Epileptic activity on foramen ovale electrodes is associated with sleep and tau pathology in Alzheimer's disease.

Both sleep alterations and epileptiform activity are associated with the accumulation of amyloid-ß and tau pathology and are currently investigated for potential therapeutic interventions in Alzheimer's disease (AD). However, a bidirectional intertwining relation between sleep and neuronal hyperexcitability might modulate the effects of AD pathology on the corresponding associations. To investigate this, we performed multiple day simultaneous foramen ovale (FO) plus scalp EEG and polysomnography (PSG) recordings and acquired 18F-MK6240 tau PET-MR in three patients in the prodromal stage of AD and in two patients with mild and moderate dementia due to AD, respectively. As an eligibility criterion for the present study, subjects either had a history of a recent seizure (n = 2) or subclinical epileptiform activity (SEA) on a previous scalp EEG taken in a research context (n = 3). The 18F-MK6240 standard uptake value ratio (SUVR) and asymmetry index (AI) were calculated in a priori defined volumes of interest (VOIs). Linear mixed effects models were used to study associations between interictal epileptiform discharges (IEDs), PSG parameters and 18F-MK6240 SUVR. Epileptiform activity was bilateral but asymmetrically present on FO electrodes in all patients and ≥ 95% of IEDs were not visible on scalp EEG. In one patient two focal seizures were detected on FO electrodes, both without visual scalp EEG correlate. We observed lateralized periodic discharges, brief potentially ictal rhythmic discharges and lateralized rhythmic delta activity on FO electrodes in four patients. Unlike scalp EEG, intracranial electrodes showed a lateralization of epileptiform activity. Although the amount of IEDs on intracranial electrodes was not associated to the 18F-MK6240 SUVR binding in different VOIs, there was a congruent asymmetry of the 18F-MK6240 binding towards the most epileptic hemisphere for the mesial (P = 0.007) and lateral temporal cortex (P = 0.006). IEDs on intracranial electrodes were most abundant during slow wave sleep (SWS) (92/h) and N2 (81/h), followed by N1 (33/h) and least frequent during wakefulness (17/h) and REM sleep (9/h). The extent of IEDs during sleep was not reflected in the relative time in each sleep stage spent (REM% (P = 0.415), N1% (P = 0.668), N2% (P = 0.442), SWS% (P = 0.988)), and not associated with the arousal index (P = 0.317), apnea-hypopnea index (P = 0.846) or oxygen desaturation index (P = 0.746). Together, our observations suggest a multi-directional interaction between sleep, epileptiform activity and tau pathology in AD.

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.

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.

The nature of the relationship of psychomotor slowing with negative symptomatology in schizophrenia.

INTRODUCTION: Psychomotor slowing is an important feature of schizophrenia and the relation with negative symptoms is not fully understood. This study aims, first, to investigate the association between negative symptoms and psychomotor slowing. Second, we want to investigate whether fine motor slowing reflects clinically observable gross motor slowing. METHODS: In 53 stabilised adult patients with schizophrenia, negative symptoms were assessed using the Positive and Negative Syndrome Scale negative subscale (PANSS-N) with two calculated factors entering the analysis: an expressivity factor and a volitional factor. Psychomotor slowing was assessed by using a modified version of the Salpêtrière Retardation Rating Scale, the Finger Tapping Test, and a writing task measuring fine psychomotor slowing. RESULTS: Negative symptomatology is associated with difficulties in the initiation of fine motor movements, r=.334, p<.05, whilst planning and execution are not. The volitional factor, r=-.407, p=.005, but not the expressivity factor, r=.060, p=.689, is significantly associated with psychomotor slowing. No associations between fine and clinically observable gross psychomotor functioning were found. CONCLUSIONS: These findings indicate that higher values of negative symptomatology-more specifically the volitional deficit cluster-affect motor initiation, indicating a heterogeneity in the PANSS-N factorial structure, and that gross and fine psychomotor functioning are affected independently.

Physiological Profiling of Agitation in Dementia: Insights From Wearable Sensor Data.

Background and Objectives: The number of people with dementia is expected to triple to 152 million in 2050, with 90% having accompanying behavioral and psychological symptoms (BPSD). Agitation is among the most critical BPSD and can lead to decreased quality of life for people with dementia and their caregivers. This study aims to explore objective quantification of agitation in people with dementia by analyzing the relationships between physiological and movement data from wearables and observational measures of agitation. Research Design and Methods: The data presented here is from 30 people with dementia, each included for 1 week, collected following our previously published multimodal data collection protocol. This observational protocol has a cross-sectional repeated measures design, encompassing data from both wearable and fixed sensors. Generalized linear mixed models were used to quantify the relationship between data from different wearable sensor modalities and agitation, as well as motor and verbal agitation specifically. Results: Several features from wearable data are significantly associated with agitation, at least the p < .05 level (absolute ß: 0.224-0.753). Additionally, different features are informative depending on the agitation type or the patient the data were collected from. Adding context with key confounding variables (time of day, movement, and temperature) allows for a clearer interpretation of feature differences when a person with dementia is agitated. Discussion and Implications: The features shown to be significantly different, across the study population, suggest possible autonomic nervous system activation when agitated. Differences when splitting the data by agitation type point toward a need for future detection models to tailor to the primary type of agitation expressed. Finally, patient-specific differences in features indicate a need for patient- or group-level model personalization. The findings reported in this study both reinforce and add to the fundamental understanding of and can be used to drive the objective quantification of agitation.

Identification of rare copy number variants in high burden schizophrenia families.

Over the last years, genome-wide studies consistently showed an increased burden of rare copy number variants (CNVs) in schizophrenia patients, supporting the "common disease, rare variant" hypothesis in at least a subset of patients. We hypothesize that in families with a high burden of disease, and thus probably a high genetic load influencing disease susceptibility, rare CNVs might be involved in the etiology of schizophrenia. We performed a genome-wide CNV analysis in the index patients of eight families with multiple schizophrenia affected members, and consecutively performed a detailed family analysis for the most relevant CNVs. One index patient showed a DRD5 containing duplication. A second index patient presented with an NRXN1 containing deletion and two adjacent duplications containing MYT1L and SNTG2. Detailed analysis in the subsequent families showed segregation of the identified CNVs. With this study we show the importance of screening high burden families for rare CNVs, which will not only broaden our knowledge concerning the molecular genetic mechanisms involved in schizophrenia but also allow the use of the obtained genetic data to provide better clinical care to these families in general and to non-symptomatic causal CNV carriers in particular.

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.

Aggression Severity as a Predictor of Mortality in Dementia.

OBJECTIVES: In psychogeriatric units for patients with dementia and behavioral problems, aggression is prevalent. Predictions and timely interventions of aggression are essential to create a safe environment and prevent adverse outcomes. Our study aimed to determine whether aggression severity early during admission to these units could be used as an indicator of adverse outcomes. DESIGN: During one year, all aggressive incidents on a psychogeriatric unit were systematically recorded using the Revised Staff Observation of Aggression Scale (SOAS-R). The study investigated the link between the severity of incidents within the first 48 hours of admission and adverse outcomes. SETTING AND PARTICIPANTS: All patients included in the study were admitted to a psychogeriatric unit for dementia and behavioral problems between November 2020 and October 2021. METHODS: The study population was categorized into groups according to the level of aggression severity during the first 48 hours of admission. The impact of aggression severity on the duration of admission, aggression frequency and severity during admission, medication usage at discharge, discharge destination, and mortality risk were examined. RESULTS: During the initial 2 days of admission, 9 of 88 patients had 1 or more severe aggression incidents. An early manifestation of severe aggression was significantly associated with more incidents during hospitalization, a higher total SOAS-R score, and a sevenfold higher 1-year mortality risk compared with patients who did not or only mildly manifested aggression in the first 48 hours of admission. CONCLUSIONS AND IMPLICATIONS: An early manifestation of aggression not only poses a direct safety risk to all involved but is also an early indicator of patients at risk for more detrimental outcomes, specifically mortality risk. By identifying patients at higher risk for adverse outcomes early, health care providers can provide preventive or timelier interventions, mitigating the risk of adverse outcomes and optimizing care services.

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.

Acoustic stimulation as a promising technique to enhance slow-wave sleep in Alzheimer's disease: results of a pilot study.

STUDY OBJECTIVES: Sleep disturbances are common in people with Alzheimer's disease (AD), and a reduction in slow-wave activity is the most striking underlying change. Acoustic stimulation has emerged as a promising approach to enhance slow-wave activity in healthy adults and people with amnestic mild cognitive impairment. In this phase 1 study we investigated, for the first time, the feasibility of acoustic stimulation in AD and piloted the effect on slow-wave sleep (SWS). METHODS: Eleven adults with mild to moderate AD first wore the DREEM 2 headband for 2 nights to establish a baseline registration. Using machine learning, the DREEM 2 headband automatically scores sleep stages in real time. Subsequently, the participants wore the headband for 14 consecutive "stimulation nights" at home. During these nights, the device applied phase-locked acoustic stimulation of 40-dB pink noise delivered over 2 bone-conductance transducers targeted to the up-phase of the delta wave or SHAM, if it detected SWS in sufficiently high-quality data. RESULTS: Results of the DREEM 2 headband algorithm show a significant average increase in SWS (minutes) [t(3.17) = 33.57, P = .019] between the beginning and end of the intervention, almost twice as much time was spent in SWS. Consensus scoring of electroencephalography data confirmed this trend of more time spent in SWS [t(2.4) = 26.07, P = .053]. CONCLUSIONS: Our phase 1 study provided the first evidence that targeted acoustic stimuli is feasible and could increase SWS in AD significantly. Future studies should further test and optimize the effect of stimulation on SWS in AD in a large randomized controlled trial. CITATION: Van den Bulcke L, Peeters A-M, Heremans E, et al. Acoustic stimulation as a promising technique to enhance slow-wave sleep in Alzheimer's disease: results of a pilot study. J Clin Sleep Med. 2023;19(12):2107-2112.

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.

Rare copy number variants in neuropsychiatric disorders: Specific phenotype or not?

From a number of genome-wide association studies it was shown that de novo and/or rare copy number variants (CNVs) are found at an increased frequency in neuropsychiatric diseases. In this study we examined the prevalence of CNVs in six genomic regions (1q21.1, 2p16.3, 3q29, 15q11.2, 15q13.3, and 16p11.2) previously implicated in neuropsychiatric diseases. Hereto, a cohort of four neuropsychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, and intellectual disability) and control individuals from three different populations was used in combination with Multilpex Amplicon Quantifiaction (MAQ) assays, capable of high resolution (kb range) and custom-tailored CNV detection. Our results confirm the etiological candidacy of the six selected CNV regions for neuropsychiatric diseases. It is possible that CNVs in these regions can result in disturbed brain development and in this way lead to an increased susceptibility for different neuropsychiatric disorders, dependent on additional genetic and environmental factors. Our results also suggest that the neurodevelopmental component is larger in the etiology of schizophrenia and intellectual disability than in mood disorders. Finally, our data suggest that deletions are in general more pathogenic than duplications. Given the high frequency of the examined CNVs (1-2%) in patients of different neuropsychiatric disorders, screening of large cohorts with an affordable and feasible method like the MAQ assays used in this study is likely to result in important progress in unraveling the genetic factors leading to an increased susceptibility for several psychiatric disorders.

Identification of a CACNA2D4 deletion in late onset bipolar disorder patients and implications for the involvement of voltage-dependent calcium channels in psychiatric disorders.

The GWAS-based association of CACNA1C with bipolar disorder (BPD) is one of the strongest genetic findings to date. CACNA1C belongs to the family of CACN genes encoding voltage-dependent calcium channels (VDCCs). VDCCs are involved in brain circuits and cognitive processes implicated in BPD and schizophrenia (SZ). Recently, it was shown that rare copy number variations (CNVs) are found at an increased frequency in SZ and to a lesser extent also in BPD, suggesting the involvement of CNVs in the causation of these diseases. We hypothesize that CNVs in CACN genes can influence the susceptibility to BPD, SZ, and/or schizoaffective disorder (SZA). A search for CNVs in eight CACN genes in a patient-control sample of European decent was performed. A total of 709 BP patients, 645 SZ patients, 189 SZA patients, and 1,470 control individuals were screened using the Multiplex Amplicon Quantification (MAQ) method. We found a rare, partial deletion of 35.7 kb in CACNA2D4 in two unrelated late onset bipolar I patients and in one control individual. All three deletions shared the same breakpoints removing exons 17-26 of CACNA2D4, comprising part of the CACHE domain. Based on the data we cannot claim causality to BPD of the identified CACNA2D4 deletion but nevertheless this deletion can be important in unraveling the underlying processes leading to psychiatric diseases in general and BPD in particular.

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.

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.

Voice Reactivity as a Response to Acute Hypobaric Hypoxia at High Altitude.

BACKGROUND: Although the understanding of hypobaric hypoxia is increasing, it remains a hazard in aviation medicine. This study examined the feasibility of detecting voice markers sensitive to acute hypobaric hypoxia in an early presymptomatic (PRE-SYMP) stage.METHOD: Eight subjects qualified with hypobaric training completed a series of standardized speech tests in a hypobaric chamber at 20,000 ft and 25,000 ft (6096 and 7620 m) of altitude. Voice response patterns were analyzed in terms of fundamental frequency (F0), F0 range, and voice onset time (VOT). We hypothesized a PRE-SYMP compensatory stage in voice reactivity.RESULTS: There was a different dose-response reactivity course at 20,000 ft vs. 25,000 ft, nonlinear to altitude. At 20,000 ft, our hypothesis was confirmed. In comparison to sea level, a PRE-SYMP compensatory stage could be distinguished, characterized by a decreased F0 range, decreased VOT, and increased F0. During a transitional (TRANS) stage, in comparison with sea level, the F0-range reset, VOT decreased, and F0 increased. During a symptomatic (SYMP) stage, F0 increased, F0 range increased, and VOT decreased. At 25,000 ft, in comparison to sea level, voice reactivity showed increased F0 and F0 range and decreased VOT in a PRE-SYMP stage and increased F0 and F0 range in the SYMP stage.DISCUSSION: The compensatory PRE-SYMP stage is suggested to be the expression of ongoing bottom-up and top-down regulatory mechanisms, whereas the 25,000-ft results are interpreted as a combination of tonic and phasic voice reactivity. This tonic component needs to be foreseen in sea level baseline measures.Van Puyvelde M, Neyt X, Vanderlinden W, Van den Bossche M, Bucovaz T, De Winne T, Pattyn N. Voice reactivity as a response to acute hypobaric hypoxia at high altitude. Aerosp Med Hum Perform. 2020; 91(6):471-478.