Photo-oxygenation of histidine residue inhibits α-synuclein aggregation.

Aggregation of α-synuclein (α-syn) into amyloid is the pathological hallmark of several neurodegenerative disorders, including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. It is widely accepted that α-syn aggregation is associated with neurodegeneration, although the mechanisms are not yet fully understood. Therefore, the inhibition of α-syn aggregation is a potential therapeutic approach against these diseases. This study used the photocatalyst for α-syn photo-oxygenation, which selectively adds oxygen atoms to fibrils. Our findings demonstrate that photo-oxygenation using this photocatalyst successfully inhibits α-syn aggregation, particularly by reducing its seeding ability. Notably, we also discovered that photo-oxygenation of the histidine at the 50th residue in α-syn aggregates is responsible for the inhibitory effect. These findings indicate that photo-oxygenation of the histidine residue in α-syn is a potential therapeutic strategy for synucleinopathies.

Clinicopathological study of dementia with grains presenting with parkinsonism compared with a typical case.

Argyrophilic grain disease (AGD) is one of the major pathological backgrounds of senile dementia. Dementia with grains refers to cases of dementia for which AGD is the sole background pathology responsible for dementia. Recent studies have suggested an association between dementia with grains and parkinsonism. In this study, we aimed to present two autopsy cases of dementia with grains. Case 1 was an 85-year-old man who exhibited amnestic dementia and parkinsonism, including postural instability, upward gaze palsy, and neck and trunk rigidity. The patient was clinically diagnosed with progressive supranuclear palsy and Alzheimer's disease. Case 2 was a 90-year-old man with pure amnestic dementia, clinically diagnosed as Alzheimer's disease. Recently, we used cryo-electron microscopy to confirm that the tau accumulated in both cases had the same three-dimensional structure. In this study, we compared the detailed clinical picture and neuropathological findings using classical staining and immunostaining methods. Both cases exhibited argyrophilic grains and tau-immunoreactive structures in the brainstem and basal ganglia, especially in the nigrostriatal and limbic systems. However, Case 1 had more tau immunoreactive structures. Considering the absence of other disease-specific structures such as tufted astrocytes, astrocytic plaques and globular glial inclusions, lack of conspicuous cerebrovascular disease, and no history of medications that could cause parkinsonism, our findings suggest an association between AGD in the nigrostriatal system and parkinsonism.

Proteomic profile of nuclei containing p62-positive inclusions in a patient with neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the neurons, glial cells, and other somatic cells. Although CGG repeat expansions in NOTCH2NLC have been identified in most East Asian patients with NIID, the pathophysiology of NIID remains unclear. Ubiquitin- and p62-positive intranuclear inclusions are the pathological hallmark of NIID. Targeted immunostaining studies have identified several other proteins present in these inclusions. However, the global molecular changes within nuclei with these inclusions remained unclear. Herein, we analyzed the proteomic profile of nuclei with p62-positive inclusions in a NIID patient with CGG repeat expansion in NOTCH2NLC to discover candidate proteins involved in the NIID pathophysiology. We used fluorescence-activated cell sorting and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify each protein identified in the nuclei with p62-positive inclusions. The distribution of increased proteins was confirmed via immunofluorescence in autopsy brain samples from three patients with genetically confirmed NIID. Overall, 526 proteins were identified, of which 243 were consistently quantified using MS. A 1.4-fold increase was consistently observed for 20 proteins in nuclei with p62-positive inclusions compared to those without. Fifteen proteins identified with medium or high confidence in the LC-MS/MS analysis were further evaluated. Gene ontology enrichment analysis showed enrichment of several terms, including poly(A) RNA binding, nucleosomal DNA binding, and protein binding. Immunofluorescence studies confirmed that the fluorescent intensities of increased RNA-binding proteins identified by proteomic analysis, namely hnRNP A2/B1, hnRNP A3, and hnRNP C1/C2, were higher in the nuclei with p62-positive inclusions than in those without, which were not confined to the intranuclear inclusions. We identified several increased proteins in nuclei with p62-positive inclusions. Although larger studies are needed to validate our results, these proteomic data may form the basis for understanding the pathophysiology of NIID.

Transcriptional downregulation of FAM3C/ILEI in the Alzheimer's brain.

Amyloid-ß (Aß) accumulation in the brain triggers the pathogenic cascade for Alzheimer's disease (AD) development. The secretory protein FAM3C (also named ILEI) is a candidate for an endogenous suppressor of Aß production. In this study, we found that FAM3C expression was transcriptionally downregulated in the AD brain. To determine the transcriptional mechanism of the human FAM3C gene, we delineated the minimal 5'-flanking sequence required for basal promoter activity. From a database search for DNA-binding motifs, expression analysis using cultured cells, and promoter DNA-binding assays, we identified SP1 and EBF1 as candidate basal transcription factors for FAM3C, and found that SMAD1 was a putative inducible transcription factor and KLF6 was a transcription repressor for FAM3C. Genomic deletion of the basal promoter sequence from HEK293 and Neuro-2a cells markedly reduced endogenous expression of FAM3C and abrogated SP1- or EBF1-mediated induction of FAM3C. Nuclear protein extracts from AD brains contained lower levels of SP1 and EBF1 than did those from control brains, although the relative mRNA levels of these factors did not differ significantly between the groups. Additionally, the ability of nuclear SP1 and EBF1 in AD brains to bind with the basal promoter sequence-containing DNA probe was reduced compared with the binding ability of these factors in control brains. Thus, the transcriptional downregulation of FAM3C in the AD brain is attributable to the reduced nuclear levels and genomic DNA binding of SP1 and EBF1. An expressional decline in FAM3C may be a risk factor for Aß accumulation and eventually AD development.

Long-term survival from progressive multifocal leukoencephalopathy in living-donor liver transplant recipient with preformed donor-specific antibody.

Intensive immunosuppression has enabled liver transplantation even in recipients with preformed donor-specific antibodies (DSA), an independent risk factor for graft rejection. However, these recipients may also be at high risk of progressive multifocal encephalopathy (PML) due to the comorbid immunosuppressed status. A 58-year-old woman presented with self-limited focal-to-bilateral tonic-clonic seizures 9 months after liver transplantation. She was desensitized using rituximab and plasma exchange before transplantation and was subsequently treated with steroids, tacrolimus, and everolimus after transplantation for her preformed DSA. Neurological examination revealed mild acalculia and agraphia. Cranial MRI showed asymmetric, cortex-sparing white matter lesions that increased over a week in the left frontal, left parietal, and right parieto-occipital lobes. Polymerase chain reaction (PCR) of the cerebrospinal fluid for the JC supported the diagnosis of PML. Immune reconstitution by reducing the immunosuppressant dose stopped lesion expansion, and PCR of the cerebrospinal fluid for the JC virus became negative. Graft rejection occurred 2 months after immune reconstitution, requiring readjustment of immunosuppressants. Forty-eight months after PML onset, the patient lived at home without disabling deficits. Intensive immunosuppression may predispose recipients to PML after liver transplantation with preformed DSA. Early immune reconstitution and careful monitoring of graft rejection may help improve outcomes.

Far-field potential of the compound muscle action potential as a reliable marker in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Reliable neurophysiological markers in amyotrophic lateral sclerosis (ALS) are of great interest. The compound muscle action potential (CMAP) amplitude has been a conventional marker, although it is greatly influenced by the electrode position. We propose the far-field potential of the CMAP (FFP-CMAP) as a new neurophysiological marker in ALS. METHODS: Patients with ALS and age-matched healthy controls were enrolled. We used a proximal reference (pref) in addition to the conventional distal reference (dref). Routine CMAP was recorded from the belly-dref lead and FFP-CMAP from the dref-pref lead for the ulnar and tibial nerves. Multiple point stimulation motor unit number estimation (MUNE) was also examined in the ulnar nerve. Inter-rater reproducibility was evaluated by two examiners, and some patients were followed up every 3 mo for 1 y. RESULTS: We tested 17 patients with ALS and 10 controls. The amplitudes of routine CMAP and FFP-CMAP in the ulnar and tibial nerves, and hypothenar MUNE value in the ulnar nerve were significantly decreased in ALS compared to controls. Ulnar FFP-CMAP achieved the highest inter-rater intraclass correlation coefficient (ICC) value (0.942) when compared with routine CMAP (0.880) and MUNE (0.839). The tibial FFP-CMAP had a higher ICC value (0.986) than the routine CMAP (0.697). In this way, the FFP-CMAP showed high inter-rater reproducibility because its shape was not much influenced by the electrode position. During 1-y follow-up, decline of CMAP, FFP, and MUNE showed significant correlations with the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R). DISCUSSION: The FFP-CMAP shows promise as a reliable marker for ALS.

Correlations between cerebrospinal fluid homovanillic acid and dopamine transporter SPECT in degenerative parkinsonian syndromes.

Both cerebrospinal fluid (CSF) homovanillic acid (HVA) and striatal dopamine transporter (DAT) binding on single-photon emission computed tomography (SPECT) reflect nigrostriatal dopaminergic function, but studies on the relationship between the two have been limited. It is also unknown whether the reported variance in striatal DAT binding among diseases reflects the pathophysiology or characteristics of the subjects. We included 70 patients with Parkinson's disease (PD), 12 with progressive supranuclear palsy (PSP), 12 with multiple system atrophy, six with corticobasal syndrome, and nine with Alzheimer's disease as disease control, who underwent both CSF analysis and 123I-N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane (123I-ioflupane) SPECT. We evaluated the correlation between CSF HVA concentration and the specific binding ratio (SBR) of striatal DAT binding. We also compared the SBR for each diagnosis, controlling for CSF HVA concentration. The correlations between the two were significant in patients with PD (r = 0.34, p = 0.004) and PSP (r = 0.77, p = 0.004). The mean SBR value was the lowest in patients with PSP and was significantly lower in patients with PSP than in those with PD (p = 0.037) after adjusting for CSF HVA concentration. Our study demonstrates that striatal DAT binding correlates with CSF HVA concentration in both PD and PSP, and striatal DAT reduction would be more advanced in PSP than in PD at an equivalent dopamine level. Striatal DAT binding may correlate with dopamine levels in the brain. The pathophysiology of each diagnosis may explain this difference.

State-of-the-art of lumbar puncture and its place in the journey of patients with Alzheimer's disease.

Recent advances in developing disease-modifying therapies (DMT) for Alzheimer's disease (AD), and the recognition that AD pathophysiology emerges decades before clinical symptoms, necessitate a paradigm shift of health-care systems toward biomarker-guided early detection, diagnosis, and therapeutic decision-making. Appropriate incorporation of cerebrospinal fluid biomarker analysis in clinical practice is an essential step toward system readiness for accommodating the demand of AD diagnosis and proper use of DMTs-once they become available. However, the use of lumbar puncture (LP) in individuals with suspected neurodegenerative diseases such as AD is inconsistent, and the perception of its utility and safety differs considerably among medical specialties as well as among regions and countries. This review describes the state-of-the-art evidence concerning the safety profile of LP in older adults, discusses the risk factors for LP-associated adverse events, and provides recommendations and an outlook for optimized use and global implementation of LP in individuals with suspected AD.

Need of care in interpreting Google Trends-based COVID-19 infodemiological study results: potential risk of false-positivity.

BACKGROUND: Google Trends (GT) is being used as an epidemiological tool to study coronavirus disease (COVID-19) by identifying keywords in search trends that are predictive for the COVID-19 epidemiological burden. However, many of the earlier GT-based studies include potential statistical fallacies by measuring the correlation between non-stationary time sequences without adjusting for multiple comparisons or the confounding of media coverage, leading to concerns about the increased risk of obtaining false-positive results. In this study, we aimed to apply statistically more favorable methods to validate the earlier GT-based COVID-19 study results. METHODS: We extracted the relative GT search volume for keywords associated with COVID-19 symptoms, and evaluated their Granger-causality to weekly COVID-19 positivity in eight English-speaking countries and Japan. In addition, the impact of media coverage on keywords with significant Granger-causality was further evaluated using Japanese regional data. RESULTS: Our Granger causality-based approach largely decreased (by up to approximately one-third) the number of keywords identified as having a significant temporal relationship with the COVID-19 trend when compared to those identified by Pearson or Spearman's rank correlation-based approach. "Sense of smell" and "loss of smell" were the most reliable GT keywords across all the evaluated countries; however, when adjusted with their media coverage, these keyword trends did not Granger-cause the COVID-19 positivity trends (in Japan). CONCLUSIONS: Our results suggest that some of the search keywords reported as candidate predictive measures in earlier GT-based COVID-19 studies may potentially be unreliable; therefore, caution is necessary when interpreting published GT-based study results.

Differences in lesion characteristics and patient background associated with the medium-term clinical outcomes of bare-metal and first-, second- and third-generation drug-eluting stents.

We investigated the lesion characteristics and patient background factors associated with the medium-term incidence of major adverse cardiac events (MACEs) for bare-metal stents (BMS) and 1st-, 2nd- and 3rd-generation drug-eluting stents (DES) using the PCI-Registry (FU-Registry). Between January 2003 and March 2016, 2967 cases/3508 lesions for which percutaneous coronary intervention was performed at Fukuoka University Hospital and related facilities were enrolled. Patients were divided into BMS and 1st-, 2nd- and 3rd-generation drug-eluting stent (DES) groups. The incidence of MACEs in the BMS group (26.2%) was significantly higher than those in the 1st, 2nd and 3rd DES groups (18.0%, 12.5%, and 11.0%, respectively). The incidence of MACEs in the BMS group was strongly associated with insulin use, hemodialysis, low high-density lipoprotein cholesterol, stent minimum lesion diameter, stent length, severe calcification and a small vessel diameter of less than 2.5 mm. Some of these factors showed no association with MACEs among the drug-elution groups, and only hemodialysis, arteriosclerosis obliterans and severe calcification showed a strong correlation in the 2nd DES group. In the 3rd DES group, none of the factors considered were associated with MACEs. In conclusion, in stent implantation, the number of factors associated with MACEs has gradually decreased as the stent generation increased.

Efficacy and Cost-effectiveness of Promotion Methods to Recruit Participants to an Online Screening Registry for Alzheimer Disease Prevention Trials: Observational Study.

BACKGROUND: Web-based screening may be suitable for identifying individuals with presymptomatic latent diseases for recruitment to clinical studies, as such people do not often visit hospitals in the presymptomatic stage. The promotion of such online screening studies is critical to their success, although it remains uncertain how the effectiveness of such promotion can differ, depending on the different promotion methods, domains of interest, or countries of implementation. OBJECTIVE: The Japanese Trial-Ready Cohort (J-TRC) web study is our ongoing online screening registry to identify individuals with presymptomatic Alzheimer disease (AD), aimed at facilitating the clinical trials for AD prevention. Within the first 9 months of its 2019 launch, the J-TRC web study recruited thousands of online participants via multiple methods of promotion, including press releases, newspaper advertisements, web advertisements, or direct email invitations. Here, we aimed to quantitatively evaluate efficacy and cost-effectiveness of each of these multimodal promotion methods. METHODS: We applied the vector-autoregression model to assess the degree of contribution of each type of promotion to the following target metrics: number of daily visitors to the J-TRC website, number of daily registrants to the J-TRC web study, daily rate of registration among visitors, daily rate of eligible participants among registrants, and median age of daily registrants. The average cost-effectiveness for each promotion method was also calculated using the total cost and the coefficients in the vector-autoregression model. RESULTS: During the first 9 months of the reviewed period from October 31, 2019 to June 17, 2020, there were 48,334 website visitors and 4429 registrations (9.16% of 48,334 visitors), of which 3081 (69.56%) were eligible registrations. Initial press release reports and newspaper advertisements had a marked effect on increasing the number of daily visitors and daily registrants. Web advertisements significantly contributed to the increase in daily visitors (P<.001) but not to the daily registrants, and it also lowered the rate of registrations and the median age of daily registrants. Website visitors from the direct email invitation sent to other cognitive registries seem to have registered with the highest reliability. The calculated average cost-effectiveness for the initial press release was US $24.60 per visitor and US $96.10 per registrant, while the calculated average cost-effectiveness for the newspaper advertisements was US $28.60 per visitor and US $227.90 per registrant. CONCLUSIONS: Our multivariate time-series analysis showed that each promotion method had different features in their effect of recruiting participants to the J-TRC web study. Under the advertisement condition settings thus far, newspaper advertisements and initial press releases were the most effective promotion methods, with fair cost-effectiveness that was equivalent to earlier online studies. These results can provide important suggestions for future promotions for the recruitment of presymptomatic participants to AD clinical trials in Japan.

Impact of visit-to-visit variability in blood pressure on coronary plaque as assessed by integrated backscatter intravascular ultrasound.

INTRODUCTION: Visit-to-visit variability (VVV) in blood pressure (BP) has been reported to be a strong predictor of cardiovascular disease. However, the association between VVV in BP and coronary plaque composition has not been fully elucidated. METHODS: One hundred-two consecutive patients with coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI) using integrated backscatter (IB) intravascular ultrasound (IVUS), and who had at least six clinic visits a year before PCI were included. We measured systolic and diastolic BP (SBP and DBP) at each visit and determined VVV in BP expressed as the standard deviation of the average BP. Grayscale and IB IVUS examinations were performed for the culprit lesion of a coronary artery just before PCI. RESULTS: There were no significant associations between the average SBP or DBP and various IVUS parameters. However, VVV in SBP was positively correlated with both the percentage (%) of atheroma volume (ß = 0.23, p = .02) and % lipid volume (ß = 0.53, p < .0001). VVV in DBP was positively correlated with % lipid volume (ß = 0.24, p = .01), while there was no significant correlation between VVV in DBP and % atheroma volume. A  multivariable linear regression analysis showed that VVV in SBP was independently associated with % atheroma volume (p = .04) and % lipid volume (p < .001). CONCLUSIONS: Larger VVV in SBP was significantly associated with an increased plaque burden and lipid composition at the culprit lesion of a coronary artery in CAD patients. The improvement of VVV in SBP may contribute to the regression and stabilization of coronary plaques.

Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by pathology of accumulated amyloid ß (Aß) and phosphorylated tau proteins in the brain. Postmortem degradation and cellular complexity within the brain have limited approaches to molecularly define the causal relationship between pathological features and neuronal dysfunction in AD. To overcome these limitations, we analyzed the neuron-specific DNA methylome of postmortem brain samples from AD patients, which allowed differentially hypomethylated region of the BRCA1 promoter to be identified. Expression of BRCA1 was significantly up-regulated in AD brains, consistent with its hypomethylation. BRCA1 protein levels were also elevated in response to DNA damage induced by Aß. BRCA1 became mislocalized to the cytoplasm and highly insoluble in a tau-dependent manner, resulting in DNA fragmentation in both in vitro cellular and in vivo mouse models. BRCA1 dysfunction under Aß burden is consistent with concomitant deterioration of genomic integrity and synaptic plasticity. The Brca1 promoter region of AD model mice brain was similarly hypomethylated, indicating an epigenetic mechanism underlying BRCA1 regulation in AD. Our results suggest deterioration of DNA integrity as a central contributing factor in AD pathogenesis. Moreover, these data demonstrate the technical feasibility of using neuron-specific DNA methylome analysis to facilitate discovery of etiological candidates in sporadic neurodegenerative diseases.

Neurological and related adverse events in immune checkpoint inhibitors: a pharmacovigilance study from the Japanese Adverse Drug Event Report database.

INTRODUCTION: Immune checkpoint inhibitors (ICPI), a breakthrough immunotherapy for cancer, can cause serious neurological adverse events (AEs). We aimed to investigate the characteristics of the neurological and related AEs associated with ICPI treatment, using a large pharmacovigilance database from Japan. METHODS: We conducted disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database containing 566,698 patient cases recorded between April 2004 and March 2019, to detect neurological and related AE signals associated with ICPI treatment by calculating reporting odds ratio (ROR). RESULTS: Among 7604 cases with ICPI usage, we identified 583 cases (7.67%) with a significantly high reporting of neurological and related AEs (lower 95% of the ROR > 1), including myasthenia gravis (MG), inflammatory myositis, non-infectious encephalitis/myelitis, non-infectious meningitis, hypophysitis/hypopituitarism, and peripheral neuropathy including Guillain-Barre syndrome (GBS). Among the ICPI subtypes, when compared to nivolumab as a reference, number of hypophysitis, hypopituitarism, and meningitis reports from the use of ipilimumab and number of encephalitis/myelitis and meningitis reports from the use of anti-programmed cell death-ligand-1 (PD-L1) agents were significantly higher. Additionally, time to AE onset of symptoms post administration was short in meningitis (median 21 days), MG (median 28 days), myositis (median 28 days), and encephalitis/myelitis (median 32.5 days), while it was longer in peripheral neuropathy (median 42 days), hypophysitis (median 94 days), and hypopituitarism (median 112 days). CONCLUSIONS: Our results showed characteristic features of neurological and related AEs associated with each ICPI subtype, reported in a large number of Japanese patients. This would help in prompt identification and treatment of neurological AEs associated with ICPI treatment.

Influence of chronic kidney disease on coronary plaque components in coronary artery disease patients with both diabetes mellitus and hypertension.

Chronic kidney disease (CKD) is well known to be associated with an increased incidence of coronary artery disease (CAD). Diabetes mellitus (DM) and hypertension (HTN), both of which are traditional risk factors for CAD, are the two most common causes of CKD. However, the influence of CKD on coronary atherosclerosis in CAD patients who have both DM and HTN remains uncertain. In these patients, we examined the relationship between CKD and coronary plaque using integrated backscatter intravascular ultrasound (IB IVUS). Two hundred two CAD patients with both DM and HTN who underwent percutaneous coronary intervention using IB IVUS were included. The patients were divided into two groups: CKD group (n = 106) and non-CKD group (n = 96). Gray-scale and IB IVUS examinations were conducted for the non-culprit segment of a coronary artery. As a result, although there was no significant difference in the percentage of plaque volume, the percentage of lipid volume was significantly higher in the CKD group than in the non-CKD group [median (IQR): 56.7% (45.4-67.0%) vs. 52.0% (38.3-60.2%), p = 0.03]. In all of the patients, estimated glomerular filtration rate levels were negatively correlated with the percentage of lipid volume (r = - 0.15, p = 0.03) and positively correlated with the percentage of fibrosis volume (r = 0.15, p = 0.04). A multivariate regression analysis showed that CKD was an independent predictor associated with the increased lipid volume (ß = 0.15, p = 0.047) and decreased fibrosis volume (ß = - 0.16, p = 0.03) in coronary plaques. In conclusion, among CAD patients who had both DM and HTN, CKD was associated with lipid-rich coronary plaques. CKD may contribute to the vulnerability of coronary plaque in these very high-risk patients.

Fragility Index in Randomized Controlled Trials of Ischemic Stroke.

OBJECTIVE: The fragility index (FI), a minimum number of events in 1 arm of a clinical trial required to revert the statistically significant result to nonsignificant, has recently been developed as an easy-to-understand novel metric to evaluate the robustness of randomized controlled trials (RCTs). Here, we evaluated the FI of RCTs in the field of neurology, particularly in studies of ischemic stroke. METHODS: Previous literature published between June 1, 2012 and May 31, 2018 were reviewed from the MEDLINE database by the authors. The original article reporting the significant RCT result, of which a dichotomous outcome was set as its primary outcome measure, was included to evaluate the robustness of the result by calculating the FI. In addition, recent studies examining FI in other clinical fields were reviewed and summarized. RESULTS: In the 25 eligible RCT studies, the median total number of study participants was 206 (inter quartile range: 144-450) and the median FI was 7 (inter quartile range: 4-15.0). The FI showed a strong negative correlation with the observed P value. There was no significant difference in the FI between RCTs with and without acute settings. Our median FI was higher than the median FI of 2.5 of previous studies examining FI in other clinical fields, as only 20% (5 of 25) of studies included in our study had an FI less than 2.5. CONCLUSION: Our results suggest that many RCTs in the field of ischemic stroke have a fair robustness, when compared to those in other clinical fields.

Impact of the triglyceride level on coronary plaque components in female patients with coronary artery disease treated with statins.

Several studies have reported that elevated triglyceride (TG) levels may be more strongly associated with an increased risk of coronary artery disease (CAD) in females than in males. We examined gender differences in the relationship between TG levels and coronary atherosclerosis using integrated backscatter intravascular ultrasound (IB IVUS) in CAD patients treated with statins. Three hundred seventy-eight CAD patients (105 females and 273 males) who underwent percutaneous coronary intervention using IB IVUS, and who were already receiving statin treatment, were included. Gray-scale and IB IVUS examinations were performed for the non-culprit segment of a coronary artery and fasting serum TG concentrations were measured. We found that TG levels were significantly correlated with increased lipid (r = 0.40, p < 0.001) and decreased fibrous (r = - 0.37, p < 0.001) plaque components in females, but not in males. Low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels were not related to either the gray-scale or IB IVUS parameters in both genders. After adjustment for conventional coronary risk factors by a multivariate stepwise regression analysis, higher TG levels in females were independently associated with increased lipid (ß = 0.31, p< 0.001) contents in coronary plaques. In conclusion, among CAD patients treated with statins, TG levels were associated with lipid-rich coronary plaques in females, but not in males. TG levels may be more important indicators of residual risk after statin treatment in females than in males.

Associations between microalbuminuria and parameters of flow-mediated vasodilatation obtained by continuous measurement approaches.

The associations between microalbuminuria and various parameters of flow-mediated vasodilatation (FMD) are not completely understood. We retrospectively analyzed 265 consecutive patients who underwent coronary angiography and in whom we could measure FMD and the urine albumin-creatinine ratio (UACR). Using 15 continuous measurement approaches, we measured FMD as the magnitude of the percentage change in the brachial artery diameter from baseline to peak (bFMD), the maximum FMD rate calculated as the maximal slope of dilation (FMD-MDR), and the integrated FMD response calculated as the area under the dilation curve during the 60- and 120-s dilation periods (FMD-AUC60 and FMD-AUC120). We divided the patients into two groups according to UACR: normoalbuminuria (NOR, n = 211) and microalbuminuria (MIC, n = 54). The MIC group showed a significantly higher percentage of coronary artery disease than the NOR group. FMD-AUC60 and FMD-AUC120, but not FMD-MDR, in the MIC group were significantly lower than those in the NOR group. On the other hand, bFMD in the MIC group tended to be lower than that in the NOR group, but this difference was not significant. A multiple regression analysis indicated that FMD-AUC120 and diabetes mellitus were predictors of MIC. Finally, we defined the cut-off value of FMD-AUC120 for the presence of MIC in all patients as 8.4 mm x second (sensitivity 0.640, specificity 0.588) by a receiver-operating characteristic curve analysis. In conclusion, this study provides more definitive evidence for the association of microalbuminuria with endothelial dysfunction. FMD-AUC120 may be a superior marker for MIC.

Japanese and North American Alzheimer's Disease Neuroimaging Initiative studies: Harmonization for international trials.

INTRODUCTION: We conducted Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) and compared the basic characteristics and progression profiles with those of ADNI in North America. METHODS: A total of 537 Japanese subjects with normal cognition, late amnestic mild cognitive impairment (LMCI), or mild Alzheimer's disease (AD) were enrolled using the same criteria as ADNI. Rates of changes in representative cognitive or functional measures were compared for amyloid positron emission tomography- or cerebrospinal fluid amyloid ß(1-42)-positive LMCI and mild AD between J-ADNI and ADNI. RESULTS: Amyloid positivity rates were significantly higher in normal cognition of ADNI but at similar levels in LMCI and mild AD between J-ADNI and ADNI. Profiles of decline in cognitive or functional measures in amyloid-positive LMCI in J-ADNI (n = 75) and ADNI (n = 269) were remarkably similar, whereas those in mild AD were milder in J-ADNI (n = 73) compared with ADNI (n = 230). DISCUSSION: These results support the feasibility of bridging of clinical trials in the prodromal stage of AD between Asia and western countries.

Molecular Mechanisms of Oligodendrocyte Regeneration in White Matter-Related Diseases.

Even in adult brains, restorative mechanisms are still retained to maintain the microenvironment. Under the pathological conditions of central nervous system (CNS) diseases, several immature cells in the brain would be activated as a compensative response. As the concept of the neurovascular unit emphasizes, cell-cell interactions play important roles in this restorative process. White matter damage and oligodendrocyte loss are representative characteristics for many neurodegenerative diseases. In response to oligodendrocyte damage, residual oligodendrocyte precursor cells (OPCs) initiate their proliferation and differentiation for the purpose of remyelination. Although mechanisms of oligodendrogenesis and remyelination in CNS diseases are still mostly unknown and understudied, accumulated evidence now suggests that support from neighboring cells is necessary for OPC proliferation and differentiation. In this review, we first overview basic mechanisms of interaction between oligodendrocyte lineage cells and neighboring cells, and then introduce how oligodendrogenesis occurs under the conditions of neurodegenerative diseases, focusing on vascular cognitive impairment syndrome, Alzheimer's disease, and multiple sclerosis.