Emilio Fernandez-Espejo

The authors hypothesize that idiopathic Parkinson’s disease may result from an alteration in microvascular flow at a “critical point” in the nervous system that is characterized by pigmented cells that express neuromelanin and/or lipofuscin. “Critical points” include the olfactory epithelium/bulb, the autonomic nervous system, the enteric nervous system, the prefrontal–cortico-pontine network, and the amygdala. Hypoxia–ischemia following blood flow disturbance would recruit and activate leukocytes and induce the infiltration of peripheral immune cells into neural tissue. The excess of toxic factors produced by hyperactive immune cells, such as myeloperoxidase and its derivatives, would cause the oxidation of lipids, proteins, and biogenic monoamines such as dopamine, which in turn would facilitate the accumulation and precipitation of neuromelanin, lipofuscin, and alpha-synuclein. In addition, neuromelanin and lipofuscin precipitates may accentuate the misfolding and aggregation of alpha-synuclein. This “amplification” mechanism could help explain the crucial role of pigmented neurons in the onset of Parkinson’s disease pathology, triggering abnormal neurotoxic alpha-synuclein spread throughout the nervous system from the “critical point” of origin, and enabling a self-perpetuating degenerative process. The proposed hypothesis may have implications for the identification of new therapeutic targets, early prevention strategies, and the development of vascular and/or immune biomarkers.

Background: The blood concentration of myeloperoxidase (MPO) is related to the severity of many age‐related inflammatory diseases. However, it is unknown whether enzyme activity in the blood provides information on the degree of functional disability of Parkinson's disease (PD), a multifactorial disease in which aging and inflammation play an important role.Objective: The aim of the study was to discern the relationship between MPO activity in blood serum and the clinical characteristics of PD, assessed by disease rating scales and neuroimaging methods.Methods: This cross‐sectional study included 217 participants (114 patients and 103 controls). Disease rating scales included the Hoehn‐Yahr scale, the International Parkinson and Movement Disorder Society‐sponsored revision of the Unified Parkinson's Disease Rating Scale motor section (MDS‐UPDRS), and the Schwab‐England Daily Living scale. The neuroimaging study was based on dopamine transporter single‐photon emission computed tomography (DAT‐SPECT) and specific binding ratio (SBR) quantification of ¹²³I‐Ioflupane on basal ganglia.Results: The findings revealed that serum MPO activity significantly increased in PD patients (P < 0.0001). MPO activity correlated with the degree of clinical impairment measured with rating scales and with striatal DAT availability assessed with DAT‐SPECT. Multivariate linear regression, correcting for all confounding factors, shows that the Hoehn‐Yahr staging (P = 0.004) and left striatum specific binding ratio (SBR) (P < 0.05) are predictors of serum MPO activity, along with dysthyroidism and statins use (P < 0.005). MPO activity cutoff greater than 40.350 U/L differentiated patients from controls with good accuracy (78.9%).Conclusions: In PD, MPO activity in blood serum is associated with the stage of functional disability, apart from dysthyroidism and use of statins, assessed with the Hoehn‐Yahr scale and striatal DAT binding.

Elevated levels of the inflammatory enzyme myeloperoxidase (MPO) in the blood are associated with the development of age-related inflammatory diseases. Given that age, inflammation, and blood MPO play a role in the pathogenesis of Parkinson´s disease (PD), we hypothesized that serum MPO could be associated with PD status. This case-control study (199 participants) was conducted using an extensive protocol, and the concentration and activity of MPO in blood serum were measured. The findings reveal that serum MPO concentration and activity are significantly increased in the patients, and that rates of PD in all individuals are associated with increasing tertiles of MPO concentration and activity. In multivariate logistic regression model adjusting for confounding factors, MPO activity (not concentration) is the factor that is most associated with PD status (OR, 6.921, P = 0.001). Mental depression is directly associated with MPO activity and with PD status (OR, 0.121, B = −2.108, P = 0.002). The use of statins or nonsteroidal anti-inflammatory drugs significantly reduces serum MPO activity, but the possible association with the odds of having PD does not survive correction for multiple testing. In summary, both serum MPO concentration and activity are increased in patients with PD, but only MPO enzyme activity is associated with PD status. These findings may have implications for the evaluation of PD.

Background: Depression is the most common psychiatric disorder diagnosed in patients with Parkinson's disease (PD). A direct role in PD depression for loss of dopaminergic terminals and dopamine‐transporter (DAT) expression in the striatum is revealed by many studies.Objectives: The objective was to discern the relationship between DAT neuroimaging and risk of depression in PD.Methods: One hundred and ninety‐eight PD patients (101 with depression, 97 without depression) were evaluated using an extensive protocol from 2015 to 2023. DAT availability at striatal terminals was assessed with single‐photon emission computed tomography with ¹²³I‐Ioflupane. Specific binding ratio (SBR) of ¹²³I‐Ioflupane and the whole striatum asymmetry index (SASI) were calculated. Data were analyzed with univariate/multivariate models as well as receiver operating characteristic (ROC) curves.Results: A logistic regression model adjusting for confounding risk factors of depression indicates that SASI and PD duration are associated with the odds of having parkinsonian depression. SASI is the strongest predictor of risk of parkinsonian depression. Following ROC analysis, SASI is found to be an accurate factor for detecting parkinsonian depression because a cutoff value of 3.4895 of SASI shows good accuracy (0.813), sensitivity (81.1%), and specificity (80%). Higher SASI is also linked to more disease‐related limitations in activities of daily living.Conclusion: The whole SASI is the strongest predictor of risk of parkinsonian depression. The findings could be valuable in evaluating depression in PD patients.

Background: Myeloperoxidase (MPO) and advanced oxidation protein products, or AOPP (a type of MPO-derived chlorinated adducts), have been implicated in Parkinson´s disease (PD). Human MPO also show sex-based differences in PD. The objective was to study the relationship of MPO and AOPP in the cerebrospinal fluid (CSF) with motor features of idiopathic PD in male and female patients. Methods: MPO concentration and activity and AOPP content were measured in the CSF and serum in 34 patients and 30 controls. CSF leukocytes and the integrity of the blood-brain barrier were evaluated. Correlations of MPO and AOPP with clinical variables were examined. Results: The blood-brain barrier was intact and CSF leukocyte count was normal in all patients. CSF MPO concentration and activity were similar in the cohort of patients and controls, but CSF MPO content was significantly higher in male patients than in PD women (p = 0.0084). CSF MPO concentration correlated with disease duration in male and female patients (p < 0.01). CSF MPO concentration was significantly higher in men with disease duration ≥12 years versus the remainder of the male subjects (p < 0.01). Changes in CSF MPO in women were not significant. Serum MPO concentration and activity were significantly higher in all PD patients relative to controls (p < 0.0001). CSF MPO was not correlated with serum MPO. Serum AOPP were detected in all patients, but CSF AOPP was undetectable in 53% of patients. AOPP were not quantifiable in controls. Conclusions: CSF MPO is not a good biomarker for PD because mean CSF MPO concentration and activity are not different between the cohort of patients and controls. CSF MPO concentration positively correlated with disease duration in men and women, but CSF MPO is significantly enhanced only in male patients with disease duration longer than 12 years. It can be hypothesized that the MPO-related immune response in early-stage PD might be weak in all patients, but then the MPO-related immune response is progressively enhanced in men, not women. Since the blood-brain barrier is intact, and CSF MPO is not correlated with serum MPO, CSF myeloperoxidase would reflect MPO content in brain cells, not blood-derived cells. Finally, serum AOPP was detected in all patients, but not controls, which is consistent with the occurrence of chlorinative stress in blood serum in PD. The study of CSF AOPP as biomarker could not be assessed because the ELISA assay was hampered by its detection limit in the CSF.

Objectives. Myeloperoxidase (MPO) has been implicated in Parkinson´s disease (PD). The objective was to look at the relationship of MPO concentration in serum and cerebrospinal fluid (CSF) with clinical variables of PD. Methods. In this prospective, observational, and cross-sectional study, MPO concentration in serum and the CSF was analyzed in 36 patients with idiopathic PD and 30 controls, who were enrolled from 2012 to 2017. In the group of patients, correlation of MPO content with demographic, clinical and tomographic variables was examined. The extent and degree of nigrostriatal dopaminergic cell loss was evaluated by using SPECT and 123I-Ioflupane, radioligand that has binding affinity for dopamine-transporter (DAT). Results. Serum MPO concentration, not CSF MPO content, was significantly higher in the patients (p<.0001). Significant correlation values were found between serum MPO concentration and rating scales of motor severity (Hoehn-Yahr, MDS-UPDRS part-III), and percentage reduction of DAT binding on basal ganglia (p<.0001). Patients with moderate-advanced disease (Hoehn-Yahr stage 3) showed significantly higher serum MPO content relative to patients with early disease (Hoehn-Yahr stages 1-2, p<.0001). DAT binding was reduced on all striatal regions, and signal reduction was higher in the putamen relative to the caudate nucleus (p<.0001). Percentage reduction of DAT binding on the striatum and putamen significantly correlated with rating scales of motor severity. Conclusions. Myeloperoxidase content in serum is increased in PD patients and correlates with motor severity degree and loss of dopamine-transporter binding on basal ganglia. The results allow proposing that the measurement of MPO level in serum could be useful for PD diagnosis, and that the inhibition of serum MPO would be a promising therapeutic tool. The study also confirms that the putamen shows higher reduction of DAT binding than the caudate nucleus, and degree of nigrostriatal dopaminergic cell loss is well quantified with rating scales of motor severity.