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Advancements in Brain Diseases: Exploring the Complexities and Pursuing Therapeutic Breakthroughs

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Submitted:

08 September 2023

Posted:

11 September 2023

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Abstract
Brain disorders pose a significant global healthcare challenge due to their complexity and profound impact on individuals and society. This review explores recent advancements in brain disease research, deepening our understanding and progress towards treatments. Technological innovations, like high-resolution imaging and optogenetics, play a pivotal role in illuminating cellular structures and dissecting neural circuits. Genetic analysis identifies dis-ease-associated genes and mutations, yet translating findings to clinical applications remains challenging. Epigenomics, transcriptomics, and proteomics provide molecular insights, un-covering disrupted pathways in conditions like Alzheimer's disease. Stem cell models elucidate developmental mechanisms, and immunotherapies, including CAR T cells, emerge as prom-ising strategies for brain cancers like glioblastoma. Genome editing tools, exemplified by CRISPR, enable precise modification of disease genes in models, deepening our understanding of pathogenesis. Multifaceted approaches integrating human studies, animal models, and bi-oinformatics propel the field forward. However, complexities persist, as disease specificity for cell types or brain regions remains an enigma, and genetic factors interact with environmental influences, highlighting disease intricacies. Ultimately, interdisciplinary efforts combining bi-ophysical and psychospiritual perspectives are essential to fully understand brain health and unlock transformative treatments for these debilitating disorders. A comprehensive under-standing of brain disorders is vital to improve the quality of life for millions and alleviate the global burden of neurological afflictions. Continued collaborative research will lead to an era of improved brain health worldwide.
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1. Introduction

James Parkinson's seminal work, "An Essay on the Shaking Palsy," penned more than two centuries ago, marked the inception of our understanding of Parkinson's disease (PD) [3]. Since then, PD has emerged as a focal point of rigorous scientific inquiry and medical exploration, transcending the boundaries of mere motor disturbances to reveal a complex interplay of genetic, environmental, and pathological factors [4].
PD, characterized by the cardinal motor features of tremor, rigidity, bradykinesia, and postural instability, represents but a fraction of its intricate manifestations, which extend beyond these observable parameters [5,6]. Central to the investigation of PD is the unraveling of its genetic underpinnings, a task that has witnessed remarkable advancements in recent years[7]. Genetic analysis has unveiled an array of disease-associated genes, shedding profound light on the origins of PD and even enabling earlier diagnoses in pre-symptomatic stages[8,9,10]. Yet, the translation of these promising genetic discoveries into practical clinical applications remains an enduring challenge[11,12]. Compounding the complexity of PD is its clinical heterogeneity, leading to the classification of various clinical subtypes that reflect biological and pathophysiological differences among individuals with PD[13,14]. This diversity underscores the imperative for personalized and precision treatment approaches, particularly in the quest for disease modification[15].
While numerous pharmacological agents have been designed to modify the disease or alleviate symptoms, their journey through clinical trials has been marked by formidable challenges, often resulting in failure to meet primary endpoints[16,17]. These hurdles encompass the clinical diversity of PD populations, patient selection intricacies, the absence of suitable preclinical models for sporadic PD, the quest for a definitive disease biomarker, and the determination of the optimal time frame for disease-modifying interventions [18,19]. Nevertheless, the relentless pursuit of effective therapies persists, with a growing focus on nondopaminergic approaches that target various facets of the disease[6,15]. These approaches encompass small-molecule inhibitors, calcium channel blockers, iron chelators, anti-inflammatory agents, and immunotherapies, each showing promise in animal studies and paving the way for human clinical trials[11,20,21]. Beyond pharmacological interventions, the PD research landscape also explores non-pharmacological avenues, including gene therapies, neurotrophic factors, cell restoration therapies, and the electrical modulation of neural circuits through deep brain stimulation (DBS)[22]. These offer alternative pathways for intervention and disease modification [23,24].
In this extensive review, we meticulously document the significant milestones in Parkinson's disease (PD) research spanning the past two centuries, while also shedding light on the present challenges. These challenges are intricately intertwined with the multifaceted origins of PD, prompting a compelling need for innovative therapeutic solutions. Within these pages, we explore the emerging developments that hold the potential to shape the future landscape of PD research, with a particular emphasis on the critical roles played by pre-motor symptoms and early diagnosis in the pursuit of more effective treatment strategies. Our journey takes us through the transformative evolution of PD, transcending its origins as a mere clinical description. Instead, it emerges as a complex interplay of genetic, environmental, and molecular factors, underscoring the rapid advancement of critical fields such as genetics, drug discovery, and drug delivery systems. These disciplines now stand as essential pillars in our ongoing quest to unravel the intricacies of this enigmatic neurological disorder. As we navigate the promising horizons of PD research, we acknowledge the path illuminated by the accumulated knowledge and innovations of the past two centuries. The remarkable voyage from James Parkinson's initial observations to our current state of understanding serves as a testament to the steadfast commitment to unveil the mysteries concealed within this challenging neurological condition. Looking ahead, we anticipate exciting new developments on the horizon that will continue to enrich our comprehension of PD, with a heightened focus on the pivotal roles played by pre-motor symptoms and early diagnosis, as we endeavor to forge more effective therapeutic avenues for those affected by PD.

2. Two Centuries of Parkinson's Disease: Insights and Innovations

Two centuries have elapsed since James Parkinson penned his groundbreaking "Essay on the Shaking Palsy," providing the world with the initial glimpse into a condition characterized by tremors at rest, bradykinesia, and akinesia [1]. While this essay marked the first formal description of what would later bear his name, Parkinson's Disease (PD), it wasn't until half a century later that the contributions of Jean-Martin Charcot began to define the clinical and anatomopathological foundations of PD [2]. Subsequent years witnessed further revelations in the understanding of this enigmatic disorder (Figure 1).
In 1893, Blocq and Marinescu observed resting tremors in a patient, reminiscent of parkinsonian symptoms, attributed to a tuberculous granuloma affecting the ipsilateral Substantia nigra pars compacta (SNc)[25]. Building upon this observation, Brissaud speculated that the SNc might be the epicenter of PD pathology [26]. It wasn't until two decades later that Trétiakoff uncovered neuropathological transformations in the SNc of PD patients, including a significant reduction in neuromelanin content and the presence of cytoplasmic inclusions known as Lewy bodies (LB) [27]. These inclusions, previously described by James Lewy, became a focal point of neuropathological investigations[28]. The combined hallmark of dopaminergic neuron loss in the SNc and the presence of LB solidified as the anatomopathological signature and diagnostic criterion for PD [29].
With diagnostic criteria established, the foremost challenge remained effective treatment[18]. The first neurosurgery targeting the basal ganglia (BG) for PD treatment occurred in 1940[30]. Progress accelerated in the late 1950s and mid-1960s with the discovery of dopamine (DA) as a neurotransmitter and its pivotal role in the striatum [31]. Carlsson's revelation of DA's functional significance, supported by experiments demonstrating reserpine's motor activity reduction, reversed by L-3,4-dihydroxyphenylalanine (L-DOPA) administration, marked a significant turning point in our understanding of motor control in the BG [32]. Ehringer and Hornykiewicz further delineated the striatal DA deficiency in PD [10], while subsequent studies revealed dopaminergic nigrostriatal projections and emphasized the significance of the dorsolateral striatum, primarily affected in PD [33]. The L-DOPA era was inaugurated when Cotzias demonstrated the anti-parkinsonian effects of L-DOPA administration [34].
A groundbreaking moment occurred in 1983 when Langston and colleagues unveiled a group of drug users who developed acute parkinsonism after exposure to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)[35]. MPTP exposure induced an acute syndrome mirroring PD, as MPP+ (MPTP metabolite) wreaked havoc on dopaminergic neurons within the substantia nigra through mitochondrial matrix and electron transport chain disruptions [36]. It was subsequently observed that PD patients exhibited a marked reduction in complex I activity in the SNc [37]. The identification of certain PD patients harboring polymorphisms in genes associated with complex I subunits hinted at a potential vulnerability factor [[38]. MPTP-based models enabled researchers to replicate PD hallmarks both in vitro and in vivo [16]. While pharmacological DA treatments enjoyed success, cell-based DA replacement approaches proved less fruitful [39].
In the late 1990s, genetic analysis advances led to the identification of mutations in the SNCA gene, encoding alpha-synuclein (α-syn), as the first genetic cause of PD [40]. Notably, α-syn was recognized as the primary component of LB, ushering in a new era of understanding [41]. Braak and colleagues proposed a pathological staging of PD based on these findings [42]. Subsequent years saw the identification of numerous other genes implicated in PD pathogenesis [39]. These genetic revelations opened new avenues for potential therapies, underpinned by the development of experimental models utilizing transgenic animals bearing PD-associated mutations[43]. Alongside these advances, neurotoxin-based animal models, such as MPTP or 6-OHDA, contributed valuable insights into potential disease intervention targets [32].
Contemporary research has extended into the intriguing realm of gut microbiota's potential link to PD etiology, opening novel avenues of investigation [44]. The focus now encompasses decoding pre-symptomatic phases and translating scientific progress into disease-modifying therapies for PD [45]. Exciting approaches with less invasive technologies like gamma knife or focused ultrasound have emerged for PD motor symptom treatment [46]. These developments herald a promising future in our quest to understand and combat Parkinson's Disease (PD) comprehensively.

3. Genetic Mysteries of Parkinson's Disease

The elucidation of the genetic underpinnings of familial Parkinson's Disease (PD) began in 1997 when the p.Ala30Thr missense mutation in the alpha-synuclein gene (SNCA) was identified[47]. This mutation was found in a large German family spanning four generations, as well as in three unrelated Greek families, where PD appeared in two to three generations[13,48]. Subsequently, several other pathogenetically significant missense mutations in SNCA were discovered, including p.Ala30Pro, p.Glu46Lys, p.Gly51Asp, p.Ala53Glu, and p.Ala53Thr[49]. It was noted that mutations altering gene dosage through duplications and triplications, without affecting protein structure, could also contribute to PD[50]. The prevalence of SNCA mutations is relatively low, occurring in approximately 0.2% of sporadic PD cases and 1-2% of familial PD cases[51]. However, these mutations link different forms of the disease and underscore the crucial role of alpha-synuclein structural and functional abnormalities in PD pathogenesis[52]. Over time, the list of genes implicated in familial PD has expanded, with more than 10 genes now definitively linked to Mendelian PD[53]. The table provides concise descriptions of these genes and their roles in PD pathogenesis. However, ongoing research continues to explore the contributions of these and other genes to PD's etiopathogenesis[25,54].
One intriguing case is the ubiquitin carboxy-terminal hydrolase UCHL1 (PARK5) gene, which was identified in a German family with late-onset PD[55]. Despite this initial discovery, subsequent familial PD cases with UCHL1 mutations have been rare[50]. Nevertheless, various polymorphic variants of UCHL1, particularly the p.Ser18Tyr missense mutation, have been extensively studied in sporadic PD[56]. Despite conflicting results, comprehensive meta-analyses across different populations failed to establish a significant association between this polymorphism and PD risk[57]. Studies in transgenic mice with UCHL1 mutations have yielded mixed outcomes, adding complexity to the gene's role in PD[58]. While some mice displayed neurodegeneration and altered alpha-synuclein metabolism, others did not[59]. The p.Ser18Tyr variant, in particular, exhibited antioxidant activity and reduced neurodegeneration risk in carriers[60].
Another noteworthy gene, not included in the table, is the GBA gene, responsible for glucocerebrosidase production. Mutations in this gene were originally identified in Gaucher disease patients, characterized by systemic issues and neurological disturbances[61]. Over 300 pathogenetically significant GBA mutations have been described, and they play a definite role in PD development[62]. However, even homozygous carriers of GBA mutations may not all develop parkinsonism[63]. For example, only about 9% of individuals homozygous for the Asn370Ser mutation (associated with mild Gaucher disease without severe neurological symptoms) develop parkinsonism[55]. Additionally, heterozygous carriers of GBA mutations, who comprise about 10% of carriers, have an increased risk of developing PD[64]. The penetrance of these mutations, meaning the likelihood of developing PD, is estimated at 30% by the age of 80[62]. Different mutations predominate in various ethnic groups[65].
Leucine-rich repeat kinase 2 (LRRK2) gene mutations also exhibit reduced penetrance. Despite over 100 known LRRK2 mutations, only six have clear familial associations[66]. For instance, the p.Gly2019Ser mutation, the most common LRRK2 variant, has an 85% penetrance by age 80[67]. However, penetrance can vary among different ethnic groups and is even lower for mutations in codon 1441[68]. In general, it is believed that monogenic forms of PD account for 5-10% of cases, with LRRK2 and PRKN being the major contributors to autosomal dominant and autosomal recessive forms, respectively[21,69]. However, the precise risk assessment based solely on the presence of these mutations remains challenging[70].
Moreover, the frequency of pathogenetically significant mutations in major PD-associated genes varies among populations, emphasizing the need for comprehensive genetic analysis and the search for new PD-related genes[71]. While various commercial genetic testing panels are available, they should be supplemented with detailed familial and phenotypic information for optimal accuracy[72]. Notably, a core panel of five genes, including PRKN, LRRK2, SNCA, PINK1, and PARK7, offers comparable efficiency to extensive gene panels[73,74,75](Table 1).

4. Multifaceted Challenges of Parkinson's Disease: Navigating Motor and Non-Motor Symptoms

Parkinson's disease presents a multifaceted spectrum of symptoms that encompass both motor and non-motor manifestations, and understanding these complexities is vital in providing effective care and management for individuals affected by this progressive neurodegenerative condition[77].
Motor symptoms of Parkinson's often include bradykinesia, characterized by the gradual reduction in movement speed[5]. This can lead to difficulties in performing everyday activities and a noticeable slowing down of tasks. Stiff and rigid muscles can limit one's range of motion, resulting in discomfort and making simple movements challenging[41]. A hallmark symptom of Parkinson's is the resting tremor, typically beginning in a limb, most commonly the hand or fingers[78]. Postural issues may develop, causing a stooped posture, and balance problems can contribute to falls and injuries[79]. Gait problems, such as freezing, shuffling steps, drooped shoulders, and a lack of arm swing, further impact mobility[80]. Facial expressions often become reduced, referred to as "masking," which can affect interpersonal interactions[3] (Figure 2).
On the non-motor side, Parkinson's introduces a host of other challenges[81]. Cognitive impairment varies in severity, ranging from mild memory difficulties and reduced ability to multitask to more severe cognitive decline and dementia[80]. Depression and anxiety are not mere emotional reactions to the diagnosis; they are integral parts of the disease, linked to changes in brain chemistry[5]. Sleep disturbances, including REM Sleep Disorder and Restless Legs Syndrome, disrupt rest and can lead to fatigue[24]. Loss of the sense of smell is often an early indicator of Parkinson's, occurring before other symptoms become apparent[13]. Constipation and speech changes, such as quieter or breathy voices, can also manifest. Swallowing difficulties may affect chewing, tongue movement, and the ability to consume food or liquids comfortably[82]. Vision difficulties can arise due to changes in eye movement, stemming from the loss of dopamine-producing neurons. Lastly, apathy, marked by a general lack of motivation and emotional expression, alongside fatigue, can impact an individual's quality of life[83].

5. Advancing Parkinson's Care: Technology's Transformative Impact

Understanding and effectively managing Parkinson's disease (PD) is a complex and evolving challenge in the realm of healthcare[84]. As this debilitating neurodegenerative disorder progresses, individuals with PD often experience a wide array of motor symptoms, cognitive changes, and fluctuations in their condition[85]. To address these complexities, researchers and healthcare professionals have increasingly turned to innovative technological solutions to monitor and assess various facets of PD[86]. One such technological advancement is Electromyography (EMG), which offers a unique window into the progression of PD[87]. By analyzing muscle activity and tremors, EMG provides valuable insights into the severity and development of motor symptoms in PD patients[88]. It allows for a more objective and precise assessment, facilitating tailored treatment strategies[60].
In parallel, Electroencephalogram (EEG) technology has emerged as a powerful tool for monitoring PD. By tracking changes in brain wave patterns, EEG helps in understanding the cognitive aspects of the disease and its impact on motor control[86]. This information aids in disease monitoring and enables healthcare providers to make informed decisions regarding treatment plans[89]. Brain imaging modalities and 3D motion analysis systems represent another dimension of PD assessment[90]. These technologies offer detailed insights into brain structures and movement patterns, shedding light on how PD affects both the brain and motor function. Such comprehensive assessments contribute to a more holistic understanding of the disease's progression[91].
Wearable sensors have transformed the landscape of PD monitoring by providing continuous, real-time data on movement and posture[92]. These sensors, including accelerometers and gyroscopes, offer objective measurements of gait, balance, and motor fluctuations[87]. They enable early detection of symptoms, personalized treatment adjustments, and improved patient care[93]. Physical activity monitoring for people with PD (PWP) has become increasingly important in assessing disease progression and the effectiveness of interventions[54]. Wearable devices and smartphone applications allow for remote monitoring, encouraging physical activity and enabling healthcare providers to track patient progress more effectively[94].
Levodopa Induced Dyskinesia (LID) is a common challenge in PD treatment. Technology aids in the identification of LID episodes, facilitating medication adjustments to minimize these side effects and enhance the patient's quality of life[95].In the realm of symptom severity estimation, technology assists in quantifying the impact of core PD symptoms such as tremors, bradykinesia, and dyskinesia. These objective assessments provide valuable support for clinical evaluations[5].
Moreover, the integration of web-based applications into PD home monitoring systems enhances convenience and data collection. Patients can self-report symptoms, fostering a more personalized approach to care[80]. Gait impairment is a hallmark of PD, and advanced gait analysis technologies enable a more detailed assessment of this aspect. These assessments inform treatment strategies and help in implementing fall prevention measures[78]. In recent years, technology has extended its reach into uncontrolled home environments, allowing for the monitoring of PD motor symptoms in real-world settings. This approach provides a more accurate depiction of the daily challenges faced by individuals with PD[96].
Lastly, audio sensors have been employed to capture vocal and speech patterns in PD patients[97]. These sensors assist in the assessment of speech impairments, which are common in PD, and provide insights into the disease's progression[98]. Overall, the integration of these various technological approaches represents a significant leap forward in the assessment and management of Parkinson's disease (Figure 3). By offering objective, real-time data and insights, these technologies enhance early diagnosis, enable personalized treatment plans, and ultimately improve the quality of life for individuals living with PD.

6. Revolutionary Advancements: Cutting-Edge Technologies Transforming the Clinical Evaluation, and Therapies for Parkinson's Disease"

Over the past decade, a wave of innovative technology-driven tools and therapeutic approaches has emerged, aimed at revolutionizing the way we diagnose, clinically assess, and treat individuals with movement disorders, particularly Parkinson's Disease[28]. This remarkable progress has been made possible by the ever-evolving landscape of molecular and cellular techniques, coupled with extraordinary advancements in technology. These breakthroughs collectively represent a significant milestone in enhancing our overall comprehension of this complex disease[99].

6.1. Innovative Approaches for Enhanced Parkinson's Disease Therapy: Targeted Drug Delivery Systems

For decades, various therapies have been introduced for the clinical management of Parkinson's Disease (PD) using available medications[100]. However, a significant challenge remains in effectively delivering drugs to the central nervous system (CNS) due to the protective blood-brain barrier (BBB)[101]. Recent advancements in micro- and nanosystems have shown promise in improving drug transport to the brain, circumventing BBB limitations and enhancing the therapeutic properties of both conventional and novel drug molecules[90].
Micro-/nano-drug delivery systems (DDSs) offer versatile options for localized treatment through direct brain administration or systemic delivery to the CNS[102]. These DDSs can be classified as either biodegradable or non-biodegradable, depending on the material and formulation[103]. Numerous preclinical studies have explored different micro-/nano-DDSs for drug and small molecule delivery to the brain, demonstrating varying degrees of success in providing neuroprotection[104]. Beyond the parenteral route, alternative administration methods such as buccal, subcutaneous, and intranasal delivery have gained attention for improving the onset time and bioavailability of dopaminergic drugs[105]. Intranasal administration, in particular, offers a non-invasive way to bypass the BBB through olfactory and trigeminal pathways, enhancing bioavailability and reducing the required drug concentrations[106]. Considering that many PD patients experience dysphagia as their condition progresses, efforts have been directed toward developing novel formulations to facilitate drug delivery at lower concentrations, further improving treatment outcomes[107].
Polymeric nanoparticles have emerged as a promising option for theranostic drug delivery due to their ability to facilitate drug transport across the blood-brain barrier (BBB), enabling the delivery of otherwise impermeable drugs like dopamine (DA)[108]. Surface-modified polymeric nanoparticles have shown successful outcomes, including reduced anxiety and improved motor function upon incorporating DA[109]. Additionally, solid lipid nanoparticles (SLNs) offer advantages such as biocompatibility and high drug-loading capacity[110]. By modifying their surfaces and sizes, SLNs can enhance drug targeting and bioavailability, making them suitable for central nervous system (CNS) drug delivery, as demonstrated in studies involving drugs like apomorphine and rotigotine, which showed enhanced drug uptake and sustained release[111]. Microencapsulation techniques have been employed to create long-acting injection products with controlled drug release, reducing systemic toxicity and achieving therapeutic drug concentrations in specific regions[112]. Liposomes, known for their versatility in encapsulating hydrophilic and lipophilic drugs, have been valuable for targeted drug delivery to the brain through surface modifications[104]. Intranasal and transdermal liposomal formulations have demonstrated potential in improving drug bioavailability while reducing side effects[113] (Figure 4).

6.2. Focused Ultrasound: Pioneering Non-Invasive Solutions for Neurological Disorders

In recent years, focused ultrasound (FUS) therapies have emerged as transformative modalities in the management of neurological disorders[114]. This non-invasive technique involves the precise application of focused acoustic energy (ultrasound) to specific regions of the brain. Guided by magnetic resonance imaging (MR), MR-guided FUS (MRgFUS) has enabled computer-calibrated targeting, ensuring a high degree of accuracy and real-time feedback on treatment effectiveness[115] (Figure 5).
Initial investigations into MRgFUS thalamotomy for essential tremor yielded encouraging results, with a marked reduction in hand tremors observed [116]. In the context of Parkinson's disease (PD), MRgFUS is being explored as a non-invasive means of ablating brain areas responsible for the disease's motor symptoms[117]. Notably, the application of MRgFUS to the pallidothalamic tract in PD patients in 2014 resulted in significant clinical improvements [118]. Subsequent studies targeting the ventral intermediate thalamic nuclei (Vim) reported noteworthy reductions in mean UPDRS scores post-procedure in PD patients [119]. In a recent pilot study, MRgFUS unilateral subthalamotomy was found to be well-tolerated and effective in improving motor symptoms in noticeably asymmetric PD patients [120].
Several critical questions remain unanswered, including the optimal target for treating PD symptoms and the potential need for individualized target selection[121]. Additionally, long-term durability of FUS ablation outcomes and the safety and feasibility of bilateral procedures require further investigation[122]. The non-invasive nature of this approach, coupled with its immediate and seemingly enduring clinical benefits, renders it a compelling option for individuals who may be unsuitable or averse to deep brain stimulation (DBS) therapy[123]. To solidify the preliminary findings and evaluate the potential utility of ablative FUS therapy in treating PD patients, rigorous large-scale randomized controlled trials are imperative[124]. Furthermore, ongoing research explores other FUS applications, such as opening the blood-brain barrier (BBB) and neuromodulation [125].Notably, low-intensity ultrasound has demonstrated the ability to reduce α-synuclein levels in PC12 cells [116]. Recent advancements combining MRgFUS with intravenous microbubbles and a shRNA sequence targeting α-synuclein have resulted in reduced α-synuclein immunoreactivity in various brain regions, offering promise for altering the progression of Lewy body pathology, particularly in conjunction with early disease diagnosis [126]. In summary, FUS technology presents a compelling frontier in the treatment of neurological disorders, with particular promise in the management of Parkinson's disease. Further research and clinical validation are essential to unlock its full potential for improving patient outcomes and altering the course of neurodegenerative diseases.

6.3. Advancements in Deep Brain Stimulation (DBS) for Parkinson's Disease

In recent years, device-aided therapies have evolved to become indispensable tools in the treatment of advanced Parkinson's disease (PD) patients[127]. These therapies, including levodopa–carbidopa infusion gel (LCIG), subcutaneous apomorphine pump infusion, and deep brain stimulation (DBS), have undergone rigorous scrutiny in large prospective clinical studies, establishing their safety, validity, and remarkable efficacy [128].
DBS, in particular, stands out as a transformative surgical approach that entails the precise implantation of one or more electrodes into specific regions of the brain[87]. Over the years, a substantial body of evidence has consistently demonstrated the effectiveness of DBS in addressing motor fluctuations, reducing dyskinesia, and significantly enhancing the overall quality of life in advanced PD patients, whether the target is the subthalamic nucleus (STN) or the globus pallidus internus (GPi) [129]. What is particularly noteworthy is the enduring nature of these benefits, with positive outcomes persisting for more than a decade [130]. Even in patients with a relatively shorter disease duration, DBS has showcased its superiority over best medical treatment regimens in terms of motor improvement and quality of life [131].
The landscape of deep brain stimulation has witnessed a remarkable evolution driven by innovations in neurosurgical techniques, including the advent of asleep surgery[132]. Further, specialized devices such as microelectrodes have enabled more precise and targeted electrode placements[128]. The refinement of programming and stimulation algorithms has also played a pivotal role in optimizing patient outcomes[87]. A milestone achievement in this progress is the introduction of directional electrodes, heralding a new era in DBS[131]. These electrodes allow for segmented stimulation, significantly enhancing precision in therapeutic targeting. Directional electrodes hold the promise of minimizing adverse effects commonly associated with conventional DBS approaches [130] (Figure 6).
To further elevate the management of motor fluctuations and minimize the adverse effects of DBS, researchers and clinicians are increasingly turning to adaptive DBS (aDBS)[128]. This innovative approach aims to personalize stimulation by continuously monitoring local field potentials (LFP) directly from the stimulating electrode. aDBS activates stimulation only when LFP beta power surpasses a customized threshold, providing real-time modulation of stimulation parameters[87]. Preliminary findings are promising, indicating that aDBS surpasses conventional DBS in terms of improving motor scores and effectively controlling levodopa-induced dyskinesias[132]. However, to firmly establish the sustained benefit and efficacy of this groundbreaking strategy, more extensive research encompassing longer timeframes and larger patient cohorts is indispensable [87].
In summary, the remarkable progress in deep brain stimulation represents a beacon of hope for individuals battling Parkinson's disease. As we delve deeper into the realm of personalized and responsive treatment modalities, the future of DBS holds the potential to further enhance the lives of PD patients and transform the landscape of neurological healthcare.

7. Conclusion

In the foreseeable future, the aging population in developed nations will inevitably amplify the burden of neurodegenerative diseases. Parkinson's Disease (PD) poses a unique challenge as its treatment demands a personalized approach, striking a delicate balance between symptom management, drug dosage, side effect mitigation, and patient expectations. This presents clinicians and researchers with an urgent call for a symbiotic relationship between medicine and research. Two centuries have elapsed since the publication of James Parkinson's seminal essay, during which our comprehension of this disease has undergone remarkable progress, continually forging new tools and avenues for exploration. Presently, fields such as functional genetics, novel molecular mechanisms, brain imaging, and biomarker detection stand as the guiding lights in our research strategies. Nevertheless, despite the substantial headway made, the quest for an improved early clinical diagnosis and a definitive cure remains unfulfilled. In this context, research into drug delivery mechanisms emerges as a beacon of hope, potentially offering safer and more efficacious treatments for PD. Years of investigation have underscored the importance of considering environmental factors alongside genetics when scrutinizing the progression of PD. However, there is an imperative need for further research to unravel the intricate mechanisms by which this pathology propagates from cell to cell within the brain and from other organs to the central nervous system. Crucially, studies should also be directed towards the development of early diagnostic tools and a deeper understanding of the distinct susceptibilities of pathogenic factors affecting dopaminergic neurons. PD is entangled with a complex web of pathophysiological processes encompassing α-synuclein aggregation, neuroinflammation, mitochondrial dysfunction, neuronal vulnerability, iron deposition, and neural network alterations. Given the interplay among these multifaceted pathways and the clinical diversity observed, a targeted therapeutic approach becomes imperative.Although current treatment options offer symptomatic relief, advances in high-throughput screening methods for small molecules, improved disease modeling, and progress in analytical technologies promise to usher in novel compounds and repurposed drugs. Immunotherapies hold the potential to stimulate the body's response to α-synuclein, introducing a novel mechanism of action. Within the realm of cell-based therapies, insights gained from research have illuminated the path forward, with some induced pluripotent stem cell (iPSC) therapies offering the prospect of personalized treatment.
Furthermore, the advent of adaptive Deep Brain Stimulation (DBS) and optogenetically inspired DBS opens doors to more precise targeting. Collectively, these advancements underscore a promising future for PD therapies. As we stand at the nexus of innovation and discovery, it is imperative that we harness these breakthroughs to alleviate the suffering caused by Parkinson's Disease and strive toward a future where its treatment and prevention are not just aspirations, but realities.

Author Contributions

AAM contributed to the writing and revision of the manuscript. IH prepared the review, conducting editing tasks, and overseeing the project's progress and KM contributed to the project by assisting with data visualization.

Funding

This research receives no external funding

Conflicts of Interest

The authors affirm that the research was conducted independently, without any commercial or financial affiliations that might pose a potential conflict of interest.

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Figure 1. Charting the Evolution: Milestones in Parkinson's Disease Research from 1800 to Present. Adopted and modified from [1].
Figure 1. Charting the Evolution: Milestones in Parkinson's Disease Research from 1800 to Present. Adopted and modified from [1].
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Figure 2. Navigating the Spectrum: Illustrating Motor and Non-Motor Symptoms of Parkinson's Disease.
Figure 2. Navigating the Spectrum: Illustrating Motor and Non-Motor Symptoms of Parkinson's Disease.
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Figure 3. Comprehensive Overview: Summarizing Assessment Techniques for Parkinson's Disease (PD).
Figure 3. Comprehensive Overview: Summarizing Assessment Techniques for Parkinson's Disease (PD).
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Figure 4. Exploring the Frontier: Investigating Drug Delivery Systems for Advancing Parkinson's Disease Treatment.
Figure 4. Exploring the Frontier: Investigating Drug Delivery Systems for Advancing Parkinson's Disease Treatment.
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Figure 5. Comparing Basal Ganglia Circuits: Normal, PD-Affected, and Theoretical Modulation via Focused Ultrasound STN Stimulation. Colors indicate excitatory (green) and inhibitory (red) pathways. Line thickness and style denote signaling strength. Red cross marks SNpc neuron degeneration, while the yellow star highlights STN stimulation. Abbreviations: GPi = globus pallidus internus; GPe = globus pallidus externus; SNpc = substantia nigra pars compacta; SNpr = substantia nigra pars reticulata; STN = subthalamic nucleus.
Figure 5. Comparing Basal Ganglia Circuits: Normal, PD-Affected, and Theoretical Modulation via Focused Ultrasound STN Stimulation. Colors indicate excitatory (green) and inhibitory (red) pathways. Line thickness and style denote signaling strength. Red cross marks SNpc neuron degeneration, while the yellow star highlights STN stimulation. Abbreviations: GPi = globus pallidus internus; GPe = globus pallidus externus; SNpc = substantia nigra pars compacta; SNpr = substantia nigra pars reticulata; STN = subthalamic nucleus.
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Figure 6. Beyond Deep Brain Stimulation: Emerging Interest in Non-Invasive and Optogenetic Stimulation Modalities for Parkinson's Disease. Non-invasive electrical stimulation, achieved through temporal interference of electric fields, offers localized stimulation. Optogenetic stimulation involves delivering opsins to specific neurons, enabling light-sensitive channel expression for direct light-based stimulation. Alternatively, certain brain-delivered nanoparticles can convert extracranial infrared light to visible light, facilitating non-invasive optogenetic neuron stimulation. While electrical stimulation tends to be non-specific, optogenetic approaches hold promise for precise neuron targeting. Figure adopted from [2].
Figure 6. Beyond Deep Brain Stimulation: Emerging Interest in Non-Invasive and Optogenetic Stimulation Modalities for Parkinson's Disease. Non-invasive electrical stimulation, achieved through temporal interference of electric fields, offers localized stimulation. Optogenetic stimulation involves delivering opsins to specific neurons, enabling light-sensitive channel expression for direct light-based stimulation. Alternatively, certain brain-delivered nanoparticles can convert extracranial infrared light to visible light, facilitating non-invasive optogenetic neuron stimulation. While electrical stimulation tends to be non-specific, optogenetic approaches hold promise for precise neuron targeting. Figure adopted from [2].
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Table 1. List of genes reported to be linked with Parkinson disease. Data for PD genes adopted from [76].
Table 1. List of genes reported to be linked with Parkinson disease. Data for PD genes adopted from [76].
GENE Year of Discovery Reported Variants Frequency Inheritance Confidence as a PD Gene
SNCA * 1997, 2003 Missense or multiplication Very rare Dominant Very high
PRKN * 1998 Missense or loss of function Rare Recessive Very high
UCHL1 1998 Missense Unclear Dominant Low
PARK7 * 2003 Missense Very rare Recessive Very high
LRRK2 * 2004 Missense Common Dominant Very high
PINK1 * 2004 Missense or loss of function Rare Recessive Very high
POLG 2004 Missense or loss of function Rare Dominant High
HTRA2 2005 Missense Unclear Dominant Low
ATP13A2 * 2006 Missense or loss of function Very rare Recessive Very high
FBXO7 * 2008 Missense Very rare Recessive Very high
GIGYF2 2008 Missense Unclear Dominant Low
GBA * 2009 Missense or loss of function Common Dominant (incomplete penetrance) Very high
PLA2G6 * 2009 Missense or loss of function Rare Recessive Very high
EIF4G1 2011 Missense Unclear Dominant Low
VPS35 * 2011 Missense Very rare Dominant Very high
DNAJC6 2012 Missense or loss of function Very rare Recessive High
SYNJ1 2013 Missense or loss of function Very rare Recessive High
DNAJC13 2014 Missense Unclear Dominant Low
TMEM230 2016 Missense Unclear Dominant Low
VPS13C 2016 Missense or loss of function Rare Recessive High
LRP10 2018 Missense or loss of function Unclear Dominant Low
NUS1 2018 Missense Unclear Recessive Low
COL6A3 2022 Missense Rare Dominant High
TH 2022 Missense Unclear Dominant High
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Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
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