Anales de la RANM

64 A N A L E S R A N M R E V I S T A F U N D A D A E N 1 8 7 9 SERUM MYELOPEROXIDASE AND PARKINSON´S DISEASE Fernández-Espejo E An RANM. 2022;139(01): 56 - 66 This study demonstrates, for the first time to the best of our knowledge, that myeloperoxidase concen- tration in blood serum, not in the CSF, is signifi- cantly higher in PD patients than in healthy indivi- duals, and that serum MPO level and reduction of dopamine-transporter binding on basal ganglia are directly linked to each other. Serum MPO concentration positively correlates with degree of motor severity of PD, and patients with moderate- advanced disease (Hoehn-Yahr stage 3) present higher MPO levels than early diseased patients. The study also confirms that: a) there is a reliable reduction of dopaminergic neuronal terminals on all striatal nuclei in PD, as measured with DAT-SPECT, b) the putamen shows higher loss of DAT binding than the caudate nucleus, and c) degree of nigros- triatal dopaminergic cell loss is well quantified with rating scales of motor severity (25, 26, 30-34). MPO has been implicated in the pathogenesis of PD. This enzyme holds promise as biomarker for diagnosis and prognosis of the disease (1-5), and it has been proposed to be a target for antipar- kinsonian treatment (10, 22, 23). According to our findings, serum MPO could be a promising biomarker for diagnosis of PD, although larger studies are required to confirm it. The involvement of serum MPO in diseased patients, rather than CSF MPO, points to the implication of MPO-positive blood-derived cells, rather than brain microglia, in the pathogenesis of PD, in accordance with Gellhaar et al (10). On the other hand, MPO cytotoxicity suggests that inhibiting MPO would be useful for antiparkinsonian treatment. Jucaite et al (23) have used AZD3241, selective inhibitor of MPO, for treatment of PD patients in a clinic trial. These authors provide support for proof of mechanisms of AZD3241, although they recognize that longer treatment is required to know if the effects are beneficial for therapy. Since oxidative stress and inflammation are involved in PD pathogenesis (6, 15-17), it can be deduced that MPO, a pro-oxidative and pro-inflammatory molecule, might play a role in this neurodegenerative disease. Blood phagocytes (neutrophils and monocytes/macrophages) are the main source of MPO, and they release hypochlo- rite and other reactive species that can damage neurons (3-6, 18-21). In this context, it is of great interest that, in other neuropathological conditions such as cerebral ischemia, peripheral phagocytes accumulate close to the damaged brain area and release substantial amount of hypochlo- rite that penetrates the brain parenchyma (11). The number of MPO-positive cells positively correlates with the volume of ischemic damage, and blood MPO concentration is highly related to stroke severity (35-37). MPO levels are found to be elevated in blood for three weeks after the ischemic episode, then returning to normal (36). If ischemia persisted, sustained elevation of the number of MPO-expressing phagocytes and MPO content in blood would occur (37). Similar phenomena might take place in human PD. Although the results of epidemiological studies of the relationship between Parkinson's disease and stroke are conflicting (38, 39), it can be raised up the hypothesis that PD onset would be associated with stroke in the substantia nigra . In this context, it is noteworthy that hyperten- sion was observed to be more frequent in the cohort of patients relative to controls, and high blood pressure is a major risk factor for stroke (40). Following stroke, peripheral phagocytes would accumulate around the substantia nigra , and nigral dopaminergic neurons would be exposed to the deleterious effects of hypochlorite. It is worth noting that hypochlorite and dopamine react preferentially with each other at physiolo- gical concentrations, and they form toxic chloro- dopamine, melanic chlorinated precipitates, and aggregates of α-synuclein, the “hallmark” protein of PD pathogenesis (6, 7). Likely a self-perpetuating process is triggered, more phagocytes would be recruited infiltra- ting the mesencephalic region, and excess of MPO-derived products would cause continuous neuron damage. Further investigation on these topics is warranted. The study has some limitations that should be acknowledged. We are unable to infer causation, because it is a cross-sectional design, not a longitu- dinal study. Sample size was relativelly small, and larger studies are required. Serum MPO activity was not measured, and biochemical studies of enzymatic activity are also required to support the value of serum MPO as pathogenic factor in PD. Strengths of our study include well-characterized patients with PD, rigorous collection of data, the use of a very reliable SPECT technique, the use of Bonferroni correction to avoid making type I errors, and the analysis of two biofluids that are in close contact with brain tissue. This study demonstrates that concentration of the enzyme myeloperoxidase in blood serum, but not in the CSF, is significantly higher in PD patients than in healthy individuals, and that serum MPO level and reduction of dopamine-transporter binding on basal ganglia, an indirect measure of dopami- nergic neuronal loss in the substantia nigra , are directly linked to each other. Serum MPO concen- tration positively correlates with degree of motor severity of PD. These results would allow improving diagnosis of PD, and they open new avenues for treatment. The study also confirms that: a) there is a reliable reduction of DAT binding on all striatal regions in PD, b) the putamen shows higher reduction of DAT binding than the caudate nucleus, and c) degree of nigrostriatal dopaminergic cell loss is well quanti- fied with rating scales of motor severity. 4. DISCUSSION 4. CONCLUSIONS