A functional 'low road' subcortical fear processing pathway in adults with autism spectrum disorder

Thesis (M.A.)--Boston UniversityEmotion processing has been reported to occur via a fast ‘low road’ pathway using coarse visual information and projecting from the superior colliculus to the amygdala via the pulvinar. Abnormal development in such an important pathway has been suggested to be related to reduced social orienting in children with autism spectrum disorders (ASD). It may also be a contributor in the aberrant development of cortical circuits involved in face processing. Our objective was to further investigate previous supporting evidence for an abnormal subcortical pathway in adults with ASD during fearful face processing by monitoring differences in spatial frequency-dependencies. Participants included 17 individuals with ASD and 20 typically developing controls. The ASD group met diagnostic criteria on the Autism Diagnostic Interview – Revised (ADI- R), Autism Diagnostic Observation Schedule (ADOS), and Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV). No facial feature preference was identified for gaze fixation for either group. The ASD group was attentive and accurate to a gender discrimination task though statistically less so than typically developing (TD) controls. Both the ASD and control groups showed significant activation in the right fusiform face area (FFA) and left occipital face area (OFA). The control group exhibited additional significant responses in the bilateral amygdala, pulvinar, and lateral geniculate nucleus (LGN), while the ASD group exhibited significant responses in the left pulvinar and left LGN. In group comparisons, the controls showed significantly greater activation in the bilateral amygdala, OFA, and right LGN. No brain region showed significantly greater activation in the ASD group compared to TD controls. Thus, basic face identification mechanisms appear to be functional in ASD with possible functional abnormalities in face categorizing mechanisms and early visual processing systems. While individuals with ASD failed to engage the amygdala and had variable activation in the pulvinar, these results do not implicate a dysfunctional 'low road' pathway. In fact, relative to neutral stimuli, the amygdala showed similar activation patterns for low-spatial frequency fearful images in both groups. This finding directs focus to other possible areas of neural abnormalities which may contribute to early-emerging deficits in social orienting and attention, the presumed antecedents to abnormalities in social cognition and face-selective cortical specialization

Spinal cord injury and neurogenic lower urinary tract dysfunction: what do we know and where are we going?

One of the well reported but difficult to manage symptoms of spinal cord injury (SCI) is neurogenic lower urinary tract dysfunction (NLUTD). The type of NLUTD is variable based on location and extent of injury. SCI affects more males and NLUTD is especially debilitating for men with incomplete injury. This review summarizes the anatomical basis of NLUTD in SCI and discusses current diagnostic and management strategies that are being utilized clinically. The last two sections address new innovations and emerging discoveries with the goal of increasing scientific interest in improving treatment options for people with SCI. Areas warranting further investigation are pinpointed to address current gaps in knowledge and/or appropriate technology

Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

Chronic Traumatic Encephalopathy: Update on Current Clinical Diagnosis and Management

Chronic traumatic encephalopathy is a disease afflicting individuals exposed to repetitive neurotrauma. Unfortunately, diagnosis is made by postmortem pathologic analysis, and treatment options are primarily symptomatic. In this clinical update, we review clinical and pathologic diagnostic criteria and recommended symptomatic treatments. We also review animal models and recent discoveries from pre-clinical studies. Furthermore, we highlight the recent advances in diagnosis using diffusor tensor imaging, functional magnetic resonance imaging, positron emission tomography, and the fluid biomarkers t-tau, sTREM2, CCL11, NFL, and GFAP. We also provide an update on emerging pharmaceutical treatments, including immunotherapies and those that target tau acetylation, tau phosphorylation, and inflammation. Lastly, we highlight the current literature gaps and guide future directions to further improve clinical diagnosis and management of patients suffering from this condition

Cerebral amyloid angiopathy: early presentation in a patient with prior neurosurgical interventions: Case report

Background: Cerebral amyloid angiopathy (CAA) has classically been described as a disease of the elderly. Genetic predisposition has been linked to the APOE e3/e3 allele. Evidence suggests that brain insult in the form of injury, prior surgical intervention, or radiation can exacerbate the clearance of toxic proteins in patients susceptible to CAA. Case: We describe a unique case of CAA in a 30-year-old male who had prior surgical interventions for spina bifida, Chiari malformation, and hydrocephalus as a child. Conclusions: The case is used to teach important components regarding diagnosis, clinical suspicion, and highlight the need for further investigation regarding the emerging role of the glymphatic system and its role in clinical pathology

The Cognitive and Behavioral Phenotype of the 16p11.2 Deletion in a Clinically Ascertained Population

BackgroundDeletion of the recurrent ~600 kb BP4-BP5 chromosomal region 16p11.2 has been associated with a wide range of neurodevelopmental outcomes.MethodsTo clarify the phenotype of 16p11.2 deletion, we examined the psychiatric and developmental presentation of predominantly clinically referred individuals, with a particular emphasis on broader autism phenotype characteristics in individuals with recurrent ~600 kb chromosome 16p11.2 deletions. Using an extensive standardized assessment battery across three clinical sites, 85 individuals with the 16p11.2 deletion and 153 familial control subjects were evaluated for symptom presentation and clinical diagnosis.ResultsIndividuals with the 16p11.2 deletion presented with a high frequency of psychiatric and developmental disorders (>90%). The most commonly diagnosed conditions were developmental coordination disorder, phonologic processing disorder, expressive and receptive language disorders (71% of individuals >3 years old with a speech and language-related disorder), and autism spectrum disorder. Individuals with the 16p11.2 deletion not meeting diagnostic criteria for autism spectrum disorder had a significantly higher prevalence of autism-related characteristics compared with the familial noncarrier control group. Individuals with the 16p11.2 deletion had a range of intellectual ability, but IQ scores were 26 points lower than noncarrier family members on average.ConclusionsClinically referred individuals with the 16p11.2 deletion have high rates of psychiatric and developmental disorders and provide a genetically well-defined group to study the emergence of developmental difficulties, particularly associated with the broader autism phenotype

Inosine to Increase Serum and Cerebrospinal Fluid Urate in Parkinson Disease

Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD). To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial. The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled. Participants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month. The prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid. RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability. Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD. clinicaltrials.gov Identifier: NCT00833690

Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study

International audienceBackground: 16p11.2 breakpoint 4 to 5 copy number variants (CNVs) increase the risk for developing autism spectrum disorder, schizophrenia, and language and cognitive impairment. In this multisite study, we aimed to quantify the effect of 16p11.2 CNVs on brain structure.Methods: Using voxel- and surface-based brain morphometric methods, we analyzed structural magnetic resonance imaging collected at seven sites from 78 individuals with a deletion, 71 individuals with a duplication, and 212 individuals without a CNV.Results: Beyond the 16p11.2-related mirror effect on global brain morphometry, we observe regional mirror differences in the insula (deletion > control > duplication). Other regions are preferentially affected by either the deletion or the duplication: the calcarine cortex and transverse temporal gyrus (deletion > control; Cohen's d > 1), the superior and middle temporal gyri (deletion duplication; -0.5 > Cohen's d > -1). Measures of cognition, language, and social responsiveness and the presence of psychiatric diagnoses do not influence these results.Conclusions: The global and regional effects on brain morphometry due to 16p11.2 CNVs generalize across site, computational method, age, and sex. Effect sizes on neuroimaging and cognitive traits are comparable. Findings partially overlap with results of meta-analyses performed across psychiatric disorders. However, the lack of correlation between morphometric and clinical measures suggests that CNV-associated brain changes contribute to clinical manifestations but require additional factors for the development of the disorder. These findings highlight the power of genetic risk factors as a complement to studying groups defined by behavioral criteria