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      Neural Network Aided Detection of Huntington Disease

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      Journal of Clinical Medicine
      MDPI AG

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          Abstract

          Huntington Disease (HD) is a degenerative neurological disease that causes a significant impact on the quality of life of the patient and eventually death. In this paper we present an approach to create a biomarker using as an input DNA CpG methylation data to identify HD patients. DNA CpG methylation is a well-known epigenetic marker for disease state. Technological advances have made it possible to quickly analyze hundreds of thousands of CpGs. This large amount of information might introduce noise as potentially not all DNA CpG methylation levels will be related to the presence of the illness. In this paper, we were able to reduce the number of CpGs considered from hundreds of thousands to 237 using a non-linear approach. It will be shown that using only these 237 CpGs and non-linear techniques such as artificial neural networks makes it possible to accurately differentiate between control and HD patients. An underlying assumption in this paper is that there are no indications suggesting that the process is linear and therefore non-linear techniques, such as artificial neural networks, are a valid tool to analyze this complex disease. The proposed approach is able to accurately distinguish between control and HD patients using DNA CpG methylation data as an input and non-linear forecasting techniques. It should be noted that the dataset analyzed is relatively small. However, the results seem relatively consistent and the analysis can be repeated with larger data-sets as they become available.

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          Most cited references58

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          DNA methylation and its basic function.

          In the mammalian genome, DNA methylation is an epigenetic mechanism involving the transfer of a methyl group onto the C5 position of the cytosine to form 5-methylcytosine. DNA methylation regulates gene expression by recruiting proteins involved in gene repression or by inhibiting the binding of transcription factor(s) to DNA. During development, the pattern of DNA methylation in the genome changes as a result of a dynamic process involving both de novo DNA methylation and demethylation. As a consequence, differentiated cells develop a stable and unique DNA methylation pattern that regulates tissue-specific gene transcription. In this chapter, we will review the process of DNA methylation and demethylation in the nervous system. We will describe the DNA (de)methylation machinery and its association with other epigenetic mechanisms such as histone modifications and noncoding RNAs. Intriguingly, postmitotic neurons still express DNA methyltransferases and components involved in DNA demethylation. Moreover, neuronal activity can modulate their pattern of DNA methylation in response to physiological and environmental stimuli. The precise regulation of DNA methylation is essential for normal cognitive function. Indeed, when DNA methylation is altered as a result of developmental mutations or environmental risk factors, such as drug exposure and neural injury, mental impairment is a common side effect. The investigation into DNA methylation continues to show a rich and complex picture about epigenetic gene regulation in the central nervous system and provides possible therapeutic targets for the treatment of neuropsychiatric disorders.
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            Huntington disease.

            Huntington disease is devastating to patients and their families - with autosomal dominant inheritance, onset typically in the prime of adult life, progressive course, and a combination of motor, cognitive and behavioural features. The disease is caused by an expanded CAG trinucleotide repeat (of variable length) in HTT, the gene that encodes the protein huntingtin. In mutation carriers, huntingtin is produced with abnormally long polyglutamine sequences that confer toxic gains of function and predispose the protein to fragmentation, resulting in neuronal dysfunction and death. In this Primer, we review the epidemiology of Huntington disease, noting that prevalence is higher than previously thought, geographically variable and increasing. We describe the relationship between CAG repeat length and clinical phenotype, as well as the concept of genetic modifiers of the disease. We discuss normal huntingtin protein function, evidence for differential toxicity of mutant huntingtin variants, theories of huntingtin aggregation and the many different mechanisms of Huntington disease pathogenesis. We describe the genetic and clinical diagnosis of the condition, its clinical assessment and the multidisciplinary management of symptoms, given the absence of effective disease-modifying therapies. We review past and present clinical trials and therapeutic strategies under investigation, including impending trials of targeted huntingtin-lowering drugs and the progress in development of biomarkers that will support the next generation of trials. For an illustrated summary of this Primer, visit: http://go.nature.com/hPMENh.
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              DNA methylation aging clocks: challenges and recommendations

              Epigenetic clocks comprise a set of CpG sites whose DNA methylation levels measure subject age. These clocks are acknowledged as a highly accurate molecular correlate of chronological age in humans and other vertebrates. Also, extensive research is aimed at their potential to quantify biological aging rates and test longevity or rejuvenating interventions. Here, we discuss key challenges to understand clock mechanisms and biomarker utility. This requires dissecting the drivers and regulators of age-related changes in single-cell, tissue- and disease-specific models, as well as exploring other epigenomic marks, longitudinal and diverse population studies, and non-human models. We also highlight important ethical issues in forensic age determination and predicting the trajectory of biological aging in an individual.
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                Author and article information

                Contributors
                (View ORCID Profile)
                (View ORCID Profile)
                Journal
                JCMOHK
                Journal of Clinical Medicine
                JCM
                MDPI AG
                2077-0383
                April 2022
                April 10 2022
                : 11
                : 8
                : 2110
                Article
                10.3390/jcm11082110
                eca83121-3368-4129-8aea-90dd1176338b
                © 2022

                https://creativecommons.org/licenses/by/4.0/

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