Normal platelet mitochondrial complex I activity in Huntington's disease

Two small case series of platelet mitochondrial complex I activity assays in Huntington's Disease (HD) report discrepant results. We measured platelet complex I and complex I/III activity in 21 subjects with early gene-positive HD and 14 age-matched controls. The 21 participants with HD that we studied are greater than the total of 16 in the two previously published of platelet ETS activity in HD. Reductions > 10% were excluded with 80% confidence. A systemic defect in complex I activity is not present in early HD when striatal neuronal degeneration is already present.     

Cerebral glucose utilization and platelet mitochondrial complex I activity in schizophrenia: A FDG-PET study

Altered cerebral energy metabolism and mitochondrial dysfunction in periphery and in brain are implicated in the pathophysiology of schizophrenia. This study investigated whether cerebral glucose metabolism (rCGM) abnormalities are linked to altered mitochondrial complex I activity in the periphery, in schizophrenia. Sixteen schizophrenic patients, 8 with total positive PANSS score >or=20 (high positive schizophrenics; HPS), and 8 with total positive score 相似文献   

Mitochondrial complex I, II/III, and IV activities in familial and sporadic Parkinson's disease

A possible role of mitochondrial respiratory chain dysfunction in the pathogenesis of sporadic Parkinson's disease (PD) has been described. There are only a few reports concerning mitochondrial involvement in familial Parkinson's disease. The present study investigated mitochondrial complex I-IV activity in patients with sporadic and familial PD, compared to controls. Platelets were isolated from venous blood and platelet mitochondria were obtained through sonication and differential centrifugation. Complex I, II/III, and IV activities were measured in 17 patients with family history of Parkinson's disease (PDF), 15 patients with sporadic Parkinson disease (PDS), and 17 age-matched, healthy controls. The mitochondrial enzyme activities did not differ significantly between patient groups and controls. In addition, there was no correlation between mitochondrial complex activities and age, severity of disease, or age at onset of disease in the patient groups. In this study, the data indicate no significant differences in mitochondrial complex I-IV activities in PDF and PDS.     

Platelet mitochondrial complex I and I+III activities do not correlate with cerebral mitochondrial oxidative metabolism

Assays of mitochondrial electron transport system (ETS) activity in circulating blood platelets have been used to investigate the cause of neurodegenerative diseases. However, the correspondence between platelet ETS function and cerebral mitochondrial metabolism is not well characterized. To assess the validity of using platelet ETS activity to infer cerebral mitochondrial metabolism, we measured platelet ETS activity (complex I and complex I+III), cerebral metabolic rate of oxygen (CMRO₂), and the CMRO₂/cerebral metabolic rate for glucose ratio in 40 subjects: 7 with never-medicated Parkinson''s disease, 13 with genetically proved Huntington''s disease, and 20 normal controls. We found no correlation between in vivo measures of cerebral mitochondrial oxidative metabolism and ex vivo assays of platelet complex I and complex I+III activity performed on blood collected immediately before cerebral metabolism studies. We saw no evidence of a threshold effect when comparing platelet complex I and complex I+III activity with cerebral oxidative metabolism across a 4- to 10-fold range of platelet ETS activity. On the basis of these data, we conclude that measures of mitochondrial complex I and I+III activity in platelets within the ranges we have studied do not correlate with oxidative function of cerebral mitochondria.     

Distinct metabolomic signature in cerebrospinal fluid in early parkinson's disease

Objective: The purpose of this study was to profile cerebrospinal fluid (CSF) from early‐stage PD patients for disease‐related metabolic changes and to determine a robust biomarker signature for early‐stage PD diagnosis. Methods: By applying a non‐targeted and mass spectrometry‐driven approach, we investigated the CSF metabolome of 44 early‐stage sporadic PD patients yet without treatment (DeNoPa cohort). We compared all detected metabolite levels with those measured in CSF of 43 age‐ and gender‐matched healthy controls. After this analysis, we validated the results in an independent PD study cohort (Tübingen cohort). Results: We identified that dehydroascorbic acid levels were significantly lower and fructose, mannose, and threonic acid levels were significantly higher (P < .05) in PD patients when compared with healthy controls. These changes reflect pathological oxidative stress responses, as well as protein glycation/glycosylation reactions in PD. Using a machine learning approach based on logistic regression, we successfully predicted the origin (PD patients vs healthy controls) in a second (n = 18) as well as in a third and completely independent validation set (n = 36). The biomarker signature is composed of the three markers—mannose, threonic acid, and fructose—and allows for sample classification with a sensitivity of 0.790 and a specificity of 0.800. Conclusion: We identified PD‐specific metabolic changes in CSF that were associated with antioxidative stress response, glycation, and inflammation. Our results disentangle the complexity of the CSF metabolome to unravel metabolome changes related to early‐stage PD. The detected biomarkers help understanding PD pathogenesis and can be applied as biomarkers to increase clinical diagnosis accuracy and patient care in early‐stage PD. © 2017 International Parkinson and Movement Disorder Society     

Novel mutations of mitochondrial complex I in pathologically proven Parkinson disease

Complete sequence analysis of all mitochondrial complex I genes was performed in 22 cases of neuropathologically confirmed idiopathic Parkinson disease (PD). DNA from the substantia nigra was used as a template for polymerase chain reaction-based genomic sequencing. Seven novel mutations causing the exchange of amino acids were detected in subunit genes ND1 (3992 C/T, 4024 A/G), ND4 (11253 T/C, 12084 C/T), ND5 (13711 G/A, 13768 T/C), and ND6 (14582 T/C). In addition, five known missense mutations affecting the ND1 (3335 T/C, 3338 T/C), ND2 (5460 G/A), ND3 (10398 A/G), and ND5 (13966 A/G) genes as well as three secondary LHON mutations (4216 T/C, 4917 A/G, 13708 G/A) were found in the PD group. Among the novel mutations, the 11253 T/C transition which changes a conserved isoleucine residue into threonine is most likely to be of functional relevance. Furthermore, 43 synonymous polymorphisms were detected in PD brains, including 20 novel sequence variants. Haplogroup analysis revealed that most unique missense mutations were found in PD cases belonging to the D^c haplogroup. Our data are in line with the view that PD is not a single disease entity but comprises a genetically heterogeneous group of disorders. The results of our study further suggest that 90% or more of all idiopathic PD cases are not due to sequence variation of mitochondrial complex I, but that mitochondrial mutations may play a pathogenic role in a subset of PD patients. Received: November 24, 1997 / Accepted: December 18, 1997     

Plasma profiles of adrenocorticotropic hormone,cortisol, growth hormone and prolactin in patients with untreated parkinson's disease

Summary Plasma profiles of prolactin, growth hormone, adrenocorticotropic hormone (ACTH) and cortisol were evaluated in a group of untreated patients with idiopathic Parkinson's disease and a group of healthy age-matched controls. Plasma integrated concentrations of all hormones except prolactin were significantly lower in the patients as compared with the controls; however, prolactin nocturnal peak concentration was significantly elevated in the patients; nocturnal growth hormone levels were significantly reduced in the Parkinson group; ACTH and cortisol plasma concentrations were also consistently lower during most of the day in the patients with Parkinson's disease. These data confirm the presence of a hypothalamic disturbance in patients with idopathic Parkinson's disease, which can affect pituitary function.     

BDNF increases rat brain mitochondrial respiratory coupling at complex I, but not complex II

Brain-derived neurotrophic factor (BDNF) governs both the selective survival of neurons during development and the experience-based regulation of synaptic strength throughout life. BDNF produced a concentration-dependent increase in the respiratory control index (RCI, a measure of the efficiency of respiratory coupling, ATP synthesis and organelle integrity) of rat brain mitochondria. This effect was mediated via a MAP kinase pathway and highly specific for oxidation of glutamate plus malate (complex I) by brain mitochondria. The oxidation by brain mitochondria of the complex II substrate succinate was unaffected by BDNF. The failure of BDNF to modify respiratory activity associated with mitochondrial preparations isolated from rat liver indicates that the actions of the neurotrophin are tissue specific. BDNF also increased the RCI values associated with Ca2+ -induced respiration to a similar extent. This is the first demonstration that BDNF, in addition to modifying neuronal plasticity, can modify brain metabolism and the efficiency of oxygen utilization. The finding that neurotrophins can alter mitochondrial oxidative efficiency has important implications for neurodegenerative and psychiatric diseases.     

Lyssavirus phosphoproteins increase mitochondrial complex I activity and levels of reactive oxygen species

We have previously demonstrated that serine residues at positions 162 and 166 of the rabies virus (RABV) phosphoprotein (P) are critical for oxidative stress induced by CVS in cultured cells. We have now evaluated the P of two street RABV variants and Mokola (MOK) virus. The P of these viruses, like CVS, induces an increase in complex I activities and reactive oxygen species levels in transfected cells. Although the sequence homology of P is only 45% with MOK (higher for street viruses) and CVS, serine residues are conserved at positions 162 and 166, suggesting their potential importance in oxidative stress.     

Bimanual coordination dysfunction in early, untreated Parkinson's disease

Bimanual coordination involves the simultaneous performance of either symmetrical (in-phase) or asymmetrical (anti-phase) movements with both hands and is known to be impaired in Parkinson's disease (PD). At present, it is unclear whether this aspect of motor function is already impaired in early stage, untreated PD patients. Therefore, we investigated the accuracy of bimanual coordination in 13 early stage, untreated PD patients and 13 age- and sex-matched healthy controls. Each subject performed bimanual coordination tasks at two different movement frequencies (1 and 1.75 Hz) and with two different phase relationships (in-phase and anti-phase). The percentage of unsuccessful trials (as a measure of overall task performance) in PD patients was significantly higher than in healthy subjects. PD patients performed high frequency in-phase and anti-phase bimanual coordination tasks less accurately with their non-dominant hand than healthy subjects. Furthermore, PD patients had more difficulty than healthy subjects in maintaining a constant phase relationship between the hands in the anti-phase condition at low movement frequency. This study demonstrates that bimanual coordination dysfunction is a very early sign of PD. Bimanual coordination tasks, in particular those involving high frequency anti-phase movements, might prove useful in the early diagnosis of PD.     

Temporal lobe changes in early,untreated Parkinson's disease

The purpose of this study was to determine if focal cortical abnormalities may occur in early Parkinson's disease (PD). We studied 26 untreated patients with early PD and 14 healthy control subjects, with cognitive screening and magnetic resonance imaging (MRI). Voxel‐based morphometry was used to assess for the presence of localized cortical grey matter (GM) and/or subcortical white matter (WM) changes. Patient and control groups showed no differences in age or gender distribution. Females had a greater GM% than males (P = 0.001). Comparison of patients and controls revealed no difference in local GM volumes. In PD, however, there was decreased WM volume in the anterior right fusiform gyrus and superior temporal gyrus. There were no correlations between the California Verbal Learning Test long delay free recall, Judgment of Line Orientation, Trail Making A or B and either the GM or WM localized volumes. These results suggest that right anterior temporal lobe changes occur in untreated patients with PD. The earliest changes may occur in subcortical white matter rather than temporal cortex. © 2009 Movement Disorder Society     

Genetic variation of the mitochondrial complex I subunit NDUFV2 and Parkinson's disease

NADH dehydrogenase ubiquinone flavoprotein 2 (NDUFV2), encoding a subunit of mitochondrial complex I, is a candidate gene for several neuronal diseases; schizophrenia, bipolar disorder and Parkinson disease (PD). We screened the entire coding region of NDUFV2 in 33 familial PD patients of North African Arab-Berber ethnicity in which all known genetic forms of PD had been excluded. We detected one novel substitution p.K209R (c.626A > G) in one PD proband. Segregation analysis within the family is inconclusive due to small sample size, but consistent with an autosomal dominant mode of inheritance. Subsequent screening of this mutation in ethnically matched sporadic PD patients (n = 238) and controls (n = 371) identified p.K209R in one additional patient. The clinical features of the mutation carriers revealed a mild form of parkinsonism with a prognosis similar to idiopathic PD. Our findings suggest further studies addressing the role of NDUFV2 variation in PD may be warranted.     

Mitochondrial complex I and II activities of lymphocytes and platelets in Parkinson's disease

Summary Mitochondrial Complex I deficiencies have been described not only in the brain but also in the skeletal muscle and platelets in Parkinson's disease (PD). We report activities of Complex I, II, III, and IV in lymphocytes and platelets in 20 patients with PD and age-matched controls. A small but a significant decrease in the platelet Complex I activity was found in PD (9.14±1.86 units/mg protein) compared with that in the control (12.37±2.66 units/mg protein) (P=0.0002). The lymphocyte Complex I activity was about the same between PD and the control. The activity of Complex II was slightly diminished in both platelets and lymphocytes in PD. Rather small decrease in the platelet Complex I activity in PD may be clinically non-significant. But it may indicate the presence of a qualitatively similar abnormality in platelets as in the nigro-striatal neurons. The cause for decrease in the Complex II activity is unknown at this moment. Further studies seem necessary.     

Low platelet monoamine oxidase activity in pathological gambling

Decreased platelet monoamine oxidase (MAO) activity has been reported in association with sensation-seeking personality type and in some mental disorders associated with a lack of impulse control. Pathological gambling itself has been related with both sensation-seeking and reduced impulse control. Platelet MAO activity was investigated in 15 DSM-III-R pathological gamblers from our outpatient clinic. Gamblers had a significantly lower platelet MAO activity than a group of 25 healthy controls. The range of MAO levels in gamblers was also significantly shorter than in controls. In controls, platelet MAO levels showed the previously described negative correlations with sensation-seeking scores but not in gamblers. The findings are consistent with previous studies showing an association of low platelet MAO activity with impulse control disorders and raise some interesting therapeutic alternatives for pathological gambling.