Chiaki Isobe

Alterations of 3-nitrotyrosine concentration in the cerebrospinal fluid during aging and in patients with Alzheimer's disease

To investigate the significance of nitric oxide (NO)-mediated neuron death in aging and Alzheimers disease (AD), the 3-nitrotyrosine concentration in the cerebrospinal fluid (CSF) was investigated in neurologically normal controls and patients with AD. The 3-nitrotyrosine concentration and the 3-nitrotyrosine/tyrosine ratio significantly increased with advancing age, whereas the tyrosine concentration was unaltered. In patients with AD, the 3-nitrotyrosine concentration and the 3-nitrotyrosine/tyrosine ratio increased significantly (>six-fold) compared with controls of similar age, and increased significantly with decreasing cognitive functions, whereas the tyrosine concentration did not change. These findings suggest that an activation of tyrosine nitration, increase in nitrated tyrosine-containing proteins, and/or its degradation may be involved in brain aging and play an important role in the pathogenesis of AD.

Remarkable increase in cerebrospinal fluid 3‐nitrotyrosine in patients with sporadic amyotrophic lateral sclerosis

To investigate the significance of peroxynitrite‐mediated oxidative damage in the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS), the concentrations of 3‐nitrotyrosine and tyrosine in the cerebrospinal fluid (CSF) of patients with SALS were determined. The concentration of 3‐nitrotyrosine and the 3‐nitrotyrosine/ tyrosine ratio in patients with SALS were approximately seven times those of controls. Thus, the present findings in living patients provide in vivo evidence for a possible role of peroxynitrite, a mediator of oxidative stress, and increased nitration of tyrosine residues in the pathogenesis of SALS. Ann Neurol 1999;46:129–131

Alteration of 8-hydroxyguanosine concentrations in the cerebrospinal fluid and serum from patients with Parkinson's disease

In order to investigate the possible role of oxidative RNA damage in the pathogenesis of Parkinsons disease (PD), the concentrations of the oxidative stress marker 8-hydroxyguanosine (8-OHG) were measured in the cerebrospinal fluid (CSF) and the serum of patients with PD and control subjects. The concentration of 8-OHG in CSF in PD patients was approximately three-fold that in controls (P < 0.001). The concentration of 8-OHG in CSF decreased significantly with the duration of disease (r(s) = -0.46, P < 0.05). However, the concentration of 8-OHG in serum was not significantly altered in PD patients compared to that in controls. In addition, the concentration of 8-OHG in CSF showed no correlation with that in serum in both the controls and PD patients suggesting that the 8-OHG concentrations in the CSF do not reflect those in serum and may be probably reflect those in brain tissue. These in vivo findings suggest a possible role of 8-OHG and increased oxidative RNA damage in the early stage of the development of PD.

Increase in oxidized NO products and reduction in oxidized glutathione in cerebrospinal fluid from patients with sporadic form of amyotrophic lateral sclerosis.

To determine the role of free radical mechanisms in the pathogenesis of amyotrophic lateral sclerosis (ALS), cerebrospinal fluid concentrations of oxidized nitric oxide (NO) products (nitrite and nitrate) and reduced and oxidized forms of glutathione (GSH and GSSG, respectively) were compared between patients with the sporadic form of ALS (SALS) and controls. In the SALS patients, the nitrate levels were significantly higher (by 73%) in contrast to remarkably lower GSSG/GSH ratio, approximately 3-fold, compared to controls. These results suggest that NO production or oxidation is activated in SALS patients, leading to a decrease in superoxide radicals to oxidize GSH. The subsequent generation of a highly reactive anion, peroxynitrite, may play a causal role in the pathogenesis of SALS.

Reduction in asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in the cerebrospinal fluid during aging and in patients with Alzheimer's disease

To investigate the significance of nitric oxide (NO) -mediated neuron death in aging and Alzheimers disease (AD), the concentration of asymmetrical dimethylarginine (ADMA), an endogenous NO synthase inhibitor, in the cerebrospinal fluid was determined in neurologically normal controls and patients with AD. The ADMA concentration significantly decreased with age, whereas the arginine concentration was unaltered. In patients with AD, the ADMA concentration was significantly decreased, compared with controls of a similar age (-48%, P=0.0001), and it significantly decreased with decreasing cognitive functions (r(s)=0.58, P<0.05), whereas the arginine concentration did not change. These findings suggest that ADMA may play an important role in regulating NO synthesis in brain aging and AD.

The cerebrospinal fluid oxidized NO metabolites, nitrite and nitrate, in Alzheimer's disease and vascular dementia of Binswanger type and multiple small infarct type.

Summary. The concentration of the nitric oxide (NO) metabolites nitrite (NO2−) and nitrate (NO3−) in the cerebrospinal fluid from patients with Alzheimers disease (AD), vascular dementia of the Binswanger type (VDBT) or multiple small infarct type (MSID), and controls were determined using high performance liquid chromatography. The nitrite concentration was significantly higher in VDBT/MSID patients than in controls (p < 0.005). The nitrate concentration and the combined nitrite and nitrate concentration was significantly higher in both AD (p < 0.05) and VDBT/MSID (p < 0.001) patients than in controls, with these concentrations being significantly greater in VDBT/MSID than AD patients (p < 0.005). The combined nitrite and nitrate concentration significantly decreased as the severitry of dementia progressed in AD (rs = 0.70, p < 0.01), but remained elevated in all stages of VDBT/MSID. These results suggest that NO production or oxidation in the brain increases in the early stage of AD and then decreases as neuronal cell loss progresses, but increases throughout the course of disease in VDBT/MSID, which may in part contribute to neuronal degeneration in both conditions.

A Remarkable Increase in Total Homocysteine Concentrations in the CSF of Migraine Patients With Aura

(Headache 2010;50:1561‐1569)

Increase of oxidized/total coenzyme Q-10 ratio in cerebrospinal fluid in patients with Parkinson’s disease

The concentrations of oxidized coenzyme Q-10 (CoQ-10) and reduced CoQ-10 in the cerebrospinal fluid (CSF) of patients with Parkinsons disease (PD) was examined in order to determine whether the balance in oxidized and reduced CoQ-10 is related to the pathogenesis of PD. The percentage of oxidized/total CoQ-10 (%CoQ-10) in the CSF was significantly higher in the untreated PD group (80.3+/-17.9%) compared to the normal control group (68.2+/-20.4%) (p<0.05). The %CoQ-10 in the CSF of PD patients showed significant negative correlation with the duration of illness. These findings in living patients provide in vivo evidence for a possible role for %CoQ-10 in the pathogenesis in the early stages of PD development.

Homocysteine may contribute to pathogenesis of RNA damage in brains with Alzheimer's disease.

Background: The pathogenesis of Alzheimer’s disease (AD) is related to homocysteine (HC), but the details are unknown. Objective: We aimed to measure the cerebrospinal fluid (CSF) concentrations of 8-hydroxyguanosine (8-OHG), considering RNA oxidative damage marker, free HC and total HC in the CSF of patients with AD and in normal control subjects. Method and Patients: Subjects were 18 untreated patients with AD (M/F = 7/11) and 15 age-matched controls (M/F = 9/6), with a mean age ± SD of 67.4 ± 5.0 years for patients and of 65.7 ± 9.2 years for controls. The concentrations of free HC, total HC and 8-OHG in the CSF of AD patients were measured by high-performance liquid chromatography using an electrochemical detector. The control subjects were neurologically normal patients who underwent lumbar spinal anesthesia for minor surgery. Results: Total HC and 8-OHG concentrations were significantly increased, and there was a significant positive correlation between total HC and 8-OHG concentrations. However, the concentration of 8-OHG in the CSF showed no correlation with 8-OHG in serum and was not significantly altered in AD patients. Conclusion: These results suggest that total HC and 8-OHG are positively correlated and may be related to AD pathogenesis due to RNA-associated oxidative damage linked to total HC.

Increase in the oxidized/total coenzyme Q-10 ratio in the cerebrospinal fluid of Alzheimer's disease patients.

Background/Aim: The contribution of mitochondrial dysfunction and oxidative stress to the pathogenesis of Alzheimer’s disease (AD) has previously been described. We aimed to investigate whether the balance between the oxidized and reduced forms of coenzyme Q-10 (CoQ-10) is related to the pathogenesis of AD. Materials and Method: Thirty patients with AD (69.0 ± 4.1 years) and 30 healthy control subjects (63.8 ± 16.4 years) were enrolled in this study. Concentrations of oxidized CoQ-10 and reduced CoQ-10 were measured by high-performance liquid chromatography using an electrochemical detector. Results: The percentage of oxidized/total CoQ-10 in the cerebrospinal fluid (%CoQ-10, CSF) was significantly higher in the untreated AD group (78.2 ± 18.8%) than in the control group (41.3 ± 10.4%, p < 0.001), and there was a significant negative correlation between %CoQ-10 and the duration of the illness (rs = –0.93, p < 0.001). Conclusion: These findings in living AD patients suggest a possible role for %CoQ-10 in the pathogenesis of the early stage of AD development.