Constance M. Moore

Familial Adenomatous Polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene presenting with numerous colorectal adenomatous polyps and a near 100% risk of colon cancer. Preliminary research findings from our group indicate that FAP patients experience significant deficits across many cognitive domains. In the current study, fMRI brain metrics in a FAP population and matched controls were used to further the mechanistic understanding of reported cognitive deficits. This research identified and characterized any possible differences in resting brain networks and associations between neural network changes and cognition from 34 participants (18 FAP patients, 16 healthy controls). Functional connectivity analysis was performed using FSL with independent component analysis (ICA) to identify functional networks. Significant differences between cases and controls were observed in 8 well-established resting state networks. With the addition of an aggregate cognitive measure as a covariate, these differences were virtually non-existent, indicating a strong correlation between cognition and brain activity at the network level. The data indicate robust and pervasive effects on functional neural network activity among FAP patients and these effects are likely involved in cognitive deficits associated with this disease.

Canavan disease (CD) is a debilitating and lethal leukodystrophy caused by mutations in the aspartoacylase ( ASPA ) gene and the resulting defect in N -acetylaspartate (NAA) metabolism in the CNS and peripheral tissues. Recombinant adeno-associated virus (rAAV) has the ability to cross the blood-brain barrier and widely transduce the CNS. We developed a rAAV-based and optimized gene replacement therapy, which achieves early, complete, and sustained rescue of the lethal disease phenotype in CD mice. Our treatment results in a super-mouse phenotype, increasing motor performance of treated CD mice beyond that of WT control mice. We demonstrate that this rescue is oligodendrocyte independent, and that gene correction in astrocytes is sufficient, suggesting that the establishment of an astrocyte-based alternative metabolic sink for NAA is a key mechanism for efficacious disease rescue and the super-mouse phenotype. Importantly, the use of clinically translatable high-field imaging tools enables the noninvasive monitoring and prediction of therapeutic outcomes for CD and might enable further investigation of NAA-related cognitive function.

Objective: We aimed to determine the effect of an open-label 8 week Vitamin D ₃ supplementation on manic symptoms, anterior cingulate cortex (ACC) glutamate, and γ-aminobutyric acid (GABA) in youth exhibiting symptoms of mania; that is, patients with bipolar spectrum disorders (BSD). We hypothesized that an 8 week Vitamin D ₃ supplementation would improve symptoms of mania, decrease ACC glutamate, and increase ACC GABA in BSD patients. Single time point metabolite levels were also evaluated in typically developing children (TD). Methods: The BSD group included patients not only diagnosed with BD but also those exhibiting bipolar symptomology, including BD not otherwise specified (BD-NOS) and subthreshold mood ratings (Young Mania Rating Scale [YMRS] ≥8 and Clinical Global Impressions - Severity [CGI-S] ≥3). Inclusion criteria were: male or female participants, 6–17 years old. Sixteen youth with BSD exhibiting manic symptoms and 19 TD were included. BSD patients were asked to a take daily dose (2000 IU) of Vitamin D ₃ (for 8 weeks) as a supplement. Neuroimaging data were acquired in both groups at baseline, and also for the BSD group at the end of 8 week Vitamin D ₃ supplementation. Results: Baseline ACC GABA/creatine (Cr) was lower in BSD than in TD ( F [1,31]=8.91, p =0.007). Following an 8 week Vitamin D ₃ supplementation, in BSD patients, there was a significant decrease in YMRS scores ( t =−3.66, p =0.002, df =15) and Children's Depression Rating Scale (CDRS) scores ( t =−2.93, p =0.01, df =15); and a significant increase in ACC GABA ( t =3.18, p =0.007, df =14). Conclusions: Following an 8 week open label trial with Vitamin D ₃ , BSD patients exhibited improvement in their mood symptoms in conjunction with their brain neurochemistry.

Sports-related concussions are currently diagnosed through multi-domain assessment by a medical professional and may utilize neurocognitive testing as an aid. However, these tests have only been able to detect differences in the days to week post-concussion. Here, we investigate a measure of brain function, namely resting state functional connectivity, which may detect residual brain differences in the weeks to months after concussion. Twenty-one student athletes (9 concussed within 6 months of enrollment; 12 non-concussed; between ages 18 and 22 years) were recruited for this study. All participants completed the Wisconsin Card Sorting Task and the Color-Word Interference Test. Neuroimaging data, specifically resting state functional Magnetic Resonance Imaging data, were acquired to examine resting state functional connectivity. Two sample t-tests were used to compare the neurocognitive scores and resting state functional connectivity patterns among concussed and non-concussed participants. Correlations between neurocognitive scores and resting state functional connectivity measures were also determined across all subjects. There were no significant differences in neurocognitive performance between concussed and non-concussed groups. Concussed subjects had significantly increased connections between areas of the brain that underlie executive function. Across all subjects, better neurocognitive performance corresponded to stronger brain connectivity. Even at rest, brains of concussed athletes may have to ‘work harder’ than their healthy peers to achieve similar neurocognitive results. Resting state brain connectivity may be able to detect prolonged brain differences in concussed athletes in a more quantitative manner than neurocognitive test scores.

Research exploring Bipolar Disorder (BD) phenotypes and mitochondrial dysfunction, particularly in younger subjects, has been insufficient to date. Previous studies have found abnormal cerebral pH levels in adults with BD, which may be directly linked to abnormal mitochondrial activity. To date no such studies have been reported in children with BD. Phosphorus Magnetic Resonance Spectroscopy (³¹P MRS) was used to determine pH, phopshocreatine (PCr) and inorganic phosphate (Pi) levels in 8 subjects with BD and 8 healthy comparison subjects (HCS) ages 11 to 20 years old. There was no significant difference in pH between the patients and HCS. However, frontal pH values for patients with BD increased with age, contrary to studies of HCS and the pH values in the frontal lobe correlated negatively with the YMRS values. Global Pi was significantly lower in subjects with BD compared with HCS. There were no significant differences in PCr between the groups. Global PCr-to-Pi ratio (PCr/Pi) was significantly higher in subjects with BD compared with HCS. The change in Pi levels for the patients with BD coupled with the no difference in PCr levels, suggest an altered mitochondrial phosphorylation. However, our findings require further investigation of the underlying mechanisms with the notion that a mitochondrial dysfunction may manifest itself differently in children than that in adults. Further investigations with larger patient populations are necessary to draw further conclusions.

Objective Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric disorder affecting 5% of children. Methylphenidate (MPH) is a common medication for ADHD. Studies examining MPH’s effect on pediatric ADHD patients’ brain function using functional magnetic resonance imaging (fMRI) have not been compiled. The goals of this systematic review were to determine (1) which areas of the brain in pediatric ADHD patients are modulated by a single dose of MPH, (2) whether areas modulated by MPH differ by task type performed during fMRI data acquisition, and (3) whether changes in brain activation due to MPH relate to clinical improvements in ADHD-related symptoms. Methods We searched the electronic databases PubMed and PsycINFO (1967–2011) using the following terms: ADHD AND (methylphenidate OR MPH OR ritalin) AND (neuroimaging OR MRI OR fMRI OR BOLD OR event related), and identified 200 abstracts, 9 of which were reviewed based on predefined criteria. Results In ADHD patients the middle and inferior frontal gyri, basal ganglia, and cerebellum were most often affected by MPH. The middle and inferior frontal gyri were frequently affected by MPH during inhibitory control tasks. Correlation between brain regions and clinical improvement was not possible due to the lack of symptom improvement measures within the included studies. Conclusions Throughout nine task-based fMRI studies investigating MPH’s effect on the brains of pediatric patients with ADHD, MPH resulted in increased activation within frontal lobes, basal ganglia, and cerebellum. In most cases, this increase “normalized” activation of at least some brain areas to that seen in typically developing children.