Molecular mechanisms linking type 2 diabetes mellitus and late-onset Alzheimer's disease: A systematic review and qualitative meta-analysis.

Research evidence indicating common metabolic mechanisms through which type 2 diabetes mellitus (T2DM) increases risk of late-onset Alzheimer's dementia (LOAD) has accumulated over recent decades. The aim of this systematic review is to provide a comprehensive review of common mechanisms, which have hitherto been discussed in separate perspectives, and to assemble and evaluate candidate loci and epigenetic modifications contributing to polygenic risk linkages between T2DM and LOAD. For the systematic review on pathophysiological mechanisms, both human and animal studies up to December 2023 are included. For the qualitative meta-analysis of genomic bases, human association studies were examined; for epigenetic mechanisms, data from human studies and animal models were accepted. Papers describing pathophysiological studies were identified in databases, and further literature gathered from cited work. For genomic and epigenomic studies, literature mining was conducted by formalised search codes using Boolean operators in search engines, and augmented by GeneRif citations in Entrez Gene, and other sources (WikiGenes, etc.). For the systematic review of pathophysiological mechanisms, 923 publications were evaluated, and 138 gene loci extracted for testing candidate risk linkages. 3 57 publications were evaluated for genomic association and descriptions of epigenomic modifications. Overall accumulated results highlight insulin signalling, inflammation and inflammasome pathways, proteolysis, gluconeogenesis and glycolysis, glycosylation, lipoprotein metabolism and oxidation, cell cycle regulation or survival, autophagic-lysosomal pathways, and energy. Documented findings suggest interplay between brain insulin resistance, neuroinflammation, insult compensatory mechanisms, and peripheral metabolic dysregulation in T2DM and LOAD linkage. The results allow for more streamlined longitudinal studies of T2DM-LOAD risk linkages.

Corrigendum: Neuroendocrinological and Epigenetic Mechanisms Subserving Autonomic Imbalance and HPA Dysfunction in the Metabolic Syndrome.

[This corrects the article DOI: 10.3389/fnins.2016.00142.].

Research evidence from studies on filial imprinting, attachment, and early life stress: a new route for scientific integration.

Attachment is a concept that was developed and researched in developmental psychology in uptake of findings on filial imprinting from ethology. In the present period, however, attachment concepts are increasingly applied to and investigated in animal research, thereby translating back criteria that were established for human infants. It herein appears that findings on filial imprinting are becoming more and more forgotten, whilst basic findings in human infants are not reflected in investigations on attachment in animals. To re-integrate both domains, the present article undertakes the effort in briefly reviewing and recapitulating basic findings in human attachment and recent research on filial imprinting. In specific, replicated were critical roles of the conversion of thyroid prohormone by 2 iodothyronine deiodinase (Dio2) into triiodothyronine (T3) in the regulation of the timing of imprinting learning. Because of the interactions of T3 with oxytocinergic and dopaminergic neurones of the hypothalamic paraventricular nucleus, these findings provide new neuroendocrinological insight for possible relations with both attachment and metabolic sequelae of early life stress. Necessary is a mutual integration of all recent advances in the yet separated fields.

Early Life Stress and Epigenetics in Late-onset Alzheimer's Dementia: A Systematic Review.

Involvement of life stress in Late-Onset Alzheimer's Disease (LOAD) has been evinced in longitudinal cohort epidemiological studies, and endocrinologic evidence suggests involvements of catecholamine and corticosteroid systems in LOAD. Early Life Stress (ELS) rodent models have successfully demonstrated sequelae of maternal separation resulting in LOAD-analogous pathology, thereby supporting a role of insulin receptor signalling pertaining to GSK-3beta facilitated tau hyper-phosphorylation and amyloidogenic processing. Discussed are relevant ELS studies, and findings from three mitogen-activated protein kinase pathways (JNK/SAPK pathway, ERK pathway, p38/MAPK pathway) relevant for mediating environmental stresses. Further considered were the roles of autophagy impairment, neuroinflammation, and brain insulin resistance. For the meta-analytic evaluation, 224 candidate gene loci were extracted from reviews of animal studies of LOAD pathophysiological mechanisms, of which 60 had no positive results in human LOAD association studies. These loci were combined with 89 gene loci confirmed as LOAD risk genes in previous GWAS and WES. Of the 313 risk gene loci evaluated, there were 35 human reports on epigenomic modifications in terms of methylation or histone acetylation. 64 microRNA gene regulation mechanisms were published for the compiled loci. Genomic association studies support close relations of both noradrenergic and glucocorticoid systems with LOAD. For HPA involvement, a CRHR1 haplotype with MAPT was described, but further association of only HSD11B1 with LOAD found; however, association of FKBP1 and NC3R1 polymorphisms was documented in support of stress influence to LOAD. In the brain insulin system, IGF2R, INSR, INSRR, and plasticity regulator ARC, were associated with LOAD. Pertaining to compromised myelin stability in LOAD, relevant associations were found for BIN1, RELN, SORL1, SORCS1, CNP, MAG, and MOG. Regarding epigenetic modifications, both methylation variability and de-acetylation were reported for LOAD. The majority of up-to-date epigenomic findings include reported modifications in the well-known LOAD core pathology loci MAPT, BACE1, APP (with FOS, EGR1), PSEN1, PSEN2, and highlight a central role of BDNF. Pertaining to ELS, relevant loci are FKBP5, EGR1, GSK3B; critical roles of inflammation are indicated by CRP, TNFA, NFKB1 modifications; for cholesterol biosynthesis, DHCR24; for myelin stability BIN1, SORL1, CNP; pertaining to (epi)genetic mechanisms, hTERT, MBD2, DNMT1, MTHFR2. Findings on gene regulation were accumulated for BACE1, MAPK signalling, TLR4, BDNF, insulin signalling, with most reports for miR-132 and miR-27. Unclear in epigenomic studies remains the role of noradrenergic signalling, previously demonstrated by neuropathological findings of childhood nucleus caeruleus degeneration for LOAD tauopathy.

Anger Traits Associated With Cardiovascular Risk Biomarkers in the Metabolic Syndrome.

BACKGROUND: Recent studies have shown that different personality traits contribute to mortality in different subtypes of cardiovascular disease (CVD). Anger traits have been shown to promote the constellation of the metabolic syndrome (MetS), which in turn increases CVD risks. OBJECTIVE: To determine covariation of anger traits with CVD biomarkers, we examined patients (N = 101; 34 men and 67 women; age, 45.6 ± 13.96 years) in a nationally sampled treatment cohort for MetS in the Ukrainian governmental healthcare system. METHODS: Data collection was conducted in 2007. Laboratory data of single components of the MetS according to International Diabetes Federation Consensus were dependent measures in regression models with self-reported overt aggressivity and covert hostility in the Buss-Durkee Hostility Inventory and sociodemographic data. Structural equation models (SEMs) were tested. RESULTS: The SEM results are in favor of a sex-adjusted 2-factor solution R = 0.723), as indicated by equation-level Bentler-Raykov goodness-of-fit coefficients of 0.81 to 0.97 for paths to biological variables. Two latent components, 1 relating to aggressivity and the other to hostility, combine lipid/obesity-related measures and cholesterol-related measures, respectively. CONCLUSIONS: The SEM results suggest that CVD-risk biomarker variables in this MetS sample (a) associate into 2 distinct profiles and (b) that 1 profile associates with overt anger, whereas the other associates with covert hostility. These results could contribute to more personalized prevention and care in CVD patients.

Neuroendocrinological and Epigenetic Mechanisms Subserving Autonomic Imbalance and HPA Dysfunction in the Metabolic Syndrome.

Impact of environmental stress upon pathophysiology of the metabolic syndrome (MetS) has been substantiated by epidemiological, psychophysiological, and endocrinological studies. This review discusses recent advances in the understanding of causative roles of nutritional factors, sympathomedullo-adrenal (SMA) and hypothalamic-pituitary adrenocortical (HPA) axes, and adipose tissue chronic low-grade inflammation processes in MetS. Disturbances in the neuroendocrine systems for leptin, melanocortin, and neuropeptide Y (NPY)/agouti-related protein systems have been found resulting directly in MetS-like conditions. The review identifies candidate risk genes from factors shown critical for the functioning of each of these neuroendocrine signaling cascades. In its meta-analytic part, recent studies in epigenetic modification (histone methylation, acetylation, phosphorylation, ubiquitination) and posttranscriptional gene regulation by microRNAs are evaluated. Several studies suggest modification mechanisms of early life stress (ELS) and diet-induced obesity (DIO) programming in the hypothalamic regions with populations of POMC-expressing neurons. Epigenetic modifications were found in cortisol (here HSD11B1 expression), melanocortin, leptin, NPY, and adiponectin genes. With respect to adiposity genes, epigenetic modifications were documented for fat mass gene cluster APOA1/C3/A4/A5, and the lipolysis gene LIPE. With regard to inflammatory, immune and subcellular metabolism, PPARG, NKBF1, TNFA, TCF7C2, and those genes expressing cytochrome P450 family enzymes involved in steroidogenesis and in hepatic lipoproteins were documented for epigenetic modifications.

Trait anxiety but not state anxiety level associates with biomarkers for hypertension in the metabolic syndrome.

Various studies link hypertension with anxiety; however, it remains unclarified if such relations are present in the metabolic syndrome (MetS). We studied cross-sectionally the interrelations of self-reported anxiety (Spielberger STAI), and MetS components in MetS patients. We investigated a nationally sampled treatment cohort for MetS with familial Type 2 diabetes risk. N = 101 patients fulfilling International Diabetes Federation criteria for MetS participated. Both laboratory and nonlaboratory measures were included. Structural equation models (SEM) were adjusted. The final SEM had an R(2) = .998 with the obesity component linking to waist, BMI, and degree of adiposity, and the hypertension component linking to systolic blood pressure, pulse pressure, total cholesterol, and trait anxiety. For state anxiety, no significant regressive causal path could be estimated. SEM supports the assumption of an interaction of pulse pressure, systolic blood pressure, cholesterol metabolism, and high trait anxiety in the pathophysiology of hypertension in MetS.

Cognitive load and autonomic response patterns under negative priming demand in depersonalization-derealization disorder.

Previous studies have yielded evidence for cognitive processing abnormalities and alterations of autonomic functioning in depersonalization-derealization disorder (DPRD). However, multimodal neuroimaging and psychophysiology studies have not yet been conducted to test for functional and effective connectivity under cognitive stress in patients with DPRD. DPRD and non-referred control subjects underwent a combined Stroop/negative priming task, and the neural correlates of Stroop interference effect, negative priming effect, error rates, cognitive load span and average amplitude of skin conductance responses were ascertained for both groups. Evoked haemodynamic responses for basic Stroop/negative priming activations were compared. For basic Stroop to neutral contrast, patients with DPRD differed in the location (inferior vs. superior lobule) of the parietal region involved, but showed similar activations in the left frontal region. In addition, patients with DPRD also co-activated the dorsomedial prefrontal cortex (BA9) and posterior cingulate cortex (BA31), which were also found to be the main between-group difference regions. These regions furthermore showed connectivity with frequency of depersonalization states. Evoked haemodynamic responses drawn from regions of interest indicated significant between-group differences in 30-40% of time points. Brain-behaviour correlations differed mainly in laterality, yet only slightly in regions. A reversal of autonomic patterning became evident in patients with DPRD for cognitive load spans, indicating less effective arousal suppression under cognitive stress - patients with DPRD showed positive associations of cognitive load with autonomic responses, whereas controls exhibit respective inverse association. Overall, the results of the present study show only minor executive cognitive peculiarities, but further support the notion of abnormalities in autonomic functioning in patients with DPRD.

Dissociable brain correlates for depression, anxiety, dissociation, and somatization in depersonalization-derealization disorder.

OBJECTIVE: The cerebral mechanisms of traits associated with depersonalization-derealization disorder (DPRD) remain poorly understood. METHOD: Happy and sad emotion expressions were presented to DPRD and non-referred control (NC) subjects in an implicit event-related functional magnetic resonance imaging (fMRI) design, and correlated with self report scales reflecting typical co-morbidities of DPRD: depression, dissociation, anxiety, somatization. RESULTS: Significant differences between the slopes of the two groups were observed for somatization in the right temporal operculum (happy) and ventral striatum, bilaterally (sad). Discriminative regions for symptoms of depression were the right pulvinar (happy) and left amygdala (sad). For dissociation, discriminative regions were the left mesial inferior temporal gyrus (happy) and left supramarginal gyrus (sad). For state anxiety, discriminative regions were the left inferior frontal gyrus (happy) and parahippocampal gyrus (sad). For trait anxiety, discriminative regions were the right caudate head (happy) and left superior temporal gyrus (sad). Discussion The ascertained brain regions are in line with previous findings for the respective traits. The findings suggest separate brain systems for each trait. CONCLUSION: Our results do not justify any bias for a certain nosological category in DPRD.

Alexithymia as a risk factor for type 2 diabetes mellitus in the metabolic syndrome: a cross-sectional study.

Alexithymia is a clinical trait consisting of diminished introspective and interoceptive capacities that has been shown to implicate elevated autonomic outflow and to bias for hypertension. To estimate relative risk associated with alexithymia in the metabolic syndrome (MetS), we conducted a cross-sectional analysis of patients with manifest type 2 diabetes mellitus (T2DM) or familial diabetes risk (N=101; 67 females; age 45.6±13.96) in a nationwide sampled treatment cohort for MetS in the Ukrainian governmental health care system. Laboratory data of single components of the MetS according to International Diabetes Federation Consensus were dependent measures in multivariable regression models with self-reported alexithymia severity (TAS-20) and socio-demographic data. TAS-20 as the sole surviving psychometric predictor for T2DM in the simplest regression equation provided the best model fit: OR 1.073, Z=19.04, (95%CIs 1.065-1.081). For microalbuminuria, the best fitting model was OR 1.030, Z=3.49 (95%CIs 1.013-1.048). TAS-20 predicted also triglyceride level at Wald-χ(2)=1299.27, Z=36.05 (95%CIs 0.052-0.058) and blood pressure maximum at Wald-χ(2)=2309.05, Z=48.05 (95%CIs 2.402-2.606). Our results show that alexithymia severity contributes to MetS by covarying with several of its single components, and that it may be a substantial concurrent indicator of T2DM and cardiovascular risks in MetS.

Interoceptive-reflective regions differentiate alexithymia traits in depersonalization disorder.

It is unclear to what degree depersonalization disorder (DPD) and alexithymia share abnormal brain mechanisms of emotional dysregulation. We compared cerebral processing of facial expressions of emotion in individuals with DPD to normal controls (NC). We presented happy and sad emotion expressions in increasing intensities from neutral (0%) through mild (50%) to intense (100%) to DPD and non-referred NC subjects in an implicit event-related fMRI design, and correlated respective brain activations with responses on the 20-item Toronto Alexithymia Scale (TAS-20) and its three subscales F1-F3. The TAS-20 predicts clinical diagnosis of DPD with a unique variance proportion of 38%. Differential regression analysis was utilized to ascertain brain regions for each alexithymia subscale. Differential regions of total alexithymia severity for happy emotion were the globus pallidus externus; for identifying feelings (TAS-20 F1 subscale), the right anterior insula; for description of feelings (F2), the right dorsal mid-anterior cingulate gyrus (BA 24); and for externally oriented cognitive style (F3), the left paracingulate gyrus (BA 32). For sad emotion, the differential region for the total TAS-20 score was the dorsal anterior cingulate gyrus (BA 24); for TAS-20 F1, the left inferior anterior insula; for TAS-20 F2, the right PCC (BA 31); and for TAS-20 F3, the right orbital gyrus (BA 10). Supporting our hypotheses, the ascertained brain regions for TAS-20 subscales subserve interoception, monitoring and reflection of internal states and emotion. The presented analyses provide evidence that alexithymia plays a substantial role in emotional dysregulation in DPD, presumably based on restrictions in interoception.

Predictors of early person reference development: maternal language input, attachment and neurodevelopmental markers.

In a longitudinal natural language development study in Germany, the acquisition of verbal symbols for present persons, absent persons, inanimate things and the mother-toddler dyad was investigated. Following the notion that verbal referent use is more developed in ostensive contexts, symbolic play situations were coded for verbal person reference by means of noun and pronoun use. Depending on attachment classifications at twelve months of age, effects of attachment classification and maternal language input were studied up to 36 months in four time points. Hierarchical regression analyses revealed that, except for mother absence, maternal verbal referent input rates at 17 and 36 months were stronger predictors for all referent types than any of the attachment organizations, or any other social or biological predictor variable. Attachment effects accounted for up to 9.8% of unique variance proportions in the person reference variables. Perinatal and familial measures predicted person references dependent on reference type. The results of this investigation indicate that mother-reference, self-reference and thing-reference develop in similar quantities measured from the 17-month time point, but are dependent of attachment quality.

Somatization severity associated with postero-medial complex structures.

Somatisation is a frequent problem in various psychiatric disorders, yet the cerebral mechanisms of somatisation remain unexamined. To test if somatisation is susceptible to emotional states, we investigated relationships between somatisation severity, neural effective connectivity, and autonomic responses to emotional facial expressions. Volunteering participants (N = 20) were presented with facial expressions of happy and sad emotion at three intensity levels (0%-50%-100%) in a fast implicit ER-fMRI design with concurrent derivation of skin conductance levels (SCL). Self-reported somatisation severity as assessed with Rief's SOMS-2 index was correlated with neural response controlling for other clinical traits to ascertain brain bases of somatisation. Regression analyses estimated effective connectivity of main clusters so determined with peripheral autonomic responses. Regions in which magnitude of activity correlated with somatisation severity consisted in both happy and sad conditions of the anterior ventral precuneus (BA7), along with posterior cingulate gyrus (PCC, BA23, sad condition) and anteromedial thalamus (happy condition).

Cerebral and autonomic responses to emotional facial expressions in depersonalisation disorder.

BACKGROUND: Depersonalisation disorder is characterised by emotion suppression, but the cerebral mechanisms of this symptom are not yet fully understood. AIMS: To compare brain activation and autonomic responses of individuals with the disorder and healthy controls. METHOD: Happy and sad emotion expressions in increasing intensities (neutral to intense) were presented in an implicit event-related functional magnetic resonance imaging (fMRI) design with simultaneous measurement of autonomic responses. RESULTS: Participants with depersonalisation disorder showed fMRI signal decreases, whereas the control group showed signal increases in response to emotion intensity increases in both happy and sad expressions. The analysis of evoked haemodynamic responses from regions exhibiting functional connectivity between central and autonomic nervous systems indicated that in depersonalisation disorder initial modulations of haemodynamic response occurred significantly earlier (2 s post-stimulus) than in the control group (4-6 s post-stimulus). CONCLUSIONS: The results suggest that fMRI signal decreases are possible correlates of emotion suppression in depersonalisation disorder.

Impact of familiarity upon children's developing facial expression recognition.

BACKGROUND: The impact of personal familiarity upon children's developing emotion-processing has been largely ignored in previous research, yet may prove particularly important given the emotional salience of such stimuli and children's greater exposure to familiar others compared to strangers. We examined the impact of personal familiarity upon developing facial expression recognition (FER). METHODS: Participants included 153 children, 4-15 years old. We employed dynamic expressions of five emotions (happy, sad, anger, fear, disgust), posed by familiar (parents, teachers) and unfamiliar identities. RESULTS: Accuracy improved with age for recognising sad and fear expressions, but not anger. Children tended to correctly recognise happiness and fear at lower intensities. The impact of familiarity on FER depended on emotion-category. Familiarity did not affect recognition of sad expressions, but children were less accurate at recognising anger, fear, and disgust in familiar individuals compared to strangers. CONCLUSION: Personal familiarity may exert a distracting effect on children's performance. Findings highlight the importance of incorporating different emotion-categories and familiarity when examining the development of FER. Clinical implications are discussed.

Limbic and prefrontal responses to facial emotion expressions in depersonalization.

Depersonalization disorder, characterized by emotional detachment, has been associated with increased prefrontal cortical and decreased autonomic activity to emotional stimuli. Event-related fMRI with simultaneous measurements of skin conductance levels occurred in nine depersonalization disorder patients and 12 normal controls to neutral, mild and intense happy and sad facial expressions. Patients, but not controls, showed decreases in subcortical limbic activity to increasingly intense happy and sad facial expressions, respectively. For both happy and sad expressions, negative correlations between skin conductance measures in bilateral dorsal prefrontal cortices occurred only in depersonalization disorder patients. Abnormal decreases in limbic activity to increasingly intense emotional expressions, and increases in dorsal prefrontal cortical activity to emotionally arousing stimuli may underlie the emotional detachment of depersonalization disorder.

Human attachment security is mediated by the amygdala: evidence from combined fMRI and psychophysiological measures.

The neural basis of human attachment security remains unexamined. Using event-related functional magnetic resonance imaging (fMRI) and simultaneous recordings of skin conductance levels, we measured neural and autonomic responses in healthy adult individuals during a semantic conceptual priming task measuring human attachment security "by proxy". Performance during a stress but not a neutral prime condition was associated with response in bilateral amygdalae. Furthermore, levels of activity within bilateral amygdalae were highly positively correlated with attachment insecurity and autonomic response during the stress prime condition. We thereby demonstrate a key role of the amygdala in mediating autonomic activity associated with human attachment insecurity.

[Consensus paper on the terminological differentiation of various aspect of body experience]. / Konsensuspapier zur terminologischen Abgrenzung von Teilaspekten des Körpererlebens in Forschung und Praxis.

In the past, phenomenological research on subjective body experience was characterised by vaguely defined terminology and methodological shortcomings. The term "body image" has been applied heterogeneously in literature in order to describe a variety of bodily phenomena. In this paper, the German terminology applied to the phenomenology of body experiences is described systematically. In developing a systematic terminology the authors refer to scientific evidence as well as recent reviews, and closely adhere to definitions commonly used in English literature. Different perspectives are utilised, particularly anthropological concepts and theories from developmental and self-psychology. Distinct aspects of body experience are described within the context of a network of external determinants and along a continuum between somatic and mental anchor points. Applying the term "body experience" as umbrella term, different aspects are defined: perceptive (body schema/-perceive), affective (body-cathexis), cognitive-evaluative (body-image, body-ego) and body-consciousness. It is emphasized, that the distinct description of functional levels has to be taken as an approximation of the reality of integrated body experience.