Ayami Okuzumi

Identification of novel biomarkers for Parkinson's disease by metabolomic technologies

Objective The pathogenesis of Parkinsons disease (PD) involves complex interactions between environmental and genetic factors. Metabolomics can shed light on alterations in metabolic pathways in many diseases, including neurodegenerative diseases. In the present study, we attempted to elucidate the candidate metabolic pathway(s) associated with PD. Methods Serum samples were collected from 35 individuals with idiopathic PD without dementia and 15 healthy age-matched control participants without PD. This analysis used a combination of three independent platforms: ultrahigh-performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) optimised for basic species, UPLC/MS/MS optimised for acidic species and gas chromatography/MS (GC/MS). Results The metabolomic profiles of PD were clearly different from normal controls. PD profiles had significantly lower levels of tryptophan, caffeine and its metabolites, bilirubin and ergothioneine, and significantly higher levels of levodopa metabolites and biliverdin than those of normal controls. Alterations in the bilirubin/biliverdin ratio and ergothioneine can indicate oxidative stress intensity and may suggest elevated oxidative stress and/or insufficient ability for scavenging free radicals, which could contribute to PD pathogenesis. Decreased serum tryptophan level is associated with psychiatric problems in PD. A decrease in serum caffeine levels is consistent with an inverse association of caffeine consumption with development of PD based on past epidemiological studies. Conclusions Metabolomic analysis detected biomarkers associated with PD pathogenesis and disease progression. Since critical metabolic biomarkers need to be identified in PD, future studies should include assay validation and replication in independent cohorts.

Neurite orientation dispersion and density imaging in the substantia nigra in idiopathic Parkinson disease

AbstractObjectivesWe used neurite orientation dispersion and density imaging (NODDI) to quantify changes in the substantia nigra pars compacta (SNpc) and striatum in Parkinson disease (PD).MethodsDiffusion-weighted magnetic resonance images were acquired from 58 PD patients and 36 age- and sex-matched controls. The intracellular volume fraction (Vic), orientation dispersion index (OD), and isotropic volume fraction (Viso) of the basal ganglia were compared between groups. Multivariate logistic regression analysis determined which diffusion parameters were independent predictors of PD. Receiver operating characteristic (ROC) analysis compared the diagnostic accuracies of the evaluated indices. Pearson coefficient analysis correlated each diffusional parameter with disease severity.ResultsVic in the contralateral SNpc and putamen were significantly lower in PD patients than in healthy controls (P < 0.00058). Vic and OD in the SNpc and putamen showed significant negative correlations (P < 0.05) with disease severity. Multivariate logistic analysis revealed that Vic (P = 0.0000046) and mean diffusivity (P = 0.019) in the contralateral SNpc were the independent predictors of PD. In the ROC analysis, Vic in the contralateral SNpc showed the best diagnostic performance (mean cutoff, 0.62; sensitivity, 0.88; specificity, 0.83).ConclusionNODDI is likely to be useful for diagnosing PD and assessing its progression.Key Points• Neurite orientation dispersion and density imaging (NODDI) is a new diffusion MRI technique • NODDI estimates neurite microstructure more specifically than diffusion tensor imaging • By using NODDI, nigrostriatal alterations in PD can be evaluated in vivo • NOODI is useful for diagnosing PD and assessing its disease progression

Aging, aortic arch calcification, and multiple brain infarcts are associated with aortogenic brain embolism.

Background: Mobile or ulcerated aortic plaques (MUAPs) on transesophageal echocardiography (TEE) can cause aortogenic brain embolism. Aortic arch calcification (AoAC) on chest X-ray represents systemic atherosclerosis. This study focused on AoAC on chest X-ray and its link with atheromatous aortic plaques (AAPs) on TEE in stroke patients. The aim of the present study was to assess the relationship between AoAC and AAPs in unexplained stroke patients. Methods: A total of 178 patients (mean age: 64 ± 15 years; 115 males) with ischemic stroke who underwent TEE were enrolled. The patients were classified based on TEE findings: (1) AAPs <4 mm; (2) AAPs ≥4 mm, and (3) MUAPs. The extent of AoAC on chest X-ray was divided into 4 grades (0-3). Clinical characteristics including AoAC were compared among the 3 groups. Multiple logistic regression analysis was performed to identify the independent factors associated with MUAPs. An original diagnostic criterion was defined as a potential indicator of MUAPs in unexplained stroke patients. Results: 104 (58%) patients had AAPs <4 mm, 46 (26%) had AAPs ≥4 mm, and 28 (16%) had MUAPs. Older age (OR: 1.14; 95% CI: 1.06-1.24; p = 0.001), AoAC (OR: 2.35; 95% CI: 1.30-4.24; p = 0.005), and multiple infarctions in multiple vascular territories (VTs) demonstrated on diffusion-weighted imaging (DWI) (OR: 2.58; 95% CI: 1.35-4.92; p = 0.004) were independently associated with MUAPs. The CAM score was defined as consisting of the degree of AoAC (0-3 points), age (≥70 years: 1 point), and DWI findings (multiple infarctions in 1 VT: 1 point; 2 VTs: 2 points; more than 3 VTs: 3 points). The prevalence of MUAPs was substantially increased in patients with medium risk (CAM score 3-4, OR: 7.68; 95% CI: 2.89-20.44; p < 0.001) and high risk (CAM score 5-7, OR: 20.63; 95% CI: 5.12-83.06; p < 0.001). Conclusions: Older age, advanced AoAC, and multiple infarctions in multiple VTs are associated with aortogenic brain embolism. The CAM score can be useful for the diagnosis of aortogenic brain embolism.

Impact of low-density lipoprotein to high-density lipoprotein ratio on aortic arch atherosclerosis in unexplained stroke

The ratio of low- (LDL-C) to high- (HDL-C) density lipoprotein cholesterol serves as a positive predictor of atherosclerosis including coronary artery disease. We assessed the contribution of the LDL-C/HDL-C ratio to atheromatous aortic plaques (AAPs) in patients with unexplained ischemic stroke. One hundred thirty-seven patients (age, 65±14years; 87 male) with ischemic stroke underwent transesophageal echocardiography (TEE) and enrolled to the study. Patients were classified based on TEE findings: (1) AAPs<4mm in thickness; (2) AAPs≥4mm; and (3) mobile or ulcerated aortic plaques (MUAPs). We assessed clinical characteristics and biochemical findings, and investigated the relationship between AAPs and the LDL-C/HDL-C ratio of stroke patients. 84 (61%) patients had AAPs<4mm, 29 (21%) had AAPs≥4mm, and 24 (18%) had MUAPs. Older age (OR: 1.18; 95% CI: 1.08 to 1.30; p=0.001), and LDL-C/HDL-C ratio (OR: 2.94; 95% CI: 1.10 to 7.87; p=0.032) were significantly associated with MUAPs. The incidence of MUAPs substantially increased in patients with LDL-C/HDL-C ratios of >2.23 (p<0.001) when the ratios were divided into quartiles. The LDL-C/HDL-C ratio was closely associated with MUAPs. An elevated LDL-C/HDL-C ratio could be a positive predictor of aortogenic brain embolism.

Gray Matter Abnormalities in Idiopathic Parkinson's Disease: Evaluation by Diffusional Kurtosis Imaging and Neurite Orientation Dispersion and Density Imaging

Mapping gray matter (GM) pathology in Parkinsons disease (PD) with conventional MRI is challenging, and the need for more sensitive brain imaging techniques is essential to facilitate early diagnosis and assessment of disease severity. GM microstructure was assessed with GM‐based spatial statistics applied to diffusion kurtosis imaging (DKI) and neurite orientation dispersion imaging (NODDI) in 30 participants with PD and 28 age‐ and gender‐matched controls. These were compared with currently used assessment methods such as diffusion tensor imaging (DTI), voxel‐based morphometry (VBM), and surface‐based cortical thickness analysis. Linear discriminant analysis (LDA) was also used to test whether subject diagnosis could be predicted based on a linear combination of regional diffusion metrics. Significant differences in GM microstructure were observed in the striatum and the frontal, temporal, limbic, and paralimbic areas in PD patients using DKI and NODDI. Significant correlations between motor deficits and GM microstructure were also noted in these areas. Traditional VBM and surface‐based cortical thickness analyses failed to detect any GM differences. LDA indicated that mean kurtosis (MK) and intra cellular volume fraction (ICVF) were the most accurate predictors of diagnostic status. In conclusion, DKI and NODDI can detect cerebral GM abnormalities in PD in a more sensitive manner when compared with conventional methods. Hence, these methods may be useful for the diagnosis of PD and assessment of motor deficits. Hum Brain Mapp 38:3704–3722, 2017.

Decreased long-chain acylcarnitines from insufficient β-oxidation as potential early diagnostic markers for Parkinson’s disease

Increasing evidence shows that metabolic abnormalities in body fluids are distinguishing features of the pathophysiology of Parkinson’s disease. However, a non-invasive approach has not been established in the earliest or pre-symptomatic phases. Here, we report comprehensive double-cohort analyses of the metabolome using capillary electrophoresis/liquid chromatography mass-spectrometry. The plasma analyses identified 18 Parkinson’s disease-specific metabolites and revealed decreased levels of seven long-chain acylcarnitines in two Parkinson’s disease cohorts (n = 109, 145) compared with controls (n = 32, 45), respectively. Furthermore, statistically significant decreases in five long-chain acylcarnitines were detected in Hoehn and Yahr stage I. Likewise, decreased levels of acylcarnitine(16:0), a decreased ratio of acylcarnitine(16:0) to fatty acid(16:0), and an increased index of carnitine palmitoyltransferase 1 were identified in Hoehn and Yahr stage I of both cohorts, suggesting of initial β-oxidation suppression. Receiver operating characteristic curves produced using 12–14 long-chain acylcarnitines provided a large area of under the curve, high specificity and moderate sensitivity for diagnosing Parkinson’s disease. Our data demonstrate that a primary decrement of mitochondrial β-oxidation and that 12–14 long-chain acylcarnitines decreases would be promising diagnostic biomarkers for Parkinson’s disease.

Serum caffeine and metabolites are reliable biomarkers of early Parkinson disease

Objective To investigate the kinetics and metabolism of caffeine in serum from patients with Parkinson disease (PD) and controls using liquid chromatography–mass spectrometry. Methods Levels of caffeine and its 11 metabolites in serum from 108 patients with PD and 31 age-matched healthy controls were examined by liquid chromatography–mass spectrometry. Mutations in caffeine-associated genes were screened by direct sequencing. Results Serum levels of caffeine and 9 of its downstream metabolites were significantly decreased even in patients with early PD, unrelated to total caffeine intake or disease severity. No significant genetic variations in CYP1A2 or CYP2E1, encoding cytochrome P450 enzymes primarily involved in metabolizing caffeine in humans, were detected compared with controls. Likewise, caffeine concentrations in patients with PD with motor complications were significantly decreased compared with those without motor complications. No associations between disease severity and single nucleotide variants of the ADORA2A gene encoding adenosine 2A receptor were detected, implying a dissociation of receptor sensitivity changes and phenotype. The profile of serum caffeine and metabolite levels was identified as a potential diagnostic biomarker by receiver operating characteristic curve analysis. Conclusion Absolute lower levels of caffeine and caffeine metabolite profiles are promising diagnostic biomarkers for early PD. This is consistent with the neuroprotective effect of caffeine previously revealed by epidemiologic and experimental studies. Classification of evidence This study provides Class III evidence that decreased serum levels of caffeine and its metabolites identify patients with PD.

A Patient with the GLA p.E66Q Mutation Exhibiting Vascular Parkinsonism and Bilateral Pulvinar Lesions

A 76-year-old man was admitted to our hospital due to gait difficulty. Brain imaging indicated bilateral pulvinar lesions and moderate white matter lesions. The serum α-galactosidase A levels were measured for the differential diagnosis of bilateral pulvinar lesions and were found to be abnormally low. Therefore, the patient was suspected to have variant Fabry disease. A GLA mutation analysis showed the p.E66Q mutation, which is speculated to be a functional polymorphism rather than a disease-causing mutation of Fabry disease. Enzyme replacement therapy did not result in a marked improvement, however, the disease progression stopped.

Ophthalmic nerve hypertrophy in chronic inflammatory demyelinating polyradiculoneuropathy

A 59-year-old woman with a long-standing diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) developed facial numbness and exophthalmos. Sural nerve biopsy revealed onion bulb formation consistent with CIDP. Neurologic examinations revealed distal dominant muscle atrophy with areflexia and impairment of all sensory modalities; cranial nerve involvement, including bilateral exophthalmos, left-side facial palsy, and left-side periorbital hypoesthesia; and swelling of the sural and subclavian nerves. MRI demonstrated marked thickening of bilateral ophthalmic nerves (figure). Such a finding has been reported rarely in the literature.1 Neurologists should be aware that patients with CIDP might show exophthalmos due to ophthalmic nerve hypertrophy.

Neuromelanin imaging and midbrain volumetry in progressive supranuclear palsy and Parkinson's disease: Neuromelanin-MRI and Midbrain Volumetry

Background Nigral degeneration patterns differ between PSP and PD. However, the relationship between nigral degeneration and midbrain atrophy in PSP remains unclear.