Chigumi Ohtsuka

Changes in substantia nigra and locus coeruleus in patients with early-stage Parkinson's disease using neuromelanin-sensitive MR imaging

Neuromelanin-sensitive magnetic resonance imaging is able to visualize changes associated with neuronal loss in the substantia nigra pars compacta (SNc) and locus coeruleus (LC) in patients with Parkinsons disease (PD). However, the diagnostic accuracy of this technique in the early stages of PD remains unknown. Therefore, changes in the SNc and LC observed using neuromelanin imaging were evaluated in patients with early PD. The signal intensities of the lateral, central, and medial parts of the SNc and that of the LC were measured, and the contrast ratios (CRs) were calculated against the adjacent white matter structures. CRs in the lateral part of the SNc and in the LC were significantly reduced in the early PD group when compared with the controls. Sensitivities and specificities in discriminating early PD patients from healthy controls were 73% and 87% in lateral SNc and 82% and 90% in LC, respectively. Neuromelanin imaging can depict signal alterations in the lateral part of the SNc and in the LC in patients with PD, even in its early stage, and can discriminate between these patients and healthy individuals with high sensitivities and specificities.

Differentiation of early-stage parkinsonisms using neuromelanin-sensitive magnetic resonance imaging.

PURPOSE The purpose of this study was to investigate whether the signal intensity of the substantia nigra pars compacta (SNc) and locus coeruleus (LC) on neuromelanin-sensitive magnetic resonance imaging (MRI) can discriminate early-stage parkinsonism disorders, for which differential diagnosis is generally difficult. METHODS Neuromelanin-sensitive MRI at 3 T was performed in 53 patients with early parkinsonism and 22 healthy controls. After an observation period of >1.5 year, the patients were clinically diagnosed with Parkinsons disease (PD; n = 30), multiple system atrophy with predominant parkinsonism (MSA-P; n = 10), or progressive supranuclear palsy syndrome (PSPS; n = 13). The signal intensity of the lateral, central, and medial parts of the SNc and the LC were measured and the contrast ratios (CR) against adjacent white-matter structures was calculated. RESULTS The CR of the lateral SNc was lower in the PD and MSA-P groups than in the PSPS and control groups (p = 0.0001-0.05). The CR of the LC was lower in the PD group than in the other groups (p = 0.0001-0.05). Sensitivity and specificity of the CRs for discriminating PD from MSA-P was 60% and 90%, respectively, those for PD/PSPS were 63-88% and 77-92%, respectively, and those for MSA-P/PSPS were 80% and 85%, respectively. These properties were comparable or better to MIBG scintigraphy. CONCLUSIONS Neuromelanin-sensitive MRI can depict differences in signal intensity of the lateral SNc and the LC among the parkinsonism disorders at their early stages.

Increased mitochondrial oxidative damage and oxidative DNA damage contributes to the neurodegenerative process in sporadic amyotrophic lateral sclerosis

To investigate the possibility that mitochondrial oxidative damage or oxidative DNA damage or both contribute to the neurodegenerative process of sporadic amyotrophic lateral sclerosis (sALS), this study used high-performance liquid chromatography with an electrochemical detector to measure the concentrations of the reduced and oxidized forms of coenzyme Q10 (CoQ10) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in the cerebrospinal fluid (CSF) of 17 patients with sALS and 17 age-matched controls with no neurological diseases. The percentage of oxidized CoQ10 in the CSF of sALS patients was greater than that in the CSF of controls (p<0.002) and was negatively correlated with the duration of illness (ρ=−0.61, p<0.01). The concentration of 8-OHdG in the CSF of sALS patients was greater than that in the CSF of controls (p<0.005) and was positively correlated with the duration of illness (ρ=0.53, p<0.005). The percentage of oxidized CoQ10 was correlated with the concentrations of 8-OHdG in the CSF of sALS patients (ρ=−0.53, p<0.05). These results suggest that both mitochondrial oxidative damage and oxidative DNA damage play important roles in the pathogenesis of sporadic amyotrophic lateral sclerosis.

Increased mitochondrial oxidative damage in patients with sporadic amyotrophic lateral sclerosis

To investigate whether mitochondrial oxidative damage contributes to the pathogenesis of sporadic amyotrophic lateral sclerosis (sALS), we used high-performance liquid chromatography with an electrochemical detector to measure the concentrations of the reduced and oxidized forms of coenzyme Q10 (CoQ10) in the cerebrospinal fluid (CSF) of 30 patients with sALS and 17 age-matched controls with no neurological diseases. The percentage of oxidized CoQ10 in the CSF of sALS patients were significantly greater than those in the CSF of controls (P<0.002) and were negatively correlated with duration of illness (rho=-0.64, P<0.001). These results suggest that mitochondrial oxidative damage contributes to the pathogenesis of sporadic amyotrophic lateral sclerosis.

Homocysteine, Another Risk Factor for Alzheimer Disease, Impairs Apolipoprotein E3 Function

Apolipoprotein E (apoE) ϵ4 and hyperhomocysteinemia are risk factors for Alzheimer disease (AD). The dimerization of apoE3 by disulfide bonds between cysteine residues enhances apoE3 function to generate HDL. Because homocysteine (Hcy) harbors a thiol group, we examined whether Hcy interferes with the dimerization of apoE3 and thereby impairs apoE3 function. We found that Hcy inhibits the dimerization of apoE3 and reduces apoE3-mediated HDL generation to a level similar to that by apoE4, whereas Hcy does not affect apoE4 function. Western blot analysis of cerebrospinal fluid showed that the ratio of apoE3 dimers was significantly lower in the samples from the patients with hyperhomocysteinemia than in those that from control subjects. Hyperhomocysteinemia induced by subcutaneous injection of Hcy to apoE3 knock-in mice decreased the level of the apoE3 dimer in the brain homogenate. Because apoE-HDL plays a role in amyloid β-protein clearance, these results suggest that two different risk factors, apoE4 and hyperhomocysteinemia, may share a common mechanism that accelerates the pathogenesis of AD in terms of reduced HDL generation.

Differentiation among parkinsonisms using quantitative diffusion kurtosis imaging.

Differential diagnoses among Parkinson’s disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy syndrome (PSPS) are often difficult. Hence, we investigated whether diffusion kurtosis imaging (DKI) could detect pathological changes that occur in these disorders and be used to differentiate between such patients. Fourteen patients (five with PD, four MSA, and five PSPS) and six healthy controls were examined using a 1.5-T scanner. Mean kurtosis (MK), fractional anisotropy, and mean diffusivity maps were generated, and these values of the midbrain tegmentum (MBT) and pontine crossing tract (PCT), as well as MBT/PCT ratios, were obtained. We found no significant differences in MBT and PCT values on DKI maps among the groups. In contrast, MBT/PCT ratios from MK maps were significantly increased in the MSA group and decreased in the PSPS group compared with the other groups. MBT/PCT ratios from mean diffusivity maps showed a significant increase in the PSPS group. Therefore, quantitative DKI analyses, particularly the MBT/PCT ratio from MK maps, can differentiate patients with parkinsonisms.

Randomized, double-blind, multicenter trial of hydrogen water for Parkinson's disease: LETTERS: NEW OBSERVATIONS

Oxidative stress might be involved in Parkinson’s disease (PD) progression. Molecular hydrogen (H2) water has been shown to reduce oxidative stress and dopaminergic neuronal cell loss in a PD model. A previous randomized, doubleblind study showed that drinking 1,000 mL of H2 water per day for 48 weeks significantly improved the total Unified Parkinson’s Disease Rating Scale (UPDRS) scores of patients with PD and treated with levodopa. We conducted a longer and larger scale H2 water trial that also included patients who were not treated with levodopa. A placebo-controlled, randomized, double-blind, parallel-group (1:1) clinical trial was performed in 14 hospitals (trial registration UMIN000010014). The inclusion criteria, ethical considerations, randomization, blinding, procedures, statistical analyses, and characteristics of the 178 enrolled Japanese participants with PD (93 women and 85 men; an error in this number exists in the previous report) were described previously. At the baseline visit, the groups were well matched (Supplementary Table 1). The reasons for discontinuation of the study were disease progression, adverse events, unwillingness to proceed, and failure to comply with the protocol (Supplementary Table 2 and Supplementary Figure 1). There were no significant differences in the change in the total UPDRS score from baseline to the 72nd week between the H2-water group (1.6 ± 14.0 [mean ± standard deviation]) and the placebo water group (0.8 ± 9.6; t test, P = .939; analysis of variance, P = .538; Table 1). There were no significant differences in changes in the scores on parts II and III of the UPDRS, the individual parts of the UPDRS, the Hoehn and Yahr stage, and the Parkinson’s Disease Questionnaire-39 *Corresponding author: Dr. Asako Yoritaka, Department of Neurology, Juntendo University Koshigaya Hospital. Fukuroyama 560, Koshigayashi, Saitama, Japan, 343-0032; ayori@juntendo.ac.jp