Neuroanatomical Correlates of Intelligence in Healthy Young Adults: The Role of Basal Ganglia Volume

Background: In neuropsychiatric diseases with basal ganglia involvement, higher cognitive functions are often impaired. In this exploratory study, we examined healthy young adults to gain detailed insight into the relationship between basal ganglia volume and cognitive abilities under non-pathological conditions. Methodology/Principal Findings: We investigated 137 healthy adults that were between the ages of 21 and 35 years with similar educational backgrounds. Magnetic resonance imaging (MRI) was performed, and volumes of basal ganglia nuclei in both hemispheres were calculated using FreeSurfer software. The cognitive assessment consisted of verbal, numeric and figural aspects of intelligence for either the fluid or the crystallised intelligence factor using the intelligence test Intelligenz-Struktur- Test (I-S-T 2000 R). Our data revealed significant correlations of the caudate nucleus and pallidum volumes with figural and numeric aspects of intelligence, but not with verbal intelligence. Interestingly, figural intelligence associations were dependent on sex and intelligence factor;in females, the pallidum volumes were correlated with crystallised figural intelligence (r=0.372, p=0.01),whereas in males, the caudate volumes were correlated with fluid figural intelligence (r=0.507, p=0.01). Numeric intelligence was correlated with right-lateralised caudate nucleus volumes for both females and males, but only for crystallised intelligence (r=0.306, p=0.04 and r=0.459, p=0.04, respectively). The associations were not mediated by prefrontal cortical subfield volumes when controlling with partial correlation analyses. Conclusions/Significance: The findings of our exploratory analysis indicate that figural and numeric intelligence aspects, but not verbal aspects, are strongly associated with basal ganglia volumes. Unlike numeric intelligence, the type of figural intelligence appears to be related to distinct basal ganglia nuclei in a sex-specific manner. Subcortical brain structures thus may contribute substantially to cognitive performance

Physical Activity and Body Composition Are Associated With Severity and Risk of Depression, and Serum Lipids

Background Physical activity and a healthy body composition are said to reduce the risk of major depressive disorder. Nonetheless, deeper insight is needed into which specific forms of physical activity (and their relation to body composition) are effective in improving and preventing depressive symptoms. Methods We compared different self-reported physical activities of the Global Physical Activity Questionnaire and body composition measures between patients with a current major depressive episode (MDE; N = 130) and healthy control subjects (N = 61). These parameters were also tested for correlations with depression severity and serum lipid levels in patients and controls. Results Patients with a current MDE reported significantly fewer hours spent on total physical activity, walking or bicycling for travel, and vigorous-intensity activities at leisure than healthy control subjects. More time spent on vigorous-intensity activities at work, less time spent on walking or bicycling for travel, higher body fat mass, and lower body muscle mass correlated significantly with stronger depression severity. Physical activity and body measures correlated significantly with serum lipid levels. Limitations Self-reports of physical activity, only short-term follow-up of 20 days, cross-sectional study design without examination of causal role of exercise. Conclusions More time spent on traveling by foot or by bike is especially associated with a lower risk of and milder depression. These results highlight the differential role of physical activity in depression

The Common Acid Sphingomyelinase Polymorphism p.G508R is Associated with Self-Reported Allergy

Background: Acid sphingomyelinase (ASM) is a key regulator of ceramide-dependent signalling pathways. Among others, activation of ASM can be induced by CD95 or cytokine signalling and by cellular stress resulting from inflammation or infection. Increased ASM activity was observed in a variety of human diseases including inflammatory and neuropsychiatric disorders. We hypothesized that basal ASM activity might influence the susceptibility for common human diseases. Methods: The general health condition of 100 young people was assessed using a questionnaire. The ASM polymorphism rs1050239 (c.1522G>A;encoding p.G508R) was determined from genomic DNA. Activities of secretory (S-) and lysosomal (L-) ASM were measured in blood plasma and peripheral blood cells respectively. Results: The polymorphism rs1050239 was significantly associated with self-reported allergy (p=4.68x10(-4);adjusted p-value for multiple testing 0.007). Allergy was more prevalent in carriers of the minor A allele compared to non-carriers (p=0.00015;odds ratio=6.5, 95% CI 2.15-21.7). S-ASM activity was significantly associated with rs1050239 (p=5.3x10(-7)) and decreased with the number of A alleles in a gene-dosage dependent manner. In allergic patients, S-ASM activity was moderately decreased (p=0.034). L-ASM activity was significantly lower in subjects homozygous for the minor A allele (p=0.025) but not different between allergic and non-allergic subjects (p=0.318). Conclusion: Our analysis provides evidence for an involvement of ASM in the pathophysiology of allergy, which is in line with previous reports addressing the role of sphingolipids in this disorder. Further studies should clarify the mechanism linking rs1050239 to allergy. The ASM pathway might be useful for predicting allergic disposition and disease course and as a therapeutic target. Copyright (C) 2014 S. Karger AG, Base

Apathy in patients with Alzheimer's disease is a cost-driving factor.

BACKGROUND Apathy is the most frequent neuropsychiatric symptom in patients with dementia of the Alzheimer's type (DAT). We analyzed the influence of apathy on the resource use of DAT patients and their caregivers. METHODS Included were baseline data of 107 DAT patients from a randomized clinical trial on apathy treatment. The Resource Utilization in Dementia (RUD) instrument assessed costs over a 1-month period prior to baseline. Cost predictors were determined via a least absolute shrinkage and selection operator (LASSO). RESULTS On average, total monthly costs were €3070, of which €2711 accounted for caregivers' and €359 for patients' costs. An increase of one point in the Apathy Evaluation Scale resulted in a 4.1% increase in total costs. DISCUSSION Apathy is a significant cost driving factor for total costs in mild to moderate DAT. Effective treatment of apathy might be associated with reduced overall costs in DAT

Influence of brain-derived neurotrophic factor and apolipoprotein E genetic variants on memory performance in young healthy adults

Hintergrund und Ziele: Sowohl die Varianten des brain-derived neurotrophic factors (BDNF) als auch die Isoformen des Apolipoproteins E (APOE) werden mit Lern- und Gedächtnisprozessen, aber auch mit mnestischen Defiziten und Amnesie im Rahmen einer dementiellen Erkrankung in Verbindung gebracht. Dementsprechend wurden diese Geno-Phänotyp-Assoziationen überwiegend bei Probanden bzw. Patienten im höheren Lebensalter geprüft. Inwieweit isolierte und interagierende Effekte der Polymorphismen Val66Met und APOE-epsilon4 unter Berücksichtigung demographischer Einflussvariablen auch auf die mnestischen Leistungen junger gesunder Probanden vorliegen, soll im Folgenden explorativ untersucht werden. Methoden: Im Rahmen des GENES-Projektes (Erforschung der Beziehung ausgewählter Genotypen zu hirnmorphologischen Normabweichungen und deren neuropsychologische Messbarkeit; Psychiatrische und Psychotherapeutische Klinik des Universitätsklinikums Erlangen, Arbeitgsruppe: Prof. Dr. med. J. Kornhuber) wurden 140 gesunde europide Studenten (46 Männer, 94 Frauen) mit einem durchschnittlichen Alter von 25 Jahren und einer mittleren Ausbildungsdauer von 17 Jahren rekrutiert. Nach einer Genotypisierung der funktionalen Varianten von BDNF (Val66Met) und APOE (APOE-E4) wurden die Teilnehmer einer umfangreichen neuropsychologischen Testung mit dem Inventar zur Gedächtnisdiagnostik (IGD) unterzogen. Jenes erfasst die in den etablierten Modellen beschriebenen zeitlichen und inhaltlichen Dimensionen sowie verarbeitungsspezifischen Prozesse des Gedächtnisses und ermöglicht so eine differenzierte Betrachtung der interessierenden Geno-Phänotyp-Assoziationen. Ergebnisse: Nach einer deskriptiven Datenanalyse wurden die IGD-Testprofile auf phänotypische Unterschiede geprüft. Auch wurde der Einfluss von Alter, Geschlecht, Bildung und Epistase (BDNF*APOE) faktoriell analysiert. Um den Zusammenhang zwischen den einzelnen Phänotypen untereinander und mit den demographischen Variablen beschreiben zu können, wurden bivariate Korrelationen berechnet. Schließlich wurde mittels linearer Regressionsanalysen der altersabhängige Verlauf der mnestischen Leistungen für BDNF Val66Met und APOE-E4 prognostiziert. Als primäre Ergebnisse sind festzuhalten: (1) die BDNF Methionin-Träger unterliegen signifikant den Val-Val Trägern bzgl. des Kurzzeit-/Arbeitsgedächtnisses (insbesondere der Zahlenspanne und Exekutiven Kontrolle), des Primings und des Gesamtscores als globales Gedächtnismaß; keinen signifikanten Leistungsunterschied gibt es hinsichtlich des Vorkommens bzw. Fehlens der APOE E4-Variante. (2) Epistatische Hinweise liegen für die Val-Val Gruppe (schlechtere Ergebnisse im visuellen Arbeits-/Gedächtnis bei gleichzeitigem Vorkommen von E4) und die Nicht-E4 Träger (negativer Effekt von Methionin auf Zahlenspanne, Exekutive Kontrolle, Priming, Gesamtscore, Kurzzeit-/Arbeitsgedächtnis und verbales Gedächtnis) vor. (3) Bezüglich des Gesamtscores, Kurzzeit-/Arbeitsgedächtnisses und des verbalen Gedächtnisses nähern sich die „überlegenen“ Val-Val Träger den „benachteiligten“ Met-Trägern mit den Jahren an und sind diesen im weiteren Lebensverlauf möglicherweise sogar unterlegen. Ein ähnliches Phänomen ist für die APOE-Varianten zu beobachten. Schlussfolgerung: Die Ergebnisse lassen eine Assoziation zwischen BDNF Val66Met und den mnestischen Leistungen junger, gesunder Probanden vermuten. Die funktionalen Varianten des APOE hingegen scheinen nur im Falle des gemeinsamen Vorkommens mit BDNF-Met eine signifikante Rolle zu spielen. Beide Polymorphismen modulieren den altersbedingten Verlauf einzelner Gedächtnisfunktionen.Background and objectives: Both the variants of the brain-derived neurotrophic factors (BDNF) and the isoforms of apolipoprotein E (APOE) are believed to be associated with learning and memory processes, as well as with memory deficits and amnesia related to dementia. Thus, these geno-phenotype associations have been primarily tested on elderly subjects or patients. This study aims to explore the extent to which isolated and interacting effects of the polymorphisms Val66met and APOE epsilon 4 on the memory performance of young, healthy adults exist, while taking demographic influence variables into account. Method: As part of the GENES Project (research on the relationship of selected genotypes and morphologic brain deviation and their neuropsychological measurability; Erlangen University Hospital Department of Psychiatry and Psychotherapy; group headed by Prof. J. Kornhuber, MD), 140 healthy Caucasian students (46 men, 94 women) with an average age of 25 years and an average of 17 years of education were recruited. After genotyping the functional variants of the BDNF (Val66Met) and APOE (APOE E4), participants underwent comprehensive neuropsychological testing with the inventory for memory diagnostics (IMD). This inventory records the temporal and content-related dimensions as well as memory processes specific to information processing and thus allowes a differentiated examination of the geno-phenotype associations of interest. Results: After descriptive data analysis, the IMD test profiles were examined for phenotypical differences. In addition, factor analysis was used to determine the impact of age, sex, education and epistasis (BDNF*APOE). Bivariant correlations were calculated in order to describe the interrelation between individual phenotypes and the demographic variables. Finally, the age-dependent course of memory performance for BDNF Val66Met and APOE E4 was predicted using linear regression analyses. The primary results are as follows: (1) The BDNF methionine carriers (Met carriers) are significantly inferior to Val-Val carriers with respect to short term memory/working memory (particularly digit span and executive control), as well as priming and overall score as a global measure of memory; there was no significant performance difference regarding the presence or absence of the APOE E4 variant. (2) There are indications of epistasis for the Val-Val group (worse results for the visual working memory with the simultaneous occurrence of E4) and the non-E4 carriers (negative effect of methionine on the digit span, executive control, priming, overall score, short term memory/working memory and verbal memory). (3) The “disadvantaged” Met carriers seem to approach the “advantaged“ Val-Val carriers in terms of the overall score, short term memory/working memory and verbal memory over the years and over time possibly might be at an advantage over these carriers later on in life. A similar phenomenon can be observed for the APOE variants. Conclusion: The results suggest an association between BDNF Val66Met and the memory performance of young, healthy participants. The functional variants of APOE, however, only seem to play a significant role in the case of simultaneous occurrence with BDNF-Met. Both polymorphisms modulate the age-related course of individual memory functions

The common acid sphingomyelinase polymorphism p.G508R is associated with self-reported allergy

Background: Acid sphingomyelinase (ASM) is a key regulator of ceramide-dependent signalling pathways. Among others, activation of ASM can be induced by CD95 or cytokine signalling and by cellular stress resulting from inflammation or infection. Increased ASM activity was observed in a variety of human diseases including inflammatory and neuropsychiatric disorders. We hypothesized that basal ASM activity might influence the susceptibility for common human diseases. Methods: The general health condition of 100 young people was assessed using a questionnaire. The ASM polymorphism rs1050239 (c.1522G\u3eA; encoding p.G508R) was determined from genomic DNA. Activities of secretory (S-) and lysosomal (L-) ASM were measured in blood plasma and peripheral blood cells respectively. Results: The polymorphism rs1050239 was significantly associated with self-reported allergy (p=4.68×10-4; adjusted p-value for multiple testing 0.007). Allergy was more prevalent in carriers of the minor A allele compared to non-carriers (p=0.00015; odds ratio=6.5, 95% CI 2.15-21.7). S-ASM activity was significantly associated with rs1050239 (p=5.3×10-7) and decreased with the number of A alleles in a gene-dosage dependent manner. In allergic patients, S-ASM activity was moderately decreased (p=0.034). L-ASM activity was significantly lower in subjects homozygous for the minor A allele (p=0.025) but not different between allergic and non-allergic subjects (p=0.318). Conclusion: Our analysis provides evidence for an involvement of ASM in the pathophysiology of allergy, which is in line with previous reports addressing the role of sphingolipids in this disorder. Further studies should clarify the mechanism linking rs1050239 to allergy. The ASM pathway might be useful for predicting allergic disposition and disease course and as a therapeutic target

Alpha-Synuclein RNA Expression is Increased in Major Depression

Alpha-synuclein (SNCA) is a small membrane protein that plays an important role in neuro-psychiatric diseases. It is best known for its abnormal subcellular aggregation in Lewy bodies that serves as a hallmark of Parkinson’s disease (PD). Due to the high comorbidity of PD with depression, we investigated the role of SNCA in patients suffering from major depressive disorder (MDD). SNCA mRNA expression levels were analyzed in peripheral blood cells of MDD patients and a healthy control group. SNCA mRNA expression was positively correlated with severity of depression as indicated by psychometric assessment. We found a significant increase in SNCA mRNA expression levels in severely depressed patients compared with controls. Thus, SNCA analysis could be a helpful target in the search for biomarkers of MDD

Unsuitable readability levels of patient information pertaining to dementia and related diseases: a comparative analysis

Background: Our study investigated the readability of printed material about dementia that is offered to patients and caregivers. Methods: Comparisons of various brochures (at least three standard pages in length) on dementia and related disorders were made using automated measuring by the SMOG readability index grade. Results: 118 brochures were assessed (25 in English, 93 in German), for which the mean readability was found to be high school/college level as measured by the SMOG readability index (grade 13.6 ± 1.8). No differences in readability were observed between materials produced by pharmaceutical companies and other sources. Furthermore, recently published brochures were not more readable than older ones. Shorter brochures, English brochures and those containing medical facts were easier to read than longer ones, those written in German or brochures primarily addressing psychosocial care/social issues. The sentence length was above the 20 word recommendation in 25% of the brochures. The average font size of the brochure texts was small (mean font size 11.1 ± 1.6 point) with only 25% of brochures having a font size of 12 or more, as recommended. Conclusions: Written patient information and educational material of more than three standard pages is often published at unsuitably high readability levels using small fonts. Information material about dementia should be designed and tested prior to distribution among patients and caregivers. Future studies should address material shorter than three pages and material for younger caregivers

Ex vivo glucocorticoid receptor-mediated IL-10 response predicts the course of depression severity

Directly measuring hypothalamic pituitary adrenal (HPA) axis function, an important player in affective disorders, is intensive and invasive. A crucial component of this system, the activity of the glucocorticoid receptor (GR), can be assessed ex vivo instead. Here, we investigated GR sensitivity in patients with major depressive disorder (MDD) to determine its predictive potential. Psychometric data and blood samples were collected from patients experiencing a major depressive episode (MDE, n = 87), healthy control subjects (n = 49), and patients with remitted MDD (n = 31) at baseline and (for patients) after median 20 days of follow-up after treatment as usual. Blood cells were stimulated ex vivo with lipopolysaccharide and the effect was suppressed by increasing dexamethasone (DEX) concentrations. The resultant cytokine secretion profile (for IL-6, IL-10, and TNF-α) was considered indicative of GR activity. Higher baseline scores of the Montgomery-Åsberg Depression Rating Scale (MADRS) were associated with a stronger decrease of logIC IL-6 (indicating an increase of GR sensitivity). Higher baseline logEC IL-10 (indicating a lower GR sensitivity) and a stronger reduction of logEC IL-10 (indicating a stronger increase in GR sensitivity) were associated with a stronger decrease in the MADRS score. Patients with remitted MDD showed higher logIC TNF-α values (indicating lower GR sensitivity) in comparison to patients with a current MDD at baseline and follow-up. Initially low GR sensitivity measured ex vivo in peripheral blood cells that increases over the course of treatment could serve as a predictive marker for stronger improvement in depression severity

No Evidence for Effects of a High-Frequency Repetitive Transcranial Magnetic Stimulation Series on Verbal and Figural Fluency and TAP Task Performance in Healthy Male Volunteers

Background: Study results on cognitive effects of repetitive transcranial magnetic stimulation (rTMS) in healthy people are inconsistent. Moreover, former trials performed exclusively single-session stimulations. This sham-controlled study analyzed the influence of 9 serial high-frequency rTMS on cognition. Methods: 44 young healthy male volunteers received active or sham rTMS. We evaluated verbal fluency tasks, the Ruff Figural Fluency Test and different Test for Attentional Performance tasks (alertness, go/no-go, divided attention, working memory, flexibility) prior to the first stimulation, immediately (within 5–30 min) after stimulation on day 5 and on day 10 (1 day after the last stimulation). Results: Overall, our statistical analyses revealed no significant cognitive effects of serial rTMS. Conclusion: In this sham-controlled study design, 9 serial rTMS over the left dorsolateral prefrontal cortex (targeted by the 5-cm rule) did neither enhance nor impair the assessed cognitive functions in healthy male volunteers