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Introduction The syndromes of thrombotic microangiopathy (TMA) are diverse and represent severe endothelial damage caused by various mechanisms. The complement system plays a major role in a subset of patients with TMA, and its recognition is of clinical importance because it guides choice and duration of treatment. Methods We studied a well-defined cohort of patients with TMA and hypothesized that assessment of serum-induced ex vivo C5b9 formation on the endothelium and screening for rare variants in complement genes can better categorize TMA. Results Massive ex vivo C5b9 formation was found in all patients with primary atypical hemolytic uremic syndrome (n/N = 11/11) and in 59% of patients with TMA and coexisting conditions (n/N = 30/51). Massive ex vivo C5b9 formation was associated with rare genetic variants (45% [n/N = 20/44] vs. 0% [n/N = 0/21] patients with normal ex vivo C5b9 formation; P < 0.001). Massive ex vivo C5b9 formation was associated with favorable renal response to therapeutic complement inhibition in patients with TMA and coexisting conditions (86% [n/N = 12/14] vs. 31% [n/N = 5/16] of untreated patients; P < 0.001), indicating complement-mediated TMA rather than secondary disease. Among treated patients, the odds ratio for 1-year kidney survival was 12.0 (95% confidence interval 1.2-115.4). TMA recurrence was linked to rare genetic variants in all cases. Patients with normal ex vivo C5b9 formation had an acute, nonrelapsing form of TMA. Conclusions Ex vivo C5b9 formation and genetic testing appears to categorize TMAs into different groups because it identifies complement as a driving factor of disease, with potential therapeutic and prognostic implications., Graphical abstract

The etiology of psychotic disorders is still unknown, but in a subgroup of patients symptoms might be caused by an autoimmune reaction. In this study, we tested patterns of autoimmune reactivity against potentially novel hippocampal antigens. Serum of a cohort of 621 individuals with psychotic disorders and 257 controls were first tested for reactivity on neuropil of rat brain sections. Brain reactive sera (67 diseased, 27 healthy) were further tested for antibody binding to glutamic acid decarboxylase (GAD) isotype 65 and 67 by cell-based assay (CBA). A sub-cohort of 199 individuals with psychotic disorders and 152 controls was tested for the prevalence of anti-nuclear antibodies (ANA) on HEp2-substrate as well as for reactivity to double-stranded DNA, ribosomal P (RPP), and cardiolipin (CL). Incubation of rat brain with serum resulted in unidentified hippocampal binding patterns in both diseased and control groups. Upon screening with GAD CBA, one of these patterns was identified as GAD65 in one individual with schizophrenia and also in one healthy individual. Two diseased and two healthy individuals had low antibody levels targeting GAD67 by CBA. Antibody reactivity on HEp-2-substrate was increased in patients with schizoaffective disorder, but only in 3 patients did antibody testing hint at a possible diagnosis of systemic lupus erythematosus. Although reactivity of serum to intracellular antigens might be increased in patients with psychotic disorder, no specific targets could be identified. GAD antibodies are very rare and do not seem increased in serum of patients with psychotic disorders. ispartof: Schizophrenia Research vol:228 pages:462-471 ispartof: location:Netherlands status: Published online

The ACR/EULAR classification criteria for systemic sclerosis (SSc) entail three autoantibodies: anti-centromere antibodies (ACA), anti-topoisomerase I antibodies (ATA), and anti-RNA-polymerase III antibodies (ARA). The importance of ACA and ATA in the classification criteria is evidence based, but the diagnostic value is overestimated by clinicians. Fortunately, these autoantibodies are characterized by good agreement between different immuno-assays. Inclusion of ARA, however, is based on limited evidence and is related to limited agreement between different immuno-assays. Harmonization of immuno-assays in terms of interpretation based on likelihood ratio's may improve future classification criteria for SSc and this needs to be achieved by close collaboration between clinicians, laboratory specialists and the diagnostic industry.

Introduction: Gamma-knife Ventral Capsulotomy (GVC) has been suggested as an efficacious treatment for a subset of patients with treatment refractory obsessive compulsive disorder (OCD). Research question: the goal of this study was to investigate neural correlates of GVC and investigate the predictive value of white matter tracts that are known to be associated with clinical outcome to Deep Brain Stimulation (DBS). Material and methods: MR images of 8 treatment-refractory OCD patients with a minimum follow-up of 3-years who underwent GVC were used to correlate lesion characteristics with symptom improvement. This exploratory study investigated relations between differences in cortical grey matter structure and subcortical structures before and after GVC for responding and non-responding patients (n ¼ 6). Normative diffusion MRI- based tractography was used to determine networks associated with successful lesions. Results: the mean total Y-BOCS reduction was 19.6 after three years, resulting in a response rate of 63%.The strongest correlation with symptom improvement was found for a decrease of the left ventral diencephalon volume (r ¼ 0.83, p ¼ 0.039). Discriminative tractography suggest streamlines connecting the prefrontal cortex with the subthalamic nucleus to be associated with clinical response. However, results could not be validated either implicating interpatient anatomical variability or reflecting the relative small sample size as a limitation. Discussion/Conclusion: taken together, the present study highlights the efficacy of GVC in patients with treatment-refractory OCD. Our results are suggestive of GVC treatment efficacy being mediated by the involvement of a subpart of the ALIC connecting the PFC and the STN., NA

Nowadays, the importance of detection of myositis-specific antibodies (MSA) and myositis-associated antibodies (MAA) in diagnosis and in delineating disease subsets of idiopathic inflammatory myopathy (IIM) is highly acknowledged by IIM experts. Consequently, MSA/MAA are increasingly integrated in expert-based myositis (sub)classification criteria as well as in routine diagnostics. In contrast, MSA/MAA are under-represented in data-based (sub)classification criteria, mostly related to the lack of sufficient data on the wide spectrum of MSA/MAA in large multicenter cohorts. Unfortunately, the current commercially available assays to detect MSA/MAA show variable analytical and clinical performance characteristics. This challenges the design of prospective multicenter studies on MSA/MAA as well as the optimization of their routine clinical use. Additional validation studies and continuous harmonization initiatives on MSA/MAA detection from the pre-analytical to the post-analytical phase (e.g. from defining request criteria to guidelines for reporting), will be needed to overcome these hurdles. To speed up this process, we encourage close collaborations between IIM clinical experts, laboratory professionals and diagnostic companies. ispartof: JOURNAL OF TRANSLATIONAL AUTOIMMUNITY vol:5 ispartof: location:Netherlands status: published

The classification and diagnosis of systemic autoimmune diseases are frequently based on a collection of criteria composed of clinical, laboratory, imaging, and pathology elements that are strongly associated with the respective disease. Autoantibodies are a distinctive hallmark and have a prominent position in the classification criteria of many autoimmune diseases. The indirect immunofluorescence assay on HEp-2 cells (HEp-2 IFA), historically known as the antinuclear antibody test, is a method capable of detecting a wide spectrum of autoantibodies. A positive HEp-2 IFA test is part of the classification criteria for systemic lupus erythematosus (SLE) and juvenile idiopathic arthritis (JIA), as well as the diagnostic criteria for autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). A positive HEp-2 IFA test can appear as different morphological patterns that are indicative of the most probable autoantibody specificities in the sample. Only some of the HEp-2 IFA patterns are associated with the specific autoantibodies relevant to SLE, JIA, AIH, and PBC, whereas some other patterns occur mainly in non-related conditions and even in apparently healthy individuals. This paper provides a critical review on the subject and proposes that the classification and diagnostic criteria for SLE, JIA, AIH, and PBC could be improved by a modification on the HEp-2 IFA (ANA) criterion in that the staining patterns accepted for each of these diseases should be restricted according to the respective relevant autoantibody specificities., Highlights • Autoantibodies play a prominent role in the classification or diagnostic criteria of many autoimmune diseases. • ANA test is part of the classification criteria for SLE and JIA, as well as the diagnostic criteria for AIH. • Different HEp-2 IFA patterns indicate different autoantibodies and only some are associated with a specific disease. • ANA classification/diagnostic criteria should reflect the HEp-2 IFA patterns associated to the relevant autoantibodies.

The development, progression, diagnosis and treatment of autoimmune diseases, such as multiple sclerosis (MS), are convoluted processes which remain incompletely understood. Multiple studies demonstrated that the interleukin (IL)-2 – IL-2 receptor (IL-2R) pathway plays a pivotal role within these processes. The most striking functions of the IL-2 – IL-2R pathway are the differential induction of autoimmune responses and tolerance. This paradoxical function of the IL-2 – IL-2R pathway may be an attractive therapeutic target for autoimmune diseases such as MS. However, the exact mechanisms that lead to autoimmunity or tolerance remain to be elucidated. Furthermore, another factor of this pathway, the soluble form of the IL-2R (sIL-2R), further complicates understanding the role of the IL-2 – IL-2R pathway in MS. The challenge is to unravel these mechanisms to prevent, diagnose and recover MS. In this review, first, the current knowledge of MS and the IL-2 – IL-2R pathway are summarized. Second, the key findings of the relation between the IL-2 – IL-2R pathway and MS have been highlighted. Eventually, this review may launch broad interest in the IL-2 – IL-2R pathway propelling further research in autoimmune diseases, including MS., Highlights • The IL-2 – IL-2R pathway determines the balance between immunity and tolerance. • The IL-2 – IL-2R pathway is involved in the pathogenesis of multiple sclerosis. • The role of soluble IL-2R is controversial and requires further investigation.

Myelin is vital for healthy neuronal development, and can therefore provide valuable information regarding neuronal maturation. Anatomical and diffusion weighted images (DWI) possess information related to the myelin content and the current study investigates whether quantitative myelin markers can be extracted from anatomical and DWI using neural networks. Thirteen volunteers (mean age 29y) are included, and for each subject, a residual neural network was trained using spatially undersampled reference myelin-water markers. The network is trained on a voxel-by-voxel basis, resulting in a large amount of training data for each volunteer. The inputs used are the anatomical contrasts (cT1w, cT2w), the standardized T1w/T2w ratio, estimates of the relaxation times (T1, T2) and their ratio (T1/T2), and common DWI metrics (FA, RD, MD, λ1, λ2, λ3). Furthermore, to estimate the added value of the DWI metrics, neural networks were trained using either the combined set (DWI, T1w and T2w) or only the anatomical (T1w and T2w) images. The reconstructed myelin-water maps are in good agreement with the reference myelin-water content in terms of the coefficient of variation (CoV) and the intraclass correlation coefficient (ICC). A 6-fold undersampling using both anatomical and DWI metrics resulted in ICC = 0.68 and CoV = 5.9%. Moreover, using twice the training data (3-fold undersampling) resulted in an ICC that is comparable to the reproducibility of the myelin-water imaging itself (CoV = 5.5% vs. CoV = 6.7% and ICC = 0.74 vs ICC = 0.80). To achieve this, beside the T1w, T2w images, DWI is required. This preliminary study shows the potential of machine learning approaches to extract specific myelin-content from anatomical and diffusion-weighted scans.

Background: During descending aortic repair, critically decreased blood flow to the myelum can result in ischemic spinal cord injury and transient or permanent paraplegia. Assessment of motor evoked potentials (MEPs) has been shown to be a valuable tool which allows to detect spinal cord ischemia (SCI) intraoperatively within a therapeutic window suitable to prevent progression to paraparesis or paraplegia. MEP monitoring is not feasible during postoperative care in the awakening patient. Therefore, ancillary techniques to monitor integrity of spinal cord function are needed to detect delayed spinal cord ischemia. Objective: The purpose of this study is to evaluate whether assessment of long loop reflexes (LLR; F-waves) and paraspinal muscle oximetry using Near-Infrared Spectroscopy (NIRS) are feasible and valid in detecting delayed SCI. Methods: We aim to include patients from three tertiary referral centers undergoing aortic repair with MEP monitoring in this study.F-wave measurements and paraspinal NIRS oximetry will be operated intra- and postoperatively. Measurement characteristics and feasibility will be assessed in the first 25 patients. Subsequently, a second cohort of 75 patients will be investigated to determine the sensitivity and specificity of F-waves and NIRS in detecting perioperative SCI. In this context for the MEP group SCI is defined intraoperatively as significant MEP changes and postoperatively as newly developed paraplegia. Conclusions: A clinical study design and protocol is proposed to assess if F-waves and/or NIRS-based paraspinal oximetry are feasible and valid in detecting and monitoring for occurrences of delayed SCI. Keywords: Spinal cord ischemia, Neurophysiological monitoring techniques, NIRS oximetry, Descending aortic repair, Thoracoabdominal aortic aneurysm repair

Selective attention has been found to decline with aging, possibly depending on the sensory modality through which targets and distractors are presented. We investigated the capacity of older adults to improve performance on visual and auditory selective attention tasks. 31 younger (mean age = 22.8 years, SD = 2.1) and 29 older participants (mean age = 69.5 years, SD = 5.8) performed visual and auditory tasks with and without unimodal and cross-modal distraction across five practice sessions. Reaction time decreased with practice in both age groups. Strikingly, this performance improvement was similar across the age groups. Moreover, distractor modality did not affect performance gains in either age group. Older adults were disproportionally affected by cross-modal visual distraction, however, corroborating previous studies. This age-related effect was mitigated during the practice sessions. Finally, there was no transfer of practice to neuropsychological test performance. These results suggest a high capacity of older individuals to improve selective attention functions within and across sensory modalities.

Purpose The brains of patients with epilepsy may exhibit various morphological abnormalities, which are often not directly visible on structural MR images, as they may be focally subtle or related to a more large-scale inconspicuous disorganization of brain structures. To explore the relation between structural brain organization and epilepsy characteristics, including severity and cognitive co-morbidity, we determined structural covariance networks (SCNs). SCNs represent interregional correlations of morphologic measures, for instance in terms of cortical thickness, between various large-scale distributed brain regions. Methods Thirty-eight patients with focal seizures of all subtypes and 21 healthy controls underwent structural MRI, neurological, and IQ assessment. Cortical thickness was derived from the structural MRIs using FreeSurfer. Subsequently, SCNs were constructed on a group-level based on correlations of the cortical thicknesses between various brain regions. Individual SCNs for the epilepsy patients were extracted by adding the respective patient to the control group prior to the SCN construction (i.e. add-one-patient approach). Calculated network measures, i.e. path length, clustering coefficient and betweenness centrality were correlated with characteristics related to the severity of epilepsy, including seizure history and age at onset of epilepsy, and cognitive performance. Results Stronger clustering in the individual SCN was associated with a higher number of focal to bilateral tonic-clonic seizures during life time, a younger age at onset, and lower cognitive performance. The path length of the individual SCN was not related to the severity of epilepsy or cognitive performance. Higher betweenness centrality of the left cuneus and lower betweenness centrality of the right rostral middle frontal gyrus were associated with increased drug load and younger age at onset, respectively. Conclusions These results indicate that the correlations between interregional variations of cortical thickness reflect disease characteristics or responses to the disease and deficits in patients with epilepsy with focal seizures., Highlights • Interregional cortical thicknesses relations reflect the severity of epilepsy • Stronger clustering is associated with more seizures in patients with epilepsy • Stronger clustering is associated with younger onset age in patients with epilepsy • Stronger clustering is associated with lower IQ in patients with epilepsy • Betweenness centrality is associated with drug load and age at onset

Background: Diffusion tensor imaging (DTI) studies in psychotic disorder have shown reduced FA, often interpreted as disturbed white matter integrity. The observed 'dysintegrity' may be of multifactorial origin, as changes in FA are thought to reflect a combination of changes in myelination, fiber organization and number of axons. Examining the structural substrate of the diffusion tensor in individuals with (risk for) psychotic disorder may provide better understanding of the underlying structural changes.Methods: DTI scans were acquired from 85 patients with psychotic disorder, 93 siblings of patients with psychotic disorder and 80 controls. Cross-sectional group comparisons were performed using Tract -Based Spatial Statistics (TBSS) on six DTI measures: axial diffusivity (AXD), radial diffusivity (RD), mean diffusivity (MD), and the case linear (CL), case planar (CP) and case spherical (CS) tensor shape measures.Results: AXD did not differ between the groups. RD and CS values were significantly increased in patients compared to controls and siblings, with no significant differences between the latter two groups. MD was higher in patients compared to controls (but not siblings), with no difference between siblings and controls. CL was smaller in patients than in siblings and controls, and CP was smaller in both patients and siblings as compared to controls.Conclusion: The differences between individuals with psychotic disorder and healthy controls, derived from detailed diffusion data analyses, suggest less fiber orientation and increased free water movement in the patients. There was some evidence for association with familial risk expressed by decreased fiber orientation. (C) 2017 Elsevier B.V. All rights reserved.

We introduce a new approach to monitoring the activity of smartphone users based on their physical interactions with the interface. Typical events are taps, scrolling and typing, carried out to interact with apps. As compared to other measures, this directly encapsulates potential problematic physical smartphone behaviour as a signal. The approach contrasts against conventions such as self-reporting or timing activity sessions, and it focusses on active rather than passive smartphone activity. Using this alternative method, we collected all user interface interaction events from a sample of 64 participants over a period of 8 weeks, using a bespoke monitoring app called Tymer. User Smartphone Addiction was seen to significantly correlate with high levels of interaction with Lifestyle apps, particularly for female users. Interactions with Social apps in general were also associated with Smartphone Addiction. In particular, user interactions with Snapchat correlated with Smartphone Addiction, represented across all types of interface interaction. This is significant given the widespread usage of Snapchat by teenagers, and we hypothesise that the app's design provides a particularly strong pathway in support of Smartphone Addiction.

Intra-Subject Variability (ISV), a potential index of catecholaminergic regulation, is elevated in several disorders linked with altered dopamine function. ISV has typically been defined as reaction time standard deviation. However, the ex-Gaussian and spectral measures capture different aspects and may delineate different underlying sources of ISV; thus reflecting different facets of the construct. We examined the impact of factors associated with dopamine metabolism, namely, Catechol-O-Methyltransferase Val158Met (COMT) genotype and Working Memory (WM) and response-switching on ISV facets in young healthy adults. The Met allele was associated with overall increased variability. The rather exclusive sensitivity of ex-Gaussian tau to frequencies below 0.025 Hz and the quasi-periodic structure of particularly slow responses support the interpretation of tau as low frequency fluctuations of neuronal networks. Sigma, by contrast, may reflect neural noise. Regarding cognitive demands, a WM load-related increase in variability was present for all genotypes and all ISV facets. Contrastingly, ISV facets reacted differently to variations in response-switching as, across genotypes, sigma was elevated for rare target trials whereas tau was elevated for frequent standard trials, particularly for Met homozygotes. Our findings support the significant role of COMT in regulating behavioural ISV with its facetted structure and presumed underlying neural processes.

Introduction Cerebral small vessel disease (cSVD) is associated with microvascular and parenchymal alterations. Intravoxel incoherent motion (IVIM) MRI has been proposed to simultaneously measure both the microvascular perfusion and parenchymal diffusivity. This study aimed to evaluate the application of IVIM in cSVD to assess the microvasculature and parenchymal microstructure. Methods Seventy-three patients with cSVD (age 70 ± 11 y) and thirty-nine controls (age 69 ± 12 y) underwent IVIM imaging (3T). Group differences of the perfusion volume fraction f and the parenchymal diffusivity D were investigated using multivariable linear regression accounted for age, sex and cardiovascular factors. To examine the relation between the IVIM measures and the disease severity on structural MRI, white matter hyperintensity (WMH) load served as surrogate measure of the disease severity. Results Patients had a larger f (p, Highlights • The application of IVIM in cSVD was investigated. • IVIM shows a predicted microstructure impairment in cSVD. • Unexpected increased perfusion volume fraction is observed using IVIM. • Perfusion volume fraction and parenchymal diffusivity increase with disease severity. • IVIM imaging may provide a potential surrogate marker for the progression of cSVD.

Introduction Philosophers, cognitive and social psychologists and laypeople often subscribe to the view that willpower is central to recovery from addiction. But there are reasons to suspect that willpower is much less important to explaining recovery than this view suggests. Methods Here we report findings from a qualitative longitudinal study on how substance dependent people see their agency and self-control, and how their self-control develops over time. 69 opioid, alcohol and methamphetamine dependent people were interviewed over a 3 year period. Results Most of the participants described themselves as strong willed; in fact, as very strong willed. However, there seemed no correlation between having a (self-assessed) strong will and recovery status. Rather, the number of strategies cited by participants distinguished those in stable recovery from those who were not. Participants in recovery were also more enthusiastic about strategies than those who have not succeeded in controlling substance use. Willpower remained important, but was itself used strategically. Conclusions People with addiction seem not to be short on willpower; rather, recovery is dependent on developing strategies to preserve willpower by controlling the environment., Highlights • Presents evidence that the use of strategies may be more important than willpower in recovery from addiction • Provides a theoretical framework for understanding the deployment of strategies to enable recovery • Provides evidence that addicted people may be high in willpower and that recovery is independent of the state of the will

Multiple sclerosis (MS) is characterized by a disturbed immune homeostasis and low serum vitamin D levels are associated with an increased disease activity. While vitamin D has been hypothesized to promote the maintenance of immune homeostasis, vitamin D supplementation could be of benefit to patients with MS. The SOLAR study investigated the effects of high dose vitamin D 3 supplementation on clinical outcomes in a randomized controlled trial. Here we present the immune regulatory effects, investigated in the SOLARIUM sub-study. Thirty Dutch relapsing remitting (RR) MS patients treated with IFNβ-1a received high dose vitamin D 3 supplementation and 23 patients received placebo during a period of 48 weeks. Lymphocytes were phenotypically characterized by flow cytometry and in vitro cytokine secretion was assessed in the presence or absence of 1,25(OH) 2 D 3 using Luminex technology. Changes in immune regulatory parameters were determined within subjects as well as between treatment groups. The proportion of cells in the immune regulatory cell compartment (nTreg, iTreg and Breg) was not altered upon high dose vitamin D 3 supplementation. Proportions of T helper subsets were not affected by vitamin D 3 , except for the proportion of IL4 + Th cells, which decreased in the placebo but not in the vitamin D 3 group. T cell cytokine secretion increased, most pronounced for IL5 and latency activated protein of TGFβ, in the placebo group but not in the vitamin D 3 group. Lymphocytes remained equally reactive to in vitro 1,25(OH) 2 D 3 . In conclusion, high dose vitamin D 3 supplementation did not result in a relative increase in lymphocytes with a regulatory phenotype. However, this study supports the hypothesis that vitamin D contributes to the maintenance of immune homeostasis by preventing further disturbance of the T cell compartment early in the disease course of MS.

We report a child with Lennox–Gastaut syndrome with an increase in seizure frequency and loss of psychomotor skills due to a disintegrated cervical VNS lead, not detected during standard device monitoring. The lead was completely removed and replaced by a new 303 lead on the same nerve segment. After reinitiating VNS, side effects forced us to switch it off, resulting in immediate seizure recurrence. EEG recording demonstrated a non-convulsive status epilepticus that was halted by reinitiating VNS therapy. Thereafter, he remained seizure free for eight months, and regained psychomotor development., Highlights • Routine VNS device monitoring may not always detect lead dysfunction. • Seizure recurrence and loss of psychomotor skills may imply lead dysfunction. • Complete VNS revision may yield excellent results in LGS. • VNS revision can correct clinical deterioration associated with lead dysfunction.

Background Grey matter (GM) atrophy in Alzheimer's disease (AD) is most commonly modeled as a function of time. However, this approach does not take into account inter-individual differences in initial disease severity or changes due to aging. Here, we modeled GM atrophy within individuals across the AD clinical spectrum as a function of time, aging and MMSE, as a proxy for disease severity, and investigated how these models influence estimates of GM atrophy. Methods We selected 523 individuals from ADNI (100 preclinical AD, 288 prodromal AD, 135 AD dementia) with abnormal baseline amyloid PET/CSF and ≥1 year of MRI follow-up. We calculated total and 90 regional GM volumes for 2281 MRI scans (median [IQR]; 4 [3–5] scans per individual over 2 [1.6–4] years) and used linear mixed models to investigate atrophy as a function of time, aging and decline on MMSE. Analyses included clinical stage as interaction with the predictor and were corrected for baseline age, sex, education, field strength and total intracranial volume. We repeated analyses for a sample of participants with normal amyloid (n = 387) to assess whether associations were specific for amyloid pathology. Results Using time or aging as predictors, amyloid abnormal participants annually declined −1.29 ± 0.08 points and − 0.28 ± 0.03 points respectively on the MMSE and −12.23 ± 0.47 cm3 and −8.87 ± 0.34 respectively in total GM volume (p, Highlights • Modeling atrophy as a function of time or aging show similar anatomical patterns. • GM atrophy as a function of time or aging seems nonspecific for amyloid pathology. • GM atrophy as a function of MMSE shows involvement of different anatomical patterns. • Atrophy modeled based on time or age was steeper than modeled based on MMSE. • Atrophy patterns based on MMSE were specific for amyloid pathology.

There is increasing interest in exploring the use of functional MRI neurofeedback (fMRI-NF) as a therapeutic technique for a range of neurological conditions such as stroke and Parkinson's disease (PD). One main therapeutic potential of fMRI-NF is to enhance volitional control of damaged or dysfunctional neural nodes and networks via a closed-loop feedback model using mental imagery as the catalyst of self-regulation. The choice of target node/network and direction of regulation (increase or decrease activity) are central design considerations in fMRI-NF studies. Whilst it remains unclear whether the primary motor cortex (M1) can be activated during motor imagery, the supplementary motor area (SMA) has been robustly activated during motor imagery. Such differences in the regulation potential between primary and supplementary motor cortex are important because these areas can be differentially affected by a stroke or PD, and the choice of fMRI-NF target and grade of self-regulation of activity likely have substantial influence on the clinical effects and cost effectiveness of NF-based interventions. In this study we therefore investigated firstly whether healthy subjects would be able to achieve self-regulation of the hand-representation areas of M1 and the SMA using fMRI-NF training. There was a significant decrease in M1 neural activity during fMRI-NF, whereas SMA neural activity was increased, albeit not with the predicated graded effect. This study has important implications for fMRI-NF protocols that employ motor imagery to modulate activity in specific target regions of the brain and to determine how they may be tailored for neurorehabilitation.

Introduction: Apolipoprotein E (APOE) epsilon 4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid beta(A beta) pathology. Methods: We included 3451 A beta+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE epsilon 4 prevalence in relation to age, sex, education, and geographical location. Results: The APOE epsilon 4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in A beta+ cognitively normal and A beta+ mild cognitive impairment (P

BackgroundType D personality – the combination of negative affectivity (NA) and social inhibition (SI) – has been associated with depression but little is known about underlying mechanisms. We examined whether (1) Type D is a vulnerability factor for depression in general, (2) Type D is associated with inflammation or endothelial dysfunction, and (3) these biomarkers alter the possible association between Type D and depression.MethodsIn the Maastricht Study, 712 subjects underwent assessment of NA, SI and Type D personality (DS14), depressive disorder (Mini-International Neuropsychiatric Interview) and depressive symptoms (Patient Health Questionnaire-9). Plasma biomarkers of inflammation (hsCRP, SAA, sICAM-1, IL-6, IL-8, TNF-α) and endothelial dysfunction (sVCAM-1, sICAM-1, E-selectin, vWF) were measured with sandwich immunoassays or ELISA and combined into standardized sumscores.ResultsRegarding personality, 49% of the study population was low in NA and SI, 22% had SI only, 12% NA only and 17% had Type D. Depressive disorder and depressive symptoms were significantly more prevalent in Type D versus the other three personality subgroups. Multivariable regression analyses showed that Type D was associated with inflammation (β=0.228, p=0.014) and endothelial dysfunction (β=0.216, p=0.022). After adjustment for these biomarkers, Type D remained independently associated with increased vulnerability to depressive disorder (OR=13.20, pConclusionsType D personality may be a vulnerability factor for depression, irrespective of levels of inflammation or endothelial dysfunction. Future research should examine possible underlying mechanisms.

Background Dysconnectivity in schizophrenia can be understood in terms of dysfunctional integration of a distributed network of brain regions. Here we propose a new methodology to analyze complex networks based on semi-metric behavior, whereby higher levels of semi-metricity may represent a higher level of redundancy and dispersed communication. It was hypothesized that individuals with (increased risk for) psychotic disorder would have more semi-metric paths compared to controls and that this would be associated with symptoms. Methods Resting-state functional MRI scans were obtained from 73 patients with psychotic disorder, 83 unaffected siblings and 72 controls. Semi-metric percentages (SMP) at the whole brain, hemispheric and lobar level were the dependent variables in a multilevel random regression analysis to investigate group differences. SMP was further examined in relation to symptomatology (i.e., psychotic/cognitive symptoms). Results At the whole brain and hemispheric level, patients had a significantly higher SMP compared to siblings and controls, with no difference between the latter. In the combined sibling and control group, individuals with high schizotypy had intermediate SMP values in the left hemisphere with respect to patients and individuals with low schizotypy. Exploratory analyses in patients revealed higher SMP in 12 out of 42 lobar divisions compared to controls, of which some were associated with worse PANSS symptomatology (i.e., positive symptoms, excitement and emotional distress) and worse cognitive performance on attention and emotion processing tasks. In the combined group of patients and controls, working memory, attention and social cognition were associated with higher SMP. Discussion The results are suggestive of more dispersed network communication in patients with psychotic disorder, with some evidence for trait-based network alterations in high-schizotypy individuals. Dispersed communication may contribute to the clinical phenotype in psychotic disorder. In addition, higher SMP may contribute to neuro- and social cognition, independent of psychosis risk., Highlights • Higher SMP was observed at whole brain and hemispheric level in psychotic disorder. • In patients, lobar SMP was associated with psychotic and cognitive symptoms. • Trait-based SMP alterations were observed in high schizotypy individuals.

In many brain diseases it can be qualitatively observed that spatial patterns in blood oxygenation level dependent (BOLD) activation maps appear more (diffusively) distributed than in healthy controls. However, measures that can quantitatively characterize this spatial distributiveness in individual subjects are lacking. In this study, we propose a number of spatial heterogeneity measures to characterize brain activation maps. The proposed methods focus on different aspects of heterogeneity, including the shape (compactness), complexity in the distribution of activated regions (fractal dimension and co-occurrence matrix), and gappiness between activated regions (lacunarity). To this end, functional MRI derived activation maps of a language and a motor task were obtained in language impaired children with (Rolandic) epilepsy and compared to age-matched healthy controls. Group analysis of the activation maps revealed no significant differences between patients and controls for both tasks. However, for the language task the activation maps in patients appeared more heterogeneous than in controls. Lacunarity was the best measure to discriminate activation patterns of patients from controls (sensitivity 74%, specificity 70%) and illustrates the increased irregularity of gaps between activated regions in patients. The combination of heterogeneity measures and a support vector machine approach yielded further increase in sensitivity and specificity to 78% and 80%, respectively. This illustrates that activation distributions in impaired brains can be complex and more heterogeneous than in normal brains and cannot be captured fully by a single quantity. In conclusion, heterogeneity analysis has potential to robustly characterize the increased distributiveness of brain activation in individual patients., Highlights • A number of spatial heterogeneity measures of activation maps were explored in children with Rolandic epilepsy and language impairment • Proposed measures capture the complexity, shape and distribution of brain activation patterns • For a language task all proposed measures revealed that patients exhibit more heterogeneous activation patterns than controls, whereas for a motor task no differences appeared • Spatial heterogeneity of activation patterns is a complex feature that cannot be captured by one single measure, but shape and lacunarity represented the best descriptive measures

New mutations for Huntington disease (HD) originate from CAG repeat expansion of intermediate alleles (27-35 CAG). Expansions of such alleles into the pathological range (>= 36 CAG) have been exclusively observed in paternal transmission. We report the occurrence of a new mutation that defies the paternal expansion bias normally observed in HD. A maternal intermediate allele with 33 CAG repeats expanded in transmission to 48 CAG repeats causing a de novo case of HD in the family. Retrospectively, the mother presented with cognitive decline, but HD was never considered in the differential diagnosis. She was diagnosed with dementia and testing for HD was only performed after her daughter had been diagnosed. This observation of an intermediate allele expanding into the full penetrance HD range after maternal transmission has important implications for genetic counselling of females with intermediate repeats. (C) 2014 Elsevier Masson SAS. All rights reserved.