Differentiation Between Multiple System Atrophy and Other Spinocerebellar Degenerations Using Diffusion Kurtosis Imaging.

RATIONALE AND OBJECTIVE: Differentiation between multiple system atrophy (MSA) and other spinocerebellar degenerations showing cerebellar ataxia is often difficult. Hence, we investigated whether magnetic resonance diffusion kurtosis imaging (DKI) could detect pathological changes that occur in these patients and be used for differential diagnosis. METHODS: Thirty-six subjects (12 patients with MSA accompanied by predominant cerebellar ataxia [MSA-C], 10 patients with spinocerebellar ataxias [SCAs] or sporadic adult-onset ataxia of unknown etiology [SAOA], and 14 healthy controls) were examined using 1.5- or 3-T magnetic resonance scanners. From the DKI data, the mean kurtosis, fractional anisotropy, and mean diffusivity values of the pontine crossing tract (PCT), middle cerebellar peduncle, and cerebellum were automatically measured, and the ratios against the values of the corpus callosum were calculated. RESULTS: We found significant decreases in mean kurtosis and fractional anisotropy ratios in the PCT and middle cerebellar peduncle, and a significant increase in the mean diffusivity ratio in the PCT in the MSA-C group, as compared with the SCA/SAOA and control groups (p < 0.027-0.001). Among these metrics, there were no significant differences in the diagnostic performance. By contrast, the ratios in the cerebellum showed no significant differences between the MSA-C and SCA/SAOA groups but were significantly altered when compared with the controls (p < 0.001). CONCLUSION: Quantitative DKI analyses can be used to differentiate between patients with MSA-C and those with SCA/SAOA.

Differential diagnosis of parkinsonism by a combined use of diffusion kurtosis imaging and quantitative susceptibility mapping.

PURPOSE: We investigated whether diffusion kurtosis imaging (DKI) and quantitative susceptibility mapping (QSM) could detect pathological changes that occur in Parkinson's disease (PD), multiple system atrophy with predominant parkinsonism (MSA-P) or predominant cerebellar ataxia (MSA-C), and progressive supranuclear palsy syndrome (PSPS) and thus be used for differential diagnosis that is often difficult. METHODS: Seventy patients (41 with PD, 6 with MSA-P, 7 with MSA-C, 16 with PSPS) and 20 healthy controls were examined using a 3.0 T MRI scanner. From DKI and QSM data, we automatically obtained mean kurtosis (MK), fractional anisotropy (FA), and mean diffusivity (MD) values of the midbrain tegmentum (MBT), pontine crossing tract (PCT), and superior/middle cerebellar peduncles (CPs), which were used to calculate diffusion MBT/PCT ratios (dMPRs) and diffusion superior/middle CP ratios (dCPRs), as well as MS (magnetic susceptibility) values of the anterior/posterior putamen (PUa and PUp) and globus pallidus (GP). RESULTS: dMPRs of MK were significantly decreased in PSPS and increased in MSA-C compared with the other groups, while dCPRs of MK showed significant differences only between MSA-C and PD, PSPS, or control. MS values were significantly increased in the PUp of MSA-P and in the PUa and GP of PSPS compared with those in PD. The combined use of MK-dMPR and MS-PUp showed sensitivities of 83-100% and specificities of 81-100% for discriminating among the disease groups, respectively. CONCLUSION: A quantitative assessment using DKI and QSM analyses, particularly MK-dMPR and MS-PUp values, can readily identify patients with parkinsonism.

A randomized double-blind multi-center trial of hydrogen water for Parkinson's disease: protocol and baseline characteristics.

BACKGROUND: Our previous randomized double-blind study showed that drinking hydrogen (H2) water for 48 weeks significantly improved the total Unified Parkinson's Disease Rating Scale (UPDRS) score of Parkinson's disease (PD) patients treated with levodopa. We aim to confirm this result using a randomized double-blind placebo-controlled multi-center trial. METHODS: Changes in the total UPDRS scores from baseline to the 8(th), 24(th), 48(th), and 72(nd) weeks, and after the 8(th) week, will be evaluated. The primary endpoint of the efficacy of this treatment in PD is the change in the total UPDRS score from baseline to the 72(nd) week. The changes in UPDRS part II, UPDRS part III, each UPDRS score, PD Questionnaire-39 (PDQ-39), and the modified Hoehn and Yahr stage at these same time-points, as well as the duration until the protocol is finished because additional levodopa is required or until the disease progresses, will also be analyzed. Adverse events and screening laboratory studies will also be examined. Participants in the hydrogen water group will drink 1000 mL/day of H2 water, and those in the placebo water group will drink normal water. One-hundred-and-seventy-eight participants with PD (88 women, 90 men; mean age: 64.2 [SD 9.2] years, total UPDRS: 23.7 [11.8], with levodopa medication: 154 participants, without levodopa medication: 24 participants; daily levodopa dose: 344.1 [202.8] mg, total levodopa equivalent dose: 592.0 [317.6] mg) were enrolled in 14 hospitals and were randomized. DISCUSSION: This study will confirm whether H2 water can improve PD symptoms. TRIAL REGISTRATION: UMIN000010014 (February, 13, 2013).

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.

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 Parkinson's 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.

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 Parkinson's 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.

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 ß-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.

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 (rho=-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 (rho=0.53, p<0.005). The percentage of oxidized CoQ10 was correlated with the concentrations of 8-OHdG in the CSF of sALS patients (rho=-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.