Subclinical epileptiform activity and sleep disturbances in Alzheimer's disease.

INTRODUCTION: Subclinical epileptiform activity (SEA) and sleep disturbances are frequent in Alzheimer's disease (AD). Both have an important relation to cognition and potential therapeutic implications. We aimed to study a possible relationship between SEA and sleep disturbances in AD. METHODS: In this cross-sectional study, we performed a 24-h ambulatory EEG and polysomnography in 48 AD patients without diagnosis of epilepsy and 34 control subjects. RESULTS: SEA, mainly detected in frontotemporal brain regions during N2 with a median of three spikes/night [IQR1-17], was three times more prevalent in AD. AD patients had lower sleep efficacy, longer wake after sleep onset, more awakenings, more N1%, less REM sleep and a higher apnea-hypopnea index (AHI) and oxygen desaturation index (ODI). Sleep was not different between AD subgroup with SEA (AD-Epi+) and without SEA (AD-Epi-); however, compared to controls, REM% was decreased and AHI and ODI were increased in the AD-Epi+ subgroup. DISCUSSION: Decreased REM sleep and more severe sleep-disordered breathing might be related to SEA in AD. These results could have diagnostic and therapeutic implications and warrant further study at the intersection between sleep and epileptiform activity in AD.

Facial expression recognition deficits in frontotemporal dementia and Alzheimer's disease: a meta-analytic investigation of effects of phenotypic variant, task modality, geographical region and symptomatic specificity.

Deficits in social cognition may be present in frontotemporal dementia (FTD) and Alzheimer's disease (AD). Here, we conduct a qualitative synthesis and meta-analysis of facial expression recognition studies in which we compare the deficits between both disorders. Furthermore, we investigate the specificity of the deficit regarding phenotypic variant, domain-specificity, emotion category, task modality, and geographical region. The results reveal that both FTD and AD are associated with facial expression recognition deficits, that this deficit is more pronounced in FTD compared to AD and that this applies for the behavioral as well as for language FTD-variants, with no difference between the latter two. In both disorders, overall emotion recognition was most frequently impaired, followed by recognition of anger in FTD and by fear in AD. Verbal categorization was the most frequently used task, although matching or intensity rating tasks may be more specific. Studies from Oceania revealed larger deficits. On the other hand, non-emotional control tasks were more impacted by AD than by FTD. The present findings sharpen the social cognitive phenotype of FTD and AD, and support the use of social cognition assessment in late-life neuropsychiatric disorders.

A paleo-neurologic investigation of the social brain hypothesis in frontotemporal dementia.

The social brain hypothesis posits that a disproportionate encephalization in primates enabled to adapt behavior to a social context. Also, it has been proposed that phylogenetically recent brain areas are disproportionally affected by neurodegeneration. Using structural and functional magnetic resonance imaging, the present study investigates brain-behavior associations and neural integrity of hyperspecialized and domain-general cortical social brain areas in behavioral variant frontotemporal dementia (bvFTD). The results revealed that both structure and function of hyperspecialized social areas in the middle portion of the superior temporal sulcus (STS) are compromised in bvFTD, while no deterioration was observed in domain general social areas in the posterior STS. While the structural findings adhered to an anterior-posterior gradient, the functional group differences only occurred in the hyperspecialized locations. Activity in specialized regions was associated with structural integrity of the amygdala and with social deficits in bvFTD. In conclusion, the results are in line with the paleo-neurology hypothesis positing that neurodegeneration primarily hits cortical areas showing increased specialization, but also with the compatible alternative explanation that anterior STS regions degenerate earlier, based on stronger connections to and trans-neuronal spreading from regions affected early in bvFTD.

Toward Quantification of Agitation in People With Dementia Using Multimodal Sensing.

Background and Objectives: Agitation, a critical behavioral and psychological symptom in dementia, has a profound impact on a patients' quality of life as well as their caregivers'. Autonomous and objective characterization of agitation with multimodal systems has the potential to capture key patient responses or agitation triggers. Research Design and Methods: In this article, we describe our multimodal system design that encompasses contextual parameters, physiological parameters, and psychological parameters. This design is the first to include all three of these facets in an n > 1 study. Using a combination of fixed and wearable sensors and a custom-made app for psychological annotation, we aim to identify physiological markers and contextual triggers of agitation. Results: A discussion of both the clinical as well as the technical implementation of the to-date data collection protocol is presented, as well as initial insights into pilot study data collection. Discussion and Implications: The ongoing data collection moves us toward improved agitation quantification and subsequent prediction, eventually enabling just-in-time intervention.

How non-rapid eye movement sleep and Alzheimer pathology are linked.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by the presence of senile plaques and neurofibrillary tangles. Research attempts to identify characteristic factors that are associated with the presence of the AD pathology on the one hand and that increase the risk of developing AD on the other. Changes in non-rapid eye movement (NREM) sleep may meet both requirements for various reasons. First, NREM-sleep is important for optimal memory function. In addition, studies report that the presence of AD pathology is associated with NREM-sleep changes. Finally, more and more results appear to suggest that sleep problems are not only a symptom of AD but can also increase the risk of AD. Several of these studies suggest that it is primarily a lack of NREM-sleep that is responsible for this increased risk. However, the majority investigated sleep only through subjective reporting, as a result of which NREM-sleep could not be analyzed separately. The aim of this literature study is therefore to present the results of the studies that relate the AD pathology and NREM-sleep (registered by electroencephalography). Furthermore, we try to evaluate whether NREM-sleep analysis could be used to support the diagnosis of AD and whether NREM-sleep deficiency could be a causal factor in the development of AD.

Hippocampal volume change following ECT is mediated by rs699947 in the promotor region of VEGF.

Several studies have shown that electroconvulsive therapy (ECT) results in increased hippocampal volume. It is likely that a multitude of mechanisms including neurogenesis, gliogenesis, synaptogenesis, angiogenesis, and vasculogenesis contribute to this volume increase. Neurotrophins, like vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) seem to play a crucial mediating role in several of these mechanisms. We hypothesized that two regulatory SNPs in the VEGF and BDNF gene influence the changes in hippocampal volume following ECT. We combined genotyping and brain MRI assessment in a sample of older adults suffering from major depressive disorder to test this hypothesis. Our results show an effect of rs699947 (in the promotor region of VEGF) on hippocampal volume changes following ECT. However, we did not find a clear effect of rs6265 (in BDNF). To the best of our knowledge, this is the first study investigating possible genetic mechanisms involved in hippocampal volume change during ECT treatment.

Clinical validation of the Psychotic Depression Assessment Scale (PDAS) against independent global severity ratings in older adults.

OBJECTIVES: According to a recent study, ratings on the Psychotic Depression Assessment Scale (PDAS) obtained via a dedicated semi-structured interview are valid measures of the severity of psychotic depression. This study aimed to further test the validity, scalability and responsiveness of the PDAS in older adults using independent ratings on the Clinical Global Impression Scale - Severity (CGI-S) and the Montgomery-Asberg Depression Rating Scale (MADRS) as references. METHODS: Ratings were performed at admission and discharge at two old age psychiatric wards in Flanders, Belgium. In total, 62 older adults (mean age: 74.3 years) with psychotic depression were included. The PDAS was rated by trained nurses using the semi-structured PDAS interview. Senior psychiatrists scored the participants on the CGI-S. Psychologists or experienced nurses rated participants on the MADRS. Clinical validity was assessed by correlating the PDAS total scores with CGI-S ratings and MADRS total scores. Mokken analysis was performed to assess the scalability of the PDAS. Responsiveness was assessed by comparing the proportion of participants in remission (PDAS total score <8 at study baseline and endpoint). RESULTS: The Spearman correlation coefficients were 0.76 and 0.79 for the PDAS versus CGI-S and PDAS versus MADRS, respectively. The Mokken analysis yielded a Loevinger coefficient of 0.46, which is indicative of scalability. At admission, no participants met the PDAS remission criterion. At discharge, 54% (95% confidence interval: 47%-60%) of the patients met this criterion. CONCLUSION: The PDAS appears to be a clinically valid, scalable and responsive measure of the severity of psychotic depression in older adults.

Longitudinal evaluation of the psychomotor syndrome in schizophrenia.

Little is known about the longitudinal course of psychomotor signs and symptoms after illness onset in schizophrenia. Therefore, a 1-year follow-up study was conducted in which patients with schizophrenia were assessed three times with an extensive battery of psychomotor rating scales and tests. The syndromic structure of psychomotor symptoms was also studied. In accordance with a neurodevelopmental view on schizophrenia, psychomotor functioning was found to remain stable or improve slightly. Prospective studies with longer follow-up periods are needed to rule out the possibility of neurodegeneration in subgroups of patients and to evaluate possible covariation in the course of psychomotor symptoms.

Less cognitive and neurological deficits in schizophrenia patients carrying risk variant in ZNF804A.

BACKGROUND: The rs1344706 single nucleotide polymorphism in the ZNF804A gene is a common variant with strong evidence for association with schizophrenia. Recent studies show an association of rs1344706 with cognitive functioning, and there is some evidence suggesting that the risk allele may increase susceptibility for a subtype of schizophrenia with relatively spared cognition. METHODS: We tested the effect of rs1344706 genotype in 89 schizophrenia patients on 3 basic cognitive domains (working memory, processing speed and attention) shown to be severely impaired in schizophrenia. Also we investigated the effect of rs1344706 on the severity of neurological soft signs, subtle impairments in motor and sensory functions highly frequent in schizophrenia patients. Neurological soft signs and cognitive deficits are central features of schizophrenia and are tightly linked with clinical, social and functional outcome. RESULTS: Our results show an association of higher rs1344706 risk allele load with improved performance on processing speed and with fewer neurological soft signs. CONCLUSIONS: Together with other studies, our findings suggest that ZNF804A is associated with a subtype of schizophrenia with better cognitive and neurological functioning. Discovery of the specific pathways through which ZNF804A is exerting this effect may lead to better prevention, diagnosis and treatment for a specific group of schizophrenia patients.

Co-occurrence of Marfan syndrome and schizophrenia: what can be learned?

We report on a young female patient diagnosed with Marfan syndrome upon admission to the psychiatric hospital for a first psychosis. Mutation analysis of FBN1 identified a de novo nonsense mutation (p.Glu178X). This finding implies co-occurrence of schizophrenia and Marfan syndrome, an observation that has been reported several times in the past. Although, this co-occurrence can be coincidental, several arguments provide strong evidence that Marfan syndrome and schizophrenia might share common etiological pathways. This observation can be important in light of both the etiology of schizophrenia and the diagnosis of Marfan syndrome.

Sequencing of DISC1 pathway genes reveals increased burden of rare missense variants in schizophrenia patients from a northern Swedish population.

In recent years, DISC1 has emerged as one of the most credible and best supported candidate genes for schizophrenia and related neuropsychiatric disorders. Furthermore, increasing evidence--both genetic and functional--indicates that many of its protein interaction partners are also involved in the development of these diseases. In this study, we applied a pooled sample 454 sequencing strategy, to explore the contribution of genetic variation in DISC1 and 10 of its interaction partners (ATF5, Grb2, FEZ1, LIS-1, PDE4B, NDE1, NDEL1, TRAF3IP1, YWHAE, and ZNF365) to schizophrenia susceptibility in an isolated northern Swedish population. Mutation burden analysis of the identified variants in a population of 486 SZ patients and 514 control individuals, revealed that non-synonymous rare variants with a MAF<0.01 were significantly more present in patients compared to controls (8.64% versus 4.7%, P = 0.018), providing further evidence for the involvement of DISC1 and some of its interaction partners in psychiatric disorders. This increased burden of rare missense variants was even more striking in a subgroup of early onset patients (12.9% versus 4.7%, P = 0.0004), highlighting the importance of studying subgroups of patients and identifying endophenotypes. Upon investigation of the potential functional effects associated with the identified missense variants, we found that ∼90% of these variants reside in intrinsically disordered protein regions. The observed increase in mutation burden in patients provides further support for the role of the DISC1 pathway in schizophrenia. Furthermore, this study presents the first evidence supporting the involvement of mutations within intrinsically disordered protein regions in the pathogenesis of psychiatric disorders. As many important biological functions depend directly on the disordered state, alteration of this disorder in key pathways may represent an intriguing new disease mechanism for schizophrenia and related neuropsychiatric diseases. Further research into this unexplored domain will be required to elucidate the role of the identified variants in schizophrenia etiology.

PCM1 and schizophrenia: a replication study in the Northern Swedish population.

Previous studies implicated centrosomal dysfunction as a source of various neuropsychiatric disorders, including schizophrenia (SZ). Two recent reports [Gurling et al., 2006; Datta et al., 2008. Mol Psychiatry] described an association between polymorphisms in the PCM1 gene and SZ in a UK/Scottish population. In this study, we aimed to replicate these findings in a Northern Swedish association sample of 486 research subjects with SZ and 512 unrelated control individuals. We genotyped 12 previously described SNP markers and carried out haplotype analyses using the same multi-marker haplotypes previously reported. Though we could not replicate the association with SNPs rs445422 and rs208747, we did observe a significant protective association with intronic SNP rs13276297. Furthermore, we performed a meta-analysis comprising 1,794 SZ patients and 1,553 controls, which confirmed the previously reported association with rs445422 and rs208747. These data provide further evidence that PCM1-though certainly not a major risk factor in the Northern Swedish population-cannot be ruled out as a contributor to SZ risk and/or protection, and deserves further replication in larger populations to elucidate its role in disease etiology.