State of the Art: Prerequisites, Prevention and Treatment of Neurodegenerative Diseases

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: 31 December 2024 | Viewed by 24226

Special Issue Editors


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Guest Editor
Federal Research Center Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Lavrentieva Ave. 10, 630090 Novosibirsk, Russia
Interests: Alzheimer’s disease; neurodegeneration; aging; neurogenesis; glial cells

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Guest Editor
Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Lavrentyeva Ave., 630090 Novosibirsk, Russia
Interests: neurobiology and brain physiology; genetics; Alzheimer’s disease

Special Issue Information

Dear Colleagues,

Progress in modern medicine leads to an increase in human lifespans. However, along with this advantage, it also leads to an increasing rate of age-related diseases. Among them, neurodegenerative disorders leading to the development of dementia seem to have the most burden on patients and caregivers. The hallmark of neurodegenerative disorders is their incurability; besides, most of them are difficult to diagnose and distinguish from one another, especially at early stages. Furthermore, some neurodegenerative disorders may last asymptomatically for years and decades. Middle age is widely held as a critical period for the launch of pathological processes, but the question of when exactly neurodegeneration begins to develop and what contributes to its onset still remains open. The risk factors of consequent cognitive impairment later in life and accelerated brain aging could be formed already in the early postnatal period of life, during the completion of brain development. Thus, it determines the relevance of studies directed on investigations of risk factors, early diagnosis, prevention and treatment of neurodegenerative disorders.

Dr. Ekaterina Rudnitskaya
Dr. Nataliya Kolosova
Guest Editors

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Keywords

  • neurodegeneration
  • aging
  • dementia
  • disability
  • early diagnosis

Published Papers (12 papers)

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Research

Jump to: Review

21 pages, 1319 KiB  
Article
Integrating Demographics and Imaging Features for Various Stages of Dementia Classification: Feed Forward Neural Network Multi-Class Approach
by Eva Y. W. Cheung, Ricky W. K. Wu, Ellie S. M. Chu and Henry K. F. Mak
Biomedicines 2024, 12(4), 896; https://doi.org/10.3390/biomedicines12040896 - 18 Apr 2024
Viewed by 560
Abstract
Background: MRI magnetization-prepared rapid acquisition (MPRAGE) is an easily available imaging modality for dementia diagnosis. Previous studies suggested that volumetric analysis plays a crucial role in various stages of dementia classification. In this study, volumetry, radiomics and demographics were integrated as inputs to [...] Read more.
Background: MRI magnetization-prepared rapid acquisition (MPRAGE) is an easily available imaging modality for dementia diagnosis. Previous studies suggested that volumetric analysis plays a crucial role in various stages of dementia classification. In this study, volumetry, radiomics and demographics were integrated as inputs to develop an artificial intelligence model for various stages, including Alzheimer’s disease (AD), mild cognitive decline (MCI) and cognitive normal (CN) dementia classifications. Method: The Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset was separated into training and testing groups, and the Open Access Series of Imaging Studies (OASIS) dataset was used as the second testing group. The MRI MPRAGE image was reoriented via statistical parametric mapping (SPM12). Freesurfer was employed for brain segmentation, and 45 regional brain volumes were retrieved. The 3D Slicer software was employed for 107 radiomics feature extractions from within the whole brain. Data on patient demographics were collected from the datasets. The feed-forward neural network (FFNN) and the other most common artificial intelligence algorithms, including support vector machine (SVM), ensemble classifier (EC) and decision tree (DT), were used to build the models using various features. Results: The integration of brain regional volumes, radiomics and patient demographics attained the highest overall accuracy at 76.57% and 73.14% in ADNI and OASIS testing, respectively. The subclass accuracies in MCI, AD and CN were 78.29%, 89.71% and 85.14%, respectively, in ADNI testing, as well as 74.86%, 88% and 83.43% in OASIS testing. Balanced sensitivity and specificity were obtained for all subclass classifications in MCI, AD and CN. Conclusion: The FFNN yielded good overall accuracy for MCI, AD and CN categorization, with balanced subclass accuracy, sensitivity and specificity. The proposed FFNN model is simple, and it may support the triage of patients for further confirmation of the diagnosis. Full article
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15 pages, 2807 KiB  
Article
Natural Fatty Acid Guards against Brain Endothelial Cell Death and Microvascular Pathology following Ischemic Insult in the Presence of Acute Hyperglycemia
by Zaib Ali Shaheryar, Mahtab Ahmad Khan, Huma Hameed, Muhammad Naveed Mushtaq, Sajjad Muhammad, Gamal A. Shazly, Ali Irfan and Yousef A. Bin Jardan
Biomedicines 2023, 11(12), 3342; https://doi.org/10.3390/biomedicines11123342 - 18 Dec 2023
Viewed by 895
Abstract
Ischemic stroke is worsened by the presence of sudden high blood sugar levels, even in individuals without pre-existing diabetes. This elevated glucose concentration hampers the ability of energy-starved brain cells to efficiently use it as a source of energy. Consequently, this leads to [...] Read more.
Ischemic stroke is worsened by the presence of sudden high blood sugar levels, even in individuals without pre-existing diabetes. This elevated glucose concentration hampers the ability of energy-starved brain cells to efficiently use it as a source of energy. Consequently, this leads to the production of abundant amounts of toxic glucose metabolites, which trigger oxidative stress in the brain milieu, particularly in the microvasculature of the brain. A prominent feature of this oxidative stress is the demise of endothelial cells, causing detrimental changes in blood vessels, including a reduction in their vascular diameter, a decreased efficiency of vessel proliferation, and the impaired integrity of tight junctions. These vascular pathologies contributed to an increase in the volume of damaged tissues (infarct), an exacerbation of brain swelling (edema), and a decline in cognitive and motor functions. In a mouse model of ischemic stroke with induced acute hyperglycemia, a naturally occurring saturated fatty acid provides protective cover to the microvasculature by preventing damage related to oxidative stress. Our current research revealed that lauric acid (LA) attenuated infarct volume and reduced brain edema by reducing endothelial cell death, enhancing vessels’ diameter, promoting vascular angiogenesis, and stabilizing barrier functions. Animals administered with this natural compound showed a significant reduction in 4-HNE-positive vessels. In conclusion, natural saturated fatty acids help to preserve brain microvascular functions following ischemic insults in the presence of acute hyperglycemia. Full article
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10 pages, 831 KiB  
Article
Risk of New-Onset Dementia in Patients with Chronic Kidney Disease on Statin Users: A Population-Based Cohort Study
by Gwo-Ping Jong, Tsung-Kun Lin, Jing-Yang Huang, Pei-Lun Liao, Tsung-Yuan Yang and Lung-Fa Pan
Biomedicines 2023, 11(4), 1073; https://doi.org/10.3390/biomedicines11041073 - 2 Apr 2023
Viewed by 1312
Abstract
Patients with chronic kidney disease (CKD) are at a higher risk for developing dementia than the general population. Clinical studies have investigated the effects of statin use on new-onset dementia (NOD) in patients with CKD; however, the findings are inconsistent. This study examines [...] Read more.
Patients with chronic kidney disease (CKD) are at a higher risk for developing dementia than the general population. Clinical studies have investigated the effects of statin use on new-onset dementia (NOD) in patients with CKD; however, the findings are inconsistent. This study examines the association between the use of statins and NOD in patients with CKD. We conducted a nationwide retrospective cohort study using the Taiwan Health Insurance Review and Assessment Service database (2003–2016). The primary outcome assessed the risk of incident dementia by estimating the hazard ratios and 95% confidence intervals. Therefore, multiple Cox regression models were conducted to analyse the association between statin use and NOD in patients with CKD. There were 24,090 participants with statin use and 28,049 participants without statin use in patients with new-diagnosed CKD; the NOD event was 1390 and 1608, respectively. There was a trend of reduction association between statin users and NOD events after adjusted sex, age, comorbidities, and concurrent medication (adjusted HR 0.93, 95% CI 0.87 to 1.00) in the 14 years of the follow-up. Sensitivity test for the propensity score 1:1 matched analyses showed similar results (adjusted HR 0.91, 95% CI 0.81 to 1.02). The subgroup analysis also identified the use of statins as having a trend against developing NOD in patients with hypertension. In conclusion, statin therapy may effectively reduce the risk of NOD in patients with CKD. More studies are needed to credibly evaluate the effects of statin therapy on the prevention of NOD in patients with CKD. Full article
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21 pages, 2068 KiB  
Article
A Comparative Study of Two Models of Intraluminal Filament Middle Cerebral Artery Occlusion in Rats: Long-Lasting Accumulation of Corticosterone and Interleukins in the Hippocampus and Frontal Cortex in Koizumi Model
by Mikhail V. Onufriev, Mikhail Y. Stepanichev, Yulia V. Moiseeva, Marina Y. Zhanina, Olga A. Nedogreeva, Pavel A. Kostryukov, Natalia A. Lazareva and Natalia V. Gulyaeva
Biomedicines 2022, 10(12), 3119; https://doi.org/10.3390/biomedicines10123119 - 2 Dec 2022
Cited by 3 | Viewed by 1788
Abstract
Recently, we have shown the differences in the early response of corticosterone and inflammatory cytokines in the hippocampus and frontal cortex (FC) of rats with middle cerebral artery occlusion (MCAO), according to the methods of Longa et al. (LM) and Koizumi et al. [...] Read more.
Recently, we have shown the differences in the early response of corticosterone and inflammatory cytokines in the hippocampus and frontal cortex (FC) of rats with middle cerebral artery occlusion (MCAO), according to the methods of Longa et al. (LM) and Koizumi et al. (KM) which were used as alternatives in preclinical studies to induce stroke in rodents. In the present study, corticosterone and proinflammatory cytokines were assessed 3 months after MCAO. The most relevant changes detected during the first days after MCAO became even more obvious after 3 months. In particular, the MCAO-KM (but not the MCAO-LM) group showed significant accumulation of corticosterone and IL1β in both the ipsilateral and contralateral hippocampus and FC. An accumulation of TNFα was detected in the ipsilateral hippocampus and FC in the MCAO-KM group. Thus, unlike the MCAO-LM, the MCAO-KM may predispose the hippocampus and FC of rats to long-lasting bilateral corticosterone-dependent distant neuroinflammatory damage. Unexpectedly, only the MCAO-LM rats demonstrated some memory deficit in a one-trial step-through passive avoidance test. The differences between the two MCAO models, particularly associated with the long-lasting increase in glucocorticoid and proinflammatory cytokine accumulation in the limbic structures in the MCAO-KM, should be considered in the planning of preclinical experiments, and the interpretation and translation of received results. Full article
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21 pages, 3606 KiB  
Article
Delayed Formation of Neonatal Reflexes and of Locomotor Skills Is Associated with Poor Maternal Behavior in OXYS Rats Prone to Alzheimer’s Disease-like Pathology
by Tatiana Kozlova, Ekaterina Rudnitskaya, Alena Burnyasheva, Natalia Stefanova, Daniil Peunov and Nataliya Kolosova
Biomedicines 2022, 10(11), 2910; https://doi.org/10.3390/biomedicines10112910 - 12 Nov 2022
Cited by 2 | Viewed by 1603
Abstract
Postnatal brain development is characterized by high plasticity with critical windows of opportunity where any intervention may positively or adversely influence postnatal growth and lead to long-lasting consequences later in life. Poor maternal care is among these interventions. Here, we found that senescence-accelerated [...] Read more.
Postnatal brain development is characterized by high plasticity with critical windows of opportunity where any intervention may positively or adversely influence postnatal growth and lead to long-lasting consequences later in life. Poor maternal care is among these interventions. Here, we found that senescence-accelerated OXYS rats prone to an Alzheimer’s disease-like pathology are characterized by more passive maternal behavior and insufficient care for pups as compared to control (Wistar) rats. OXYS pups demonstrated a delay in physical development (of auricle detachment, of emergence of pelage and incisors, of eye opening, and of vaginal opening in females) and late manifestation of reflexes and locomotor skills. All observed behavioral abnormalities are connected either with poor coordination of limbs’ movements or with a decrease in motivation and development of depression-like behavior. It is possible that their manifestations can be promoted by the features of maternal behavior of OXYS rats. Overall, these early-life events may have long-lasting consequences and contribute to neurodegeneration and development of the Alzheimer’s disease-like pathology later in life. Full article
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11 pages, 2243 KiB  
Article
«One Small Step for Mouse»: High CO2 Inhalation as a New Therapeutic Strategy for Parkinson’s Disease
by Alexander D. Nadeev, Kristina A. Kritskaya, Evgeniya I. Fedotova and Alexey V. Berezhnov
Biomedicines 2022, 10(11), 2832; https://doi.org/10.3390/biomedicines10112832 - 6 Nov 2022
Cited by 3 | Viewed by 1720
Abstract
Parkinson’s disease (PD) is a ubiquitous neurodegenerative disorder for which no effective treatment strategies are available. Existing pharmacotherapy is aimed only at correcting symptoms and slowing the progression of the disease, mainly by replenishing dopamine deficiency. It is assumed that mitochondrial dysfunction plays [...] Read more.
Parkinson’s disease (PD) is a ubiquitous neurodegenerative disorder for which no effective treatment strategies are available. Existing pharmacotherapy is aimed only at correcting symptoms and slowing the progression of the disease, mainly by replenishing dopamine deficiency. It is assumed that mitochondrial dysfunction plays a key role in the pathogenesis of PD. It has been suggested that activation of specific degradation of damaged mitochondria (mitophagy) may prevent cell death. An almost exclusive way to initiate mitophagy is acidification of intracellular pH. We attempted to implement transient brain acidification using two experimental therapy strategies: forced moderate physical activity and high CO2 inhalation. The beneficial effects of CO2 supplementation on behavioral aspects were demonstrated in a rotenone-induced PD model. Mice treated with CO2 restored their exploratory behavior and total locomotor activity lost after rotenone administration. Additionally, this treatment enabled the removal of impaired coordination. We have illustrated this therapeutic strategy using histological studies of brain sections to confirm the survival of nigrostriatal areas. These findings suggest that high CO2 inhalation presumably initiates mitophagy via transient brain acidification, and can treat PD-like symptoms in a rodent rotenone model of PD. Full article
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15 pages, 707 KiB  
Article
Modified SqueezeNet Architecture for Parkinson’s Disease Detection Based on Keypress Data
by Lucas Salvador Bernardo, Robertas Damaševičius, Sai Ho Ling, Victor Hugo C. de Albuquerque and João Manuel R. S. Tavares
Biomedicines 2022, 10(11), 2746; https://doi.org/10.3390/biomedicines10112746 - 28 Oct 2022
Cited by 12 | Viewed by 2196
Abstract
Parkinson’s disease (PD) is the most common form of Parkinsonism, which is a group of neurological disorders with PD-like motor impairments. The disease affects over 6 million people worldwide and is characterized by motor and non-motor symptoms. The affected person has trouble in [...] Read more.
Parkinson’s disease (PD) is the most common form of Parkinsonism, which is a group of neurological disorders with PD-like motor impairments. The disease affects over 6 million people worldwide and is characterized by motor and non-motor symptoms. The affected person has trouble in controlling movements, which may affect simple daily-life tasks, such as typing on a computer. We propose the application of a modified SqueezeNet convolutional neural network (CNN) for detecting PD based on the subject’s key-typing patterns. First, the data are pre-processed using data standardization and the Synthetic Minority Oversampling Technique (SMOTE), and then a Continuous Wavelet Transformation is applied to generate spectrograms used for training and testing a modified SqueezeNet model. The modified SqueezeNet model achieved an accuracy of 90%, representing a noticeable improvement in comparison to other approaches. Full article
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19 pages, 8013 KiB  
Article
Level of Amyloid-β (Aβ) Binding Leading to Differential Effects on Resting State Functional Connectivity in Major Brain Networks
by Eva Y. W. Cheung, Anson C. M. Chau, Yat-Fung Shea, Patrick K. C. Chiu, Joseph S. K. Kwan and Henry K. F. Mak
Biomedicines 2022, 10(9), 2321; https://doi.org/10.3390/biomedicines10092321 - 19 Sep 2022
Cited by 3 | Viewed by 1831
Abstract
Introduction: Amyloid-β protein (Aβ) is one of the biomarkers for Alzheimer’s disease (AD). The recent application of interhemispheric functional connectivity (IFC) in resting-state fMRI has been used as a non-invasive diagnostic tool for early dementia. In this study, we focused on the level [...] Read more.
Introduction: Amyloid-β protein (Aβ) is one of the biomarkers for Alzheimer’s disease (AD). The recent application of interhemispheric functional connectivity (IFC) in resting-state fMRI has been used as a non-invasive diagnostic tool for early dementia. In this study, we focused on the level of Aβ accumulated and its effects on the major functional networks, including default mode network (DMN), central executive network (CEN), salience network (SN), self-referential network (SRN) and sensory motor network (SMN). Methods: 58 participants (27 Hi Aβ (HiAmy) and 31 low Aβ (LowAmy)) and 25 healthy controls (HC) were recruited. [18F]flutemetamol PET/CT was performed for diseased groups, and MRI scanning was done for all participants. Voxel-by-voxel correlation analysis was done for both groups in all networks. Results: In HiAmy, IFC was reduced in all networks except SN. A negative correlation in DMN, CEN, SRN and SMN suggests high Aβ related to IFC reduction; However, a positive correlation in SN suggests high Aβ related to an increase in IFC. In LowAmy, IFC increased in CEN, SMN, SN and SRN. Positive correlation in all major brain networks. Conclusion: The level of Aβ accumulated demonstrated differential effects on IFC in various brain networks. As the treatment to reduce Aβ plaque deposition is available in the market, it may be an option for the HiAmy group to improve their IFC in major brain networks. Full article
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Review

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18 pages, 1700 KiB  
Review
Bridging Retinal and Cerebral Neurodegeneration: A Focus on Crosslinks between Alzheimer–Perusini’s Disease and Retinal Dystrophies
by Luigi Donato, Domenico Mordà, Concetta Scimone, Simona Alibrandi, Rosalia D’Angelo and Antonina Sidoti
Biomedicines 2023, 11(12), 3258; https://doi.org/10.3390/biomedicines11123258 - 8 Dec 2023
Viewed by 1239
Abstract
In the early stages of Alzheimer–Perusini’s disease (AD), individuals often experience vision-related issues such as color vision impairment, reduced contrast sensitivity, and visual acuity problems. As the disease progresses, there is a connection with glaucoma and age-related macular degeneration (AMD) leading to retinal [...] Read more.
In the early stages of Alzheimer–Perusini’s disease (AD), individuals often experience vision-related issues such as color vision impairment, reduced contrast sensitivity, and visual acuity problems. As the disease progresses, there is a connection with glaucoma and age-related macular degeneration (AMD) leading to retinal cell death. The retina’s involvement suggests a link with the hippocampus, where most AD forms start. A thinning of the retinal nerve fiber layer (RNFL) due to the loss of retinal ganglion cells (RGCs) is seen as a potential AD diagnostic marker using electroretinography (ERG) and optical coherence tomography (OCT). Amyloid beta fragments (Aβ), found in the eye’s vitreous and aqueous humor, are also present in the cerebrospinal fluid (CSF) and accumulate in the retina. Aβ is known to cause tau hyperphosphorylation, leading to its buildup in various retinal layers. However, diseases like AD are now seen as mixed proteinopathies, with deposits of the prion protein (PrP) and α-synuclein found in affected brains and retinas. Glial cells, especially microglial cells, play a crucial role in these diseases, maintaining immunoproteostasis. Studies have shown similarities between retinal and brain microglia in terms of transcription factor expression and morphotypes. All these findings constitute a good start to achieving better comprehension of neurodegeneration in both the eye and the brain. New insights will be able to bring the scientific community closer to specific disease-modifying therapies. Full article
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32 pages, 3202 KiB  
Review
How Many Alzheimer–Perusini’s Atypical Forms Do We Still Have to Discover?
by Luigi Donato, Domenico Mordà, Concetta Scimone, Simona Alibrandi, Rosalia D’Angelo and Antonina Sidoti
Biomedicines 2023, 11(7), 2035; https://doi.org/10.3390/biomedicines11072035 - 19 Jul 2023
Cited by 1 | Viewed by 1616
Abstract
Alzheimer–Perusini’s (AD) disease represents the most spread dementia around the world and constitutes a serious problem for public health. It was first described by the two physicians from whom it took its name. Nowadays, we have extensively expanded our knowledge about this disease. [...] Read more.
Alzheimer–Perusini’s (AD) disease represents the most spread dementia around the world and constitutes a serious problem for public health. It was first described by the two physicians from whom it took its name. Nowadays, we have extensively expanded our knowledge about this disease. Starting from a merely clinical and histopathologic description, we have now reached better molecular comprehension. For instance, we passed from an old conceptualization of the disease based on plaques and tangles to a more modern vision of mixed proteinopathy in a one-to-one relationship with an alteration of specific glial and neuronal phenotypes. However, no disease-modifying therapies are yet available. It is likely that the only way to find a few “magic bullets” is to deepen this aspect more and more until we are able to draw up specific molecular profiles for single AD cases. This review reports the most recent classifications of AD atypical variants in order to summarize all the clinical evidence using several discrimina (for example, post mortem neurofibrillary tangle density, cerebral atrophy, or FDG-PET studies). The better defined four atypical forms are posterior cortical atrophy (PCA), logopenic variant of primary progressive aphasia (LvPPA), behavioral/dysexecutive variant and AD with corticobasal degeneration (CBS). Moreover, we discuss the usefulness of such classifications before outlining the molecular–genetic aspects focusing on microglial activity or, more generally, immune system control of neuroinflammation and neurodegeneration. Full article
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13 pages, 2355 KiB  
Review
Neuron Protection by EDTA May Explain the Successful Outcomes of Toxic Metal Chelation Therapy in Neurodegenerative Diseases
by Maria Elena Ferrero
Biomedicines 2022, 10(10), 2476; https://doi.org/10.3390/biomedicines10102476 - 4 Oct 2022
Cited by 7 | Viewed by 3466
Abstract
Many mechanisms have been related to the etiopathogenesis of neurodegenerative diseases (NDs) such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease. In this context, the detrimental role of environmental agents has also been highlighted. Studies focused on the role of [...] Read more.
Many mechanisms have been related to the etiopathogenesis of neurodegenerative diseases (NDs) such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease. In this context, the detrimental role of environmental agents has also been highlighted. Studies focused on the role of toxic metals in the pathogenesis of ND demonstrate the efficacy of treatment with the chelating agent calcium disodium ethylenediaminetetraacetic acid (EDTA) in eliminating toxic metal burden in all ND patients, improving their symptoms. Lead, cadmium, aluminum, nickel, and mercury were the most important toxic metals detected in these patients. Here, I provide an updated review on the damage to neurons promoted by toxic metals and on the impact of EDTA chelation therapy in ND patients, along with the clinical description of a representative case. Full article
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31 pages, 2309 KiB  
Review
Therapeutic Strategies in Huntington’s Disease: From Genetic Defect to Gene Therapy
by Anamaria Jurcau and Maria Carolina Jurcau
Biomedicines 2022, 10(8), 1895; https://doi.org/10.3390/biomedicines10081895 - 5 Aug 2022
Cited by 13 | Viewed by 4567
Abstract
Despite the identification of an expanded CAG repeat on exon 1 of the huntingtin gene located on chromosome 1 as the genetic defect causing Huntington’s disease almost 30 years ago, currently approved therapies provide only limited symptomatic relief and do not influence the [...] Read more.
Despite the identification of an expanded CAG repeat on exon 1 of the huntingtin gene located on chromosome 1 as the genetic defect causing Huntington’s disease almost 30 years ago, currently approved therapies provide only limited symptomatic relief and do not influence the age of onset or disease progression rate. Research has identified various intricate pathogenic cascades which lead to neuronal degeneration, but therapies interfering with these mechanisms have been marked by many failures and remain to be validated. Exciting new opportunities are opened by the emerging techniques which target the mutant protein DNA and RNA, allowing for “gene editing”. Although some issues relating to “off-target” effects or immune-mediated side effects need to be solved, these strategies, combined with stem cell therapies and more traditional approaches targeting specific pathogenic cascades, such as excitotoxicity and bioavailability of neurotrophic factors, could lead to significant improvement of the outcomes of treated Huntington’s disease patients. Full article
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