Neurodegenerative Diseases: Multifactorial Degenerative Processes, Biomarkers and Therapeutic Approaches (First Edition)

Neurodegenerative diseases are one of the leading causes of morbidity and disability worldwide, afflicting millions of individuals. These diseases emerge as a result of multiple factors, sharing pathogenic pathway that includes mitochondrial dysfunction, misfolded protein aggregation, and oxidative stress. Genetic and environmental factors have been identified to play a key role in neurodegeneration and modifying the risk of the disease. The association of neurodegenerative diseases to genetic factors and environmental agent’s exposure is not well conclusive. As a consequence, studying the interplay of genetic and environmental factors in neurodegenerative diseases can help researchers better understand gene and therapy and disease progression. In this chapter, an attempt has been made to discuss the multifactorial degenerative process and the role of genetic and environmental factors in common neurodegenerative diseases. Understanding the mechanisms of disease initiation and progression is crucial for disease prevention and modification of disease risk. These information would be helpful in the exploration of therapeutic options against these diseases.

Parkinson’s disease (PD) is a first most common motor neurodegenerative disorder and caused due to degeneration of dopaminergic neurons of nigrostriatal pathway of brain. Brain is the most active organ of human body which receives, process and command the responses utilizing approximately twenty percent of body’s total energy. Mitochondrion is the cellular powerhouse produces ATP by utilizing various complexes of electron transport chain. This ATP is the energy source of cells and is being used for physiological functions of the cells, indicating the critical role of mitochondrial functionality in cellular physiology. In PD pathology the impaired bioenergetics is the known and critical factor which essentially requires for cellular physiological responses and failed to maintain it will lead to self-destruction of cell, termed as apoptosis. Neuronal apoptosis is the inescapable event in PD pathology and suggest the implications of cellular bioenergetics and the close conjunction of mitochondrion functionality and disease pathology. In this chapter mitochondrion functionality and its correlation with various neurodegenerative signalling pathways during PD pathology will be discussed.

Protein aggregation-related diseases primarily affect the central nervous system and are involved in the pathogenesis of multiple neurodegenerative diseases as well as several rare hereditary disorders that involve the deposition of protein aggregates in the brain. These diseases include Alzheimer's, Parkinson, Huntington's disease, Prion diseases, amyotrophic lateral sclerosis, familial amyloid polyneuropathy, etc. The aggregates usually consist of fibers containing misfolded protein with a betasheet conformation. As a result, proteins’ secondary structures change from α-helix to β-sheet, leading to the accumulation of harmful misfolded protein aggregates in the CNS. The misfolding, subsequent aggregation and accumulation of proteins in neurodegenerative diseases lead to cellular dysfunction, loss of synaptic connections and brain damage. This chapter discusses some of the important neurodegenerative diseases resulting from protein misfolding and explains the pathological mechanisms behind brain damage.

The altered redox state leads to oxidative stress through the extravagant synthesis of reactive oxygen species (ROS) and inhibition of the antioxidant system. The high oxygen demand in nervous tissue makes it vulnerable to ROS, and the presence of peroxidation-prone lipid cells worsens the situation. We now understand that oxidative stress plays a role in the pathophysiology of neurodegenerative diseases such as Parkinson's disease, Motor neuron disease, and Alzheimer's disease. In spite of the fact that there is no lasting cure for any of these diseases, antioxidant treatments have been promoted as ways to treat and discourse neurodegenerative diseases. However, the results regarding their efficacy are contradictory. This chapter examines the role played by oxidative stress in the etiology of neurodegenerative diseases and how they lead to brain dysfunction in people. It will later provide an overview of antioxidants as a therapeutic option for oxidative stress-induced damage.

Parkinson disease is a progressive neurodegenerative disorder that affects motor control of the body. The disorder is associated with the loss of neurons due to formation of protein aggregates that leads to the development of apoptosis and degeneration of the neurons. The disease progresses slowly, making it difficult to identify it at early stage. But the availability of potential therapeutic biomarkers in analysis and early identification of PD is of great importance. The current review discusses here the molecular biology, pathophysiology and availability of potential biomarkers associated with the PD condition.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the central nervous system and the leading cause of dementia in elder people. The clinical symptoms of AD are memory loss and cognitive dysfunction. Pathologically, AD is characterized by the deposition of β-amyloid plaques and neurofibrillary tangles of hyperphosphrylated tau protein in the brain and neurodegeneration. However, the cause of AD is not known. Various genetic and non genetic factors have been involved in the pathogenesis. The main genetic risk factor of AD is E4 allele of apolipoprotein E. Currently; no effective treatment is available for AD. Only two classes of drugs namely acetylcholinesterase inhibitor (Galantamine, Rivastigmine, Donepezil), and N-methy- -D-aspartate receptor antagonist (Memantine) are available for AD treatment. These drugs have limited effectiveness and disagreeable side-effects in AD patients. This chapter focuses on the molecular biology, pathophysiology of the disease and various diagnostic and prognostic biomarkers for the management of AD.

Huntington's disease (HD), a hereditary autosomal dominant neurodegenerative disorder is characterised by weak cognitive and motor functions. The symptoms most commonly prevail among 30-50 years age group people. The coordination and movement abilities gradually worsen, and mental abilities mostly decline that progress towards dementia. The basis behind the HD disease is neuronal death due to mutations in huntingtin (HTT) protein, a protein required for the development and survival of neurons. There is an increase in the number of CAG repeats that generally code for glutamine within the HTT gene, resulting in an expansion of polyglutamine chain in HTT protein. This mutated HTT protein is toxic causing neuronal death and motor dysfunction. There is no known therapy for this disease other than suggestive relief treatment approaches. The review will be discussing here the molecular mechanism, pathophysiology and the potential biomarkers associated with HD.

In the brain, multiple sclerosis is a chronic disease caused by immunemediated neurodegeneration. About 2.5 million people around the world suffer from multiple sclerosis (MS), and women are more prone to it. Neither clinical nor imaging biomarkers are used to diagnose or characterize the disease. Molecular biomarkers have been developed from immunology and neurobiology because they are well matched with causal path mechanisms and other disease characteristics, thus, limiting the number of molecular biomarkers used in clinical practice. Currently, the chapter discusses the attribute of flawless MS biomarkers and the challenges associated with developing newer biomarkers. The study also discusses the discovery of biomarkers from the blood and cerebrospinal fluid (CSF) that are useful for diagnosing MS, predicting its prognosis, and evaluating its therapeutic response and side effects.

Neurodegeneration is a progressive process that occurs with normal aging with accelerated loss of normal functioning and structure of neurons. The physiological aging of neurons can be expedited by many different factors like neurodegenerative diseases (NDs) including frontotemporal lobe degeneration (FTLD), Alzheimer's disease (AD), dementia with Lewy bodies (DLB), vascular dementia (VaD), etc. In the clinical view, the symptoms of different types of neurological disorders have a high degree of similarity, making it difficult for differential diagnosis. Clinicians need strong expertise to reach a correct diagnosis for a particular disease as there are so many established clinical guidelines for the diagnosis of different types of neurological disorders. Here, in this chapter, we shall focus to understand the different molecular diagnostic tools and immunological markers used for the detection of neurodegenerative disorders.

Neurodegenerative disease such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, and the spinocerebellar ataxias is major health threat specifically in the elderly population. Currently, the disease diagnosis and progression is tracked through the clinical estimation which only gives a rough estimate of the disease severity. So the biomarkers serve as an essential tool in the disease diagnosis and disease progression. High-throughput omics-based technologies have facilitated the discovery of new biomarkers. The analytic methods underlying the basic omics-based technologies, genomics, transcriptomics, and metabolomics are now been extensively useful in the identification of novel biomarkers. These new candidate biomarkers are helpful in the clinical management of neurological disorders.

The most common neurodegenerative diseases (ND) include Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD), as well as frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Protein misfolding and aggregation are the key hallmarks of these neurodegenerative diseases, which may lead to cell death, axonal regeneration failure, demyelination, and overall neuronal structural and functional deficits. Usually, ND is diagnosed at a very advanced stage and conventional therapies are directed at treating neurological symptoms but have no effect on disease progression. In general, several pathological processes contributes to misfolding proteins/protein aggregates and their postconsequences, including impairment of autophagy, microtubule destabilization, neuroinflammation, proteostasis, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress, calcium homeostasis, and neurogenesis impairment. Indeed, several signaling pathways critically linked with these pathological processes are now becoming attractive targets and investigated for their beneficial effects by restricting the progression of ND. In particular, certain signaling mechanisms and proteins found to show an integral involvement in the pathogenesis of ND and had shown promising results in preclinical and/or clinical contexts. For ex; novel autophagy stimulators, drugs acting on mTOR, NRF2, TLR, purinergic signaling; drugs acting on neuroinflammatory signaling pathways, Heat Shock Proteins (HSP), sestrins, sirtuins, some PDE-inhibitors, miRNA’s have gained a lot of attention in the therapy of ND and are included in the following discussion.

Medicinal plants have been used since ages for the treatment of human diseases in the Indian medicinal system of Ayurveda. Parkinson's diseases (PD) on the other hand is a kind of neurodegenerative disorder that shows debilitating symptoms; and the treatment of the disease rely on the symptomatic management. The drugs available for the treatment of the disease show severe side effects on prolonged usage. Thus, many medicinal plants and their derivative natural compounds have been tested for their anti-Parkinsonian activity with minimal side effects. Mucuna pruriens, Withania somnifera, Tinospora cordifolia are the example of medicinal plants that have shown anti-Parkinsonian activity while the natural compounds found in medicinal plants like Baicalein, curcumin, Ginseng, Resveratol have also maintained the nerve cell function and prevented the neuronal death. Thus, the polyphenols and other bioactive constituent of medicinal plants should be further studied for their therapeutic intervention against PD.

Physical and mental well-being is treasure for mankind in a competitive and progressive global scenario. For a country, result oriented tasks can be accomplished only with its healthy population. Along with many diseases of global concern, neurological disorders have drawn concern globally as these are sharing an increasing proportion in global burden of diseases. Further cases of neurodegenerative disorders, majorly affecting aged population, have been recently reported to record a considerable increase which has complicated the health and care-giving (old age homes) services as part of public health. Many public health policies have been laid down by many developed and developing countries in accordance of WHO guidelines which in turn based on GBD studies, made till date. Major share of neurodegenerative disorders is contributed by Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis & Multiple Sclerosis. The recent past has witnessed growing number of deaths and disability adjusted life years, DALY, caused by neurodegenerative diseases. Public health services and related government policies are not enough, according to WHO, to properly address the current situation. Lack of public awareness towards neurological disorders of all kind, is one of the major challenges to Figure out actual data; for prevalence of neuro-disorders.