Development of informant-reported or self-reported MCI-J questionnaire.

Several studies have reported a high prevalence of missed and delayed mild cognitive impairment (MCI) or mild dementia diagnosis, which could lead to delayed treatment and increased patient and caregiver burden. OBJECTIVES: This study aimed to develop a new questionnaire for nonprofessionals to help detect early signs of MCI and dementia. Respondents included patients, family caregivers, or health professionals. Scores are calculated based on the respondent type and age of subject. METHODS: This study consisted of four steps and included 461 respondents. Steps 1-3 were conducted by a working group, and step 4, by 67 specialist members of the Japanese Society of Geriatric Psychiatry. A scoring algorithm was created and predictive diagnostic probability was analyzed using misdiscrimination rate and cross-validation after item selection to establish a cut-off value for MCI or dementia symptoms. Alzheimer's disease, Lewy body dementia, and frontotemporal dementia were diagnosed. RESULTS: The prediction error rate for patient or informant respondents was confirmed from the evaluation results of 13 items. Sensitivity and specificity were 90.6% and 56.6%, respectively, with a cut-off score of 2. Overall, 82% (61 pairs) of respondents received a definitive diagnosis following a diagnosis from the questionnaire. CONCLUSIONS: This questionnaire could promote earlier presentation to clinical settings for treatment. The high sensitivity indicates the utility of this instrument, but it is not meant as a definitive diagnostic tool and should be followed with a professional assessment.

Genetic association between RAGE polymorphisms and Alzheimer's disease and Lewy body dementias in a Japanese cohort: a case-control study.

BACKGROUND/AIMS: Interaction of receptor for advanced glycation end products (RAGE) with amyloid-ß increases amplification of oxidative stress and plays pathological roles in Alzheimer's disease (AD). Oxidative stress leads to α-synuclein aggregation and is also a major contributing factor in the pathogenesis of Lewy body dementias (LBDs). Therefore, we aimed to investigate whether RAGE gene polymorphisms were associated with AD and LBDs. METHODS: Four single nucleotide polymorphisms (SNPs)-rs1800624, rs1800625, rs184003, and rs2070600-of the gene were analyzed using a case-control study design comprising 288 AD patients, 76 LBDs patients, and 105 age-matched controls. RESULTS: Linkage disequilibrium (LD) examination showed strong LD from rs1800624 to rs2070600 on the gene (1.1 kb) in our cases in Japan. Rs184003 was associated with an increased risk of AD. Although there were no statistical associations for the other three SNPs, haplotypic analyses detected genetic associations between AD and the RAGE gene. Although relatively few cases were studied, results from the SNPs showed that they did not modify the risk of developing LBDs in the Japanese population. CONCLUSION: Our findings suggested that polymorphisms in the RAGE gene are involved in genetic susceptibility to AD. Copyright © 2016 John Wiley & Sons, Ltd.

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.

Serum insulin-like growth factor-I and amyloid beta protein in Alzheimer's disease: relationship with cognitive function.

AIMS: Previous studies have suggested that insulin-like growth factor-I (IGF-I) deficiency may lead to cognitive deficits in neurodegenerative diseases such as Alzheimer's disease. The present study aimed to investigate the possible relationship between cognitive function and concentration of IGF-I or amyloid beta protein (Aß) in serum in Alzheimer's patients. METHODS: A total of 81 Japanese patients were enrolled in this study. Concentrations of IGF-I, Aß42, and Aß40 in serum were measured. Two neuropsychological tests, Mini-Mental State Examination and Hasegawa's Dementia Scale-Revised (HDS-R), were also performed. Linear correlations among the age, serum IGF-I, serum Aß42 or Aß40, Aß42/Aß40 ratio, Mini-Mental State Examination or HDS-R total score, and the scores for six HDS-R subscales were analyzed by regression analysis. RESULTS: IGF-I showed a significant negative correlation with age (ß = -0.357, P = 0.002) and a positive correlation with Aß42/Aß40 ratio (ß = 0.318, P = 0.007). Serum IGF-I and both the Mini-Mental State Examination and the HDS-R total score also correlated (ß = 0.505, ß = 0.524, P < 0.01). Among the HDS-R subscales, 'Recall' (ρ = 0.379, P < 0.01), 'Verbal fluency' (ρ = 0.360, P < 0.01), and 'Attention and calculation' (ρ = 0.389, P < 0.01) showed significant positive correlations with serum IGF-I. CONCLUSION: The results, specifically that lower serum IGF-I was associated with cognitive impairment, suggest that metabolism of IGF-I may be involved in the pathogenesis of cognitive deficits in Alzheimer's disease.

Association of copy number polymorphisms at the promoter and translated region of COMT with Japanese patients with schizophrenia.

Chromosome 22q11.2 deletion syndrome and genetic variations including single-nucleotide polymorphism (SNP) and copy number variation (CNV) in catechol-O-methyltransferase (COMT) situated at 22q11.2 remains controversial. Here, the genetic relationship between COMT and Japanese patients with schizophrenia was investigated by examining whether the SNPs correlated with schizophrenia based on a common disease-common variant hypothesis. Additionally, 22q11.2DS were screened based on a common disease-rare variant hypothesis; low-frequency CNVs situated at two COMT promoters and exons were investigated based on the low-frequency variants with an intermediate effect; and positive findings from the first stage were reconfirmed using a second-stage replication study including a larger sample size. Eight SNPs and 10 CNVs were investigated using Taqman SNP and CNV quantitative real-time polymerase chain reaction method. For the first-stage analysis, 513 unrelated Japanese patients with schizophrenia and 705 healthy controls were examined. For the second-stage replication study, positive findings from the first stage were further investigated using a larger sample size, namely 1,854 patients with schizophrenia and 2,137 controls. The first-stage analysis showed significant associations among schizophrenia, intronic SNP rs165774, CNV6 situated at promoter 1, CNV8 at exon 6, and CNV9 at exon 7. The second-stage study showed that intronic SNP rs165774 (χ(2) = 8.327, P = 0.0039), CNV6 (χ(2) = 19.66, P = 0.00005), and CNV8 (χ(2) = 16.57, P = 0.00025) were significantly associated with schizophrenia. Large and rare CNVs as well as low-frequency CNVs and relatively small CNVs, namely <30 kb in COMT, may be genetic risk factors for schizophrenia.

[Tokyo Metropolitan Dementia-related Disease Medical Center and Current Problems of Outreach project for Early-stage Dementia].

There are twelve dementia-related disease medical centers including psychiatric hospitals in the Tokyo Metropolitan Area. Few psychiatric hospitals or long-term care hospitals exist in our area (Bunkyo, Chiyoda, Taito, Minato, and Chuo wards) and we receive requests for hospital transfer of demented patients. Since the Tokyo Metropolitan Government estimates that the numbers of aged persons will increase rapidly, a project for detecting and diagnosing early-stage dementias, the 'outreach project', has started. We visit people who show some cognitive symptoms and evaluate their cognitive functions and mental and physical status. Then, we support them to undergo medical examinations or receive appropriate care if needed. Most of the people we visited were women living alone who did not receive any care. Several cases were detected as early-stage dementia based on our evaluations. On the other hand, there were some cases suggested to be psychiatric diseases, such as schizophrenia, with people showing some social or behavioral problems. Psychiatrists hope to attentively work for dementia patients with co-medicals in local areas.

Association between the catechol-O-methyltransferase polymorphism Val158Met and Alzheimer's disease in a Japanese population.

OBJECTIVE: Catechol-O-methyltransferase (COMT) plays an important role in dopamine degradation, which is associated with the pathophysiology of Alzheimer's disease (AD) and alcoholism. A functional COMT polymorphism, Val158Met (rs4680 G > A), affects the onset of AD and is associated with alcohol dependence through dopamine receptor sensitivity in the prefrontal cortex. METHODS: The aim of this case-control study (398 cases and 149 controls) was to investigate whether Val158Met polymorphism influences the onset of AD stratified according to alcohol consumption and apolipoprotein E (APOE) status. We also used single photon-emission computed tomography (SPECT) to analyse 26 patients with AD with the polymorphism. RESULTS: As a function of APOE status, the genotypic frequencies of rs4680 in patients with AD did not differ from those in controls. We detected a significant association between high alcohol consumption in patients with AD (HAC-AD group) and the polymorphism in genotypic and allelic frequencies. Logistic regression analyses demonstrated that the presence of the APOE genotype with rs4680 increased the risk for HAC-AD synergistically. Hyperperfusion in the right sub-lobar insula of patients with the G/G genotype was found compared with that of patients with the G/A genotype. SPECT studies showed a relationship between the polymorphism and compensatory reactions for dysfunctions of dopaminergic neurotransmission in AD pathophysiology. CONCLUSION: Although genetic association between the polymorphism and the onset of AD in a Japanese population were not observed, the polymorphism affected the risk for HAC-AD.

Associations of common copy number variants in glutathione S-transferase mu 1 and D-dopachrome tautomerase-like protein genes with risk of schizophrenia in a Japanese population.

Oxidative-stress, genetic regions of interest (1p13 and 22q11), and common copy number variations (CNVs) may play roles in the pathophysiology of schizophrenia. In the present study, we confirmed associations between schizophrenia and the common CNVs in the glutathione (GSH)-related genes GSTT1, DDTL, and GSTM1 using quantitative real-time polymerase chain reaction analyses of 620 patients with schizophrenia and in 622 controls. No significant differences in GSTT1 copy number distributions were found between patient groups. However, frequencies of characterized CNVs and assumed gain alleles of DDTL and GSTM1 were significantly higher in patients with schizophrenia. In agreement with a previous report, the present data indicate that gains in the CNV alleles DDTL and GSTM1 are genetic risk factors in Japanese patients with schizophrenia, and suggest involvement of micro-inflammation and oxidative stress in the pathophysiology of schizophrenia.

Polymorphisms in the aldehyde dehydrogenase 2 and dopamine ß hydroxylase genes are not associated with Alzheimer's disease.

Since ethanol and its metabolite, acetaldehyde, are directly neurotoxic, alcohol intake could affect the development of Alzheimer's disease (AD). Mitochondrial aldehyde dehydrogenase 2 (ALDH2) metabolizes acetaldehyde into acetate and also protects against oxidative stress, playing an important role in the development of AD. The activity of dopamine ß hydroxylase (DBH) is reduced in the hippocampus and neocortex in the AD brain. DBH is also involved in the pathophysiology of alcoholism. The aim of this study was to investigate whether polymorphisms of both ALDH2 and DBH genes were associated with AD. ALDH2*2 and two functional single nucleotide polymorphisms (SNPs) of the DBH gene were analyzed using a case-control study design. Our case-control data set consisted of 201 AD patients and 130 age-matched controls. We also analyzed stratifying by alcohol consumption and apolipoprotein E (APOE) genotypes. There were no associations between the SNPs studied here and the onset of AD. No synergetic associations were found among the SNPs, APOE and the risk for AD. Although high alcohol consumption AD (HAC-AD) patients were analyzed in detail, the current three SNPs were not related with HAC-AD. ALDH2*2 and functional SNPs of the DBH gene did not modify the risk for AD. Since our data set was constructed only with AD in a Japanese population, further detailed genetic analyses with other ethnic groups would be needed.

Safety and tolerability of immune globulin intravenous (human), 10% solution in Japanese subjects with mild to moderate Alzheimer's disease.

BACKGROUND: Immune globulin intravenous (IGIV), 10% is a donor-derived polyclonal human immunoglobulin G antibody mixture that has potent immune modulatory properties and contains conformation selective anti-amyloid antibodies. We evaluated the safety and tolerability of multiple doses of IGIV, 10% in Japanese patients with mild to moderate Alzheimer's disease. METHODS: Among the 16 subjects, 12 subjects were assigned to the IGIV group and 4 subjects to the placebo group. Subjects received a total of six infusions of either IGIV at a dose of 0.2 or 0.4 g/kg, or placebo every 2 weeks. RESULTS: A total of 33 treatment-emergent adverse events (TEAE) occurred in 14 subjects: 13 TEAE in five subjects in both the IGIV 0.2 and 0.4 g/kg groups, and 7 TEAE in four subjects in the placebo group. The most common TEAE in the IGIV subjects were nasopharyngitis, injection-site swelling, and erythema. All 26 TEAE in the IGIV group were considered to be mild. Only one mild TEAE (rash) was considered to be possibly related to the study drug. There were no significant differences in incidence of TEAE between the treatment groups. Four serious TEAE were reported, and all of these were considered to be unrelated to the study treatment. Other assessments related to safety revealed neither clinically significant abnormal values nor findings in the study. CONCLUSION: IGIV is generally safe and well tolerated with multiple intravenous infusions at doses of 0.2 g/kg and 0.4 g/kg in Japanese patients with mild to moderate Alzheimer's disease.

Genetic association between APOA1 and APOD polymorphisms and Alzheimer's disease in a Japanese population.

Alterations in lipoproteins are involved in the pathophysiology of Alzheimer's disease (AD). For sporadic AD, the Apolipoprotein E (APOE) is recognized as a sole genetic risk factor. Apolipoprotein A1 (APOA1) has been suggested to bind amyloid ß and promoter polymorphisms of the APOA1 gene were likely to affect the onset of the disease. Apolipoprotein D (APOD) expression is upregulating in AD brain and evidences showed APOD polymorphisms affect the risk for AD. The aim of this study was to investigate whether polymorphisms of both APOA1 and APOD genes are associated with early-onset AD (EOAD) and late-onset AD (LOAD). Common single nucleotide polymorphisms (SNPs) of the two genes were analyzed using a case-control study design. There were no associations between the two SNPs of the APOA1 gene and the onset of AD. No synergetic associations were found among the APOA1 SNPs, APOE and the risk for AD. Rs7659, 3' UTR polymorphism of the APOD gene was associated with EOAD in APOEε4 (-) subgroup. We were unable to show any impact of the other two SNPs of the APOD gene on the risk for AD. Our results suggest that the variation of the APOD gene modifies the risk for AD. Further association studies for APOD 3' UTR polymorphisms with other ethnic groups would be needed.

Changes in Mini-Mental State Examination score in Alzheimer's disease patients after stopping habitual drinking.

BACKGROUND: Globally, Alzheimer's disease (AD) is becoming an increasing problem as the population ages, and the effects of lifestyle factors on cognitive decline need to be better understood. This study examined the effects of alcohol abstinence on cognitive decline in AD. METHODS: Cognitive function after alcohol abstinence was retrospectively reviewed in AD patients (high and low alcohol consumption groups) and then compared with an alcohol-naïve AD group. The alcohol-naïve AD group included 18 outpatients with no history of habitual drinking. The alcohol-abstinence AD group included 20 outpatients who stopped drinking after their diagnoses. The latter group was classified into high and low groups depending on the amount of they drank before abstinence. Cognitive function was evaluated with the Mini-Mental State Examination at baseline, 6 months, and 12 months. For statistical analyses, a repeated measures, two-factor anova and post-hoc multiple comparisons were performed using the Bonferroni method. RESULTS: There was a significant effect of time on Mini-Mental State Examination score, but there was no difference in the baseline scores of the alcohol-naïve and alcohol-abstinence AD groups. The score was significantly lower at 6 and 12 months than at baseline in the alcohol-naïve group, but no significant difference was seen in the alcohol-abstinence group. There was a significant interaction between time and alcohol consumption subgroup on the score, with no difference in baseline score between the low and high consumption groups. The score was significantly lower only in the high consumption group at 12 months. CONCLUSIONS : In AD patients with a history of habitual drinking, abstinence was effective for reducing cognitive decline during the clinical course. However, such an effect was not seen in patients who had consumed high amounts of alcohol before diagnosis of AD.

Differential effects of acute exercise on emotional memory in men and women.

Exercise may change emotional memory, which is associated with the induction of mental disorders such as depression and anxiety. This effect of exercise may be influenced by exercise-induced cortisol release. Depending on sex, cortisol exerts differential effects on emotional memory consolidation. However, whether acute exercise and exercise-induced cortisol release have sex-dependent effects on emotional memory has not been established. Therefore, first, we aimed to determine the effects of acute exercise on emotional memory, separately for men and women, in a within-subjects design. Second, we aimed to examine whether the effects of acute exercise on emotional memory are related to the effects of exercise-induced cortisol release, separately for men and women. Sixteen healthy men and 15 healthy women were presented with positive and negative emotional images, followed by either rest or a vigorous-intensity cycling exercise condition using a within-subjects design on separate days. Salivary cortisol was measured before presenting the emotional images presentation and 20 min after each intervention. Emotional memory was assessed two days later. Vigorous-intensity exercise decreased emotional memory in women, whereas there was no change in men after rest or exercise. Cortisol levels increased after exercise intervention in both men and women, although there was no association between cortisol levels and emotional memory. These findings demonstrate that the effect of a single bout of vigorous-intensity exercise on emotional memory differs between men and women and is associated with decreased emotional memory in women.

A Pilot Study on Cerebral Blood Flow and Mini-Mental State Examination to Predict Amyloid Deposition in Preclinical Alzheimer's Disease.

Background: Earlier differential diagnosis of dementia remains a major challenge. Although amyloid deposition by positron emission tomography is an emerging standard for the diagnosis of Alzheimer's disease, it is too expensive for routine use in clinical settings. We conducted a pilot study on the potential usefulness of single-photon emission computed tomography and the Mini-Mental State Examination to predict amyloid positron emission tomography positivity in preclinical Alzheimer's disease. Methods: Eighteen subjects, including 11 with mild cognitive impairment and 7 with subjective cognitive decline, underwent 18F-florbetapir positron emission tomography, 99mTc-ethylcysteinate dimer cerebral perfusion single-photon emission computed tomography, and the Mini-Mental State Examination. For the assessment of amyloid deposition, visual judgment as a qualitative method and a semiautomatic software analysis as a quantitative method were used. Results: Six subjects were judged as amyloid positive, including 4 mild cognitive impairment and 2 subjective cognitive decline subjects. Compared to the amyloid positron emission tomography-negative group, this group showed a statistically significant difference in the Mini-Mental State Examination recall score [2 (1 : 3) vs. 3 (2 : 3), P = .041] and single-photon emission computed tomography findings from the amyloid-negative group. In the mild cognitive impairment subgroup, correlations were found between amyloid deposition and single-photon emission computed tomography indicators, while in the subjective cognitive decline subgroup, only the Mini-Mental State Examination recall score correlated with amyloid deposition. Conclusion: The Mini-Mental State Examination recall score and single-photon emission computed tomography indicators may be worthwhile for further evaluation as predictors of amyloid deposition in the preclinical stage.

Dietary Intake in Older Patients with Dementia Prior to and After the Onset of Coronavirus Disease 2019.

This was an observational study of hospitalized patients with dementia who developed COVID-19. The disease course, dietary intake, and disease severity (mild/severe) were evaluated. Twenty-nine patients with a median age of 84 years, with both mild (18) and severe conditions, (11) were evaluated. Mild group had decreased food intake from the day of symptom onset. In the severe group, the decline began the day before symptom onset. On day 30 of the disease, the median food intake of the mild group returned to levels observed prior to symptom onset, in contrast to those in the severe group.

Lack of genetic association of the UCHL1 gene with Alzheimer's disease and Parkinson's disease with dementia.

BACKGROUND/AIMS: Several candidate genes were suggested to modify the susceptibility to both Alzheimer's disease (AD) and Parkinson's disease (PD). Symptoms of dementia are found in approximately 30% of PD patients. Both apolipoprotein E (APO E) and ubiquitin carboxyl-terminal esterase L1 (UCHL1) are neuropathogenic proteins for both diseases. The aim of this study was to investigate whether polymorphisms of both genes are associated with AD and PD with dementia (PDD). METHODS: The APO E polymorphism and 5 common single-nucleotide polymorphisms (SNPs) of the UCHL1 gene were analyzed using a case-control study design. RESULTS: Although APO E4 affected the onset of AD, the 5 SNPs of the UCHL1 gene were not associated with risk for AD. Linkage disequilibrium (LD) analysis of our Japanese data set showed that the SNPs of the UCHL1 gene are part of one LD block. Although one SNP, rs4861387, of the UCHL1 gene showed marginal association with PDD, we did not detect any association between the other SNPs and PDD. CONCLUSION: The common SNPs of UCHL1 are not major risk factors for AD. Since our analyses on PDD are preliminary, further genetic studies on APO E, UCHL1 and PD with and without dementia are needed.

No associations found between the genes situated at 6p22.1, HIST1H2BJ, PRSS16, and PGBD1 in Japanese patients diagnosed with schizophrenia.

Recent GWAS demonstrated an association between candidate genes located at region 6p22.1 and schizophrenia. This region has been reported to house certain candidate SNPs, which may be associated with schizophrenia at HIST1H2BJ, PRSS16, and PGBD1. These genes may presumably be associated with pathophysiology in schizophrenia, namely epigenetics and psychoneuroimmunology. A three-step study was undertaken to focus on these genes with the following aims: (1) whether these genes may be associated in Japanese patients with schizophrenia by performing a 1st stage case-control study (514 cases and 706 controls) using Japanese tagging SNPs; (2) if the genetic regions of interest for the disease from the 1st stage of analyses were found, re-sequencing was performed to search for new mutations; (3) finally, a replication study was undertaken to confirm positive findings from the 1st stage were reconfirmed using a larger number of subjects (2,583 cases and 2,903 controls) during a 2nd stage multicenter replication study in Japan. Genotyping was performed using TaqMan PCR method for the selected nine tagging SNPs. Although three SNPs situated at the 3' side of PGBD1; rs3800324, rs3800327, and rs2142730, and two-window haplotypes between rs3800327 and rs2142730 showed positive associations with schizophrenia, these associations did not have enough power to sustain significance during the 2nd stage replication study. In addition, re-sequencing for exons 5 and 6 situated at this region did not express any new mutations for schizophrenia. Taken together these results indicate that the genes HIST1H2BJ, PRSS16, and PGBD1 were not associated with Japanese patients with schizophrenia.