Numerous attempts to develop an early diagnosis of Parkinson's disease (PD) by searching biomarkers in biological fluids were unsuccessful. The drawback of this methodology is searching markers in patients at the clinical stage without guarantee that they are also characteristic of either preclinical stage or prodromal stage (preclinical-prodromal stage). We attempted to upgrade this methodology by selecting only markers that are found both in patients and in PD animal models. HPLC and RT-PCR were used to estimate the concentration of amino acids, catecholamines/metabolites in plasma and gene expression in lymphocytes in 36 untreated early-stage PD patients and 52 controls, and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice at modeling the clinical ("symptomatic") stage and preclinical-prodromal ("presymptomatic") stage of PD. It was shown that among 13 blood markers found in patients, 7 markers are characteristic of parkinsonian symptomatic mice and 3 markers of both symptomatic and presymptomatic mice. According to our suggestion, the detection of the same marker in patients and symptomatic animals indicates adequate reproduction of pathogenesis along the corresponding metabolic pathway, whereas the detection of the same marker in presymptomatic animals indicates its specificity for preclinical-prodromal stage. This means that the minority of markers found in patients-decreased concentration of L-3,4-dihydroxyphenylalanine (L-DOPA) and dihydroxyphenylacetic acid (DOPAC) and increased dopamine D3 receptor gene expression-are specific for preclinical-prodromal stage and are suitable for early diagnosis of PD. Thus, we upgraded a current methodology for development of early diagnosis of PD by searching blood markers not only in patients but also in parkinsonian animals.

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An important approach to an early diagnosis of Parkinsons disease (PD) is screening for peripheral biomarkers in patients at the early clinical stage. In this study, we evaluated catecholamine concentration changes in the tear fluid of untreated PD patients as biomarkers. Norepinephrine and dopamine concentrations in the tear fluid of patients were found to increase compared to those in age controls, which was especially pronounced on the side where motor symptoms appeared. On the contrary, the epinephrine concentration in the tear fluid of patients was reduced bilaterally. Since there was no reason to consider the markers found in the clinical stage of PD as markers of the preclinical stage, we additionally studied the tear fluid composition in mouse neurotoxic models of PD preclinical and clinical stages. The norepinephrine concentration in the tear fluid of mice from the clinical stage model was found to be higher than that in controls; in the preclinical stage model, the norepinephrine concentration had a tendency to increase. Therefore, both PD patients and mice from PD preclinical and clinical stage models manifest unidirectional changes in their tear fluid compositions, which may be considered as promising biomarkers for the development of early diagnosis.

This review provides information onthe non-motor peripheral manifestations of Parkinsons disease (PD) associated with a pathology of the visual analyzer and the auxiliary apparatus of the eye. The relationship between neurodegenerative processes that take place in the brain and in the eye opens new prospects to use preventive ophthalmologic examination todiagnose PD long before the characteristic motor symptoms appear. This will encourage the use of neuroprotective therapy, which stops, or at least slows down, neuronal death, instead of the current replacement therapy with dopamine agonists. Animportant result of an eye examination of patients with PD may be a non-invasive identification of new peripheral biomarkers manifesting themselvesas changes in the composition of the lacrimal fluid.

Development of differential and early (preclinical) diagnostics of Parkinson’s disease (PD) is among the priorities in neuroscience. We searched for changes in the level of catecholamines and α-2-macroglobulin activity in the tear fluid (TF) in PD patients at an early clinical stage. It was shown that TF in patients is characterized by an increased level of noradrenaline mainly on the ipsilateral side of pronounced motor symptoms (72%, p = 0.049), a decreased level of adrenaline on both sides (ipsilateral—53%, p = 0.004; contralateral—42%, p = 0.02), and an increased α-2-macroglobulin activity on both sides (ipsilateral—53%, p = 0.03; contralateral—56%, p = 0.037) compared to controls. These changes are considered as potential biomarkers for differential diagnosis. Similar changes in the TF were found in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice when modeling clinical and preclinical stages of PD. These data show the adequacy of models to the pathogenesis of PD along the selected metabolic pathways, and also suggest that the found TF changes can be considered as potential biomarkers for preclinical diagnosis of PD. In Parkinsonian mice, the level of catecholamines also changes in the lacrimal glands, which makes it possible to consider them as one of the sources of catecholamines in the TF.