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Study on Genotypes and Phenotypes of Neurodegenerative Diseases
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Study on Genotypes and Phenotypes of Neurodegenerative Diseases

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (5 September 2023) | Viewed by 26155

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Claudia Ricci

E-Mail Website
Guest Editor
Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
Interests: neurogenetics; motor neuron diseases; amyotrophic lateral sclerosis; cerebral cavernous malformations; genotype-phenotype correlations; gene variant consequences; microRNAs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Genetic factors are key players in the pathogenesis of several neurodegenerative diseases, acting both as monogenic causes in inherited forms and modulatory factors in multifactorial/sporadic diseases. With the recent advances in cost-effective genetic analyses, the knolwledge of genetic bases of several neurodegenerative disorders has made great strides, improving the understanding of mechanisms underpinning the pathogenesis of these conditions.

Neurodegenerative diseases display a certain degree of genetic heterogeneity; in other words, the presentation and severity of disease may vary from individual to individual. In some cases, the same phenotype can be determined by different variants in different genes. On the other hand, the same mutation may be associated with phenotypic heterogeneity, also in the same family. However, in some cases, a specific variant may be related to a uniform phenotype, proving helpful for diagnostic and prognostic aims. In the precision medicine era, a better characterization of genotype–phenotype correlations may allow to improve the therapeutic approaches, evaluating the individual drug response and guiding gene-focused clinical trials.

This Special Issue aims to provide an updated overview of the “Study on Genotypes and Phenotypes of Neurodegenerative Diseases”. Contributions related but not limited to Alzheimer's disease and other dementias, Parkinson's disease, and motor neurone diseases  are welcomed, including original research articles and full and mini-reviews.

Dr. Claudia Ricci
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

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

  • neurodegenerative diseases
  • genetic variants
  • genotype
  • phenotype
  • genotype–phenotype correlations

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Published Papers (12 papers)

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Editorial

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4 pages, 159 KiB  
Editorial
Study on Genotypes and Phenotypes of Neurodegenerative Diseases
by Claudia Ricci
Genes 2024, 15(6), 786; https://doi.org/10.3390/genes15060786 - 14 Jun 2024
Viewed by 721
Abstract
Neurodegenerative diseases are a heterogeneous group of age-related disorders that are characterised by the gradual degeneration or death of neurons in the central or peripheral nervous system [...] Full article
(This article belongs to the Special Issue Study on Genotypes and Phenotypes of Neurodegenerative Diseases)

Research

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12 pages, 4604 KiB  
Article
Novel Genetic and Phenotypic Expansion in GOSR2-Related Progressive Myoclonus Epilepsy
by Lea Hentrich, Mered Parnes, Timothy Edward Lotze, Rohini Coorg, Tom J. de Koning, Kha M. Nguyen, Calvin K. Yip, Heinz Jungbluth, Anne Koy and Hormos Salimi Dafsari
Genes 2023, 14(10), 1860; https://doi.org/10.3390/genes14101860 - 25 Sep 2023
Cited by 6 | Viewed by 1698
Abstract
Biallelic variants in the Golgi SNAP receptor complex member 2 gene (GOSR2) have been reported in progressive myoclonus epilepsy with neurodegeneration. Typical clinical features include ataxia and areflexia during early childhood, followed by seizures, scoliosis, dysarthria, and myoclonus. Here, we report [...] Read more.
Biallelic variants in the Golgi SNAP receptor complex member 2 gene (GOSR2) have been reported in progressive myoclonus epilepsy with neurodegeneration. Typical clinical features include ataxia and areflexia during early childhood, followed by seizures, scoliosis, dysarthria, and myoclonus. Here, we report two novel patients from unrelated families with a GOSR2-related disorder and novel genetic and clinical findings. The first patient, a male compound heterozygous for the GOSR2 splice site variant c.336+1G>A and the novel c.364G>A,p.Glu122Lys missense variant showed global developmental delay and seizures at the age of 2 years, followed by myoclonus at the age of 8 years with partial response to clonazepam. The second patient, a female homozygous for the GOSR2 founder variant p.Gly144Trp, showed only mild fine motor developmental delay and generalized tonic–clonic seizures triggered by infections during adolescence, with seizure remission on levetiracetam. The associated movement disorder progressed atypically slowly during adolescence compared to its usual speed, from initial intention tremor and myoclonus to ataxia, hyporeflexia, dysmetria, and dystonia. These findings expand the genotype–phenotype spectrum of GOSR2-related disorders and suggest that GOSR2 should be included in the consideration of monogenetic causes of dystonia, global developmental delay, and seizures. Full article
(This article belongs to the Special Issue Study on Genotypes and Phenotypes of Neurodegenerative Diseases)
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18 pages, 1864 KiB  
Article
Exome-Wide Association Study Identified Clusters of Pleiotropic Genetic Associations with Alzheimer’s Disease and Thirteen Cardiovascular Traits
by Yury Loika, Elena Loiko, Irina Culminskaya and Alexander M. Kulminski
Genes 2023, 14(10), 1834; https://doi.org/10.3390/genes14101834 - 22 Sep 2023
Cited by 3 | Viewed by 1542
Abstract
Alzheimer’s disease (AD) and cardiovascular traits might share underlying causes. We sought to identify clusters of cardiovascular traits that share genetic factors with AD. We conducted a univariate exome-wide association study and pair-wise pleiotropic analysis focused on AD and 16 cardiovascular traits—6 diseases [...] Read more.
Alzheimer’s disease (AD) and cardiovascular traits might share underlying causes. We sought to identify clusters of cardiovascular traits that share genetic factors with AD. We conducted a univariate exome-wide association study and pair-wise pleiotropic analysis focused on AD and 16 cardiovascular traits—6 diseases and 10 cardio-metabolic risk factors—for 188,260 UK biobank participants. Our analysis pinpointed nine genetic markers in the APOE gene region and four loci mapped to the CDK11, OBP2B, TPM1, and SMARCA4 genes, which demonstrated associations with AD at p ≤ 5 × 10−4 and pleiotropic associations at p ≤ 5 × 10−8. Using hierarchical cluster analysis, we grouped the phenotypes from these pleiotropic associations into seven clusters. Lipids were divided into three clusters: low-density lipoprotein and total cholesterol, high-density lipoprotein cholesterol, and triglycerides. This split might differentiate the lipid-related mechanisms of AD. The clustering of body mass index (BMI) with weight but not height indicates that weight defines BMI-AD pleiotropy. The remaining two clusters included (i) coronary heart disease and myocardial infarction; and (ii) hypertension, diabetes mellitus (DM), systolic and diastolic blood pressure. We found that all AD protective alleles were associated with larger weight and higher DM risk. Three of the four (75%) clusters of traits, which were significantly correlated with AD, demonstrated antagonistic genetic heterogeneity, characterized by different directions of the genetic associations and trait correlations. Our findings suggest that shared genetic factors between AD and cardiovascular traits mostly affect them in an antagonistic manner. Full article
(This article belongs to the Special Issue Study on Genotypes and Phenotypes of Neurodegenerative Diseases)
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12 pages, 2898 KiB  
Article
Factors Associated with Large Cup-to-Disc Ratio and Blindness in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) Study
by Anusha Mamidipaka, Isabel Di Rosa, Roy Lee, Yan Zhu, Yineng Chen, Rebecca Salowe, Victoria Addis, Prithvi Sankar, Ebenezer Daniel, Gui-Shuang Ying and Joan M. O’Brien
Genes 2023, 14(9), 1809; https://doi.org/10.3390/genes14091809 - 16 Sep 2023
Cited by 4 | Viewed by 3009
Abstract
Background/Aims: Primary open-angle glaucoma (POAG) disproportionately affects individuals of African ancestry. In these patients’ eyes, a large cup-to-disc ratio (LCDR > 0.90) suggests greater retinal ganglion cell loss, though these patients often display varied visual ability. This study investigated the prevalence and risk [...] Read more.
Background/Aims: Primary open-angle glaucoma (POAG) disproportionately affects individuals of African ancestry. In these patients’ eyes, a large cup-to-disc ratio (LCDR > 0.90) suggests greater retinal ganglion cell loss, though these patients often display varied visual ability. This study investigated the prevalence and risk factors associated with LCDR in African ancestry individuals with POAG and explored the differences between blind (>20/200) and not blind (≤20/200) LCDR eyes. Methods: A case–control methodology was used to investigate the demographic, optic disc, and genetic risk factors of subjects in the Primary Open-Angle African American Glaucoma Genetics Study. Risk factors were analyzed using univariable and multivariable logistic regression models with inter-eye correlation adjusted using generalized estimating equations. Results: Out of 5605 eyes with POAG, 1440 eyes (25.7%) had LCDR. In the multivariable analysis, LCDR was associated with previous glaucoma surgery (OR = 1.72), increased intraocular pressure (OR = 1.04), decreased mean deviation (OR = 1.08), increased pattern standard deviation (OR = 1.06), thinner retinal nerve fiber layer (OR = 1.05), nasalization of vessels (OR = 2.67), bayonetting of vessels (OR = 1.98), visible pores in the lamina cribrosa (OR = 1.68), and a bean-shaped cup (OR = 2.11). Of LCDR eyes, 30.1% were classified as blind (≤20/200). In the multivariable analysis, the statistically significant risk factors of blindness in LCDR eyes were previous glaucoma surgery (OR = 1.72), increased intraocular pressure (OR = 1.05), decreased mean deviation (OR = 1.04), and decreased pattern standard deviation (OR = 0.90). Conclusions: These findings underscore the importance of close monitoring of intraocular pressure and visual function in African ancestry POAG patients, particularly those with LCDR, to preserve visual function. Full article
(This article belongs to the Special Issue Study on Genotypes and Phenotypes of Neurodegenerative Diseases)
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14 pages, 1290 KiB  
Article
Integrative Analysis Unveils the Correlation of Aminoacyl-tRNA Biosynthesis Metabolites with the Methylation of the SEPSECS Gene in Huntington’s Disease Brain Tissue
by Sangeetha Vishweswaraiah, Ali Yilmaz, Nazia Saiyed, Abdullah Khalid, Purvesh R. Koladiya, Xiaobei Pan, Shirin Macias, Andrew C. Robinson, David Mann, Brian D. Green, Ieva Kerševičiūte, Juozas Gordevičius, Uppala Radhakrishna and Stewart F. Graham
Genes 2023, 14(9), 1752; https://doi.org/10.3390/genes14091752 - 2 Sep 2023
Cited by 1 | Viewed by 1874
Abstract
The impact of environmental factors on epigenetic changes is well established, and cellular function is determined not only by the genome but also by interacting partners such as metabolites. Given the significant impact of metabolism on disease progression, exploring the interaction between the [...] Read more.
The impact of environmental factors on epigenetic changes is well established, and cellular function is determined not only by the genome but also by interacting partners such as metabolites. Given the significant impact of metabolism on disease progression, exploring the interaction between the metabolome and epigenome may offer new insights into Huntington’s disease (HD) diagnosis and treatment. Using fourteen post-mortem HD cases and fourteen control subjects, we performed metabolomic profiling of human postmortem brain tissue (striatum and frontal lobe), and we performed DNA methylome profiling using the same frontal lobe tissue. Along with finding several perturbed metabolites and differentially methylated loci, Aminoacyl-tRNA biosynthesis (adj p-value = 0.0098) was the most significantly perturbed metabolic pathway with which two CpGs of the SEPSECS gene were correlated. This study improves our understanding of molecular biomarker connections and, importantly, increases our knowledge of metabolic alterations driving HD progression. Full article
(This article belongs to the Special Issue Study on Genotypes and Phenotypes of Neurodegenerative Diseases)
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20 pages, 3403 KiB  
Article
Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral Phenotype
by Camille Bouchard, Catherine Gérard, Solange Gni-fiene Yanyabé, Nathalie Majeau, Malek Aloui, Gabrielle Buisson, Pouiré Yameogo, Vanessa Couture and Jacques P. Tremblay
Genes 2023, 14(8), 1654; https://doi.org/10.3390/genes14081654 - 19 Aug 2023
Cited by 2 | Viewed by 2467
Abstract
Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by a GAA repeat in the intron 1 of the frataxin gene (FXN) leading to a lower expression of the frataxin protein. The YG8sR mice are Knock-Out (KO) for their murine frataxin gene but [...] Read more.
Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by a GAA repeat in the intron 1 of the frataxin gene (FXN) leading to a lower expression of the frataxin protein. The YG8sR mice are Knock-Out (KO) for their murine frataxin gene but contain a human frataxin transgene derived from an FRDA patient with 300 GAA repeats. These mice are used as a FRDA model but even with a low frataxin concentration, their phenotype is mild. We aimed to find an optimized mouse model with a phenotype comparable to the human patients to study the impact of therapy on the phenotype. We compared two mouse models: the YG8sR injected with an AAV. PHP.B coding for a shRNA targeting the human frataxin gene and the YG8-800, a new mouse model with a human transgene containing 800 GAA repeats. Both mouse models were compared to Y47R mice containing nine GAA repeats that were considered healthy mice. Behavior tests (parallel rod floor apparatus, hanging test, inverted T beam, and notched beam test) were carried out from 2 to 11 months and significant differences were noticed for both YG8sR mice injected with an anti-FXN shRNA and the YG8-800 mice compared to healthy mice. In conclusion, YG8sR mice have a slight phenotype, and injecting them with an AAV-PHP.B expressing an shRNA targeting frataxin does increase their phenotype. The YG8-800 mice have a phenotype comparable to the human ataxic phenotype. Full article
(This article belongs to the Special Issue Study on Genotypes and Phenotypes of Neurodegenerative Diseases)
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12 pages, 899 KiB  
Article
Genome-Wide Epistasis Study of Cerebrospinal Fluid Hyperphosphorylated Tau in ADNI Cohort
by Dandan Chen, Jin Li, Hongwei Liu, Xiaolong Liu, Chenghao Zhang, Haoran Luo, Yiming Wei, Yang Xi, Hong Liang and Qiushi Zhang
Genes 2023, 14(7), 1322; https://doi.org/10.3390/genes14071322 - 23 Jun 2023
Cited by 2 | Viewed by 1768
Abstract
Alzheimer’s disease (AD) is the main cause of dementia worldwide, and the genetic mechanism of which is not yet fully understood. Much evidence has accumulated over the past decade to suggest that after the first large-scale genome-wide association studies (GWAS) were conducted, the [...] Read more.
Alzheimer’s disease (AD) is the main cause of dementia worldwide, and the genetic mechanism of which is not yet fully understood. Much evidence has accumulated over the past decade to suggest that after the first large-scale genome-wide association studies (GWAS) were conducted, the problem of “missing heritability” in AD is still a great challenge. Epistasis has been considered as one of the main causes of “missing heritability” in AD, which has been largely ignored in human genetics. The focus of current genome-wide epistasis studies is usually on single nucleotide polymorphisms (SNPs) that have significant individual effects, and the amount of heritability explained by which was very low. Moreover, AD is characterized by progressive cognitive decline and neuronal damage, and some studies have suggested that hyperphosphorylated tau (P-tau) mediates neuronal death by inducing necroptosis and inflammation in AD. Therefore, this study focused on identifying epistasis between two-marker interactions at marginal main effects across the whole genome using cerebrospinal fluid (CSF) P-tau as quantitative trait (QT). We sought to detect interactions between SNPs in a multi-GPU based linear regression method by using age, gender, and clinical diagnostic status (cds) as covariates. We then used the STRING online tool to perform the PPI network and identify two-marker epistasis at the level of gene–gene interaction. A total of 758 SNP pairs were found to be statistically significant. Particularly, between the marginal main effect SNP pairs, highly significant SNP–SNP interactions were identified, which explained a relatively high variance at the P-tau level. In addition, 331 AD-related genes were identified, 10 gene–gene interaction pairs were replicated in the PPI network. The identified gene-gene interactions and genes showed associations with AD in terms of neuroinflammation and neurodegeneration, neuronal cells activation and brain development, thereby leading to cognitive decline in AD, which is indirectly associated with the P-tau pathological feature of AD and in turn supports the results of this study. Thus, the results of our study might be beneficial for explaining part of the “missing heritability” of AD. Full article
(This article belongs to the Special Issue Study on Genotypes and Phenotypes of Neurodegenerative Diseases)
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17 pages, 2225 KiB  
Article
A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes
by Katarzyna Gaweda-Walerych, Emilia J. Sitek, Małgorzata Borczyk, Ewa Narożańska, Bogna Brockhuis, Michał Korostyński, Michał Schinwelski, Mariusz Siemiński, Jarosław Sławek and Cezary Zekanowski
Genes 2022, 13(12), 2361; https://doi.org/10.3390/genes13122361 - 14 Dec 2022
Cited by 3 | Viewed by 2108
Abstract
Our aim was to analyze the phenotypic-genetic correlations in a patient diagnosed with early onset corticobasal syndrome with progressive non-fluent aphasia (CBS-PNFA), characterized by predominant apraxia of speech, accompanied by prominent right-sided upper-limb limb-kinetic apraxia, alien limb phenomenon, synkinesis, myoclonus, mild cortical sensory [...] Read more.
Our aim was to analyze the phenotypic-genetic correlations in a patient diagnosed with early onset corticobasal syndrome with progressive non-fluent aphasia (CBS-PNFA), characterized by predominant apraxia of speech, accompanied by prominent right-sided upper-limb limb-kinetic apraxia, alien limb phenomenon, synkinesis, myoclonus, mild cortical sensory loss, and right-sided hemispatial neglect. Whole-exome sequencing (WES) identified rare single heterozygous variants in ATP7B (c.3207C>A), SORL1 (c.352G>A), SETX (c.2385_2387delAAA), and FOXP1 (c.1762G>A) genes. The functional analysis revealed that the deletion in the SETX gene changed the splicing pattern, which was accompanied by lower SETX mRNA levels in the patient’s fibroblasts, suggesting loss-of-function as the underlying mechanism. In addition, the patient’s fibroblasts demonstrated altered mitochondrial architecture with decreased connectivity, compared to the control individuals. This is the first association of the CBS-PNFA phenotype with the most common ATP7B pathogenic variant p.H1069Q, previously linked to Wilson’s disease, and early onset Parkinson’s disease. This study expands the complex clinical spectrum related to variants in well-known disease genes, such as ATP7B, SORL1, SETX, and FOXP1, corroborating the hypothesis of oligogenic inheritance. To date, the FOXP1 gene has been linked exclusively to neurodevelopmental speech disorders, while our study highlights its possible relevance for adult-onset progressive apraxia of speech, which guarantees further study. Full article
(This article belongs to the Special Issue Study on Genotypes and Phenotypes of Neurodegenerative Diseases)
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Review

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20 pages, 3264 KiB  
Review
The Role of IgLON Cell Adhesion Molecules in Neurodegenerative Diseases
by Marco Salluzzo, Clara Vianello, Sandra Abdullatef, Roberto Rimondini, Giovanni Piccoli and Lucia Carboni
Genes 2023, 14(10), 1886; https://doi.org/10.3390/genes14101886 - 28 Sep 2023
Cited by 5 | Viewed by 2598
Abstract
In the brain, cell adhesion molecules (CAMs) are critical for neurite outgrowth, axonal fasciculation, neuronal survival and migration, and synapse formation and maintenance. Among CAMs, the IgLON family comprises five members: Opioid Binding Protein/Cell Adhesion Molecule Like (OPCML or OBCAM), Limbic System Associated [...] Read more.
In the brain, cell adhesion molecules (CAMs) are critical for neurite outgrowth, axonal fasciculation, neuronal survival and migration, and synapse formation and maintenance. Among CAMs, the IgLON family comprises five members: Opioid Binding Protein/Cell Adhesion Molecule Like (OPCML or OBCAM), Limbic System Associated Membrane Protein (LSAMP), neurotrimin (NTM), Neuronal Growth Regulator 1 (NEGR1), and IgLON5. IgLONs exhibit three N-terminal C2 immunoglobulin domains; several glycosylation sites; and a glycosylphosphatidylinositol anchoring to the membrane. Interactions as homo- or heterodimers in cis and in trans, as well as binding to other molecules, appear critical for their functions. Shedding by metalloproteases generates soluble factors interacting with cellular receptors and activating signal transduction. The aim of this review was to analyse the available data implicating a role for IgLONs in neuropsychiatric disorders. Starting from the identification of a pathological role for antibodies against IgLON5 in an autoimmune neurodegenerative disease with a poorly understood mechanism of action, accumulating evidence links IgLONs to neuropsychiatric disorders, albeit with still undefined mechanisms which will require future thorough investigations. Full article
(This article belongs to the Special Issue Study on Genotypes and Phenotypes of Neurodegenerative Diseases)
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13 pages, 1111 KiB  
Review
INPP5D/SHIP1: Expression, Regulation and Roles in Alzheimer’s Disease Pathophysiology
by Edward O. Olufunmilayo and R. M. Damian Holsinger
Genes 2023, 14(10), 1845; https://doi.org/10.3390/genes14101845 - 23 Sep 2023
Cited by 2 | Viewed by 2223
Abstract
Alzheimer’s disease (AD) is the most common form of dementia, accounting for approximately 38.5 million cases of all-cause dementia. Over 60% of these individuals live in low- and middle-income countries and are the worst affected, especially by its deleterious effects on the productivity [...] Read more.
Alzheimer’s disease (AD) is the most common form of dementia, accounting for approximately 38.5 million cases of all-cause dementia. Over 60% of these individuals live in low- and middle-income countries and are the worst affected, especially by its deleterious effects on the productivity of both patients and caregivers. Numerous risk factors for the disease have been identified and our understanding of gene–environment interactions have shed light on several gene variants that contribute to the most common, sporadic form of AD. Microglial cells, the innate immune cells of the central nervous system (CNS), have long been established as guardians of the brain by providing neuroprotection and maintaining cellular homeostasis. A protein with a myriad of effects on various important signaling pathways that is expressed in microglia is the Src Homology 2 (SH2) domain-containing Inositol 5′ Phosphatase 1 (SHIP1) protein. Encoded by the INPP5D (Inositol Polyphosphate-5-Phosphatase D) gene, SHIP1 has diminutive effects on most microglia signaling processes. Polymorphisms of the INPP5D gene have been found to be associated with a significantly increased risk of AD. Several studies have elucidated mechanistic processes by which SHIP1 exerts its perturbations on signaling processes in peripheral immune cells. However, current knowledge of the controllers of INPP5D/SHIP1 expression and the idiosyncrasies of its influences on signaling processes in microglia and their relevance to AD pathophysiology is limited. In this review, we summarize these discoveries and discuss the potential of leveraging INPP5D/SHIP1 as a therapeutic target for Alzheimer’s disease. Full article
(This article belongs to the Special Issue Study on Genotypes and Phenotypes of Neurodegenerative Diseases)
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22 pages, 1425 KiB  
Review
Outcome Measures and Biomarkers for Clinical Trials in Hereditary Spastic Paraplegia: A Scoping Review
by Sue-Faye Siow, Dennis Yeow, Laura I. Rudaks, Fangzhi Jia, Gautam Wali, Carolyn M. Sue and Kishore R. Kumar
Genes 2023, 14(9), 1756; https://doi.org/10.3390/genes14091756 - 3 Sep 2023
Cited by 5 | Viewed by 1921
Abstract
Hereditary spastic paraplegia (HSP) is characterized by progressive lower limb spasticity. There is no disease-modifying treatment currently available. Therefore, standardized, validated outcome measures to facilitate clinical trials are urgently needed. We performed a scoping review of outcome measures and biomarkers for HSP to [...] Read more.
Hereditary spastic paraplegia (HSP) is characterized by progressive lower limb spasticity. There is no disease-modifying treatment currently available. Therefore, standardized, validated outcome measures to facilitate clinical trials are urgently needed. We performed a scoping review of outcome measures and biomarkers for HSP to provide recommendations for future studies and identify areas for further research. We searched Embase, Medline, Scopus, Web of Science, and the Central Cochrane database. Seventy studies met the inclusion criteria, and eighty-three outcome measures were identified. The Spastic Paraplegia Rating Scale (SPRS) was the most widely used (27 studies), followed by the modified Ashworth Scale (18 studies) and magnetic resonance imaging (17 studies). Patient-reported outcome measures (PROMs) were infrequently used to assess treatment outcomes (28% of interventional studies). Diffusion tensor imaging, gait analysis and neurofilament light chain levels were the most promising biomarkers in terms of being able to differentiate patients from controls and correlate with clinical disease severity. Overall, we found variability and inconsistencies in use of outcome measures with a paucity of longitudinal data. We highlight the need for (1) a standardized set of core outcome measures, (2) validation of existing biomarkers, and (3) inclusion of PROMs in HSP clinical trials. Full article
(This article belongs to the Special Issue Study on Genotypes and Phenotypes of Neurodegenerative Diseases)
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16 pages, 2050 KiB  
Review
Distribution, Function, and Expression of the Apelinergic System in the Healthy and Diseased Mammalian Brain
by Martin N. Ivanov, Dimo S. Stoyanov, Stoyan P. Pavlov and Anton. B. Tonchev
Genes 2022, 13(11), 2172; https://doi.org/10.3390/genes13112172 - 21 Nov 2022
Cited by 11 | Viewed by 2876
Abstract
Apelin, a peptide initially isolated from bovine stomach extract, is an endogenous ligand for the Apelin Receptor (APLNR). Subsequently, a second peptide, ELABELA, that can bind to the receptor has been identified. The Apelin receptor and its endogenous ligands are widely distributed in [...] Read more.
Apelin, a peptide initially isolated from bovine stomach extract, is an endogenous ligand for the Apelin Receptor (APLNR). Subsequently, a second peptide, ELABELA, that can bind to the receptor has been identified. The Apelin receptor and its endogenous ligands are widely distributed in mammalian organs. A growing body of evidence suggests that this system participates in various signaling cascades that can regulate cell proliferation, blood pressure, fluid homeostasis, feeding behavior, and pituitary hormone release. Additional research has been done to elucidate the system’s potential role in neurogenesis, the pathophysiology of Glioblastoma multiforme, and the protective effects of apelin peptides on some neurological and psychiatric disorders-ischemic stroke, epilepsy, Parkinson’s, and Alzheimer’s disease. This review discusses the current knowledge on the apelinergic system’s involvement in brain physiology in health and disease. Full article
(This article belongs to the Special Issue Study on Genotypes and Phenotypes of Neurodegenerative Diseases)
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