linking entities in a post-processing step) or by converting such formats to other graph-generic formats.
Concluding, contextualizing and formalizing knowledge in the form of disease maps enables cataloging crosstalk across molecular players and pathways in a particular disease. By doing so, the analysis of disease modeling supports investi-gating disease aetiology by generating novel mechanistic hypotheses. However, the expansion and maintenance of disease maps is crucial in order to continue integrating the knowledge coming from novel literature. Furthermore, in the particular case of neurological disorders, disease maps could incorporate other aspects and biological scales related to the condition such as imaging readouts (e.g., volume of region brains), biomarkers, and clinical features (e.g., psychologi-cal tests). Finally, future overarching approaches that connect these computable knowledge templates to real multi-scale and multimodal cohorts could shed some light on the mechanisms underlying aetiology of these complex disorders.
1.5.1 Alzheimer’s disease
Alzheimer’s disease (AD) is a neurodegenerative disease that progressively affects memory, thinking, and behavior by inducing neuronal dysfunction. This condition is the most predominant form of dementia and is the neurological disorder with the highest prevalence in the population [80, 81]. Although multiple hypotheses have been proposed [82–86], little is known about its multifactorial aetiology.
The variety of mechanisms implicated (or thought to be) and the vast number of possible chemicals to target them can explain why, despite the billions invested by pharmaceutical companies, there still is no cure for AD, only treatments that relieve patients from their symptoms [87]. Other reasons could be attributed to the fact that patients are treated in advanced stages of the disease (i.e., treatment comes too late) [88] or trials are conducted in highly heterogeneous patient groups (i.e., drugs might work exclusively in a subpopulation).
Today, it is estimated that about 50 million people live with some form of dementia. The majority of the cases exist in developed countries where patients can be diagnosed and have access to health care. By 2050, when the population pyramids of developing countries evolve from their current expansive shapes (i.e., bell-curved) to stationary ones (i.e., rectangular shape), this number is expected to be tripled [89]. However, the number of scientific publications related to dementia is ten times smaller than the cancer field [89]. The combination of this under-representation together with the future demographic outlooks could explain why western countries have set dementia as a public health priority and have launched numerous projects addressing this issue.
Although there exist multiple types of dementia, there tends to be agreement in the literature on the subdivision of AD into two main subtypes [90–92]:
• Familial AD.This subtype is related to mutations involved in AD-related genes, such as APP, PSEN1 and PSEN2. New insights on these etiological agents are essential for a better understanding of the pathogenesis of AD.
• Sporadic AD.Accounting for about 95% of all cases, sporadic AD presents the same symptoms as the previous subtype though it cannot be distin-guished from the familial form since the etiology of this form has yet to be fully elucidated. It is believed that it is caused by environmental factors as well as a genetic component.
1.5.2 Parkinson’s disease
Parkinson’s disease (PD), the second most common neurodegenerative disease, is characterized by a series of unknown detrimental changes in the central nervous system that lead to dysfunction in the motor system. PD pathophysiology is associated with a deterioration of the dopamine release system that ultimately disrupts motor system skills, translating into unstable and unplanned movements.
Hence, trembling movements are the most common symptom at early stages. Later stages, however, develop into cognitive decline and behavioral issues as the areas of the brain become affected [93]. Unfortunately, although some of the symptoms can be alleviated, as of yet there is no cure for PD.
Epidemiologically, PD is a highly prevalent condition as studies indicate ap-proximately ten million patients are affected worldwide [94]. However, this num-ber is expected to double in the next decades due to an increase in aging popula-tions, longer disease durapopula-tions, and environmental as well as social risk factors [95]. Conversely to AD, this condition is more prevalent in men with a 1.6 to 1 ratio [96]. This difference is believed to be attributed to the neuroprotective effect of estrogen in women [97–99].
Since PD is a multifactorial condition and its pathophysiology has yet to be fully understood, various studies have been conducted and found numerous mechanisms to be associated with PD(Figure 5). According to the possible etiology and clinical implications, two subtypes of PD can be characterized [102]:
• Familial or monogenic PD.Accounting for approximately 5% of the diag-nosed cases of PD, this subtype is caused by inheritable monogenic genetic variants, such as SNCA, PINK1, and LRRK2 [103]. Typical traits of this PD subtype are both early onset (around forty years) and accelerated disease progression.
• Idiopathic or sporadic PD.Idiopathic PD constitutes roughly 90% of diag-nosed PD cases. Men of age 80 years represent the majority of the cases and the average age of diagnosis is 55 years old. In contrast to familial PD, the pathogenesis of this type is gradual and its pathophysiology is associated with epigenetic and environmental factors [104].
Figure 5:Schematic representation of the crosstalk between different mechanisms impli-cated in PD pathophysiology. Both Mitochondrial dysfunction (A) and neuroinflammation (B) result in a cascade of cellular events that lead to apoptosis such as generation of Reac-tive Oxygen Species (ROS) (E), mitochondrial fission/fragmentation (C) or ATP depletion.
Cellular responses to these changes include alteration in gene expression (H) or autophagy and mitophagy (D). These processes are related with the aggregation of proteins such as synuclein and activation of the ubiquitin system, both of which are disease hallmarks.
Finally, excitotoxicity (I) caused by a dysregulation in the influx of Ca 2+ is also related to mitochondrial dysfunction through the depolarization of its membrane. This figure has been adapted from [100, 101].
1.5.3 Post-traumatic stress disorder
PTSD is a common psychiatric disorder that can occur in individuals after a traumatic event [105]. This condition is diagnosed by psychologists based on the presentation of four characteristic symptom: intrusions, avoidance, negative
cognitions/mood, and hyperarousal [106]. While PTSD pathophysiology is not yet fully understood, research suggests that numerous neurological systems that regulate mental and physical health functions are implicated [107]. Furthermore, PTSD symptoms complicate its diagnosis. In fact, it was not officially recognized as a condition until 1980 by the American Psychiatric Association [108].
From the epidemiological point of view, [105] has a prevalence around 3.5%
in the United States [106]. Globally, although trauma exposure is unequally dis-tributed due to cultural differences and the presence of local conflicts, this condi-tion is present in around 10% of the total populacondi-tion at some point of their lives [109]. Finally, it is important to note these figures can be considered conservative as epidemiological studies indicate that over 70% of the population experiences a traumatic event [109, 110].
Besides the epidemiological figures, PTSD has a significant impact on our economy and society. Economically, the costs derived from this condition are related to the health resources used, such as medication, and resources lost in terms of productivity and presenteeism. Due to the difficulty in estimating economic cost-of-illness, there have been no studies focusing on the global economic impact of PTSD. However, a local study based in Northern Ireland reported surprisingly large figures for such a small region [111]. Similarly to neurodegenerative diseases, the social impact is not restricted to patients but also to families, relatives, and the care staff who suffer from prolonged stress, depression and other psychological disorders.
The principal treatments for PTSD patients are psychotherapy and medica-tion. The most common prescriptions are antidepressants that act as a Selective Serotonin Re-uptake Inhibitors (SSRIs) (e.g., Zoloft and Paxil). However, the mech-anism of action of these drugs is still unknown, and such generic medication is prescribed for multiple other psychiatric disorders. Furthermore, the benefits of these drugs may be outweighed by their numerous side effects [112]. Since we still lack the mechanistic understanding about the pathophysiological changes occurring in the brain that lead to this disorder, it is critical to start by analyz-ing biomarker data in order to pinpoint endophenotypic traits implicated in this disorder. In addition, biomarker discovery, as in neurodegenerative diseases, is essential for detecting symptomatic patients at an early stage of the disease so they can be immediately treated at a early stage of the disease for more timely treatments.