Impaired brain energy metabolism in the BACHD mouse model of Huntington's disease: critical role of astrocyte–neuron interactions

Huntington''s disease (HD) is caused by cytosine-adenine-guanine (CAG) repeat expansions in the huntingtin (Htt) gene. Although early energy metabolic alterations in HD are likely to contribute to later neurodegenerative processes, the cellular and molecular mechanisms responsible for these metabolic alterations are not well characterized. Using the BACHD mice that express the full-length mutant huntingtin (mHtt) protein with 97 glutamine repeats, we first demonstrated localized in vivo changes in brain glucose use reminiscent of what is observed in premanifest HD carriers. Using biochemical, molecular, and functional analyses on different primary cell culture models from BACHD mice, we observed that mHtt does not directly affect metabolic activity in a cell autonomous manner. However, coculture of neurons with astrocytes from wild-type or BACHD mice identified mutant astrocytes as a source of adverse non-cell autonomous effects on neuron energy metabolism possibly by increasing oxidative stress. These results suggest that astrocyte-to-neuron signaling is involved in early energy metabolic alterations in HD.     

SET translocation is associated with increase in caspase cleaved amyloid precursor protein in CA1 of Alzheimer and Down syndrome patients

Caspase cleaved amyloid precursor protein (APPcc) and SET are increased and mislocalized in the neuronal cytoplasm in Alzheimer Disease (AD) brains. Translocated SET to the cytoplasm can induce tau hyperphosphorylation. To elucidate the putative relationships between mislocalized APPcc and SET, we studied their level and distribution in the hippocampus of 5 controls, 3 Down syndrome and 10 Alzheimer patients. In Down syndrome and Alzheimer patients, APPcc and SET levels were increased in CA1 and the frequency of both localizations in the neuronal cytoplasm was high in CA1, and low in CA4. As the increase of APPcc is already present at early stages of AD, we overexpressed APPcc in CA1 and the dentate gyrus neurons of adult mice with a lentiviral construct. APPcc overexpression in CA1 and not in the dentate gyrus induced endogenous SET translocation and tau hyperphosphorylation. These data suggest that increase in APPcc in CA1 neurons could be an early event leading to the translocation of SET and the progression of AD through tau hyperphosphorylation.     

Awareness of risk factors for type 2 diabetes in women with current and former gestational diabetes mellitus (GDM): Implications for future primary diabetes prevention

AimsTo assess the awareness of risk factors for type 2 diabetes and lifestyle changes that can decrease such risks in women with GDM.MethodsThe study comprised responses to health questionnaires by 319 women: 31 pregnant women with current GDM (CGDM), 88 women with previous GDM (PGDM), 100 pregnant women without DM (PWDM) and 100 non-pregnant women without DM (NPWDM). The CGDM group answered the questionnaires at the initiation and 4 weeks after participating in formal education on GDM. Two types of awareness scores (AS) were established. One AS was about the risks associated with GDM (GDMR), and the other was related to the awareness of lifestyle changes that can decrease the risks of type 2 diabetes (DM2R).ResultsThe PGDM group had the highest GDMR and DM2R scores (9.55 ± 2.66) (13.2 ± 2.26) compared with the other groups (CGDM 7.48 ± 3.14, NPWDM 6.10 ± 3.17, PWDM 2.89 ± 2.48) (p < 0.05) and (NPWDM 12.05 ± 2.73, CGDM 11.29 ± 2.45, PWDM 8.27 ± 4.14) (p < 0.05). The CGDM group increased the GDMR score from 7.48 ± 3.14 to 10.54 ± 2.57 (p < 0.0001) and the DM2R score from 11.29 ± 2.45 to 14.04 ± 1.26 (p < 0.001).ConclusionsWomen had limited awareness of risk factors for type 2 diabetes and lifestyle modifications that can decrease such risk of diabetes. AS were higher in women with current and previous GDM after receiving formal education.     

Utility of Functional MRI in Pediatric Neurology

Functional MRI (fMRI), a tool increasingly used to study cognitive function, is also an important tool for understanding not only normal development in healthy children, but also abnormal development, as seen in children with epilepsy, attention-deficit/hyperactivity disorder, and autism. Since its inception almost 15 years ago, fMRI has seen an explosion in its use and applications in the adult literature. However, only recently has it found a home in pediatric neurology. New adaptations in study design and technologic advances, especially the study of resting state functional connectivity as well as the use of passive task design in sedated children, have increased the utility of functional imaging in pediatrics to help us gain understanding into the developing brain at work. This article reviews the background of fMRI in pediatrics and highlights the most recent literature and clinical applications.     

Congenital diaphragmatic hernia: new models,new ideas

An animal model for congenital diaphragmatic hernia following interference with the development of the primary lung bud by 2,4-dinitro-p-diphenylether (nitrofen) is described. It has been used for pathogenetic studies to evaluate the presence of pulmonary hypoplasia and a closing defect of the diaphragm. Functional studies revealed abnormal surfactant levels and differences in pressure/volume curves following birth and during artificial ventilation for 6 h together with a disturbed antioxidant enzyme response. This animal model opens up new ways of studying the effects of prenatal hormonal modulation (corticosteroids, thyrotrophin-releasing hormone) on lung development as a novel therapeutic modality.     

Angiolymphoid hyperplasia with eosinophilia or Kimura's disease

A rare affection of unknown etiology that is benign but frequently recurrent, Kimura's disease involves infiltration of the dermis and hypodermis usually of the face. Documented data exists describing clinical findings and results of histopathology that are analogous but are grouped under other names: angiolymphoid hyperplasia with eosinophilia, pyogenic pseudogranuloma, atypical pyogenic granuloma. A case followed up for 13 years is reported.     

A Korean kindred with autosomal dominant nocturnal frontal lobe epilepsy and mental retardation

BACKGROUND: A Korean family had distinctive clinical and neuroimaging features and carried the same genetic mutation that was found in a previously described Japanese kindred with autosomal dominant nocturnal frontal lobe epilepsy. OBJECTIVE: To describe the first Korean family with autosomal dominant nocturnal frontal lobe epilepsy. METHODS: Members of a large family, including 9 affected individuals from 3 generations, underwent a comprehensive genetic, clinical, electroencephalographic, neuropsychological, and neuroimaging evaluation. Affected members were tested for possible mutations in transmembrane regions 1 through 3 of the neuronal nicotinic acetylcholine receptor alpha4 subunit (CHRNA4) by direct sequencing and subsequent restriction analysis. RESULTS: Seizures began in childhood, presenting as nocturnal episodes of staring, confusion, shouting, perioral movements, unintelligible speech, and hand waving. Some patients had ictal or interictal epileptiform activity in the temporal and/or frontocentral areas. Neurological examination and brain magnetic resonance imaging results showed no abnormalities, except that all patients available for testing had mild to moderate mental retardation. Fluorodeoxyglucose F 18 with positron emission tomography showed mild decreased glucose uptake in the superior and middle frontal regions, more so on the left than on the right. Patient response to carbamazepine was poor. All affected members were heterozygous for the CHRNA4 Ser252Leu mutation. CONCLUSIONS: Disorders associated with mutations in the transmembrane region 2 of CHRNA4 are genetically and phenotypically heterogeneous. Distinctive features of this kindred include (1) mental retardation in all affected members available for testing, (2) abnormal brain findings on fluorodeoxyglucose F 18 with positron emission tomography, (3) poor response to carbamazepine, and (4) full penetrance.     

Alzheimer's disease patients display gender dimorphism in circulating anorectic adipokines

Among neurodegenerative diseases, Alzheimer's disease (AD) is a leading cause of death in elderly individuals. AD is characterized, among other clinical findings, by unexplained weight loss, cachexia and altered immune function. To explore whether any relationship between gender and circulating levels of several eating-controlling metabolites exist, we evaluated leptin, tumor necrosis factor (TNF)-alpha, triiodothyronine (T(3)), free (F) thyroxine (T(4)), TSH, PRL, insulin (INS), and cortisol in 15 AD-treated patients (age range 55-82 years): 9 postmenopausal females (without hormone replacement therapy) and 6 males. The results (mean +/- SEM) indicated that circulating leptin levels were significantly (p < 0.05) higher in female AD (40.34 +/- 11.1 ng/ml) than in male AD (6.07 +/- 1.39 ng/ml) patients. The difference found in circulating leptin levels was noticed regardless of BMI (26.75 +/- 1.77 and 24.55 +/- 1.93 kg/m(2), in females and males, respectively) and waist:hip ratios (0.91 +/- 0.03 and 0.94 +/- 0.02, in females and males, respectively). Moreover, serum TNF-alpha concentrations were also significantly (p < 0.02) higher in AD females (12.24 +/- 1.47 pg/ml) than in AD males (6.62 +/- 1.44 pg/ml), regardless of TNF-alpha:BMI ratios (0.50 +/- 0.09 and 0.28 +/- 0.08, in females and males, respectively; p > 0.05). Finally, no differences were observed between gender (in female and male AD patients, respectively) in circulating levels of T(3) (151.33 +/- 9.91 vs. 116 +/- 17.04 ng/dl), FT(4) (1.26 +/- 0.08 vs. 1.24 +/- 0.06 ng/dl), TSH (1.28 +/- 0.16 vs. 2.46 +/- 0.67 microIU/ml), PRL (10.53 +/- 2.47 vs. 12.61 +/- 2.37 ng/ml), INS (11.76 +/- 1.95 vs. 8.59 +/- 1.34 microIU/ml) and cortisol (15.71 +/- 1.23 vs. 12.63 +/- 1.47 microg/dl). These results indicate that our AD group of patients, with normal corticoadrenal and thyroid functions and normoprolactinemia, displayed a gender-related characteristic in the circulating levels of two very important anorectic signals, leptin and TNF-alpha, being both higher in female than in male AD patients, regardless of BMI. Our study suggests that increased circulating levels of both anorexigenic adipokines may contribute to the metabolic changes observed in AD females.