement learning as well as in the pathophysiology of different movement disorders, such as dystonia. Although the role of opioids in drug reward and addiction is well established, their involvement in motor dysfunction remains largely unexplored.Methods: We used a multidisciplinary approach to investigate the responses to mu activation in 2 mouse models of DYT1 dystonia (Tor1a+/Δgag mice, Tor1a+/- torsinA null mice, and their respective wild-types). We performed electrophysiological recordings to characterize the pharmacological effects of receptor activation in cholinergic interneurons as well as the underlying ionic currents. In addition, an analysis of the receptor expression was performed both at the protein and mRNA level.Results: In mutant mice, selective mu receptor activation caused a stronger G-protein-dependent, dose-dependent inhibition of firing activity in cholinergic interneurons when compared with controls. In Tor1a+/- mice, our electrophysiological analysis showed an abnormal involvement of calcium-activated potassium channels. Moreover, in both models we found increased levels of mu receptor protein. In addition, both total mRNA and the mu opioid receptor splice variant 1S (MOR-1S) splice variant of the mu receptor gene transcript, specifically enriched in striatum, were selectively upregulated.Conclusion: Mice with the DYT1 dystonia mutation exhibit an enhanced response to mu receptor activation, dependent on selective receptor gene upregulation. Our data suggest a novel role for striatal opioid signaling in motor control, and more important, identify mu opioid receptors as potential targets for pharmacological intervention in dystonia. © 2017 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

We studied the properties of dopaminergic neurons in the substantia nigra pars compacta ( SNpc) and ventral tegmental area ( VTA) in mice expressing the enhanced green fluorescent protein ( eGFP) under the control of the tyrosine hydroxylase promoter ( TH- GFP). By using a practical map of cell positioning in distinct SNpc and VTA subregions in horizontal midbrain slices we saw that the spontaneous firing, membrane properties, cell body size and magnitude of the hyperpolarization-activated current ( Ih) in TH- GFP-positive neurons ( TH- GFP+) vary significantly among subregions, following a mediolateral gradient. Block of Ih with Zd7288 inhibited firing in the most lateral subregions, but had little effect in the intermediate/medial VTA. In addition, TH- GFP+ cells were excited by Met5-Enkephalin. Extracellular recordings from a large neuron number showed that all TH- GFP+ cells were inhibited by dopamine, suggesting that this is a reliable approach for identifying dopaminergic neurons in vitro. Simultaneous recordings from dopamine-sensitive and dopamine-insensitive neurons showed that dopamine-insensitive cells (putative non-dopaminergic neurons) are unaffected by Zd7288 but inhibited by Met5-Enkephalin. Under patch-clamp, dopamine generated a quantitatively similar outward current in most TH- GFP+ neurons, although medial VTA cells showed reduced dopamine sensitivity. Pargyline prolonged the dopamine current, whereas cocaine enhanced dopamine-mediated responses in both the SNpc and the VTA. Our work provides new insights into the variability in mouse midbrain dopaminergic neurons along the medial-lateral axis and points to the necessity of a combination of different electrophysiological and pharmacological approaches for reliably identifying these cells to distinguish them from non-dopaminergic neurons in the midbrain. [ABSTRACT FROM AUTHOR]

Parkinson's disease ( PD) is a common neurodegenerative disorder with prominent loss of nigro-striatal dopaminergic neurons. The resultant dopamine ( DA) deficiency underlies the onset of typical motor symptoms ( MS). Nonetheless, individuals affected by PD usually show a plethora of nonmotor symptoms ( NMS), part of which may precede the onset of motor signs. Besides DA neuron degeneration, a key neuropathological alteration in the PD brain is Lewy pathology. This is characterized by abnormal intraneuronal (Lewy bodies) and intraneuritic (Lewy neurites) deposits of fibrillary aggregates mainly composed of α-synuclein. Lewy pathology has been hypothesized to progress in a stereotypical pattern over the course of PD and α-synuclein mutations and multiplications have been found to cause monogenic forms of the disease, thus raising the question as to whether this protein is pathogenic in this disorder. Findings showing that the majority of α-synuclein aggregates in PD are located at presynapses and this underlies the onset of synaptic and axonal degeneration, coupled to the fact that functional connectivity changes correlate with disease progression, strengthen this idea. Indeed, by altering the proper action of key molecules involved in the control of neurotransmitter release and re-cycling as well as synaptic and structural plasticity, α-synuclein deposition may crucially impair axonal trafficking, resulting in a series of noxious events, whose pressure may inevitably degenerate into neuronal damage and death. Here, we provide a timely overview of the molecular features of synaptic loss in PD and disclose their possible translation into clinical symptoms through functional disconnection. [ABSTRACT FROM AUTHOR]

Narcolepsy is characterized by hypocretin deficiency due to the loss of hypothalamic orexinergic neurons, and is associated with both the human leucocyte antigen DQB1*06:02 and the T cell receptor polymorphism. The above relationship suggests autoimmune/inflammatory processes underlying the loss of orexinergic neurons in narcolepsy. To test the autoimmune/inflammatory hypothesis by means of cerebrospinal fluid (CSF) levels of beta-amyloid1-42 and/or total tau proteins in a sample of narcoleptic patients, we analysed 16 narcoleptic patients and 16 healthy controls. Beta-amyloid1-42 CSF levels were significantly lower in narcoleptic patients compared with healthy controls. We also documented pathologically low levels of CSF beta-amyloid1-42 (<500 pg mL-1) in six of 16 narcoleptic patients (37.5%). We hypothesize that the significant decrease of the CSF beta-amyloid1-42 levels in narcoleptic patients may support both the inflammatory/autoimmune hypothesis as the basis of the pathogenesis of narcolepsy and the prevalence of an 'amyloidogenic' pathway caused by the deficiency of the alpha-secretases enzymes. [ABSTRACT FROM AUTHOR]

For many years after its discovery, hydrogen peroxide (H₂O₂) was viewed as a toxic molecule to human tissues; however, in light of recent findings, it is being recognized as an ubiquitous endogenous molecule of life as its biological role has been better elucidated. Indeed, increasing evidence suggests that H₂O₂ may act as a second messenger with a pro-survival role in several physiological processes. In addition, our group has recently demonstrated neuroprotective effects of H₂O₂ on in vitro and in vivo ischaemic models through a catalase (CAT) enzyme-mediated mechanism. Therefore, the present review summarizes experimental data supporting a neuroprotective potential of H₂O₂ in ischaemic stroke that has been principally achieved by means of pharmacological and genetic strategies that modify either the activity or the expression of the superoxide dismutase (SOD), glutathione peroxidase (GPx) and CAT enzymes, which are key regulators of H₂O₂ metabolism. It also critically discusses a translational impact concerning the role played by H₂O₂ in ischaemic stroke. Based on these data, we hope that further research will be done in order to better understand the mechanisms underlying H₂O₂ functions and to promote successful H₂O₂ signalling based therapy in ischaemic stroke. [ABSTRACT FROM AUTHOR]

P2X receptors mediate a variety of physiological actions, including smooth muscle contraction, neuro-endocrine secretion and synaptic transmission. Among P2X receptors, the P2X3 subtype is expressed in sensory neurons of dorsal root- and trigeminal-ganglia, where it performs a well-recognized role in sensory and pain transmission. Recent evidence indicates that the strength of P2X3-mediated responses is modulated in vivo by altering the number of receptors at the plasma membrane. In the present study, we investigate the trafficking properties of P2X3 receptor in transfected HEK293 cells and in primary cultures of dorsal root ganglion neurons, finding that P2X3 receptor undergoes rapid constitutive and cholesterol-dependent endocytosis. We also show that endocytosis is accompanied by preferential targeting of the receptor to late endosomes/lysosomes, with subsequent degradation. Furthermore, we observe that at steady state the receptor localizes predominantly in lamp1-positive intracellular structures, with a minor fraction present at the plasma membrane. Finally, the level of functional receptor expressed on the cell surface is rapidly up-regulated in response to agonist stimulation, which also augments receptor endocytosis. The findings presented in this work underscore a very dynamic trafficking behavior of P2X3 receptor and disclose a possible mechanism for the rapid modulation of ATP-mediated responses potentially relevant during physiological and pathological conditions. [ABSTRACT FROM AUTHOR]

Background and Purpose: Nutrition is the result of a complex interaction among environmental, homeostatic and reward-related processes. Accumulating evidence supports key roles for the dopaminergic neurons of the ventral midbrain in regulating feeding behaviour. For this reason, in the present study, we have investigated the electrophysiological effects of two centrally acting anorexic agents, fenfluramine and sibutramine, on these cells.Experimental Approach: Rat midbrain slices were used to make intracellular recordings from dopaminergic neurons of the substantia nigra and the ventral tegmental area. Gamma-aminobutyric acid (GABA)-mediated synaptic transmission was assessed from the inhibitory postsynaptic potentials (IPSPs) mediated by GABA(A) and GABA(B) receptors.Key Results: Fenfluramine and sibutramine reduced, concentration-dependently, the GABA(B) IPSPs, without affecting the GABA(A)-mediated potentials. This effect is presynaptic, as postsynaptic membrane responses induced by application of a GABA(B) receptor agonist, baclofen, were not affected by the two drugs. Furthermore, the selective 5-hydroxytriptamine 1B (5-HT(1B)) receptor antagonist, SB216641, blocked the reduction of GABA(B) IPSPs caused by fenfluramine and sibutramine, indicating that the receptor mediating this effect is 5-HT(1B).Conclusions and Implications: Two anorexic agents, fenfluramine and sibutramine, induced the activation of 5-HT(1B) receptors located on presynaptic GABAergic terminals, thus reducing the release of GABA. This action can alter the strength of synaptic afferents that modify the activity of dopaminergic neurons, inducing neuronal excitation. Our results reveal an additional mechanism of action for fenfluramine and sibutramine that might contribute to reducing food intake, by influencing the pleasurable and motor aspects of feeding behaviour. [ABSTRACT FROM AUTHOR]

Aripiprazole (AP), a dopamine (DA) D2 receptor partial agonist, has recently been used to reduce schizophrenic symptoms, while tetrabenazine (TBZ), a DA depletor, has been used to treat hyperkinesias in Huntington's disease (HD). The aim of this study is to define the role of AP on chorea, motor performance, and functional disability, and to compare the effects of AP vs. TBZ in a small study of six patients with HD. Both AP and TBZ increased the Unified Huntington's Disease Rating Scale (UHDRS) chorea score in a similar way. However, AP caused less sedation and sleepiness than TBZ and was better tolerated by the patients on the trial. Moreover, AP showed a slight but not significant improvement of depression in the patients as compared to TBZ. A larger group of patients and a longer period of observation are an important prerequisite for further evaluations of AP's therapeutic use. © 2008 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusions Rapid eye movement (REM) sleep behavior disorder (RBD) may precede motor symptoms in Parkinson's disease (PD) by years. According to a recent hypothesis, premotor RBD (pRBD) is a marker of the PD body‐first subtype, where synucleinopathy originates from the peripheral autonomic nervous system. Conversely, in the brain‐first subtype, pathology would arise in the brain. Functional connectivity (FC) could provide additional insight into the neurodegenerative process of these putative PD subtypes.We aim to analyze the possible FC differences between early‐stage PD patients with (PDpRBD+) and without (PDpRBD−) pRBD using high‐density electroencephalography (EEG).We enrolled 28 PDpRBD+, 35 PDpRBD−, and 35 healthy controls (HC). Data were recorded with a 64‐channel EEG system, and a source‐reconstruction method was used to identify brain‐region activity. FC was calculated using the weighted phase‐lag index in θ, α, β, and low‐γ bands. Statistical analysis was conducted using network‐based statistic.We found a significant trend of decreased α‐FC across PDpRBD+, PDpRBD−, and HC, mainly in prefrontal and temporal areas. The altered α‐FC correlated with Montreal Cognitive Assessment scores in PDpRBD+ and, to a lesser extent, PDpRBD− and with gait/postural disturbances in PDpRBD+ patients only. PDpRBD+ and PDpRBD− had similarly increased FC than HC in a β band network, predominantly involving sensorimotor and limbic areas. The increased β network FC was related to bradykinesia severity in both PD subgroups.Compared to PDpRBD− (brain‐first subtype), PDpRBD+ group (body‐first subtype) demonstrates specific EEG‐FC dysfunctions in the α band, which may reflect early involvement of the cholinergic ascending system. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The article discusses a study regarding the possibility of measuring cerebrospinal fluid (CSF) orexin-A using enzyme-linked immunosorbent assay (ELISA), as opposed to use of radioimmunoassay (RIA). It discusses the measurement of CSF orexin-A as an essential element in the diagnosis of narcolepsy type 1. It discusses the need for a new controlled method for assessing CSF orexin-A concentration, with methods such as fluoroimmunoassay, mass spectrometry, and ELISA, already in use.

Background Objective Methods Results Conclusions Peripheral immune cells critically contribute to the clinical‐pathological progression of neurodegenerative diseases and also represent a reliable frame for translational applications. However, data on progressive supranuclear palsy (PSP) are almost scarce in this regard.Our goal is to provide a broad biological characterization of peripheral immune cells in a selected PSP cohort.Seventy‐one PSP patients scored on the PSP Rating Scale (PSPRS), and 59 controls were enrolled. The blood cell count was collected, together with the neutrophil‐to‐lymphocyte ratio (NLR) calculation. In a subgroup of patients and controls, the peripheral blood mononuclear cells (PBMCs) were analyzed by the mitochondrial bioenergetic performance and the western blot assay of the nuclear factor erythroid 2‐related factor (NRF2)/heme oxygenase 1 (HO‐1) pathway and the total tau (t‐tau) and phosphorylated tau (p‐tau) proteins. Case–control comparison and correlation analyses were performed.PSP patients had a NLR higher than controls, with increased circulating neutrophils. The leukocyte metabolism was also globally increased and the NRF2/HO‐1 pathway activated in patients. P‐tau, but not t‐tau, significantly accumulated in PSP PBMCs and inversely correlated with the PSPRS.PSP displays a systemic inflammatory shift of the peripheral immunity, which may justify a metabolic reprogramming of the blood leukocytes. Consistently, the NRF2/HO‐1 pathway, a master regulator of inflammatory and metabolic response, was activated. PBMCs also engulf tau proteins, especially p‐tau, in a way inverse to the disease severity, allowing for a peripheral tracking of tauopathy in patients. Immunometabolic targets may, therefore, gain relevance to PSP in biomarker or therapeutic purposes. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Summary Obstructive sleep apnea (OSA) causes sleep fragmentation and excessive daytime sleepiness (EDS). OSA has been hypothesised to impair the circadian sleep–wake rhythm, and this dysregulation may in turn exacerbate OSA‐related diurnal symptoms. Hence, this study aimed to assess the sleep–wake rhythm through actigraphy, and its relationship with EDS in patients with untreated OSA. Patients with moderate–severe OSA (apnea–hypopnea index ≥15/h) and healthy controls (HC) underwent a 7‐day actigraphic recording to evaluate the sleep–wake rhythm. Participants underwent a sleep medicine visit and completed the self‐report questionnaires assessing EDS (Epworth sleepiness scale, ESS), sleep quality (Pittsburgh sleep quality index, PSQI), and chronotype (morningness‐eveningness questionnaire, MEQ). This study included 48 OSA patients (72.9% males; mean age 56.48 ± 9.53 years), and 22 HC (45.5% males; mean age 53.73 ± 18.20 years). After controlling for MEQ scores, actigraphic recording showed that the OSA patients present a lower sleep time (p = 0.011) and sleep efficiency (p = 0.013), as well as a higher sleep latency (p = 0.047), and sleep fragmentation (p = 0.029) than the HC. Regarding the sleep‐wake rhythm actigraphic parameters, the OSA patients showed a lower average activity during the most active 10‐hour period (p = 0.036) and a lower day/night activity ratio (p = 0.007) than the HC. Patients with OSA also reported higher ESS (p = 0.005) and PSQI scores (p < 0.001), and a chronotype less of morning type (p = 0.027) than the HC. In conclusion, this study documented a reduced diurnal motor activity and lower day/night activity ratio in OSA patients than in controls. These findings suggest a dysregulation of the circadian sleep–wake rhythm in OSA, possibly related to both EDS and reduced daytime motor activity. [ABSTRACT FROM AUTHOR]