Masahiko Takaya

The impact of a genome-wide supported psychosis variant in the ZNF804A gene on memory function in schizophrenia†

A recent genome‐wide association study showed that a variant (rs1344706) in the ZNF804A gene was associated with schizophrenia and bipolar disorder. Replication studies supported the evidence for association between this variant in the ZNF804A gene and schizophrenia and that this variant is the most likely susceptibility variant. Subsequent functional magnetic resonance imaging studies in healthy subjects demonstrated the association of the high‐risk ZNF804A variant with neural activation during a memory task and a theory of mind task. As these cognitive performances are disturbed in patients with schizophrenia, this gene may play a role in cognitive dysfunction in schizophrenia. The aim of the current study was to investigate the potential relationship between this ZNF804A polymorphism and memory function. The effects of the high‐risk ZNF804A genotype, diagnosis, and genotype–diagnosis interaction on verbal memory, visual memory (VisM), attention/concentration, and delayed recall (measured by the Wechsler Memory Scale‐Revised) were analyzed by two‐way analysis of covariance in 113 patients with schizophrenia and 184 healthy subjects. Consistent with previous studies, patients with schizophrenia exhibited poorer performance on all indices as compared to healthy control subjects (P < 0.001). A significant ZNF804A genotype–diagnosis interaction was found for VisM performance (P = 0.0012). Patients with the high‐risk T/T genotype scored significantly lower on VisM than G carriers did (P = 0.018). In contrast, there was no genotype effect for any index in the healthy control subjects (P > 0.05). Our data suggest that rs1344706 may be related to memory dysfunction in schizophrenia.

Neuropsychiatric Symptoms in Patients with Idiopathic Normal Pressure Hydrocephalus

Objective: To clarify the characteristics of neuropsychiatric symptoms in patients with idiopathic normal pressure hydrocephalus (iNPH). Methods: Neuropsychiatric symptoms of 64 iNPH patients with mild triad symptoms from three kinds of hospitals were evaluated with the Neuropsychiatric Inventory (NPI) and compared with 126 patients with Alzheimer’s disease (AD). Results: The most frequently observed neuropsychiatric symptom in the iNPH patients was apathy followed by anxiety and aggression. No symptom was more prevalent or more severe in iNPH than in AD. The severity of cognitive impairment was correlated with both aberrant motor activity and apathy. Conclusions: Neuropsychiatric symptoms were mild in patients with iNPH and apathy was the most prevalent symptom. The correlation between neuropsychiatric symptoms and cognitive impairment in iNPH appears to arise from a common pathology in the frontal lobe.

Neuroimaging studies in patients with Charles Bonnet Syndrome

Charles Bonnet Syndrome (CBS) is characterized by complex formed and recurrent visual hallucinations in psychologically normal people, and is often associated with eye pathology. Many psychiatrists have taken an interest in CBS because this syndrome could provide clues to the mechanisms underlying visual hallucinations. In the present paper, we review previous neuroimaging studies in patients with CBS and summarize the results of these studies. There could be a fundamental dysfunction in the primary and secondary visual cortices in some patients with CBS, and transient cortical activation occurs in the inferior lateral temporal cortex during the appearance of visual hallucinations in CBS patients. External visual stimuli are perceived in the retina and are transmitted to the primary visual cortex (Brodmann area (BA) 17). The stimuli are transmitted from BA 17 to the secondary visual cortex (BA 18) and then to the visual association cortices (BA 19 and BA 37). In general, our perception of external visual stimuli normally has an inhibitory effect on the endogenous activation of the visual cortex. Visual loss due to certain conditions, of which eye pathology is the most commonly postulated in CBS patients, produces a state of sensory deprivation that releases the visual cortex from regulation by external stimuli, resulting in visual hallucinations (cortical release phenomenon). The results of previous neuroimaging studies suggest that the cortical release phenomenon hypothesis for the occurrence of visual hallucinations in patients with CBS is plausible. In addition, the results indicate that not only eye pathology, but also dysfunction in the primary and secondary visual cortices could result in deprivation of external visual stimuli.

Global cerebral hypoperfusion in preclinical stage of idiopathic normal pressure hydrocephalus.

In patients with idiopathic normal pressure hydrocephalus (iNPH), ventriculomegaly and narrowed subarachnoid spaces at the high convexity appear in magnetic resonance (MR) images before the occurrence of objective symptoms. In addition, quantitative regional cerebral blood flow (rCBF) has been reported to be reduced in iNPH patients with objective symptoms. To determine whether reduced rCBF is responsible for the appearance of symptoms, we compared rCBF in patients with suspected iNPH with no objective triad symptoms (NOS), iNPH patients with apparent objective triad symptoms (AOS) and normal control subjects (NC). Regional CBF was quantified in 35 Regions-of-interest (ROIs) by 123I-IMP single photon emission computed tomography (SPECT) using the autoradiography (ARG) method. Multiple comparisons showed that, in all brain regions examined except for in the frontal white matter, rCBF in the NOS group was significantly lower than that in the NC group, but in all brain regions, not significantly different from that of the AOS group. These results suggest that factors other than rCBF in the resting state are responsible for the occurrence of objective symptoms of iNPH.

KIBRA genetic polymorphism influences episodic memory in Alzheimer's disease, but does not show association with disease in a Japanese cohort

Background/Aims: A single-nucleotide polymorphism (SNP) in the KIBRA gene, rs17070145, was reported to be significantly associated with episodic memory in cognitively normal cohorts. This observation has expanded genetic studies on KIBRA to Alzheimer’s disease (AD). Importantly, the association between KIBRA and episodic memory in AD has never been addressed. In this study, we investigated whether the KIBRA rs17070145 SNP influences AD episodic memory and the disease in a Japanese cohort. Methods: Blood samples from 346 AD patients and 375 normal cognitive controls were collected and genotyped for rs17070145. Episodic memory was measured in 32 AD patients, diagnosed for the first time, by use of the Rivermead Behavioral Memory Test (RBMT). Results: We found that KIBRA C allele carriers scored significantly lower than KIBRA non-C carriers on both RBMT total profile score (p = 0.042, effect size = 0.84) and RBMT total screening score (p < 0.001, effect size = 1.42). The KIBRA gene did not show association with AD in our Japanese cohort. Conclusion: Our results evidence a strong association between the KIBRA gene and episodic memory impairment in AD, but show no influence on AD in our Japanese cohort. We propose that KIBRA might have an effect similar to cognitive reserve.

Decreased alpha event-related synchronization in the left posterior temporal cortex in schizophrenia: A magnetoencephalography-beamformer study

Alpha rhythm is one of the most prominent electromagnetic changes in the brain, and electroencephalography (EEG) alpha reactivity disturbance may sometimes represent an early sign of cerebral dysfunction. Although magnetoencephalography (MEG) has a better spatial resolution than EEG, it has not extensively been used to explore alpha-power change deficits in schizophrenia as a possible neurophysiological marker of the disease. The purpose of this study was to use MEG to identify abnormalities in alpha synchronization induced by eye-closing in schizophrenia patients compared to healthy controls, and to investigate whether alpha reactivity deficits correlate with clinical features of the disorder. MEG data were recorded in 22 schizophrenia patients and 20 age- and gender-matched controls during eyes-open/eyes-closed resting states. Cortical sources of event-related synchronization (ERS) were estimated using multiple source beamformer, and BrainVoyager was used for statistic group analysis. A significant decrease in ERS in the upper alpha band (10-13 Hz) was found in the left posterior temporal region in schizophrenia patients relative to controls, and this activity showed correlation with visual memory scores. This upper alpha ERS deficit may indicate left temporal dysfunction and visual-information processing impairment in schizophrenia, and upon further confirmation it might represent a neurophysiological state marker of the disorder.

Different characteristics of cognitive impairment in elderly schizophrenia and Alzheimer's disease in the mild cognitive impairment stage.

We compared indices of the revised version of the Wechsler Memory Scale (WMS-R) and scaled scores of the five subtests of the revised version of the Wechsler Adult Intelligence Scale (WAIS-R) in 30 elderly schizophrenia (ES) patients and 25 Alzheimer’s disease (AD) patients in the amnestic mild cognitive impairment (aMCI) stage (AD-aMCI). In the WMS-R, attention/concentration was rated lower and delayed recall was rated higher in ES than in AD-aMCI, although general memory was comparable in the two groups. In WAIS-R, digit symbol substitution, similarity, picture completion, and block design scores were significantly lower in ES than in AD-aMCI, but the information scores were comparable between the two groups. Delayed recall and forgetfulness were less impaired, and attention, working memory and executive function were more impaired in ES than in AD-aMCI. These results should help clinicians to distinguish ES combined with AD-aMCI from ES alone.

Cognitive impairment before changes appear on [18F]‐fluoro‐D‐glucose positron emission tomography images in a patient with possible early‐stage cerebellar‐predominant multiple system atrophy

Multiple system atrophy (MSA) is a sporadic, rapidly progressive neurodegenerative disorder characterized by autonomic dysfunction combined with parkinsonism or cerebellar ataxia. Patients with MSA typically suffer from cognitive disorders and rapid eye movement sleep behaviour disorder. 18F‐fluorodeoxyglucose‐positron emission tomography is used to assess MSA. However, the relationship between the clinical features and findings on 18F‐fluorodeoxyglucose‐positron emission tomography in patients with MSA has not yet been investigated. Here we report a case of possible early‐stage cerebellar‐type MSA. We concluded that cerebellar‐type MSA or other factors, such as rapid eye movement sleep behaviour disorder or obstructive sleep apnoea cognitive impairment, could appear before changes are visible on 18F‐fluorodeoxyglucose‐positron emission tomography images. Additionally, we concluded that the cognitive impairment could derive from cerebellar‐type MSA itself, not from other factors such as rapid eye movement sleep behaviour disorder or sleep apnoea syndrome.

Memantine treatment for neuropsychiatric symptoms in a patient with probable idiopathic normal pressure hydrocephalus: a case report

IntroductionPatients with idiopathic normal pressure hydrocephalus often show neuropsychiatric symptoms besides the triad of ‘classic’ symptoms. Memantine has been reported to have positive effects on the neuropsychiatric symptoms of patients with Alzheimer’s disease and patients with dementia with Lewy bodies. We administered memantine to a Japanese patient with probable idiopathic normal pressure hydrocephalus, hoping that this treatment would have positive effects on the neuropsychiatric symptoms of his idiopathic normal pressure hydrocephalus.Case presentationAn 80-year-old right-handed Japanese man was diagnosed as having probable idiopathic normal pressure hydrocephalus and showed neuropsychiatric symptoms as well as the triad of classic symptoms of idiopathic normal pressure hydrocephalus. We treated our patient with memantine by increasing, decreasing, and then again increasing the dose of memantine. We evaluated his neuropsychiatric symptoms using the Neuropsychiatric Inventory at baseline, after the dose was increased to 20mg/day, after the dose was decreased to 5mg/day, and after the dose was increased again to 15mg/day. We simultaneously evaluated the triad of symptoms and conducted neuropsychological tests. In addition, we evaluated the psychological distress of our patient’s caregiver using the Zarit Caregiver Burden Interview.ConclusionsMemantine had positive effects on the neuropsychiatric symptoms of our patient with idiopathic normal pressure hydrocephalus. Although none of his triad of classic symptoms, including cognitive abilities, improved, the psychological distress of our patient’s caregiver improved.

Pareidolic illusions of a patient with suspected late-onset, sleep-related epilepsy: Pareidolic illusion in epilepsy

The face version of the noise pareidolia test (FVNPT) is a valid and reliable surrogate marker of visual hallucinations in dementia with Lewy bodies (DLB). Visual hallucinations also often occur in epilepsy, but unlike in patients with DLB, they usually are not concrete. There has been no report describing the FVNPT results of patients with epilepsy. Here we describe the case of a patient with suspected lateonset, sleep-related epilepsy with pareidolic illusions as shown by FVNPT. A 68-year-old woman who lived with her husband consulted our clinic and claimed that over the past year she had often clearly seen human faces on the ceiling as she lay awake in bed at night before falling asleep. She had no significant past medical history. She knew that the faces did not exist and were visual hallucinations—that is, she had insight into her visual hallucinations. Her husband claimed that he had observed her talking and demonstrating abnormal behaviours in her sleep. Both she and her husband confirmed that she did not experience excessive daytime sleepiness. Parkinsonism, ataxia, constipation, fluctuations in cognition, and olfactory disturbance were not observed. We suspected rapid eye movement (REM) sleep behaviour disorder, which may represent one of the preclinical symptoms of DLB. The scores of neuropsychological tests were as follows: