Perspectives of adolescents with neurofibromatosis 1 and cutaneous neurofibromas: Implications for clinical trials.

BACKGROUND/AIMS: More than 99% of individuals with neurofibromatosis 1 develop cutaneous neurofibromas, benign nerve sheath tumors that manifest as nodules on the skin. These cutaneous neurofibromas emerge with age, appearing most commonly in adolescence. Nevertheless, few data have been published on how adolescents with neurofibromatosis 1 feel about cutaneous neurofibromas. The purpose of this study was to assess the perspectives of adolescents with neurofibromatosis 1 and their caregivers regarding cutaneous neurofibroma morbidity, treatment options, and acceptable risks-benefits of treatment. METHODS: An online survey was distributed through the world's largest NF registry. Eligibility criteria included self-reported neurofibromatosis 1 diagnosis, adolescent child ages 12-17 years, ≥1 cutaneous neurofibroma, and ability to read English. The survey was designed to collect details about the adolescent's cutaneous neurofibromas, views on morbidity related to cutaneous neurofibromas, social and emotional impact of cutaneous neurofibromas, communication regarding cutaneous neurofibromas, and views regarding current and potential future cutaneous neurofibroma treatment. RESULTS: Survey respondents included 28 adolescents and 32 caregivers. Adolescents reported having several negative feelings about cutaneous neurofibromas, particularly feeling worried about the potential progression of their cutaneous neurofibromas (50%). Pruritus (34%), location (34%), appearance (31%), and number (31%) were the most bothersome cutaneous neurofibroma features. Topical medication (77%-96%), followed by oral medication (54%-93%), was the most preferred treatment modality. Adolescents and caregivers most often replied that cutaneous neurofibroma treatment should be initiated when cutaneous neurofibromas become bothersome. The majority of respondents were willing to treat cutaneous neurofibromas for at least 1 year (64%-75%). Adolescent and caregivers were least willing to risk pain (72%-78%) and nausea/vomiting (59%-81%) as a cutaneous neurofibroma treatment side effect. CONCLUSIONS: These data indicate that adolescents with neurofibromatosis 1 are negatively impacted by their cutaneous neurofibromas, and that both adolescents and their caregivers would be willing to try longer-term experimental treatments.

Perspectives of adults with neurofibromatosis regarding the design of psychosocial trials: Results from an anonymous online survey.

BACKGROUND/AIMS: Individuals with neurofibromatosis, including neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2)-related schwannomatosis (SWN), and other forms of SWN, often experience disease manifestations and mental health difficulties for which psychosocial interventions may help. An anonymous online survey of adults with neurofibromatosis assessed their physical, social, and emotional well-being and preferences about psychosocial interventions to inform clinical trial design. METHODS: Neurofibromatosis clinical researchers and patient representatives from the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration developed the survey. Eligibility criteria included age ≥ 18 years, self-reported diagnosis of NF1, NF2, or SWN, and ability to read and understand English. The online survey was distributed internationally by the Neurofibromatosis Registry and other neurofibromatosis foundations from June to August 2020. RESULTS: Surveys were completed by 630 adults (18-81 years of age; M = 45.5) with NF1 (78%), NF2 (14%), and SWN (8%) who were mostly White, not Hispanic/Latino, female, and from the United States. The majority (91%) reported that their neurofibromatosis symptoms had at least some impact on daily life. In the total sample, 51% endorsed a mental health diagnosis, and 27% without a diagnosis believed they had an undiagnosed mental health condition. Participants indicated that neurofibromatosis affected their emotional (44%), physical (38%), and social (35%) functioning to a high degree. Few reported ever having participated in a drug (6%) or psychosocial (7%) clinical trial, yet 68% reported they "probably" or "definitely" would want to participate in a psychosocial trial if it targeted a relevant concern. Top treatment targets were anxiety, healthier lifestyle, and daily stress. Top barriers to participating in psychosocial trials were distance to clinic, costs, and time commitment. Respondents preferred interventions delivered by clinicians via individual sessions or a combination of group and individual sessions, with limited in-person and mostly remote participation. There were no significant group differences by neurofibromatosis type in willingness to participate in psychosocial trials (p = 0.27). Regarding interest in intervention targets, adults with SWN were more likely to prefer psychosocial trials for pain support compared to those with NF1 (p < 0.001) and NF2 (p < 0.001). CONCLUSION: This study conducted the largest survey assessing physical symptoms, mental health needs, and preferences for psychosocial trials in adults with neurofibromatosis. Results indicate a high prevalence of disease manifestations, psychosocial difficulties, and untreated mental health problems in adults with neurofibromatosis and a high degree of willingness to participate in psychosocial clinical trials. Patient preferences should be considered when designing and implementing psychosocial interventions to develop the most feasible and meaningful studies.

Recommendations for assessing appearance concerns related to plexiform and cutaneous neurofibromas in neurofibromatosis 1 clinical trials.

BACKGROUND/AIMS: Individuals with neurofibromatosis 1 may experience changes in their appearance due to physical manifestations of the disorders and/or treatment sequelae. Appearance concerns related to these physical changes can lead to psychological distress and poorer quality of life. While many neurofibromatosis 1 clinical trials focus on assessing changes in tumor volume, evaluating patients' perspectives on corresponding changes in symptoms such as physical appearance can be key secondary outcomes. We aimed to determine whether any existing patient-reported outcome measures are appropriate for evaluating changes in appearance concerns within neurofibromatosis 1 clinical trials. METHODS: After updating our previously published systematic review process, we used it to identify and rate existing patient-reported outcome measures related to disfigurement and appearance. Using a systematic literature search and initial triage process, we focused on identifying patient-reported outcome measures that could be used to evaluate changes in appearance concerns in plexiform or cutaneous neurofibroma clinical trials in neurofibromatosis 1. Our revised Patient-Reported Outcome Rating and Acceptance Tool for Endpoints then was used to evaluate each published patient-reported outcome measures in five domains, including (1) respondent characteristics, (2) content validity, (3) scoring format and interpretability, (4) psychometric data, and (5) feasibility. The highest-rated patient-reported outcome measures were then re-reviewed in a side-by-side comparison to generate a final consensus recommendation. RESULTS: Eleven measures assessing appearance concerns were reviewed and rated; no measures were explicitly designed to assess appearance concerns related to neurofibromatosis 1. The FACE-Q Craniofacial Module-Appearance Distress scale was the top-rated measure for potential use in neurofibromatosis 1 clinical trials. Strengths of the measure included that it was rigorously developed, included individuals with neurofibromatosis 1 in the validation sample, was applicable to children and adults, covered item topics deemed important by neurofibromatosis 1 patient representatives, exhibited good psychometric properties, and was feasible for use in neurofibromatosis 1 trials. Limitations included a lack of validation in older adults, no published information regarding sensitivity to change in clinical trials, and limited availability in languages other than English. CONCLUSION: The Response Evaluation in Neurofibromatosis and Schwannomatosis patient-reported outcome working group currently recommends the FACE-Q Craniofacial Module Appearance Distress scale to evaluate patient-reported changes in appearance concerns in clinical trials for neurofibromatosis 1-related plexiform or cutaneous neurofibromas. Additional research is needed to validate this measure in people with neurofibromatosis 1, including older adults and those with tumors in various body locations, and explore the effects of nontumor manifestations on appearance concerns in people with neurofibromatosis 1 and schwannomatosis.

Consensus-Based Best Practice Guidelines for the Management of Spinal Deformity and Associated Tumors in Pediatric Neurofibromatosis Type 1: Screening and Surveillance, Surgical Intervention, and Medical Therapy.

BACKGROUND: Spinal conditions, such as scoliosis and spinal tumors, are prevalent in neurofibromatosis type 1 (NF1). Despite the recognized importance of their early detection and treatment, there remain knowledge gaps in how to approach these manifestations. The purpose of this study was to utilize the experience of a multidisciplinary committee of experts to establish consensus-based best practice guidelines (BPGs) for spinal screening and surveillance, surgical intervention, and medical therapy in pediatric patients with NF1. METHODS: Using the results of a prior systematic review, 10 key questions that required further assessment were first identified. A committee of 20 experts across medical specialties was then chosen based on their clinical experience with spinal deformity and tumors in NF1. These were 9 orthopaedic surgeons, 4 neuro-oncologists/oncologists, 3 neurosurgeons, 2 neurologists, 1 pulmonologist, and 1 clinical geneticist. An initial online survey on current practices and opinions was conducted, followed by 2 additional surveys via a formal consensus-based modified Delphi method. The final survey involved voting on agreement or disagreement with 35 recommendations. Items reaching consensus (≥70% agreement or disagreement) were included in the final BPGs. RESULTS: Consensus was reached for 30 total recommendations on the management of spinal deformity and tumors in NF1. These were 11 recommendations on screening and surveillance, 16 on surgical intervention, and 3 on medical therapy. Five recommendations did not achieve consensus and were excluded from the BPGs. CONCLUSION: We present a set of consensus-based BPGs comprised of 30 recommendations for spinal screening and surveillance, surgical intervention, and medical therapy in pediatric NF1.

Impact of the coronavirus pandemic on mental health and health care in adults with neurofibromatosis: Patient perspectives from an online survey.

The coronavirus pandemic increased anxiety and stress and prevented access to health care worldwide; it is unclear how COVID-19 affected adults with a multisystem genetic disorder such as neurofibromatosis (NF). An anonymous online survey was distributed through an international registry and foundations to adults with NF (June-August 2020) to assess the impact of the pandemic on mental health and NF health care. Six hundred and thirteen adults (18-81 years; M = 45.7) with NF1 (77.8%), NF2 (14.2%), and schwannomatosis (7.8%) provided complete responses. Respondents rated moderate-to-high amounts of worry about the impact of COVID-19 on their emotional (46.3%) and physical health (46.7%), and 54.8% endorsed moderate-to-high pandemic-related stress. Adults with diagnosed/suspected mental health disorders or moderate-to-severe NF symptom impact as well as females endorsed higher COVID-19 stress (ps < 0.01). Less than half who missed a doctor's appointment for their NF care (43.4%) used telehealth. Of these, 33.3% and 46.2% reported that telehealth met their needs to a moderate or high degree, respectively. Results indicated that subgroups of adults with NF experience higher COVID-19-related worries and stress and may need additional support. Furthermore, telehealth is under-utilized and could help NF providers connect with patients, although improved delivery and patient training may facilitate expanded use of these services.

Perspective of Adults With Neurofibromatosis 1 and Cutaneous Neurofibromas: Implications for Clinical Trials.

OBJECTIVE: To assess the perspectives of adults with neurofibromatosis 1 (NF1) regarding cutaneous neurofibroma (cNF) morbidity, treatment options, and acceptable risk-benefit ratio to facilitate the design of patient-centered clinical trials. METHODS: An online survey developed by multidisciplinary experts and patient representatives of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) cNF Working Group was distributed to adults with NF1 (n = 3,734) in the largest international database of individuals with any form of NF. Eligibility criteria included self-reported NF1 diagnosis, age ≥18 years, ≥1 cNF, and ability to read English. RESULTS: A total of 548 adults with NF1 responded to the survey. Respondents ranked appearance, number, and then location as the most bothersome features of raised cNF. Seventy-five percent of respondents considered a partial decrease of 33%-66% in the number or size of cNF as a meaningful response to experimental treatments. Most respondents (48%-58%) were willing to try available cNF treatments but were not aware of options outside of surgical removal. Regarding experimental agents, respondents favored topical, then oral medications. Most individuals (>65%) reported being "very much" or "extremely willing" to try experimental treatments, especially those with the highest cNF burden. Many respondents were not willing to tolerate side effects like nausea/vomiting (51%) and rash (46%). The greatest barriers to participation in cNF clinical trials were cost of participation and need to take time off work. CONCLUSIONS: Most adults with NF1 are willing to consider experimental therapies for treatment of cNF. These data will guide the design of patient-centered clinical trials for adults with cNF.

Recommendations for Social Skills End Points for Clinical Trials in Neurofibromatosis Type 1.

OBJECTIVE: To review parent-report social skills measures to identify and recommend consensus outcomes for use in clinical trials of social deficit in children and adolescents (ages 6-18 years) with neurofibromatosis type 1 (NF1). METHODS: Searches were conducted via PubMed and ClinicalTrials.gov to identity social skills outcome measures with English language versions used in clinical trials in the past 5 years with populations with known social skills deficits, including attention-deficit/hyperactivity disorder and autism spectrum disorder (ASD). Measures were rated by the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Neurocognitive Committee on patient characteristics, use in published studies, domains assessed, availability of standard scores, psychometric properties, and feasibility to determine their appropriateness for use in NF1 clinical trials. RESULTS: Two measures were ultimately recommended by the committee: the Social Responsiveness Scale-2 (SRS-2) and the Social Skills Improvement System-Rating Scale (SSIS-RS). CONCLUSIONS: Each of the 2 measures assesses different aspects of social functioning. The SSIS-RS is appropriate for studies focused on broader social functioning; the SRS-2 is best for studies targeting problematic social behaviors associated with ASD. Researchers will need to consider the goals of their study when choosing a measure, and specific recommendations for their use are provided.

Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial.

Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1fl/fl;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to -36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement.

Cognition, ADHD Symptoms, and Functional Impairment in Children and Adolescents With Neurofibromatosis Type 1.

Objective: We examined the contribution of attention and executive cognitive processes to ADHD symptomatology in NF1, as well as the relationships between cognition and ADHD symptoms with functional outcomes. Methods: The study sample consisted of 141 children and adolescents with NF1. Children were administered neuropsychological tests that assessed attention and executive function, from which latent cognitive variables were derived. ADHD symptomatology, adaptive skills, and quality of life (QoL) were assessed using parent-rated questionnaires. Path analyses were conducted to test relationships among cognitive functioning, ADHD symptomatology, and functional outcomes. Results: Significant deficits were observed on all outcome variables. Cognitive variables did not predict ADHD symptomatology. Neither did they predict functional outcomes. However, elevated ADHD symptomatology significantly predicted functional outcomes. Conclusion: Irrespective of cognitive deficits, elevated ADHD symptoms in children with NF1 negatively impact daily functioning and emphasize the importance of interventions aimed at minimizing ADHD symptoms in NF1.

The Use of MEK Inhibitors in Neurofibromatosis Type 1-Associated Tumors and Management of Toxicities.

Early-phase clinical trials using oral inhibitors of MEK, the mitogen-activated protein kinase kinase, have demonstrated benefit for patients with neurofibromatosis type 1 (NF1)-associated tumors, particularly progressive low-grade gliomas and plexiform neurofibromas. Given this potential of MEK inhibition as an effective medical therapy, the use of targeted agents in the NF1 population is likely to increase substantially. For clinicians with limited experience prescribing MEK inhibitors, concern about managing these treatments may be a barrier to use. In this manuscript, the Clinical Care Advisory Board of the Children's Tumor Foundation reviews the published experience with MEK inhibitors in NF1 and outlines recommendations for side-effect management, as well as monitoring guidelines. These recommendations can serve as a beginning framework for NF providers seeking to provide the most effective treatments for their patients. IMPLICATIONS FOR PRACTICE: Neurofibromatosis type 1 (NF1) clinical care is on the cusp of a transformative shift. With the success of recent clinical trials using MEK inhibitors, an increasing number of NF1 patients are being treated with MEK inhibitors for both plexiform neurofibromas and low-grade gliomas. The use of MEK inhibitors is likely to increase substantially in NF1. Given these changes, the Clinical Care Advisory Board of the Children's Tumor Foundation has identified a need within the NF1 clinical community for guidance for the safe and effective use of MEK inhibitors for NF1-related tumors. This article provides a review of the published experience of MEK inhibitors in NF1 and provides recommendations for monitoring and management of side effects.

Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1.

OBJECTIVE: Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism-based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test-retest reliability of the measures and the application of data reduction techniques to improve reproducibility. METHODS: Data were analyzed from the STARS clinical trial (n = 146), a multi-center double-blind placebo-controlled phase II trial of lovastatin, conducted by the NF Clinical Trials Consortium. Intra-class correlation coefficients were generated between pre- and post-performances (16-week interval) on neuropsychological endpoints in the placebo group to determine test-retest reliabilities. Confirmatory factor analysis was used to reduce data into cognitive domains and account for measurement error. RESULTS: Test-retest reliabilities were highly variable, with most endpoints demonstrating unacceptably low reproducibility. Data reduction confirmed four distinct neuropsychological domains: executive functioning/attention, visuospatial ability, memory, and behavior. Test-retest reliabilities of latent factors improved to acceptable levels for clinical trials. Applicability and utility of our model was demonstrated by homogeneous effect sizes in the reanalyzed efficacy data. INTERPRETATION: These data demonstrate that single observed endpoints are not appropriate to determine efficacy, partly accounting for the poor test-retest reliability of cognitive outcomes in clinical trials in neurodevelopmental disorders. Recommendations to improve reproducibility are outlined to guide future trial design.

Multicenter, Prospective, Phase II and Biomarker Study of High-Dose Bevacizumab as Induction Therapy in Patients With Neurofibromatosis Type 2 and Progressive Vestibular Schwannoma.

PURPOSE: Bevacizumab treatment at 7.5 mg/kg every 3 weeks results in improved hearing in approximately 35%-40% of patients with neurofibromatosis type 2 (NF2) and progressive vestibular schwannomas (VSs). However, the optimal dose is unknown. In this multicenter phase II and biomarker study, we evaluated the efficacy and safety of high-dose bevacizumab in pediatric and adult patients with NF2 with progressive VS. PATIENTS AND METHODS: Bevacizumab was given for 6 months at 10 mg/kg every 2 weeks, followed by 18 months at 5 mg/kg every 3 weeks. The primary end point was hearing response defined by word recognition score (WRS) at 6 months. Secondary end points included toxicity, radiographic response, quality of life (QOL), and plasma biomarkers. RESULTS: Twenty-two participants with NF2 (median age, 23 years) with progressive hearing loss in the target ear (median baseline WRS, 53%) were enrolled. Nine (41%) of 22 participants achieved a hearing response at 6 months (1 of 7 children and 8 of 15 adults; P = .08). Radiographic response was seen in 7 (32%) of 22 patients with VS at 6 months (7 of 15 adults and 0 of 7 children; P = .05). Common mild to moderate adverse events included hypertension, fatigue, headache, and irregular menstruation. Improvement in NF2-related QOL and reduction in tinnitus-related distress were reported in 30% and 60% of participants, respectively. Paradoxically, high-dose bevacizumab treatment was not associated with a significant decrease in free vascular endothelial growth factor but was associated with increased carbonic anhydrase IX, hepatocyte growth factor, placental growth factor, stromal cell-derived factor 1α, and basic fibroblast growth factor concentrations in plasma. CONCLUSION: High-dose bevacizumab seems to be no more effective than standard-dose bevacizumab for treatment of patients with NF2 with hearing loss. In contrast to adults, pediatric participants did not experience tumor shrinkage. However, adult and pediatric participants reported similar improvement in QOL during induction. Novel approaches using bevacizumab should be considered for children with NF2.

Reduced higher dimensional temporal dynamism in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a common single gene disorder resulting in multi-organ involvement. In addition to physical manifestations such as characteristic pigmentary changes, nerve sheath tumors, and skeletal abnormalities, NF1 is also associated with increased rates of learning disabilities, attention deficit hyperactivity disorder, and autism spectrum disorder. While there are established NF1-related structural brain anomalies, including brain overgrowth and white matter disruptions, little is known regarding patterns of functional connectivity in NF1. Here, we sought to investigate functional network connectivity (FNC) in a well-characterized sample of NF1 participants (n = 30) vs. age- and sex-matched healthy controls (n = 30). We conducted a comprehensive investigation of both static as well as dynamic FNC and meta-state analysis, a novel approach to examine higher-dimensional temporal dynamism of whole-brain connectivity. We found that static FNC of the cognitive control domain is altered in NF1 participants. Specifically, connectivity between anterior cognitive control areas and the cerebellum is decreased, whereas connectivity within the cognitive control domain is increased in NF1 participants relative to healthy controls. These alterations are independent of IQ. Dynamic FNC analysis revealed that NF1 participants spent more time in a state characterized by whole-brain hypoconnectivity relative to healthy controls. However, connectivity strength of dynamic states did not differ between NF1 participants and healthy controls. NF1 participants exhibited also reduced higher-dimensional dynamism of whole-brain connectivity, suggesting that temporal fluctuations of FNC are reduced. Given that similar findings have been observed in individuals with schizophrenia, higher occurrence of hypoconnected dynamic states and reduced temporal dynamism may be more general indicators of global brain dysfunction and not specific to either disorder.

Neurocutaneous Disorders.

PURPOSE OF REVIEW: This article presents an up-to-date summary of the genetic etiology, diagnostic criteria, clinical features, and current management recommendations for the most common neurocutaneous disorders encountered in clinical adult and pediatric neurology practices. RECENT FINDINGS: The phakomatoses are a phenotypically and genetically diverse group of multisystem disorders that primarily affect the skin and central nervous system. A greater understanding of the genetic and biological underpinnings of numerous neurocutaneous disorders has led to better clinical characterization, more refined diagnostic criteria, and improved treatments in neurofibromatosis type 1, Legius syndrome, neurofibromatosis type 2, Noonan syndrome with multiple lentigines, tuberous sclerosis complex, Sturge-Weber syndrome, and incontinentia pigmenti. SUMMARY: Neurologists require a basic knowledge of and familiarity with a wide variety of neurocutaneous disorders because of the frequent involvement of the central and peripheral nervous systems. A simple routine skin examination can often open a broad differential diagnosis and lead to improved patient care.

Spatial working memory in neurofibromatosis 1: Altered neural activity and functional connectivity.

BACKGROUND: Neurofibromatosis Type 1 (NF1) is a genetic disorder that disrupts central nervous system development and neuronal function. Cognitively, NF1 is characterized by difficulties with executive control and visuospatial abilities. Little is known about the neural substrates underlying these deficits. The current study utilized Blood-Oxygen-Level-Dependent (BOLD) functional MRI (fMRI) to explore the neural correlates of spatial working memory (WM) deficits in patients with NF1. METHODS: BOLD images were acquired from 23 adults with NF1 (age M = 32.69; 61% male) and 25 matched healthy controls (age M = 33.08; 64% male) during an in-scanner visuo-spatial WM task. Whole brain functional and psycho-physiological interaction analyses were utilized to investigate neural activity and functional connectivity, respectively, during visuo-spatial WM performance. Participants also completed behavioral measures of spatial reasoning and verbal WM. RESULTS: Relative to healthy controls, participants with NF1 showed reduced recruitment of key components of WM circuitry, the left dorsolateral prefrontal cortex and right parietal cortex. In addition, healthy controls exhibited greater simultaneous deactivation between the posterior cingulate cortex (PCC) and temporal regions than NF1 patients. In contrast, NF1 patients showed greater PCC and bilateral parietal connectivity with visual cortices as well as between the PCC and the cerebellum. In NF1 participants, increased functional coupling of the PCC with frontal and parietal regions was associated with better spatial reasoning and WM performance, respectively; these relationships were not observed in controls. CONCLUSIONS: Dysfunctional engagement of WM circuitry, and aberrant functional connectivity of 'task-negative' regions in NF1 patients may underlie spatial WM difficulties characteristic of the disorder.

Risky Decision Making in Neurofibromatosis Type 1: An Exploratory Study.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a monogenic disorder affecting cognitive function. About one third of children with NF1 have attentional disorders, and the cognitive phenotype is characterized by impairment in prefrontally-mediated functions. Mouse models of NF1 show irregularities in GABA release and striatal dopamine metabolism. We hypothesized that youth with NF1 would show abnormal behavior and neural activity on a task of risk-taking reliant on prefrontal-striatal circuits. METHODS: Youth with NF1 (N=29) and demographically comparable healthy controls (N=22), ages 8-19, were administered a developmentally sensitive gambling task, in which they chose between low-risk gambles with a high probability of obtaining a small reward, and high-risk gambles with a low probability of obtaining a large reward. We used functional magnetic resonance imaging (fMRI) to investigate neural activity associated with risky decision making, as well as age-associated changes in these behavioral and neural processes. RESULTS: Behaviorally, youth with NF1 tended to make fewer risky decisions than controls. Neuroimaging analyses revealed significantly reduced neural activity across multiple brain regions involved in higher-order semantic processing and motivation (i.e., anterior cingulate, paracingulate, supramarginal, and angular gyri) in patients with NF1 relative to controls during the task. We also observed atypical age-associated changes in neural activity in patients with NF1, such that during risk taking, neural activity tended to decrease with age in controls, whereas it tended to increase with age in patients with NF1. CONCLUSIONS: Findings suggest that developmental trajectories of neural activity during risky decision-making may be disrupted in youth with NF1.

Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1.

OBJECTIVE: To assess the efficacy of lovastatin on visuospatial learning and attention for treating cognitive and behavioral deficits in children with neurofibromatosis type 1 (NF1). METHODS: A multicenter, international, randomized, double-blind, placebo-controlled trial was conducted between July 2009 and May 2014 as part of the NF Clinical Trials Consortium. Children with NF1 aged 8-15 years were screened for visuospatial learning or attention deficits (n = 272); 146 children demonstrated deficits at baseline and were randomly assigned to lovastatin (n = 74; 40 mg/d) or placebo (n = 70). Treatment was administered once daily for 16 weeks. Primary outcomes were total errors on the Cambridge Neuropsychological Test Automated Battery Paired Associate Learning task (visuospatial learning) and the Score subtest from the Test of Everyday Attention for Children (sustained attention). Secondary outcomes measured executive function, attention, visuospatial skills, behavior, and quality of life. Primary analyses were performed on the intention-to-treat population. RESULTS: Lovastatin had no significant effect on primary outcomes after 16 weeks of treatment: visuospatial learning (Cohen d = -0.15, 95% confidence interval -0.47 to 0.18) or sustained attention (Cohen d = 0.19, 95% confidence interval -0.14 to 0.53). Lovastatin was well tolerated, with no increase in reported adverse events compared to placebo. CONCLUSIONS: Lovastatin administered once daily for 16 weeks did not improve visuospatial learning or attention in children with NF1 and is not recommended for amelioration of cognitive deficits in this population. CLINICALTRIALSGOV IDENTIFIER: This study was registered at ClinicalTrials.gov (NCT00853580) and Australian New Zealand Clinical Trials Registry (ACTRN12607000560493). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for children with NF1, lovastatin does not improve visuospatial learning or attention deficits.

A randomized placebo-controlled lovastatin trial for neurobehavioral function in neurofibromatosis I.

OBJECTIVE: Lovastatin has been shown to reverse learning deficits in a mouse model of Neurofibromatosis Type 1 (NF1), a common monogenic disorder caused by a mutation in the Ras-MAPK pathway and associated with learning disabilities. We conducted a randomized double-blind placebo-controlled trial to assess lovastatin's effects on cognition and behavior in patients with NF1. METHOD: Forty-four NF1 patients (mean age 25.7+/-11.6 years; 64% female) were randomly assigned to 14 weeks of lovastatin (N = 23; maximum dose of 80 mg/day for adult participants and 40 mg/day for children) or placebo (N = 21). Based on findings in the mouse model, primary outcome measures were nonverbal learning and working memory. Secondary outcome measures included verbal memory, attention, and self/parent-reported behavioral problems, as well as tolerability of medication. Participants also underwent neuroimaging assessments at baseline and 14 weeks, to determine whether neural biomarkers were associated with treatment response. Linear mixed models assessed for differential treatment effects on outcome measures. RESULTS: Twelve participants dropped from the study prior to completion (8 placebo, 4 lovastatin), resulting in 32 completers (15 placebo, 17 lovastatin). Lovastatin was well-tolerated, with no serious adverse events. Differential improvement favoring lovastatin treatment was observed for one primary (working memory; effect size f (2) = 0.70, P < 0.01) and two secondary outcome measures (verbal memory, f (2) = 0.19, P = 0.02, and adult self-reported internalizing problems, f (2) = 0.26, P = 0.03). Exploratory moderator analyses revealed that higher baseline neural activity in frontal regions was associated with larger treatment effects. INTERPRETATION: These preliminary results suggest beneficial effects of lovastatin on some learning and memory functions, as well as internalizing symptoms in patients with NF1.

Resting state functional MRI reveals abnormal network connectivity in neurofibromatosis 1.

Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the neurofibromin 1 gene at locus 17q11.2. Individuals with NF1 have an increased incidence of learning disabilities, attention deficits, and autism spectrum disorders. As a single-gene disorder, NF1 represents a valuable model for understanding gene-brain-behavior relationships. While mouse models have elucidated molecular and cellular mechanisms underlying learning deficits associated with this mutation, little is known about functional brain architecture in human subjects with NF1. To address this question, we used resting state functional connectivity magnetic resonance imaging (rs-fcMRI) to elucidate the intrinsic network structure of 30 NF1 participants compared with 30 healthy demographically matched controls during an eyes-open rs-fcMRI scan. Novel statistical methods were employed to quantify differences in local connectivity (edge strength) and modularity structure, in combination with traditional global graph theory applications. Our findings suggest that individuals with NF1 have reduced anterior-posterior connectivity, weaker bilateral edges, and altered modularity clustering relative to healthy controls. Further, edge strength and modular clustering indices were correlated with IQ and internalizing symptoms. These findings suggest that Ras signaling disruption may lead to abnormal functional brain connectivity; further investigation into the functional consequences of these alterations in both humans and in animal models is warranted.