Future Prospects in Parkinson’s Disease Diagnosis and Treatment

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease with a rapidly increasing incidence and prevalence. Although it affects more than 6 million people worldwide, it is predicted to be doubled by 2040. Current criteria used in the diagnosis of PD include the presence of bradykinesia as well as the presence of rest tremor and/or rigidity, but the clinic is multifaceted and includes many non-motor symptoms. Non-motor symptoms may occur in the prodromal period, years before clinically evident Parkinson’s disease. During this period, diagnosing the disease will likely be even more important when disease-modifying treatments are available. Currently, there is no single biomarker that can be used in the diagnosis of PD and no disease-modifying treatment is available. Identification of biomarkers in early diagnosis will enable the most effective use of disease-modifying therapies and will shed light on possible underlying pathologies, studies in this area have gained momentum in recent years. Molecular imaging methods, genetic studies, salivary gland and skin biopsies, metabolomics, lysosomal pathway are some of them. In this article, besides the current diagnosis and treatment methods of the disease, biomarkers and treatments that are expected to be better understood in the near future will be mentioned.

INTRODUCTION

Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by the degeneration of dopaminergic neurons in the substansia nigra pars compacta. PD progresses with motor symptoms such as resting tremor, bradykinesia, rigidity, and postural instability. Non-motor symptoms are also common and may occur years before the onset of the disease (1,2). PD has a heterogeneous pathogenesis, and although years have passed since its definition, there is still no disease-modifying treatment (3). Numerous protein and molecular pathways are involved in its pathophysiology. The most important marker of these is alpha-synuclein (αS) (4). A better understanding of (αS) accumulation and other underlying pathological mechanisms has brought new approaches to diagnosis and treatment. In this article, we will discuss biomarkers under active research that can be used in the diagnosis of PD, current treatment targets, and recent approaches, including active and passive immunization studies at preclinical and clinical stages.

New Findings on Parkinson’s Disease Pathology

Salivary glands and pharynx biopsy

Autopsy studies on PD have shown that the salivary glands have relatively high concentrations of aS aggregates. Based on this, Lewy bodies (LBs) were investigated in samples taken from minor salivary glands and submandibular salivary glands. In samples taken from the minor salivary gland, LBs was observed in all cases in the PD group, but not in the control group (5). In samples taken from the submandibular salivary gland, LBs was detected in 75% of PD. Since dysphagia is one of the symptoms leading to serious complications in PD, pharyngeal autopsy studies have been performed and phosphorylated-alphasynuclein (P-αS) aggregates have been demonstrated in the sensory nerve axons of the pharynx. It seems to be a suitable method because it is minimally invasive and reproducible (6).

Highlights

• Using a biomarker panel containing alpha-synuclein (αS) rather than a single biomarker will increase sensivity in diagnosis.

• Detection of phosphorylated-alphasynuclein (P-αS) in skin biopsy is very sensitive in the diagnosis of Parkinson’s disease.

• SNCA, GBA and LRRK2 mutations are prominent in gene-targeted therapy strategies.

• Active immunization Phase I studies have yielded succussful results, while passive immunization is in Phase II.

Skin biopsy

One of the most promising biomarkers. P-αS accumulations in epidermal and dermal nerve fibers were examined in punch biopsy taken from the skin. In idiopathic PD (IPD), skin biopsies were taken from the cervical paravertebral region, thigh, and distal leg. While P-αS was observed in all samples taken from the cervical region, this rate was found to be 52% and 24% in the thigh and leg, respectively, and it was concluded that P-αS accumulation is a sensitive biomarker in the proximal skin nerve fibers. P-αS accumulation was not observed in the control group and in Parkinson’s patients with other pathologies (7). Studies have suggested that P-αS detection in cutaneous nerve fibers may support the diagnosis of synucleinopathy, and that detection of P-αS in sympathetic nerve fibers is valuable in differentiating PD from MSA since it is not seen in postganglionic sympathetic skin nerve fibers in MSA. Detection of proximal P-αS accumulation in IPD also showed the possibility of antidromic spread (8). Skin biopsy is an easy-to-apply and minimally invasive method, making it a suitable method to use in clinical practice.

Imaging Methods in Parkinson’s Disease

Imaging methods are important in increasing the accuracy of differential diagnosis in patients with parkinsonism and are one of the most developing areas. Magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) are some of these methods.

Structural MRI

Structural imaging techniques, computed tomography and MRI, are insufficient to identify dopaminergic deficits in PD. However, it is useful in identifying structural lesions that cause parkinsonism and distinguishing it from other atypical forms (9). In recent years, studies with 3-Tesla MRI SWI (susceptibility-weighted imaging) sequence in IPD have attracted attention. Swallow tail sign finding in the substantia nigra was showed on SWI sections. This finding showed over 94% sensitivity and specificity in differentiating IPD from healthy controls. However, since this finding has been shown in many neurodegenerative diseases, it was thought that it is not a reliable biomarker for PD on its own (10).

Functional MRI

Functional MRI provides the evaluation of functional connections in the brain while at rest or active. While a decrease was observed in the striatum, supplementary motor area, occipital cortex and middle frontal gyrus, an increase was observed in the thalamus, cerebellum and superior parietal lobe in PD (sensitivity 91%, specificity 89%). This method helps to distinguish PD from healthy controls and to determine the level of disease (11).

Molecular imaging

Significant decreases in vesicular monoamine transporter type-2, dopamine transporter (DAT), and L-aromatic amino acid decarboxylase were observed in presynaptic dopaminergic function imaging with PET and SPECT in PD (12). Signal loss is usually asymmetrical and clinically evident in the putamen contralateral to the affected side. All DaTSCANTM studies showed high sensitivity and specificity in differentiating PD from its forms such as essential tremor, vascular and drug-induced parkinsonism (13,14). However, it is not effective in differentiating PD from other atypical parkinsonism syndromes. This distinction can be facilitated by the use of PET with postsynaptic dopaminergic ligands, but it is very expensive and available only in some specialized centers. Another pathognomonic feature of PD is impairment of the sympathetic nervous system, which can be detected by demonstrating a decrease in cardiac 123I-methaiodobenzylguanidine (123I-mIBG) SPECT uptake. This can be used to differentiate PD and atypical forms (15). The data obtained from studies performed with 18F-fludeoxyglucose (18F-FDG) PET imaging showed certain metabolic patterns and was also found to be useful in differentiating PD from other atypical forms (16). Given that the mechanisms underlying neurodegeneration and loss of dopaminergic signalling in PD are still unclear, recent studies with PET have focused on new potential targets. One of them is phosphodiesterase 10A (PDE10A), which may play a key role in cAMP and cGMP signalling cascades in basal ganglia. PDE10A in the caudate, putamen and globus pallidus was lower in PD compared to healthy controls. These findings support the hypothesis that PDE10A may be a new treatment target in alleviating the symptoms of PD (17).

Transcranial sonography (TS)

The echogenicity of the substantia nigra (SN) is widely investigated in PD. Although the exact etiology is unknown, hyperechogenicity is observed, possibly due to iron deposition secondary to nigral pathology. TS helps to distinguish PD from other atypical forms when performed by experienced hands, but SN hyperechogenicity is observed also in PSP, CBD, and LBD to varying degrees (18).

Biomarkers in Parkinson’s Disease

Although the diagnosis of PD is mainly based on clinical features, significant progress has been made in biomarker studies in recent years. One reason for this is that the rate of misdiagnosis is around 20% due to clinical overlap with other parkinsonism etiologies, and another reason is that there is still no disease-modifying treatment despite the advances in its pathology. The development of biomarkers is important as it will provide objective evidence in following the progression of the disease and monitoring the response to treatment, as well as early and accurate diagnosis. Biomarkers have been studied mostly in CSF as they better reflect the ongoing pathological process. Studies have allowed us to better understand the molecular and biological processes that occur in the brain (19).

Alpha-synuclein (aS)

Great attention has been paid to studies of αS as a promising biomarker. Although it has been shown that total-αS (T-αS) levels in CSF in PD are lower than in the control group, it is still not satisfactory to distinguish PD from the control group due to its sensitivity and specificity (78-88% and 40-57%) (20). Since T-αS alone was found to be low in other atypical Parkinson’s syndromes, it was not found to be supportive in the differential diagnosis. P-αS levels were found to be increased in PD compared to the control group. In order to increase the diagnostic accuracy, the ratio of oligomeric-aS (O-αS) and O-αS/T-αS in CSF was investigated and it was found to be high in PD (21). In recent years, two ultrasensitive protein amplification techniques; protein misfolding cyclic amplification (PMCA) and real-time quacking-induced conversion (RT-QuIC) have been introduced. These techniques provided high diagnostic accuracy in detecting misfolded αS and its aggregates, and distinguishing PD from the control group (22).

Amyloid-beta (Aβ) and tau protein

Amyloid plaques and tau-containing neurofibrillary tangles can be seen in PD. Aβ and tau protein can interact with αS and can increase mutual accumulation of each other and contribute to cognitive effects (23). A decrease in CSF Aβ₄₂ levels can be seen in PD, but it is not sufficient on its own for diagnosis. The role of tau species in PD is not clear yet. In different studies, total-tau and phosphorylated-tau levels in PD differed considerably (19).

Neurofilament light chain (NfL)

NfL arises following axonal damage and membrane disruption and is released into the interstitial space. It has been studied in neurodegeneration because of reflecting axonal damage (24). In MSA and PSP, higher levels were detected in CSF compared to PD, which is consistent with aggressive neurodegeneration (25). Another study showed that CSF NfL levels were higher in Parkinson’s patients with cognitive impairment than in those without. Since NfL levels correlate with age, the lack of age-specific reference values is an obstacle to distinguishing PD from elderly controls (26).

Lysosomal biomarkers

The autophagy-lysosomal pathway is an important pathway in preventing the intracellular accumulation of damaged proteins. Mutations in the GBA gene cause a decrease in the activity of the glucocerebrosidase enzyme (GCase), which is involved in this pathway, and an increase in toxic O-α-S levels. GCase activity in CSF was significantly decreased in PD and LBD compared to the control group (27). CSF GCase activity was found to be lower in PD carrying a GBA mutation compared to sporadic PD. In some studies, CSF GCase activity was found to be low in PD independent of GBA mutations. This is partly due to the effect of aging. Apart from GBA, there are many genes associated with the lysosomal pathway in PD, and many candidate lysosomal metabolism markers have been investigated. β-hexosaminidase and β-galactosidase are some of these, and their levels were found to be lower in sporadic PD and PD with GBA mutations compared to controls (28,29). In addition, an increase was observed in the levels of GCase products, ceramides, in PD and LBD, and it was determined that ceramides also mediated αS aggregation. When GCase activity was combined with the O-α-S /T-α-S ratio, it was found to be successful in differentiating PD from the control group (30).

Inflammatory biomarkers

Immune system components in CSF have been investigated as biomarkers in PD. A shift from classical monocytes (CD14+/CD16-) to non-classical monocytes (CD14+/CD16+) has been observed in PD. Two indicators are promising in this area. These are monocyte chemoattractant protein-1 (MCP-1) and chitinase-3-like protein-1 (YKL-40). Increased CSF MCP-1 levels were observed in PD and MSA compared to controls. Although these markers are diagnostically inadequate, they have been correlated with motor progression in PD. YKL-40 was found to be associated with cognitive impairment in PD and showed inconsistent results in PD, atypical parkinsonism, and control groups (31). Another inflammatory marker, C-reactive protein, was found to be high in CSF in PD and atypical parkinsonism syndromes and correlated with the severity of motor symptoms and non-motor symptoms in these patients. Although many inflammatory markers have been studied in PD, it could not reach statistical significance due to its limited effect on its own (19).

Metabolomics

Metabolomics has attracted attention in recent years and many new metabolic pathways have been described in the pathogenesis of PD. Altered metabolic profiles have been demonstrated in PD and atypical Parkinson’s syndromes. In different studies, 14 CSF metabolites have been identified to distinguish PD from controls with high accuracy (32). CSF dehydroascorbic acid, fructose, mannose and threonic acid, proline, and homovanillic acid levels are some of these parameters studied and showed varying results. This showed us the complexity of multiple metabolic pathways involved in the pathogenesis of PD (19).

Genetic perspective

Understanding the genetic basis of PD has provided fundamental insights into the pathogenesis of PD and has led to the development of gene-targeted therapy strategies. Genetic PD includes autosomal dominant (SNCA, LRKK2), and autosomal recessive forms (parkin, PINK1, and DJ-1) and GBA, the most common genetic risk factor. In addition to mutations, transcriptional or post-transcriptional gene products in CSF can be used as markers reflecting underlying pathophysiological processes in PD. aS encoded by SNCA and GCase encoded by GBA are among these markers (33).

LRKK2 encodes a multifunctional protein containing a kinase domain and plays a role in cytoskeletal structure, mitochondrial function and autophagy. LRKK2 inhibition has been proposed as an effective therapeutic strategy, as many of the pathogenic variants increase kinase activity. LRKK2 was first detected in exosomes derived from CSF. CSF levels were found to be much higher when compared to other body fluids (34). However, when PD with LRKK2 mutation, PD without LRKK2 mutation or controls were compared, no significant difference was observed in CSF levels (35).

Studies on CSF levels of PINK1, Parkin and DJ-1, which play a role in mitochondrial function, have shown inconsistent results. CSF levels of circulating cell-mitochondrial DNA (ccf-mtDNA) released from cells in response to oxidative stress were also found to be paradoxically low. Again, in different studies with microRNAs (miRNA), significant miRNAs were found in the CSF that can be used in the differential diagnosis of PD. However, due to the inconsistencies between miRNA studies and the lack of methodological approach and reproducibility, their use seems to be difficult for now (19).

Treatment Approaches in PD

Currently, treatment of PD is aimed only at relieving related motor symptoms and it does not prevent progression. A disease-modifying approach is an important unmet area in the treatment of PD. To this end, new therapeutic targets are being investigated. Current treatments include dopamine precursors and dopamine agonists, as well as drugs that increase dopamine release using monoamine oxidase-B (MAO-B) and catechol-O-methyl-transferase (COMT) inhibitors (36). These drugs provide significant improvement in motor symptoms, especially in the early stages, but become insufficient over time (37). Glutamate antagonists and anticholinergics are other agents used in symptomatic treatment (36). Some of these are device-assisted therapies that include subcutaneous injection of apomorphine and levodopa-carbidopa intestinal gel, providing continuous dopaminergic stimulation. Surgical options are high-frequency deep brain stimulation (DBS) or lesion surgery interventions. Direct lesion surgery with magnetic resonance focused ultrasound at high frequencies is a new FDA-approved lesion technique and is very effective against tremor (38). In recent years, reorganization according to feedback signals with adaptive DBS has received great attention. Adaptive DBS is a responsive system that can detect physiological signals, automatically adjust stimulation, limit adverse effects and reduce battery cost, and includes adaptive closed-loop modes. By automatically measuring the activity in dynamic tissue, it adjusts the stimulation voltage and allows individualization of DBS treatment. While exciting, it is still at an early stage and the efficacy and side-effect profiles in patients are not clear. Developments expected from DBS systems in the near future are improvements in electrode and implanted pulse generator design, miniaturization and cranialization, rechargeable batteries, compatibility with wireless networks, and longer battery life (39).

Sublingual apomorphine

It is a thin strip film form of apomorphine placed under the tongue. Studies have shown that it acts as quickly as injection and is superior to injection in terms of ease of use. A phase III study investigating the safety and efficacy of the sublingual form of apomorphine has been completed. Although short-term studies have resulted in positive results, long-term studies are ongoing (40).

Accordion pill

It is another method developed to maintain a certain level of levodopa and to provide a continuous flow of levodopa. The drug is made into a multi-layered structure and placed in a capsule. The capsule dissolves in the stomach and the drug is released over time from the layers containing levodopa. In a Phase II study measuring pharmacokinetics and efficacy, compared with existing levodopa/carbidopa treatment, the therapeutic benefit increased by more than 2 hours in the group taking the accordion pill. A randomized controlled Phase III study is ongoing (41).

αS-targeted therapies

These treatments include inhibiting αS aggregation, reducing αS production, increasing αS degradation, and inhibiting extracellular αS uptake (Table 1). Although inhibiting the aggregation process of αS may reduce toxic effects, the toxic species of αS have not yet been identified, limiting the therapeutic efficacy of these approaches (42). The αS misfolding inhibitors NPT200-11 and NPT088 are two candidates currently undergoing clinical trials. In animal studies, NPT200-11 has been shown to reduce αS aggregation and neuroinflammation in the cortex (43). Another way is to use intrabody/nanobodies with high selectivity to targeted epitopes. They prevent oligomerization by interfering with the αS amyloid non-beta component (NAC) or C-terminal regions (44). VH14*PEST acts by binding directly to the NAC region (45). Another way is through RNA interference. It is aimed to reduce the endogenous αS expression by direct delivery of small inhibitory RNA (siRNA) to the striatum. Beta2-adrenoreceptor agonists (β2AR) also act by increasing the degradation of αS mRNA levels (46).

Table 1.

Ongoing studies targeting alpha-synuclein (αS)

Mechanism	Compound	Sponsor	Phase/current state	n (number of patients)	RCT number
Inhibition of αS aggregation	NPT200-11	Neuropore	Phase I completed	55	NCT02606682
Inhibition of αS aggregation	NPT-088	Proclara	Phase I completed	n/a	n/a
Inhibition of αS aggregation	Anle138b	n/a	Preclinical	-	n/a
Inhibition of αS aggregation	CLR01	n/a	Preclinical	-	n/a n/a
Inhibition of αS aggregation	PBT434	n/a	Phase I	70	n/a
Increasing αS degradation	Rapamisin	NYU Langone Health	Phase II active	56	NCT03589976
Increasing αS degradation	miRNA-101	n/a	Preclinical	-	n/a
Increasing αS degradation	TLR4-agonist MPLA	n/a	Preclinical	-	n/a
Nanobodies	VH14*PEST	n/a	Preclinical	-	n/a

αS: alfa-sinüklein; miRNA: microRNA; MPLA: monophosphoryl lipid A; TLR4: toll-like receptor.

Increasing αS degradation is an approach to reduce the αS level. Rapamycin is one of the most important drugs known to regulate the autophagic pathway. A decrease in aS aggregates and an improvement in motor functions were observed with rapamycin. Molecules such as trehalose that activate autophagy independently of the mTOR pathway have also been studied but have not been found to be effective (45). Anti-cancer drugs acting by inhibiting the Abelson murine leukemia virus oncogene (c-Abl) have physiological roles such as DNA repair and autophagy. Nilotinib is the most important c-Abl inhibitor studied so far. It has been shown to reduce αS expression and protect against αS toxicity in animal studies, but in the Phase II study, it was thought as not needing to be further studied due to low CSF transmission, no biomarker effect, and a tendency to worsen motor functions (47). The lymphocyte activation gene 3 (LAG3) receptor is a transmembrane protein and it regulates T cell-mediated immune reaction. As a result of the high-affinity binding of fibrillar αS to the LAG3 protein on the cell surface, it has been shown that pathological αS is taken up into neurons by endocytosis and causes structural and functional toxicity. Therefore, it was thought that LAG3 inhibition might be effective in reducing αS aggregation (48).

LRRK2 inhibitors

Leucine-rich repeat kinase 2 (LRRK2) is a serine/threonine kinase. Increased activity of LRRK2 has been found to mediate pathogenic phenotypes associated with PD. It has been reported that LRRK2 inhibition reduces the production of proinflammatory cytokines in microglia, improves neuroinflammation and prevents neuronal loss (49). To date, four types of LRRK2 inhibitors with different potencies have been identified. Of these, MLi-2 and PF-06685360 are potent third generation inhibitors with favorable pharmacological properties (36). DNL201 is a safe and well tolerated agent without significant side effects. Phase Ib research is ongoing for mild to moderate PD with and without LRRK2 mutation. Phase I study of another LRRK2 inhibitor, DNL151, has been completed and Phase Ib is ongoing (50).

Glucocerebrosidase (GCase) agonists

GCase is an enzyme that plays a role in lysosomal autophagy. Although the mechanisms by which GBA causes PD are not fully understood, it has been shown that decreased GCase activity results in αS accumulation, while high αS levels delay GCase function (27). Based on this, GCase enzyme activation was thought to have therapeutic potential. Isophagomine is one of the first GCase chaperones to undergo clinical trials in Gaucher, but its study was discontinued because it did not provide clinical improvement in PD. Ambroxol is a GCase chaperone used as a mucolytic drug and modulates αS levels by increasing GCase activity in the brain in patients with GBA mutations. Study results show that ambroxol treatment is safe and well tolerated (51). On the other hand, GCase enzyme activator LTI291 is a very new agent and it has been shown that the dose-dependent brain penetration of the drug, which is in the 1-month phase Ib trial, is good (52).

Adenosine receptor antagonists

A2AR antagonists are a group that can be effective both in symptomatic treatment and as neuroprotectives. They are indirectly effective and they provide improvement in motor movements. More than 25 studies have been conducted on A2AR antagonists. Of these, only istradefillin has been approved by the FDA for adjunctive therapy to reduce off periods. (36)

5-HT1A receptor agonists

Activation of 5-HT1A receptors has been shown to reduce dyskinesia in PD. Despite promising results in experimental studies, sarizotan, a 5-HT1A agonist, had a minor effect on dyskinesia compared to placebo in phase III studies (36).

Glucagon peptide 1 (GLP1) agonists

In preclinical studies, they were found to be effective on neurogenesis, neuroprotection and the prevention of nigrostriatal damage. Exenatidine is thought to be able to cross the blood-brain barrier and provide neuroprotective effects, however, ongoing studies (Phase III) suggest that it is symptomatic rather than disease-modifying. Liraglutide and lixinatide are other agents studied. (53)

Calcium channel blockers

Studies support the disease-modifying effect of calcium channel blockers in PD. Isradipine, a calcium channel blocker, was studied in the STEADY-PD III study. It has been observed that symptomatic drug needs are delayed in patients with early stage PD receiving isradipine and that they needed a lower drug dose at the end of the study. (54)

Immunotherapy in PD

Immunotherapy aims to create a neuroprotective state by altering the patient’s immune system and cerebral microenvironment. Continuing immunotherapy studies in PD are below (Table 2). Regulatory T cells (Treg) induced by GM-CSF have been found to reduce microglial inflammation and protect dopaminergic neurons (36). LBT-3627 has been shown to inhibit microinflammation in animal models, but there is no clinical study yet. The second strategy in immunotherapy in PD is passive and active immunotherapies. Antibodies that cannot enter the cell target the extracellular αS (55). In active immunization, two vaccines against αS, PD01A and PD03A, were found successful in preclinical studies. DNA-based vaccination techniques (pVAX1-IL-4/SYN-B) target pre-aggregation substrates but have been found to be ineffective in αS-based animal models. There are many agents studied in passive immunization. The first passive immunotherapeutic agent, PRX002/RG7935 (prasinezumab), was well tolerated in studies. BIIB054 (cinpanemab) is an IgG1 monoclonal antibody that binds to its N-terminal on αS and was found unsuccessful in phase II (SPARK) and terminated (36,56).

Table 2.

Ongoing clinical studies in immunotherapeutic approaches

Class	Agent	Target/effect mechanism	Clinical study code	Phase	Situation
Immunomodulator treatments	GM-CSF (sargramostim)	Increases Tregs	NCT03790670	Phase Ib	Ongoing
	LBT-3627	VIPR2 agonist	n/a	n/a	n/a
Active immunization	PD01A	Binding to the αS-C terminal	NCT02618941	Phase I	Completed
	PD03A		NCT02267434	Phase I	Completed
Passive immunization	Prasinezumab (PASADENA)	IgG1 monoclonal antibody targeting αS-C terminal epitopes	NCT04777331	Phase IIb	Ongoing
	Lu AF82422	IgG1 monoclonal antibody targeting the αS-C terminal	NCT03611569	Phase I	Completed

αS: alpha-synuclein; IgG1: Immunoglobulin G1; Treg: T regulatory cell; VIPR2: vasoactive intestinal peptide receptor 2.

CONCLUSION

Many important studies on the pathophysiology of PD have paved the way for the development of innovative drugs for the treatment of PD. Biomarkers emerging from the preclinical and prodromal phases have been the focus of these developments. CSF P-αS levels reflecting αS pathology, O-αS/T-αS ratio, CSF GCase activity, genetic biomarkers and data obtained from skin biopsy have been promising in this regard. Other biomarkers were not found to be significant on their own in the diagnosis, and the idea of using a biomarker panel rather than a single biomarker was born. At this point, αS should form the basis of this panel in light of the pathophysiological evidence. Although biomarkers can be used to monitor the disease, the need for repeated lumbar puncture and the invasiveness of the procedure limit their use. Another disadvantage is that there is no standardization in the applied techniques. Currently, there is no treatment option that can replace dopaminergic treatments used in PD. Current research has focused on preventing αS-induced neuron death, which is at the center of the pathology. Many new molecules and methods are currently being investigated. More successful results will be obtained when the genetic factors and effects that vary between individuals can be determined and the mechanism of onset and progression of the disease is better understood. In this context, neuroprotective treatment methods, which have been studied intensively in recent years, show promise in the treatment of PD.