The Cellular Dysfunction of the Brain-Blood Barrier from Endothelial Cells to Astrocytes: The Pathway towards Neurotransmitter Impairment in Schizophrenia.

Schizophrenia (SCZ) is an articulated psychiatric syndrome characterized by a combination of genetic, epigenetic, and environmental factors. Our intention is to present a pathogenetic model combining SCZ alterations and the main cellular actors of the blood-brain barrier (BBB): endothelial cells (ECs), pericytes, and astrocytes. The homeostasis of the BBB is preserved by the neurovascular unit which is constituted by ECs, astrocytes and microglia, neurons, and the extracellular matrix. The role of the BBB is strictly linked to its ability to preserve the biochemical integrity of brain parenchyma integrity. In SCZ, there is an increased BBB permeability, demonstrated by elevated levels of albumin and immunoglobulins in the cerebrospinal fluid, and this is the result of an intrinsic endothelial impairment. Increased BBB permeability would lead to enhanced concentrations of neurotoxic and neuroactive molecules in the brain. The pathogenetic involvement of astrocytes in SCZ reverberates its consequences on BBB, together with the impact on its permeability and selectivity represented by the EC and pericyte damage occurring in the psychotic picture. Understanding the strict interaction between ECs and astrocytes, and its consequent impact on cognition, is diriment not only for comprehension of neurotransmitter dyshomeostasis in SCZ, but also for focusing on other potential therapeutic targets.

Pointing in cervical dystonia patients.

Introduction: The normal hemispheric balance can be altered by the asymmetric sensorimotor signal elicited by Cervical Dystonia (CD), leading to motor and cognitive deficits. Methods: Directional errors, peak velocities, movement and reaction times of pointing towards out-of-reach targets in the horizontal plane were analysed in 18 CD patients and in 11 aged-matched healthy controls. Results: CD patients displayed a larger scatter of individual trials around the average pointing direction (variable error) than normal subjects, whatever the arm used, and the target pointed. When pointing in the left hemispace, all subjects showed a left deviation (constant error) with respect to the target position, which was significantly larger in CD patients than controls, whatever the direction of the abnormal neck torsion could be. Reaction times were larger and peak velocities lower in CD patients than controls. Discussion: Deficits in the pointing precision of CD patients may arise from a disruption of motor commands related to the sensorimotor imbalance, from a subtle increase in shoulder rigidity or from a reduced agonists activation. Their larger left bias in pointing to left targets could be due to an increased right parietal dominance, independently upon the direction of head roll/jaw rotation which expands the left space representation and/or increases left spatial attention. These deficits may potentially extend to tracking and gazing objects in the left hemispace, leading to reduced skills in spatial-dependent motor and cognitive performance.

The Cerebellum's Role in Affective Disorders: The Onset of Its Social Dimension.

Major Depressive Disorder (MDD) and Bipolar Disorder (BD) are the most frequent mental disorders whose indeterminate etiopathogenesis spurs to explore new aetiologic scenarios. In light of the neuropsychiatric symptoms characterizing Cerebellar Cognitive Affective Syndrome (CCAS), the objective of this narrative review is to analyze the involvement of the cerebellum (Cbm) in the onset of these conditions. It aims at detecting the repercussions of the Cbm activities on mood disorders based on its functional subdivision in vestibulocerebellum (vCbm), pontocerebellum (pCbm) and spinocerebellum (sCbm). Despite the Cbm having been, for decades, associated with somato-motor functions, the described intercellular pathways, without forgiving the molecular impairment and the alteration in the volumetric relationships, make the Cbm a new important therapeutic target for MDD and BD. Given that numerous studies have showed its activation during mnestic activities and socio-emotional events, this review highlights in the Cbm, in which the altered external space perception (vCbm) is strictly linked to the cognitive-limbic Cbm (pCbm and sCbm), a crucial role in the MDD and BD pathogenesis. Finally, by the analysis of the cerebellar activity, this study aims at underlying not only the Cbm involvement in affective disorders, but also its role in social relationship building.

Astrocytes as Neuroimmunocytes in Alzheimer's Disease: A Biochemical Tool in the Neuron-Glia Crosstalk along the Pathogenetic Pathways.

This work aimed at assessing Alzheimer's disease (AD) pathogenesis through the investigation of the astrocytic role to transduce the load of amyloid-beta (Aß) into neuronal death. The backbone of this review is focused on the deepening of the molecular pathways eliciting the activation of astrocytes crucial phenomena in the understanding of AD as an autoimmune pathology. The complex relations among astrocytes, Aß and tau, together with the role played by the tripartite synapsis are discussed. A review of studies published from 1979 to 2023 on Scopus, PubMed and Google Scholar databases was conducted. The selected papers focused not only on the morphological and metabolic characteristics of astrocytes, but also on the latest notions about their multifunctional involvement in AD pathogenesis. Astrocytes participate in crucial pathways, including pruning and sprouting, by which the AD neurodegeneration evolves from an aggregopathy to neuroinflammation, loss of synapses and neuronal death. A1 astrocytes stimulate the production of pro-inflammatory molecules which have been correlated with the progression of AD cognitive impairment. Further research is needed to "hold back" the A1 polarization and, thus, to slow the worsening of the disease. AD clinical expression is the result of dysfunctional neuronal interactions, but this is only the end of a process involving a plurality of protagonists. One of these is the astrocyte, whose importance this work intends to put under the spotlight in the AD scenario, reflecting the multifaceted nature of this disease in the functional versatility of this glial population.

Retrospective observational study on the use of acetyl-L-carnitine in ALS.

ALCAR (Acetyl-L-carnitine) is a donor of acetyl groups and increases the intracellular levels of carnitine, the primary transporter of fatty acids across the mitochondrial membranes. In vivo studies showed that ALCAR decrease oxidative stress markers and pro-inflammatory cytokines. In a previous double-blind placebo-controlled phase II trial showed positive effects on self-sufficiency (defined as a score of 3+ on the ALSFRS-R items for swallowing, cutting food and handling utensils, and walking) ALSFRS-R total score and FVC. We conducted an observational, retrospective, multicentre, case-control study to provide additional data on the effects of ALCAR in subjects with ALS in Italy. Subjects treated with ALCAR 1.5 g/day or 3 g/day were included and matched with not treated subjects by sex, age at diagnosis, site of onset, and time from diagnosis to baseline, (45 subjects per group). ALCAR 3 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 23 (51.1%) treated subjects (adj. OR 1.18, 95% CI 0.46-3.02). No statistically significant differences were detected in ALSFRS nor FVC nor self-sufficiency. ALCAR 1.5 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 32 (71.1%) treated subjects (adj. OR 0.27, 95% CI 0.10-0.71). For ALSFRS-R, a mean slope of - 1.0 was observed in treated subjects compared to - 1.4 in those not treated (p = 0.0575). No statistically significant difference was detected in the FVC nor self-sufficiency. Additional evidence should be provided to confirm the efficacy of the drug and provide a rationale for the dosage.

Ultrastructural and Molecular Investigation on Peripheral Leukocytes in Alzheimer's Disease Patients.

Thriving literature underlines white blood cell involvement in the inflammatory processes of Alzheimer's Disease (AD). Among leukocytes, lymphocytes have been considered sentinels of neuroinflammation for years, but recent findings highlighted the pivotal role of neutrophils. Since neutrophils that infiltrate the brain through the brain vascular vessels may affect the immune function of microglia in the brain, a close investigation of the interaction between these cells is important in understanding neuroinflammatory phenomena and the immunological aftermaths that follow. This study aimed to observe how peripheral leukocyte features change at different stages of AD to identify potential molecular markers when the first features of pathological neurodegeneration arise. For this purpose, the examined patients were divided into Mild Cognitive Impairment (MCI) and severely impaired patients (DAT) based on their Cognitive Dementia Rating (CDR). The evaluation of the neutrophil-to-lymphocytes ratio and the morphology and function of leukocytes showed a close relationship between the ultrastructural and the molecular features in AD progression and suggested putative markers for the early stages of the disease.

Methods for informing people with amyotrophic lateral sclerosis/motor neuron disease of their diagnosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), causes increasing physical impairment and disability. People with ALS/MND face huge physical challenges, and the diagnosis can be a source of great psychological distress for both people with ALS/MND and their carers. In such a context, how news of the diagnosis is broken is important. At present, there are no systematic reviews of methods for informing people with ALS/MND of their diagnosis. OBJECTIVES: To examine the effects and effectiveness of different methods for informing people of a diagnosis of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND), including effects on the person's knowledge and understanding of their disease, its treatment, and care; and on coping and adjustment to the effects of ALS/MND, its treatment, and care. SEARCH METHODS: We searched the Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, and two trials registers (February 2022). We contacted individuals or organisations to locate studies. We contacted study authors to obtain additional unpublished data. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) and quasi-RCTs of techniques for informing people with ALS/MND of their diagnosis. We planned to include adults (aged 17 years or over) with ALS/MND, according to the El Escorial criteria. DATA COLLECTION AND ANALYSIS: Three review authors independently reviewed the results of the search to identify RCTs, and three review authors identified non-randomised studies to include in the discussion section. We planned that two review authors would independently extract data, and three would assess the risk of bias in any included trials. MAIN RESULTS: We did not identify any RCTs that met our inclusion criteria. AUTHORS' CONCLUSIONS: There are no RCTs that evaluate different communication strategies for breaking the bad news for people diagnosed with ALS/MND. Focused research studies are needed to assess the effectiveness and efficacy of different communication methods.

Effect of RNS60 in amyotrophic lateral sclerosis: a phase II multicentre, randomized, double-blind, placebo-controlled trial.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. RNS60 is an immunomodulatory and neuroprotective investigational product that has shown efficacy in animal models of ALS and other neurodegenerative diseases. Its administration has been safe and well tolerated in ALS subjects in previous early phase trials. METHODS: This was a phase II, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial. Participants diagnosed with definite, probable or probable laboratory-supported ALS were assigned to receive RNS60 or placebo administered for 24 weeks intravenously (375 ml) once a week and via nebulization (4 ml/day) on non-infusion days, followed by an additional 24 weeks off-treatment. The primary objective was to measure the effects of RNS60 treatment on selected biomarkers of inflammation and neurodegeneration in peripheral blood. Secondary objectives were to measure the effect of RNS60 on functional impairment (ALS Functional Rating Scale-Revised), a measure of self-sufficiency, respiratory function (forced vital capacity, FVC), quality of life (ALS Assessment Questionnaire-40, ALSAQ-40) and survival. Tolerability and safety were assessed. RESULTS: Seventy-four participants were assigned to RNS60 and 73 to placebo. Assessed biomarkers did not differ between arms. The mean rate of decline in FVC and the eating and drinking domain of ALSAQ-40 was slower in the RNS60 arm (FVC, difference 0.41 per week, standard error 0.16, p = 0.0101; ALSAQ-40, difference -0.19 per week, standard error 0.10, p = 0.0319). Adverse events were similar in the two arms. In a post hoc analysis, neurofilament light chain increased over time in bulbar onset placebo participants whilst remaining stable in those treated with RNS60. CONCLUSIONS: The positive effects of RNS60 on selected measures of respiratory and bulbar function warrant further investigation.

Blood Analytes as Biomarkers of Mechanisms Involved in Alzheimer's Disease Progression.

Alzheimer's disease (AD) is the leading cause of dementia, but the pathogenetic factors are not yet well known, and the relationships between brain and systemic biochemical derangements and disease onset and progression are unclear. We aim to focus on blood biomarkers for an accurate prognosis of the disease. We used a dataset characterized by longitudinal findings collected over the past 10 years from 90 AD patients. The dataset included 277 observations (both clinical and biochemical ones, encompassing blood analytes encompassing routine profiles for different organs, together with immunoinflammatory and oxidative markers). Subjects were grouped into four severity classes according to the Clinical Dementia Rating (CDR) Scale: mild (CDR = 0.5 and CDR = 1), moderate (CDR = 2), severe (CDR = 3) and very severe (CDR = 4 and CDR = 5). Statistical models were used for the identification of potential blood markers of AD progression. Moreover, we employed the Pathfinder tool of the Reactome database to investigate the biological pathways in which the analytes of interest could be involved. Statistical results reveal an inverse significant relation between four analytes (high-density cholesterol, total cholesterol, iron and ferritin) with AD severity. In addition, the Reactome database suggests that such analytes could be involved in pathways that are altered in AD progression. Indeed, the identified blood markers include molecules that reflect the heterogeneous pathogenetic mechanisms of AD. The combination of such blood analytes might be an early indicator of AD progression and constitute useful therapeutic targets.

Effects of Global Warming on Patients with Dementia, Motor Neuron or Parkinson's Diseases: A Comparison among Cortical and Subcortical Disorders.

Exposure to global warming can be dangerous for health and can lead to an increase in the prevalence of neurological diseases worldwide. Such an effect is more evident in populations that are less prepared to cope with enhanced environmental temperatures. In this work, we extend our previous research on the link between climate change and Parkinson's disease (PD) to also include Alzheimer's Disease and other Dementias (AD/D) and Amyotrophic Lateral Sclerosis/Motor Neuron Diseases (ALS/MND). One hundred and eighty-four world countries were clustered into four groups according to their climate indices (warming and annual average temperature). Variations between 1990 and 2016 in the diseases' indices (prevalence, deaths, and disability-adjusted life years) and climate indices for the four clusters were analyzed. Unlike our previous work on PD, we did not find any significant correlation between warming and epidemiological indices for AD/D and ALS/MND patients. A significantly lower increment in prevalence in countries with higher temperatures was found for ALS/MND patients. It can be argued that the discordant findings between AD/D or ALS/MND and PD might be related to the different features of the neuronal types involved and the pathophysiology of thermoregulation. The neurons of AD/D and ALS/MND patients are less vulnerable to heat-related degeneration effects than PD patients. PD patients' substantia nigra pars compacta (SNpc), which are constitutively frailer due to their morphology and function, fall down under an overwhelming oxidative stress caused by climate warming.

Raman spectroscopy and multivariate analysis as potential tool to follow Alzheimer's disease progression.

Raman spectroscopy is an emerging tool in the research and diagnosis of different diseases, including neurodegenerative disorders. In this work, blood serum samples collected from healthy controls and dementia patients were analysed by Raman spectroscopy to develop a classification model for the diagnosis of dementia of Alzheimer's type (DAT). Raman spectra were processed by means of multivariate tools for multivariate analysis. Lower concentration levels of carotenoids were detected in blood serum from patients, which allowed for a good discrimination with respect to controls, such as 93% of correct predictions on the test set with random forest. We also hypothesize that carotenoid levels might be informative about the severity and progression of the disease, since the intensity of carotenoid signals decreased from the early stage to more severe patients. These encouraging results suggest the possibility to use Raman spectroscopy for the analysis of alternative biofluids (e.g. saliva) and the unobtrusive diagnosis of other neurodegenerative disorders.

2-Year-Old and 3-Year-Old Italian ALS Patients with Novel ALS2 Mutations: Identification of Key Metabolites in Their Serum and Plasma.

Pathogenic variants in ALS2 have been detected mostly in juvenile cases of amyotrophic lateral sclerosis (ALS), affecting mainly children and teenagers. Patients with ALS2 mutations demonstrate early onset cortical involvement in ALS. Currently, there are no effective treatment options. There is an immense need to reveal the underlying causes of the disease and to identify potential biomarkers. To shed light onto the metabolomic events that are perturbed with respect to ALS2 mutations, we investigated the metabolites present in the serum and plasma of a three-year-old female patient (AO) harboring pathogenic variants in ALS2, together with her relatives, healthy male and female controls, as well as another two-year-old patient DH, who had mutations at different locations and domains of ALS2. Serum and plasma samples were analyzed with a quantitative metabolomic approach to reveal the identity of metabolites present in serum and plasma. This study not only shed light onto the perturbed cellular pathways, but also began to reveal the presence of a distinct set of key metabolites that are selectively present or absent with respect to ALS2 mutations, laying the foundation for utilizing metabolites as potential biomarkers for a subset of ALS.

Climate change and neurodegenerative diseases.

The climate change induced global warming, and in particular the increased frequency and intensity of heat waves, have been linked to health problems. Among them, scientific works have been reporting an increased incidence of neurological diseases, encompassing also neurodegenerative ones, such as Dementia of Alzheimer's type, Parkinson's Disease, and Motor Neuron Diseases. Although the increase in prevalence of neurodegenerative diseases is well documented by literature reports, the link between global warming and the enhanced prevalence of such diseases remains elusive. This is the main theme of our work, which aims to examine the connection between high temperature exposure and neurodegenerative diseases. Firstly, we evaluate the influence of high temperatures exposure on the pathophysiology of these disorders. Secondly, we discuss its effects on the thermoregulation, already compromised in affected patients, and its interference with processes of excitotoxicity, oxidative stress and neuroinflammation, all of them related with neurodegeneration. Finally, we investigate chronic versus acute stressors on body warming, and put forward a possible interpretation of the beneficial or detrimental effects on the brain, which is responsible for the incidence or progression of neurological disorders.

Proteomics Profiling of Neuron-Derived Small Extracellular Vesicles from Human Plasma: Enabling Single-Subject Analysis.

Small extracellular vesicles have been intensively studied as a source of biomarkers in neurodegenerative disorders. The possibility to isolate neuron-derived small extracellular vesicles (NDsEV) from blood represents a potential window into brain pathological processes. To date, the absence of sensitive NDsEV isolation and full proteome characterization methods has meant their protein content has been underexplored, particularly for individual patients. Here, we report a rapid method based on an immunoplate covalently coated with mouse monoclonal anti-L1CAM antibody for the isolation and the proteome characterization of plasma-NDsEV from individual Parkinson's disease (PD) patients. We isolated round-shaped vesicles with morphological characteristics consistent with exosomes. On average, 349 ± 38 protein groups were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, 20 of which are annotated in the Human Protein Atlas as being highly expressed in the brain, and 213 were shared with a reference NDsEV dataset obtained from cultured human neurons. Moreover, this approach enabled the identification of 23 proteins belonging to the Parkinson disease KEGG pathway, as well as proteins previously reported as PD circulating biomarkers.

Using blood data for the differential diagnosis and prognosis of motor neuron diseases: a new dataset for machine learning applications.

Early differential diagnosis of several motor neuron diseases (MNDs) is extremely challenging due to the high number of overlapped symptoms. The routine clinical practice is based on clinical history and examination, usually accompanied by electrophysiological tests. However, although previous studies have demonstrated the involvement of altered metabolic pathways, biomarker-based monitoring tools are still far from being applied. In this study, we aim at characterizing and discriminating patients with involvement of both upper and lower motor neurons (i.e., amyotrophic lateral sclerosis (ALS) patients) from those with selective involvement of the lower motor neuron (LMND), by using blood data exclusively. To this end, in the last ten years, we built a database including 692 blood data and related clinical observations from 55 ALS and LMND patients. Each blood sample was described by 108 analytes. Starting from this outstanding number of features, we performed a characterization of the two groups of patients through statistical and classification analyses of blood data. Specifically, we implemented a support vector machine with recursive feature elimination (SVM-RFE) to automatically diagnose each patient into the ALS or LMND groups and to recognize whether they had a fast or slow disease progression. The classification strategy through the RFE algorithm also allowed us to reveal the most informative subset of blood analytes including novel potential biomarkers of MNDs. Our results show that we successfully devised subject-independent classifiers for the differential diagnosis and prognosis of ALS and LMND with remarkable average accuracy (up to 94%), using blood data exclusively.

VGF peptides as novel biomarkers in Parkinson's disease.

Parkinson's disease (PD) is characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra (SN). At disease onset, a diagnosis is often difficult. VGF peptides are abundant in the SN and peripheral circulation; hence, we investigate whether their plasma profile may reflect the brain dopamine reduction. Using antibodies against the VGF C-terminal portion, we analyzed the rat brain and human plasma, with immunohistochemistry and ELISA. Rats were unilaterally lesioned with 6-hyroxydopamine and sacrificed either 3 or 6 weeks later with or without levodopa treatment. Plasma samples were obtained from PD patients, either at the time of diagnosis (group 1, drug naïve, n = 23) or upon dopamine replacement (group 2, 1-6 years, n = 24; group 3, > 6 years, n = 16), compared with age-matched control subjects (group 4, n = 21). Assessment of the olfactory function was carried out in group 2 using the "Sniffin' Sticks" test. VGF immunoreactivity was present in GABAergic neurons and, on the lesioned side, it was reduced at 3 weeks and abolished at 6 weeks after lesion. Conversely, upon levopoda, VGF labeling was restored. In PD patients, VGF levels were reduced at the time of diagnosis (1504 ± 587 vs. 643 ± 348 pmol/mL, means ± S.E.M: control vs. naïve; p < 0.05) but were comparable with the controls after long-term drug treatment (> 6 years). A linear correlation was demonstrated between VGF immunoreactivity and disease duration, levodopa equivalent dose and olfactory dysfunction. Plasma VGF levels may represent a useful biomarker, especially in the early stages of PD.

Exercise training in ad libitum and food-restricted old rats: effects on metabolic and physiological parameters.

Aging is accompanied by a decline in the healthy function of multiple organs, leading to increased incidence and mortality from diseases such as cancer and inflammatory, cardiovascular and neurodegenerative diseases. Dietary restriction is the most effective experimental intervention known to consistently slow the aging process and with positive effects on health span in different organisms, from invertebrates to mammals. Age is also associated with progressive decline in physical activity levels in a wide range of animal species: therefore, regular physical exercise could represent a safe intervention to antagonize aging. In this research we explore the effects of exercise training initiated in late middle aged rats fed with different lifelong dietary regimens: one group was fed ad libitum and the second group was subjected to every-other-day fasting. These two groups might represent examples of "normal" aging and "successful" aging. The study shows the effects of exercise and food restriction and their interaction on plasma levels of total antioxidant capacity, lactate, amino acids, and on products of protein oxidation in soleus and tibialis anterior muscles. In addition, we evaluated body composition measurement by bioelectrical impedance analysis and muscle strength by grasping test. Results show that late-onset exercise training has the potential to improve some metabolic and physiological parameters in rats with the same "chronological age" but different "biological age", without negative effects, and highlight the relevance of a personalised and selected exercise protocol, since the responsiveness to exercise may depend on the individual's "biological age".

Diaphragm ultrasonography in amyotrophic lateral sclerosis: a diagnostic tool to assess ventilatory dysfunction and disease severity.

BACKGROUND: Respiratory failure represents an unavoidable step in patients with amyotrophic lateral sclerosis (ALS) and other motor neuron diseases (MND). The development of diaphragm ultrasonography (DUS) provides an alternative useful and risk-free tool to supply clinical, functional, and neurophysiological assessment of respiratory muscle weakness. Our aim was to evaluate if sonographic changes (thickness and echogenicity in the costal portion of the diaphragm, at rest and during respiratory movements) may be used in ALS patients to assess disease severity over time, to rule out any risk or discomfort due to traditional neurophysiological investigations. METHODS: Twenty ALS patients (mean age, 64.6 ± 10.5 years) were enrolled and data were compared with age-matched healthy volunteers; DUS data were correlated with respiratory function and disease severity scale. Examinations were performed using Telemed Echo-wave II or Esaote MyLabGamma devices in conventional B-Mode. RESULTS: Mean resting thickness was reduced in all cases; changes in thickness during inspiration and expiration were also reduced (p < 0.0001) and lost in severe cases (n = 3). In bulbar-onset disease, respiratory scores were strictly correlated with the difference in diaphragm thickness between full inspiration-and expiration-as well as on the diaphragm thickness in expiration (p < 0.001). CONCLUSIONS: DUS represents a simple, painless, and risk-free tool; moreover, it provides useful functional and structural insights to the understanding of diaphragm function and the degree of respiratory failure in ALS.