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Mild traumatic brain injury (mTBI) is a growing health concern in the context of an aging population. Older adults comprise a distinct population, with an increased vulnerability for mTBI due to comorbid diseases and age-associated frailty compared with the adult population. The aim of this study was to assess the recovery course and determinants of outcome in a large cohort of older patients with mTBI. For this study, 154 patients aged ≥60 years with mTBI admitted to the Emergency Department were investigated in a prospective observational cohort (ReCONNECT study). Demographics and injury characteristics (computed tomography scan, Glasgow Coma Scale) were determined on admission. Early determinants of outcome were assessed at 2 weeks post-injury (e.g., early post-traumatic complaints and emotional distress) with validated questionnaires. Quality of life (QoL) was determined at 3 months with the World Health Organization Quality of Life Scale-Shortened Version. Functional outcome was determined at 3 (early) and 6 months (long term) post-injury with the Glasgow Outcome Scale Extended (GOSE). Logistic regression analyses identified predictors of outcome with dichotomized GOSE scores as dependent variable (incomplete recovery was defined by GOSE ≤ 7 and complete recovery by GOSE 8). Complete recovery was observed in 42% of patients at 3 months post-injury without significant sex differences. More early post-traumatic complaints were present in patients with incomplete recovery, compared with patients with complete recovery ( p < 0.001). Scores on overall QoL, general health-related QoL and all subdomains were lower for patients with incomplete recovery compared with patients with complete recovery ( p < 0.05). Incomplete recovery at 3 months post-injury was predicted by increased physical frailty and early post-traumatic complaints (Nagelkerke R 2 = 0.25). At 6 months post-injury, 53% of patients had complete recovery with higher frequency in males (60%) compared with females (42%) ( p = 0.025). None of the investigated variables significantly predicted long-term outcome at 6 months post-injury (Nagelkerke R 2 = 0.14), which might be explained by the changing cohort characteristics over time due to age-related morbidity. Our results demonstrate that almost half of older patients with mTBI show complete recovery with complaints and physical frailty as predictors of outcome at 3 months post-injury. Recovery still improves after 3 months and further follow-up is necessary to identify other factors that are associated with long-term outcomes in this specific category of patients with mTBI. The recovery course in older patients with mTBI is dynamic and further research on factors associated with long-term outcomes in this specific patient population is imperative to enhance treatment strategies.

Background: Neuropsychological symptoms in the Cognitive, Energetic, Behavioural, and Affective (CEBA) domains are common in people with multiple sclerosis (PwMS) and can negatively affect societal participation. The current study aims to investigate whether there are combinations of symptoms in the different CEBA domains that consistently occur together, that is, if there are CEBA profiles that can be identified. If so, this study aims to develop a screening instrument identifying CEBA profiles in PwMS to select the most suitable neuropsychological rehabilitation treatment for a given CEBA profile and consequently improve the societal participation of PwMS., Methods: This study is an observational, prospective cohort study consisting of 3 phases. Phase 1 focuses on the identification of CEBA profiles in a large sample of PwMS (n = 300). Phase 2 focuses on validating these CEBA profiles through replication of results in a new sample (n = 100) and on the development of the screening instrument. Phase 3 focuses on qualitatively evaluating in a small group of PwMS whether the selected treatment is suitable for the given CEBA profile or whether existing neuropsychological treatments should be adapted to meet the needs of PwMS suffering from symptoms in multiple CEBA domains simultaneously. Primary outcome is the CEBA profile, which will be derived from performance on neuropsychological assessment consisting of tests and questionnaires regarding the CEBA domains using a latent profile analysis. Inclusion criteria include MS diagnosis, sufficient ability in the Dutch language, and an age between 18 and 70 years., Discussion: The results of the current study will contribute to a more comprehensive understanding of the entire spectrum of neuropsychological symptoms in PwMS. Identification of possible CEBA profiles, and accordingly, the development of a screening instrument determining the CEBA profile of PwMS in clinical practice, contributes to the timely referral of PwMS to the most suitable neuropsychological rehabilitation treatment. If necessary, adjustments to existing treatments will be suggested in order to sufficiently meet the needs of PwMS. All of this with the ultimate aim to improve societal participation, and thereby quality of life, of PwMS., Trial Registration: Dutch Central Committee on Research Involving Human Subjects (CCMO) NL83954.042.23; ClinicalTrials.gov NCT06016309., (© 2024. The Author(s).)

Angiographically negative subarachnoid hemorrhage (anSAH) has traditionally been considered a benign condition, mainly because of favorable outcomes in the acute stage in comparison to the often negative acute outcomes of aneurysmal subarachnoid hemorrhage. However, a growing body of research in recent years shows that anSAH often leads to cognitive impairments, emotional distress, and difficulties in resuming work or other daily life activities. Therefore, in this position paper, we call for a change in neurological care and a shift in patient communication, emphasizing the importance of addressing patient needs and fostering realistic expectations rather than solely focusing on the benign nature of the condition., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background : Older adults (OAs) with mild traumatic brain injury (OA-mTBI) are a growing population, but studies on long-term outcomes and quality of life are scarce. Our aim was to determine the health-related quality of life (HRQoL) in OA-mTBI one year after injury and to assess the early predictors of HRQoL. Methods : Data from a prospective follow-up study of 164 older (≥60 years) and 289 younger mTBI patients (<60 years) admitted to the emergency department were analyzed. Post-traumatic complaints, emotional distress and coping were evaluated 2 weeks post-injury using standardized questionnaires. At 12 months post-injury, HRQoL and functional recovery were determined with the abbreviated version of the World Health Organization Quality of Life scale and Glasgow Outcome Scale Extended (GOSE), respectively. Results : One year post-injury, 80% (n = 131) of the OA-mTBI rated their HRQoL as "good" or "very good", which was comparable to younger patients (79% (n = 226), p = 0.72). Incomplete recovery (GOSE <8) was present in 43% (n = 69) of OA-mTBI, with 67% (n = 46) reporting good HRQoL. Two weeks post-injury, fewer OA-mTBI had (≥2) post-traumatic complaints compared to younger patients (68% vs. 80%, p = 0.01). In the multivariable analyses, only depression-related symptoms (OR = 1.20 for each symptom, 95% CI = 1.01-1.34, p < 0.01) were predictors of poor HRQoL in OA-mTBI. Conclusions : Similar to younger patients, most OA-mTBI rated their HRQoL as good at one year after injury, although a considerable proportion showed incomplete recovery according to the GOSE, suggesting a disability paradox. Depression-related symptoms emerged as a significant predictor for poor HRQoL and can be identified as an early target for treatment after mTBI.

Objective: Aneurysmal subarachnoid hemorrhage (aSAH) and angiographically negative subarachnoid hemorrhage (anSAH) cause an abrupt rise in intracranial pressure, resulting in shearing forces, causing damage to the white matter tracts. This study aims to investigate whole-brain white matter abnormalities with diffusion kurtosis imaging (DKI) after both aSAH and anSAH and explores whether these abnormalities are associated with impaired cognitive functioning., Methods: Five months post-ictus, 34 patients with aSAH, 24 patients with anSAH and 17 healthy controls (HC) underwent DKI MRI scanning and neuropsychological assessment (measuring verbal memory, psychomotor speed, executive control, and social cognition). Differences in DKI measures (fractional anisotropy, mean diffusivity, axial diffusivity [AD], radial diffusivity, and mean kurtosis) were examined using tract-based spatial statistics. Significant voxel masks were then correlated with neuropsychological scores., Results: All DKI measures differed significantly between patients with aSAH and HC, but no significant differences were found between patients with anSAH and HC. Although the two SAH groups did not differ significantly on all DKI parameters, effect sizes indicated that the anSAH group might be more similar to HC. Cognitive impairments were found for both SAH groups relative to HC. No significant associations were found between these impairments and white matter abnormalities in the aSAH group, but lower psychomotor speed scores were associated with higher AD values (r = -0.41, p = 0.04) in patients with anSAH., Conclusions: Patients with aSAH showed significant white matter diffusion abnormalities, while the anSAH group, despite cognitive deficits, did not. However, there were no significant differences between the SAH groups, and no correlations between DKI metrics and cognitive measures, except for one test on psychomotor speed in the anSAH group. Overall, this study suggests that while anSAH may not be as severe as aSAH, it is still not a benign condition. Further research with larger anSAH cohorts is necessary to gain a more precise understanding of white matter injuries, particularly regarding their prevalence., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Research has shown that maladaptive personality characteristics, such as Neuroticism, are associated with poor outcome after mild traumatic brain injury (mTBI). The current exploratory study investigated the neural underpinnings of this process using dynamic functional network connectivity (dFNC) analyses of resting-state (rs) fMRI, and diffusion MRI (dMRI). Twenty-seven mTBI patients and 21 healthy controls (HC) were included. After measuring the Big Five personality dimensions, principal component analysis (PCA) was used to obtain a superordinate factor representing emotional instability, consisting of high Neuroticism, moderate Openness, and low Extraversion, Agreeableness, and Conscientiousness. Persistent symptoms were measured using the head injury symptom checklist at six months post-injury; symptom severity (i.e., sum of all items) was used for further analyses. For patients, brain MRI was performed in the sub-acute phase (~1 month) post-injury. Following parcellation of rs-fMRI using independent component analysis, leading eigenvector dynamic analysis (LEiDA) was performed to compute dynamic phase-locking brain states. Main patterns of brain diffusion were computed using tract-based spatial statistics followed by PCA. No differences in phase-locking state measures were found between patients and HC. Regarding dMRI, a trend significant decrease in fractional anisotropy was found in patients relative to HC, particularly in the fornix, genu of the corpus callosum, anterior and posterior corona radiata. Visiting one specific phase-locking state was associated with lower symptom severity after mTBI. This state was characterized by two clearly delineated communities (each community consisting of areas with synchronized phases): one representing an executive/saliency system, with a strong contribution of the insulae and basal ganglia; the other representing the canonical default mode network. In patients who scored high on emotional instability, this relationship was even more pronounced. Dynamic phase-locking states were not related to findings on dMRI. Altogether, our results provide preliminary evidence for the coupling between personality and dFNC in the development of long-term symptoms after mTBI., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 van der Horn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

To investigate the impact of frontal macro-structural lesions on intrinsic network measures, we examined brain network function during resting-state fMRI in patients with frontal lesions in the subacute phase after mild to moderate traumatic brain injury. Additionally, network function was related to neuropsychological performances. 17 patients with frontal lesions, identified on admission CT after mild to moderate trauma, were compared to 30 traumatic brain injury patients without frontal lesions and 20 healthy controls. Three months post-injury, we acquired fMRI scans and neuropsychological assessments (measuring frontal executive functions and information processing speed). Using independent component analysis, the activity of and connectivity between network components (largely located in the prefrontal cortex) and relations with neuropsychological measures were examined and compared across groups. The analysis yielded five predominantly frontal components: anterior and posterior part of the default mode network, left and right frontoparietal network and salience network. No significant differences concerning fMRI measures were found across groups. However, the frontal lesions group performed significantly worse on neuropsychological tests than the other two groups. Additionally, the frontal lesions group showed a significant positive association of stronger default mode network-salience network connectivity with better executive performances. Our findings suggest that, on fMRI level, frontal network measures are not largely affected by frontal lesions following a mild to moderate traumatic brain injury. Yet, patients with damage to the frontal structures did show poorer executive abilities which might to some degree be related to altered frontal network connectivity between the default mode network and salience network., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Rakers et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Neurocognitive impairment is common in kidney transplant recipients (KTRs). Adequate brain functioning requires energy and neurotransmitter activity, for which iron is essential. We aimed to investigate iron deficiency (ID) as a potentially modifiable risk factor for cognitive impairment in KTRs., Methods: We analyzed stable KTRs participating in the TransplantLines Biobank and Cohort study. Participants underwent neuropsychological tests for memory, mental speed, and attention and executive functioning. ID was defined as ferritin <100 µg/mL or 100-299 µg/mL with transferrin saturation (TSAT) ≤20%. Associations between iron status and norm scores of neurocognitive outcomes, corrected for age, sex and education, were assessed using multivariable linear regression analyses adjusted for potential confounders including hemoglobin., Results: We included 166 KTRs [median (IQR) age 57 (45-65) years, 59% male, estimated glomerular filtration rate 51±18 mL/min/1.73 m2]. Time since transplantation was 5.8 (1.0-12.0) years. Prevalence of ID was 65%. ID was independently associated with lower scores for mental speed (std.β = -0.19, P = .02) and attention and executive functioning (std.β = -0.19, P = .02), and tended to be associated with worse memory (std.β = -0.16, P = .07). Lower plasma ferritin levels were associated with worse memory (std.β = 0.23, P = .007), mental speed (std.β = 0.34, P < .001), and attention and executive functioning (std.β = 0.30, P = .001). Lower TSAT was associated with worse memory (std.β = 0.19, P = .04) and mental speed (std.β = 0.27, P = .003), and tended to be associated with worse attention and executive functioning (std.β = 0.16, P = .08)., Conclusions: Iron-deficient KTRs performed worse on neurocognitive tasks measuring memory, mental speed, and attention and executive functioning. These findings set the stage for prospective studies addressing whether ID correction restores cognitive function after kidney transplantation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Introduction: Iron deficiency (ID) is common and has been associated with an excess mortality risk in kidney transplant recipients (KTRs). In patients with chronic heart failure and ID, intravenous iron improves exercise capacity and quality of life. Whether these beneficial effects also occur in KTRs is unknown. The main objective of this trial is to address whether intravenous iron improves exercise tolerance in iron-deficient KTRs., Methods and Analysis: The Effect of Ferric Carboxymaltose on Exercise Capacity after Kidney Transplantation study is a multicentre, double-blind, randomised, placebo-controlled clinical trial that will include 158 iron-deficient KTRs. ID is defined as plasma ferritin <100 µg/L or plasma ferritin 100-299 µg/L with transferrin saturation <20%. Patients are randomised to receive 10 mL of ferric carboxymaltose (50 mg Fe 3+ /mL, intravenously) or placebo (0.9% sodium chloride solution) every 6 weeks, four dosages in total. The primary endpoint is change in exercise capacity, as quantified by the 6 min walk test, between the first study visit and the end of follow-up, 24 weeks later. Secondary endpoints include changes in haemoglobin levels and iron status, quality of life, systolic and diastolic heart function, skeletal muscle strength, bone and mineral parameters, neurocognitive function and safety endpoints. Tertiary (explorative) outcomes are changes in gut microbiota and lymphocyte proliferation and function., Ethics and Dissemination: The protocol of this study has been approved by the medical ethical committee of the University Medical Centre Groningen (METc 2018/482;) and is being conducted in accordance with the principles of the Declaration of Helsinki, the Standard Protocol Items: Recommendations for Interventional Trials checklist and the Good Clinical Practice guidelines provided by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. Study results will be disseminated through publications in peer-reviewed journals and conference presentations., Trial Registration Number: NCT03769441., Competing Interests: Competing interests: JSJV has received consultancy fees from Vifor Pharma (to employer). MFE has declared receiving consultant fees from Vifor Pharma; serving on the Advisory Board for Cablon Medical; and receiving speakers bureaus from Vifor Pharma. CAJMG takes part in the advisory board of Vifor Pharma, GlaxoSmithKline and Pharmacosmos. PvdM received consultancy fees and/or grants from Novartis, Pharmacosmos, Vifor Pharma, AstraZeneca, Pfizer, Abbott, Pharma Nord, Novo Nordisk and Ionis. MdB has consultancy agreements with Amgen, Astellas, AstraZeneca, Bayer, Kyowa Kirin, Vifor Fresenius Medical Care Renal Pharma and Sanofi Genzyme and received grant support from Sanofi Genzyme and Vifor Pharma (all to employer)., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cognitive impairment is often present shortly after transplantation in kidney transplant recipients (KTR). To date, it is unknown whether these impairments persist in thelong term, to what extent they are associated with disease-related variables and whether they affect societal participation and quality of life (QoL) of KTR., Method: This study was part of the TransplantLines Biobank & Cohort Study in the University Medical Center Groningen. A total of 131 KTR, with a mean age of 53.6 years (SD = 13.5) transplanted ≥1 year ago (M = 11.2 years, range 1-41.7 years), were included and compared with 306 healthy controls (HC). KTR and HC were well matched; there were no significant differences regarding age, sex and education. All participants were assessed with neuropsychological tests measuring memory, mental speed, attention and executive functioning, and with questionnaires examining societal participation and QoL., Results: Compared with HC, KTR performed significantly worse on memory, mental speed and measures of executive functioning (all P-values <0.05). Moreover, 16% of KTR met the criteria for mild cognitive impairment (MCI), compared with 2.6% of the HC. MCI in KTR was not significantly correlated with age- and disease-related variables. Poorer cognitive functioning was significantly related to lower levels of societal participation and to lower QoL (all P-values <0.01)., Conclusions: This study shows long-term cognitive impairments in KTR, which are not related to disease-related variables. Neuropsychological assessment is important to timely signal these impairments, given their serious negative impact on societal participation and QoL., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Early Onset Dystonia (EOD) is thought to result from basal ganglia dysfunction, structures also involved in non-motor functions, like regulation of behavior, mood and anxiety. Problems in these domains have been found in proxy-reports but not yet in self-reports of EOD patients. The main questions are whether proxy-reports differ from those of patients and how problems relate to everyday social functioning. Subjective complaints about executive problems (BRIEF) and symptoms of depression and anxiety (CBCL) were obtained through a cross-sectional questionnaire study conducted on 45 EOD patients. Scores were in the normal range in patients and proxies. Proxy-rated behavior regulation was correlated with the estimated number of friends and quality of relations. Proxy-reported scores of depression correlated with the quality of relations and were higher than self-reports of adolescent/young adult patients. EOD patients and proxies do not seem to experience problematic regulation of behavior, mood and anxiety. Still, our study revealed two important aspects: (1) all measures were related to the estimated quality of relations with others, relating questionnaires to everyday social functioning; (2) proxies reported more symptoms of depression than patients. This may indicate overestimation by proxies or higher sensitivity of proxies to these symptoms, implying underestimation of problems by patients.

Background: A subarachnoid hemorrhage is a hemorrhage in the subarachnoid space that is often caused by the rupture of an aneurysm. Patients who survive a subarachnoid hemorrhage have a high risk of complications and a negative long-term outcome., Objective: The aim of the Imaging, Cognition and Outcome of Neuropsychological functioning after Subarachnoid hemorrhage (ICONS) study is to investigate whether and to what extent deficits exist in multiple domains after subarachnoid hemorrhage, including cognition, emotion and behavior, and to investigate whether brain damage can be detected in patients with subarachnoid hemorrhage. We aim to determine which early measures of cognition, emotion and behavior, and brain damage in the subacute stage play a role in long-term recovery after subarachnoid hemorrhage. Recovery is defined as functioning at a societal participation level, with a focus on resuming and maintaining work, leisure activities, and social relationships over the long term., Methods: The ICONS study is an observational, prospective, single-center cohort study. The study includes patients with subarachnoid hemorrhage admitted to the Neurosurgery Unit of the University Medical Centre Groningen in the Netherlands. The inclusion criteria include diagnosis of an aneurysmal subarachnoid hemorrhage or an angiographically negative subarachnoid hemorrhage, sufficient ability in the Dutch language, and age older than 18 years. Patients will undergo neuropsychological assessment and magnetic resonance imaging 6 months after the subarachnoid hemorrhage. Furthermore, patients will be asked to fill in questionnaires on multiple psychosocial measures and undergo a structured interview at 6 months, 1 year, and 2 years after the subarachnoid hemorrhage. The primary outcome measure of the ICONS study is societal participation 1 year after the subarachnoid hemorrhage, measured with the Dutch version of the Impact on Participation and Autonomy questionnaire., Results: The study was launched in December 2019 and recruitment is expected to continue until June 2023. At the time of the acceptance of this paper, 76 patients and 69 healthy controls have been included. The first results are expected in early 2023., Conclusions: The ICONS study is the first to collect and combine data after subarachnoid hemorrhage in a variety of domains, including cognition, emotion and behavior, and brain damage. The results will contribute to a more comprehensive understanding of the consequences of both aneurysmal subarachnoid hemorrhage and angiographically negative subarachnoid hemorrhage, which may ultimately optimize timely treatment for this patient group by setting realistic and attainable goals to improve daily functioning., Trial Registration: Netherlands Trial Register NL7803; https://trialsearch.who.int/Trial2.aspx?TrialID=NL7803., International Registered Report Identifier (irrid): DERR1-10.2196/38190., (©Sara Khosdelazad, Lieke S Jorna, Rob J M Groen, Sandra E Rakers, Marieke E Timmerman, Ronald J H Borra, Anouk van der Hoorn, Jacoba M Spikman, Anne M Buunk. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 29.09.2022.)

Impaired interplay between sensory and motor function may be an important, often overlooked cause of the decreased daily functioning and impaired health-related quality of life (HRQoL) of kidney transplant recipients (KTR). We assessed this interplay using a hand dexterity test, and investigated its potential associations with daily functioning and HRQoL among KTR enrolled at the TransplantLines Biobank and Cohort Study. A total of 309 KTR (58% male, mean age 56 ± 13 years) at median 4 [IQR: 1-11] years after transplantation were included. Impaired hand dexterity, as defined by a test performance slower than the 95th percentile of an age- and sex-specific reference population, was observed in 71 (23%) KTR. Worse hand dexterity was independently associated with worse performance on almost all measures of physical capacity, activities of daily living and societal participation. Finally, hand dexterity was independently associated with physical HRQoL (standardized beta - 0.22, 95%CI - 0.34 to - 0.09, P < 0.001). In conclusion, impaired interplay between sensory and motor function, as assessed by hand dexterity, is prevalent among KTR. In addition, poor hand dexterity was associated with impaired daily functioning and limited physical HRQoL. Impaired interplay between sensory and motor function may be therefore an important, hitherto overlooked, phenomenon in KTR., (© 2022. The Author(s).)

Research on patients with low-grade gliomas (LGGs) showed neurocognitive impairments in various domains. However, social cognition has barely been investigated. Facial emotion recognition is a vital aspect of social cognition, but whether emotion recognition is affected in LGG patients is unclear. Therefore, we aimed to investigate the effect of LGG and resection by examining emotion recognition pre- and postoperatively. Additionally, the relationships among emotion recognition and general cognition and tumor location were investigated. Thirty patients with LGG who underwent resective surgery were included and matched with 63 healthy control participants (HCs). Emotion recognition was measured with the Facial Expressions of Emotion-Stimuli and Tests (FEEST) and general cognition with neuropsychological tests. Correlations and within-group and between-group comparisons were calculated. Before surgery, patients performed significantly worse than the HCs on FEEST-Total and FEEST-Anger. Paired comparisons showed no significant differences between FEEST scores before and post-surgery. No significant correlations with general cognition and tumor location were found. To conclude, the results of this study indicate that the tumor itself contributes significantly to social cognitive dysfunction and that surgery causes no additional deficit. Impairments were not related to general cognitive deficits or tumor location. Consequently, incorporating tests for emotion recognition into the neuropsychological assessment of patients with LGG is important.

Aim: To investigate the clinical relevance of the radiotherapy (RT) dose bath in patients treated for lower grade glioma (LGG)., Methods: Patients (n = 17) treated with RT for LGG were assessed with neurocognitive function (NCF) tests and structural Magnetic Resonance Imaging (MRI) and categorized in subgroups based on tumour lateralisation. RT dose, volumetric results and cerebral microbleed (CMB) number were extracted for contralateral cerebrum, contralateral hippocampus, and cerebellum. The RT clinical target volume (CTV) was included in the analysis as a surrogate for focal tumour and other treatment effects. The relationships between RT dose, CTV, NCF and radiological outcome were analysed per subgroup., Results: The subgroup with left-sided tumours (n = 10) performed significantly lower on verbal tests. The RT dose to the right cerebrum, as well as CTV, were related to poorer performance on tests for processing speed, attention, and visuospatial abilities, and more CMB.In the subgroup with right-sided tumours (n = 7), RT dose in the left cerebrum was related to lower verbal memory performance, (immediate and delayed recall, r = -0.821, p = 0.023 and r = -0.937, p = 0.002, respectively), and RT dose to the left hippocampus was related to hippocampal volume (r = -0.857, p = 0.014), without correlation between CTV and NCF., Conclusion: By using a novel approach, we were able to investigate the clinical relevance of the RT dose bath in patients with LGG more specifically. We used combined MRI-derived and NCF outcome measures to assess radiation-induced brain damage, and observed potential RT effects on the left-sided brain resulting in lower verbal memory performance and hippocampus volume., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Introduction: Post-operative delirium (POD) is associated with increased morbidity and mortality rates in older patients. Neuroinflammation, the activation of the intrinsic immune system of the brain, seems to be one of the mechanisms behind the development of POD. The aim of this study was to explore the association between the perioperative inflammatory response and the development of POD in a cohort of older oncological patients in need for surgery., Methods: In this prospective cohort study, patients 65 years and older in need for oncologic surgery were included. Inflammatory markers C-reactive protein (CRP), interleukin-1 beta (IL-1β), IL-6, IL10 and Neutrophil gelatinase-associated lipocalin (NGAL) were measured in plasma samples pre- and post-operatively. Delirium Observation Screening Scale (DOS) was used as screening instrument for POD in the first week after surgery. In case of positive screening, diagnosis of POD was assessed by a clinician., Results: Between 2010 and 2016, plasma samples of 311 patients with median age of 72 years (range 65-89) were collected. A total of 38 (12%) patients developed POD in the first week after surgery. The perioperative increase in plasma levels of IL-10 and NGAL were associated with POD in multivariate logistic regression analysis (OR 1.33 [1.09-1.63] P = 0.005 and OR 1.30 [1.03-1.64], P = 0.026, respectively). The biomarkers CRP, IL-1β and IL-6 were not significantly associated with POD., Conclusions: Increased surgery-evoked inflammatory responses of IL-10 and NGAL are associated with the development of POD in older oncological patients. The outcomes of this study contribute to understanding the aetiology of neuroinflammation and the development of POD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Spinocerebellar ataxia type 3 (SCA3) is a rare genetic neurodegenerative disease. The neurobiological basis of SCA3 is still poorly understood, and up until now resting-state fMRI (rs-fMRI) has not been used to study this disease. In the current study we investigated (multi-echo) rs-fMRI data from patients with genetically confirmed SCA3 (n = 17) and matched healthy subjects (n = 16). Using independent component analysis (ICA) and subsequent regression with bootstrap resampling, we identified a pattern of differences between patients and healthy subjects, which we coined the fMRI SCA3 related pattern (fSCA3-RP) comprising cerebellum, anterior striatum and various cortical regions. Individual fSCA3-RP scores were highly correlated with a previously published 18 F-FDG PET pattern found in the same sample (rho = 0.78, P = 0.0003). Also, a high correlation was found with the Scale for Assessment and Rating of Ataxia scores (r = 0.63, P = 0.007). No correlations were found with neuropsychological test scores, nor with levels of grey matter atrophy. Compared with the 18 F-FDG PET pattern, the fSCA3-RP included a more extensive contribution of the mediofrontal cortex, putatively representing changes in default network activity. This rs-fMRI identification of additional regions is proposed to reflect a consequence of the nature of the BOLD technique, enabling measurement of dynamic network activity, compared to the more static 18 F-FDG PET methodology. Altogether, our findings shed new light on the neural substrate of SCA3, and encourage further validation of the fSCA3-RP to assess its potential contribution as imaging biomarker for future research and clinical use., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Prediction of long-term recovery of a poststroke cognitive disorder (PSCD) is currently inaccurate. We assessed whether diffusion-weighted imaging (DWI)-based measures of brain connectivity predict cognitive recovery 1 year after stroke in patients with PSCD in addition to conventional clinical, neuropsychological, and imaging variables., Methods: This prospective monocenter cohort study included 217 consecutive patients with a clinical diagnosis of ischemic stroke, aged ≥50 years, and Montreal Cognitive Assessment score below 26 during hospitalization. Five weeks after stroke, patients underwent DWI magnetic resonance imaging. Neuropsychological assessment was performed 5 weeks and 1 year after stroke and was used to classify PSCD as absent, modest, or marked. Cognitive recovery was operationalized as a shift to a better PSCD category over time. We evaluated 4 DWI-based measures of brain connectivity: global network efficiency and mean connectivity strength, both weighted for mean diffusivity and fractional anisotropy. Conventional predictors were age, sex, level of education, clinical stroke characteristics, neuropsychological variables, and magnetic resonance imaging findings (eg, infarct size). DWI-based measures of brain connectivity were added to a multivariable model to assess additive predictive value., Results: Of 135 patients (mean age, 71 years; 95 men [70%]) with PSCD 5 weeks after ischemic stroke, 41 (30%) showed cognitive recovery. Three of 4 brain connectivity measures met the predefined threshold of P <0.1 in univariable regression analysis. There was no added value of these measures to a multivariable model that included level of education and infarct size as significant predictors of cognitive recovery., Conclusions: Current DWI-based measures of brain connectivity appear to predict recovery of PSCD but at present have no added value over conventional predictors.

Facial expressions have a communicatory function and the ability to read them is a prerequisite for understanding feelings and thoughts of other individuals. Impairments in recognition of facial emotional expressions are frequently found in patients with neurological conditions (e.g. stroke, traumatic brain injury, frontotemporal dementia). Hence, a standard neuropsychological assessment should include measurement of emotion recognition. However, there is debate regarding which tests are most suitable. The current study evaluates and compares three different emotion recognition tests. 84 healthy participants were included and assessed with three tests, in varying order: a. Ekman 60 Faces Test (FEEST) b. Emotion Recognition Task (ERT) c. Emotion Evaluation Test (EET). The tests differ in type of stimuli from static photographs (FEEST) to more dynamic stimuli in the form of morphed photographs (ERT) to videos (EET). Comparing performances on the three tests, the lowest total scores (67.3% correct answers) were found for the ERT. Significant, but moderate correlations were found between the total scores of the three tests, but nearly all correlations between the same emotions across different tests were not significant. Furthermore, we found cross-over effects of the FEEST and EET to the ERT; participants attained higher total scores on the ERT when another emotion recognition test had been administered beforehand. Moreover, the ERT proved to be sensitive to the effects of age and education. The present findings indicate that despite some overlap, each emotion recognition test measures a unique part of the construct. The ERT seemed to be the most difficult test: performances were lowest and influenced by differences in age and education and it was the only test that showed a learning effect after practice with other tests. This highlights the importance of appropriate norms., Competing Interests: The authors report no conflict of interest.

Introduction: Deficits of emotion recognition after ischemic stroke are often overlooked by clinicians, and are mostly not spontaneously reported by patients. However, impaired emotion recognition after stroke negatively affects the ability to return to work and the quality of life. It is still unknown how often impairments of emotion recognition occur shortly after ischemic stroke. We aimed to estimate the occurrence of impaired emotion recognition after ischemic stroke and to characterise these patients with impaired emotion recognition., Patients and Methods: Two hundred thirty patients were included, derived from a prospective study of cognitive recovery. Five weeks after ischemic stroke a neuropsychological assessment was performed, including an emotion recognition task (i.e. Ekman 60-faces test). Emotion recognition was regarded as impaired if the total score was below the fifth percentile for a large independent reference sample., Results: Emotion recognition was impaired in 33.5% of patients. Patients with impaired emotion recognition were more likely to have an abnormal Montreal Cognitive Assessment during hospitalisation, and 5 weeks after their stroke, a higher proportion of them had a vascular cognitive disorder (VCD). Even 20% of patients without VCD had impaired emotion recognition. Discussion: Emotion recognition was often impaired after ischemic stroke. This is clinically relevant, since impaired emotion recognition negatively impacts social functioning. Conclusion: Even when there was no cognitive disorder in traditional cognitive domains, emotion recognition was impaired in 1 out of 5 patients. Clinicians should systematically ask patients and their caregivers about deficits in emotion recognition, and, if needed, test for these deficits., (© European Stroke Organisation 2020.)

Background: Parkinson's Disease (PD) is a heterogeneous, progressive neurodegenerative disorder which is characterized by a variety of motor and non-motor symptoms. To date, no disease modifying treatment for PD exists. Here, the study protocol of the Dutch Parkinson Cohort (DUPARC) is described. DUPARC is a longitudinal cohort study aimed at deeply phenotyping de novo PD patients who are treatment-naïve at baseline, to discover and validate biomarkers for PD progression, subtypes and pathophysiology., Methods/design: DUPARC is a prospective cohort study in which 150 de novo PD subjects will be recruited through a collaborative network of PD treating neurologists in the northern part of the Netherlands (Parkinson Platform Northern Netherlands, PPNN). Participants will receive follow-up assessments after 1 year and 3 years, with the intention of an extended follow-up with 3 year intervals. Subjects are extensively characterized to primarily assess objectives within three major domains of PD: cognition, gastrointestinal function and vision. This includes brain magnetic resonance imaging (MRI); brain cholinergic PET-imaging with fluoroethoxybenzovesamicol (FEOBV-PET); brain dopaminergic PET-imaging with fluorodopa (FDOPA-PET); detailed neuropsychological assessments, covering all cognitive domains; gut microbiome composition; intestinal wall permeability; optical coherence tomography (OCT); genotyping; motor and non-motor symptoms; overall clinical status and lifestyle factors, including a dietary assessment; storage of blood and feces for additional analyses of inflammation and metabolic parameters. Since the start of the inclusion, at the end of 2017, over 100 PD subjects with a confirmed dopaminergic deficit on FDOPA-PET have been included., Discussion: DUPARC is the first study to combine data within, but not limited to, the non-motor domains of cognition, gastrointestinal function and vision in PD subjects over time. As a de novo PD cohort, with treatment naïve subjects at baseline, DUPARC provides a unique opportunity for biomarker discovery and validation without the possible confounding influences of dopaminergic medication., Trial Registration: NCT04180865; registered retrospectively, November 28th 2019.

Introduction: Behavioral disturbances are found in 50-60% of traumatic brain injury (TBI) survivors with an enormous impact on daily functioning and level of recovery. However, whether typical profiles can be distinguished and how these relate to provided care is unclear. The purpose of this study is to specify the characteristics of behavioral disturbances in patients with various severity of TBI and the impact on functional outcome. Furthermore, the pathways of care after hospital discharge for patients and their care givers are analyzed. Methods: We performed a retrospective cohort study comprising 226 patients with mild TBI (mTBI; n = 107) and moderate-to-severe TBI (mod/sevTBI; n = 119) treated at the outpatient clinic and/or rehabilitation center of our university hospital between 2010 and 2015. Inclusion criteria were: behavioral disturbances as determined with the Differential Outcome Scale and age ≥16 years. Functional outcome was determined by the Glasgow Outcome Scale Extended and return to work (RTW) at six months to one year post-injury. Behavioral impairments and pathway of care were derived from medical files and scored according to predefined criteria. Results: Overall 24% of patients showed serious behavioral disturbances; three times higher in mod/sevTBI (35%) compared to mTBI (13%). mTBI patients mostly showed irritation (82%) and anger (49%), while mod/sevTBI patients mostly showed irritation (65%) and disinhibition (55%). Most (92%) patients returned home, half of the patients did not RTW. Deficits in judgment and decision-making increased risk of no RTW 10-fold. One in ten patients was (temporarily) admitted to a nursing home or psychiatric institution. 13% Of caregivers received support for dealing with impairments of patients and 13% of the mTBI and 17% of the mod/sevTBI patients experienced relational problems. Conclusions: The spectrum of behavioral disturbances differs between TBI severity categories and serious behavioral disturbances are present in a quarter of patients. Only half of the patients resumed work regardless of severity of injury suggesting that particularly the presence and not the severity of long-term behavioral disturbances interferes with RTW. Most patients returned home despite these behavioral disturbances. These findings underline the importance of early identification and appropriate treatment of behavioral disturbances in TBI patients., (Copyright © 2020 Timmer, Jacobs, Schonherr, Spikman and van der Naalt.)

Background and Purpose- It is uncertain what determines the potential for cognitive recovery after ischemic stroke. The extent to which strategic areas of the brain network, so-called hubs, are affected by the infarct could be a key factor. We developed a lesion impact score, which estimates the damage to network hubs by integrating information on infarct size with healthy brain network topology. We verified whether the lesion impact score indeed reflects global network disturbances in patients and assessed if it could predict cognitive recovery. Methods- Seventy-five ischemic stroke patients without signs of a prestroke cognitive disorder were included, all with evidence of a cognitive disorder during hospitalization. A brain magnetic resonance imaging and neuropsychological assessment were performed 5 weeks (±1 week) after stroke. Neuropsychological testing was repeated after 1 year to assess cognitive recovery. Brain networks were reconstructed from diffusion-weighted data and consisted of 90 gray matter regions (ie, network nodes). A standard brain network map, indicating the hub-score of each node, was obtained from network data of 44 cognitively healthy adults. For each patient, we calculated the lesion impact score by multiplying the percentage of node volume affected by the infarct with the node's corresponding hub-score. The patients' maximum lesion impact score was used as outcome predictor. Results- A higher lesion impact score in patients, indicating an increasing infarct size in nodes with a higher hub-score, was related to lower global brain network efficiency (β=-0.528 [-0.776 to -0.277]; P <0.001), independent of age, brain volume, infarct volume, and white matter hyperintensity severity. A lower lesion impact score, however, was an independent predictor of cognitive recovery 1 year after stroke (odds ratio=0.434 [0.193-0.978]; P =0.044). Conclusions- We introduced a lesion impact score that combines information on infarct size and network topology to predict long-term recovery after stroke. This score can potentially be used in a clinical setting, also without availability of high-resolution diffusion-weighted magnetic resonance imaging.

Introduction: Cognitive deficits are frequently found after subarachnoid hemorrhage (SAH), but their influence on return to work is largely unknown. To improve identification of those patients at-risk for long-term return to work problems, we aimed to examine the value of cognitive deficits in the prediction of long-term return to work after subarachnoid hemorrhage., Methods: SAH patients (N = 71) who were employed before SAH and were able to undergo neuropsychological assessment, were included. Demographic characteristics and acute SAH-related variables (SAH-type and external cerebrospinal fluid drainage) were taken into account. Neuropsychological tests for memory, speed, attention, executive function, and emotion recognition and a questionnaire for executive functions were used. Return to work was assessed using the Role Resumption List., Results: Results showed that patients with incomplete return to work had significantly lower scores on neuropsychological measures for complex attention and executive functions (p < 0.05) compared to patients with complete return to work. Return to work could not be significantly predicted using only demographic characteristics and acute SAH-related variables, but adding measures of complex attention and executive functions resulted in a prognostic model that could reliably distinguish between complete and incomplete return to work. Statistically significant predictors in the final model were cerebrospinal fluid drainage and scores on a questionnaire for executive functions: patients with cerebrospinal fluid drainage and higher scores on the a questionnaire for executive functions were less likely to return to work., Discussion: Together, these findings show that neuropsychological measures, especially for complex attention and executive functions, have added value to acute SAH-related and demographic variables in the prediction of long-term return to work after SAH., Competing Interests: The authors have declared that no competing interests exist.

Background and Purpose: Behavioural changes after stroke might be explained by social cognition impairments. The aim of the present study was to investigate whether performances on social cognition tests (including emotion recognition, Theory of Mind (ToM), empathy and behaviour regulation) were associated with behavioural deficits (as measured by proxy ratings) in a group of patients with relatively mild stroke., Methods: Prospective cohort study in which 119 patients underwent neuropsychological assessment with tests for social cognition (emotion recognition, ToM, empathy, and behaviour regulation) 3-4 years post stroke. Test scores were compared with scores of 50 healthy controls. Behavioural problems were assessed with the Dysexecutive Questionnaire (DEX) self rating and proxy rating scales. Pearson correlations were used to determine the relationship between the social cognition measures and DEX scores., Results: Patients performed significantly worse on emotion recognition, ToM and behaviour regulation tests than controls. Mean DEX-self score did not differ significantly from the mean DEX-proxy score. DEX-proxy ratings correlated with tests for emotion recognition, empathy, and behavioural regulation (lower scores on these items were associated with more problems on the DEX-proxy scale)., Conclusions: Social cognition impairments are present in the long term after stroke, even in a group of mildly affected stroke patients. Most of these impairments also turned out to be associated with a broad range of behavioural problems as rated by proxies of the patients. This strengthens the proposal that social cognition impairments are part of the underlying mechanism of behavioural change. Since tests for social cognition can be administered in an early stage, this would allow for timely identification of patients at risk for behavioural problems in the long term., Competing Interests: The authors have declared that no competing interests exist.

Introduction: In the past decades, short-term results after solid organ transplantation have markedly improved. Disappointingly, this has not been accompanied by parallel improvements in long-term outcomes after transplantation. To improve graft and recipient outcomes, identification of potentially modifiable risk factors and development of biomarkers are required. We provide the rationale and design of a large prospective cohort study of solid organ transplant recipients (TransplantLines)., Methods and Analysis: TransplantLines is designed as a single-centre, prospective cohort study and biobank including all different types of solid organ transplant recipients as well as living organ donors. Data will be collected from transplant candidates before transplantation, during transplantation, at 3 months, 6 months, 1 year, 2 years and 5 years, and subsequently every 5 years after transplantation. Data from living organ donors will be collected before donation, during donation, at 3 months, 1 year and 5 years after donation, and subsequently every 5 years. The primary outcomes are mortality and graft failure. The secondary outcomes will be cause-specific mortality, cause-specific graft failure and rejection. The tertiary outcomes will be other health problems, including diabetes, obesity, hypertension, hypercholesterolaemia and cardiovascular disease, and disturbances that relate to quality of life, that is, physical and psychological functioning, including quality of sleep, and neurological problems such as tremor and polyneuropathy., Ethics and Dissemination: Ethical approval has been obtained from the relevant local ethics committee. The TransplantLines cohort study is designed to deliver pioneering insights into transplantation and donation outcomes. The study design allows comprehensive data collection on perioperative care, nutrition, social and psychological functioning, and biochemical parameters. This may provide a rationale for future intervention strategies to more individualised, patient-centred transplant care and individualisation of treatment., Trial Registration Number: NCT03272841., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Persistent post-concussion symptoms (PPCS) occur frequently after mild traumatic brain injury (mTBI). The identification of patients at risk for poor outcome remains challenging because valid prediction models are missing. The objectives of the current study were to assess the quality and clinical value of prediction models for PPCS and to develop a new model based on the synthesis of existing models and addition of complaints at the emergency department (ED). Patients with mTBI (Glasgow Coma Scale score 13-15) were recruited prospectively from three Dutch level I trauma centers between 2013 and 2015 in the UPFRONT study. PPCS were assessed using the Head Injury Severity Checklist at six months post-injury. Two prediction models (Stulemeijer 2008; Cnossen 2017) were examined for calibration and discrimination. The final model comprised variables of existing models with the addition of headache, nausea/vomiting, and neck pain at ED, using logistic regression and bootstrap validation. Overall, 591 patients (mean age 51years, 41% female) were included; PPCS developed in 241 (41%). Existing models performed poorly at external validation (area under the curve [AUC]: 0.57-0.64). The newly developed model included female sex (odds ratio [OR] 1.48, 95% confidence interval [CI] [1.01-2.18]), neck pain (OR 2.58, [1.39-4.78]), two-week post-concussion symptoms (OR 4.89, [3.19-7.49]) and two-week post-traumatic stress (OR 2.98, [1.88-4.73]) as significant predictors. Discrimination of this model was adequate (AUC after bootstrap validation: 0.75). Existing prediction models for PPCS perform poorly. A new model performs reasonably with predictive factors already discernible at ED warranting further external validation. Prediction research in mTBI should be improved by standardizing definitions and data collection and by using sound methodology.

Background: Cognitive impairment is common after acute ischemic stroke, affecting up to 75% of the patients. About half of the patients will show recovery, whereas the others will remain cognitively impaired or deteriorate. It is difficult to predict these different cognitive outcomes., Objective: The objective of this study is to investigate whether diffusion tensor imaging-based measures of brain connectivity predict cognitive recovery after 1 year, in addition to patient characteristics and stroke severity. A specific premise of the Prediction of Cognitive Recovery After Stroke (PROCRAS) study is that it is conducted in a daily practice setting., Methods: The PROCRAS study is a prospective, mono-center cohort study conducted in a large teaching hospital in the Netherlands. A total of 350 patients suffering from an ischemic stroke who screen positive for cognitive impairment on the Montreal Cognitive Assessment (MoCA<26) in the acute stage will undergo a 3Tesla-Magnetic Resonance Imaging (3T-MRI) with a diffusion-weighted sequence and a neuropsychological assessment. Patients will be classified as being unimpaired, as having a mild vascular cognitive disorder, or as having a major vascular cognitive disorder. One year after stroke, patients will undergo follow-up neuropsychological assessment. The primary endpoint is recovery of cognitive function 1 year after stroke in patients with a confirmed poststroke cognitive disorder. The secondary endpoint is deterioration of cognitive function in the first year after stroke., Results: The study is already ongoing for 1.5 years, and thus far, 252 patients have provided written informed consent. Final results are expected in June 2019., Conclusions: The PROCRAS study will show the additional predictive value of diffusion tensor imaging-based measures of brain connectivity for cognitive outcome at 1 year in patients with a poststroke cognitive disorder in a daily clinical practice setting., Registered Report Identifier: RR1-10.2196/9431., (©Hugo P Aben, Yael D Reijmer, Johanna MA Visser-Meily, Jacoba M Spikman, Jeroen de Bresser, Geert Jan Biessels, Paul LM de Kort. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 28.05.2018.)

Introduction: We aimed to uncover the pattern of network-level changes in neuronal function in Spinocerebellar ataxia type 3 (SCA3)., Methods: 17 genetically-confirmed SCA3 patients and 16 controls underwent structural MRI and static resting-state [ 18 F]‑Fluoro‑deoxyglucose Positron Emission Tomography (FDG-PET) imaging. A SCA3-related pattern (SCA3-RP) was identified using a multivariate method (scaled subprofile model and principal component analysis (SSM PCA)). Participants were evaluated with the Scale for Assessment and Rating of Ataxia (SARA) and with neuropsychological examination including tests for language, executive dysfunction, memory, and information processing speed. The relationships between SCA3-RP expression and clinical scores were explored. Voxel based morphology (VBM) was applied on MRI-T1 images to assess possible correlations between FDG reduction and grey matter atrophy., Results: The SCA3-RP disclosed relative hypometabolism of the cerebellum, caudate nucleus and posterior parietal cortex, and relatively increased metabolism in somatosensory areas and the limbic system. This topography, which was not explained by regional atrophy, correlated significantly with ataxia (SARA) scores (ρ = 0.72; P  = 0.001). SCA3 patients showed significant deficits in executive function and information processing speed, but only letter fluency correlated with SCA3-RP expression (ρ = 0.51; P  = 0.04, uncorrected for multiple comparisons)., Conclusion: The SCA3 metabolic profile reflects network-level alterations which are primarily associated with the motor features of the disease. Striatum decreases additional to cerebellar hypometabolism underscores an intrinsic extrapyramidal involvement in SCA3. Cerebellar-posterior parietal hypometabolism together with anterior parietal (sensory) cortex hypermetabolism may reflect a shift from impaired feedforward to compensatory feedback processing in higher-order motor control. The demonstrated SCA3-RP provides basic insight in cerebral network changes in this disease.

Aim: Cognitive impairments have been established as part of the non-motor phenomenology of adult dystonia. In childhood dystonia, the extent of cognitive impairments is less clear. This systematic review aims to present an overview of the existing literature to elucidate the cognitive profile of primary and secondary childhood dystonia., Method: Studies focusing on cognition in childhood dystonia were searched in MEDLINE and PsychInfo up to October 2017. We included studies on idiopathic and genetic forms of dystonia as well as dystonia secondary to cerebral palsy and inborn errors of metabolism., Results: Thirty-four studies of the initial 527 were included. Studies for primary dystonia showed intact cognition and IQ, but mild working memory and processing speed deficits. Studies on secondary dystonia showed more pronounced cognitive deficits and lower IQ scores with frequent intellectual disability. Data are missing for attention, language, and executive functioning., Interpretation: This systematic review shows possible cognitive impairments in childhood dystonia. The severity of cognitive impairment seems to intensify with increasing neurological abnormalities. However, the available data on cognition in childhood dystonia are very limited and not all domains have been investigated yet. This underlines the need for future research using standardized neuropsychological procedures in this group., What This Paper Adds: There is limited data on cognition in childhood dystonia. Primary dystonia showed intact cognition and IQ, but mild working memory and processing speed deficits. Secondary dystonia showed more pronounced deficits and lower IQ, with frequent intellectual disability. There is a strong need for case-control studies assessing cognition using standardized neuropsychological tests., (© 2017 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

The objective of this study was to examine longitudinal functional connectivity of resting-state networks in patients with and without complaints after uncomplicated mild traumatic brain injury (mTBI). Second, we aimed to determine the value of network connectivity in predicting persistent complaints, anxiety, depression and long-term outcome. Thirty mTBI patients with three or more post-traumatic complaints at 2 weeks post-injury, 19 without complaints, and 20 matched healthy controls were selected for this study. Resting-state functional MRI (fMRI) was performed in patients at 1 month and 3 months post-injury, and once in healthy controls. Independent component analysis (ICA) was used to investigate the default mode, executive and salience networks. Persistent post-traumatic complaints, anxiety, and depression were measured at 3 months post-injury, and outcome was determined at 1 year post-injury. Within the group with complaints, higher functional connectivity between the anterior and posterior components of the default mode network at 1 month post-injury was associated with a greater number of complaints at 3 months post-injury (ρ = 0.59, p = 0.001). Minor longitudinal changes in functional connectivity were found for patients with and without complaints after mTBI, which were limited to connectivity within the precuneus component of the default mode network. No significant results were found for the executive and salience networks. Current results suggest that the default mode network may serve as a biomarker of persistent complaints in patients with uncomplicated mTBI.

Many patients do not return to work (RTW) after mild traumatic brain injury (mTBI) because of persistent complaints that are often resistant to therapy in the chronic phase. Recent studies suggest that psychological interventions should be implemented early post-injury to prevent patients from developing chronic complaints. This study is a randomized, controlled trial that examines the effectiveness of a newly developed cognitive behavioral therapy (CBT) intervention (CBTi) compared to telephonic counseling (TC) in at-risk mTBI patients (patients with high reports of early complaints). Patients underwent either five sessions of CBT treatment or five phone conversations starting 4-6 weeks post-trauma. The main outcome measure was RTW 6 and 12 months post-trauma. Secondary measures comprised functional outcome at 6 and 12 months, and depression, anxiety, and reported post-traumatic complaints at 3, 6, and 12 months post-injury. After excluding dropouts, CBTi consisted of 39 patients and TC of 45 patients. No significant differences were found with regard to RTW, with 65% of CBTi patients and 67% of TC patients reporting a RTW at previous level. However, TC patients reported fewer complaints at 3 (8 vs. 6; p = 0.010) and 12 months post-injury (9 vs. 5; p = 0.006), and more patients in the TC group showed a full recovery 12 months post-injury compared to the CBTi group (62% vs. 39%). The results of this study suggest that early follow-up of at-risk patients can have a positive influence on patients' well-being, and that a low-intensive, low-cost telephonic intervention might be more effective than a CBT intervention at improving outcome in at-risk patients.

In this study, structural connectivity after mild traumatic brain injury (mTBI) was examined from a network perspective, with a particular focus on post-traumatic complaints. Fifty-three patients with and without self-reported complaints at 2 weeks after uncomplicated mTBI were included, in addition to 20 matched healthy controls. Diffusion weighted imaging was performed at 4 weeks post-injury, and neuropsychological tests measuring processing speed and verbal memory were administered at 3 months post-injury to determine cognitive outcome. Structural connectivity was investigated using whole brain tractography and subsequent graph theory analysis. In patients with mTBI, eigenvector centrality within the left temporal pole was lower than in healthy controls. In patients without complaints, global and mean local efficiency were lower than in patients with complaints, although no differences were found between either subgroup and the group of healthy controls. Neuropsychological test scores were similar for patients with mTBI and healthy controls. However, patients with complaints showed higher processing speed than patients without complaints. Within the total mTBI group, a trend was found toward a correlation between lower network clustering and higher processing speed. Additionally, significant correlations were found between higher betweenness centrality values of language areas and lower verbal memory scores in patients with mTBI. In conclusion, our findings may indicate that global graph measures of the structural connectome are associated with pre- and/or non-injury-related factors that determine the susceptibility to developing (persistent) complaints after mTBI. Further, correlations between graph measures and neuropsychological test scores could suggest early compensatory mechanisms to maintain adequate cognitive performance.

Mild traumatic brain injury (mTBI) is one of the most common neurological disorders worldwide. Posttraumatic complaints are frequently reported, interfering with outcome. However, a consistent neural substrate has not yet been found. We used graph analysis to further unravel the complex interactions between functional brain networks, complaints, anxiety and depression in the sub-acute stage after mTBI. This study included 54 patients with uncomplicated mTBI and 20 matched healthy controls. Posttraumatic complaints, anxiety and depression were measured at two weeks post-injury. Patients were selected based on presence (n = 34) or absence (n = 20) of complaints. Resting-state fMRI scans were made approximately four weeks post-injury. High order independent component analysis resulted in 89 neural components that were included in subsequent graph analyses. No differences in graph measures were found between patients with mTBI and healthy controls. Regarding the two patient subgroups, degree, strength, local efficiency and eigenvector centrality of the bilateral posterior cingulate/precuneus and bilateral parahippocampal gyrus were higher, and eigenvector centrality of the frontal pole/ bilateral middle & superior frontal gyrus was lower in patients with complaints compared to patients without complaints. In patients with mTBI, higher degree, strength and eigenvector centrality of default mode network components were related to higher depression scores, and higher degree and eigenvector centrality of executive network components were related to lower depression scores. In patients without complaints, one extra module was found compared to patients with complaints and healthy controls, consisting of the cingulate areas. In conclusion, this research extends the knowledge of functional network connectivity after mTBI. Specifically, our results suggest that an imbalance in the function of the default mode- and executive network plays a central role in the interaction between emotion regulation and the persistence of posttraumatic complaints., Competing Interests: The authors have declared that no competing interests exist.

Non-hospitalized mild traumatic brain injury (mTBI) patients comprise a substantial part of the trauma population. For these patients, guidelines recommend specialized follow-up only in the case of persistent complaints or problems in returning to previous activities. This study describes injury and outcome characteristics of non-hospitalized mTBI patients, and the possibility of predicting which of the non-hospitalized patients will return to the outpatient neurology clinic. Data from all non-hospitalized mTBI patients (Glasgow Coma Scale [GCS] score 13-15, n = 462) from a prospective follow-up study on mTBI (UPFRONT-study) conducted in three level 1 trauma centers were analyzed. At 2 weeks, and 3 and 6 months after injury, patients completed questionnaires on post-traumatic complaints, depression, anxiety, outpatient follow-up, and resumption of activities. Most patients were male (57%), with a mean age of 40 years (range 16-91 years). Injuries were most often caused by traffic accidents (32%) or falls (39%). Six months after injury, 36% showed incomplete recovery as defined by the Glasgow Outcome Scale - Extended (GOS-E). Twenty-five percent of the non-hospitalized patients returned to the outpatient neurology clinic within 6 months after injury, of which one third had not completely resumed pre-injury activities. Regression analyses showed an increased risk for outpatient follow-up for patients scoring above the cutoff value for anxiety (odds ratio [OR] = 3.0), depression (OR = 3.5), or both (OR = 3.7) 2 weeks after injury. Our findings underline that clinicians and researchers should be aware of recovery for all mTBI patients, preventing their transition into a forgotten minority.

Although most patients recover fully following mild traumatic brain injury (mTBI), a minority (15-25%) of all patients develop persistent post-traumatic complaints (PTC) that interfere with the resumption of previous activities. An early identification of patients who are at risk for PTC is currently performed by measuring the number of complaints in the acute phase. However, only part of this group will actually develop persisting complaints, stressing the need for studies on additional risk factors. This study aimed to compare this group of patients with many complaints with patients with few and no complaints to identify potential additional discriminating characteristics and to evaluate which of these factors have the most predictive value for being at risk. We evaluated coping style, presence of psychiatric history, injury characteristics, mood-related symptoms, and post-traumatic stress. We included 820 patients (Glasgow Coma Scale [GCS] score 13-15) admitted to three level-1 trauma centers as part of the UPFRONT-study. At 2 weeks after injury, 60% reported three or more complaints (PTC-high), 25% reported few complaints (PTC-low), and 15% reported no complaints (PTC-zero). Results showed that PTC-high consisted of more females (78% vs. 73% and 52%, p < 0.001), were more likely to have a psychiatric history (7% vs. 2% and 5%), and had a higher number of reported depression (22% vs. 6% and 3%, p < 0.001), anxiety (25% vs. 7% and 5%), and post-traumatic stress (37% vs. 27% and 19%, p < 0.001) than the PTC-low and PTC-zero groups. We conclude that in addition to reported complaints, psychological factors such as coping style, depression, anxiety, and post-traumatic stress symptoms had the highest predictive value and should be taken into account in the identification of at-risk patients for future treatment studies.

Fear is an important emotional reaction that guides decision making in situations of ambiguity or uncertainty. Both recognition of facial expressions of fear and decision making ability can be impaired after traumatic brain injury (TBI), in particular when the frontal lobe is damaged. So far, it has not been investigated how recognition of fear influences risk behavior in healthy subjects and TBI patients. The ability to recognize fear is thought to be related to the ability to experience fear and to use it as a warning signal to guide decision making. We hypothesized that a better ability to recognize fear would be related to a better regulation of risk behavior, with healthy controls outperforming TBI patients. To investigate this, 59 healthy subjects and 49 TBI patients were assessed with a test for emotion recognition (Facial Expression of Emotion: Stimuli and Tests) and a gambling task (Iowa Gambling Task (IGT)). The results showed that, regardless of post traumatic amnesia duration or the presence of frontal lesions, patients were more impaired than healthy controls on both fear recognition and decision making. In both groups, a significant relationship was found between better fear recognition, the development of an advantageous strategy across the IGT and less risk behavior in the last blocks of the IGT. Educational level moderated this relationship in the final block of the IGT. This study has important clinical implications, indicating that impaired decision making and risk behavior after TBI can be preceded by deficits in the processing of fear., Competing Interests: The authors have declared that no competing interests exist.

Background: Niemann-Pick type C (NP-C) is a rare autosomal recessive progressive neurodegenerative disorder caused by mutations in the NP-C 1 or 2 gene. Besides visceral symptoms, presentation in adolescent and adult onset variants is often with neurological symptoms. The most frequently reported presenting symptoms of NP-C in adulthood are psychiatric symptoms (38 %), cognitive decline (23 %) and ataxia (20 %). Myoclonus can be present, but its value in early diagnosis and the evolving clinical phenotype in NP-C is unclear. In this paper we present eight Dutch cases of NP-C of whom five with myoclonus., Methods: Eight patients with genetically confirmed NP-C were recruited from two Dutch University Medical Centers. A structured interview and neuropsychological tests (for working and verbal memory, attention and emotion recognition) were performed. Movement disorders were assessed using a standardized video protocol. Quality of life was evaluated by questionnaires (Rand-36, SIP-68, HAQ). In four of the five patients with myoclonic jerks simultaneous EEG with EMG was performed., Results: A movement disorder was the initial neurological symptom in six patients: three with myoclonus and three with ataxia. Two others presented with psychosis. Four experienced cognitive deficits early in the course of the disease. Patients showed cognitive deficits in all investigated domains. Five patients showed myoclonic jerks, including negative myoclonus. In all registered patients EEG-EMG coherence analysis and/or back-averaging proved a cortical origin of myoclonus. Patients with more severe movement disorders experienced significantly more physical disabilities., Conclusions: Presenting neurological symptoms of NP-C include movement disorders, psychosis and cognitive deficits. At current neurological examination movement disorders were seen in all patients. The incidence of myoclonus in our cohort was considerably higher (63 %) than in previous publications and it was the presenting symptom in 38 %. A cortical origin of myoclonus was demonstrated. Our data suggest that myoclonus may be overlooked in patients with NP-C. All patients scored significantly lower on physical domains of HRQoL. Symptomatic treatment of movement disorders may improve physical functioning and subsequently HRQoL.

Objectives: To assess the role of brain networks in emotion regulation and post-traumatic complaints in the sub-acute phase after non-complicated mild traumatic brain injury (mTBI)., Experimental Design: Fifty-four patients with mTBI (34 with and 20 without complaints) and 20 healthy controls (group-matched for age, sex, education, and handedness) were included. Resting-state fMRI was performed at four weeks post-injury. Static and dynamic functional connectivity were studied within and between the default mode, executive (frontoparietal and bilateral frontal network), and salience network. The hospital anxiety and depression scale (HADS) was used to measure anxiety (HADS-A) and depression (HADS-D)., Principal Observations: Regarding within-network functional connectivity, none of the selected brain networks were different between groups. Regarding between-network interactions, patients with complaints exhibited lower functional connectivity between the bilateral frontal and salience network compared to patients without complaints. In the total patient group, higher HADS-D scores were related to lower functional connectivity between the bilateral frontal network and both the right frontoparietal and salience network, and to higher connectivity between the right frontoparietal and salience network. Furthermore, whereas higher HADS-D scores were associated with lower connectivity within the parietal midline areas of the bilateral frontal network, higher HADS-A scores were related to lower connectivity within medial prefrontal areas of the bilateral frontal network., Conclusions: Functional interactions of the executive and salience networks were related to emotion regulation and complaints after mTBI, with a key role for the bilateral frontal network. These findings may have implications for future studies on the effect of psychological interventions., (© 2016 Wiley Periodicals, Inc.)

A substantial number of patients (30% to 50%) sustains a mild traumatic brain injury (mTBI) while they are under the influence of alcohol. An acute alcohol intoxication (AAI) at the time of injury has been subject of research in severe TBI, but little is known about the relation between AAI and mTBI. This study aimed to describe the characteristics of this intoxicated subgroup and evaluate recovery and outcome in comparison to sober mTBI patients. We included 528 mTBI patients (Glasgow Coma Scale [GCS] score 13-15) admitted to two Level 1 trauma centers as part of a prospective follow-up study. We compared clinical characteristics, demographics, and injury mechanism between groups. Post-concussive complaints, mood disorders, and post-traumatic stress-related complaints were assessed at 2 weeks post-injury, and outcome at 6 months with the Glasgow Outcome Scale Extended (GOSE). Thirty-three percent of the mTBI patients were intoxicated. Results showed that the intoxicated group was younger (36 vs. 40 years; p = 0.001) and were more frequently of male gender (78% vs. 60%; p < .001). The groups also differed in injury related characteristics, with intoxicated patients more frequently sustaining falls or violence-related injuries. The intoxicated group was assessed with a lower GCS score and had a higher hospital admission rate. However, at 2 weeks post-injury, intoxicated patients reported less complaints than the non-alcohol group and showed a better recovery at 6 months (average GOSE scores 7 vs. 7.3; p = 0.030). We conclude that AAI in mTBI represents a characteristically different group, which has implications for prevention measures, as well as the course of recovery.

The majority of patients with traumatic brain injury (TBI) sustain a mild injury (mTBI). One out of 4 patients experiences persistent complaints, despite their often normal neuropsychological test results and the absence of structural brain damage on conventional neuroimaging. Susceptibility to develop persistent complaints is thought to be affected by interindividual differences in adaptation, which can also be influenced by preinjury psychological factors. Coping is a key construct of adaptation and refers to strategies to deal with new situations and serious life events. An important element of coping is the ability to regulate emotions and stress. The prefrontal cortex is a crucial area in this regulation process, given that it exerts a top-down influence on the amygdala and other subcortical structures involved in emotion processing. However, little is known about the role of the prefrontal cortex and associated brain networks in emotion regulation and adaptation post-mTBI. Especially, the influence of prefrontal dysfunction on development of persistent postconcussive complaints is poorly understood. In this article, we aim to integrate findings from functional and structural MRI studies on this topic. Alterations within the default mode, executive and salience network have been found in relation to complaints post-mTBI. Dysfunction of the medial prefrontal cortex may impair network dynamics for emotion regulation and adaptation post-mTBI, resulting in persistent post-concussive complaints.

Behavioral problems are serious consequences of moderate to severe traumatic brain injury (TBI) and have a negative impact on outcome. There may be two types: neurobehavioral problems, manifesting as inadequate social behavior resulting from prefrontal system damage, and affective behavioral problems, resulting from emotional distress as a reaction to the brain injury. In the present study we investigated whether these two types of behavioral problems, as indicated by proxies, could be distinguished in a group of chronic TBI patients and whether early indicators of prefrontal damage on imaging could predict long-term neurobehavioral problems. Computed tomography (CT) imaging data on admission were used to identify frontal lesions. Three hundred twenty-three moderate to severe TBI survivors received 2 to 16 years post-trauma an aftercare survey with seven questions asking for changes in behavior and affect, presented both to patients and their proxies. One hundred eighty-six patients (59%) answered the behavioral questions; 42% had frontal lesions on CT. Ordinal common factor analysis on proxy scores yielded two factors, with behavior and affective items clearly separated and the anger item mediocre related to both factors. Three scales were created: Behavior, Affective and Anger. Frontal patients scored significantly higher on the Behavior and Anger scales. Logistic regression analysis showed a fourfold increase of long-term neurobehavioral problems in patients with frontal lesions. Long-term neurobehavioral problems were significantly correlated to one-year outcome and return to work in the long term. We conclude that in patients with moderate to severe TBI neurobehavioral and affective problems can be distinguished. Early CT frontal abnormalities predict long-term neurobehavioral problems, but not affective problems.

Traumatic brain injury (TBI) is a leading cause of disability, specifically among younger adults. Behavioral changes are common after moderate to severe TBI and have adverse consequences for social and vocational functioning. It is hypothesized that deficits in social cognition, including facial affect recognition, might underlie these behavioral changes. Measurement of behavioral deficits is complicated, because the rating scales used rely on subjective judgement, often lack specificity and many patients provide unrealistically positive reports of their functioning due to impaired self-awareness. Accordingly, it is important to find performance based tests that allow objective and early identification of these problems. In the present study 51 moderate to severe TBI patients in the sub-acute and chronic stage were assessed with a test for emotion recognition (FEEST) and a questionnaire for behavioral problems (DEX) with a self and proxy rated version. Patients performed worse on the total score and on the negative emotion subscores of the FEEST than a matched group of 31 healthy controls. Patients also exhibited significantly more behavioral problems on both the DEX self and proxy rated version, but proxy ratings revealed more severe problems. No significant correlation was found between FEEST scores and DEX self ratings. However, impaired emotion recognition in the patients, and in particular of Sadness and Anger, was significantly correlated with behavioral problems as rated by proxies and with impaired self-awareness. This is the first study to find these associations, strengthening the proposed recognition of social signals as a condition for adequate social functioning. Hence, deficits in emotion recognition can be conceived as markers for behavioral problems and lack of insight in TBI patients. This finding is also of clinical importance since, unlike behavioral problems, emotion recognition can be objectively measured early after injury, allowing for early detection and treatment of these problems.

Impairments in social behavior are frequently found in moderate to severe traumatic brain injury (TBI) patients and are associated with an unfavorable outcome with regard to return to work and social reintegration. Neuropsychological tests measuring aspects of social cognition are thought to be sensitive to these problems. However, little is known about the effect of general cognitive problems on these tests, nor about their sensitivity to injury severity and frontal lesions. In the present study 28 chronic TBI patients with a moderate to severe TBI were assessed with tests for social cognition (emotion recognition, Theory of Mind, and empathy), and for general, non-social cognition (memory, mental speed, attention, and executive function). The patients performed significantly worse than healthy controls on all measures, with the highest effect size for the emotion recognition test, the Facial Expressions of Emotion-Stimuli and Tests (FEEST). Correlation analyses yielded no significant (partial) correlations between social and non-social cognition tests. Consequently, poor performance on social cognition tests was not due to general cognitive deficits. In addition, the emotion recognition test was the only measure that was significantly related to post-traumatic amnesia (PTA) duration, Glasgow Coma Scale (GCS) score, and the presence of prefrontal lesions. Hence, we conclude that social cognition tests are a valuable supplement to a standard neuropsychological examination, and we strongly recommend the incorporation of measurements of social cognition in clinical practice. Preferably, a broader range of social cognition tests would be applied, since our study demonstrated that each of the measures represents a unique aspect of social cognition, but if capacity is limited, at least a test for emotion recognition should be included.

In patients with moderate to severe traumatic brain injury (TBI), impairments of self-awareness are frequently found and associated with worse functional outcome and poor compliance with rehabilitation. The aim of this study was to investigate whether indications of impaired self-awareness could be found in TBI patients with frontal lesions and executive function deficits. Twenty-two TBI patients with focal frontal injuries were compared to 29 TBI patients without focal frontal injuries visible on neuroimaging. No differences were found on several outcome measures, including the Glasgow Outcome Scale-Extended (GOS-E), the Differential Outcome Scale (DOS), and return to work (RTW), although the frontal injury patients were more severely injured as indicated by the Glasgow Coma Scale (GCS) and duration of post-traumatic amnesia (PTA), and had impaired performance on a neuropsychological test of executive functioning. Even more so, the frontal injury group had a significantly lower score on the Sickness Impact Profile (SIP), indicating that they had fewer complaints than the patients without frontal injury, and scored significantly higher on the percentage of recovery (PoR) score, which expresses the extent of recovery as a percentage of their previous level of functioning. In contrast to the non-frontal-injury group, their PoR scores were not related to RTW, reflecting an erroneous perception of their actual working status. The positive results on these different outcome measures, which are partly or entirely self-reported, were seen as an indication of an impaired self-evaluative ability in the frontal injury patients. To determine outcome in a patient with frontal injuries and executive dysfunction, the judgment of several relevant other persons in the patient's life (e.g., partners, therapists, and employers) of the patient's daily life functioning should be sought.