Visual pathway function and structure in Wolfram syndrome: Patient age, variation and progression

Background/aimsTo report alterations in visual acuity and visual pathway structure over an interval of 1–3 years in a cohort of children, adolescents and young adults who have Wolfram syndrome (WFS) and to describe the range of disease severity evident in patients with WFS whose ages differed by as much as 20 years at first examination.MethodsAnnual, prospective ophthalmological examinations were performed in conjunction with retinal nerve fibre layer (RNFL) analysis. Diffusion tensor MRI-derived fractional anisotropy was used to assess the microstructural integrity of the optic radiations (OR FA).ResultsMean age of the 23 patients with WFS in the study was 13.8 years (range 5–25 years). Mean log minimum angle resolution visual acuity was 0.66 (20/91). RNFL thickness was subnormal in even the youngest patients with WFS. Average RNFL thickness in patients with WFS was 57±8 µ or ~40% thinner than that measured in normal (94±10 µ) children and adolescents (P&lt;0.01). Lower OR FA correlated with worse visual acuity (P=0.006). Subsequent examinations showed declines (P&lt;0.05) in visual acuity, RNFL thickness and OR FA at follow-up intervals of 12–36 months. However, a wide range of disease severity was evident across ages: some of the youngest patients at their first examination had deficits more severe than the oldest patients.ConclusionThe genetic mutation of WFS causes damage to both pregeniculate and postgeniculate regions of the visual pathway. The damage is progressive. The decline in visual pathway structure is accompanied by declines of visual function. Disease severity differs widely in individual patients and cannot be predicted from their age.</jats:sec

Pretreatment cognitive and neural differences between sapropterin dihydrochloride responders and non-responders with phenylketonuria

Sapropterin dihydrochloride (BH4) reduces phenylalanine (Phe) levels and improves white matter integrity in a subset of individuals with phenylketonuria (PKU) known as “responders.” Although prior research has identified biochemical and genotypic differences between BH4 responders and non-responders, cognitive and neural differences remain largely unexplored. To this end, we compared intelligence and white matter integrity prior to treatment with BH4 in 13 subsequent BH4 responders with PKU, 16 subsequent BH4 non-responders with PKU, and 12 healthy controls. Results indicated poorer intelligence and white matter integrity in non-responders compared to responders prior to treatment. In addition, poorer white matter integrity was associated with greater variability in Phe across the lifetime in non-responders but not in responders. These results underscore the importance of considering PKU as a multi-faceted, multi-dimensional disorder and point to the need for additional research to delineate characteristics that predict response to treatment with BH4

Cas Adaptor Proteins Coordinate Sensory Axon Fasciculation.

Development of complex neural circuits like the peripheral somatosensory system requires intricate mechanisms to ensure axons make proper connections. While much is known about ligand-receptor pairs required for dorsal root ganglion (DRG) axon guidance, very little is known about the cytoplasmic effectors that mediate cellular responses triggered by these guidance cues. Here we show that members of the Cas family of cytoplasmic signaling adaptors are highly phosphorylated in central projections of the DRG as they enter the spinal cord. Furthermore, we provide genetic evidence that Cas proteins regulate fasciculation of DRG sensory projections. These data establish an evolutionarily conserved requirement for Cas adaptor proteins during peripheral nervous system axon pathfinding. They also provide insight into the interplay between axonal fasciculation and adhesion to the substrate

Neuroinflammation and white matter alterations in obesity assessed by Diffusion Basis Spectrum Imaging

Human obesity is associated with low-grade chronic systemic inflammation, alterations in brain structure and function, and cognitive impairment. Rodent models of obesity show that high-calorie diets cause brain inflammation (neuroinflammation) in multiple regions, including the hippocampus, and impairments in hippocampal-dependent memory tasks. To determine if similar effects exist in humans with obesity, we applied Diffusion Basis Spectrum Imaging (DBSI) to evaluate neuroinflammation and axonal integrity. We examined diffusion-weighted magnetic resonance imaging (MRI) data in two independent cohorts of obese and non-obese individuals (Cohort 1: 25 obese/21 non-obese; Cohort 2: 18 obese/41 non-obese). We applied Tract-based Spatial Statistics (TBSS) to allow whole-brain white matter (WM) analyses and compare DBSI-derived isotropic and anisotropic diffusion measures between the obese and non-obese groups. In both cohorts, the obese group had significantly greater DBSI-derived restricted fraction (DBSI-RF; an indicator of neuroinflammation-related cellularity), and significantly lower DBSI-derived fiber fraction (DBSI-FF; an indicator of apparent axonal density) in several WM tracts (all correcte

Fibroblast growth factor receptor signaling promotes radial glial identity and interacts with Notch1 signaling in telencephalic progenitors

The Notch and fibroblast growth factor (FGF) pathways both regulate cell fate specification during mammalian neural development. We have shown previously that Notch1 activation in the murine forebrain promotes radial glial identity. This result, together with recent evidence that radial glia can be progenitors, suggested that Notch1 signaling might promote progenitor and radial glial character simultaneously. Consistent with this idea, we found that in addition to promoting radial glial character in vivo, activated Notch 1 (ActN1) increased the frequency of embryonic day 14.5 (E14.5) ganglionic eminence (GE) progenitors that grew into neurospheres in FGF2. Constitutive activation of C-promoter binding factor (CBF1), a Notch pathway effector, also increased neurosphere frequency in FGF2, suggesting that the effect of Notch1 on FGF responsiveness is mediated by CBF1. The observation that ActN1 promoted FGF responsiveness in telencephalic progenitors prompted us to examine the effect of FGF pathway activation in vivo. We focused on FGFR2 because it is expressed in radial glia in the GEs where ActN1 increases FGF2 neurosphere frequency, but not in the septum where it does not. Like ActN1, activated FGFR2 (ActFGFR2) promoted radial glial character in vivo. However, unlike ActN1, ActFGFR2 did not enhance neurosphere frequency at E14.5. Additional analysis demonstrated that, unexpectedly, neither ActFGFR2 nor ActFGFR1 could replace the need for ligand in promoting neurosphere proliferation. This study suggests that telencephalic progenitors with radial glial morphology are maintained by interactions between the Notch and FGF pathways, and that the mechanisms by which FGF signaling promotes radial glial character in vivo and progenitor proliferation in vitro can be uncoupled

Relationship between age and white matter integrity in children with phenylketonuria

Diffusion tensor imaging (DTI) has shown poorer microstructural white matter integrity in children with phenylketonuria (PKU), specifically decreases in mean diffusivity (MD), in comparison with healthy children. However, little research has been conducted to investigate the relationship between age and white matter integrity in this population. The present study examined group differences in the relationship between age and MD across a range of brain regions in 31 children with early- and continuously-treated PKU and 51 healthy control children. Relationships among MD, age, and group were explored using hierarchical linear regression and Pearson correlation. Results indicated a stronger age-related decrease in MD for children with PKU in comparison with healthy children in 4 of the 10 brain regions examined, suggesting that the trajectory of white matter development is abnormal in children with PKU. Further research using longitudinal methodology is needed to fully elucidate our understanding of white matter development in children with PKU

White matter integrity of contralesional and transcallosal tracts may predict response to upper limb task-specific training in chronic stroke

OBJECTIVE: To investigate white matter (WM) plasticity induced by intensive upper limb (UL) task specific training (TST) in chronic stroke. METHODS: Diffusion tensor imaging data and UL function measured by the Action Research Arm Test (ARAT) were collected in 30 individuals with chronic stroke prior to and after intensive TST. ANOVAs tested the effects of training on the entire sample and on the Responders [ΔARAT ≥ 5.8, N = 13] and Non-Responders [ΔARAT \u3c 5.8, N = 17] groups. Baseline fractional anisotropy (FA) values were correlated with ARATpost TST controlling for baseline ARAT and age to identify voxels predictive of response to TST. RESULTS: While ARAT scores increased following training (p \u3c 0.0001), FA changes within major WM tracts were not significant at p \u3c 0.05. In the Responder group, larger baseline FA of both contralesional (CL) and transcallosal tracts predicted larger ARAT scores post-TST. Subcortical lesions and more severe damage to transcallosal tracts were more pronounced in the Non-Responder than in the Responder group. CONCLUSIONS: The motor improvements post-TST in the Responder group may reflect the engagement of interhemispheric processes not available to the Non-Responder group. Future studies should clarify differences in the role of CL and transcallosal pathways as biomarkers of recovery in response to training for individuals with cortical and subcortical stroke. This knowledge may help to identify sources of heterogeneity in stroke recovery, which is necessary for the development of customized rehabilitation interventions

Enteric glia express proteolipid protein 1 and are a transcriptionally unique population of glia in the mammalian nervous system

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/113731/1/glia22876.pd

Adult Turner syndrome associated with chylous ascites and vascular anomalies

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66334/1/j.1399-0004.1987.tb02799.x.pd

Neuroinflammation in the amygdala is associated with recent depressive symptoms

BACKGROUND: Converging evidence suggests that elevated inflammation may contribute to depression. Yet, the link between peripheral inflammation and neuroinflammation in depression is unclear. Here, using data from the UK Biobank, we estimated associations among depression, C-reactive protein (CRP) as a measure of peripheral inflammation, and neuroinflammation as indexed by diffusion basis spectral imaging-based restricted fraction (DBSI-RF). METHODS: DBSI-RF was derived from diffusion-weighted imaging data (N = 11,512) for whole-brain gray matter (global-RF), and regions of interest in the bilateral amygdala (amygdala-RF) and hippocampus (hippocampus-RF), and CRP was estimated from blood (serum) samples. Self-reported recent depression symptoms were measured using a 4-item assessment. Linear regressions were used to estimate associations between CRP and DBSI-RFs with depression while adjusting for the following covariates: age, sex, body mass index, smoking, drinking, and medical conditions. RESULTS: Elevated CRP was associated with higher depression symptoms (β = 0.04, false discovery rate-corrected p \u3c .005) and reduced global-RF (β = -0.03, false discovery rate-corrected p \u3c .001). Higher amygdala-RF was associated with elevated depression-an effect resilient to added covariates and CRP (β = 0.02, false discovery rate-corrected p \u3c .05). Interestingly, this association was stronger in individuals with a lifetime history of depression (β = 0.07, p \u3c .005) than in those without (β = 0.03, p \u3c .05). Associations between global-RF or hippocampus-RF with depression were not significant, and no DBSI-RF indices indirectly linked CRP with depression (i.e., mediation effect). CONCLUSIONS: Peripheral inflammation and DBSI-RF neuroinflammation in the amygdala are independently associated with depression, consistent with animal studies suggesting distinct pathways of peripheral inflammation and neuroinflammation in the pathophysiology of depression and with investigations highlighting the role of the amygdala in stress-induced inflammation and depression