Association between behavioural and psychological symptoms of dementia and residence status in patients with Alzheimer's disease.

BACKGROUND: Examining the relationship between the behavioural and psychological symptoms of dementia (BPSD) and residence status is crucial to improving BPSD and reducing the burden on caregivers. However, studies on how BPSD differ between individuals living at home and those in institutional settings are lacking. We conducted a questionnaire survey among healthcare providers (HCPs) involved in dementia care and nursing to clarify the characteristics of BPSD by residence status in patients with Alzheimer's disease (AD) living at home or in facilities. METHODS: We sent questionnaires to HCPs and asked them to answer questions on up to five cases that needed treatment for BPSD and who received long-term care insurance services from 1 April 2016 to 31 March 2017. Responses were received for 371 cases, of which 130 diagnosed with AD were analyzed. The patients were divided into two groups: patients with AD living at home (home care group) and patients with AD living in facilities (facility care group). A Chi-square test was used to identify differences between the two groups. A binomial logistic regression analysis was also conducted to clarify the association between residence status and BPSD. RESULTS: Of the 130 patients, 72 lived at home (home care group) and 58 resided in facilities (facility care group). None of the background factors was significantly different between the two groups. The Chi-square test indicated that sleep disturbance was significantly more common in the facility care group (60.3% in the facility care group vs. 33.3% in the home care group, P = 0.003), while the logistic regression analysis indicated that sleep disturbance was significantly associated with residence status (odds ratio: 2.529, P = 0.038). CONCLUSIONS: Sleep disturbances were more frequently observed among patients with AD living in institutions than among those living in their homes.

The Multicomponent Day-Care Program Prevents Volume Reduction in a Memory-Related Brain Area in Patients with Mild Cognitive Impairment.

INTRODUCTION: Mild cognitive impairment (MCI) is considered an important period for interventions to prevent progression to dementia. Nonpharmacological interventions for MCI include exercise training, cognitive intervention, and music therapy. These play an important role in improving cognitive function, but their effects on brain plasticity in individuals with MCI are largely unknown. We investigated the effects of a multicomponent day-care program provided by the University of Tsukuba Hospital on the longitudinal brain volume changes in MCI patients. METHODS: MCI patients who participated in the multicomponent day-care program and underwent whole-brain magnetic resonance imaging (MRI) twice during their participation (n = 14), were included. We divided them into two groups according to their attendance rate and conducted a between-group analysis of longitudinal volume changes in the whole cerebral cortex. Regional brain volumes derived from the patients' MRI were calculated with Freesurfer 6.0.0. RESULTS: The neuroimaging analysis demonstrated that the left rostral anterior cingulate cortex volume was significantly preserved in the high-attendance group compared to that of the low-attendance group. CONCLUSION: Our results suggest that continuous participation in a multicomponent day-care program could help prevent a volume reduction in memory-related brain areas in patients with MCI.

Relationships between the Fear of COVID-19 Scale and regional brain atrophy in mild cognitive impairment.

BACKGROUND: Several studies have reported that the pandemic of coronavirus disease 2019 (COVID-19) influenced cognitive function in the elderly. However, the effect of COVID-19-related fear on brain atrophy has not been evaluated. In this study, we evaluated the relation between brain atrophy and the effect of COVID-19-related fear by analysing changes in brain volume over time using magnetic resonance imaging (MRI). METHODS: Participants were 25 Japanese patients with mild cognitive impairment (MCI) or subjective cognitive decline (SCD), who underwent 1.5-tesla MRI scan twice, once before and once after the pandemic outbreak of COVID-19, and the Fear of Coronavirus Disease 2019 Scale (FCV-19S) assessment during that period. We computed regional brain atrophy per day between the 1st and 2nd scan, and evaluated the relation between the FCV-19S scores and regional shrinkage. RESULTS: There was significant positive correlation between the total FCV-19S score and volume reduction per day in the right posterior cingulate cortex. Regarding the subscales of FCV-19S, we found significant positive correlation between factor 2 of the FCV-19S and shrinkage of the right posterior cingulate cortex. CONCLUSIONS: There was positive correlation between the FCV-19S score and regional brain atrophy per day. Although it is already known that the psychological effects surrounding the COVID-19 pandemic cause cognitive function decline, our results further suggest that anxiety and fear related to COVID-19 cause regional brain atrophy.

Effects of a multicomponent day-care program on cerebral blood flow in patients with mild cognitive impairment.

BACKGROUND: Mild cognitive impairment (MCI) is a prodromal phase of dementia and is considered an important period for intervention to prevent conversion to dementia. It has been well established that multicomponent day-care programs including exercise training, cognitive intervention and music therapy have beneficial effects on cognition, but the effects on cerebral blood flow (CBF) in MCI remain unknown. This study examined whether a multicomponent day-care program would have beneficial effects on the longitudinal changes of CBF in MCI patients. METHODS: Participants were 24 patients with MCI attending a day-care program; they underwent two 99 mTc-ethyl cysteinate dimer single photon emission computed tomography scans during the study period. We evaluated the association between the changes of regional cerebral blood flow and the attendance rate. RESULTS: There was a significant negative correlation between the reduction of regional CBF in the right parietal region and the attendance rate. We found no significant relation between the baseline CBF images and the attendance rate. CONCLUSIONS: Our results suggest that continuous participation in a multicomponent day-care program might prevent reduction in brain activity in patients with MCI.

Visualizing the Process of Disaster Mental Health Services in the Joso Flood by Network Analyses of Emails.

Joso City, Ibaraki Prefecture, Japan was severely affected by flooding of the River Kinugawa in September 2015. Local psychiatric organizations immediately began providing disaster mental health services (DMHS). In post-disaster settings, DMHS involving organizational interventions by multiple regional institutions are required to support disaster victims. However, little is known about the process of coordinating multiple institutions or determining whether appropriate support has been provided. To elucidate the characteristics of communications that enable effective disaster medical team formation, we conducted network analyses of sender-recipient pairs of emails during the period of DMHS activity. The network analysis is a research method that represents various objects as a network of nodes and edges and explores their structural characteristics. We obtained 2,450 time-series emails from five core members of DMHS, including 32,865 pairs of senders and recipients. The network generated by the emails was scale-free, and its structure changed according to the phases of disaster recovery. In the ultra-acute phase, which lasted about 1 week, spreading information and recruiting people to provide disaster support was given the highest priority. In the acute phase, which lasted about 1 month, support and swift decision-making were essential for directing large numbers of staff. In the mid- to long-term phase, support for staff to share information and experience in small groups was observed. Network analyses have revealed that disaster medical teams must change their communication styles during the mission to adapt to different health needs corresponding to each post-disaster phase.

Imaging studies of kleptomania in a middle-aged woman with obsessive-compulsive disorder: a case report.

A 57-year-old woman who had been arrested for shoplifting visited our hospital. She was diagnosed with kleptomania. She had previously been diagnosed with CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome and obsessive-compulsive disorder. Cranial magnetic resonance imaging showed mild atrophy of the bilateral dorsolateral prefrontal cortices, left hippocampus, and occipital cortex, as well as diffuse mild T2 hyperintensity in the deep and subcortical white matter, including the frontal region. During a single-photon emission computed tomography scan, significant hyperperfusion was observed in the right ventral striatum, including the nucleus accumbens, ventral thalamus, and right ventrolateral prefrontal areas. Patchy hypoperfusion was found in the bilateral posterior cingulate, parietal, and occipital regions. The patient's neurocognitive function was normal, except for slight impairment of her executive function. Her symptoms and neuroimaging findings were not suggestive of a specific neurocognitive disorder. Hyperactivity of the right ventral striatum may contribute to both obsessive-compulsive disorder and kleptomania. Although frontotemporal lobar degeneration is a major neurocognitive disorder related to illegal behaviours, CREST syndrome-induced white matter microstructural damage in the orbitofrontal lobe could have caused our patient's kleptomania.

Sequencing and expression analyses of the synaptic lipid raft adapter gene PAG1 in schizophrenia.

Disruption of synaptic networks has been advocated in the pathogenesis of psychiatric diseases like schizophrenia. The majority of synaptic proteins involved in neuronal communications are localized in lipid rafts. These rafts form the platform for coordinating neuronal signal transduction, by clustering interacting partners. The PAG1 protein is a transmembrane adaptor protein in the lipid raft signaling cluster that regulates Src family kinases (SFKs), a convergent point for multiple pathways regulating N-methyl-D-aspartate (NMDA) receptors. Reports of de novo missense mutations in PAG1 and SFK mediated reductions in tyrosine phosphorylation of NMDA receptor subunit proteins in schizophrenia patients, point to a putative role in schizophrenia pathogenesis. To evaluate this, we resequenced the entire coding region of PAG1 in Japanese schizophrenia patients (n = 1,140) and controls (n = 1,140). We identified eight missense variants, of which four were previously unreported. Case-control genetic association analysis of these variants in a larger cohort (n = 4,182) showed neither a statistically significant association of the individual variants with schizophrenia, nor any increased burden of the rare alleles in the patient group. Expression levels of PAG1 in post-mortem brain samples from schizophrenia patients and controls also showed no significant differences. To assess the precise role of PAG1 in schizophrenia, future studies with larger sample sizes are needed.

A Case of Anorexia Nervosa with Focal Cortical Dysplasia.

Anorexia nervosa (AN) is a fatal condition associated with extreme underweight and undernutrition. It is more common in young females, with a female-to-male ratio of 10 : 1. Focal cortical dysplasia (FCD) is characterized by dysplasia of the cerebral cortex and is a common cause of pharmacoresistant epilepsy. However, FCD associated with AN has never been reported. We report the first case of AN in a 12-year-old male diagnosed with FCD-type 2 on head magnetic resonance imaging (MRI). He became concerned about lower abdominal distention and began reducing his food intake. He was admitted to our hospital after weight loss of 10 kg in a 1 year. Head MRI showed a localized high-signal area from the cortex to the white matter of the fusiform gyrus near the left hippocampus, with no associated decreased blood flow or electroencephalography (EEG) abnormalities. These findings were characteristic of FCD type II. In males with AN, the search for underlying disease is particularly important. The pathophysiology of the association between AN and FCD is unclear. However, both conditions are reportedly associated with autism spectrum disorder. Further cases are needed to clarify whether FCD is associated with eating disorders.

A novel approach for assessing neuromodulation using phase-locked information measured with TMS-EEG.

Neuromodulation therapies such as electroconvulsive therapy (ECT) are used to treat several neuropsychiatric disorders, including major depressive disorder (MDD). Recent work has highlighted the use of combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) to evaluate the therapeutic effects of neuromodulation; particularly, the phase locking factor (PLF) and phase locking value (PLV) can reportedly assess neuromodulation-induced functional changes in cortical networks. To examine changes in TMS-induced PLV and PLF before and after ECT, and their relationship with depression severity in patients with MDD, TMS-EEG and the Montgomery-Åsberg Depression Rating Scale (MADRS; depression severity) were implemented before and after ECT in 10 patients with MDD. Single-pulse TMS was applied to the visual and motor areas to induce phase propagation in the visuo-motor network at rest. Functional changes were assessed using PLF and PLV data. Pre-ECT TMS-induced alpha band (9-12 Hz) PLV was negatively correlated with depression severity, and increments of post-ECT from pre-ECT TMS-induced alpha band PLV were positively correlated with the reduction in depression severity. Moreover, we found a negative correlation between pre-ECT TMS-induced PLF at TMS-destination and depression severity. Finally, differences in post-ECT TMS-induced PLF peak latencies between visual and motor areas were positively correlated with depression severity. TMS-EEG-based PLV and PLF may be used to assess the therapeutic effects of neuromodulation and depressive states, respectively. Furthermore, our results provide new insights about the neural mechanisms of ECT and depression.

Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology.

Mice with the C3H background show greater behavioral propensity for schizophrenia, including lower prepulse inhibition (PPI), than C57BL/6 (B6) mice. To characterize as-yet-unknown pathophysiologies of schizophrenia, we undertook proteomics analysis of the brain in these strains, and detected elevated levels of Mpst, a hydrogen sulfide (H2 S)/polysulfide-producing enzyme, and greater sulfide deposition in C3H than B6 mice. Mpst-deficient mice exhibited improved PPI with reduced storage sulfide levels, while Mpst-transgenic (Tg) mice showed deteriorated PPI, suggesting that "sulfide stress" may be linked to PPI impairment. Analysis of human samples demonstrated that the H2 S/polysulfides production system is upregulated in schizophrenia. Mechanistically, the Mpst-Tg brain revealed dampened energy metabolism, while maternal immune activation model mice showed upregulation of genes for H2 S/polysulfides production along with typical antioxidative genes, partly via epigenetic modifications. These results suggest that inflammatory/oxidative insults in early brain development result in upregulated H2 S/polysulfides production as an antioxidative response, which in turn cause deficits in bioenergetic processes. Collectively, this study presents a novel aspect of the neurodevelopmental theory for schizophrenia, unraveling a role of excess H2 S/polysulfides production.

Genetic and expression analyses of FZD3 in schizophrenia.

BACKGROUND: Wnt signaling plays important roles in neurodevelopmental processes. Frizzled is a receptor of Wnt protein, and the Frizzled 3 (FZD3) gene was recently reported to be associated with schizophrenia. Our study attempted to confirm associations between FZD3 and schizophrenia in Japanese family and case-control samples. METHODS: Genetic associations were evaluated using family-based transmission tests (212 families, 643 subjects) and case--control analysis (540 schizophrenia patients, 540 control sample). Six single nucleotide polymorphisms (SNPs) on the FZD3 locus were genotyped, and levels of FZD3 mRNA expression in postmortem brains were examined. RESULTS: Neither family- nor population-based studies supported associations between FZD3 and schizophrenia. FZD3 expression was unaltered in schizophrenic brains. CONCLUSIONS: Although two prior studies have reported associations using limited numbers of SNPs on FZD3, our intensive study failed to support any major contribution of FZD3 to schizophrenia susceptibility.

A case of neurosyphilis showing a marked improvement of clinical symptoms and cerebral blood flow on single photon emission computed tomography with quantitative penicillin treatment.

A 31-year-old woman manifested significant emotional symptoms and personality change due to neurosyphilis; her clinical symptoms were improved with quantitative penicillin treatment. On admission, magnetic resonance imaging (MRI) showed no abnormal findings, while N-isopropyl-p-[123I] iodoamphetamine single photon emission computed tomography (123I-IMP SPECT) initially showed a remarkable increase in cerebral blood flow (CBF) in the cerebral cortex. This increase disappeared after improvement of the patient's clinical symptoms with treatment. It appears that the increase in CBF might have reflected an active inflammatory state of neurosyphilis and that its disappearance might therefore represent successful treatment with penicillin for neurosyphilis. Our case study suggests that single photon emission computed tomography (SPECT) is a useful method for evaluating an inflammatory state and for assessing the effect of therapy on neurosyphilis.

Exon resequencing of H3K9 methyltransferase complex genes, EHMT1, EHTM2 and WIZ, in Japanese autism subjects.

BACKGROUND: Histone H3 methylation at lysine 9 (H3K9) is a conserved epigenetic signal, mediating heterochromatin formation by trimethylation, and transcriptional silencing by dimethylation. Defective GLP (Ehmt1) and G9a (Ehmt2) histone lysine methyltransferases, involved in mono and dimethylation of H3K9, confer autistic phenotypes and behavioral abnormalities in animal models. Moreover, EHMT1 loss of function results in Kleefstra syndrome, characterized by severe intellectual disability, developmental delays and psychiatric disorders. We examined the possible role of histone methyltransferases in the etiology of autism spectrum disorders (ASD) and suggest that rare functional variants in these genes that regulate H3K9 methylation may be associated with ASD. METHODS: Since G9a-GLP-Wiz forms a heteromeric methyltransferase complex, all the protein-coding regions and exon/intron boundaries of EHMT1, EHMT2 and WIZ were sequenced in Japanese ASD subjects. The detected variants were prioritized based on novelty and functionality. The expression levels of these genes were tested in blood cells and postmortem brain samples from ASD and control subjects. Expression of EHMT1 and EHMT2 isoforms were determined by digital PCR. RESULTS: We identified six nonsynonymous variants: three in EHMT1, two in EHMT2 and one in WIZ. Two variants, the EHMT1 ankyrin repeat domain (Lys968Arg) and EHMT2 SET domain (Thr961Ile) variants were present exclusively in cases, but showed no statistically significant association with ASD. The EHMT2 transcript expression was significantly elevated in the peripheral blood cells of ASD when compared with control samples; but not for EHMT1 and WIZ. Gene expression levels of EHMT1, EHMT2 and WIZ in Brodmann area (BA) 9, BA21, BA40 and the dorsal raphe nucleus (DoRN) regions from postmortem brain samples showed no significant changes between ASD and control subjects. Nor did expression levels of EHMT1 and EHMT2 isoforms in the prefrontal cortex differ significantly between ASD and control groups. CONCLUSIONS: We identified two novel rare missense variants in the EHMT1 and EHMT2 genes of ASD patients. We surmise that these variants alone may not be sufficient to exert a significant effect on ASD pathogenesis. The elevated expression of EHMT2 in the peripheral blood cells may support the notion of a restrictive chromatin state in ASD, similar to schizophrenia.

Altered cortical CDC42 signaling pathways in schizophrenia: implications for dendritic spine deficits.

BACKGROUND: Spine density on the basilar dendrites of pyramidal neurons is lower in layer 3, but not in layers 5 and 6, in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia. The expression of CDC42 (cell division cycle 42), a RhoGTPase that regulates the outgrowth of the actin cytoskeleton and promotes spine formation, is also lower in schizophrenia; however, CDC42 mRNA is lower across layers 3-6, suggesting that other lamina-specific molecular alterations are critical for the spine deficits in the illness. The CDC42 effector proteins 3 and 4 (CDC42EP3, CDC42EP4) are preferentially expressed in DLPFC layers 2 and 3, and CDC42EP3 appears to assemble septin filaments in spine necks. Therefore, alterations in CDC42EP3 could contribute to the lamina-specific spine deficits in schizophrenia. METHODS: We measured transcript levels of CDC42, CDC42EP3, CDC42EP4; their interacting proteins (septins [SEPT2, 3, 5, 6, 7, 8, and 11], anillin), and other spine-specific proteins (spinophilin, PSD-95, and synaptopodin) in the DLPFC from 31 subjects with schizophrenia and matched normal comparison subjects. RESULTS: The expression of CDC42EP3 mRNA was significantly increased by 19.7%, and SEPT7 mRNA was significantly decreased by 6.9% in subjects with schizophrenia. Cortical levels of CDC42EP3 and SEPT7 mRNAs were not altered in monkeys chronically exposed to antipsychotic medications. CONCLUSIONS: Activated CDC42 is thought to disrupt septin filaments transiently in spine necks, allowing the molecular translocations required for synaptic potentiation. Thus, altered CDC42 signaling via CDC42EP3 may perturb synaptic plasticity and contribute to the spine deficits observed in layer 3 pyramidal neurons in schizophrenia.

Failure to support a genetic contribution of AKT1 polymorphisms and altered AKT signaling in schizophrenia.

The protein kinase v-akt murine thymoma viral oncogene homolog (AKT) gene family comprises three human homologs that phosphorylate and inactivate glycogen synthase kinase 3beta (GSK3beta). Studies have reported the genetic association of AKT1 with schizophrenia. Additionally, decreased AKT1 protein expression and the reduced phosphorylation of GSK3beta were reported in this disease, leading to a new theory of attenuated AKT1-GSK3beta signaling in schizophrenia pathogenesis. We have evaluated this theory by performing both genetic and protein expression analyses. A family based association test of AKT1 did not show association with schizophrenia in Japanese subjects. The expression levels of total AKT, AKT1 and phosphorylated GSK3beta detected in the schizophrenic brains from two different brain banks also failed to support the theory. In addition, no attenuated AKT-GSK3beta signaling was observed in the lymphocytes from Japanese schizophrenics, contrasting with previous findings. Importantly, we found that the level of phosphorylated GSK3beta at Ser9 tended to be inversely correlated with postmortem intervals, and that the phosphorylation levels of AKT were inversely correlated with brain pH, issues not assessed in the previous study. These data introduce a note of caution when estimating the phosphorylation levels of GSK3beta and AKT in postmortem brains. Collectively, this study failed to support reduced signaling of the AKT-GSK3beta molecular cascade in schizophrenia.

Genetic association analyses of PHOX2B and ASCL1 in neuropsychiatric disorders: evidence for association of ASCL1 with Parkinson's disease.

We previously identified frequent deletion/insertion polymorphisms in the 20-alanine homopolymer stretch of PHOX2B (PMX2B), the gene for a transcription factor that plays important roles in the development of oculomotor nerves and catecholaminergic neurons and regulates the expression of both tyrosine hydroxylase and dopamine beta-hydroxylase genes. An association was detected between gene polymorphisms and overall schizophrenia, and more specifically, schizophrenia with ocular misalignment. These prior results implied the existence of other schizophrenia susceptibility genes that interact with PHOX2B to increase risk of the combined phenotype. ASCL1 was considered as a candidate interacting partner of PHOX2B, as ASCL1 is a transcription factor that co-regulates catecholamine-synthesizing enzymes with PHOX2B. The genetic contributions of PHOX2B and ASCL1 were examined separately, along with epistatic interactions with broader candidate phenotypes. These phenotypes included not only schizophrenia, but also bipolar affective disorder and Parkinson's disease (PD), each of which involve catecholaminergic function. The current case-control analyses detected nominal associations between polyglutamine length variations in ASCL1 and PD (P=0.018), but supported neither the previously observed weak association between PHOX2B and general schizophrenia, nor other gene-disease correlations. Logistic regression analysis revealed the effect of ASCL1 dominant x PHOX2B additive (P=0.008) as an epistatic gene-gene interaction increasing risk of PD. ASCL1 controls development of the locus coeruleus (LC), and accumulating evidence suggests that the LC confers protective effects against the dopaminergic neurodegeneration inherent in PD. The present genetic data may thus suggest that polyglutamine length polymorphisms in ASCL1 could influence predispositions to PD through the fine-tuning of LC integrity.