Neurodegeneration No More: Cutting-Edge Technologies and Therapies in the Evolution of Neurodegenerative Disease Management

A topical collection in Biomedicines (ISSN 2227-9059). This collection belongs to the section "Neurobiology and Clinical Neuroscience".

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Editors


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Collection Editor
Danube Neuroscience Research Laboratory, HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, University of Szeged (HUN-REN-SZTE), Tisza Lajos krt. 113, H-6725 Szeged, Hungary
Interests: depression; anxiety; dementia pain; their comorbidities nature; translational research in neurological diseases and psychiatric disorders
Special Issues, Collections and Topics in MDPI journals

E-Mail Website1 Website2
Collection Editor
1. Department of Psychology, University of Turin, Turin, Italy
2. Center for Studies and Research in Cognitive Neuroscience, Department of Psychology, University of Bologna, Bologna, Italy
Interests: NIBS techniques; TMS; skin conductance; heart rate variability; fear conditioning; fear learning; learning; neuropsychology; prefrontal cortex; amygdala; hippocampus; anxiety; depression; working memory; PTSD; skin conductance responses; psychophysiology; error-related negativity; EEG; tDCS; Alzheimer’s disease; PIT; stress-related disorders; Parkinson’s disease; resilience; memory; neurologic patients; cognitive decisions; fMRI; translational and molecular psychiatry
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Collection Editor
Department of Psychology, University of Turin, Turin, Italy
Interests: magnetic resonance imaging; human brain mapping; meta-research; connectomics; brain connectivity; computational neuroscience; Bayesian statistics; fMRI; meta-analysis; clinical trials; DTI; default mode network; Alzheimer’s disease; biological psychiatry; autism; cerebellum; translational neuroimaging

Topical Collection Information

Dear Colleagues,

Neurodegenerative diseases are a group of disorders that affect the structure and function of the central nervous system, leading to the progressive loss of cognitive, motor, and sensory abilities. They include Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and many others. Neurodegenerative diseases pose a major challenge for public health as they affect millions of people worldwide and have no cure. Moreover, they are associated with a high burden of disability, morbidity, mortality, and socioeconomic costs.

In recent years, significant advances have been made in the understanding of the pathophysiology, epidemiology, and genetics of neurodegenerative diseases, as well as in the development of novel diagnostic tools, therapeutic interventions, and rehabilitation strategies. Non-invasive brain stimulation (NIBS) techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), have shown potential to improve both motor and nonmotor symptoms in patients with neurodegenerative diseases like Alzheimer’s and Parkinson’s. These techniques are of particular interest for the treatment of cognitive impairment in Alzheimer’s disease and axial disturbances in Parkinson’s disease, where conventional pharmacological therapies have shown limited effects. Recent evidence suggests that NIBS may have a neuroprotective effect, potentially slowing disease progression and modulating the aggregation state of pathological proteins. However, many gaps and challenges remain in the field, such as the identification of reliable biomarkers, the elucidation of the environmental and lifestyle factors that modulate disease risk and progression, the optimization of clinical trials and drug delivery systems, and improvements in the quality of life and care of patients and caregivers. Moreover, the potential of NIBS to influence disease progression over time remains poorly understood, along with ongoing investigations into the development of standardized stimulation protocols for the precise targeting of deep brain regions.

This Topical Collection aims to showcase the latest research and innovations in the field of neurodegenerative diseases, covering a wide range of topics, such as the following:

  • Risk factors, such as genetic and environmental, that influence the onset and course of neurodegenerative diseases;
  • Prodromal symptoms and early diagnosis, using advanced imaging techniques, biomarkers, and digital technologies;
  • Comorbidities, such as psychiatric, metabolic, and cardiovascular disorders, that affect or are affected by neurodegenerative diseases;
  • Novel therapeutic targets and treatments, such as gene therapy, stem cell therapy, immunotherapy, medicinal plants, phytocompounds, and neuroprotective agents;
  • Role of oxidative stress and inflammation as triggers of neurodegenerative conditions;
  • Quality-of-life-oriented rehabilitation, such as cognitive, physical, and psychosocial interventions that enhance the functioning and well-being of patients and caregivers;
  • Innovative translational research, such as bench-to-bed and bed-to-bench, and modeling, such as in vitro and in vivo;
  • Non-invasive brain stimulation (NIBS) as a therapeutic intervention that may offer neuroprotective effects and improve symptoms in neurodegenerative diseases.

We invite researchers and clinicians from various disciplines and backgrounds to submit their original articles and reviews to this Topical Collection contribute to the advancement of knowledge and practice in the field of neurodegenerative diseases. We hope that this Topical Collection will provide a comprehensive and up-to-date overview of the current state and future directions of the field and will stimulate further research and collaboration among the scientific community.

Dr. Masaru Tanaka
Dr. Simone Battaglia
Dr. Donato Liloia
Collection Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Alzheimer’s disease
  • frontotemporal lobar degeneration
  • Parkinson’s disease
  • aging decline
  • mild cognitive impairment
  • multiple sclerosis
  • stroke
  • acquired brain damage
  • altered cognitive processes
  • brain functional impairment
  • neurocognitive disorders
  • cognitive, behavioral, and functional disorders
  • acquired trauma
  • brain plasticity and connectivity
  • non-invasive brain stimulation
  • diagnosis and treatment
  • functional evidence of altered cognition and connectivity
  • blood-based biomarkers
  • disease heterogeneity
  • prognosis
  • protein aggregation
  • inflammation
  • oxidative stress
  • medicinal plants
  • phytocompounds

Published Papers (16 papers)

2024

18 pages, 1251 KiB  
Review
Metabolic Dysfunction in Parkinson’s Disease: Unraveling the Glucose–Lipid Connection
by Jeswinder Sian-Hulsmann, Peter Riederer and Tanja Maria Michel
Biomedicines 2024, 12(12), 2841; https://doi.org/10.3390/biomedicines12122841 - 13 Dec 2024
Viewed by 377
Abstract
Despite many years of research into the complex neurobiology of Parkinson’s disease, the precise aetiology cannot be pinpointed down to one causative agent but rather a multitude of mechanisms. Current treatment options can alleviate symptomsbut only slightly slow down the progression and not [...] Read more.
Despite many years of research into the complex neurobiology of Parkinson’s disease, the precise aetiology cannot be pinpointed down to one causative agent but rather a multitude of mechanisms. Current treatment options can alleviate symptomsbut only slightly slow down the progression and not cure the disease and its underlying causes. Factors that play a role in causing the debilitating neurodegenerative psycho-motoric symptoms include genetic alterations, oxidative stress, neuroinflammation, general inflammation, neurotoxins, iron toxicity, environmental influences, and mitochondrial dysfunction. Recent findings suggest that the characteristic abnormal protein aggregation of alpha-synuclein and destruction of substantia nigra neurons might be due to mitochondrial dysfunction related to disturbances in lipid and glucose metabolism along with insulin resistance. The latter mechanism of action might be mediated by insulin receptor substrate docking to proteins that are involved in neuronal survival and signaling related to cell destruction. The increased risk of developing Type 2 Diabetes Mellitus endorses a connection between metabolic dysfunction and neurodegeneration. Here, we explore and highlight the potential role of glycolipid cellular insults in the pathophysiology of the disorder, opening up new promising avenues for the treatment of PD. Thus, antidiabetic drugs may be employed as neuromodulators to hinder the progression of the disorder. Full article
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38 pages, 3256 KiB  
Review
Harnessing Brain Plasticity: The Therapeutic Power of Repetitive Transcranial Magnetic Stimulation (rTMS) and Theta Burst Stimulation (TBS) in Neurotransmitter Modulation, Receptor Dynamics, and Neuroimaging for Neurological Innovations
by Minoo Sharbafshaaer, Giovanni Cirillo, Fabrizio Esposito, Gioacchino Tedeschi and Francesca Trojsi
Biomedicines 2024, 12(11), 2506; https://doi.org/10.3390/biomedicines12112506 - 1 Nov 2024
Viewed by 3092
Abstract
Transcranial magnetic stimulation (TMS) methods have become exciting techniques for altering brain activity and improving synaptic plasticity, earning recognition as valuable non-medicine treatments for a wide range of neurological disorders. Among these methods, repetitive TMS (rTMS) and theta-burst stimulation (TBS) show significant promise [...] Read more.
Transcranial magnetic stimulation (TMS) methods have become exciting techniques for altering brain activity and improving synaptic plasticity, earning recognition as valuable non-medicine treatments for a wide range of neurological disorders. Among these methods, repetitive TMS (rTMS) and theta-burst stimulation (TBS) show significant promise in improving outcomes for adults with complex neurological and neurodegenerative conditions, such as Alzheimer’s disease, stroke, Parkinson’s disease, etc. However, optimizing their effects remains a challenge due to variability in how patients respond and a limited understanding of how these techniques interact with crucial neurotransmitter systems. This narrative review explores the mechanisms of rTMS and TBS, which enhance neuroplasticity and functional improvement. We specifically focus on their effects on GABAergic and glutamatergic pathways and how they interact with key receptors like N-Methyl-D-Aspartate (NMDA) and AMPA receptors, which play essential roles in processes like long-term potentiation (LTP) and long-term depression (LTD). Additionally, we investigate how rTMS and TBS impact neuroplasticity and functional connectivity, particularly concerning brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase receptor type B (TrkB). Here, we highlight the significant potential of this research to expand our understanding of neuroplasticity and better treatment outcomes for patients. Through clarifying the neurobiology mechanisms behind rTMS and TBS with neuroimaging findings, we aim to develop more effective, personalized treatment plans that effectively address the challenges posed by neurological disorders and ultimately enhance the quality of neurorehabilitation services and provide future directions for patients’ care. Full article
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16 pages, 2114 KiB  
Article
Autonomic Modulation in Parkinson’s Disease Using Whole-Body Cryostimulation: A Pilot Study
by Paolo Piterà, Riccardo Cremascoli, Laura Bianchi, Francesca Borghesi, Federica Verme, Stefania Cattaldo, Elisa Prina, Stefania Mai, Pietro Cipresso, Federica Galli, Jacopo Maria Fontana, Lorenzo Priano, Alessandro Mauro and Paolo Capodaglio
Biomedicines 2024, 12(11), 2467; https://doi.org/10.3390/biomedicines12112467 - 27 Oct 2024
Viewed by 1271
Abstract
Background: Parkinson’s disease (PD) is a multifaceted neurodegenerative disorder that progressively affects both the central and peripheral nervous systems. This pilot study aimed to examine the effects of repeated whole-body cryostimulation (WBC) sessions on the sympathovagal balance in PD patients and correlate heart [...] Read more.
Background: Parkinson’s disease (PD) is a multifaceted neurodegenerative disorder that progressively affects both the central and peripheral nervous systems. This pilot study aimed to examine the effects of repeated whole-body cryostimulation (WBC) sessions on the sympathovagal balance in PD patients and correlate heart rate variability (HRV) indexes with peripheral biomarkers of the autonomic nervous system (ANS). Methods: Seventeen PD patients with mild to moderate motor severity underwent a 10-session WBC cycle over 5 consecutive days. Thirteen patients (6 males, 7 females; mean age 64.5 ± 9.01 years; mean disease duration 5.4 ± 2.3 years) completed the protocol. Cardiac autonomic activity was assessed through HRV measures including RR interval variability (RR mean, RR min, RR max), power density of high and low frequencies (HF, LF), RMSSD, and the LF/HF ratio. Systemic sympathetic activity was evaluated via circulating blood catecholamine levels. Results: Significant increases were observed in RR mean, RR min, RR max, RMSSD, and HF spectrum, indicating enhanced parasympathetic activity. Blood pressure remained stable, suggesting safety. Conclusions: These findings provide initial support to WBC as a potential “rehabilitation booster” in PD, enhancing sympathovagal balance. Further research is needed to explore the long-term benefits of WBC in PD management. Full article
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17 pages, 3163 KiB  
Systematic Review
Treatment of Parkinson’s Disease Psychosis—A Systematic Review and Multi-Methods Approach
by Olaf Rose, Sophia Huber, Eugen Trinka, Johanna Pachmayr and Stephanie Clemens
Biomedicines 2024, 12(10), 2317; https://doi.org/10.3390/biomedicines12102317 - 11 Oct 2024
Viewed by 1476
Abstract
Objectives: Parkinson’s disease psychosis (PDP) is a prevalent non-motor symptom associated with Parkinson’s disease. The treatment options for PDP are limited, and its pharmacological management remains ambiguous. This study aimed to evaluate the existing evidence in relation to clinical practice. Methods: This multi-methods [...] Read more.
Objectives: Parkinson’s disease psychosis (PDP) is a prevalent non-motor symptom associated with Parkinson’s disease. The treatment options for PDP are limited, and its pharmacological management remains ambiguous. This study aimed to evaluate the existing evidence in relation to clinical practice. Methods: This multi-methods study consisted of a systematic review of reviews, adhering to the PRISMA guidelines. The review was registered with PROSPERO. Following data extraction and assessment using the AMSTAR 2 tool, a narrative synthesis was performed. In the second phase of the study, a questionnaire was developed, validated, piloted, and distributed to the heads of specialized PD clinics in Germany and Austria. Results: The search resulted in the inclusion of eleven reviews. The quality of eight of these reviews was rated as high (n = 7) or moderate (n = 1). The reviews indicated that clozapine and pimavanserin demonstrated the highest efficacy and tolerability. Other antipsychotic medications either failed to alleviate PDP symptoms or resulted in distinct motor complications. The survey findings also favored clozapine for its efficacy in managing PDP and improving quality of life, although quetiapine was regarded as effective and pimavanserin was not available. Clinicians reported initiating antipsychotic treatment at various stages of PDP, with a tendency to reduce the dosage or discontinue D2 agonists or anticholinergics. Conclusions: The reviewed literature and the survey results consistently favored clozapine for its efficacy and tolerability in treating PDP. It may be considered the first-line treatment, with pimavanserin as an alternative option. Full article
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24 pages, 1289 KiB  
Review
Navigating the Neurobiology of Parkinson’s: The Impact and Potential of α-Synuclein
by Erlandas Paulėkas, Tadas Vanagas, Saulius Lagunavičius, Evelina Pajėdienė, Kęstutis Petrikonis and Daiva Rastenytė
Biomedicines 2024, 12(9), 2121; https://doi.org/10.3390/biomedicines12092121 - 18 Sep 2024
Cited by 1 | Viewed by 3904
Abstract
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease worldwide; therefore, since its initial description, significant progress has been made, yet a mystery remains regarding its pathogenesis and elusive root cause. The widespread distribution of pathological α-synuclein (αSyn) aggregates throughout the body [...] Read more.
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease worldwide; therefore, since its initial description, significant progress has been made, yet a mystery remains regarding its pathogenesis and elusive root cause. The widespread distribution of pathological α-synuclein (αSyn) aggregates throughout the body raises inquiries regarding the etiology, which has prompted several hypotheses, with the most prominent one being αSyn-associated proteinopathy. The identification of αSyn protein within Lewy bodies, coupled with genetic evidence linking αSyn locus duplication, triplication, as well as point mutations to familial Parkinson’s disease, has underscored the significance of αSyn in initiating and propagating Lewy body pathology throughout the brain. In monogenic and sporadic PD, the presence of early inflammation and synaptic dysfunction leads to αSyn aggregation and neuronal death through mitochondrial, lysosomal, and endosomal functional impairment. However, much remains to be understood about αSyn pathogenesis, which is heavily grounded in biomarkers and treatment strategies. In this review, we provide emerging new evidence on the current knowledge about αSyn’s pathophysiological impact on PD, and its presumable role as a specific disease biomarker or main target of disease-modifying therapies, highlighting that this understanding today offers the best potential of disease-modifying therapy in the near future. Full article
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16 pages, 1392 KiB  
Article
Enhanced Cognition and Modulation of Brain Connectivity in Mild Neurocognitive Disorder: The Promise of Transcranial Pulse Stimulation
by Heidi Ka-Ying Lo, Tommy Kwan-Hin Fong, Teris Cheung, Sze-Ting Joanna Ngan, Wai-Yan Vivian Lui, Wai-Chi Chan, Corine Sau-Man Wong, Teenie Kwan-Tung Wong and Calvin Pak-Wing Cheng
Biomedicines 2024, 12(9), 2081; https://doi.org/10.3390/biomedicines12092081 - 12 Sep 2024
Viewed by 2120
Abstract
Existing pharmacological treatments for mild neurocognitive disorder (NCD) offer limited effectiveness and adverse side effects. Transcranial pulse stimulation (TPS) utilizing ultrashort ultrasound pulses reaches deep brain regions and may circumvent conductivity issues associated with brain stimulation. This study addresses the gap in TPS [...] Read more.
Existing pharmacological treatments for mild neurocognitive disorder (NCD) offer limited effectiveness and adverse side effects. Transcranial pulse stimulation (TPS) utilizing ultrashort ultrasound pulses reaches deep brain regions and may circumvent conductivity issues associated with brain stimulation. This study addresses the gap in TPS research for mild NCD during a critical intervention period before irreversible cognitive degradation. Our objective was to explore the effectiveness and tolerability of TPS in older adults with mild NCD. In an open-label study, 17 older adults (including 10 females and 7 males) with mild NCD underwent TPS for two weeks with three sessions per week. Cognitive evaluations and fMRI scans were conducted pre- and post-intervention. The results indicated changes in functional connectivity in key brain regions, correlating with cognitive improvement at B = 0.087 (CI, 0.007–0.167; p = 0.038). However, cortical thickness measurements showed no significant differences. Here we show that TPS can enhance cognitive function within mild NCD. This proof-of-concept study suggests that TPS has potential as a non-invasive therapy used to attenuate cognitive decline, encouraging further investigation in larger randomized trials. The findings could influence clinical practice by introducing TPS as an adjunctive treatment option and potentially impact policy by promoting its inclusion in new treatment strategies for mild NCD. Full article
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16 pages, 918 KiB  
Article
Nusinersen Improves Motor Function in Type 2 and 3 Spinal Muscular Atrophy Patients across Time
by Bogdana Cavaloiu, Iulia-Elena Simina, Crisanda Vilciu, Iuliana-Anamaria Trăilă and Maria Puiu
Biomedicines 2024, 12(8), 1782; https://doi.org/10.3390/biomedicines12081782 - 6 Aug 2024
Viewed by 1766
Abstract
Spinal muscular atrophy (SMA) is a genetic disorder primarily caused by mutations in the SMN1 gene, leading to motor neuron degeneration and muscle atrophy, affecting multiple organ systems. Nusinersen treatment targets gene expression and is expected to enhance the motor function of voluntary [...] Read more.
Spinal muscular atrophy (SMA) is a genetic disorder primarily caused by mutations in the SMN1 gene, leading to motor neuron degeneration and muscle atrophy, affecting multiple organ systems. Nusinersen treatment targets gene expression and is expected to enhance the motor function of voluntary muscles in the limbs and trunk. Motor skills can be assessed through specific scales like the Revised Upper Limb Module Scale (RULM) and Hammersmith Functional Motor Scale Expanded (HFMSE). This study aims to evaluate the influence of nusinersen on the motor skills of patients with SMA Type 2 and 3 using real-world data collected over 54 months. A prospective longitudinal study was conducted on 37 SMA patients treated with nusinersen, analyzing data with R statistical software. The outcomes revealed significant improvements in motor functions, particularly in SMA Type 3 patients with higher RULM and HFSME scores. Additionally, GEE analysis identified time, type, age, and exon deletions as essential predictors of motor score improvements. The extended observation period is both a major strength and a limitation of this research, as the dropout rates could present challenges in interpretation. Variability in responses, influenced by genetic background, SMA type, and onset age, highlights the need for personalized treatment approaches. Full article
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18 pages, 1241 KiB  
Review
Circadian Interventions in Preclinical Models of Huntington’s Disease: A Narrative Review
by Derek Dell’Angelica, Karan Singh, Christopher S. Colwell and Cristina A. Ghiani
Biomedicines 2024, 12(8), 1777; https://doi.org/10.3390/biomedicines12081777 - 6 Aug 2024
Viewed by 1174
Abstract
Huntington’s Disease (HD) is a neurodegenerative disorder caused by an autosomal-dominant mutation in the huntingtin gene, which manifests with a triad of motor, cognitive and psychiatric declines. Individuals with HD often present with disturbed sleep/wake cycles, but it is still debated whether altered [...] Read more.
Huntington’s Disease (HD) is a neurodegenerative disorder caused by an autosomal-dominant mutation in the huntingtin gene, which manifests with a triad of motor, cognitive and psychiatric declines. Individuals with HD often present with disturbed sleep/wake cycles, but it is still debated whether altered circadian rhythms are intrinsic to its aetiopathology or a consequence. Conversely, it is well established that sleep/wake disturbances, perhaps acting in concert with other pathophysiological mechanisms, worsen the impact of the disease on cognitive and motor functions and are a burden to the patients and their caretakers. Currently, there is no cure to stop the progression of HD, however, preclinical research is providing cementing evidence that restoring the fluctuation of the circadian rhythms can assist in delaying the onset and slowing progression of HD. Here we highlight the application of circadian-based interventions in preclinical models and provide insights into their potential translation in clinical practice. Interventions aimed at improving sleep/wake cycles’ synchronization have shown to improve motor and cognitive deficits in HD models. Therefore, a strong support for their suitability to ameliorate HD symptoms in humans emerges from the literature, albeit with gaps in our knowledge on the underlying mechanisms and possible risks associated with their implementation. Full article
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15 pages, 1344 KiB  
Article
Preservation of Vocal Function in Amyotrophic Lateral Sclerosis (ALS) Patients Following Percutaneous Dilatational Tracheostomy (PDT) and Adjuvant Therapies
by Jae-Kook Yoo, Soon-Hee Kwon, Sul-Hee Yoon, Jeong-Eun Lee, Jong-Eun Jeon, Je-Hyuk Chung and Sang-Yoon Lee
Biomedicines 2024, 12(8), 1734; https://doi.org/10.3390/biomedicines12081734 - 2 Aug 2024
Viewed by 993
Abstract
The study aimed to evaluate the efficacy of percutaneous dilatational tracheostomy (PDT) combined with adjuvant therapies in preserving vocal function in amyotrophic lateral sclerosis (ALS) patients. Methods: We performed a retrospective analysis of 47 ALS patients who underwent PDT at the Rodem Hospital [...] Read more.
The study aimed to evaluate the efficacy of percutaneous dilatational tracheostomy (PDT) combined with adjuvant therapies in preserving vocal function in amyotrophic lateral sclerosis (ALS) patients. Methods: We performed a retrospective analysis of 47 ALS patients who underwent PDT at the Rodem Hospital from 2021 to 2023. Post-operatively, these patients were provided with a comprehensive treatment plan that included regenerative injection therapy, low-frequency electrical stimulation, respiratory rehabilitation, and swallowing rehabilitation therapy. Additionally, a balloon reduction program was implemented for effective tracheostomy tube (T-tube) management. The preservation of vocal functions was evaluated 4 weeks following the procedure. Results: While some patients maintained or slightly improved their ALSFRS-R speech scores, the overall trend indicated a decrease in speech scores post-PDT. This suggests that PDT in combination with adjuvant therapies may not universally improve vocal function, but can help maintain it in certain cases. Conclusions: Our findings indicate that PDT combined with mesotherapy, low-frequency electrical stimulation, and swallowing rehabilitation therapy may play a role in maintaining vocal function in limb type ALS patients, though further research is needed to optimize patient management and to validate these results. Full article
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33 pages, 6077 KiB  
Article
Beta2-Adrenergic Suppression of Neuroinflammation in Treatment of Parkinsonism, with Relevance for Neurodegenerative and Neoplastic Disorders
by Mario A. Inchiosa, Jr.
Biomedicines 2024, 12(8), 1720; https://doi.org/10.3390/biomedicines12081720 - 1 Aug 2024
Viewed by 1486
Abstract
There is a preliminary record suggesting that β2-adrenergic agonists may have therapeutic value in Parkinson’s disease; recent studies have proposed a possible role of these agents in suppressing the formation of α-synuclein protein, a component of Lewy bodies. The present study [...] Read more.
There is a preliminary record suggesting that β2-adrenergic agonists may have therapeutic value in Parkinson’s disease; recent studies have proposed a possible role of these agents in suppressing the formation of α-synuclein protein, a component of Lewy bodies. The present study focuses on the importance of the prototypical β2-adrenergic agonist epinephrine in relation to the incidence of Parkinson’s disease in humans, and its further investigation via synthetic selective β2-receptor agonists, such as levalbuterol. Levalbuterol exerts significant anti-inflammatory activity, a property that may suppress cytokine-mediated degeneration of dopaminergic neurons and progression of Parkinsonism. In a completely novel finding, epinephrine and certain other adrenergic agents modeled in the Harvard/MIT Broad Institute genomic database, CLUE, demonstrated strong associations with the gene-expression signatures of anti-inflammatory glucocorticoids. This prompted in vivo confirmation in mice engrafted with human peripheral blood mononuclear cells (PBMCs). Upon toxic activation with mononuclear antibodies, levalbuterol inhibited (1) the release of the eosinophil attractant chemokine eotaxin-1, which is implicated in CNS and peripheral inflammatory disorders, (2) elaboration of the tumor-promoting angiogenic factor VEGFa, and (3) release of the pro-inflammatory cytokine IL-13 from activated PBMCs. These observations suggest possible translation to Parkinson’s disease, other neurodegenerative syndromes, and malignancies, via several mechanisms. Full article
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28 pages, 15960 KiB  
Review
Cerebral Microbleeds Associate with Brain Endothelial Cell Activation-Dysfunction and Blood–Brain Barrier Dysfunction/Disruption with Increased Risk of Hemorrhagic and Ischemic Stroke
by Melvin R. Hayden
Biomedicines 2024, 12(7), 1463; https://doi.org/10.3390/biomedicines12071463 - 1 Jul 2024
Viewed by 2412
Abstract
Globally, cerebral microbleeds (CMBs) are increasingly being viewed not only as a marker for cerebral small vessel disease (SVD) but also as having an increased risk for the development of stroke (hemorrhagic/ischemic) and aging-related dementia. Recently, brain endothelial cell activation and dysfunction and [...] Read more.
Globally, cerebral microbleeds (CMBs) are increasingly being viewed not only as a marker for cerebral small vessel disease (SVD) but also as having an increased risk for the development of stroke (hemorrhagic/ischemic) and aging-related dementia. Recently, brain endothelial cell activation and dysfunction and blood–brain barrier dysfunction and/or disruption have been shown to be associated with SVD, enlarged perivascular spaces, and the development and evolution of CMBs. CMBs are a known disorder of cerebral microvessels that are visualized as 3–5 mm, smooth, round, or oval, and hypointense (black) lesions seen only on T2*-weighted gradient recall echo or susceptibility-weighted sequences MRI images. CMBs are known to occur with high prevalence in community-dwelling older individuals. Since our current global population is the oldest recorded in history and is only expected to continue to grow, we can expect the healthcare burdens associated with CMBs to also grow. Increased numbers (≥10) of CMBs should raise a red flag regarding the increased risk of large symptomatic neurologic intracerebral hemorrhages. Importantly, CMBs are also currently regarded as markers of diffuse vascular and neurodegenerative brain damage. Herein author highlights that it is essential to learn as much as we can about CMB development, evolution, and their relation to impaired cognition, dementia, and the exacerbation of neurodegeneration. Full article
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20 pages, 2376 KiB  
Article
Exploratory Tau PET/CT with [11C]PBB3 in Patients with Suspected Alzheimer’s Disease and Frontotemporal Lobar Degeneration: A Pilot Study on Correlation with PET Imaging and Cerebrospinal Fluid Biomarkers
by Joachim Strobel, Elham Yousefzadeh-Nowshahr, Katharina Deininger, Karl Peter Bohn, Christine A. F. von Arnim, Markus Otto, Christoph Solbach, Sarah Anderl-Straub, Dörte Polivka, Patrick Fissler, Gerhard Glatting, Matthias W. Riepe, Makoto Higuchi, Ambros J. Beer, Albert Ludolph and Gordon Winter
Biomedicines 2024, 12(7), 1460; https://doi.org/10.3390/biomedicines12071460 - 1 Jul 2024
Viewed by 1183
Abstract
Accurately diagnosing Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) is challenging due to overlapping symptoms and limitations of current imaging methods. This study investigates the use of [11C]PBB3 PET/CT imaging to visualize tau pathology and improve diagnostic accuracy. Given diagnostic challenges with [...] Read more.
Accurately diagnosing Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) is challenging due to overlapping symptoms and limitations of current imaging methods. This study investigates the use of [11C]PBB3 PET/CT imaging to visualize tau pathology and improve diagnostic accuracy. Given diagnostic challenges with symptoms and conventional imaging, [11C]PBB3 PET/CT’s potential to enhance accuracy was investigated by correlating tau pathology with cerebrospinal fluid (CSF) biomarkers, positron emission tomography (PET), computed tomography (CT), amyloid-beta, and Mini-Mental State Examination (MMSE). We conducted [11C]PBB3 PET/CT imaging on 24 patients with suspected AD or FTLD, alongside [11C]PiB PET/CT (13 patients) and [18F]FDG PET/CT (15 patients). Visual and quantitative assessments of [11C]PBB3 uptake using standardized uptake value ratios (SUV-Rs) and correlation analyses with clinical assessments were performed. The scans revealed distinct tau accumulation patterns; 13 patients had no or faint uptake (PBB3-negative) and 11 had moderate to pronounced uptake (PBB3-positive). Significant inverse correlations were found between [11C]PBB3 SUV-Rs and MMSE scores, but not with CSF-tau or CSF-amyloid-beta levels. Here, we show that [11C]PBB3 PET/CT imaging can reveal distinct tau accumulation patterns and correlate these with cognitive impairment in neurodegenerative diseases. Our study demonstrates the potential of [11C]PBB3-PET imaging for visualizing tau pathology and assessing disease severity, offering a promising tool for enhancing diagnostic accuracy in AD and FTLD. Further research is essential to validate these findings and refine the use of tau-specific PET imaging in clinical practice, ultimately improving patient care and treatment outcomes. Full article
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20 pages, 2220 KiB  
Article
Mitochondrial Dysfunction in Sporadic Amyotrophic Lateral Sclerosis Patients: Insights from High-Resolution Respirometry
by Petra Parvanovova, Andrea Evinova, Milan Grofik, Petra Hnilicova, Zuzana Tatarkova and Monika Turcanova-Koprusakova
Biomedicines 2024, 12(6), 1294; https://doi.org/10.3390/biomedicines12061294 - 11 Jun 2024
Viewed by 1433
Abstract
Amyotrophic lateral sclerosis is a severe neurodegenerative disease whose exact cause is still unclear. Currently, research attention is turning to the mitochondrion as a critical organelle of energy metabolism. Current knowledge is sufficient to confirm the involvement of the mitochondria in the pathophysiology [...] Read more.
Amyotrophic lateral sclerosis is a severe neurodegenerative disease whose exact cause is still unclear. Currently, research attention is turning to the mitochondrion as a critical organelle of energy metabolism. Current knowledge is sufficient to confirm the involvement of the mitochondria in the pathophysiology of the disease, since the mitochondria are involved in many processes in the cell; however, the exact mechanism of involvement is still unclear. We used peripheral blood mononuclear cells isolated from whole fresh blood from patients with amyotrophic lateral sclerosis for measurement and matched an age- and sex-matched set of healthy subjects. The group of patients consisted of patients examined and diagnosed at the neurological clinic of the University Hospital Martin. The set of controls consisted of healthy individuals who were actively searched, and controls were selected on the basis of age and sex. The group consisted of 26 patients with sporadic forms of ALS (13 women, 13 men), diagnosed based on the definitive criteria of El Escorial. The average age of patients was 54 years, and the average age of healthy controls was 56 years. We used a high-resolution O2K respirometry method, Oxygraph-2k, to measure mitochondrial respiration. Basal respiration was lower in patients by 29.48%, pyruvate-stimulated respiration (respiratory chain complex I) was lower by 29.26%, and maximal respiratory capacity was lower by 28.15%. The decrease in succinate-stimulated respiration (respiratory chain complex II) was 26.91%. Our data confirm changes in mitochondrial respiration in ALS patients, manifested by the reduced function of complex I and complex II of the respiratory chain. These defects are severe enough to confirm this disease’s hypothesized mitochondrial damage. Therefore, research interest in the future should be directed towards a deeper understanding of the involvement of mitochondria and respiratory complexes in the pathophysiology of the disease. This understanding could develop new biomarkers in diagnostics and subsequent therapeutic interventions. Full article
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14 pages, 3078 KiB  
Article
Oxytocin and Vasopressin Gene Expression in the Brain as Potential Biomarkers for Cannabidiol Therapeutic Efficacy
by Christa M. Frodella, Stephen B. Pruett, Matthew K. Ross and Barbara L. F. Kaplan
Biomedicines 2024, 12(6), 1273; https://doi.org/10.3390/biomedicines12061273 - 7 Jun 2024
Cited by 1 | Viewed by 1566
Abstract
Over the last several years, there has been increased interest in cannabidiol (CBD) to treat various ailments such as pain, anxiety, insomnia, and inflammation. The potential for CBD as an anti-inflammatory therapy has come, in part, from its demonstrated ability to suppress neuroinflammation [...] Read more.
Over the last several years, there has been increased interest in cannabidiol (CBD) to treat various ailments such as pain, anxiety, insomnia, and inflammation. The potential for CBD as an anti-inflammatory therapy has come, in part, from its demonstrated ability to suppress neuroinflammation in autoimmune diseases, such as the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). The increased use of CBD strongly suggests that more research is necessary to elucidate its safety and efficacy and determine the mechanisms by which it acts. Thus, we conducted two separate studies. In the first, RNA sequencing (RNA-Seq) analysis of brains of female mice undergoing EAE in the presence and absence of CBD was conducted to identify potential genes that mediated its neuroprotective effects when efficacious. In the second, we assessed some of the same genes in male and female mice treated with CBD in the absence of an immune stimulus. Together, these data showed that CBD modestly increased oxytocin (Oxt) and arginine vasopressin (vasopressin, Avp) gene expression in the brains of mice, regardless of whether there was active inflammation. Overall, these data suggest that Oxt and Avp might act as biomarkers for CBD exposure. Full article
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12 pages, 3617 KiB  
Article
Mild Disease Course of Experimental Autoimmune Encephalomyelitis without Pertussis Toxin: Brain Transcriptome Analysis Reveals Similar Signaling to Active Lesions in Multiple Sclerosis
by Christa M. Frodella, Stephen B. Pruett and Barbara L. F. Kaplan
Biomedicines 2024, 12(6), 1215; https://doi.org/10.3390/biomedicines12061215 - 30 May 2024
Cited by 1 | Viewed by 1095
Abstract
Experimental autoimmune encephalomyelitis (EAE) is a powerful model to study multiple sclerosis (MS). One of the approaches for EAE is to actively immunize with myelin-derived peptides with immune adjuvants. One of the commonly used immune adjuvants is pertussis toxin (PTx), without which EAE [...] Read more.
Experimental autoimmune encephalomyelitis (EAE) is a powerful model to study multiple sclerosis (MS). One of the approaches for EAE is to actively immunize with myelin-derived peptides with immune adjuvants. One of the commonly used immune adjuvants is pertussis toxin (PTx), without which EAE disease is mild with relatively longer onset. However, pertussis toxin can also inhibit G protein-coupled receptor (GPCR) signaling so it can confound investigations into the role of GPCRs in EAE or therapies designed to target GPCRs. Since EAE via active immunization without PTx results in a relatively mild disease state, we wanted to confirm that appropriate signaling molecules for the disease were being induced in one target tissue (i.e., brain). RNA-Seq analysis of whole brain tissue demonstrated that the MS signaling pathway was strongly activated in symptomatic mice. In addition, there was activation of Th1 (IFN signaling), Th2 (IL-4 signaling), and Th17 (IL-17 signaling). In comparing canonical pathways from our mouse mild EAE brains with a human MS atlas, EAE shared the most pathways with active and inactive lesions. An advantage of this approach is that disease induction is slower to develop and results in modest clinical signs, which likely more closely mimic human disease onset. Full article
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17 pages, 3161 KiB  
Article
Comparison of Protective Effects of Antidepressants Mediated by Serotonin Receptor in Aβ-Oligomer-Induced Neurotoxicity
by Ken Yamamoto, Mayumi Tsuji, Tatsunori Oguchi, Yutaro Momma, Hideaki Ohashi, Naohito Ito, Tetsuhito Nohara, Tatsuya Nakanishi, Atsushi Ishida, Masahiro Hosonuma, Toru Nishikawa, Hidetomo Murakami and Yuji Kiuchi
Biomedicines 2024, 12(6), 1158; https://doi.org/10.3390/biomedicines12061158 - 23 May 2024
Cited by 1 | Viewed by 1309
Abstract
Amyloid β-peptide (Aβ) synthesis and deposition are the primary factors underlying the pathophysiology of Alzheimer’s disease (AD). Aβ oligomer (Aβo) exerts its neurotoxic effects by inducing oxidative stress and lesions by adhering to cellular membranes. Though several antidepressants have been investigated as neuroprotective [...] Read more.
Amyloid β-peptide (Aβ) synthesis and deposition are the primary factors underlying the pathophysiology of Alzheimer’s disease (AD). Aβ oligomer (Aβo) exerts its neurotoxic effects by inducing oxidative stress and lesions by adhering to cellular membranes. Though several antidepressants have been investigated as neuroprotective agents in AD, a detailed comparison of their neuroprotection against Aβo-induced neurotoxicity is lacking. Here, we aimed to elucidate the neuroprotective effects of clinically prescribed selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants at the cellular level and establish the underlying mechanisms for their potential clinical applications. Therefore, we compared the neuroprotective effects of three antidepressants, fluoxetine (Flx), duloxetine (Dlx), and mirtazapine (Mir), by their ability to prevent oxidative stress-induced cell damage, using SH-SY5Y cells, by evaluating cell viability, generation of reactive oxygen species (ROS) and mitochondrial ROS, and peroxidation of cell membrane phospholipids. These antidepressants exhibited potent antioxidant activity (Dlx > Mir > Flx) and improved cell viability. Furthermore, pretreatment with a 5-hydroxytryptamine 1A (5-HT1A) antagonist suppressed their effects, suggesting that the 5-HT1A receptor is involved in the antioxidant mechanism of the antidepressants’ neuroprotection. These findings suggest the beneficial effects of antidepressant treatment in AD through the prevention of Aβ-induced oxidative stress. Full article
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