Increased Serum NSE and S100B Indicate Neuronal and Glial Alterations in Subjects Under 71 Years With Mild Neurocognitive Disorder/Mild Cognitive Impairment.

Background: Mild cognitive impairment (MCI) is considered a pre-stage of different dementia syndromes. Despite diagnostic criteria refined by DSM-5 and a new term for MCI - "mild neurocognitive disorder" (mild NCD) - this diagnosis is still based on clinical criteria. Methods: To link mild NCD to the underlying pathophysiology we assessed the degree of white matter hyperintensities (WMH) in the brain and peripheral biomarkers for neuronal integrity (neuron-specific enolase, NSE), plasticity (brain-derived neurotrophic factor, BDNF), and glial function (S100B) in 158 community-dwelling subjects with mild NCD and 82 healthy controls. All participants (63-79 years old) were selected from the Leipzig-population-based study of adults (LIFE). Results: Serum S100B levels were increased in mild NCD in comparison to controls (p = 0.007). Serum NSE levels were also increased but remained non-significant after Bonferroni-Holm correction (p = 0.04). Furthermore, age by group interaction was significant for S100B. In an age-stratified sub-analysis, NSE and S100B were higher in younger subjects with mild NCD below 71 years of age. Some effects were inconsistent after controlling for potentially confounding factors. The discriminatory power of the two biomarkers NSE and S100B was insufficient to establish a pathologic threshold for mild NCD. In subjects with mild NCD, WMH load correlated with serum NSE levels (r = 0.20, p = 0.01), independently of age. Conclusion: Our findings might indicate the presence of neuronal (NSE) and glial (S100B) injury in mild NCD. Future studies need to investigate whether younger subjects with mild NCD with increased biomarker levels are at risk of developing major NCD.

A mind-brain-body dataset of MRI, EEG, cognition, emotion, and peripheral physiology in young and old adults.

We present a publicly available dataset of 227 healthy participants comprising a young (N=153, 25.1±3.1 years, range 20-35 years, 45 female) and an elderly group (N=74, 67.6±4.7 years, range 59-77 years, 37 female) acquired cross-sectionally in Leipzig, Germany, between 2013 and 2015 to study mind-body-emotion interactions. During a two-day assessment, participants completed MRI at 3 Tesla (resting-state fMRI, quantitative T1 (MP2RAGE), T2-weighted, FLAIR, SWI/QSM, DWI) and a 62-channel EEG experiment at rest. During task-free resting-state fMRI, cardiovascular measures (blood pressure, heart rate, pulse, respiration) were continuously acquired. Anthropometrics, blood samples, and urine drug tests were obtained. Psychiatric symptoms were identified with Standardized Clinical Interview for DSM IV (SCID-I), Hamilton Depression Scale, and Borderline Symptoms List. Psychological assessment comprised 6 cognitive tests as well as 21 questionnaires related to emotional behavior, personality traits and tendencies, eating behavior, and addictive behavior. We provide information on study design, methods, and details of the data. This dataset is part of the larger MPI Leipzig Mind-Brain-Body database.

Lesion location matters: The relationships between white matter hyperintensities on cognition in the healthy elderly.

White matter hyperintensities (WMH) are associated with cognitive decline. We aimed to identify the spatial specificity of WMH impact on cognition in non-demented, healthy elderly. We quantified WMH volume among healthy participants of a community dwelling cohort ( n = 702, age range 60 - 82 years, mean age = 69.5 years, 46% female) and investigated the effects of WMH on cognition and behavior, specifically for executive function, memory, and motor speed performance. Lesion location influenced their effect on cognition and behavior: Frontal WMH in the proximity of the frontal ventricles mainly affected executive function and parieto-temporal WMH in the proximity of the posterior horns deteriorated memory, while WMH in the upper deep white matter-including the corticospinal tract-compromised motor speed performance. This study exposes the subtle and subclinical yet detrimental effects of WMH on cognition in healthy elderly, and strongly suggests a causal influence of WMH on cognition by demonstrating the spatial specificity of these effects.

White matter hyperintensities associated with small vessel disease impair social cognition beside attention and memory.

Age-related white matter hyperintensities (WMH) are a manifestation of white matter damage seen on magnetic resonance imaging (MRI). They are related to vascular risk factors and cognitive impairment. This study investigated the cognitive profile at different stages of WMH in a large community-dwelling sample; 849 subjects aged 21 to 79 years were classified on the 4-stage Fazekas scale according to hyperintense lesions seen on individual T2-weighted fluid-attenuated inversion recovery MRI scans. The evaluation of cognitive functioning included seven domains of cognitive performance and five domains of subjective impairment, as proposed by the DSM-5. For the first time, the impact of age-related WMH on Theory of Mind was investigated. Differences between Fazekas groups were analyzed non-parametrically and effect sizes were computed. Effect sizes revealed a slight overall cognitive decline in Fazekas groups 1 and 2 relative to healthy subjects. Fazekas group 3 presented substantial decline in social cognition, attention and memory, although characterized by a high inter-individual variability. WMH groups reported subjective cognitive decline. We demonstrate that extensive WMH are associated with specific impairment in attention, memory, social cognition, and subjective cognitive performance. The detailed neuropsychological characterization of WMH offers new therapeutic possibilities for those affected by vascular cognitive decline.

APOE e4-genotype and lifestyle interaction on cognitive performance: Results of the LIFE-Adult-study.

OBJECTIVE: Previous studies have shown that the e4-allele of the APOE gene is associated with a higher risk of developing dementia. Our study investigated whether well-known associations between lifestyle factors and cognitive functioning may be stronger in individuals who carry the dementia risk variant of the APOE gene and whether this association is amplified with older age. METHOD: Data analysis comprised 7,526 participants (aged 40- to 79-years-old) from the population-based LIFE-Adult-study. The effect of the APOE e4-allele on the association between lifestyle factors (smoking, physical activity, being overweight, occupational attainment) and cognitive performance (trail making test [TMT] B, verbal fluency test [VFT]) was analyzed via multivariate generalized linear modeling adjusted for APOE e2-allele, age, gender, education, stroke, and heart attack. RESULTS: Smoking, less physical activity, and lower occupational attainment was associated with a poorer performance in the TMT B and VFT. Neither the APOE e4-allele nor interactions with the APOE e4-allele were significantly associated with cognitive performance. The association between physical activity and occupational attainment on performance in the TMT B were stronger in older age, but the APOE gene did not modify those associations. CONCLUSIONS: Our findings suggest that the dementia risk variant of the APOE gene does not alter the association between lifestyle factors and cognitive performance in the general population aged 40- to 79-years-old. However, as lifestyle factors impact cognitive aging, research efforts should focus on establishing effective interventions promoting healthy lifestyle behaviors to counteract adverse cognitive aging processes. (PsycINFO Database Record

Central noradrenaline transporter availability in highly obese, non-depressed individuals.

PURPOSE: The brain noradrenaline (NA) system plays an important role in the central nervous control of energy balance and is thus implicated in the pathogenesis of obesity. The specific processes modulated by this neurotransmitter which lead to obesity and overeating are still a matter of debate. METHODS: We tested the hypothesis that in vivo NA transporter (NAT) availability is changed in obesity by using positron emission tomography (PET) and S,S-[11C]O-methylreboxetine (MRB) in twenty subjects comprising ten highly obese (body mass index BMI > 35 kg/m2), metabolically healthy, non-depressed individuals and ten non-obese (BMI < 30 kg/m2) healthy controls. RESULTS: Overall, we found no significant differences in binding potential (BPND) values between obese and non-obese individuals in the investigated brain regions, including the NAT-rich thalamus (0.40 ± 0.14 vs. 0.41 ± 0.18; p = 0.84) though additional discriminant analysis correctly identified individual group affiliation based on regional BPND in all but one (control) case. Furthermore, inter-regional correlation analyses indicated different BPND patterns between both groups but this did not survive testing for multiple comparions. CONCLUSIONS: Our data do not find an overall involvement of NAT changes in human obesity. However, preliminary secondary findings of distinct regional and associative patterns warrant further investigation.

In-vivo Dynamics of the Human Hippocampus across the Menstrual Cycle.

Sex hormones fluctuate during the menstrual cycle. Evidence from animal studies suggests similar subtle fluctuations in hippocampal structure, predominantly linked to estrogen. Hippocampal abnormalities have been observed in several neuropsychiatric pathologies with prominent sexual dimorphism. Yet, the potential impact of subtle sex-hormonal fluctuations on human hippocampal structure in health is unclear. We tested the feasibility of longitudinal neuroimaging in conjunction with rigorous menstrual cycle monitoring to evaluate potential changes in hippocampal microstructure associated with physiological sex-hormonal changes. Thirty longitudinal diffusion weighted imaging scans of a single healthy female subject were acquired across two full menstrual cycles. We calculated hippocampal fractional anisotropy (FA), a measure sensitive to changes in microstructural integrity, and investigated potential correlations with estrogen. We observed a significant positive correlation between FA values and estrogen in the hippocampus bilaterally, revealing a peak in FA closely paralleling ovulation. This exploratory, single-subject study demonstrates the feasibility of a longitudinal DWI scanning protocol across the menstrual cycle and is the first to link subtle endogenous hormonal fluctuations to changes in FA in vivo. In light of recent attempts to neurally phenotype single humans, our findings highlight menstrual cycle monitoring in parallel with highly sampled individual neuroimaging data to address fundamental questions about the dynamics of plasticity in the adult brain.

Higher body mass index in older adults is associated with lower gray matter volume: implications for memory performance.

Midlife obesity has been associated with increased dementia risk, yet reports on brain structure and function are mixed. We therefore assessed the effects of body mass index (BMI) on gray matter volume (GMV) and cognition in a well-characterized sample of community-dwelled older adults. GMV was measured using 3T-neuroimaging in 617 participants (258 women, 60-80 years, BMI 17-41 kg/m(2)). In addition, cognitive performance and various confounders including hypertension, diabetes, and apolipoprotein E genotype were assessed. A higher BMI correlated significantly with lower GMV in multiple brain regions, including (pre)frontal, temporal, insular and occipital cortex, thalamus, putamen, amygdala, and cerebellum, even after adjusting for confounders. In addition, lower GMV in prefrontal and thalamic areas partially mediated negative effects of (1) higher BMI and (2) higher age on memory performance. We here showed that a higher BMI in older adults is associated with widespread gray matter alterations, irrespective of obesity-related comorbidities and other confounders. Our results further indicate that a higher BMI induces structural alterations that translate into subtle impairments in memory performance in aging.

Serum BDNF correlates with connectivity in the (pre)motor hub in the aging human brain--a resting-state fMRI pilot study.

Brain-derived neurotrophic factor (BDNF) has been discussed to be involved in plasticity processes in the human brain, in particular during aging. Recently, aging and its (neurodegenerative) diseases have increasingly been conceptualized as disconnection syndromes. Here, connectivity changes in neural networks (the connectome) are suggested to be the most relevant and characteristic features for such processes or diseases. To further elucidate the impact of aging on neural networks, we investigated the interaction between plasticity processes, brain connectivity, and healthy aging by measuring levels of serum BDNF and resting-state fMRI data in 25 young (mean age 24.8 ± 2.7 (SD) years) and 23 old healthy participants (mean age, 68.6 ± 4.1 years). To identify neural hubs most essentially related to serum BDNF, we applied graph theory approaches, namely the new data-driven and parameter-free approach eigenvector centrality (EC) mapping. The analysis revealed a positive correlation between serum BDNF and EC in the premotor and motor cortex in older participants in contrast to young volunteers, where we did not detect any association. This positive relationship between serum BDNF and EC appears to be specific for older adults. Our results might indicate that the amount of physical activity and learning capacities, leading to higher BDNF levels, increases brain connectivity in (pre)motor areas in healthy aging in agreement with rodent animal studies. Pilot results have to be replicated in a larger sample including behavioral data to disentangle the cause for the relationship between BDNF levels and connectivity.

Neural synchrony indexes impaired motor slowing after errors and novelty following white matter damage.

In humans, action errors and perceptual novelty elicit activity in a shared frontostriatal brain network, allowing them to adapt their ongoing behavior to such unexpected action outcomes. Healthy and pathologic aging reduces the integrity of white matter pathways that connect individual hubs of such networks and can impair the associated cognitive functions. Here, we investigated whether structural disconnection within this network because of small-vessel disease impairs the neural processes that subserve motor slowing after errors and novelty (post-error slowing, PES; post-novel slowing, PNS). Participants with intact frontostriatal circuitry showed increased right-lateralized beta-band (12-24 Hz) synchrony between frontocentral and frontolateral electrode sites in the electroencephalogram after errors and novelty, indexing increased neural communication. Importantly, this synchrony correlated with PES and PNS across participants. Furthermore, such synchrony was reduced in participants with frontostriatal white matter damage, in line with reduced PES and PNS. The results demonstrate that behavioral change after errors and novelty result from coordinated neural activity across a frontostriatal brain network and that such cognitive control is impaired by reduced white matter integrity.

Central serotonin transporter availability in highly obese individuals compared with non-obese controls: A [(11)C] DASB positron emission tomography study.

PURPOSE: The role of the central serotonin (5-hydroxytryptamine, 5-HT) system in feeding has been extensively studied in animals with the 5-HT family of transporters (5-HTT) being identified as key molecules in the regulation of satiety and body weight. Aberrant 5-HT transmission has been implicated in the pathogenesis of human obesity by in vivo positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging techniques. However, results obtained thus far from studies of central 5-HTT availability have been inconsistent, which is thought to be brought about mainly by the low number of individuals with a high body mass index (BMI) previously used. The aim of this study was therefore to assess 5-HTT availability in the brains of highly obese otherwise healthy individuals compared with non-obese healthy controls. METHODS: We performed PET using the 5-HTT selective radiotracer [(11)C] DASB on 30 highly obese (BMI range between 35 and 55 kg/m(2)) and 15 age- and sex-matched non-obese volunteers (BMI range between 19 and 27 kg/m(2)) in a cross-sectional study design. The 5-HTT binding potential (BPND) was used as the outcome parameter. RESULTS: On a group level, there was no significant difference in 5-HTT BPND in various cortical and subcortical regions in individuals with the highest BMI compared with non-obese controls, while statistical models showed minor effects of age, sex, and the degree of depression on 5-HTT BPND. CONCLUSION: The overall finding of a lack of significantly altered 5-HTT availability together with its high variance in obese individuals justifies the investigation of individual behavioral responses to external and internal cues which may further define distinct phenotypes and subgroups in human obesity.

First evidence for glial pathology in late life minor depression: S100B is increased in males with minor depression.

Minor depression is diagnosed when a patient suffers from 2 to 4 depressive symptoms for at least 2 weeks. Though minor depression is a widespread phenomenon, its pathophysiology has hardly been studied. To get a first insight into the pathophysiological mechanisms underlying this disorder we assessed serum levels of biomarkers for plasticity, glial and neuronal function: brain-derived neurotrophic factor (BDNF), S100B and neuron specific enolase (NSE). 27 subjects with minor depressive episode and 82 healthy subjects over 60 years of age were selected from the database of the Leipzig population-based study of civilization diseases (LIFE). Serum levels of BDNF, S100B and NSE were compared between groups, and correlated with age, body-mass index (BMI), and degree of white matter hyperintensities (score on Fazekas scale). S100B was significantly increased in males with minor depression in comparison to healthy males, whereas other biomarkers did not differ between groups (p = 0.10-0.66). NSE correlated with Fazekas score in patients with minor depression (rs = 0.436, p = 0.048) and in the whole sample (rs = 0.252, p = 0.019). S100B correlated with BMI (rs = 0.246, p = 0.031) and with age in healthy subjects (rs = 0.345, p = 0.002). Increased S100B in males with minor depression, without alterations in BDNF and NSE, supports the glial hypothesis of depression. Correlation between white matter hyperintensities and NSE underscores the vascular hypothesis of late life depression.

The LIFE-Adult-Study: objectives and design of a population-based cohort study with 10,000 deeply phenotyped adults in Germany.

BACKGROUND: The LIFE-Adult-Study is a population-based cohort study, which has recently completed the baseline examination of 10,000 randomly selected participants from Leipzig, a major city with 550,000 inhabitants in the east of Germany. It is the first study of this kind and size in an urban population in the eastern part of Germany. The study is conducted by the Leipzig Research Centre for Civilization Diseases (LIFE). Our objective is to investigate prevalences, early onset markers, genetic predispositions, and the role of lifestyle factors of major civilization diseases, with primary focus on metabolic and vascular diseases, heart function, cognitive impairment, brain function, depression, sleep disorders and vigilance dysregulation, retinal and optic nerve degeneration, and allergies. METHODS/DESIGN: The study covers a main age range from 40-79 years with particular deep phenotyping in elderly participants above the age of 60. The baseline examination was conducted from August 2011 to November 2014. All participants underwent an extensive core assessment programme (5-6 h) including structured interviews, questionnaires, physical examinations, and biospecimen collection. Participants over 60 underwent two additional assessment programmes (3-4 h each) on two separate visits including deeper cognitive testing, brain magnetic resonance imaging, diagnostic interviews for depression, and electroencephalography. DISCUSSION: The participation rate was 33 %. The assessment programme was accepted well and completely passed by almost all participants. Biomarker analyses have already been performed in all participants. Genotype, transcriptome and metabolome analyses have been conducted in subgroups. The first follow-up examination will commence in 2016.

Progesterone mediates brain functional connectivity changes during the menstrual cycle-a pilot resting state MRI study.

The growing interest in intrinsic brain organization has sparked various innovative approaches to generating comprehensive connectivity-based maps of the human brain. Prior reports point to a sexual dimorphism of the structural and functional human connectome. However, it is uncertain whether subtle changes in sex hormones, as occur during the monthly menstrual cycle, substantially impact the functional architecture of the female brain. Here, we performed eigenvector centrality (EC) mapping in 32 longitudinal resting state fMRI scans of a single healthy subject without oral contraceptive use, across four menstrual cycles, and assessed estrogen and progesterone levels. To investigate associations between cycle-dependent hormones and brain connectivity, we performed correlation analyses between the EC maps and the respective hormone levels. On the whole brain level, we found a significant positive correlation between progesterone and EC in the bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral sensorimotor cortex. In a secondary region-of-interest analysis, we detected a progesterone-modulated increase in functional connectivity of both bilateral DLPFC and bilateral sensorimotor cortex with the hippocampus. Our results suggest that the menstrual cycle substantially impacts intrinsic functional connectivity, particularly in brain areas associated with contextual memory-regulation, such as the hippocampus. These findings are the first to link the subtle hormonal fluctuations that occur during the menstrual cycle, to significant changes in regional functional connectivity in the hippocampus in a longitudinal design, given the limitation of data acquisition in a single subject. Our study demonstrates the feasibility of such a longitudinal Resting-state functional Magnetic Resonance Imaging (rs-fMRI) design and illustrates a means of creating a personalized map of the human brain by integrating potential mediators of brain states, such as menstrual cycle phase.

Association of the apolipoprotein E genotype with memory performance and executive functioning in cognitively intact elderly.

OBJECTIVE: To test for a possible effect of the apolipoprotein E epsilon 4 (APOE ε4) allele on memory performance and executive functioning (EF) in cognitively intact elderly. METHOD: The authors studied 202 randomly selected and cognitively intact older adults (65+ years) of the Leipzig Research Center for Civilization Diseases Health Care Study. Intact global cognitive functioning was defined using a Mini-Mental Status Examination (MMSE) score ≥ 28. Performance in memory was assessed with the CERAD Word List and Constructional Praxis Recall, performance in EF with the Trail Making Test Part B (TMT-B). Multivariable linear regressions were used to evaluate the association between cognitive performance and APOE status, controlled for covariates. RESULTS: Among the cognitively intact older adults, 21.3% (n = 43) were carriers of the APOE ε4 allele. Carriers did not differ significantly from noncarriers in terms of age, gender, intelligence level, or performance in memory but showed a significantly lower TMT-B performance as a measure of EF (TMT-B M time/SD = 105.6/36.2 vs. 91.9/32.7 s; Mann-Whitney U = 4,313.000; p = .009). The association between lower TMT-B performance and APOE ε4 genotype remained significant in multivariable linear regression analysis. Similar findings were found for the subsample of those 78 elderly, who reached a perfect MMSE-score of 30. CONCLUSIONS: A lower EF performance in cognitively intact older APOE ε4 allele carriers might be related to an early Alzheimer's dementia (AD) prodrome. In this case, a stronger focus on first subtle changes in EF may help to improve early AD detection in those being at genetic risk.

Serum Neuron-Specific Enolase Is Related to Cerebellar Connectivity: A Resting-State Functional Magnetic Resonance Imaging Pilot Study.

Neuron-specific enolase (NSE) has been suggested as a prognostic biomarker for neuronal alterations resulting from conditions such as traumatic brain injury (TBI), neurodegenerative disease, or cardiac arrest. To validate serum NSE (sNSE) as a brain-specific biomarker, we related it to functional brain imaging data in 38 healthy adults to create a physiological framework for future studies in neuropsychiatric diseases. sNSE was measured by monoclonal two-site immunoluminometric assays, and functional connectivity was investigated with resting-state functional magnetic resonance imaging (rfMRI). To identify neural hubs most essentially related to sNSE, we applied graph theory approaches, namely, the new data-driven and parameter-free approach, eigenvector centrality mapping. sNSE and eigenvector centrality were negatively correlated in the female cerebellum, without any effects in male subjects. In cerebellar cortex, NSE expression was significantly higher than whole-brain expression as investigated in the whole brain and whole genome-wide atlas of the Allen Institute for Brain Sciences (Seattle, WA). Our study shows a specific linkage between the neuronal marker protein, sNSE, and cerebellar connectivity as measured with rfMRI in the female human brain, although this finding shall be proven in future studies including more subjects. Results suggest that the inclusion of sNSE in the analysis of imaging data is a useful approach to obtain more-specific information on the neuronal mechanisms that underlie functional connectivity at rest. Establishing such a baseline resting-state pattern that is tied to a neuronal serum marker opens new perspectives in the characterization of neuropsychiatric disorders as disconnective syndromes or nexopathies, in particular, resulting from TBI, neurodegenerative disease, or cardiac arrest, in the future.

Serotonergic modulation of intrinsic functional connectivity.

Serotonin functions as an essential neuromodulator that serves a multitude of roles, most prominently balancing mood. Serotonergic challenge has been observed to reduce intrinsic functional connectivity in brain regions implicated in mood regulation. However, the full scope of serotonergic action on functional connectivity in the human brain has not been explored. Here, we show evidence that a single dose of a serotonin reuptake inhibitor dramatically alters functional connectivity throughout the whole brain in healthy subjects (n = 22). Our network-centrality analysis reveals a widespread decrease in connectivity in most cortical and subcortical areas. In the cerebellum and thalamus, however, we find localized increases. These rapid and brain-encompassing connectivity changes linked to acute serotonin transporter blockade suggest a key role for the serotonin transporter in the modulation of the functional macroscale connectome.

Association between mental demands at work and cognitive functioning in the general population - results of the health study of the Leipzig research center for civilization diseases (LIFE).

BACKGROUND: The level of mental demands in the workplace is rising. The present study investigated whether and how mental demands at work are associated with cognitive functioning in the general population. METHODS: The analysis is based on data of the Health Study of the Leipzig Research Centre for Civilization Disease (LIFE). 2,725 participants aged 40-80 years underwent cognitive testing (Trail-Making Test, Verbal Fluency Test) and provided information on their occupational situation. Participants over the age of 65 years additionally completed the Mini-Mental State Examination. Mental demands at work were rated by a standardized classification system (O*NET). The association between mental demands and cognitive functioning was analyzed using Generalized Linear Modeling (GENLIN) adjusted for age, gender, self-regulation, working hour status, education, and health-related factors. RESULTS: Univariate as well as multivariate analyses demonstrated significant and highly consistent effects of higher mental demands on better performance in cognitive testing. The results also indicated that the effects are independent of education and intelligence. Moreover, analyses of retired individuals implied a significant association between high mental demands at work of the job they once held and a better cognitive functioning in old age. CONCLUSIONS: In sum, our findings suggest a significant association between high mental demands at work and better cognitive functioning. In this sense, higher levels of mental demands - as brought about by technological changes in the working environment - may also have beneficial effects for the society as they could increase cognitive capacity levels and might even delay cognitive decline in old age.

Early small vessel disease affects frontoparietal and cerebellar hubs in close correlation with clinical symptoms--a resting-state fMRI study.

Cerebral small vessel disease, mainly characterized by white matter lesions and lacunes, has a high clinical impact as it leads to vascular dementia. Recent studies have shown that this disease impairs frontoparietal networks. Here, we apply resting-state magnetic resonance imaging and data-driven whole-brain imaging analysis methods (eigenvector centrality) to investigate changes of the functional connectome in early small vessel disease. We show reduced connectivity in frontoparietal networks, whereas connectivity increases in the cerebellum. These functional changes are closely related to white matter lesions and typical neuropsychological deficits associated with small vessel disease.

Structural and functional MRI study of the brain, cognition and mood in long-term adequately treated Hashimoto's thyroiditis.

The current study investigated neuropsychological and underlying structural and functional brain alterations in long-term adequately treated patients with Hashimoto's thyroiditis in order to examine much discussed residual complaints in patients in relation to possible long-term neural alterations with a specific interest in the underlying autoimmune process. Eighteen patients with treated hypothyroidism due to Hashimoto's thyroiditis (mean age 32, range 18-54 years; two males; mean treatment duration 4.4 years) and 18 healthy matched control subjects underwent 3-Tesla magnetic resonance imaging (MRI). Voxel-based morphometry was used to investigate grey matter density, resting-state functional MRI to analyse the brain connectivity of areas known to be altered in hypothyroidism and event-related functional MRI to examine brain activity during associative memory encoding. Neuropsychological assessment included memory, working memory, psychomotor speed and attention. We previously reported subclinically reduced mood in this study population and investigated its neural correlates here. Thyroid stimulating hormone, free triiodthyronine, free thyroxine and thyroid peroxidase antibodies were measured in serum. We did not find cognitive deficits or alterations in grey matter density, functional connectivity or associative memory-related brain activity in comparison to the control group and cognition was unrelated to thyroid serum measures in the patient group. Thyroid peroxidase antibodies in the patient group correlated with increased grey matter density in right amygdala and enhanced connectivity between subcallosal and parahippocampal areas. Treatment duration was associated with brain structure in frontal and occipital cortex and connectivity between left amygdala and frontal cortex. Mood correlated with brain areas associated with distinct functional networks, but not with those most prominently affected in depression. In conclusion, no cognitive or neural alterations were detected in this young and otherwise healthy cohort of patients in comparison to a healthy control group and current mood status could not be related to depression-related networks. However, autoimmune activity and treatment duration showed a relationship with depression and hypothyroidism-related brain structure and function. They are thus promising factors to further investigate residual complaints despite biochemically adequate treatment in patients with Hashimoto's thyroiditis. Given the small sample size, all findings require replication.