Identifying the mental health burden in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients in Switzerland: A pilot study.

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating chronic disease of significant public health and clinical importance. It affects multiple systems in the body and has neuro-immunological characteristics. The disease is characterized by a prominent symptom called post-exertional malaise (PEM), as well as abnormalities in the immune-inflammatory pathways, mitochondrial dysfunctions and disturbances in neuroendocrine pathways. The purpose of this study was to evaluate the impact of ME/CFS on the mental health and secondary psychosocial manifestations of patients, as well as their coping mechanisms. Method: In 2021, a descriptive cross-sectional study was conducted in Switzerland. A self-administered paper questionnaire survey was used to gather data from 169 individuals diagnosed with ME/CFS. Results: The majority of the patients (90.5%) reported a lack of understanding of their disease, resulting in patients avoiding talking about the disease due to disbelief, trivialization and avoidance of negative reactions. They felt most supported by close family members (67.1%). Two thirds of the patients (68.5%) experienced stigmatization. ME/CFS had a negative impact on mental health in most patients (88.2%), leading to sadness (71%), hopelessness for relief (66.9%), suicidal thoughts (39.3%) and secondary depression (14.8%). Half of the male patients experienced at least one suicidal thought since clinical onset. Factors significantly associated with depression were the lack of cure, disabilities associated with ME/CFS, social isolation and the fact that life was not worth anymore with ME/CFS. The three main factors contributing to suicidal thoughts were (i) being told the disease was only psychosomatic (89.5%), (ii) being at the end of one's strength (80.7%) and (iii) not feeling being understood by others (80.7%). Conclusion: This study provided first time significant insights into the mental and psychological well-being of ME/CFS patients in Switzerland. The findings highlight the substantial experiences of stigmatization, secondary depression and suicidal thoughts compared to other chronic diseases, calling for an urgent need in Switzerland to improve ME/CFS patient's medical, psychological and social support, in order to alleviate the severe mental health burden associated with this overlooked somatic disease.

[Recommendations for the diagnostic and therapy of behavioural and psychological symptoms of dementia (BPSD)].

INTRODUCTION: The «Recommendations for the Diagnosis and Treatment of Behavioral and Psychological Symptoms of Dementia (BPSD)¼ were developed in parallel with the Swiss National Dementia Strategy 2014-2019 under the auspices of the Swiss Society for Geriatric Psychiatry and Psychotherapy (SGAP) and mark the beginning of a series of recommendations for geriatric psychiatric disorders. They depict the evidence-based state of knowledge about diagnostics and therapy, based on the clinical experience of the experts, and are designed for interprofessional and interdisciplinary use. The non-pharmacological intervention options and pharmacotherapy are discussed in detail. This paper is the revised version of the 2014 publication and compiles the development in this area for everyday clinical practice.

Influence of preanalytical and analytical factors on the quantification of six regulatory serum proteins.

Background: We analyzed differences in protein concentrations in human blood serum depending on the tube material and the immunoassay platform used. Materials & methods: Blood samples from study participants were collected in glass and polypropylene tubes (n = 292). Serum concentrations of six proteins (BDNF, IGF-1, VEGF-A, TGF-ß1, MCP-1 and IL-18) were assessed by using ELISAs (all biomarkers), as well as a novel fully automated immunoassay platform (all but IGF-1, n = 211). Bland-Altman analyses were conducted to investigate intrasample variability of protein concentrations. Results: Tube comparison resulted in mean biases of between -0.45 and -70.64%. Platform comparison revealed mean biases of between 21.04 and -128.10%. Conclusion: Protein concentrations can vary significantly depending on the types of tube and immunoassay used, with protein-specific differences.

This study investigated the impact of blood tube materials and measuring platforms on protein concentrations in blood samples. We collected blood serum from up to 292 study participants using glass and polypropylene tubes. The concentrations of six proteins were analyzed using a common laboratory technique called ELISA, as well as an automated platform, Ella™. The choice of tube material had small effects on two proteins (IGF-1 and IL-18), with differences of less than 1%. However, the concentrations of four other proteins (VEGF-A, MCP-1, TGF-ß1 and BDNF) varied significantly more depending on the tube material used, with differences ranging from -32.17 to -70.64%. With the two testing methods, two proteins (VEGF-A and TGF-ß1) showed only small differences, with variations of -7.68 and 11.74%, respectively. For the other four proteins, the differences were larger, from 21.04 to -128.10%. The study demonstrates the importance of having consistent, standardized methods for measuring protein levels in blood samples. The tubes and testing methods used can both change the results significantly, depending on the specific protein being measured. To make sure the measurements are accurate, we suggest creating specific guidelines for each testing method and protein. By following these guidelines, scientists can ensure that the measurements of protein levels in liquid biopsy samples are dependable and consistent.

The Behavioural Dysfunction Questionnaire discriminates behavioural variant frontotemporal dementia from Alzheimer's disease dementia and major depressive disorder.

BACKGROUND AND OBJECTIVES: Early-stage behavioural variant frontotemporal dementia (bvFTD) is often misdiagnosed, highlighting the need for new diagnostic instruments. Based on the revised diagnostic criteria for bvFTD, we developed the Behavioural Dysfunction Questionnaire (BDQ). In this explorative study, we aimed to determine the best scoring and analytical method for the BDQ to discriminate between bvFTD and non-bvFTD patients. MATERIALS AND METHODS: 34 patients with early-stage bvFTD, 56 with early-stage Alzheimer's disease dementia (ADD) and 41 with major depressive disorder (MDD) were recruited. We calculated BDQ-items with or without inclusion of a time criterion: (a) without time criterion, (b) with 10 years' time criterion (symptom presence less than 10 years), and (c) with 3 years' time criterion (symptom presentation within the first 3 years). Using these three differently calculated items, we generated six variables, i.e. 3*2 [BDQ-Global Score (BDQ-GS; domains average score); BDQ-Global Domain Score (BDQ-GDS; domains categorical score)]. Then, we performed univariate and bivariate (BDQ-GS and BDQ-GDS combined) ROC analyses. RESULTS: Models including BDQ-GS, BDQ-GDS or both variables combined discriminated similarly between groups. In contrast, models without time criterion or with 10 years' time criterion discriminated better than models including variables with 3 years' time criterion. These models discriminated highly (AUC = 85.98-87.78) between bvFTD and MDD and bvFTD and ADD, respectively. CONCLUSION: BDQ-scores without any time criterion discriminated highly between early-stage bvFTD and non-bvFTD groups, which could improve the early diagnosis of bvFTD. With its standardised procedure, the BDQ is also appropriate for repeated assessments.

Development of the Basel Version of the Awareness of Social Inference Test - Theory of Mind (BASIT-ToM) in healthy adults.

Impairments of Theory of Mind (ToM) abilities occur in a wide range of brain disorders. Therefore, reliable and ecologically valid examination of these abilities is a crucial part of any comprehensive neuropsychological assessment. An established and ecologically valid, English-language test identifying deficits in ToM abilities is "The Awareness of Social Inference Test - Social Inference Minimal (TASIT-SIM)". However, no comparable German-language ToM test currently exists. In this study, we aimed to develop the first German-language adaption of TASIT-SIM in healthy adults. We selected 13 scenes [four scenes per message type (i.e., honesty, simple sarcasm, paradoxical sarcasm) and one practice scene] out of the 30 TASIT-SIM scenes. In collaboration with a film institute, we filmed each scene at three different intensities. These intensity version scenes were then administered to 240 healthy adults, equally distributed in sex and age, ranging from 35 to 92 years. By applying Rasch analysis, we selected intensity versions that showed neither floor nor ceiling effects in the majority of ToM questions in participants whose ToM abilities were in the medium range. In conclusion, we have developed the first German-language adaption of TASIT-SIM, i.e., the "Basel Version of the Awareness of Social Inference Test - Theory of Mind (BASIT-ToM)". The BASIT-ToM incorporates the strengths of TASIT-SIM, while overcoming its limitations such as inconsistencies in cinematic realization and ceiling effects in healthy participants. Next, the BASIT-ToM needs to be validated in healthy people and clinical populations.

The Basel Version of the Awareness of Social Inference Test-Emotion Recognition (BASIT-ER): Preliminary validation analyses in healthy adults.

OBJECTIVE: Emotion recognition (ER) is commonly impaired in many brain disorders. Therefore, its reliable and ecologically valid examination is a crucial part of any comprehensive neuropsychological assessment. In this regard, an established English-language test identifying deficits in ER is "The Awareness of Social Inference Test-Emotion Evaluation Test" (TASIT-EET). However, no comparable German-language ER test currently exists. In this study, we aimed to develop and preliminarily validate the first German-language adaption of TASIT-EET in healthy adults. METHOD: We selected 22 scenes [three scenes per emotion (i.e., anger, disgust, fear, happiness, sadness, surprise, and neutral) and one practice scene] out of the 56 TASIT-EET scenes. In collaboration with a film institute and professional actors, we filmed each scene (except neutral) at three different emotional intensities. Then, we administered these intensity version scenes to 240 cognitively and mentally healthy participants, equally distributed in sex and age, ranging from 35 to 92 years. RESULTS: By applying Rasch analysis, the one intensity version per scene was selected that showed neither floor nor ceiling effects in participants whose ability in ER was in the medium range. CONCLUSIONS: We have conducted a preliminary validation of the first German-language adaption of TASIT-EET, i.e., the "Basel Version of the Awareness of Social Inference Test-Emotion Recognition" (BASIT-ER). The BASIT-ER comprises the strengths of the TASIT-EET, while it overcomes its limitations such as ceiling effects in healthy participants and the simple response format. Next, the BASIT-ER needs to be validated in clinical populations. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

[The Swiss Brain Health Registry : a national infrastructure for Alzheimer's research]. / Le Registre suisse pour la santé du cerveau - Une infrastructure nationale pour la recherche sur la maladie d'Alzheimer.

The Memory Centres of several Swiss hospitals have set up a national online registry for Alzheimer's research, called www.BHR-suisse.org. This type of registry already exists in the United States (www.brainhealthregistry.org/) and the Netherlands (https://hersenonderzoek.nl/). It contributes, as do these initiating sites, to the creation of a global database of research partnersb who wish to contribute by participating in studies on neurodegenerative diseases and more particularly on Alzheimer's disease. By registering, they provide a certain amount of information and become potential research partners. Researchers can then select a panel of volunteers according to the selection and exclusion criteria of their studies, contact them and include them in their studies.

Les centres de la mémoire de plusieurs hôpitaux suisses ont créé un Registre national suisse en ligne pour la recherche sur Alzheimer, intitulé www.bhr-suisse.org. Ce type de registre existe déjà aux États-Unis (www.brainhealthregistry.org/) et aux Pays-Bas (hersenonderzoek.nl/). Il contribue, au même titre que ces sites initiateurs, à constituer une base de données globale de partenaires de recherchea qui souhaitent apporter leur contribution en participant à des études sur les maladies neurodégénératives et, plus particulièrement, sur la maladie d'Alzheimer. En s'inscrivant, ces derniers apportent un certain nombre d'informations et deviennent de potentiels partenaires de recherche. Les chercheurs peuvent ensuite sélectionner un panel suivant les critères de sélection et d'exclusion de leurs études, contacter les volontaires et les intégrer dans ces études.

Global brain volume and N-acetyl-aspartate decline over seven decades of normal aging.

We characterize the whole-brain N-acetyl-aspartate (WBNAA) and brain tissue fractions across the adult lifespan and test the hypothesis that, despite age-related atrophy, neuronal integrity (reflected by WBNAA) is preserved in normal aging. Two-hundred-and-seven participants: 133 cognitively intact older adults (73.6 ± 7.4 mean ± standard deviation, range: 60-90 year old) and 84 young (37.9 ± 11, range: 21-59 year old) were scanned with proton magnetic resonance spectroscopy and T1-weighted MRI. Their WBNAA, fractional brain parenchyma, and gray and white matter volumes (fBPV, fGM, and fWM) were compared and modeled as functions of age and sex. Compared with young, older-adults' WBNAA was lower by ~35%, and fBPV, fGM and fWM were lower by ~10%. Linear regressions found 0.5%/year WBNAA and 0.2%/year fBPV and fGM declines, whereas fWM rose to age ~40 years, and declined thereafter. fBPV and fGM were 1.8% and 4% higher in women, with no sex decline rates difference. We conclude that contrary to our hypothesis, atrophy was accompanied by WBNAA decline. Across the entire age range, women's brains showed less atrophy than men's. Formulas to estimate WBNAA and brain tissue fractions in healthy adults are provided to help differentiate normal from abnormal aging.

Conference report: dementia research and care and its impact in Switzerland.

In October 2019, a Swiss panel of experts met for the Dementia Summit in Brunnen, Switzerland, to discuss the latest scientific findings on basic and clinical research, as well as practical and political approaches to the challenges of dementia disorders in Switzerland. Here, we present the conference summary. To study pathophysiological changes, as well as the underlying mechanism of fluid biomarker changes, excellent experimental approaches, including transgenic mouse models, are available. Current knowledge about presymptomatic disease progression is largely derived from the longitudinal study of individuals with autosomal dominant mutations (Dominantly Inherited Alzheimer Network). Importantly, more than one third of identified dementia risk factors can be modified. For example, sleep disturbances are not only associated with dementia and neurodegeneration in specific brain regions, but also precede cognitive decline and contribute to the development of brain pathology. Regarding the neuropsychological examination of dementia disorders, standardised tests of social cognition, one of the six cognitive domains that must be assessed according to the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders, are missing, but now under development. The most important new therapeutic approach in the treatment of Alzheimer’s disease is the current attempt to prevent β-amyloid accumulation. While until now clinical studies have failed because of side effects or insufficient clinical effectiveness, Biogen recently announced positive results of high doses of aducanumab, a monoclonal antibody against β-amyloid. Other approaches also show promise. In China, sodium oligomannate has been approved to treat Alzheimer's disease. The substance suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Assistive technologies for dementia patients can help identify relevant information for care and nursing, as well as measurements for clinical interventions. Dementia patients have a high risk of developing delirium, even in the home environment. Therefore, it is necessary to use and further develop multi-disciplinary and systematic detection and prevention strategies. Homecare models for dementia patients with multidisciplinary teams have been established and evaluated and should be expanded. Dementia is the third-leading cause of death in Switzerland. In palliative care for severe dementia, the improvement of quality of life is of primary importance. The goals of the National Dementia Strategy, to increase the quality of life in those affected and to reduce taboos surrounding the disease, are still unrealised. The need for further national and regional engagement in order to implement the different findings of the strategy has largely been acknowledged, and these implementations have become the core tasks of a national dementia platform.

Cerebrospinal fluid from Alzheimer's disease patients promotes tau aggregation in transgenic mice.

Tau is a microtubule stabilizing protein that forms aggregates in Alzheimer's disease (AD). Tau derived from AD patients' brains induces tau aggregation in a prion-like manner when injected into susceptible mouse models.Here we investigated whether cerebrospinal fluid (CSF) collected from patients diagnosed with probable AD or mild cognitive impairment (MCI) likely due to AD harbors a prion-like tau seeding potential. CSF was injected intrahippocampally into young P301S tau transgenic mice. CSF obtained from AD or MCI patients increased hippocampal tau hyperphosphorylation and tau tangle formation in these mice at 4 months post-seeding. Tau pathology was also accentuated in the contralateral hippocampus, and in anterior and posterior directions, indicative of spreading.We provide first evidence for in vivo prion-like properties of AD patients' CSF, accelerating tau pathology in susceptible tau transgenic mice. This demonstrates that biologically active tau seeds reach the CSF compartment in AD. Further studies may help to evaluate strain specific properties of CSF derived tau bioseeds, and to assess their diagnostic potential.

Individual differences in socioemotional sensitivity are an index of salience network function.

Connectivity in intrinsically connected networks (ICNs) may predict individual differences in cognition and behavior. The drastic alterations in socioemotional awareness of patients with behavioral variant frontotemporal dementia (bvFTD) are presumed to arise from changes in one such ICN, the salience network (SN). We examined how individual differences in SN connectivity are reflected in overt social behavior in healthy individuals and patients, both to provide neuroscientific insight into this key brain-behavior relationship, and to provide a practical tool to diagnose patients with early bvFTD. We measured SN functional connectivity and socioemotional sensitivity in 65 healthy older adults and 103 patients in the earliest stage [Clinical Dementia Rating (CDR) Scale score ≤1] of five neurodegenerative diseases [14 bvFTD, 29 Alzheimer's disease (AD), 20 progressive supranuclear palsy (PSP), 21 semantic variant primary progressive aphasia (svPPA), and 19 non-fluent variant primary progressive aphasia (nfvPPA)]. All participants underwent resting-state functional imaging and an informant described their responsiveness to subtle emotional expressions using the Revised Self-Monitoring Scale (RSMS). Higher functional connectivity in the SN, predominantly between the right anterior insula (AI) and both "hub" cortical and "interoceptive" subcortical nodes, predicted socioemotional sensitivity among healthy individuals, showing that socioemotional sensitivity is a behavioral marker of SN function, and particularly of right AI functional connectivity. The continuity of this relationship in both healthy and neurologically affected individuals highlights the role of socioemotional sensitivity as an early diagnostic marker of SN connectivity. Clinically, this is particularly important for identification of patients in the earliest stage of bvFTD, where the SN is selectively vulnerable.

Facial Emotion Recognition Performance Differentiates Between Behavioral Variant Frontotemporal Dementia and Major Depressive Disorder.

OBJECTIVE: Misdiagnosis of early behavioral variant frontotemporal dementia (bvFTD) with major depressive disorder (MDD) is not uncommon due to overlapping symptoms. The aim of this study was to improve the discrimination between these disorders using a novel facial emotion perception task. METHOD: In this prospective cohort study (July 2013-March 2016), we compared 25 patients meeting Rascovsky diagnostic criteria for bvFTD, 20 patients meeting DSM-IV criteria for MDD, 21 patients meeting McKhann diagnostic criteria for Alzheimer's disease dementia, and 31 healthy participants on a novel emotion intensity rating task comprising morphed low-intensity facial stimuli. Participants were asked to rate the intensity of morphed faces on the congruent basic emotion (eg, rating on sadness when sad face is shown) and on the 5 incongruent basic emotions (eg, rating on each of the other basic emotions when sad face is shown). RESULTS: While bvFTD patients underrated congruent emotions (P < .01), they also overrated incongruent emotions (P < .001), resulting in confusion of facial emotions. In contrast, MDD patients overrated congruent negative facial emotions (P < .001), but not incongruent facial emotions. Accordingly, ratings of congruent and incongruent emotions highly discriminated between bvFTD and MDD patients, ranging from area under the curve (AUC) = 93% to AUC = 98%. Further, an almost complete discrimination (AUC = 99%) was achieved by contrasting the 2 rating types. In contrast, Alzheimer's disease dementia patients perceived emotions similarly to healthy participants, indicating no impact of cognitive impairment on rating scores. CONCLUSIONS: Our congruent and incongruent facial emotion intensity rating task allows a detailed assessment of facial emotion perception in patient populations. By using this simple task, we achieved an almost complete discrimination between bvFTD and MDD, potentially helping improve the diagnostic certainty in early bvFTD.

Dissociation in Rating Negative Facial Emotions between Behavioral Variant Frontotemporal Dementia and Major Depressive Disorder.

OBJECTIVE: Features of behavioral variant frontotemporal dementia (bvFTD) such as executive dysfunction, apathy, and impaired empathic abilities are also observed in major depressive disorder (MDD). This may contribute to the reason why early stage bvFTD is often misdiagnosed as MDD. New assessment tools are thus needed to improve early diagnosis of bvFTD. Although emotion processing is affected in bvFTD and MDD, growing evidence indicates that the pattern of emotion processing deficits varies between the two disorders. As such, emotion processing paradigms have substantial potentials to distinguish bvFTD from MDD. DESIGN AND PARTICIPANTS: The current study compared 25 patients with bvFTD, 21 patients with MDD, 21 patients with Alzheimer disease (AD) dementia, and 31 healthy participants on a novel facial emotion intensity rating task. Stimuli comprised morphed faces from the Ekman and Friesen stimulus set containing faces of each sex with two different degrees of emotion intensity for each of the six basic emotions. MEASUREMENTS AND RESULTS: Analyses of covariance uncovered a significant dissociation between bvFTD and MDD patients in rating the intensity of negative emotions overall (i.e., bvFTD patients underrated negative emotions overall, whereas MDD patients overrated negative emotions overall compared with healthy participants). In contrast, AD dementia patients rated negative emotions similarly to healthy participants, suggesting no impact of cognitive deficits on rating facial emotions. CONCLUSIONS: By strongly differentiating bvFTD and MDDpatients through negative facial emotions, this sensitive and short rating task might help improve the early diagnosis of bvFTD.

"Now I see it, now I don't": Determining Threshold Levels of Facial Emotion Recognition for Use in Patient Populations.

The importance of including measures of emotion processing, such as tests of facial emotion recognition (FER), as part of a comprehensive neuropsychological assessment is being increasingly recognized. In clinical settings, FER tests need to be sensitive, short, and easy to administer, given the limited time available and patient limitations. Current tests, however, commonly use stimuli that either display prototypical emotions, bearing the risk of ceiling effects and unequal task difficulty, or are cognitively too demanding and time-consuming. To overcome these limitations in FER testing in patient populations, we aimed to define FER threshold levels for the six basic emotions in healthy individuals. Forty-nine healthy individuals between 52 and 79 years of age were asked to identify the six basic emotions at different intensity levels (25%, 50%, 75%, 100%, and 125% of the prototypical emotion). Analyses uncovered differing threshold levels across emotions and sex of facial stimuli, ranging from 50% up to 100% intensities. Using these findings as "healthy population benchmarks", we propose to apply these threshold levels to clinical populations either as facial emotion recognition or intensity rating tasks. As part of any comprehensive social cognition test battery, this approach should allow for a rapid and sensitive assessment of potential FER deficits.

Global N-acetylaspartate in normal subjects, mild cognitive impairment and Alzheimer's disease patients.

BACKGROUND: Mild cognitive impairment (MCI) is an intermediary state on the way to Alzheimer's disease (AD). Little is known about whole brain concentration of the neuronal marker, N-acetylaspartate (NAA) in MCI patients. OBJECTIVE: To test the hypothesis that since MCI and AD are both neurodegenerative, quantification of the NAA in their whole brain (WBNAA) could differentiate them from cognitively-intact matched controls. METHODS: Proton MR spectroscopy to quantify the WBNAA was applied to 197 subjects (86 females) 72.6 ± 8.4 years old (mean ± standard deviation). Of these, 102 were cognitively intact, 42 diagnosed as MCI, and 53 as probable AD. Their WBNAA amounts were converted into absolute concentration by dividing with the brain volume segmented from the MRI that also yielded the fractional brain volume (fBPV), an atrophy metric. RESULTS: WBNAA concentration of MCI and AD patients (10.5 ± 3.0 and 10.1 ± 2.9 mM) were not significantly different (p = 0.85). They were, however, highly significantly 25-29% lower than the 14.1 ± 2.4 mM of normal matched controls (p < 10-4). The fBPV of MCI and AD patients (72.9 ± 4.9 and 69.9 ± 4.7%) differed significantly from each other (4%, p = 0.02) and both were significantly lower than the 74.6 ± 4.4% of normal elderly (2%, p = 0.003 for MCI; 6%, p < 10-4 for AD). ROC curve analysis has shown WBNAA to have 70.5% sensitivity and 84.3% specificity to differentiate MCI or AD patients from normal elderly versus just 68.4 and 65.7% for fBPV. CONCLUSION: Low WBNAA in MCI patients compared with cognitively normal contemporaries may indicate early neuronal damage accumulation and supports the notion of MCI as an early stage of AD. It also suggests WBNAA as a potential marker of early AD pathology.

Varying strength of cognitive markers and biomarkers to predict conversion and cognitive decline in an early-stage-enriched mild cognitive impairment sample.

BACKGROUND: Several cognitive, neuroimaging, and cerebrospinal fluid (CSF) markers predict conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia. However, predictors might be more or less powerful depending on the characteristics of the MCI sample. OBJECTIVE: To investigate which cognitive markers and biomarkers predict conversion to AD dementia and course of cognitive functioning in a MCI sample with a high proportion of early-stage MCI patients. METHODS: Variables known to predict progression in MCI patients and hypothesized to predict progression in early-stage MCI patients were selected. Cognitive (long-delay free recall, regional primacy score), imaging (hippocampal and entorhinal cortex volumes, fornix fractional anisotropy), and CSF (Aß1-42/t-tau, Aß1-42) variables from 36 MCI patients were analyzed with Cox regression and mixed-effect models to determine their individual and combined abilities to predict time to conversion to AD dementia and course of global cognitive functioning, respectively. RESULTS: Those variables hypothesized to predict the course of early-stage MCI patients were most predictive for MCI progression. Specifically, regional primacy score (a measure of word-list position learning) most consistently predicted conversion to AD dementia and course of cognitive functioning. Both the prediction of conversion and course of cognitive functioning were maximized by including CSF Aß1-42 and fornix integrity biomarkers, respectively, indicating the complementary information carried by cognitive variables and biomarkers. CONCLUSION: Predictors of MCI progression need to be interpreted in light of the characteristics of the respective MCI sample. Future studies should aim to compare predictive strengths of markers between early-stage and late-stage MCI patients.

Self-awareness in neurodegenerative disease relies on neural structures mediating reward-driven attention.

Accurate self-awareness is essential for adapting one's tasks and goals to one's actual abilities. Patients with neurodegenerative diseases, particularly those with right frontal involvement, often present with poor self-awareness of their functional limitations that may exacerbate their already jeopardized decision-making and behaviour. We studied the structural neuroanatomical basis for impaired self-awareness among patients with neurodegenerative disease and healthy older adults. One hundred and twenty-four participants (78 patients with neurodegenerative diseases including Alzheimer's disease, behavioural variant frontotemporal dementia, right-temporal frontotemporal dementia, semantic variant and non-fluent variant primary progressive aphasia, and 46 healthy controls) described themselves on the Patient Competency Rating Scale, rating observable functioning across four domains (daily living activities, cognitive, emotional control, interpersonal). All participants underwent structural magnetic resonance imaging. Informants also described subjects' functioning on the same scale. Self-awareness was measured by comparing self and informant ratings. Group differences in discrepancy scores were analysed using general linear models, controlling for age, sex and disease severity. Compared with controls, patients with behavioural variant frontotemporal dementia overestimated their functioning in all domains, patients with Alzheimer's disease overestimated cognitive and emotional functioning, patients with right-temporal frontotemporal dementia overestimated interpersonal functioning, and patients with non-fluent aphasia overestimated emotional and interpersonal functioning. Patients with semantic variant aphasia did not overestimate functioning on any domain. To examine the neuroanatomic correlates of impaired self-awareness, discrepancy scores were correlated with brain volume using voxel-based morphometry. To identify the unique neural correlates of overlooking versus exaggerating deficits, overestimation and underestimation scores were analysed separately, controlling for age, sex, total intracranial volume and extent of actual functional decline. Atrophy related to overestimating one's functioning included bilateral, right greater than left frontal and subcortical regions, including dorsal superior and middle frontal gyri, lateral and medial orbitofrontal gyri, right anterior insula, putamen, thalamus, and caudate, and midbrain and pons. Thus, our patients' tendency to under-represent their functional decline was related to degeneration of domain-general dorsal frontal regions involved in attention, as well as orbitofrontal and subcortical regions likely involved in assigning a reward value to self-related processing and maintaining accurate self-knowledge. The anatomic correlates of underestimation (right rostral anterior cingulate cortex, uncorrected significance level) were distinct from overestimation and had a substantially smaller effect size. This suggests that underestimation or 'tarnishing' may be influenced by non-structural neurobiological and sociocultural factors, and should not be considered to be on a continuum with overestimation or 'polishing' of functional capacity, which appears to be more directly mediated by neural circuit dysfunction.

Neural substrates of socioemotional self-awareness in neurodegenerative disease.

BACKGROUND: Neuroimaging studies examining neural substrates of impaired self-awareness in patients with neurodegenerative diseases have shown divergent results depending on the modality (cognitive, emotional, behavioral) of awareness. Evidence is accumulating to suggest that self-awareness arises from a combination of modality-specific and large-scale supramodal neural networks. METHODS: We investigated the structural substrates of patients' tendency to overestimate or underestimate their own capacity to demonstrate empathic concern for others. Subjects' level of empathic concern was measured using the Interpersonal Reactivity Index, and subject-informant discrepancy scores were used to predict regional atrophy pattern, using voxel-based morphometry analysis. Of the 102 subjects, 83 were patients with neurodegenerative diseases such as behavioral variant frontotemporal dementia (bvFTD) or semantic variant primary progressive aphasia (svPPA); the other 19 were healthy older adults. RESULTS: bvFTD and svPPA patients typically overestimated their level of empathic concern compared to controls, and overestimating one's empathic concern predicted damage to predominantly right-hemispheric anterior infero-lateral temporal regions, whereas underestimating one's empathic concern showed no neuroanatomical basis. CONCLUSIONS: These findings suggest that overestimation and underestimation of one's capacity for empathic concern cannot be interpreted as varying degrees of the same phenomenon, but may arise from different pathophysiological processes. Damage to anterior infero-lateral temporal regions has been associated with semantic self-knowledge, emotion processing, and social perspective taking; neuropsychological functions partly associated with empathic concern itself. These findings support the hypothesis that-at least in the socioemotional domain-neural substrates of self-awareness are partly modality-specific.

Serial position effects are sensitive predictors of conversion from MCI to Alzheimer's disease dementia.

BACKGROUND: It is unclear whether the predictive strength of established cognitive variables for progression to Alzheimer's disease (AD) dementia from mild cognitive impairment (MCI) varies depending on time to conversion. We investigated which cognitive variables were best predictors, and which of these variables remained predictive for patients with longer times to conversion. METHODS: Seventy-five participants with MCI were assessed on measures of learning, memory, language, and executive function. Relative predictive strengths of these measures were analyzed using Cox regression models. RESULTS: Measures of word-list position-namely, serial position scores-together with Short Delay Free Recall of word-list learning best predicted conversion to AD dementia. However, only serial position scores predicted those participants with longer time to conversion. CONCLUSIONS: Results emphasize that the predictive strength of cognitive variables varies depending on time to conversion to dementia. Moreover, finer measures of learning captured by serial position scores were the most sensitive predictors of AD dementia.