The interplay between genetic variation and gene expression of the glucocorticoid receptor gene NR3C1 and blood cortisol levels on verbal memory and hippocampal volumes.

The hypothalamus-pituitary-adrenal axis is the main physiological stress response system and regulating the release of cortisol. The two corticoid receptors encoded by the genes NR3C1 and NR3C2 are the main players in regulating the physiological response to cortisol. This biological system has been linked to neurocognitive processes and memory, yet the mechanisms remain largely unclear. In two independent general population studies (SHIP, total sample size > 5500), we aim to diseantangle the effects of genetic variation, gene expression and cortisol on verbal memory and memory associated brain volume. Especially for NR3C1 results exhibited a consistent pattern of direct an interactive effects. All three biological layers, genetic variation (rs56149945), gene expression for NR3C1 and cortisol levels, were directly associated with verbal memory. Interactions between these components showed significant effects on verbal memory as well as hippocampal volume. For NR3C2 such a complex association pattern could not be observed. Our analyses revealed that different components of the stress response system are acting together on different aspects of cognition. Complex phenotypes, such as cognition and memory function are regulated by a complex interplay between different genetic and epigenetic features. We promote the glucocorticoid receptor NR3C1 as a main target to focus in the context of verbal memory and provided a mechanistic concept of the interaction between various biological layers spanning NR3C1 function and its effects on memory. Especially the NR3C1 transcript seemed to be a key element in this complex system.

Alexithymia Is Associated with Altered Cortical Thickness Networks in the General Population.

BACKGROUND: Alexithymia is a personality trait characterized by difficulties in identifying and describing emotions and associated with various psychiatric disorders. Neuroimaging studies found evidence for morphological and functional brain alterations in alexithymic subjects. However, the neurobiological mechanisms underlying alexithymia remain incompletely understood. METHODS: We study the association of alexithymia with cortical correlation networks in a large community-dwelling sample of the Study of Health in Pomerania. Our analysis includes data of n = 2,199 individuals (49.4% females, age = 52.1 ± 13.6 years) which were divided into a low and high alexithymic group by a median split of the Toronto Alexithymia Scale. Cortical correlation networks were constructed based on the mean thicknesses of 68 regions, and differences in centralities were investigated. RESULTS: We found a significantly increased centrality of the right paracentral lobule in the high alexithymia network after correction for multiple testing. Several other regions with motoric and sensory functions showed altered centrality on a nominally significant level. CONCLUSIONS: Finding increased centrality of the paracentral lobule, a brain area with sensory as well as motoric features and involvement in bowel and bladder voiding, may contribute to explain the association of alexithymia with functional somatic disorders and chronic pain syndromes.

Associations of trauma exposure and post-traumatic stress disorder with the activity of the renin-angiotensin-aldosterone-system in the general population.

BACKGROUND: Previous studies suggested that exposure to traumatic events during childhood and adulthood and post-traumatic stress disorder (PTSD) are associated with a dysregulation of different neuroendocrine systems. However, the activity of the renin-angiotensin-aldosterone-system (RAAS) in relation to trauma/PTSD has been largely neglected. METHODS: Traumatization, PTSD, and plasma concentrations of renin and aldosterone were measured in 3092 individuals from the general population. Subgroups according to the status of traumatization ('without trauma'; 'trauma, without PTSD', 'PTSD') were formed and compared regarding renin and aldosterone concentrations. Additionally, we calculated the associations between the number of traumata, renin, and aldosterone concentrations. Finally, associations of PTSD with renin/aldosterone levels were controlled for the number of traumata ('trauma load'). RESULTS: Levels of renin, but not aldosterone, were increased in traumatized persons without PTSD (p = 0.02) and, even stronger, with PTSD (p < 0.01). Moreover, we found a dose-response relation between the number of traumata and renin levels (ß = 0.065; p < 0.001). Regression analyses showed PTSD as a significant predictor of renin (ß = 0.38; p < 0.01). This effect was only slightly attenuated when controlled for trauma load (ß = 0.32; p < 0.01). CONCLUSIONS: Our results suggest that traumatization has lasting and cumulative effects on RAAS activity. Finding elevated renin levels in PTSD independent from trauma load supports the concept of PTSD as a disorder with specific neuroendocrine characteristics. Alternatively, elevated renin levels in traumatized persons may increase the risk for developing PTSD. Our findings contribute to explain the relationship between traumatic stress/PTSD and physical disorders.

Alexithymia and temporomandibular joint and facial pain in the general population.

BACKGROUND: Associations of alexithymia with temporomandibular pain disorders (TMD), facial pain, head pain and migraine have been described, but the role of the different dimensions of alexithymia in pain development remained incompletely understood. OBJECTIVES: We sought to investigate the associations of alexithymia and its subfactors with signs of TMD and with facial pain, head pain and migraine in the general population. METHODS: A total of 1494 subjects from the general population completed the Toronto Alexithymia Scale-20 (TAS-20) and underwent a clinical functional examination with palpation of the temporomandibular joint and masticatory muscles. Facial pain, migraine and head pain were defined by questionnaire. A set of logistic regression analyses was applied with adjustment for age, sex, education, number of traumatic events, depressive symptoms and anxiety. RESULTS: Alexithymia was associated with TMD joint pain (Odds Ratio 2.63; 95% confidence interval 1.60-4.32 for 61 TAS-20 points vs the median of the TAS-20 score) and with facial pain severity (Odds Ratio 3.22; 95% confidence interval 1.79-5.79). Differential effects of the subfactors were discovered with difficulties in identifying feelings as main predictor for joint, facial, and head pain, and externally oriented thinking (EOT) as U-shaped and strongest predictor for migraine. CONCLUSION: Alexithymia was moderately to strongly associated with signs and symptoms of TMD. These results should encourage dental practioners using the TAS-20 in clinical practice, to screen TMD, facial or head pain patients for alexithymia and could also help treating alexithymic TMD, facial or head pain patients.

Association of Brain-Derived Neurotrophic Factor and Vitamin D with Depression and Obesity: A Population-Based Study.

BACKGROUND: Depression and obesity are widespread and closely linked. Brain-derived neurotrophic factor (BDNF) and vitamin D are both assumed to be associated with depression and obesity. Little is known about the interplay between vitamin D and BDNF. We explored the putative associations and interactions between serum BDNF and vitamin D levels with depressive symptoms and abdominal obesity in a large population-based cohort. METHODS: Data were obtained from the population-based Study of Health in Pomerania (SHIP)-Trend (n = 3,926). The associations of serum BDNF and vitamin D levels with depressive symptoms (measured using the Patient Health Questionnaire) were assessed with binary and multinomial logistic regression models. The associations of serum BDNF and vitamin D levels with obesity (measured by the waist-to-hip ratio [WHR]) were assessed with binary logistic and linear regression models with restricted cubic splines. RESULTS: Logistic regression models revealed inverse associations of vitamin D with depression (OR = 0.966; 95% CI 0.951-0.981) and obesity (OR = 0.976; 95% CI 0.967-0.985). No linear association of serum BDNF with depression or obesity was found. However, linear regression models revealed a U-shaped association of BDNF with WHR (p < 0.001). CONCLUSION: Vitamin D was inversely associated with depression and obesity. BDNF was associated with abdominal obesity, but not with depression. At the population level, our results support the relevant roles of vitamin D and BDNF in mental and physical health-related outcomes.

From Childhood Trauma to Adult Dissociation: The Role of PTSD and Alexithymia.

BACKGROUND: The mechanism of how childhood trauma leads to increased risk for adult dissociation is not sufficiently understood. We sought to investigate the predicting effects and the putatively mediating roles of PTSD and alexithymia on the path from childhood trauma to adult dissociation. METHODS: A total of 666 day-clinic outpatients were administered the Childhood Trauma Questionnaire (CTQ), the Toronto Alexithymia Scale (TAS-20), the Posttraumatic Diagnostic Scale (PDS), and the Dissociative Experiences Scale (DES) and controlled for sex, age, and the Global Symptom Index (GSI). Linear regression analyses and mediation analyses were applied. RESULTS: Independent predictive effects on dissociation were found for childhood trauma, alexithymia and PDS, even after adjusting for GSI. Effects of childhood neglect on dissociation were slightly stronger than of abuse. Alexithymia did not mediate the path from childhood trauma to dissociation. Mediation by PDS was specific for childhood abuse, with all PTSD symptom clusters being significantly involved. CONCLUSIONS: Childhood abuse and neglect are important predictors of dissociation. While the effects of abuse are mediated by PTSD, the mechanism of how neglect leads to dissociation remains unclear. The results further support the predictive value of alexithymia for adult dissociation above and beyond the effects of childhood trauma, PTSD, and GSI scores.

Association between waist circumference and gray matter volume in 2344 individuals from two adult community-based samples.

We analyzed the putative association between abdominal obesity (measured in waist circumference) and gray matter volume (Study of Health in Pomerania: SHIP-2, N=758) adjusted for age and gender by applying volumetric analysis and voxel-based morphometry (VBM) with VBM8 to brain magnetic resonance (MR) imaging. We sought replication in a second, independent population sample (SHIP-TREND, N=1586). In a combined analysis (SHIP-2 and SHIP-TREND) we investigated the impact of hypertension, type II diabetes and blood lipids on the association between waist circumference and gray matter. Volumetric analysis revealed a significant inverse association between waist circumference and gray matter volume. VBM in SHIP-2 indicated distinct inverse associations in the following structures for both hemispheres: frontal lobe, temporal lobes, pre- and postcentral gyrus, supplementary motor area, supramarginal gyrus, insula, cingulate gyrus, caudate nucleus, olfactory sulcus, para-/hippocampus, gyrus rectus, amygdala, globus pallidus, putamen, cerebellum, fusiform and lingual gyrus, (pre-) cuneus and thalamus. These areas were replicated in SHIP-TREND. More than 76% of the voxels with significant gray matter volume reduction in SHIP-2 were also distinct in TREND. These brain areas are involved in cognition, attention to interoceptive signals as satiety or reward and control food intake. Due to our cross-sectional design we cannot clarify the causal direction of the association. However, previous studies described an association between subjects with higher waist circumference and future cognitive decline suggesting a progressive brain alteration in obese subjects. Pathomechanisms may involve chronic inflammation, increased oxidative stress or cellular autophagy associated with obesity.

Alexithymia and self-directedness as predictors of psychopathology and psychotherapeutic treatment outcome.

OBJECTIVE: Alexithymia, a common personality style of patients seeking psychotherapeutic help, is associated with illness severity and negative treatment outcome in various mental disorders. Still, it remains unclear how alexithymia influences psychopathology and the therapeutic processes. In previous studies, a strong association of alexithymia with self-directedness (SD), a dimension of Cloninger's Temperament and Character Inventory (TCI) has been shown. In this study, we investigated the interaction of alexithymia and SD, and their impact on general psychopathology and on treatment outcome. METHOD: 716 consecutively admitted day-clinic outpatients were examined at admission (t0) and discharge (t1). The Toronto Alexithymia Scale 20 (TAS-20), the SD subscale of the TCI and the Symptom Checklist 90 (SCL-90-R) were administered. Linear regression analyses were performed to calculate associations and the predictive power of TAS-20 and SD on psychopathology at admission and treatment outcome. ANOVA was used to calculate interactions of TAS-20 and SD on treatment outcome. A general linear model was applied to compare the outcome of four subgroups, defined by high/low TAS-20 and SD scores. RESULTS: Regression analyses revealed significant prediction of the baseline General Severity Index (GSIt0) by TAS-20 (df=4, 711; Beta: 0.385; p<0.001) and SD (Beta: -0.365; p<0.001). The whole model accounted for 41% of the explained variance. On subscale level, the 'Difficulties in identifying feelings' facet (DIF) of TAS-20 was the strongest predictor of GSIt0 (Beta: 0.478, P<0.001) and GSIt1 (Beta: 0.072, p=0.049). Therapeutic outcome measured by GSIt1 was significantly predicted by SD (df=5, 710; Beta: -0.065; p=0.041), but not by TAS-20 (Beta: 0.042; p=0.179). Change scores (∆) of TAS-20 and SD predicted GSIt1 (df=5, 710; TAS-20∆ Beta: -0.268; p<0.001; SD∆ Beta: 0.191; p<0.001) as well as GSI∆ (df=5, 710; TAS∆ Beta: 0.384; p<0.001; SD∆: -0.274; p<0.001) significantly. ANOVA revealed no significant interactions of TAS-20 and SD at admission on the treatment outcome (p>0.05). CONCLUSION: Low SD was shown to be a common problem of alexithymic patients and both, alexithymia and SD were highly associated with general symptom severity. SD was found to have a greater impact on treatment outcome while adjusting for baseline GSI. Alexithymia and SD act as independent factors with no significant interaction in their impact on psychopathology at admission and discharge. As different interventions were shown to improve SD scores in previous studies, SD may represent a relevant psychotherapeutic target, worthy to be addressed especially in alexithymic patients. Future studies should investigate other dimensions of the TCI, especially harm avoidance and reward dependence.

The neurobiology of childhood trauma-aldosterone and blood pressure changes in a community sample.

OBJECTIVE: Childhood trauma is an important risk factor for the onset and course of psychiatric disorders and particularly major depression. Recently, the renin-angiotensin-aldosterone system, one of the core stress hormone systems, has been demonstrated to be modified by childhood trauma. METHODS: Childhood trauma was obtained using the Childhood Trauma Questionnaire (CTQ) in a community-dwelling sample (N = 2038). Plasma concentrations of renin and aldosterone were measured in subjects with childhood trauma (CT; N = 385) vs. subjects without this experience (NoCT; N = 1653). Multivariable linear regression models were calculated to assess the associations between CTQ, systolic and diastolic blood pressure, renin and aldosterone concentrations, and the ratio of aldosterone and systolic blood pressure (A/SBP). RESULTS: CT subjects demonstrated higher plasma aldosterone (A) concentrations, a lower systolic and diastolic blood pressure, and a higher A/SBP. In addition, both aldosterone concentrations, as well as A/SBP, correlated with the severity of childhood trauma. These findings could not be attributed to differences in concomitant medication. CONCLUSIONS: In conclusion, childhood trauma was associated with neurobiological markers, which may impact the risk for psychiatric disorders, primarily major depression. The altered A/SBP ratio points to a desensitisation of peripheral mineralocorticoid receptor function, which may be a target for therapeutic interventions.

Vitamin D deficit is associated with accelerated brain aging in the general population.

Vitamin D deficiency has been associated with reduced neurocognitive functioning and the neurodegenerative processes. However, existing evidence on brain structural correlates of vitamin D deficiency is controversial. We sought to investigate associations of vitamin D levels with imaging patterns of brain aging. In addition, we investigated whether low vitamin D levels were associated with gray matter volumes, whole brain volumes and hippocampus volumes. Structural MRI data and vitamin D levels were obtained in 1,865 subjects from the general population. Linear regressions were applied to investigate the association of vitamin D levels and vitamin D deficiency with imaging derived brain age, total brain, gray matter and hippocampal volumes. Different sets of covariates were included. Vitamin D deficiency was significantly associated with increased brain age. Also, linear vitamin D levels were significantly associated with total brain and gray matter volumes, while no significant association with hippocampal volume was found. Further interaction analyses showed that this association was only significant for male subjects. Our results support previous findings suggesting that vitamin D-deficient individuals have an accelerated brain aging. In addition, associations between vitamin D levels and total brain/ gray matter volumes suggest neuroprotective effects of vitamin D on the brain.

Alexithymia is associated with reduced vitamin D levels, but not polymorphisms of the vitamin D binding-protein gene.

OBJECTIVE: Alexithymia is a personality trait characterized by difficulties in identifying and describing emotions, which is associated with various psychiatric disorders, including depression and posttraumatic stress disorder (PTSD). Its pathogenesis is incompletely understood but previous studies suggested that genetic as well as metabolic factors, are involved. However, no results on the role of vitamin D and the polymorphisms rs4588 and rs7041 of the vitamin D binding protein (VDBP) have been published so far. METHODS: Serum levels of total 25(OH)D were measured in two general-population samples (total n = 5733) of the Study of Health in Pomerania (SHIP). The Toronto Alexithymia Scale-20 (TAS-20) was applied to measure alexithymia. Study participants were genotyped for rs4588 and rs7041. Linear and logistic regression analyses adjusted for sex, age, waist circumference, physical activity, season and study and, when applicable, for the batch of genotyping and the first three genetic principal components, were performed. In sensitivity analyses, the models were additionally adjusted for depressive symptoms. RESULTS: 25(OH)D levels were negatively associated with TAS-20 scores (ß = -0.002; P < 0.001) and alexithymia according to the common cutoff of TAS-20>60 (ß = -0.103; P < 0.001). These results remained stable after adjusting for depressive symptoms. The tested genetic polymorphisms were not significantly associated with alexithymia. CONCLUSIONS: Our results suggest that low vitamin D levels may be involved in the pathophysiology of alexithymia. Given that no associations between alexithymia and rs4588 as well as rs7041 were observed, indicates that behavioral or nutritional features of alexithymic subjects could also explain this association.

Alexithymia is associated with increased all-cause mortality risk in men, but not in women: A 10-year follow-up study.

OBJECTIVE: Alexithymia is associated with various mental as well as physical disorders. Some evidence also suggested high alexithymia to increase mortality risk, but these results are few and based on specific sample compositions. We aimed to investigate the impact of alexithymia on mortality risk in a large population based cohort. In addition, we sought to elucidate the effects of the subfactors of alexithymia and sex differences. METHODS: In a sample of N = 1380 individuals from the Study of Health in Pomerania (SHIP), we investigated the hazard-ratio (HR) of alexithymia as obtained by the Toronto Alexithymia Scale-20 (TAS-20) on all-cause mortality over an average observation time of 10 years. Sex-by-TAS-20-interactions as well as sex-stratified analyses were performed. RESULTS: Alexithymia was significantly associated with enhanced mortality risk (HR = 1.033; 95%-CI = 1.008-1.058); p = 0.009). While sex-by-TAS-20 interactions remained insignificant, sex-stratified analyses showed that this effect was only significant in men (HR = 1.050; 95%-CI = 1.022-1.079; p ≤ 0.001), but not in women (HR: 1.008; 95%-CI = 0.960-1.057; p = 0.76). The effect was validated for the "difficulties identifying feelings" (DIF) and "difficulties describing feelings" (DDF) subfactors of the TAS-20. CONCLUSION: Our study supports and extents previous findings by indicating that mortality risk enhancing effects of alexithymia are specific to male subjects and validated for the DIF and DDF facets. Socioeconomic, clinical and metabolic factors were associated with this relationship. Finding that the impact of alexithymia remains stable in the fully adjusted models suggests that yet unidentified additional factors must be considered.

Sex effects for the interaction of dopamine related genetic variants for COMT and BDNF on declarative memory performance.

Genetic factors are assumed to contribute to memory performance, especially genes affecting the dopaminergic neurotransmission. We aimed to evaluate leading functional genetic variants of the dopamine system, Catechol-O-methyltransferase (COMT) SNP rs4680 and Brain-derived neurotropic factor (BDNF) SNP rs6265, previously found to be associated with memory performance. In two independent general population cohorts (total N = 5937) we investigated direct and interaction effects between COMT and BDNF SNPs on declarative memory performance. We found significant two-way interactions for COMT and BDNF in both cohorts but no direct genetic effects. Sensitivity analyses revealed that an interaction between COMT and BDNF was mainly carried by females. While direct associations of COMT and BDNF on memory have been reported previously, we could demonstrate that the interaction of COMT and BDNF is sex-dependent and more complex and needs further investigation. Our results could be demonstrated in two independent cohorts of valuable size.

Associations and interactions of the serotonin receptor genes 5-HT1A, 5-HT2A, and childhood trauma with alexithymia in two independent general-population samples.

Previous studies suggested that childhood trauma and a disturbed serotonergic neurotransmission are involved in the pathogenesis of alexithymia. Specifically, genetic polymorphisms of the serotonin receptors 5-HT1A and 5-HT2A were found to be associated with alexithymia. However, it is unclear whether these factors show main or interaction effects with childhood trauma on alexithymia. Data from two independent general-population cohorts of the Study of Health in Pomerania (SHIP-Trend: N=3,706, Age: range=20-83, 51.6% female, SHIP-LEGEND: N=2,162, Age: range=20-80, 52.5% female) were used. The Toronto Alexithymia Scale-20 (TAS-20) and the Childhood Trauma Questionnaire (CTQ) were applied. Genotypes of rs6295 of 5-HT1A and rs6311 of 5-HT2A were determined. Ordinary least-squared regression models with robust standard errors were applied to investigate associations of the main and interaction effects of childhood maltreatment and the polymorphisms with alexithymia. Childhood trauma, but none of the investigated polymorphisms showed main effects on alexithymia. However, childhood trauma showed significant CTQ sum score x rs6295 interactions in male subjects in both samples such that the presence of the G-allele diminished the CTQ associated increase in the TAS-20 sum scores. Our results support a strong role of early life stress and interactions with rs6295 on alexithymic personality features at least in male subjects.

Body mass index but not genetic risk is longitudinally associated with altered structural brain parameters.

Evidence from previous studies suggests that elevated body mass index (BMI) and genetic risk for obesity is associated with reduced brain volume, particularly in areas of reward-related cognition, e.g. the medial prefrontal cortex (AC-MPFC), the orbitofrontal cortex (OFC), the striatum and the thalamus. However, only few studies examined the interplay between these factors in a joint approach. Moreover, previous findings are based on cross-sectional data. We investigated the longitudinal relationship between increased BMI, brain structural magnetic resonance imaging (MRI) parameters and genetic risk scores in a cohort of n = 502 community-dwelling participants from the Study of Health in Pomerania (SHIP) with a mean follow-up-time of 4.9 years. We found that (1) increased BMI values at baseline were associated with decreased brain parameters at follow-up. These effects were particularly pronounced for the OFC and AC-MPFC. (2) The genetic predisposition for BMI had no effect on brain parameters at baseline or follow-up. (3) The interaction between the genetic score for BMI and brain parameters had no effect on BMI at baseline. Finding a significant impact of overweight, but not genetic predisposition for obesity on altered brain structure suggests that metabolic mechanisms may underlie the relationship between obesity and altered brain structure.

Vitamin D levels are associated with trait resilience but not depression in a general population sample.

INTRODUCTION: Insufficient vitamin D levels were found to be related to various psychiatric disorders and particularly depression. The functional polymorphisms rs4588 and rs7041 of the vitamin D-binding protein (also group-specific component or Gc) influence vitamin D level and activity. Resilience is considered the individual predisposition to maintain psychological functioning in the face of adversities. We sought to investigate whether associations of vitamin D levels and genotypes of rs4588 and rs7041 were associated with trait resilience and symptoms of depression. METHODS: Serum levels of total 25(OH)D were measured in a general population sample (n = 1,908) of the Study of Health in Pomerania (SHIP-1). The Resilience Scale-25 (RS-25) was applied to assess trait resilience. Lifetime depressive symptoms were assessed using the CID-S, while current depressive symptoms were measured using the Beck Depression Inventory II (BDI-II). Study participants were genotyped for rs4588 and rs7041. RESULTS: Participants with vitamin D insufficiency had lower adjusted mean RS-25 scores as compared to vitamin D replete subjects (p = .002). Linear regression analyses revealed a positive association between 25(OH)D and RS-25 scores (ß = 2.782, p = .002). Additional adjustment for BDI-II scores slightly attenuated this result (ß = 1.830 and p = .026). Symptoms of depression and the lifetime diagnosis of MDD were not significantly associated with vitamin D concentrations. rs4588 and rs7041 showed strong associations with vitamin D concentrations (both p < .001), but not RS-25 scores. CONCLUSIONS: In contrast with previous studies, our findings do not provide evidence for a strong role of vitamin D in the psychopathology of depression. However, considering the role of trait resilience as a common protective factor to different psychiatric disorders, our results support the concept of low vitamin D as a general risk factor to stress-related psychopathologies.

Functional polymorphisms of the mineralocorticoid receptor gene NR3C2 are associated with diminished memory decline: Results from a longitudinal general-population study.

BACKGROUND: The mineralocorticoid receptor (MR) in the brain has a key role in the regulation of the central stress response and is associated with memory performance. We investigated whether the genetic polymorphisms rs5522 and rs2070951 of NR3C2 showed main and interactive effects with childhood trauma on memory decline. METHODS: Declarative memory was longitudinally assessed in 1,318 participants from the community-dwelling Study of Health in Pomerania using the Verbal Learning and Memory Test (VLMT). In a subsample of 377 participants aged 60 and older, the Mini-Mental Status Examination (MMSE) was additionally applied. Mean follow-up time for the VLMT and MMSE were 6.4 and 10.7 years, respectively. RESULTS: Homozygous carriers of the G allele of rs2070951 (p < .01) and of the A allele of rs5522 (p < .001) showed higher immediate recall of words as compared to carriers of C allele (rs2070951) or the G allele (rs5522). The CG haplotype was associated with decreased recall (p < .001). Likewise, in the subsample of older patients, the AA genotype of rs5522 was associated with higher MMSE scores (p < .05). CG haplotypes showed significantly reduced MMSE scores in comparison to the reference haplotype (ß = -0.60; p < .01). CONCLUSIONS: Our results indicate that the GG genotype of rs2070951 as well as the AA genotype of rs5522 are associated with diminished memory decline.

Inflammatory markers and imaging patterns of advanced brain aging in the general population.

Inflammaging describes the complexity between low-grade chronic inflammation with the pathogenesis of brain aging and Alzheimer´s disease (AD). We aimed to find associations of inflammatory markers: i) white blood cell count (WBC), ii) high-sensitivity C-reactive protein (hs-CRP), and iii) fibrinogen with brain structures, sensitive neuroimaging markers of advanced brain aging and AD-like atrophy, and cognitive aging scores. We analyzed magnetic resonance imaging (MRI) scans of 2204 participants from the Study of Health in Pomerania-2 (SHIP-2) and SHIP-Trend (55.6% women, mean age 52.4±13.7 years). Associations of the inflammatory markers with specific brain signatures of brain aging (SPARE-BA), AD-like brain atrophy (SPARE-AD) and white matter disease (white matter hyperintensities volume (WMHV)) were investigated. Furthermore we explored their association with general brain structures including total brain volume (TBV), gray matter volume (GMV), and white matter volume (WMV), as well as cognitive scores (Nurnberger Age Inventory (NAI); Verbal Learning and Memory Test (VLMT). We adjusted for multiple vascular risk factors (VRF; e.g. smoking and blood pressure) and corresponding medication use to take their brain aging effects into account and corrected for false-discovery rate (FDR). Results:WBC was inversely associated with SPARE-BA (FDR-adjusted p=0.003), TBV (FDR-adjusted p=0.019) and GMV (FDR-adjusted p= 0.017). GMV was also inversely associated with hs-CRP (FDR-adjusted p=0.039) and fibrinogen (FDR-adjusted p=0.039). None of the inflammatory markers was associated with WMHV. Regression analysis also revealed a trend-level interaction between intake of antiinflammatory medication and hs-CRP with brain aging (SPARE-BA; FDR-adjusted p=0.062). Inflammatatory markers are associated with neuroimaging markers, with elevated WBC leading to significant acceleration in brain aging patterns but not with AD-like imaging structural changes. Given the overlap between accelerated brain aging and AD-like atrophy, increased WBC might be associated with global dementia symptoms due to this overlap in atrophy patterns. Elevated WBC may be not causal to preclinical AD dementia, but an accessory symptom of inflammaging. At population level, our results support the relevant roles of inflammatory markers on brain aging related atrophy.