Precision medicine's effective deployment demands a diverse range of approaches, approaches that are anchored in the causal inference derived from previously consolidated (and introductory) knowledge within the field. This knowledge heavily relies on convergent descriptive syndromology, also known as “lumping,” which has exaggerated a reductionist genetic determinism approach in its pursuit of associations without addressing the causal relationships. 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. Precision medicine, in a truly divergent form, demands a separation and study of distinct genetic levels, recognizing their causal interactions occurring in a non-linear fashion. This chapter scrutinizes the overlaps and differences in genetics and genomics to illuminate causal explanations for the development of Precision Medicine, a future promise for patients affected by neurodegenerative diseases.
Numerous factors intertwine to produce neurodegenerative diseases. The appearance of these is shaped by the interplay of genetic, epigenetic, and environmental factors. In light of the prevalence of these diseases, future management strategies must adopt a new perspective. If one were to take a holistic view, the phenotype—which encompasses the clinicopathological convergence—results from the perturbation of a complex system of functional protein interactions, a characteristic manifestation of systems biology's divergent nature. Systems biology, adopting a top-down perspective, commences with an unprejudiced collection of data generated via one or more 'omics approaches. The purpose is to discern the networks and associated components involved in the manifestation of a phenotype (disease), typically in the absence of pre-existing knowledge. A fundamental assumption within the top-down method is that molecular components reacting similarly to experimental perturbations are functionally connected in some manner. This methodology enables the exploration of multifaceted and relatively poorly characterized diseases, dispensing with the necessity for comprehensive expertise in the implicated mechanisms. immune exhaustion Applying a global strategy, this chapter delves into the comprehension of neurodegeneration, paying special attention to the widespread conditions of Alzheimer's and Parkinson's diseases. The fundamental purpose is to distinguish the different types of disease, even if they share comparable clinical symptoms, with the intention of ushering in an era of precision medicine for people affected by these disorders.
Parkinsons disease, a progressive neurodegenerative disorder, is marked by its association with both motor and non-motor symptoms. Misfolded α-synuclein buildup is a critical pathological element in the initiation and progression of the disease process. Although definitively categorized as a synucleinopathy, the formation of amyloid plaques, tau-laden neurofibrillary tangles, and TDP-43 protein aggregates manifests in the nigrostriatal pathway and throughout various brain regions. Inflammatory responses, particularly glial reactivity, T-cell infiltration, and heightened inflammatory cytokine expression, alongside toxic mediators released by activated glial cells, are now recognized as significant contributors to Parkinson's disease pathology. Contrary to past assumptions, copathologies are the norm (over 90%) in Parkinson's disease cases. The average Parkinson's patient is found to have three different copathologies. While microinfarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy might influence the trajectory of the disease, -synuclein, amyloid-, and TDP-43 pathologies appear not to contribute to its progression.
Implicitly, 'pathogenesis' is frequently used in place of 'pathology' when discussing neurodegenerative disorders. Pathology acts as a guide to the pathogenic pathways of neurodegenerative disorders. This clinicopathologic framework proposes that demonstrable and measurable aspects of postmortem brain tissue can elucidate premortem clinical presentations and the cause of demise, a forensic strategy for understanding neurodegenerative processes. The century-old clinicopathology framework, having yielded little correlation between pathology and clinical features, or neuronal loss, presents a need for a renewed examination of the link between proteins and degenerative processes. Two simultaneous consequences of protein aggregation in neurodegenerative disorders are the decrease in soluble, normal proteins and the increase in insoluble, abnormal proteins. Early autopsy investigations into protein aggregation demonstrate a missing initial step, an artifact. Normal, soluble proteins are absent, with only the insoluble portion offering quantifiable data. Human data, collectively examined here, suggests that protein aggregates, often termed pathology, are outcomes of various biological, toxic, and infectious exposures. However, these aggregates may not fully explain the origin or progression of neurodegenerative disorders.
Precision medicine, a patient-focused strategy, strives to translate the latest research findings into optimized intervention types and timings, ultimately benefiting individual patients. Selleck GF109203X A considerable level of interest exists in utilizing this method within treatments created to slow or halt neurodegenerative disease progression. In fact, the development of effective disease-modifying treatments (DMTs) represents a crucial and persistent gap in therapeutic options for this condition. Unlike the marked progress in oncology, precision medicine in neurodegenerative diseases encounters a plethora of obstacles. These limitations stem from our incomplete grasp of many facets of disease. A significant impediment to progress in this field is the uncertainty surrounding whether common, sporadic neurodegenerative diseases (affecting the elderly) represent a single, uniform disorder (especially concerning their pathogenesis), or a collection of related yet distinctly different disease states. In this chapter, we provide a succinct look at how insights from other medical fields might guide the development of precision medicine for DMT in neurodegenerative diseases. We evaluate the reasons for the lack of success in DMT trials to date, focusing on the crucial importance of recognizing the many facets of disease heterogeneity, and how this recognition will impact and shape future trials. We wrap up by exploring how to move from the diverse presentation of this disease to successfully utilizing precision medicine principles in neurodegenerative diseases treated with DMT.
Despite the substantial heterogeneity in Parkinson's disease (PD), the current framework predominantly relies on phenotypic categorization. In our view, this classification technique has significantly hampered the progress of therapeutic advancements, thereby diminishing our potential for developing disease-modifying interventions in Parkinson's disease. Molecular mechanisms relevant to Parkinson's Disease, alongside variations in clinical presentations and potential compensatory strategies during disease progression, have been uncovered through advancements in neuroimaging techniques. Analysis via MRI reveals subtle microstructural changes, interruptions of neural pathways, and variations in metabolic and circulatory activity. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging provide data on neurotransmitter, metabolic, and inflammatory dysfunctions, potentially aiding in differentiating disease phenotypes and predicting treatment efficacy and clinical course. Yet, the rapid progress of imaging technologies poses a challenge to understanding the significance of recent studies when considered within a new theoretical context. In this context, the need for standardized practice criteria in molecular imaging is evident, as is the need to reconsider target selection. A fundamental reworking of diagnostic procedures is required to fully utilize precision medicine. The shift must be from uniform methods to individual-specific approaches that consider inter-patient differences instead of similarities and emphasizing the prediction of patterns over the review of lost neural function.
Recognizing individuals with heightened risks for neurodegenerative conditions enables the performance of clinical trials at an earlier stage of neurodegeneration compared to previous opportunities, hopefully improving the success rate of interventions designed to slow or stop the disease's course. Parkinson's disease's lengthy pre-symptomatic phase provides opportunities, but also presents hurdles, in the assembly of high-risk individual cohorts. Individuals with genetic variations linked to an increased risk, alongside those presenting with REM sleep behavior disorder, form the most promising pool for recruitment at this time, yet multistage screening encompassing the entire population, leveraging pre-existing risk elements and early indicators, might also prove successful. This chapter delves into the hurdles associated with finding, hiring, and retaining these individuals, and presents possible solutions, supported by illustrative examples from previous research efforts.
A century's worth of medical research hasn't altered the clinicopathologic model for neurodegenerative illnesses. Clinical outcomes are determined by the pathology's specific influence on the aggregation and distribution of insoluble amyloid proteins. The model's two logical outcomes are: (1) measuring the disease-defining pathology identifies a biomarker for the disease in all affected individuals, and (2) removing that pathology should eliminate the disease entirely. The anticipated success in disease modification, guided by this model, has yet to materialize. oncolytic immunotherapy New techniques for examining living organisms have upheld, not challenged, the existing clinicopathologic model, despite the following key observations: (1) disease-defining pathology occurring alone is an infrequent autopsy finding; (2) multiple genetic and molecular pathways often converge on the same pathological outcome; (3) pathology in the absence of neurological disease is more prevalent than expected by random chance.