Senile depression (SD) is a heterogeneous syndrome. Several clinical profiles are more likely to appear in SD than in early‐life depression, but it remains unclear whether the pathophysiology is ...different. The prevalence of dementia increases with aging, and the underlying pathophysiological processes in the preclinical phase begin even before cognitive deficits or neurological signs appear. SD may be either a risk factor for developing dementia or a prodromal stage of dementia. The inconsistent findings regarding the association between SD and incident dementia may be attributable to the neuropathological heterogeneity underlying SD. Most studies have focused on patients with the clinical diagnosis of Alzheimer disease (AD) as an outcome, but several clinicopathological studies suggest that primary age‐related tauopathy and argyrophilic grain disease may account for a proportion of cases clinically misdiagnosed as AD in the elderly population. Furthermore, most AD cases have additional neuropathologic changes such as cerebrovascular disease and Lewy body disease. Here, we review the neuropathological findings linking SD to incident dementia, focusing on common age‐related neuropathologies. In particular, the roles of disturbance of neural circuity, imbalance of monoaminergic systems, dysregulation of the hypothalamic–pituitary–adrenal axis, and elevated neuroinflammatory status are discussed. Finally, we review the current treatment of SD in the context of age‐related neuropathological changes.
Aim
To assess the association between plasma amyloid β (Aβ) 42/40, phosphorylated tau (p‐τ)181, glial fibrillary acidic protein (GFAP), or neurofilament light chain (NfL) and the risk of dementia and ...to determine whether these plasma biomarkers could improve the ability to predict incident dementia in a general older population.
Methods
A total of 1346 Japanese community‐dwelling individuals aged ≥65 years without dementia were followed prospectively for 5.0 years. Plasma biomarkers were quantified using a Simoa HD‐X analyzer. A Cox proportional hazards model was used to estimate the hazard ratios of each plasma biomarker level for the risk of dementia.
Results
During the follow‐up, 151 participants developed dementia, of whom 108 had Alzheimer disease (AD) and 43 non–Alzheimer dementia (non‐AD). Lower plasma Aβ42/40 levels and higher plasma p‐τ181 levels were significantly associated with developing AD but not non‐AD, whereas significant associations were observed between higher plasma levels of GFAP and NfL and risk of both AD and non‐AD (all P for trend <0.05). In addition, adding these four plasma biomarkers into a model consisting of the total score of the dementia risk model significantly improved the predictive ability for incident dementia.
Conclusion
Our findings suggest that plasma Aβ42/40 and p‐τ181 are specific markers of AD, and plasma GFAP and NfL are potential biomarkers for all‐cause dementia in the general Japanese older population. In addition, the measurement of these plasma biomarkers may be a useful and relatively low‐invasive procedure for identifying individuals at high risk for developing dementia in clinical practice.
Aim
Despite continuing research into Alzheimer's disease (AD), its pathological mechanisms and modulating factors remain unknown. Several genes influence AD pathogenesis by affecting inflammatory ...pathways. Myocyte‐enhancer factor 2C (MEF2C) is one such candidate gene for AD.
Methods
We examined MEF2C mRNA expression levels and methylation rates of CpG on its promoter region in peripheral leukocytes from Japanese AD patients compared with age‐ and sex‐matched control subjects.
Results
In peripheral leukocytes, MEF2C mRNA expression levels in AD subjects were significantly lower than those in control subjects (0.86 ± 0.25 vs 0.99 ± 0.27, respectively, P = 0.007) and were correlated with the Alzheimer's Disease Assessment Scale (r = −0.345, P = 0.049) and the Mini Mental State Examination (r = 0.324, P = 0.02). No significant differences were found in methylation rates between AD and control subjects.
Conclusion
MEF2C mRNA expression in leukocytes may be a biological marker for cognitive decline in AD.
Abstract
Cryopreservation of whole blood is useful for DNA collection, and clinical and basic research. Blood samples in ethylenediaminetetraacetic acid disodium salt (EDTA) tubes stored at − 80 °C ...are suitable for DNA extraction, but not for high-quality RNA extraction. Herein, a new methodology for high-quality RNA extraction from human blood samples is described. Quickly thawing frozen whole blood on aluminum blocks at room temperature could minimize RNA degradation, and improve RNA yield and quality compared with thawing the samples in a 37 °C water bath. Furthermore, the use of the NucleoSpin RNA kit increased RNA yield by fivefold compared with the PAXgene Blood RNA Kit. Thawing blood samples on aluminum blocks significantly increased the DNA yield by ~ 20% compared with thawing in a 37 °C water bath or on ice. Moreover, by thawing on aluminum blocks and using the NucleoSpin RNA and QIAamp DNA Blood kits, the extraction of RNA and DNA of sufficient quality and quantity was achieved from frozen EDTA whole blood samples that were stored for up to 8.5 years. Thus, extracting RNA from frozen whole blood in EDTA tubes after long-term storage is feasible. These findings may help advance gene expression analysis, as well as biomarker research for various diseases.
Objective
The aim was to clarify whether DRD2 methylation changes in leukocytes of dementia with Lewy bodies (DLB) or Parkinson's disease (PD) patients are seen and can be used to discriminate ...between them.
Methods
Methylation rates were examined in 23 DLB subjects and 23 age‐ and sex‐matched healthy controls and 37 PD patients and 37 age‐ and sex‐matched healthy controls.
Results
Significant DRD2 DNA methylation changes were found in leukocytes of DLB and PD patients compared with healthy subjects. Discriminant analysis between DLB and PD using seven CpG sites demonstrated sensitivity and specificity of 83.8% and 90.9%, respectively. None of the CpG sites were associated with sex, age, age of onset, disease duration, and any of the neuropsychological tests in DLB and PD patients.
Conclusion
This is the first report showing that DRD2 DNA methylation rates in leukocytes were increased in DLB patients and decreased in PD patients. These results may be an important step in understanding epigenetic mechanisms underlying DLB and PD pathogenesis and providing a novel biomarker for discriminating between them.
Aim
Globally, evidence from short‐term studies is insufficient for the guidelines to uniformly recommend a particular antipsychotic(s) for the maintenance treatment of schizophrenia. Therefore, ...long‐term comprehensive evaluation of antipsychotics is required from a social rehabilitation perspective, especially for drugs that have not yet been studied. The Japan Useful Medication Program for Schizophrenia (JUMPs) is a large‐scale, long‐term naturalistic study to present pivotal 52‐week data on the continuity of second‐generation antipsychotics (SGA: aripiprazole, blonanserin, and paliperidone).
Methods
JUMPs was an open‐label, three‐arm, randomized, parallel‐group, 52‐week study. Enrolled patients had schizophrenia, were ≥20 years old, and required antipsychotic treatment or switched from previous therapy. The primary endpoint was treatment discontinuation rate over 52 weeks. Secondary outcomes included remission rate, social functioning, and quality‐of‐life scores Personal and Social Performance Scale (PSP) and EuroQol‐5 dimensions, and safety.
Results
In total, 251 patients received aripiprazole (n = 82), blonanserin (n = 85), or paliperidone (n = 84). The discontinuation rate (P = 0.9771) and remission rates (P > 0.05) over 52 weeks did not differ significantly between the three treatment groups. The discontinuation rates were 68.3%, 68.2%, and 65.5% in the aripiprazole, blonanserin, and paliperidone groups, respectively. Significant improvements (all P < 0.05) from baseline in PSP scores were observed at start of monotherapy, week 26, and week 52 in the overall cohort and blonanserin group and at week 26 in the aripiprazole group. The adverse event profile favored blonanserin.
Conclusion
All three SGAs evaluated in this study showed similar treatment discontinuation rates in patients with chronic schizophrenia in Japan.
Aim
It is difficult to diagnose dementia with Lewy bodies (DLB) because it exhibits clinical and neuropathological overlap with both Alzheimer's disease and Parkinson's disease. The α‐synuclein ...protein is a major component of Lewy bodies, and accumulation of α‐synuclein aggregates causes synaptic dysfunction in DLB. Epigenetic changes at the synuclein alpha (
SNCA
) gene may be involved in DLB pathogenesis.
Methods
We examined DNA methylation rates at 10 CpG sites located in intron 1 of
SNCA
and
SNCA
mRNA expression in peripheral leukocytes to compare DLB patients (n = 20; nine men, 11 women; age = 78.8 ± 7.7 years) with healthy controls (n = 20; eight men, 12 women; age = 77.0 ± 6.9 years).
Results
The methylation rate at CpG 4 (
P
= 0.002) and the overall mean methylation rate at these sites (P < 0.001) were significantly lower in DLB patients than in healthy controls after Bonferroni correction. Although
SNCA126
, a partial form of
SNCA
mRNA expression, was significantly increased in DLB (
P
= 0.017), there was no significant difference in total
SNCA
mRNA expression between DLB patients and healthy controls (
P
= 0.165). No correlation was observed between SCNA mRNA expression levels and blood DNA methylation rates in either DLB or healthy controls.
Conclusion
Our findings indicated that lower methylation rates may be a biomarker for DLB.
Alzheimer's disease (AD) is a progressive disease, and the number of AD patients is increasing every year as the population ages. One of the pathophysiological mechanisms of AD is thought to be the ...effect of metabolomic abnormalities. There have been several studies of metabolomic abnormalities of AD, and new biomarkers are being investigated. Metabolomic studies have been attracting attention, and the aim of this study was to identify metabolomic biomarkers associated with AD and mild cognitive impairment (MCI). Of the 927 participants in the Nakayama Study conducted in Iyo City, Ehime Prefecture, 106 were selected for this study as Control (n = 40), MCI (n = 26), and AD (n = 40) groups, matched by age and sex. Metabolomic comparisons were made across the three groups. Then, correlations between metabolites and clinical symptoms were examined. The blood mRNA levels of the ornithine metabolic enzymes were also measured. Of the plasma metabolites, significant differences were found in ornithine, uracil, and lysine. Ornithine was significantly decreased in the AD group compared to the Control and MCI groups (Control vs. AD: 97.2 vs. 77.4; P = 0.01, MCI vs. AD: 92.5 vs. 77.4; P = 0.02). Uracil and lysine were also significantly decreased in the AD group compared to the Control group (uracil, Control vs. AD: 272 vs. 235; P = 0.04, lysine, Control vs. AD: 208 vs. 176; P = 0.03). In the total sample, the MMSE score was significantly correlated with lysine, ornithine, thymine, and uracil. The Barthel index score was significantly correlated with lysine. The instrumental activities of daily living (IADL) score were significantly correlated with lysine, betaine, creatine, and thymine. In the ornithine metabolism pathway, the spermine synthase mRNA level was significantly decreased in AD. Ornithine was decreased, and mRNA expressions related to its metabolism were changed in the AD group compared to the Control and MCI groups, suggesting an association between abnormal ornithine metabolism and AD. Increased betaine and decreased methionine may also have the potential to serve as markers of higher IADL in elderly persons. Plasma metabolites may be useful for predicting the progression of AD.
Aim
Although treatment guidelines for pharmacological therapy for schizophrenia and major depressive disorder have been issued by the Japanese Societies of Neuropsychopharmacology and Mood Disorders, ...these guidelines have not been well applied by psychiatrists throughout the nation. To address this issue, we developed the ‘Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE)’ integrated education programs for psychiatrists to disseminate the clinical guidelines. Additionally, we conducted a systematic efficacy evaluation of the programs.
Methods
Four hundred thirteen out of 461 psychiatrists attended two 1‐day educational programs based on the treatment guidelines for schizophrenia and major depressive disorder from October 2016 to March 2018. We measured the participants’ clinical knowledge of the treatment guidelines using self‐completed questionnaires administered before and after the program to assess the effectiveness of the programs for improving knowledge. We also examined the relation between the participants’ demographics and their clinical knowledge scores.
Results
The clinical knowledge scores for both guidelines were significantly improved after the program. There was no correlation between clinical knowledge and participant demographics for the program on schizophrenia; however, a weak positive correlation was found between clinical knowledge and the years of professional experience for the program on major depressive disorder.
Conclusion
Our results provide evidence that educational programs on the clinical practices recommended in guidelines for schizophrenia and major depressive disorder might effectively improve participants’ clinical knowledge of the guidelines. These data are encouraging to facilitate the standardization of clinical practices for psychiatric disorders.
The pathophysiology of delayed carbon monoxide (CO) encephalopathy remains unclear. In this study, the effects of CO exposure on the dentate gyrus (DG) were investigated in a Wistar rat model by ...histochemical and molecular methods. Model rats showed significant cognitive impairment in the passive-avoidance test beginning 7 days after CO exposure. Immunohistochemistry showed that compared to the control, the cell number of SRY (sex-determining region Y)-box 2 (SOX2)
/brain lipid binding protein (BLBP)
/glial fibrillary acidic protein (GFAP)
cells in the DG was significantly less, but the number of SOX2
/GFAP
cells was not, reflecting a decreased number of type 1 and type 2a neural precursor cells. Compared to the control, the numbers of CD11b
cells and neuron glial antigen 2
cells were significantly less, but the number of SOX2
/GFAP
cells was not. Flow cytometry showed that the percent of live microglial cells isolated from the hippocampus in this CO rat model was significantly lower than in controls. Furthermore, mRNA expression of fibroblast growth factor 2 and glial cell-derived neurotrophic factor, which are neurogenic factors, was significantly decreased in that area. We conclude that, in this rat model, there is an association between delayed cognitive impairment with dysregulated adult hippocampal neurogenesis and glial changes in delayed CO encephalopathy.
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