Evidence is rapidly accumulating that rare, recurrent copy number variants represent large effect risk factors for neuropsychiatric disorders. 22q11.2 deletion syndrome (22q11DS) (velocardiofacial syndrome or DiGeorge syndrome) is the most common known contiguous gene deletion syndrome and is associated with diverse neuropsychiatric disorders across the life span. One of the most intriguing aspects of the syndrome is the variability in clinical and cognitive presentation: children with 22q11DS have high prevalence of autism spectrum, attention deficit, and anxiety disorders, as well as psychotic-like features, and up to 30% of adolescents and adults develop schizophrenia-like psychosis. Recently, cases of early-onset Parkinson's disease in adults have been reported, collectively suggesting a role for disrupted dopaminergic neurotransmission in the observed neuropsychiatric phenotypes. There is also some evidence that 22q11DS-associated autism spectrum disorder and schizophrenia represent two unrelated phenotypic manifestations, consistent with a neuropsychiatric pleiotropy model. This genetic lesion thus provides a unique model for the discovery of specific genomic risk and (potentially) protective factors for neuropsychiatric disease. Here, we provide an overview of neuropsychiatric findings to date, which highlight the value of this syndrome in mapping the developmental trajectory of dimensional phenotypes that traverse multiple diagnostic categories. Potential sources of genetic variability that may contribute to the disorder's heterogeneous presentation are reviewed. Because of its known genetic etiology, animal models can readily be developed that recapitulate specific aspects of the syndrome. Future research directions involve translational models and potential for drug screenable targets in the context of this human model system.

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.

22q11.2 deletion syndrome (22q11DS) is a neurogenetic disorder associated with elevated rates of developmental neuropsychiatric disorders and impaired executive function (EF). Disrupted brain structure-function relationships may underlie EF deficits in 22q11DS. We administered the Behavior Rating Inventory of Executive Function (BRIEF) to assess real-world EF in patients with 22q11DS and matched controls (n = 86; age 6-17 years), along with cognitive measures that tap behavioral regulation and metacognition aspects of EF. Using FreeSurfer's whole-brain vertex cortical thickness pipeline, we investigated brain structure-EF relationships in patients with 22q11DS and controls. Behaviorally, patients with 22q11DS were impaired on multiple EF measures. Right orbitofrontal cortical thickness showed a differential relationship between real-world EF in patients with 22q11DS and controls. We also observed a group difference in the relationship between behavioral regulation and metacognition measures with thickness of ventral and dorsolateral prefrontal regions, respectively. Our findings suggest that executive dysfunction characteristic of 22q11DS is underscored by altered prefrontal cortical structure.

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.

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.

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.