Systemic inflammation relates to neuroaxonal damage associated with long-term cognitive dysfunction in COVID-19 patients.

BACKGROUND AND OBJECTIVES: Cognitive deficits are increasingly recognized as a long-term sequela of severe COVID-19. The underlying processes and molecular signatures associated with these long-term neurological sequalae of COVID-19 remain largely unclear, but may be related to systemic inflammation-induced effects on the brain. We studied the systemic inflammation-brain interplay and its relation to development of long-term cognitive impairment in patients who survived severe COVID-19. Trajectories of systemic inflammation and neuroaxonal damage blood biomarkers during ICU admission were analyzed and related to long-term cognitive outcomes. METHODS: Prospective longitudinal cohort study of patients with severe COVID-19 surviving ICU admission. During admission, blood was sampled consecutively to assess levels of inflammatory cytokines and neurofilament light chain (NfL) using an ultrasensitive multiplex Luminex assay and single molecule array technique (Simoa). Cognitive functioning was evaluated using a comprehensive neuropsychological assessment six months after ICU-discharge. RESULTS: Ninety-six patients (median [IQR] age 61 [55-69] years) were enrolled from March 2020 to June 2021 and divided into two cohorts: those who received no COVID-19-related immunotherapy (n = 28) and those treated with either dexamethasone or dexamethasone and tocilizumab (n = 68). Plasma NfL concentrations increased in 95 % of patients during their ICU stay, from median [IQR] 23 [18-38] pg/mL at admission to 250 [160-271] pg/mL after 28 days, p < 0.001. Besides age, glomerular filtration rate, immunomodulatory treatment, and C-reactive protein, more specific markers of systemic inflammation at day 14 (i.e., interleukin (IL)-8, tumour necrosis factor, and IL-1 receptor antagonist) were significant predictors of blood NfL levels at day 14 of ICU admission (R2 = 44 %, p < 0.001), illustrating the association between sustained systemic inflammation and neuroaxonal damage. Twenty-six patients (27 %) exhibited cognitive impairment six months after discharge from the ICU. NfL concentrations showed a more pronounced increase in patients that developed cognitive impairment (p = 0.03). Higher NfL predicted poorer outcome in information processing speed (Trail Making Test A, r = -0.26, p = 0.01; Letter Digit Substitution Test, r = -0.24, p = 0.02). DISCUSSION: Prolonged systemic inflammation in critically ill COVID-19 patients is related to neuroaxonal damage and subsequent long-term cognitive impairment. Moreover, our findings suggest that plasma NfL concentrations during ICU stay may possess prognostic value in predicting future long-term cognitive impairment in patients that survived severe COVID-19.

Conversion of unresponsiveness to immune checkpoint inhibition by fecal microbiota transplantation in patients with metastatic melanoma: study protocol for a randomized phase Ib/IIa trial.

BACKGROUND: The gut microbiome plays an important role in immune modulation. Specifically, presence or absence of certain gut bacterial taxa has been associated with better antitumor immune responses. Furthermore, in trials using fecal microbiota transplantation (FMT) to treat melanoma patients unresponsive to immune checkpoint inhibitors (ICI), complete responses (CR), partial responses (PR), and durable stable disease (SD) have been observed. However, the underlying mechanism determining which patients will or will not respond and what the optimal FMT composition is, has not been fully elucidated, and a discrepancy in microbial taxa associated with clinical response has been observed between studies. Furthermore, it is unknown whether a change in the microbiome itself, irrespective of its origin, or FMT from ICI responding donors, is required for reversion of ICI-unresponsiveness. To address this, we will transfer microbiota of either ICI responder or nonresponder metastatic melanoma patients via FMT. METHODS: In this randomized, double-blinded phase Ib/IIa trial, 24 anti-PD1-refractory patients with advanced stage cutaneous melanoma will receive an FMT from either an ICI responding or nonresponding donor, while continuing anti-PD-1 treatment. Donors will be selected from patients with metastatic melanoma treated with anti-PD-1 therapy. Two patients with a good response (≥ 30% decrease according to RECIST 1.1 within the past 24 months) and two patients with progression (≥ 20% increase according to RECIST 1.1 within the past 3 months) will be selected as ICI responding or nonresponding donors, respectively. The primary endpoint is clinical benefit (SD, PR or CR) at 12 weeks, confirmed on a CT scan at 16 weeks. The secondary endpoint is safety, defined as the occurrence of grade ≥ 3 toxicity. Exploratory endpoints are progression-free survival and changes in the gut microbiome, metabolome, and immune cells. DISCUSSION: Transplanting fecal microbiota to restore the patients' perturbed microbiome has proven successful in several indications. However, less is known about the potential role of FMT to improve antitumor immune response. In this trial, we aim to investigate whether administration of FMT can reverse resistance to anti-PD-1 treatment in patients with advanced stage melanoma, and whether the ICI-responsiveness of the feces donor is associated with its effectiveness. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05251389 (registered 22-Feb-2022). Protocol V4.0 (08-02-2022).

The Course of Cognitive Performance during Inpatient Treatment in Patients with Alcohol Use Disorder with No, Mild or Major Neurocognitive Disorders.

AIMS: In patients with a history of chronic alcohol abuse, neurocognitive disorders (NCD) are not uncommon. The current study aimed to explore the course of cognitive performance, as measured by the Montreal Cognitive Assessment (MoCA), and everyday cognitive functioning, as measured by the Patient Competency Rating Scale (PCRS), in a large group of patients with alcohol use disorder (AUD) admitted to the Center of Excellence for Korsakov and Alcohol-related Cognitive Impairments. METHODS: A multiple time-series design was used, in which the MoCA was administered at three time points of assessment, and the PCRS was completed by both the patient and a clinician at two time points, all during clinical treatment. RESULTS: A total of 524 patients were included, 71 of whom were diagnosed with AUD only, 284 with AUD and mild NCD (ARCI) and 169 with AUD, major NCD and fulfilling criteria for Korsakoff's syndrome (KS). CONCLUSIONS: Cognitive performance improved for all three groups during treatment, sustained abstinence and recovery from AUD. A low memory performance on the MoCA without improvement over time was predictive for KS, while improvement on this domain did not differentiate between AUD and ARCI. Changes in overall cognitive performance and orientation in patients with KS were positively related to changes in everyday cognitive functioning.

Executive Dysfunction in Patients With Korsakoff's Syndrome: A Theory-Driven Approach.

AIMS: In addition to amnesia, executive deficits are prominent in Korsakoff's syndrome (KS), yet poorly studied. This study investigates the degree of executive dysfunction in patients with KS for the three main executive subcomponents shifting, updating and inhibition using novel, theory-driven paradigms. SHORT SUMMARY: Compared to healthy controls, patients with KS show impairments on the executive subcomponents shifting and updating, but not on inhibition. METHODS: Executive functions were measured with six carefully designed tasks in 36 abstinent patients with KS (mean age 62.3; 28% woman) and compared with 30 healthy non-alcoholic controls (mean age 61.8; 40% woman). ANOVAs were conducted to examine group differences and effect sizes were calculated. RESULTS: Compared to healthy controls, patients with KS were impaired on the executive subcomponents shifting and updating. No statistically significant group difference was found on the factor inhibition. CONCLUSIONS: Executive dysfunction in long-abstinent patients with alcoholic KS shows a profile in which shifting and updating ability are affected most. It also highlights that executive dysfunction is an important feature of KS and requires more attention in scientific and clinical practice, as these deficits may also affect daily functioning.

Differences in Cortical Sources of the Event-Related P3 Potential Between Young and Old Participants Indicate Frontal Compensation.

The event-related P3 potential, as elicited in auditory signal detection tasks, originates from neural activity of multiple cortical structures and presumably reflects an overlap of several cognitive processes. The fact that the P3 is affected by aging makes it a potential metric for age-related cognitive change. The P3 in older participants is thought to encompass frontal compensatory activity in addition to task-related processes. The current study investigates this by decomposing the P3 using group independent component analysis (ICA). Independent components (IC) of young and old participants were compared in order to investigate the effects of aging. Exact low-resolution tomography analysis (eLORETA) was used to compare current source densities between young and old participants for the P3-ICs to localize differences in cortical source activity for every IC. One of the P3-related ICs reflected a different constellation of cortical generators in older participants compared to younger participants, suggesting that this P3-IC reflects shifts in neural activations and compensatory processes with aging. This P3-IC was localized to the orbitofrontal/temporal, and the medio-parietal regions. For this IC, older participants showed more frontal activation and less parietal activation as measured on the scalp. The differences in cortical sources were localized in the precentral gyrus and the parahippocampal gyrus. This finding might reflect compensatory activity recruited from these cortical sources during a signal detection task.

The effect of an interactive cycling training on cognitive functioning in older adults with mild dementia: study protocol for a randomized controlled trial.

BACKGROUND: To date there is no cure or an effective disease-modifying drug to treat dementia. Available acetylcholine-esterase inhibiting drugs or memantine only produce small benefits on cognitive and behavioural functioning and their clinical relevance remains controversial. Combined cognitive-aerobic interventions are an appealing alternative or add-on to current pharmacological treatments. The primary aim of this study is to investigate the efficacy of a combined cognitive-aerobic training and a single aerobic training compared to an active control group in older adults with mild dementia. We expect to find a beneficial effect on executive functioning in both training regimes, compared to the control intervention, with the largest effect in the combined cognitive-aerobic group. Secondary, intervention effects on cognitive functioning in other domains, physical functioning, physical activity levels, activities of daily living, frailty and quality of life are studied. METHODS: The design is a single-blind, randomized controlled trial (RCT) with three groups: a combined cognitive-aerobic bicycle training (interactive cycling), a single aerobic bicycle training and a control intervention, which consists of stretching and toning exercises. Older adults with mild dementia follow a 12-week training program consisting of three training sessions of 30-40 min per week. The primary study outcome is objective executive functioning measured with a neuropsychological assessment. Secondary measures are objective cognitive functioning in other domains, physical functioning, physical activity levels, activities of daily living, frailty, mood and quality of life. The three groups are compared at baseline, after 6 and 12 weeks of training, and at 24-week follow-up. DISCUSSION: This study will provide novel information on the effects of an interactive cycling training on executive function in older adults with mild dementia. Furthermore, since this study has both a combined cognitive-aerobic training and a single aerobic training group the effectiveness of the different components of the intervention can be identified. The results of this study may be used for physical and mental activity recommendations in older adults with dementia. TRIAL REGISTRATION: The Netherlands National Trial Register NTR5581 . Registered 14 February 2016.

Diffusion tensor imaging of the hippocampus predicts the risk of dementia; the RUN DMC study.

INTRODUCTION: Cerebral small vessel disease is one of the most important risk factors for dementia, and has been related to hippocampal atrophy, which is among the first observed changes on conventional MRI in patients with dementia. However, these volumetric changes might be preceded by loss of microstructural integrity of the hippocampus for which conventional MRI is not sensitive enough. Therefore, we investigated the relation between the hippocampal diffusion parameters and the risk of incident dementia, using diffusion tensor imaging, independent of hippocampal volume. METHODS: The RUNDMC study is a prospective study among 503 elderly with small vessel disease, without dementia, with 5 years follow-up in 2012 (99.6% response-rate). Cox regression analysis was performed to calculate hazard ratios for dementia, of fractional anisotropy and mean diffusivity within the hippocampus, adjusted for demographics, hippocampal volume, and white matter. This was repeated in participants without evident hippocampal volume loss, because in these participants the visible damage might not yet have already started, whereas damage might have started on a microstructural level. RESULTS: 43 participants developed dementia (8.6%), resulting in a 5.5-year cumulative risk of 11.1% (95%CI 7.7-14.6). Higher mean diffusivity was associated with an increased 5-year risk of dementia. In the subgroup of participants with the upper half hippocampal volume, higher hippocampal mean diffusivity, more than doubled the 5-year risk of dementia. CONCLUSION: This is the first prospective study showing a relation between a higher baseline hippocampal mean diffusivity and the risk of incident dementia in elderly with small vessel disease at 5-year follow-up, independent of hippocampal volume and white matter volume.

[Alcohol-related cognitive impairment and the DSM-5]. / Alcoholgerelateerde cognitieve stoornissen in de DSM-5.

BACKGROUND: It is evident from the dsm-iv-tr that alcohol-related impairment is extremely difficult to classify accurately. As a result, cognitive deficits can easily be overlooked. The dsm-5, however, incorporates a new category, namely 'neurocognitive disorders', which may lead to significant improvements in clinical practice. AIM: To compare the classification of alcohol-related cognitive dysfunction in dsm-iv-tr and dsm-5 and to discuss the clinical relevance of the revised classification in the dsm-5. METHOD: We compare the chapters of the dsm-iv-tr and the dsm-5 concerning alcohol-related cognitive impairment and describe the changes that have been made. RESULTS: The dsm-5 puts greater emphasis on alcohol-related neurocognitive impairment. Not only does dsm-5 distinguish between the degree of severity (major or minor neurocognitive disorder), it also distinguishes between the type of impairment (non-amnestic-type versus confabulating-amnestic type). It also makes a distinction between the durations of impairment (behavioural and/or persistent disorders). CONCLUSION: The dsm-5 gives a clearer description of alcohol-related neurocognitive dysfunction than does dsm-iv-tr and it stresses the essential role of neuropsychological assessment in the classification, diagnosis, and treatment of neurocognitive disorders.

Probabilistic model-based functional parcellation reveals a robust, fine-grained subdivision of the striatum.

The striatum is involved in many different aspects of behaviour, reflected by the variety of cortical areas that provide input to this structure. This input is topographically organized and is likely to result in functionally specific signals. Such specificity can be examined using functional clustering approaches. Here, we propose a Bayesian model-based functional clustering approach applied solely to resting state striatal functional MRI timecourses to identify intrinsic striatal functional modules. Data from two sets of ten participants were used to obtain parcellations and examine their robustness. This stable clustering was used to initialize a more constrained model in order to obtain individualized parcellations in 57 additional participants. Resulting cluster time courses were used to examine functional connectivity between clusters and related to the rest of the brain in a GLM analysis. We find six distinct clusters in each hemisphere, with clear inter-hemispheric correspondence and functional relevance. These clusters exhibit functional connectivity profiles that further underscore their homologous nature and are consistent with existing notions on segregation and integration in parallel cortico-basal ganglia loops. Our findings suggest that multiple territories within both the affective and motor regions can be distinguished solely using resting state functional MRI from these regions.

Validity of the Montreal Cognitive Assessment and the HIV Dementia Scale in the assessment of cognitive impairment in HIV-1 infected patients.

The gold standard for evaluating cognitive impairments in HIV-infected patients is to administer an extensive neuropsychological assessment. This may, however, be time-consuming and hence not always feasible in the clinic. Therefore, several brief screening tools have been developed. This study determined the validity of the Montreal Cognitive Assessment (MoCA) and the HIV Dementia Scale (HDS) in detecting cognitive impairment using both the Frascati and cognitive impairment, no dementia (CIND) criteria to classify cognitive impairment in HIV-1 infected patients. The MoCA, HDS, and an extensive neuropsychological assessment, covering nine cognitive domains, were administered in a group of 102 HIV-infected patients who were all on cART and virologically suppressed for at least 1 year. Results show that the areas under the curve (AUCs) for both the MoCA and the HDS were statistically significant, using both the Frascati and the CIND criteria as gold standard. However, the AUCs for the MoCA and HDS did not differ significantly, regardless of the used classification criteria (Frascati: z = 0.37, p = 0.35; CIND: z = -0.62, p = 0.27). Sensitivity of both the MoCA and HDS were low for the recommended cutoff scores (Frascati: MoCA (<26) = 0.56, HDS (<11) = 0.26; CIND: MoCA (<26) = 0.55, HDS (<11) = 0.36). Cutoff scores with good sensitivity and adequate specificity could not be determined for both screening instruments. Therefore, the HDS and MoCA are not recommended as sole instruments to diagnose HIV-associated cognitive impairment.

Fractionation of visuo-spatial memory processes in bipolar depression: a cognitive scaffolding account.

BACKGROUND: Previous studies of neurocognitive performance in bipolar disorder (BD) have demonstrated impairments in visuo-spatial memory. The aim of the present study was to use an object-location memory (OLM) paradigm to assess specific, dissociable processes in visuo-spatial memory and examine their relationship with broader neurocognitive performance. METHOD: Fifty participants (25 patients with BD in a current depressive episode and 25 matched healthy controls) completed the OLM paradigm which assessed three different aspects of visuo-spatial memory: positional memory, object-location binding, and a combined process. Secondary neurocognitive measures of visuo-spatial memory, verbal memory, attention and executive function were also administered. RESULTS: BD patients were significantly impaired on all three OLM processes, with the largest effect in exact positional memory (d = 1.18, p < 0.0001). General deficits were also found across the secondary neurocognitive measures. Using hierarchical regression, verbal learning was found to explain significant variance on the OLM measures where object-identity was present (the object-location binding and combined processes) and accounted for the group difference. The group difference in precise positional memory remained intact. CONCLUSIONS: This study demonstrates that patients with bipolar depression manifest deficits in visuo-spatial memory, with substantial impairment in fine-grain, positional memory. The differential profile of processes underpinning the visuo-spatial memory impairment suggests a form of 'cognitive scaffolding', whereby performance on some measures can be supported by verbal memory. These results have important implications for our understanding of the functional cognitive architecture of mood disorder.

Long-term effects of oxandrolone treatment in childhood on neurocognition, quality of life and social-emotional functioning in young adults with Turner syndrome.

Turner syndrome (TS) is the result of (partial) absence of one X-chromosome. Besides short stature, gonadal dysgenesis and other physical aspects, TS women have typical psychological features. Since psychological effects of androgen exposure in childhood probably are long-lasting, we explored long-term psychological functioning after oxandrolone (Ox) therapy during childhood in adults with TS in terms of neurocognition, quality of life and social-emotional functioning. During the initial study, girls were treated with growth hormone (GH) combined with placebo (Pl), Ox 0.03 mg/kg/day, or Ox 0.06 mg/kg/day from the age of eight, and estrogen from the age of twelve. Sixty-eight women participated in the current double-blinded follow-up study (mean age 24.0 years, mean time since stopping GH/Ox 8.7 years). We found no effects on neurocognition. Concerning quality of life women treated with Ox had higher anxiety levels (STAI 37.4 ± 8.4 vs 31.8 ± 5.0, p=0.002) and higher scores on the depression subscale of the SCL-90-R (25.7 ± 10.7 vs 20.5 ± 4.7, p=0.01). Regarding social-emotional functioning, emotion perception for fearful faces was lower in the Ox-treated patients, without effect on interpersonal behavior. Our exploratory study is the first to suggest that androgen treatment in adolescence possibly has long-term effects on adult quality of life and social-emotional functioning. However, differences are small and clinical implications of our results seem limited. Therefore we would not recommend against the use of Ox in light of psychological consequences.

Impact of bedaquiline resistance probability on treatment decision for rifampicin-resistant TB.

BACKGROUND: Accurate diagnosis of bedaquiline (BDQ) resistance remains challenging. A Bayesian approach expresses this uncertainty as a probability of BDQ resistance (prBDQR) with a 95% credible interval. We investigated how prBDQR information influences BDQ prescribing decisions. METHOD: We performed a discrete choice experiment with 55 international rifampicin-resistant tuberculosis physicians. We employed mixed-effects multinomial logistic regression to quantify the effect of prBDQR, patient attributes, and contextual factors on the decision to continue BDQ or not when sequencing results become available. RESULTS: PrBDQR was the most influential factor for BDQ decision-making, three times greater than treatment response. Each percentage point increase in prBDQR resulted in 8.2% lower odds (OR 0.92, 95% CI 0.90-0.93) of continuing BDQ as a fully effective drug and 5.0% lower odds (OR 0.95, 95% CI 0.94-0.96) of continuing it but not counting it as an effective drug. The most favourable patient profile for prescribing BDQ as a fully effective drug was a patient receiving the BPaLM regimen (BDQ, pretomanid, linezolid and moxifloxacin) with low prBDQR, good 1-month treatment response, fluoroquinolone-susceptible TB, and no prior BDQ treatment. Physicians with higher discomfort with uncertainty and more years of experience with BDQ were more inclined to stop BDQ. CONCLUSION: Given the uncertainty of genotype-phenotype associations, physicians valued prBDQR for BDQ decision-making in rifampicin-resistant TB treatment.

CONTEXTE: Le diagnostic précis de la résistance à la bédaquiline (BDQ) reste difficile. Une approche bayésienne exprime cette incertitude sous la forme d'une probabilité de résistance au BDQ (prBDQR) avec un intervalle de crédibilité à 95%. Nous avons étudié comment les informations prBDQR influencent les décisions de prescription de BDQ. MÉTHODE: Nous avons réalisé une expérience à choix discret auprès de 55 médecins internationaux spécialisés dans la TB résistante à la rifampicine. Nous avons utilisé une régression logistique multinomiale à effets mixtes pour quantifier l'effet du prBDQR, des attributs du patient et des facteurs contextuels sur la décision de poursuivre ou non le BDQ lorsque les résultats du séquençage sont disponibles. RÉSULTATS: La prBDQR a été le facteur le plus influent dans la prise de décision en matière de BDQ, trois fois plus importante que la réponse au traitement. Chaque augmentation d'un point de pourcentage du prBDQR a entraîné une baisse de 8,2% des probabilités (RC 0,92 ; IC à 95% 0,90­0,93) de poursuivre le BDQ en tant que médicament pleinement efficace et une baisse de 5,0% des probabilités (RC 0,95 ; IC à 95% 0,94­0,96) de le poursuivre mais de ne pas le compter comme un médicament efficace. Le profil de patient le plus favorable à la prescription de BDQ en tant que médicament pleinement efficace était celui d'un patient recevant le régime BPaLM (BDQ, pretomanid, linezolid et moxifloxacin) avec un faible prBDQR, une bonne réponse au traitement à 1 mois, une tuberculose sensible aux fluoroquinolones et aucun traitement antérieur par BDQ. Les médecins présentant un plus grand malaise face à l'incertitude et plus d'années d'expérience avec la BDQ étaient plus enclins à arrêter la BDQ. CONCLUSION: Compte tenu de l'incertitude des associations génotype-phénotype, les médecins ont valorisé prBDQR pour la prise de décision BDQ dans le traitement de la TB RR.

Tailored guidance to apply the Estimand framework to Trials within Cohorts (TwiCs) studies.

Objective: The estimand framework offers a structured approach to define the treatment effect to be estimated in a clinical study. Defining the estimand upfront helps formulating the research question and informs study design, data collection and statistical analysis methods. Since the Trials within Cohorts (TwiCs) design has unique characteristics, the objective of this study is to describe considerations and provide guidance for formulating estimands for TwiCs studies. Methods: The key attributes of an estimand are the target population, treatments that are compared, the endpoint, intercurrent events and their handling, and the population-level summary measure. The estimand framework was applied retrospectively to two TwiCs studies: the SPONGE and UMBRELLA Fit trial. The aim is to demonstrate how the estimand framework can be implemented in TwiCs studies, thereby focusing on considerations relevant for defining the estimand. Three estimands were defined for both studies. For the SPONGE trial, estimators were derived. Results: Intercurrent events considered to occur exclusively or more frequently in TwiCs studies compared to conventional randomized trials included intervention refusal after randomization, misalignment of timing of routine cohort measurements and the intervention period, and participants in the control arm initiating treatments similar to the studied intervention. Considerations for handling refusal after randomization related to decisions on whether the target population should include all eligible participants or the subpopulation that would accept (or undergo) the intervention when offered. Considerations for handling treatment initiation in the control arm and misalignments of timing related to decisions on whether such events should be considered part of treatment policy or whether interest is in a hypothetical scenario where such events do not occur. Conclusion: The TwiCs study design has unique features that pose specific considerations when formulating an estimand. The examples in this study can provide guidance in the definition of estimands in future TwiCs studies.

Microstructural integrity of the cingulum is related to verbal memory performance in elderly with cerebral small vessel disease: the RUN DMC study.

BACKGROUND: Cerebral small vessel disease (SVD) is related to verbal memory failures. It is suggested that early white matter damage, is located, among others, in the (posterior) cingulum at an early stage in neurodegeneration. Changes in the microstructural integrity of the cingulum assessed with diffusion tensor imaging (DTI), beyond detection with conventional MRI, may precede macrostructural changes and be related to verbal memory failures. OBJECTIVE: To investigate the relation between cingular microstructural integrity and verbal memory performance in 503 non-demented elderly with cerebral SVD. METHODS: The RUN DMC study is a prospective cohort study in elderly (50-85 years) with cerebral SVD. All participants underwent T1 MPRAGE, FLAIR and DTI scanning and the Rey Auditory Verbal Learning Test. Mean diffusivity (MD) and fractional anisotropy (FA) were assessed in six different cingular regions of interests (ROIs). Linear regression analysis was used to assess the relation between verbal memory performance and cingular DTI parameters, with appropriate adjustments. Furthermore a TBSS analysis of the whole brain was performed to investigate the specificity of our findings. RESULTS: Both our ROI-based and TBSS analysis showed that FA was positively related to immediate memory, delayed recall, delayed recognition and overall verbal memory performance of the cingulum, independent of confounders. A similar distribution was seen for the inverse association with MD and verbal memory performance with TBSS analysis. No significant relations were found with psychomotor speed, visuospatial memory and MMSE. When stratified on hippocampal integrity, the MD and FA values of the cingular ROIs differed significantly between participants with a good and poor hippocampal integrity. CONCLUSION: Microstructural integrity of the cingulum, assessed by DTI, is specifically related to verbal memory performance, in elderly with SVD. Furthermore we found that when the integrity of the hippocampus is disrupted, the cingulum integrity is impaired as well.

Affective functioning and social cognition in Noonan syndrome.

BACKGROUND: Noonan syndrome (NS) is a common genetic disorder, characterized by short stature, facial dysmorphia, congenital heart defects and a mildly lowered IQ. Impairments in psychosocial functioning have often been suggested, without, however, systematic investigation in a clinical group. In this study, different aspects of affective processing, social cognition and behaviour, in addition to personal well-being, were assessed in a large group of patients with NS. METHOD: Forty adult patients with NS were compared with 40 healthy controls, matched with respect to age, sex, intelligence and education level. Facial emotion recognition was measured with the Emotion Recognition Task (ERT), alexithymia with both the 20-item Toronto Alexithymia Scale (TAS-20) and the Bermond-Vorst Alexithymia Questionnaire (BVAQ), and mentalizing with the Theory of Mind (ToM) test. The Symptom Checklist-90 Revised (SCL-90-R) and the Scale for Interpersonal Behaviour (SIB) were used to record aspects of psychological well-being and social interaction. RESULTS: Patients showed higher levels of cognitive alexithymia than controls. They also experienced more social distress, but the frequency of engaging in social situations did not differ. Facial emotion recognition was only slightly impaired. CONCLUSIONS: Higher levels of alexithymia and social discomfort are part of the behavioural phenotype of NS. However, patients with NS have relatively intact perception of emotions in others and unimpaired mentalizing. These results provide insight into the underlying mechanisms of social daily life functioning in this patient group.

Impaired Knowledge of Social Norms in Dementia and Psychiatric Disorders: Validation of the Social Norms Questionnaire-Dutch Version (SNQ-NL).

The Social Norms Questionnaire-Dutch version (SNQ-NL) measures the ability to understand and identify social boundaries. We examined the psychometric characteristics of the SNQ-NL and its ability to differentiate between patients with behavioral variant frontotemporal dementia (bvFTD; n = 23), Alzheimer's dementia (AD; n = 26), chronic psychiatric disorders (n = 27), and control participants (n = 92). Between-group differences in the Total score, Break errors, and Overadhere errors were examined and associations with demographic variables and other cognitive functions were explored. Results showed that the SNQ-NL Total Score and Break errors differed between patients with AD and bvFTD, but not between patients with bvFTD and psychiatric disorders. Modest correlations with age, sex, and education were observed. The SNQ-NL Total score and Break errors correlated significantly with emotion recognition and verbal fluency but not with processing speed or mental flexibility. In conclusion, the SNQ-NL has sufficient construct validity and can be used to investigate knowledge of social norms in clinical populations.

MART-1 TCR gene-modified peripheral blood T cells for the treatment of metastatic melanoma: a phase I/IIa clinical trial.

Background: Adoptive cell therapy with peripheral blood T cells expressing transgenic T-cell receptors (TCRs) is an innovative therapeutic approach for solid malignancies. We investigated the safety and feasibility of adoptive transfer of autologous T cells expressing melanoma antigen recognized by T cells 1 (MART-1)-specific TCR, cultured to have less differentiated phenotypes, in patients with metastatic melanoma. Materials and methods: In this phase I/IIa trial, peripheral blood T cells from HLA-A2∗02:01-positive patients with unresectable stage IIIC/IV melanoma expressing MART-1 were selected and stimulated with anti-CD3/CD28 beads, transduced with a modified MART-1(26-35)-specific 1D3 TCR (1D3HMCys) and expanded in interleukin (IL)-7 and IL-15. Patients received a single infusion of transgenic T cells in a dose-escalating manner. Feasibility, safety and objective response rate were assessed. Results: Twelve pretreated metastatic cutaneous (n = 7) and uveal (n = 5) melanoma patients were included. Patient 1 received 4.6 × 109 1D3HMCys T cells and experienced grade 5 toxicity after 9 days. Subsequent patients received 5.0 × 107 [n = 3; cohort (c) 2], 2.5 × 108 (n = 2; c3) and 1.0 × 108 (n = 6; c4) 1D3HMCys T cells. The study was prematurely terminated because of dose-dependent toxicity, concerning skin (10/12), eyes (3/12), ears (4/12) and cytokine release syndrome (5/12), with 7 patients experiencing grade 3-5 toxicity. Partial responses were seen in 2/11 (18%) assessable patients and persistence of 1D3HMCys T cells corresponded to infused cell dose. Conclusions: Production of TCR-modified cells as described leads to highly potent T cells. Partial responses were seen in 18% of patients with dose-dependent 'on-target, off-tumor' toxicity and a maximum tolerated dose of 1.0 × 108 cells.

Albuminuria and cognitive functioning in an older population: the Hoorn study.

BACKGROUND/AIMS: Markers of vascular disease elsewhere in the body may reflect vascular abnormalities in the brain relevant to age-related cognitive decline and dementia. We examined the association between albuminuria, as a marker of microvascular damage, and cognition in older individuals. METHODS: 380 individuals (age 73 ± 6 years), participating in the population-based Hoorn Study, underwent extensive neuropsychological examination in 2005-2008, and urinary albumin-to-creatinine ratios measurements in 2000-2001 (n = 378) and/or 2005-2008 (n = 346). Cognition was expressed in z-scores on 6 domains. RESULTS: In 2000-2001, 42 participants were with and 336 without albuminuria, and in 2005-2008 51 were with and 295 were without. In age-, sex- and premorbid IQ-adjusted analyses, participants with albuminuria 5-7 years earlier had slightly lower z-scores for the domains attention and executive functioning [mean difference: -0.21 (95% CI -0.40 to -0.02)] and language [-0.36 (95% CI -0.63 to -0.09)]. No statistically significant differences in cognition were found between participants with and without albuminuria at the time of neuropsychological testing. CONCLUSION: Albuminuria predicts future modest cognitive decrements, but concurrent albuminuria is unrelated to cognitive functioning. The link between albuminuria and cognitive dysfunction may convey an etiological message, but because effect sizes were modest its value in prognostic models for cognitive decline may be limited.