Macroscopic brain architecture changes and white matter pathology in acromegaly: a clinicoradiological study

Although long-term exposure of the brain to increased GH/IGF-1 likely influences cerebral functions, no in vivo studies have been directed towards changes of the brain structure in acromegaly. Here, we used high resolution magnetic resonance images to compare volumes of gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) of forty-four patients with acromegaly to an age and gender matched, healthy control group (n = 44). In addition, white matter lesions (WMLs) were quantified and graded. Patients exhibited larger GM (+3.7% compared with controls, P = 0.018) and WM volumes (+5.1%, P = 0.035) at the expense of CSF. Differences of WML counts between patients and controls were subtle, however, showing more patients in the 21–40 lesions category (P = 0.044). In conclusion, this MRI study provides first evidence that acromegalic patients exhibit disturbances of the macroscopic brain tissue architecture. Furthermore, acromegalic patients may have an increased risk of neurovascular pathology, likely due to secondary metabolic and vascular comorbidities

Growth hormone responsive neural precursor cells reside within the adult mammalian brain

The detection of growth hormone (GH) and its receptor in germinal regions of the mammalian brain prompted our investigation of GH and its role in the regulation of endogenous neural precursor cell activity. Here we report that the addition of exogenous GH significantly increased the expansion rate in long-term neurosphere cultures derived from wild-type mice, while neurospheres derived from GH null mice exhibited a reduced expansion rate. We also detected a doubling in the frequency of large (i.e. stem cell-derived) colonies for up to 120 days following a 7-day intracerebroventricular infusion of GH suggesting the activation of endogenous stem cells. Moreover, gamma irradiation induced the ablation of normally quiescent stem cells in GH-infused mice, resulting in a decline in olfactory bulb neurogenesis. These results suggest that GH activates populations of resident stem and progenitor cells, and therefore may represent a novel therapeutic target for age-related neurodegeneration and associated cognitive decline

Combined linkage and linkage disequilibrium analysis of a motor speech phenotype within families ascertained for autism risk loci

Using behavioral and genetic information from the Autism Genetics Resource Exchange (AGRE) data set we developed phenotypes and investigated linkage and association for individuals with and without Autism Spectrum Disorders (ASD) who exhibit expressive language behaviors consistent with a motor speech disorder. Speech and language variables from Autism Diagnostic Interview-Revised (ADI-R) were used to develop a motor speech phenotype associated with non-verbal or unintelligible verbal behaviors (NVMSD:ALL) and a related phenotype restricted to individuals without significant comprehension difficulties (NVMSD:C). Using Affymetrix 5.0 data, the PPL framework was employed to assess the strength of evidence for or against trait-marker linkage and linkage disequilibrium (LD) across the genome. Ingenuity Pathway Analysis (IPA) was then utilized to identify potential genes for further investigation. We identified several linkage peaks based on two related language-speech phenotypes consistent with a potential motor speech disorder: chromosomes 1q24.2, 3q25.31, 4q22.3, 5p12, 5q33.1, 17p12, 17q11.2, and 17q22 for NVMSD:ALL and 4p15.2 and 21q22.2 for NVMSD:C. While no compelling evidence of association was obtained under those peaks, we identified several potential genes of interest using IPA. Conclusion: Several linkage peaks were identified based on two motor speech phenotypes. In the absence of evidence of association under these peaks, we suggest genes for further investigation based on their biological functions. Given that autism spectrum disorders are complex with a wide range of behaviors and a large number of underlying genes, these speech phenotypes may belong to a group of several that should be considered when developing narrow, well-defined, phenotypes in the attempt to reduce genetic heterogeneity

Impaired basal and running-induced hippocampal neurogenesis coincides with reduced Akt signaling in adult R6/1 HD mice

Huntington's disease (HD) is a fatal neurodegenerative disorder affecting a range of cellular and molecular functions in the brain. Deficits in adult hippocampal neurogenesis (AHN) have been documented in the R6/1 mouse model of HD. Here we examined basal and running-induced neuronal precursor proliferation in adult female and male R6/1 HD mice. We further tested whether sequential delivery of voluntary running followed by environmental enrichment could synergistically enhance functional AHN in female R6/1 HD mice. R6/1 HD mice engaged in significantly reduced levels of voluntary running, with males showing a more severe deficit. Basal neural precursor proliferation in the hippocampal sub-granular zone remained unchanged between female and male R6/1 HD mice and neither sex significantly responded to running-induced proliferation. While discrete provision of running wheels and enriched environments doubled AHN in adult female R6/1 HD mice it did not reflect the significant 3-fold increase in female wildtypes. Nevertheless, triple-label c-Fos/BrdU/NeuN immunofluorescence and confocal microscopy provided evidence that the doubling of AHN in female R6/1 HD mice was functional. Intrinsic cellular dysfunction mediated by protein aggregates containing mutant huntingtin (mHtt) did not appear to coincide with AHN deficits. In the hippocampus of female R6/1 HD mice, proliferating precursors and 6 week old adult-generated neurons were devoid of mHtt immuno-reactive aggregates, as were endothelial, microglial and astroglial cells populating the neurogenic niche. Serum transforming growth factor-β concentrations remained unaltered in female R6/1 HD mice as did the hippocampal levels of proliferating microglia and glial fibrillarly acidic protein expression. Examining the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis showed no change in base-line serum GH between genotypes. However, despite a reduced distance, acute running increases serum GH in both female wildtype and R6/1 HD mice. Serum IGF-1 levels were increased in female R6/1 HD mice compared to wildtypes during daytime inactive period, while hippocampal levels of the IGF-1 receptor remained unchanged. Running induced Akt phosphorylation in the hippocampus of female wildtype mice, which was not reflected in R6/1 HD mice. Total Akt levels were decreased in the hippocampus of both control and running R6/1 HD mice. Our results show adult-generated hippocampal neurons in female R6/1 HD mice express c-Fos and that running and Akt signaling deficits may mediate reduced basal and running-induced AHN levels

Hippocampal Neurogenesis, Cognitive Deficits and Affective Disorder in Huntington's Disease

Huntington's disease (HD) is a neurodegenerative disorder caused by a tandem repeat expansion encoding a polyglutamine tract in the huntingtin protein. HD involves progressive psychiatric, cognitive, and motor symptoms, the selective pathogenesis of which remains to be mechanistically elucidated. There are a range of different brain regions, including the cerebral cortex and striatum, known to be affected in HD, with evidence for hippocampal dysfunction accumulating in recent years. In this review we will focus on hippocampal abnormalities, in particular, deficits of adult neurogenesis. We will discuss potential molecular mechanisms mediating disrupted hippocampal neurogenesis, and how this deficit of cellular plasticity may in turn contribute to specific cognitive and affective symptoms that are prominent in HD. The generation of transgenic animal models of HD has greatly facilitated our understanding of disease mechanisms at molecular, cellular, and systems levels. Transgenic HD mice have been found to show progressive behavioral changes, including affective, cognitive, and motor abnormalities. The discovery, in multiple transgenic lines of HD mice, that adult hippocampal neurogenesis and synaptic plasticity is disrupted, may help explain specific aspects of cognitive and affective dysfunction. Furthermore, these mouse models have provided insight into potential molecular mediators of adult neurogenesis deficits, such as disrupted serotonergic and neurotrophin signaling. Finally, a number of environmental and pharmacological interventions which are known to enhance adult hippocampal neurogenesis have been found to have beneficial affective and cognitive effects in mouse models, suggesting common molecular targets which may have therapeutic utility for HD and related diseases