Deficits In Neurofibromatosis Type 1 Research Articles

Social Behavioral Deficits with Loss of Neurofibromin Emerge from Peripheral Chemosensory Neuron Dysfunction

Neurofibromatosis type 1 (NF1) is a neurodevelopmental disorder associated with social and communicative disabilities. The cellular and circuit mechanisms by which loss of neurofibromin 1 (Nf1) results in social deficits are unknown. Here, we identify social behavioral dysregulation with Nf1 loss in Drosophila. These deficits map to primary dysfunction of a group of peripheral sensory neurons. Nf1 regulation of Ras signaling in adult ppk23+ chemosensory cells is required for normal social behaviors in flies. Loss of Nf1 attenuates ppk23+ neuronal activity in response to pheromones, and circuit-specific manipulation of Nf1 expression or neuronal activity in ppk23+ neurons rescues social deficits. This disrupted sensory processing gives rise to persistent changes in behavior beyond the social interaction, indicating a sustained effect of an acute sensory misperception. Together our data identify a specific circuit mechanism through which Nf1 regulates social behaviors and suggest social deficits in NF1 arise from propagation of sensory misinformation.

Can the Cognitive Phenotype in Neurofibromatosis Type 1 (NF1) Be Explained by Neuroimaging? A Review.

Neurofibromatosis type 1 (NF1) is one of the most frequent monogenetic disorders. It can be associated with cognitive dysfunctions in several domains such as executive functioning, language, visual perception, motor skills, social skills, memory and/or attention. Neuroimaging is becoming more and more important for a clearer understanding of the neural basis of these deficits. In recent years, several studies have used different imaging techniques to examine structural, morphological and functional alterations in NF1 disease. They have shown that NF1 patients have specific brain characteristics such as Unidentified Bright Objects (UBOs), macrocephaly, a higher volume of subcortical structures, microstructure integrity alterations, or connectivity alterations. In this review, which focuses on the studies published after the last 2 reviews of this topic (in 2010 and 2011), we report on recent structural, morphological and functional neuroimaging studies in NF1 subjects, with special focus on those that examine the neural basis of the NF1 cognitive phenotype. Although UBOs are one of the most obvious and visible elements in brain imaging, correlation studies have failed to establish a robust and reproducible link between major cognitive deficits in NF1 and their presence, number or localization. In the same vein, the results among structural studies are not consistent. Functional magnetic resonance imaging (fMRI) studies appear to be more sensitive, especially for understanding the executive function deficit that seems to be associated with a dysfunction in the right inferior frontal areas and the middle frontal areas. Similarly, fMRI studies have found that visuospatial deficits could be associated with a dysfunction in the visual cortex and especially in the magnocellular pathway involved in the processing of low spatial frequency and high temporal frequency. Connectivity studies have shown a reduction in anterior-posterior “long-range” connectivity and a deficit in deactivation in default mode network (DMN) during cognitive tasks. In conclusion, despite the contribution of new imaging techniques and despite relative advancement, the cognitive phenotype of NF1 patients is not totally understood.

Response inhibition in Attention deficit disorder and neurofibromatosis type 1 \u2013 clinically similar, neurophysiologically different

There are large overlaps in cognitive deficits occurring in attention deficit disorder (ADD) and neurodevelopmental disorders like neurofibromatosis type 1 (NF1). This overlap is mostly based on clinical measures and not on in-depth analyses of neuronal mechanisms. However, the consideration of such neuronal underpinnings is crucial when aiming to integrate measures that can lead to a better understanding of the underlying mechanisms. Inhibitory control deficits, for example, are a hallmark in ADD, but it is unclear how far there are similar deficits in NF1. We thus compared adolescent ADD and NF1 patients to healthy controls in a Go/Nogo task using behavioural and neurophysiological measures. Clinical measures of ADD-symptoms were not different between ADD and NF1. Only patients with ADD showed increased Nogo errors and reductions in components reflecting response inhibition (i.e. Nogo-P3). Early perceptual processes (P1) were changed in ADD and NF1. Clinically, patients with ADD and NF1 thus show strong similarities. This is not the case in regard to underlying cognitive control processes. This shows that in-depth analyses of neurophysiological processes are needed to determine whether the overlap between ADD and NF1 is as strong as assumed and to develop appropriate treatment strategies.

White matter microstructure of patients with neurofibromatosis type 1 and its relation to inhibitory control

Neurofibromatosis Type 1 (NF1) is commonly associated with deficits in executive functions such as working memory and inhibitory control. A valid biomarker to describe the pathological basis of these deficits in NF1 is not available. The aim of this study was to investigate whether any abnormalities in white matter integrity of the executive function related anterior thalamic radiation (ATR), cingulate bundle (CB), and superior longitudinal fasciculus (SLF) may be regarded as a pathological basis for inhibitory control deficits in adolescents with NF1. Sixteen NF1 patients and 32 healthy controls underwent 3 T DTI MRI scanning. Whole brain-, ATR-, CB-, and SLF-white matter integrity were studied using fractional anisotropy, mean (MD), radial, and axial (DA) diffusivity. Correlation analyses between white matter metrics and inhibitory control (as measured with a computerized task) were performed. Also, verbal and performance abilities (IQ-estimates) were assessed and correlated with white matter metrics. Patients showed significant whole brain- and local microstructural pathology when compared to healthy controls in all measures. In NF1-patients, whole-brain (MD: r = .646 and DA: r = .673) and ATR- (r-range: −.405–.771), but not the CB- (r-range: −.307–.472) and SLF- (r-range: −.187–.406) white matter integrity, were correlated with inhibitory control. Verbal and performance abilities were not associated with white matter pathology. In NF1, white matter abnormalities are observed throughout the brain, but damage to the ATR seems specifically, or at least most strongly related to inhibitory control. Future studies should examine whether reduced white matter integrity in other brain regions or tracts is (more strongly) associated with different aspects of the cognitive-behavioral phenotype associated with NF1.

HCN channels are a novel therapeutic target for cognitive dysfunction in Neurofibromatosis type 1.

Cognitive impairments are a major clinical feature of the common neurogenetic disease neurofibromatosis type 1 (NF1). Previous studies have demonstrated that increased neuronal inhibition underlies the learning deficits in NF1, however, the molecular mechanism underlying this cell-type specificity has remained unknown. Here, we identify an interneuron-specific attenuation of hyperpolarization-activated cyclic nucleotide-gated (HCN) current as the cause for increased inhibition in Nf1 mutants. Mechanistically, we demonstrate that HCN1 is a novel NF1-interacting protein for which loss of NF1 results in a concomitant increase of interneuron excitability. Furthermore, the HCN channel agonist lamotrigine rescued the electrophysiological and cognitive deficits in two independent Nf1 mouse models, thereby establishing the importance of HCN channel dysfunction in NF1. Together, our results provide detailed mechanistic insights into the pathophysiology of NF1-associated cognitive defects, and identify a novel target for clinical drug development.

Perfusion single photon emission computed tomography in a mouse model of neurofibromatosis type 1: towards a biomarker of neurologic deficits.

Neurofibromatosis type 1 (NF1) is a single-gene disorder affecting neurologic function in humans. The NF1+/- mouse model with germline mutation of the NF1 gene presents with deficits in learning, attention, and motor coordination, very similar to NF1 patients. The present study performed brain perfusion single-photon emission computed tomography (SPECT) in NF1+/- mice to identify possible perfusion differences as surrogate marker for altered cerebral activity in NF1. Cerebral perfusion was measured with hexamethyl-propyleneamine oxime (HMPAO) SPECT in NF1+/- mice and their wild-type littermates longitudinally at juvenile age and at young adulthood. Histology and immunohistochemistry were performed to test for structural changes. There was increased HMPAO uptake in NF1 mice in the amygdala at juvenile age, which reduced to normal levels at young adulthood. There was no genotype effect on thalamic HMPAO uptake, which was confirmed by ex vivo measurements of F-18-fluorodeoxyglucose uptake in the thalamus. Morphologic analyses showed no major structural abnormalities. However, there was some evidence of increased density of microglial somata in the amygdala of NF1-deficient mice. In conclusion, there is evidence of increased perfusion and increased density of microglia in juvenile NF1 mice specifically in the amygdala, both of which might be associated with altered synaptic plasticity and, therefore, with cognitive deficits in NF1.

Motor deficits in neurofibromatosis type 1 mice: the role of the cerebellum

Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited disease, characterized by various neurocutaneous symptoms, cognitive impairments and problems in fine and gross motor performance. Although cognitive deficits in NF1 have been attributed to increased release of the inhibitory neurotransmitter γ-amino butyric acid (GABA) in the hippocampus, the origin of the motor deficits is unknown. Cerebellar Purkinje cells, the sole output neurons of the cerebellar cortex, are GABAergic neurons and express neurofibromin at high levels, suggesting an important role for the cerebellum in the observed motor deficits in NF1. To test this, we determined the cerebellar contribution to motor problems in Nf1(+/-) mice, a validated mouse model for NF1. Using the Rotarod, a non-specific motor performance test, we confirmed that, like NF1 patients, Nf1(+/-) mice have motor deficits. Next, to evaluate the role of the cerebellum in these deficits, mice were subjected to cerebellum-specific motor performance and learning tests. Nf1(+/-) mice showed no impairment on the Erasmus ladder, as step time and number of missteps were not different. Furthermore, when compensatory eye movements were tested, no performance deficits were found in the optokinetic reflex and vestibulo-ocular reflex in the dark (VOR) or in the light (VVOR). Finally, Nf1(+/-) mice successfully completed short- and long-term VOR adaptation paradigms, tests that both depend on cerebellar function. Thus, despite the confirmed presence of motor performance problems in Nf1(+/-) mice, we found no indication of a cerebellar component. These results, combined with recent clinical data, suggest that cerebellar function is not overtly affected in NF1 patients.

Visuospatial processing in children with neurofibromatosis type 1

Neuroimaging studies investigating the neural network of visuospatial processing have revealed a right hemisphere network of activation including inferior parietal lobe, dorsolateral prefrontal cortex, and extrastriate regions. Impaired visuospatial processing, indicated by the Judgment of Line Orientation (JLO), is commonly seen in individuals with neurofibromatosis type 1 (NF-1). Nevertheless, few studies have examined the neural activity associated with visuospatial processing in NF-1, in particular, during a JLO task. This study used functional neuroimaging to explore differences in volume of activation in predefined regions of interest between 13 individuals with NF-1 and 13 controls while performing an analogue JLO task. We hypothesized that participants with NF-1 would show anomalous right hemisphere activation and therefore would recruit regions within the left hemisphere to complete the task. Multivariate analyses of variance were used to test for differences between groups in frontal, temporal, parietal, and occipital regions. Results indicate that, as predicted, controls utilized various right hemisphere regions to complete the task, while the NF-1 group tended to recruit left hemisphere regions. These results suggest that the NF-1 group has an inefficient right hemisphere network. An additional unexpected finding was that the NF-1 group showed decreased volume of activation in primary visual cortex (BA 17). Future studies are needed to examine whether the decrease in primary visual cortex is related to a deficit in basic visual processing; findings could ultimately lead to a greater understanding of the nature of deficits in NF-1 and have implications for remediation.

Neurofibromatosis type 1: New insights into neurocognitive issues

Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder with a prevalence of approximately 1 in 3500 people. Academic difficulties and school failure are the most common reported complication of NF1 in childhood and are present in 40% to 60% of the cases. They are often the most significant cause of lifetime morbidity in this population. Recent advances in the recognition and characterization of the cognitive phenotype in NF1 patients have provided a better understanding of the neuropsychologic deficits that account for the impairments in cognitive performance and social interaction. Additionally, recent advances in the understanding of molecular and cellular mechanisms underlying the cognitive deficits in NF1, as well as developments in neuroimaging and molecular genetic techniques are starting to yield a global and integrative picture of the molecular, cellular, and brain system processes affected by this condition. This review focuses on these advances, as well as recent preclinical studies that point towards potential pharmacologic interventions for NF1 patients.

Cognitive dysfunction in NFI knock-out mice may result from altered vesicular trafficking of APP/DRD3 complex

BackgroundIt has been estimated that more than 50% of patients with Neurofibromatosis type 1 (NF1) have neurobehavioral impairments which include attention deficit/hyperactivity disorder, visual/spatial learning disabilities, and a myriad of other cognitive developmental problems. The biological mechanisms by which NF1 gene mutations lead to such cognitive deficits are not well understood, although excessive Ras signaling and increased GABA mediated inhibition have been implicated. It is proposed that the cognitive deficits in NF1 are the result of dysfunctional cellular trafficking and localization of molecules downstream of the primary gene defect.ResultsTo elucidate genes involved in the pathogenic process, gene expression analysis was performed comparing the expression profiles in various brain regions for control and Nf1+/- heterozygous mice. Gene expression analysis was performed for hippocampal samples dissected from postnatal day 10, 15, and 20 mice utilizing the Affymetrix Mouse Genome chip (Murine 430 2.0). Analysis of expression profiles between Nf1+/-and wild-type animals was focused on the hippocampus because of previous studies demonstrating alterations in hippocampal LTP in the Nf1+/- mice, and the region's importance in visual/spatial learning. Network analysis identified links between neurofibromin and kinesin genes, which were down regulated in the Nf1+/- mice at postnatal days 15 and 20.ConclusionThrough this analysis, it is proposed that neurofibromin forms a binding complex with amyloid precursor protein (APP) and through filamin proteins interacts with a dopamine receptor (Drd3). Though the effects of these interactions are not yet known, this information may provide novel ideas about the pathogenesis of cognitive defects in NF1 and may facilitate the development of novel targeted therapeutic interventions.

Language and reading deficits associated with Neurofibromatosis Type 1: Evidence for a not‐so‐nonverbal learning disability

Neurofibromatosis Type 1 (NF1) is a common genetic disorder for which nonverbal learning disability (NLD) is frequently reported. In this study, verbal and nonverbal skills among NF1 school‐age children and their unaffected siblings were assessed. Results of matched‐paired comparisons were consistent with previous reports of visuospatial deficits in NF1. The results also indicate verbal weaknesses in NF1, including deficits in vocabulary and phonological awareness, and a positive correlation—among the NF1 group only—between performance on the Judgment of Line Orientation test (Benton, 1983) and several verbal tasks. The verbal deficits indicate that NLD may not be an accurate construct with which to describe the NF1 phenotype. Children with NF1 manifested skills deficits in mathematics and reading even though the incidence of discrepancy‐based reading disability (RD) or mathematics disability (MD) did not differ across groups. The NF1 profile illustrates the conceptual difficulty underlying discrepancy‐ba...