There are over 10 million Parkinson’s disease patients worldwide, accounting for 1–3% of the global population aged 60 and above [59]. Half of those aged 85 and above develop Parkinson’s disease [60]. The evolution of symptomatic therapies for Parkinson’s disease, including dopamine agonists as well as L-DOPA, has been remarkable [61]. However, a fundamental treatment for Parkinson’s disease has yet to be developed. Initiating treatment after onset does not lead to a favorable prognosis. At the onset of Parkinson’s disease, the pathogenic proteins have already accumulated in the brain, and this pathology of dopaminergic neuronal loss induces clinical symptoms. Therefore, there is an expectation for the establishment of methods to predict the onset early.

Parkinson’s disease was first diagnosed by James Parkinson in 1817, detailing its clinical features as tremor, rigidity, bradykinesia, gait disturbances, and postural instability [62]. Cognitive symptoms commonly emerge in the advanced stages of the disease [63]. Approximately 20–40% of all Parkinson’s cases develop Parkinson’s disease dementia, with an average progression time of 10 years. In total, 40% of Parkinson’s patients with severe olfactory dysfunction progress to dementia [64,65]. In this regard, the importance of the olfactory bulb as an entry site for prion-like transmission in neurodegenerative diseases is suggested [66]. Pathologically, Parkinson’s disease is characterized by the loss of dopamine-biosynthesizing neurons in the substantia nigra pars compacta. It is also denoted by the abnormal deposition of the pathogenic protein α-synuclein in the cell body and neuronal processes, forming Lewy bodies and Lewy neurites, respectively [67,68,69]. Parkinson’s disease, Parkinson’s disease dementia, and dementia with Lewy bodies share the accumulation and aggregation of the pathogenic protein α-synuclein within neurons, leading to the formation of Lewy bodies. Therefore, these Lewy body diseases are believed to share common pathological mechanisms.

The decline in motor function observed in Parkinson’s disease arises due to impaired nigrostriatal dopaminergic function [70]. Nigrostriatal dopaminergic projections centrally regulate voluntary movements, and their degeneration contributes to Parkinsonian clinical symptoms. In addition, the dopaminergic system, originating in the substantia nigra pars compacta and the ventral tegmental area, predominantly projecting to the striatum and prefrontal context, significantly influences behavioral activities [71,72,73]. Consequently, lesions in nigral neurons cause concurrent dysfunction of agonist and antagonist muscle pairs in animal models of Parkinsonism [74] and sporadic Parkinson’s disease [75]. The dopaminergic function is regulated by the neurotransmitter dopamine. This catecholamine is biosynthesized from L-tyrosine by the rate-limiting enzyme tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC) [76]. TH requires tetrahydrobiopterin, which is biosynthesized by GTP cyclohydrolase I (GTPCH1), to perform its enzymatic activity [77,78]. Because the enzymatic activity of TH protein strictly controls the rate-limiting step of dopamine biosynthesis [79], unlike those of other dopamine biosynthesizing enzymes, the expression level and activity of TH, which is precisely regulated via phosphorylation, directly affect intracellular dopamine amount.

As previously mentioned, the presence of FABPs is closely related to the maintenance of dopaminergic homeostasis and mitochondrial function in neurodegeneration. FABP3 and FABP5 are essential for the neurotoxicity expression of α-synuclein. Considering the potential for drug development targeting FABP3, researchers observed the absence of α-synuclein neurotoxicity in genetic knockout cells of FABP3. It was found that FABP3 can bind to α-synuclein in a 1:1 ratio, promoting α-synuclein-FABP3 aggregate formation [115]. Consequently, researchers attempted to create a drug that could inhibit the interaction between FABP3 and α-synuclein [126,142].

The FABP3 ligand, as a targeted drug for FABP3, inhibits α-synuclein aggregation and prevents its propagation in the brain and subsequent neuronal loss [106]. The FABP3 ligand effectively prevents the degeneration of dopaminergic neurons and restores motor dysfunction to a healthy level in a Parkinson’s disease mouse model [126]. Additionally, an α-synuclein mimicking peptide that inhibits the binding and aggregate formation of α-synuclein-FABP3 is capable of restoring memory and learning abilities in a Parkinson’s disease dementia mouse model [142]. This peptide has the potential to alleviate α-synuclein phosphorylation, which links to neurotoxicity. Researchers are currently conducting preclinical trials of small molecules targeting FABP3 (Japan Agency for Medical Research and Development (AMED), Translational Research Program 23ym0126095h0002). 

With regard to FABP5, the specific ligand for FABP5 abolishes α-synuclein accumulation and translocation to mitochondria, which alleviates neurotoxicity in Parkinson’s disease model neuronal cells [129], as well as ameliorates oligodendrocyte injury in multiple sclerosis mouse models [131] and psychosine-induced apoptosis in Krabbe disease models [130]. Furthermore, the FABP5 ligand also has the ability to ameliorate FABP3/5-induced mitochondrial injury, including lipid peroxidation and BAX-related apoptotic signaling, indicating the potential neuroprotective treatment for ischemic stroke [132,133]. In addition, regarding FABP7, the ligand alleviates FABP7-induced α-synuclein oligomerization and aggregation, thereby rescuing glial and oligodendrocytes from cell death in multiple system atrophy model cells and mice [140,141,143]. These data suggest the promising potential of unique drug developments targeting FABP to regulate dopaminergic signaling and protect neuronal homeostasis.

In recent years, there has been remarkable progress in targeted therapy for Parkinson’s disease, allowing for the precise alleviation of clinical symptoms [144,145]. However, challenges remain that affect the quality of life for patients, including subcutaneous device attachment, reduced medication efficacy due to disease progression, and the presence of OFF symptoms. In neurodegenerative diseases, post-onset treatment does not yield favorable prognoses, making fundamental treatment challenging. To overcome Parkinson’s disease, it is necessary to predict disease risk before onset and achieve early therapeutic interventions. Numerous excellent studies have been reported on diagnostic techniques for Parkinson’s disease using analyses of cerebrospinal fluid (CSF), serum, and plasma biomarkers targeting α-synuclein and other related proteins [146,147,148,149]. Additionally, recent studies have demonstrated that severe olfactory impairment is a useful early biomarker for Parkinson’s disease dementia [64,65,150,151,152].

Previously, certain reports have suggested methods to predict Parkinson’s disease using FABP3 as a biomarker in the cerebrospinal fluid or serum [2,32,153,154,155,156,157,158]. These investigations spotlight the pathogenic significance of the cerebrospinal fluid and serum FABP3 levels, indicating characteristic modifications in Parkinson’s disease, Parkinson’s disease dementia, and dementia with Lewy bodies. Elevated FABP3 levels are invariably observed in cerebrospinal fluid and serum specimens from patients with these disorders. Notably, higher FABP3 levels are observed in patients with dementia with Lewy bodies than in Parkinson’s disease dementia and Alzheimer’s disease, indicating the potential of FABP3 as a biomarker distinctive to dementia with Lewy bodies.

Therefore, with the aim of establishing a more accurate technique using plasma biomarkers to predict disease risk and discriminate potential disease types, researchers recently focused on FABP family proteins, essential for the propagation and expression of α-synuclein neurotoxicity, and developed a differential diagnostic technique for neurodegenerative disorders through a multi-marker analysis in combination with known biomarkers [31]. This method not only allows the discrimination between healthy individuals and those with Parkinson’s disease but also enables the prediction of Lewy body dementia, Alzheimer’s disease, and mild cognitive impairment. Specifically, researchers established a scoring technique that can differentiate Parkinson’s disease, Lewy body dementia, and Alzheimer’s disease from healthy individuals and also can distinguish between different neurodegenerative diseases (Figure 4) [31]. These multi-marker disease risk scores correlate with clinical symptoms in each disease, specifically mini-mental state examination (MMSE) scores and Hoehn–Yahr stages in Parkinson’s disease. The researchers hope that this technology will contribute to the differentiation of clinically challenging conditions such as Parkinson’s disease dementia, Lewy body dementia, and Alzheimer’s disease in clinical settings.

In addition to ELISA analysis, metabolomics is a useful tool for measuring biomarkers [159,160]. ELISA analysis of plasma can measure the amount of a specific protein. This method is considered very accurate and reliable when the protein to be measured is known. Therefore, understanding the pathogenetic significance of the target proteins is essential. In contrast, metabolomics analysis, on the other hand, provides a comprehensive measurement of metabolites in vivo. The advantage of this method is that measurement is possible even if the metabolite to be measured is unknown. In this respect, compared to ELISA analysis, it may require more advanced techniques to account for measurement accuracy. Previous metabolomics studies successfully revealed lipid dysregulation in Parkinson’s disease [161,162]. Through utilizing the advantages of both of these approaches and establishing more accurate and highly specific biomarker predictions, it would be possible to produce a very early diagnosis of Parkinson’s disease before its onset.