Research

14 pages, 4803 KiB

Open AccessArticle

Oral Administration of Probiotic Bacteria Alleviates Tau Phosphorylation, Aβ Accumulation, Microglia Activation, and Memory Loss in 5xFAD Mice

by Yeong Jin Kim, Bo-Ram Mun, Kyu Yeong Choi and Won-Seok Choi

Brain Sci. 2024, 14(3), 208; https://doi.org/10.3390/brainsci14030208 - 23 Feb 2024

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Abstract

The gut–brain axis (GBA) plays a significant role in various neurodegenerative disorders, such as Alzheimer’s disease (AD), and the gut microbiome (GM) can bidirectionally communicate with the brain through the GBA. Thus, recent evidence indicates that the GM may affect the pathological features [...] Read more.

The gut–brain axis (GBA) plays a significant role in various neurodegenerative disorders, such as Alzheimer’s disease (AD), and the gut microbiome (GM) can bidirectionally communicate with the brain through the GBA. Thus, recent evidence indicates that the GM may affect the pathological features and the progression of AD in humans. The aim of our study was to elucidate the impact of probiotics on the pathological features of AD in a 5xFAD model. Probiotics (Bifidobacterium lactis, Levilactobacillus brevis, and Limosilactobacillus fermentum) were orally administered in 5xFAD mice to modify the GM composition. Additionally, freeze-dried food containing phosphatidylserine was used as the positive control. Behavioral pathogenesis was assessed through the cross maze and Morris water maze tests. Our findings revealed that probiotic administration resulted in significant improvements in spatial and recognition memories. Furthermore, the neuroprotective effects of probiotics were substantiated by a reduction in amyloid-β accumulation in critical brain regions. Microglial activation in 5xFAD mice was also attenuated by probiotics in the hippocampus and cerebral cortex. Moreover, elevated tau phosphorylation in 5xFAD mice was ameliorated in the probiotics-treated group. The results highlight the potential use of probiotics as a neuroprotective intervention in AD. Full article

(This article belongs to the Special Issue Neurobiology Research on Neurodegenerative Disorders)

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13 pages, 1519 KiB

Open AccessArticle

CSF, Blood, and MRI Biomarkers in Skogholt’s Disease—A Rare Neurodegenerative Disease in a Norwegian Kindred

by Klaus Thanke Aspli, Jan O. Aaseth, Trygve Holmøy, Kaj Blennow, Henrik Zetterberg, Bjørn-Eivind Kirsebom, Tormod Fladby and Per Selnes

Brain Sci. 2023, 13(11), 1511; https://doi.org/10.3390/brainsci13111511 - 26 Oct 2023

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Abstract

Skogholt’s disease is a rare neurological disorder that is only observed in a small Norwegian kindred. It typically manifests in adulthood with uncharacteristic neurological symptoms from both the peripheral and central nervous systems. The etiology of the observed cerebral white matter lesions and [...] Read more.

Skogholt’s disease is a rare neurological disorder that is only observed in a small Norwegian kindred. It typically manifests in adulthood with uncharacteristic neurological symptoms from both the peripheral and central nervous systems. The etiology of the observed cerebral white matter lesions and peripheral myelin pathology is unclear. Increased cerebrospinal fluid (CSF) concentrations of protein have been confirmed, and recently, very high concentrations of CSF total and phosphorylated tau have been detected in Skogholt patients. The symptoms and observed biomarker changes in Skogholt’s disease are largely nonspecific, and further studies are necessary to elucidate the disease mechanisms. Here, we report the results of neurochemical analyses of plasma and CSF, as well as results from the morphometric segmentation of cerebral magnetic resonance imaging. We analyzed the biomarkers Aβ_1––42, Aβ_1–40, Aβ_x–38, Aβ_x–40, Aβ_x–42, total and phosphorylated tau, glial fibrillary acidic protein, neurofilament light chain, platelet-derived growth factor receptor beta, and beta-trace protein. All analyzed CSF biomarkers, except neurofilament light chain and Aβ_1/x–42, were increased several-fold. In blood, none of these biomarkers were significantly different between the Skogholt and control groups. MRI volumetric segmentation revealed decreases in the ventricular, white matter, and choroid plexus volumes in the Skogholt group, with an accompanying increase in white matter lesions. The cortical thickness and subcortical gray matter volumes were increased in the Skogholt group. Pathophysiological changes resulting from choroidal dysfunction and/or abnormal CSF turnover, which may cause the increases in CSF protein and brain biomarker levels, are discussed. Full article

(This article belongs to the Special Issue Neurobiology Research on Neurodegenerative Disorders)

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11 pages, 691 KiB

Open AccessArticle

Olfactory Impairment Is the Main Predictor of Higher Scores at REM Sleep Behavior Disorder (RBD) Screening Questionnaire in Parkinson’s Disease Patients

by Paolo Solla, Qian Wang, Claudia Frau, Valentina Floris, Francesco Loy, Leonardo Antonio Sechi and Carla Masala

Brain Sci. 2023, 13(4), 599; https://doi.org/10.3390/brainsci13040599 - 31 Mar 2023

Cited by 4 | Viewed by 1496

Abstract

Introduction: Olfactory impairment and REM sleep behavior disorder (RBD) are common non-motor symptoms in Parkinson’s disease (PD) patients, often preceding the onset of the specific motor symptoms and, thus, crucial for strategies directed to anticipate PD diagnosis. In this context, the specific interaction [...] Read more.

Introduction: Olfactory impairment and REM sleep behavior disorder (RBD) are common non-motor symptoms in Parkinson’s disease (PD) patients, often preceding the onset of the specific motor symptoms and, thus, crucial for strategies directed to anticipate PD diagnosis. In this context, the specific interaction between olfactory impairment and RBD has not been clearly defined. Objective: The aim of this study was to determine the possible role of olfactory impairment and other clinical characteristics as possible predictors of higher scores at RBD screening questionnaire (RBDSQ) in a large population of PD patients. Methods: In this study, 590 PD patients were included from the Parkinson’s Progression Markers Initiative. Demographic and clinical features were registered. All participants completed motor and non-motor evaluations at the baseline visit. For motor assessments, the disease severity was evaluated by the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) pars III. Regarding non-motor symptoms assessment, Montreal Cognitive Assessments (MoCA), University of Pennsylvania Smell Identification Test (UPSIT) and RBD screening questionnaire (RBDSQ) were registered. Results: Among 590 PD patients included in this study, 111 patients with possible RBD were found (18.8%). RBD was less frequent in female PD patients (p ≤ 0.011). Among patients with or without possible RBD diagnosis, statistically significant differences in MDS-UPDRS III (23.3 ± 11.4 vs. 19.7 ± 9.1, respectively, p ≤ 0.002) and in UPSIT score (19.7 ± 8.3 vs. 22.6 ± 8.0, respectively, p ≤ 0.001) were found. Moreover, significant correlations between RBDSQ versus UPDRS III score and versus UPSIT score were observed. Multivariate linear regression analysis showed that UPSIT was the most significant predictor of higher scores at RBDSQ, while the other significant predictors were UPDRS III and age. Conclusions: The severity of olfactory impairment appears tightly correlated to RBD symptoms, highlighting the role of these biomarkers for PD patients. Additionally, according to this large study, our data confirmed that RBD in PD patients exhibits peculiar gender differences. Full article

(This article belongs to the Special Issue Neurobiology Research on Neurodegenerative Disorders)

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12 pages, 2355 KiB

Open AccessArticle

The Role of Superoxide Dismutase 1 in Amyotrophic Lateral Sclerosis: Identification of Signaling Pathways, Regulators, Molecular Interaction Networks, and Biological Functions through Bioinformatics

by Sharad Kumar Suthar and Sang-Yoon Lee

Brain Sci. 2023, 13(1), 151; https://doi.org/10.3390/brainsci13010151 - 15 Jan 2023

Cited by 2 | Viewed by 2106

Abstract

Mutations in superoxide dismutase 1 (SOD1) result in misfolding and aggregation of the protein, causing neurodegenerative amyotrophic lateral sclerosis (ALS). In recent years, several new SOD1 variants that trigger ALS have been identified, making it increasingly crucial to understand the SOD1 toxicity pathway [...] Read more.

Mutations in superoxide dismutase 1 (SOD1) result in misfolding and aggregation of the protein, causing neurodegenerative amyotrophic lateral sclerosis (ALS). In recent years, several new SOD1 variants that trigger ALS have been identified, making it increasingly crucial to understand the SOD1 toxicity pathway in ALS. Here we used an integrated bioinformatics approach, including the Ingenuity Pathway Analysis (IPA) tool to analyze signaling pathways, regulators, functions, and network molecules of SOD1 with an emphasis on ALS. IPA toxicity analysis of SOD1 identified superoxide radicals’ degradation, apelin adipocyte, ALS, NRF2-mediated oxidative stress response, and sirtuin signaling as the key signaling pathways, while the toxicity of SOD1 is exerted via mitochondrial swelling and oxidative stress. IPA listed CNR1, APLN, BTG2, MAPK, DRAP1, NFE2L2, SNCA, and CG as the upstream regulators of SOD1. IPA further revealed that mutation in SOD1 results in hereditary disorders, including ALS. The exploration of the relationship between SOD1 and ALS using IPA unveiled SOD1-ALS pathway molecules. The gene ontology (GO) analysis of SOD1-ALS pathway molecules with ShinyGO reaffirmed that SOD1 toxicity results in ALS and neurodegeneration. The GO analysis further identified enriched biological processes, molecular functions, and cellular components for SOD1-ALS pathway molecules. The construction of a protein–protein interaction network of SOD1-ALS pathway molecules using STRING and further analysis of that network with Cytoscape identified ACTB followed by TP53, IL6, CASP3, SOD1, IL1B, APP, APOE, and VEGFA as the major network hubs. Taken together, our study provides insight into the molecular underpinning of SOD1’s toxicity in ALS. Full article

(This article belongs to the Special Issue Neurobiology Research on Neurodegenerative Disorders)

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9 pages, 815 KiB

Open AccessArticle

Ventriculoperitoneal Shunt Treatment Increases 7 Alpha Hy-Droxy-3-Oxo-4-Cholestenoic Acid and 24-Hydroxycholesterol Concentrations in Idiopathic Normal Pressure Hydrocephalus

by Emanuele Porru, Erik Edström, Lisa Arvidsson, Adrian Elmi-Terander, Alexander Fletcher-Sandersjöö, Anita Lövgren Sandblom, Magnus Hansson, Frida Duell and Ingemar Björkhem

Brain Sci. 2022, 12(11), 1450; https://doi.org/10.3390/brainsci12111450 - 27 Oct 2022

Viewed by 1351

Abstract

Idiopathic normal pressure hydrocephalus (iNPH) is the most common form of hydrocephalus in the adult population, and is often treated with cerebrospinal fluid (CSF) drainage using a ventriculoperitoneal (VP) shunt. Symptoms of iNPH include gait impairment, cognitive decline, and urinary incontinence. The pathophysiology [...] Read more.

Idiopathic normal pressure hydrocephalus (iNPH) is the most common form of hydrocephalus in the adult population, and is often treated with cerebrospinal fluid (CSF) drainage using a ventriculoperitoneal (VP) shunt. Symptoms of iNPH include gait impairment, cognitive decline, and urinary incontinence. The pathophysiology behind the symptoms of iNPH is still unknown, and no reliable biomarkers have been established to date. The aim of this study was to investigate the possible use of the oxysterols as biomarkers in this disease. CSF levels of the oxysterols 24S- and 27-hydroxycholesterol, as well as the major metabolite of 27-hydroxycholesterol, 7 alpha hydroxy-3-oxo-4-cholestenoic acid (7HOCA), were measured in iNPH-patients before and after treatment with a VP-shunt. Corresponding measurements were also performed in healthy controls. VP-shunt treatment significantly increased the levels of 7HOCA and 24S-hydroxycholesterol in CSF (p = 0.014 and p = 0.037, respectively). The results are discussed in relation to the beneficial effects of VP-shunt treatment. Furthermore, the possibility that CSF drainage may reduce an inhibitory effect of transiently increased pressure on the metabolic capacity of neuronal cells in the brain is discussed. This capacity includes the elimination of cholesterol by the 24S-hydroxylase mechanisms. Full article

(This article belongs to the Special Issue Neurobiology Research on Neurodegenerative Disorders)

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Review

Jump to: Research, Other

12 pages, 1197 KiB

Open AccessReview

Current Challenges in the Diagnosis of Progressive Neurocognitive Disorders: A Critical Review of the Literature and Recommendations for Primary and Secondary Care

by Chiara Abbatantuono, Federica Alfeo, Livio Clemente, Giulio Lancioni, Maria Fara De Caro, Paolo Livrea and Paolo Taurisano

Brain Sci. 2023, 13(10), 1443; https://doi.org/10.3390/brainsci13101443 - 10 Oct 2023

Cited by 1 | Viewed by 1262

Abstract

Screening for early symptoms of cognitive impairment enables timely interventions for patients and their families. Despite the advances in dementia diagnosis, the current nosography of neurocognitive disorders (NCDs) seems to overlook some clinical manifestations and predictors that could contribute to understanding the conversion [...] Read more.

Screening for early symptoms of cognitive impairment enables timely interventions for patients and their families. Despite the advances in dementia diagnosis, the current nosography of neurocognitive disorders (NCDs) seems to overlook some clinical manifestations and predictors that could contribute to understanding the conversion from an asymptomatic stage to a very mild one, eventually leading to obvious disease. The present review examines different diagnostic approaches in view of neurophysiological and neuropsychological evidence of NCD progression, which may be subdivided into: (1) preclinical stage; (2) transitional stage; (3) prodromal or mild stage; (4) major NCD. The absence of univocal criteria and the adoption of ambiguous or narrow labels might complicate the diagnostic process. In particular, it should be noted that: (1) only neuropathological hallmarks characterize preclinical NCD; (2) transitional NCD must be assessed through proactive neuropsychological protocols; (3) prodromal/mild NCDs are based on cognitive functional indicators; (4) major NCD requires well-established tools to evaluate its severity stage; (5) insight should be accounted for by both patient and informants. Therefore, the examination of evolving epidemiological and clinical features occurring at each NCD stage may orient primary and secondary care, allowing for more targeted prevention, diagnosis, and/or treatment of both cognitive and functional impairment. Full article

(This article belongs to the Special Issue Neurobiology Research on Neurodegenerative Disorders)

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19 pages, 825 KiB

Open AccessReview

by Nijee S. Luthra, Angela Clow and Daniel M. Corcos

Brain Sci. 2022, 12(12), 1695; https://doi.org/10.3390/brainsci12121695 - 10 Dec 2022

Cited by 5 | Viewed by 3345

Abstract

The pathogenesis of Parkinson’s disease (PD) is complex, multilayered, and not fully understood, resulting in a lack of effective disease-modifying treatments for this prevalent neurodegenerative condition. Symptoms of PD are heterogenous, including motor impairment as well as non-motor symptoms such as depression, cognitive [...] Read more.

The pathogenesis of Parkinson’s disease (PD) is complex, multilayered, and not fully understood, resulting in a lack of effective disease-modifying treatments for this prevalent neurodegenerative condition. Symptoms of PD are heterogenous, including motor impairment as well as non-motor symptoms such as depression, cognitive impairment, and circadian disruption. Aging and stress are important risk factors for PD, leading us to explore pathways that may either accelerate or protect against cellular aging and the detrimental effects of stress. Cortisol is a much-studied hormone that can disrupt mitochondrial function and increase oxidative stress and neuroinflammation, which are recognized as key underlying disease mechanisms in PD. The more recently discovered klotho protein, considered a general aging-suppressor, has a similarly wide range of actions but in the opposite direction to cortisol: promoting mitochondrial function while reducing oxidative stress and inflammation. Both hormones also converge on pathways of vitamin D metabolism and insulin resistance, also implicated to play a role in PD. Interestingly, aging, stress and PD associate with an increase in cortisol and decrease in klotho, while physical exercise and certain genetic variations lead to a decrease in cortisol response and increased klotho. Here, we review the interrelated opposite actions of cortisol and klotho in the pathogenesis of PD. Together they impact powerful and divergent mechanisms that may go on to influence PD-related symptoms. Better understanding of these hormones in PD would facilitate the design of effective interventions that can simultaneously impact the multiple systems involved in the pathogenesis of PD. Full article

(This article belongs to the Special Issue Neurobiology Research on Neurodegenerative Disorders)

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11 pages, 1491 KiB

Open AccessReview

Advances on Cellular Clonotypic Immunity in Amyotrophic Lateral Sclerosis

by Giuseppe Schirò, Vincenzo Di Stefano, Salvatore Iacono, Antonino Lupica, Filippo Brighina, Roberto Monastero and Carmela Rita Balistreri

Brain Sci. 2022, 12(10), 1412; https://doi.org/10.3390/brainsci12101412 - 20 Oct 2022

Cited by 2 | Viewed by 1770

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease, characterized by the progressive degeneration of the upper and lower motor neurons in the cortex and spinal cord. Although the pathogenesis of ALS remains unclear, evidence concerning the role of the clonotypic immune system [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease, characterized by the progressive degeneration of the upper and lower motor neurons in the cortex and spinal cord. Although the pathogenesis of ALS remains unclear, evidence concerning the role of the clonotypic immune system is growing. Adaptive immunity cells often appear changed in number, or in terms of their activation profiles, both peripherally and centrally; however, their role in ALS appears conflictive. Data from human and animal model studies, which are currently reported in the literature, show that each subset of lymphocytes and their mediators may mediate a protective or toxic mechanism in ALS, affecting both its progression and risk of death. In the present review, an attempt is made to shed light on the actual role of cellular clonotypic immunity in ALS by integrating recent clinical studies and experimental observations. Full article

(This article belongs to the Special Issue Neurobiology Research on Neurodegenerative Disorders)

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Other

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9 pages, 495 KiB

Open AccessBrief Report

GABA_A Receptor Benzodiazepine Binding Sites and Motor Impairments in Parkinson’s Disease

by Nicolaas I. Bohnen, Jaimie Barr, Robert Vangel, Stiven Roytman, Rebecca Paalanen, Kirk A. Frey, Peter J. H. Scott and Prabesh Kanel

Brain Sci. 2023, 13(12), 1711; https://doi.org/10.3390/brainsci13121711 - 12 Dec 2023

Cited by 1 | Viewed by 1042

Abstract

Flumazenil is an allosteric modulator of the γ-aminobutyric acid-A receptor (GABA_AR) benzodiazepine binding site that could normalize neuronal signaling and improve motor impairments in Parkinson’s disease (PD). Little is known about how regional GABA_AR availability affects motor symptoms. We [...] Read more.

Flumazenil is an allosteric modulator of the γ-aminobutyric acid-A receptor (GABA_AR) benzodiazepine binding site that could normalize neuronal signaling and improve motor impairments in Parkinson’s disease (PD). Little is known about how regional GABA_AR availability affects motor symptoms. We investigated the relationship between regional availability of GABA_AR benzodiazepine binding sites and motor impairments in PD. Methods: A total of 11 Patients with PD (males; mean age 69.0 ± 4.6 years; Hoehn and Yahr stages 2–3) underwent [¹¹C]flumazenil GABA_AR benzodiazepine binding site and [¹¹C]dihydrotetrabenazine vesicular monoamine transporter type-2 (VMAT2) PET imaging and clinical assessment. Stepwise regression analysis was used to predict regional cerebral correlates of the four cardinal UPDRS motor scores using cortical, striatal, thalamic, and cerebellar flumazenil binding estimates. Thalamic GABA_AR availability was selectively associated with axial motor scores (R² = 0.55, F = 11.0, β = −6.4, p = 0.0009). Multi-ligand analysis demonstrated significant axial motor predictor effects by both thalamic GABA_AR availability (R² = 0.47, β = −5.2, F = 7.2, p = 0.028) and striatal VMAT2 binding (R² = 0.30, β = −3.9, F = 9.1, p = 0.019; total model: R² = 0.77, F = 11.9, p = 0.0056). Post hoc analysis demonstrated that thalamic [¹¹C]methyl-4-piperidinyl propionate cholinesterase PET and K₁ flow delivery findings were not significant confounders. Findings suggest that reduced thalamic GABA_AR availability correlates with worsened axial motor impairments in PD, independent of nigrostriatal degeneration. These findings may augur novel non-dopaminergic approaches to treating axial motor impairments in PD. Full article

(This article belongs to the Special Issue Neurobiology Research on Neurodegenerative Disorders)

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