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Molecular Mechanisms in Neurodegenerative Diseases: Clinical and Therapeutic Perspectives

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Clinical Neurology".

Deadline for manuscript submissions: closed (20 April 2023) | Viewed by 24473

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Dr. Fabiola De Marchi

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ALS Centre, Neurology Unit, Maggiore della Carità University Hospital, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
Interests: neurodegeneration; amyotrophic lateral sclerosis; biomarkers; genetics
Special Issues, Collections and Topics in MDPI journals

Dr. Giacomo Tondo

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1. Neurology Unit, S. Andrea Hospital, Department of Translational Medicine, University of Piemonte Orientale, Vercelli, Italy
2. In Vivo Human Molecular and Structural Neuroimaging Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
Interests: dementia; mild cognitive impairment; biomarkers; neurodegeneration; PET imaging
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Neurodegenerative diseases are progressive and debilitating conditions that result in inexorable neural degeneration and loss. To date, none of the existing therapeutic strategies can effectively stop or modify the pathological processes leading to neurodegeneration.

In recent decades researchers have been trying to enhance the development of reliable biomarkers for neurodegenerative diseases, while medical practice has been moving toward precision medicine. However, there is still an urgent need to identify disease-specific biomarkers to improve the early diagnostic workup, favor clinical classification and prognostic models, and facilitate the development of effective disease-modifying therapies. Most neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, are characterized by the abnormal deposition of misfolded proteins in the central nervous system, resulting in neuronal degeneration and ultimately neuronal damage death. Several environmental factors have been proposed to contribute to neuronal damage and degenerative changes, and the genetic profile may also prepare the pathophysiological process underlying neurodegeneration. Distinct molecular and functional pathways may become dysregulated, including neurophysiology feedbacks, long-distance brain network organization, and neuroinflammatory responses. Pathology alterations can be detected, in vivo, by searching for cerebrospinal fluid alterations or using positron emission tomography to detect abnormal protein accumulation. Brain imaging can also reveal functional and molecular connectivity changes, and neurophysiology techniques may track additional early disease-specific dysfunctions. Genetic profiling can aid the identification of possible clinical trajectories along the neurodegenerative process, offering the possibility to test therapeutic strategies in a pre-symptomatic phase. Similarly, the investigation of neuroinflammatory responses represents a possible invaluable tool in monitoring disease progression and predicting clinical outcomes.

This Special Issue aims to highlight the current knowledge regarding neurodegeneration pathogenic mechanisms and underline possible diagnostic and therapeutic repercussions in neurodegenerative diseases.

In this Special Issue, original articles and reviews are welcome. We look forward to receiving your contributions.

Dr. Fabiola De Marchi
Dr. Giacomo Tondo
Guest Editors

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Keywords

neurodegeneration
aging
dementia
motoneuron disease
movement disorders
precision medicine
biomarkers

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Related Special Issue

Molecular Mechanisms in Neurodegenerative Diseases: Clinical and Therapeutic Perspectives—Volume II in Journal of Clinical Medicine (1 article)

Published Papers (10 papers)

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Editorial

Jump to: Research, Review

4 pages, 196 KiB

Open AccessEditorial

From Biomarkers to Precision Medicine in Neurodegenerative Diseases: Where Are We?

by Giacomo Tondo and Fabiola De Marchi

J. Clin. Med. 2022, 11(15), 4515; https://doi.org/10.3390/jcm11154515 - 3 Aug 2022

Cited by 14 | Viewed by 1973

Abstract

The biomarkers era grew in the last two decades when several technical and methodological advances have improved the research in neurodegenerative diseases [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms in Neurodegenerative Diseases: Clinical and Therapeutic Perspectives)

Research

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14 pages, 2168 KiB

Open AccessArticle

Investigating the Prognostic Role of Peripheral Inflammatory Markers in Mild Cognitive Impairment

by Giacomo Tondo, Davide Aprile, Fabiola De Marchi, Barbara Sarasso, Paola Serra, Giordana Borasio, Esther Rojo, Juan Francisco Arenillas and Cristoforo Comi

J. Clin. Med. 2023, 12(13), 4298; https://doi.org/10.3390/jcm12134298 - 27 Jun 2023

Cited by 6 | Viewed by 1545

Abstract

Growing evidence suggests that neuroinflammation plays a critical role in the pathogenesis of neurodegenerative diseases. Peripheral markers of inflammation, including blood cell counts and their ratios, such as the neutrophil-to-lymphocyte ratio (NLR), have been reported as an easily accessible and reliable proxy of central nervous system inflammation. However, the role of peripheral inflammation in dementia and Mild Cognitive Impairment (MCI) still needs to be clarified. In the current study, we aimed to assess the prognostic role of the NLR and other peripheral markers of inflammation in a sample of 130 amnestic MCI, followed up for two to five years. The Mini-Mental state examination (MMSE) score at baseline and follow-up visits was used to assess global cognitive status at each visit and the degree of cognitive decline over time. Baseline peripheral markers of inflammation included blood cell counts and ratios, specifically the NLR, the platelet-to-lymphocyte ratio (PLR), the monocyte-to-lymphocyte ratio (MLR), and the systemic immune inflammation index (SII). After classifying subjects into CONVERTERS and non-CONVERTERS (respectively, patients converting to dementia and subjects showing stability at the last available follow-up), we compared peripheral markers of inflammation among groups ed correlated them with cognitive measures, testing the ability of significant factors to predict conversion to dementia. In our cohort, CONVERTERS showed lower baseline MMSE scores (p-value = 0.004) than non-CONVERTERS. In addition, CONVERTERS had statistically elevated NLR (p-value = 0.005), PLR (p-value = 0.002), and SII levels (p-value = 0.015), besides a lower number of lymphocytes (p-value = 0.004) compared with non-CONVERTERS. In a logistic regression analysis, baseline MMSE scores and NLR predicted conversion to dementia. Tertiles analysis showed that MCI with the highest NLR values had a higher conversion risk. Our study supports the hypothesis that a dysregulation of peripheral inflammation involving both lymphocytes and neutrophils may play a role in the pathogenesis of dementia, even at the early stages of neurodegeneration, as in the MCI condition. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Neurodegenerative Diseases: Clinical and Therapeutic Perspectives)

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10 pages, 259 KiB

Open AccessArticle

Early Predictors of Disability and Cognition in Multiple Sclerosis Patients: A Long-Term Retrospective Analysis

by Eleonora Virgilio, Domizia Vecchio, Maria Francesca Sarnelli, Valentina Solara, Roberto Cantello and Cristoforo Comi

J. Clin. Med. 2023, 12(2), 685; https://doi.org/10.3390/jcm12020685 - 15 Jan 2023

Cited by 5 | Viewed by 2158

Abstract

We conducted a retrospective analysis on multiple sclerosis (MS) patients with perceived cognitive decline and long disease duration to investigate early predictors of future cognitive impairment (CI) and motor disability. Sixty-five patients complaining of cognitive decline were assessed with an extensive neuropsychological battery at the last clinical follow-up and classified as mildly impaired, severely impaired, and cognitively spared based on the results. Motor disability was assessed with EDSS, MSSS, and ARMSS. Baseline demographic, clinical, and imaging parameters were retrospectively collected and inserted in separate multivariate regression models to investigate the predictive power of future impairment. Twenty-one patients (32.3%) showed no CI, seventeen (26.2%) showed mild CI, and twenty-seven (41.5%) showed severe CI. Older and less educated patients with higher EDSS, longer disease duration, and higher white matter lesion load (WMLL) at diagnosis (particularly with cerebellar involvement) were more likely to develop CI after a mean follow-up from diagnosis of 16.5 ± 6.9 years. DMT exposure was protective. The multivariate regression analyses confirmed WMLL, disease duration, and educational levels as the parameters with significant predictive value for future CI (R2 adjusted: 0.338 p: 0.001). Older patients with progressive phenotype both at diagnosis and T1 were more likely to be not fully ambulatory at T1 (R2 adjusted: 0.796 p: 0.0001). Our results further expand knowledge on early predictors of cognitive decline and evolution over time. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Neurodegenerative Diseases: Clinical and Therapeutic Perspectives)

10 pages, 8671 KiB

Open AccessArticle

Identification of a Novel Non-Canonical Splice-Site Variant in ABCD1

by Feixia Zheng, Zhongdong Lin, Ying Hu, Xulai Shi, Qianlei Zhao and Zhenlang Lin

J. Clin. Med. 2023, 12(2), 473; https://doi.org/10.3390/jcm12020473 - 6 Jan 2023

Cited by 1 | Viewed by 1704

Abstract

Cerebral adrenoleukodystrophy (CALD) is a fatal genetic disease characterized by rapid, devastating neurological decline, with a narrow curative treatment window in the early stage. Non-canonical splice-site (NCSS) variants can easily be missed during genomic DNA analyses, and only a few of them in ABCD1 have been explored. Here, we studied a Chinese patient with clinical features similar to those of early-stage CALD but with a negative molecular diagnosis and a sibling who had presumably died of CALD. Trio-based whole-exome sequencing (trio-WES) and RNA sequencing (RNA-Seq) revealed a novel hemizygote NCSS variant c.901-25_901-9 del in ABCD1 intron 1, resulting in a complex splicing pattern. The in vitro minigene assay revealed that the c.901-25_901-9 del construct contained two aberrant transcripts that caused skipping of exon 2 and a small 48-bp deletion on left of the same exon. We identified a novel NCSS variant, that extends the spectrum of the known ABCD1 variants, and demonstrated the pathogenicity of this gene variant. Our findings highlight the importance of combining RNA-Seq and WES techniques for prompt diagnosis of leukodystrophy with NCSS variants. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Neurodegenerative Diseases: Clinical and Therapeutic Perspectives)

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12 pages, 3010 KiB

Open AccessArticle

Identification of a TPP1 Q278X Mutation in an Iranian Patient with Neuronal Ceroid Lipofuscinosis 2: Literature Review and Mutations Update

by Tayebeh Baranzehi, Dor Mohammad Kordi-Tamandani, Maryam Najafi, Ali Khajeh and Miriam Schmidts

J. Clin. Med. 2022, 11(21), 6415; https://doi.org/10.3390/jcm11216415 - 29 Oct 2022

Cited by 3 | Viewed by 2121

Abstract

Neuronal ceroid lipofuscinoses type 2 (CLN2), the most common form of Batten disease, is caused by TPP1 loss of function, resulting in tripeptidyl peptidase-1 enzyme deficiency and cerebral accumulation of lipopigments. Clinical hallmarks include epileptic seizures, vision loss, progressive movement disorder, ataxia, and eventually death. Diagnosis is often delayed due to the rarity of the conditions. Results: Here, we report a case presenting with clinical features of CLN2, carrying a homozygous novel nonsense variant in TPP1 (NM_000391:c.C832T, (p.Q278*), rs1352347549). Moreover, we performed a comprehensive literature review regarding previously identified disease-causing TPP1 mutations and genotype-phenotype correlations. Conclusion: Depending on the type of mutation, different phenotypes are observed in patients with CLN2, suggesting that the severity of phenotypes is related to the genotype of the patients. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Neurodegenerative Diseases: Clinical and Therapeutic Perspectives)

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12 pages, 1457 KiB

Open AccessArticle

Increased T-bet/GATA-3 and ROR-γt /Foxp3 Ratios in Cerebrospinal Fluid as Potential Criteria for Definite Neuro-Behçet’s Disease

by Meriam Belghith, Olfa Maghrebi, Aroua Cherif, Khadija Bahrini, Zakaria Saied, Samir Belal, Samia Ben Sassi, Mohamed-Ridha Barbouche and Mariem Kchaou

J. Clin. Med. 2022, 11(15), 4415; https://doi.org/10.3390/jcm11154415 - 29 Jul 2022

Cited by 5 | Viewed by 1818

Abstract

When the central nervous system (CNS) is the primary affected site in an initial attack of Behçet’s disease (BD), the differential diagnosis is particularly challenging. Some cases remain unclassified or qualified as probable neuro-Behçet’s disease (NBD). Several cytokines are involved in the immunopathogenesis of this disease; however, studies establishing the differential cytokine pattern between probable and definite NBD are scarce. Twenty-eight parenchymal NBD patients, diagnosed according to the International Consensus Recommendation (ICR) criteria and classified into definite (D-NBD; n = 17) and probable (P-NBD; n = 11), were sampled at their first neurological symptoms, and compared with healthy control subjects (n = 20). Oligoclonal bands (OCB) of IgG were detected by isoelectric focusing on agarose, and immunoblotting of matched serum and cerebrospinal fluid (CSF) sample pairs. T cell cytokines (INF-γ, IL-4, IL-17, and IL-10) and transcription factors related to Th1, Th2, Th17, and T regulatory populations (respectively T-bet, GATA-3, ROR-γt, and Foxp3) were studied by quantitative RT-PCR in peripheral blood mononuclear cells (PBMCs) and CSF cells. Inflammatory cytokines such as IL-6, TNF-α, and IL-1β were also analyzed. CSF OCB pattern 2 was present in only 1 out of 28 neuro-Behçet’s patients who belonged to the P-NBD group. Two D-NBD patients had OCB in CSF showing pattern 4. In the D-NBD CSF samples, IL-17 and IL-10 expressions were significantly elevated compared to P-NBD. Moreover, D-NBD patients had increased levels of T-bet/GATA-3 and ROR-γt/Foxp3 ratios compared to P-NBD. Furthermore, a significant increase of CSF IL-6 in D-NBD, compared to P-NBD and the controls, was found. In addition to the increased IL-6 level, the data obtained suggest the existence in D-NBD patients of a significantly disrupted balance between Th17 effector and T regulatory cells, as reflected by the enhanced ROR-γt/Foxp3 ratio. This could be considered as an additional criterion for definite neuro-Behçet’s disease. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Neurodegenerative Diseases: Clinical and Therapeutic Perspectives)

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9 pages, 1230 KiB

Open AccessArticle

A Telehealth Intervention for Nutritional Counseling in Amyotrophic Lateral Sclerosis Patients

by Fabiola De Marchi, Marcella Serioli, Alessandro Collo, Evelyn Gisell Belotti, Francesca Alloatti, Giampaolo Biroli, Andrea Bolioli, Roberto Cantello, Sergio Riso and Letizia Mazzini

J. Clin. Med. 2022, 11(15), 4286; https://doi.org/10.3390/jcm11154286 - 23 Jul 2022

Cited by 2 | Viewed by 2003

Abstract

Nutritional status is one of the most relevant prognostic factors in Amyotrophic Lateral Sclerosis (ALS), and close monitoring can help avoid severe weight loss over the disease course. We describe the impact of a Chatbot webapp on improving the communications between physicians, patients, and/or caregivers for dietary monitoring. We developed a chatbot that provides patients with a tool to register their meals through an intuitive and carefully designed conversational interface. Patients recorded their dietary intake twice weekly and received an adequate nutritional recommendation monthly. We monitored their functional and nutritional parameters. The data were compared with a control group followed up by standard counseling. We enrolled 26 patients. Regarding feasibility, 96% of participants completed the three-month follow-up, and 77% ended the six months. Regarding the change in weight in the Chatbot group, we observed a weight stabilization (F = 1.874, p-value: 0.310 for changes) over the telehealth compared to the control group (F = 1.710, p-value: 0.024 for changes). A telehealth approach for nutritional support is feasible and reproducible in an ALS setting: frequent monitoring turned out to help prevent further weight loss, allowing an early nutritional strategy adjustment. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Neurodegenerative Diseases: Clinical and Therapeutic Perspectives)

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Review

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42 pages, 844 KiB

Open AccessReview

Noninvasive Neuromodulation in Parkinson’s Disease: Insights from Animal Models

by Katherine Muksuris, David M. Scarisbrick, James J. Mahoney III and Mariya V. Cherkasova

J. Clin. Med. 2023, 12(17), 5448; https://doi.org/10.3390/jcm12175448 - 22 Aug 2023

Cited by 1 | Viewed by 2431

Abstract

The mainstay treatments for Parkinson’s Disease (PD) have been limited to pharmacotherapy and deep brain stimulation. While these interventions are helpful, a new wave of research is investigating noninvasive neuromodulation methods as potential treatments. Some promising avenues have included transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), electroconvulsive therapy (ECT), and focused ultrasound (FUS). While these methods are being tested in PD patients, investigations in animal models of PD have sought to elucidate their therapeutic mechanisms. In this rapid review, we assess the available animal literature on these noninvasive techniques and discuss the possible mechanisms mediating their therapeutic effects based on these findings. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Neurodegenerative Diseases: Clinical and Therapeutic Perspectives)

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16 pages, 1730 KiB

Open AccessReview

The Potential Roles of Exosomes Carrying APP and Tau Cleavage Products in Alzheimer’s Disease

by Yanfang Zhao, Yujin Gu, Qili Zhang, Hongliang Liu and Yingying Liu

J. Clin. Med. 2023, 12(5), 1883; https://doi.org/10.3390/jcm12051883 - 27 Feb 2023

Cited by 9 | Viewed by 2696

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia throughout the world. It is characterized by major amyloid plaques and neurofibrillary tangles (NFTs), which are composed of amyloid-β (Aβ) peptide and hyperphosphorylated Tau (p-Tau), respectively. Exosomes, which are secreted by cells, are single-membrane lipid bilayer vesicles found in bodily fluids and they have a diameter of 30–150 nm. Recently, they have been considered as critical carriers and biomarkers in AD, as they facilitate communication between cells and tissues by delivering proteins, lipids, and nucleic acids. This review demonstrates that exosomes are natural nanocontainers that carry APP as well as Tau cleavage products secreted by neuronal cells and that their formation is associated with the endosomal–lysosomal pathway. Moreover, these exosomes can transfer AD pathological molecules and participate in the pathophysiological process of AD; therefore, they have potential diagnostic and therapeutic value for AD and might also provide novel insights for screening and prevention of the disease. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Neurodegenerative Diseases: Clinical and Therapeutic Perspectives)

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21 pages, 1112 KiB

Open AccessReview

Research Evidence of the Role of the Glymphatic System and Its Potential Pharmacological Modulation in Neurodegenerative Diseases

by Joji Philip Verghese, Alana Terry, Edoardo Rosario de Natale and Marios Politis

J. Clin. Med. 2022, 11(23), 6964; https://doi.org/10.3390/jcm11236964 - 25 Nov 2022

Cited by 23 | Viewed by 4952

Abstract

The glymphatic system is a unique pathway that utilises end-feet Aquaporin 4 (AQP4) channels within perivascular astrocytes, which is believed to cause cerebrospinal fluid (CSF) inflow into perivascular space (PVS), providing nutrients and waste disposal of the brain parenchyma. It is theorised that the bulk flow of CSF within the PVS removes waste products, soluble proteins, and products of metabolic activity, such as amyloid-β (Aβ). In the experimental model, the glymphatic system is selectively active during slow-wave sleep, and its activity is affected by both sleep dysfunction and deprivation. Dysfunction of the glymphatic system has been proposed as a potential key driver of neurodegeneration. This hypothesis is indirectly supported by the close relationship between neurodegenerative diseases and sleep alterations, frequently occurring years before the clinical diagnosis. Therefore, a detailed characterisation of the function of the glymphatic system in human physiology and disease would shed light on its early stage pathophysiology. The study of the glymphatic system is also critical to identifying means for its pharmacological modulation, which may have the potential for disease modification. This review will critically outline the primary evidence from literature about the dysfunction of the glymphatic system in neurodegeneration and discuss the rationale and current knowledge about pharmacological modulation of the glymphatic system in the animal model and its potential clinical applications in human clinical trials. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Neurodegenerative Diseases: Clinical and Therapeutic Perspectives)

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