A divergent strategy, contingent upon a causal understanding of the accumulated (and early) knowledge base, is advocated for in the implementation of precision medicine. Descriptive syndromology, a convergent approach (often called “lumping”), has unduly relied on a reductionistic view of gene determinism in the pursuit of correlations, failing to establish causal understanding. A range of modifying factors, comprising small-effect regulatory variants and somatic mutations, play a role in the observed incomplete penetrance and variable expressivity within families affected by apparently monogenic clinical disorders. To achieve a truly divergent precision medicine approach, one must fragment, analyzing the interplay of various genetic levels, with their causal relationships operating in a non-linear pattern. This chapter undertakes a review of the convergences and divergences within the fields of genetics and genomics, with the goal of unpacking the causal mechanisms that could ultimately lead to the aspirational promise of Precision Medicine for neurodegenerative conditions.
A multitude of factors are implicated in the genesis of neurodegenerative diseases. Consequently, a confluence of genetic, epigenetic, and environmental elements play a role in their appearance. Therefore, a change in how we approach the management of these widespread diseases is needed for the future. From a holistic standpoint, the phenotype, a confluence of clinicopathological features, stems from the disturbance of a multifaceted system of functional protein interactions, a hallmark of systems biology divergence. The top-down systems biology approach initiates with the unbiased gathering of datasets derived from one or more 'omics techniques. Its objective is to pinpoint the networks and components that shape a phenotype (disease), often proceeding without pre-existing knowledge. The top-down method is predicated on the principle that molecular components demonstrating comparable responses to experimental alterations are, in some way, functionally associated. This facilitates the investigation of intricate and comparatively poorly understood ailments without necessitating in-depth familiarity with the underlying processes. Immune enhancement This chapter's exploration of neurodegeneration will employ a universal approach, with a focus on Alzheimer's and Parkinson's diseases. Distinguishing disease subtypes, despite their similar clinical presentations, is the cornerstone for realizing a future of precision medicine for individuals afflicted with these diseases.
A progressive neurodegenerative disorder, Parkinson's disease, is accompanied by a variety of motor and non-motor symptoms. During both disease initiation and progression, misfolded alpha-synuclein is a key pathological feature. While unequivocally established as a synucleinopathy, the emergence of amyloid plaques, tau-containing neurofibrillary tangles, and the presence of TDP-43 inclusions are observed in the nigrostriatal system and other brain regions. Prominent drivers of Parkinson's disease pathology are now understood to include inflammatory responses, as evidenced by glial reactivity, T-cell infiltration, increased inflammatory cytokine production, and other toxic compounds produced by activated glial cells. The majority (>90%) of Parkinson's disease cases, rather than being exceptions, now reveal a presence of copathologies. Typically, such cases display three different associated conditions. Even though microinfarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy may influence disease progression, -synuclein, amyloid-, and TDP-43 pathology do not seem to contribute to the disease's advancement.
Neurodegenerative disorders frequently use the term 'pathogenesis' to implicitly convey the meaning of 'pathology'. Through the study of pathology, one can perceive the processes leading to neurodegenerative diseases. Within a forensic approach to understanding neurodegeneration, this clinicopathologic framework hypothesizes that quantifiable and identifiable characteristics in postmortem brain tissue can explain the pre-mortem clinical symptoms and the reason for death. The century-old framework of clinicopathology, failing to demonstrate a meaningful relationship between pathology and clinical signs, or neuronal loss, makes the connection between proteins and degeneration ripe for reconsideration. Two synchronous repercussions of protein aggregation in neurodegenerative diseases are the depletion of soluble, normal proteins and the buildup of insoluble, abnormal proteins. An artifact is present in early autopsy studies concerning protein aggregation, as the initial stage is omitted. This is because soluble, normal proteins have disappeared, only permitting quantification of the insoluble residual. Our review of the combined human data indicates that protein aggregates, known as pathologies, arise from a spectrum of biological, toxic, and infectious factors. Yet these aggregates are likely not the sole explanation for the cause or development of neurodegenerative diseases.
Precision medicine, a patient-focused strategy, strives to translate the latest research findings into optimized intervention types and timings, ultimately benefiting individual patients. Protein Tyrosine Kinase inhibitor This strategy garners significant interest as a component of treatments intended to slow or stop the advancement of neurodegenerative disorders. Certainly, the lack of effective disease-modifying therapies (DMTs) continues to be a major unmet need within this specialized area of medicine. While oncology has witnessed substantial advancements, neurodegenerative precision medicine grapples with numerous obstacles. These impediments to our comprehension of many facets of diseases are major limitations. A key hurdle to breakthroughs in this domain is the unresolved issue of whether the prevalent, sporadic neurodegenerative diseases (affecting the elderly) are a single, uniform disorder (specifically pertaining to their development), or a group of related but individual diseases. The potential applications of precision medicine for DMT in neurodegenerative diseases are explored in this chapter, drawing on concisely presented lessons from other medical fields. The study examines the reasons for the failure of DMT trials, emphasizing the importance of understanding the multiple forms of disease heterogeneity and how this will shape future endeavors. In our closing remarks, we analyze the path from this disease's complexity to applying precision medicine effectively in neurodegenerative diseases treated with DMT.
While the current Parkinson's disease (PD) framework employs phenotypic classification, the considerable heterogeneity of the disease necessitates a more nuanced approach. We posit that the limitations inherent in this classification system have obstructed the progression of therapeutic innovations, leading to a restricted ability to develop disease-modifying interventions for Parkinson's Disease. Neuroimaging innovations have identified key molecular processes related to Parkinson's Disease, including variability in and across clinical types, and prospective compensatory responses throughout disease progression. Magnetic resonance imaging (MRI) provides a means of recognizing microstructural modifications, interruptions within neural pathways, and changes to metabolic and hemodynamic activity. PET and SPECT imaging, by revealing neurotransmitter, metabolic, and inflammatory dysfunctions, potentially enable the distinction of disease phenotypes and the prediction of therapeutic responses and clinical outcomes. Yet, the rapid progress of imaging technologies poses a challenge to understanding the significance of recent studies when considered within a new theoretical context. Thus, to advance molecular imaging, we must simultaneously standardize the practice criteria and reevaluate the approaches to targeting molecules. To properly apply precision medicine, a shift towards distinct diagnostic pathways is vital, instead of seeking similarities. This shift focuses on anticipating patterns of disease and individual responses, rather than analyzing already lost neural functions.
The process of identifying people at risk of developing neurodegenerative diseases allows for clinical trials focused on earlier intervention than possible before, potentially increasing the probability of success for treatments aimed at slowing or stopping the disease's course. The prodromal stage of Parkinson's disease, marked by its extended duration, presents both opportunities and difficulties for the formation of cohorts focused on individuals at risk. The current most promising recruitment strategies encompass individuals with genetic variations that predispose them to a higher risk and individuals with REM sleep behavior disorder, although an alternative strategy of multi-stage screening programs for the general population, utilizing existing risk factors and prodromal features, might also prove efficient. The identification, recruitment, and retention of these individuals presents challenges that this chapter addresses, illustrating potential solutions through existing research.
For over a century, the clinicopathologic framework for neurodegenerative diseases has persisted without alteration. The specific pathology, manifest clinically, is dependent on the load and distribution of insoluble amyloid proteins that have aggregated. This model predicts two logical outcomes. Firstly, a measurement of the disease's defining pathological characteristic serves as a biomarker for the disease in all those affected. Secondly, eliminating that pathology should result in the cessation of the disease. Despite the promise offered by this model for disease modification, substantial success has proven elusive. Maternal Biomarker Though new technologies have probed living biology, the clinicopathological model's accuracy has not been called into question. This stands in light of three vital observations: (1) disease pathology in isolation is a relatively uncommon autopsy finding; (2) multiple genetic and molecular pathways often contribute to the same pathological outcome; and (3) the presence of pathology divorced from neurological disease is more frequently seen than anticipated.