Attention Deficit Predicts Intellectual Functioning in Children with Neurofibromatosis Type 1.

AIMS: Attention deficit hyperactivity disorder (ADHD) is one of the most frequent neurocognitive impairments in neurofibromatosis type 1 (NF1) and a well-known risk factor for intellectual dysfunction in general. Since NF1 is per se associated with intellectual difficulties, this comorbidity may be crucial for the cognitive development of affected patients. In our study, we investigated if attention deficits are associated with intellectual functioning in NF1 and if children with NF1 plus ADHD differ in their intellectual and attention profiles from children affected by NF1-only or ADHD only. METHODS: 111 children aged between 6 and 12 years (53 NF1 plus ADHD, 28 NF1-only, 30 ADHD-only) performed the German version of the intelligence test WISC-IV and a continuous performance test (T.O.V.A.) to assess attention functions. Parents completed questionnaires about everyday attention and executive functions (Conners 3®, BRIEF). RESULTS: Children with NF1 plus ADHD showed significantly lower intelligence test scores (full-scale IQ: 89.39 [1.40]) than patients with NF1-only (full-scale IQ: 101.14 [1.98]; p < .001), and intellectual functioning correlated significantly with attention performance in NF1 (p < .001). As compared to NF1-only, attention, and executive functioning were impaired on several dimensions (T.O.V.A., Conners 3® and BRIEF) in NF1 plus ADHD. ADHD-only was associated with significantly higher problem scores regarding hyperactivity/impulsivity and inattention (Conners 3®). NF1-only was associated with inattentiveness when compared to the normative sample of the T.O.V.A. CONCLUSION: NF1 is associated with variable attention problems. Severe attention deficits appear to be a risk factor for intellectual dysfunction in NF1, more than NF1 without attention deficit. NF1 plus ADHD presents a specific cognitive profile, which differs from that of NF1 and from neurotypical ADHD.

Impairment of Procedural Learning and Motor Intracortical Inhibition in Neurofibromatosis Type 1 Patients.

BACKGROUND: Cognitive difficulties are the most common neurological complications in neurofibromatosis type 1 (NF1) patients. Recent animal models proposed increased GABA-mediated inhibition as one underlying mechanism directly affecting the induction of long-term potentiation (LTP) and learning. In most adult NF1 patients, apparent cognitive and attentional deficits, tumors affecting the nervous system and other confounding factors for neuroscientific studies are difficult to control for. Here we used a highly specific group of adult NF1 patients without cognitive or nervous system impairments. Such selected NF1 patients allowed us to address the following open questions: Is the learning process of acquiring a challenging motor skill impaired in NF1 patients? And is such an impairment in relation to differences in intracortical inhibition? METHODS: We used an established non-invasive, double-pulse transcranial magnetic stimulation (dp-TMS) paradigm to assess practice-related modulation of intracortical inhibition, possibly mediated by gamma-minobutyric acid (GABA)ergic-neurotransmission. This was done during an extended learning paradigm in a group of NF1 patients without any neuropsychological deficits, functioning normally in daily life and compared them to healthy age-matched controls. FINDINGS: NF1 patients experienced substantial decline in motor skill acquisition (F = 9.2, p = 0.008) over five-consecutives training days mediated through a selective reduction in the early acquisition (online) and the consolidation (offline) phase. Furthermore, there was a consistent decrease in task-related intracortical inhibition as a function of the magnitude of learning (T = 2.8, p = 0.014), especially evident after the early acquisition phase. INTERPRETATIONS: Collectively, the present results provide evidence that learning of a motor skill is impaired even in clinically intact NF1 patients based, at least partially, on a GABAergic-cortical dysfunctioning as suggested in previous animal work.

Cerebral glucose metabolism in adults with neurofibromatosis type 1.

Previous studies with positron emission tomography (PET) and the glucose analog F-18-fluorodeoxyglucose (FDG) in patients with neurofibromatosis type 1 (NF1) suggest reduced cerebral glucose metabolism in NF1 specifically in the thalamus. The latter is distinguished by extensive neural circuitry connections which makes thalamic hypoactivity in NF1 an interesting finding. Yet it is not very well confirmed, since previous studies were limited by small sample size and/or poorly matched control groups. Primary aim of the present study therefore was to compare brain FDG PET between a large sample of NF1 patients and a well-matched control group. Secondary aim was to test for an NF1-associated FDG effect in the amygdala, as increased blood flow in the amygdala has recently been detected in a mouse model of NF1. Fifty adult NF1 patients and 50 gender- and age-matched control subjects were included retrospectively. Voxel-wise comparison of brain FDG uptake was performed using the statistical parametric mapping (SPM8). Additional region-of-interest (ROI) analysis was performed using standard ROI templates. Voxel-based testing revealed a single 11.2 ml cluster of reduced FDG uptake in the thalamus of NF1 patients. There was no further significant cluster throughout the whole brain including the amygdala, neither hypo nor hyper. ROI-analysis confirmed reduction of thalamic FDG uptake in the NF1 group (p<0.0005) with a magnitude of 7.6%. In conclusion, adults with NF1 show reduced brain activity specifically in thalamus. There is no indication of abnormal brain activity in the amygdala in humans with NF1.

Impact of ADHD in adults with neurofibromatosis type 1: associated psychological and social problems.

OBJECTIVE: To analyze the psychological phenotype of ADHD, and the effect of ADHD on life satisfaction and personality in adults with neurofibromatosis type 1 (NF1). METHOD: Adults with NF1 without (n = 26) and with ADHD (n = 22), and adults with ADHD only (n = 27) completed questionnaires on personality traits and life satisfaction. Differences between groups were analyzed. RESULTS: Participants with NF1 and ADHD present an emotionally instable psychological phenotype similar to adults with ADHD only, which differed significantly from that in adults with NF1 only. Participants with NF1 and ADHD had significantly lower overall life satisfaction than NF1 participants without such symptoms, affecting general health, self-satisfaction, sexuality, and family. CONCLUSION: The authors' findings show that ADHD symptoms can persist through adulthood. These NF1 patients display problems similar to those of adults with ADHD only. This finding is highly relevant to understand the behavioral and psychological phenotype in adults with NF1 and to offer psychological and/or medical treatment.

Influence of learning disabilities on the tumour predisposition syndrome NF1--survey from adult patients' perspective.

AIM: To analyze psychosocial burdens associated with neurofibromatosis type-1 (NF1) phenotype--visible symptoms, medical complications, learning disabilities (LD)--from patients' perspective with focus on LD. PATIENTS AND METHODS: A survey of 228 adult patients with NF1 was carried-out. Symptoms to estimate disease severity and visibility, and learning disability were assessed. Outcome parameters were social situation and psychosocial aspects. RESULTS: Social situation and psychosocial aspects differed depending on NF1 phenotype. Patients with LD (n=55) were less frequently in a partnership (p=0.005) or had children (p=0.015) than those without (n=132). They also reported a higher frequency of depression (p=0.019) and sensitivity to stress (p<0.001) and more uncertainty regarding NF1-associated symptoms. These differences were significant when adjusting for disease severity and self-perceived disease visibility. CONCLUSION: Beside the psychosocial needs of patients with LD with NF1, medical management of this sub-group should include doctor-patient communication in easy language to compensate for patients' lack of knowledge about symptoms associated with cancer.

Lovastatin improves impaired synaptic plasticity and phasic alertness in patients with neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders causing learning disabilities by mutations in the neurofibromin gene, an important inhibitor of the RAS pathway. In a mouse model of NF1, a loss of function mutation of the neurofibromin gene resulted in increased gamma aminobutyric acid (GABA)-mediated inhibition which led to decreased synaptic plasticity and deficits in attentional performance. Most importantly, these defictis were normalized by lovastatin. This placebo-controlled, double blind, randomized study aimed to investigate synaptic plasticity and cognition in humans with NF1 and tried to answer the question whether potential deficits may be rescued by lovastatin. METHODS: In NF1 patients (n = 11; 19-44 years) and healthy controls (HC; n = 11; 19-31 years) paired pulse transcranial magnetic stimulation (TMS) was used to study intracortical inhibition (paired pulse) and synaptic plasticity (paired associative stimulation). On behavioural level the Test of Attentional Performance (TAP) was used. To study the effect of 200 mg lovastatin for 4 days on all these parameters, a placebo-controlled, double blind, randomized trial was performed. RESULTS: In patients with NF1, lovastatin revealed significant decrease of intracortical inhibition, significant increase of synaptic plasticity as well as significant increase of phasic alertness. Compared to HC, patients with NF1 exposed increased intracortical inhibition, impaired synaptic plasticity and deficits in phasic alertness. CONCLUSIONS: This study demonstrates, for the first time, a link between a pathological RAS pathway activity, intracortical inhibition and impaired synaptic plasticity and its rescue by lovastatin in humans. Our findings revealed mechanisms of attention disorders in humans with NF1 and support the idea of a potential clinical benefit of lovastatin as a therapeutic option.

The adverse influence of attention-deficit disorder with or without hyperactivity on cognition in neurofibromatosis type 1.

AIM: A substantial proportion of patients with neurofibromatosis type 1 (NF1) have attention-deficit disorder with or without hyperactivity (AD[H]D). This study explored the influence of AD(H)D symptoms on the intellectual profile of patients with NF1. METHOD: We retrospectively analysed neuropsychological data from 114 children (66 males, 48 females; age range 6-16y; mean age 9y 3mo [SE 3mo]) with NF1 from an NF1 outpatients department. Assessment included psychiatric diagnosis of AD(H)D (DSM-IV-TR criteria) and intelligence testing (Wechsler Intelligence Scale for Children, German version). Magnetic resonance images were available for all patients, intracranial findings being an exclusion criterion. The effects of AD(H)D symptoms on intelligence and on the cognitive profile were tested by analyses of variance. RESULTS: Patients with AD(H)D symptoms performed significantly worse than those without AD(H)D symptoms on all intelligence measures (main effects for Full-scale, Verbal, and Performance IQ; p<0.005). Subtests typically impaired in patients with NF1 (visuospatial skills and arithmetic) were not specifically influenced by AD(H)D symptoms. There were no differences between AD(H)D subtypes. INTERPRETATION: AD(H)D symptoms have a negative impact on the intellectual development of children with NF1. This impact seems to be of an unspecific nature, with a general attenuation of the cognitive profile.

Psychological burden in adult neurofibromatosis type 1 patients: impact of disease visibility on body image.

AIM: To evaluate the impact of disease visibility on psychological stress factors in neurofibromatosis type 1 (NF1) and to explore the body image of NF1 patients. METHODS: 228 adult NF1 patients participated in this cross-sectional survey. The questionnaire assessed perceived disease visibility and patients' body image. Outcome parameters were depression, distress and quality of life. Mediation models were performed to test if body experience mediated the effect of disease visibility on outcome parameters. RESULTS: Adult NF1 patients had a negative body image, expressed by bodily insecurity/uneasiness and fewer feelings of attractiveness and self-confidence. Compared to the body image of patients with other disfiguring diseases, patients with NF1 felt less attractive, displayed less self-confidence (women: p < 0.001; men: p < 0.001) and were more insecure/uneasy and sexually dissatisfied with their bodies (men: p < 0.001; women: p ≤ 0.12, d = 0.28). The found effect of disease visibility on psychological stress was completely mediated by how patients experienced their bodies. CONCLUSIONS: Our study shed light on the importance of how NF1 patients experience and appraise their own bodies. We revealed that body image is an important link between disease visibility and psychological well-being. The body image of patients can be improved with psychotherapeutic interventions.