Neuronal intranuclear inclusions are found in the brains of patients with Huntington's disease and form from the polyglutamine-expanded N-terminal region of mutant huntingtin. To explore the properties of inclusions and their involvement in cell death, mouse clonal striatal cells were transiently transfected with truncated and full-length human wild-type and mutant huntingtin cDNAs. Both normal and mutant proteins localized in the cytoplasm, and infrequently, in dispersed and perinuclear vacuoles. Only mutant huntingtin formed nuclear and cytoplasmic inclusions, which increased with polyglutamine expansion and with time after transfection. Nuclear inclusions contained primarily cleaved N-terminal products, whereas cytoplasmic inclusions contained cleaved and larger intact proteins. Cells with wild-type or mutant protein had distinct apoptotic features (membrane blebbing, shrinkage, cellular fragmentation), but those with mutant huntingtin generated the most cell fragments (apoptotic bodies). The caspase inhibitor Z-VAD-FMK significantly increased cell survival but did not diminish nuclear and cytoplasmic inclusions. In contrast, Z-DEVD-FMK significantly reduced nuclear and cytoplasmic inclusions but did not increase survival. A series of N-terminal products was formed from truncated normal and mutant proteins and from full-length mutant huntingtin but not from full-length wild-type huntingtin. One prominent N-terminal product was blocked by Z-VAD-FMK. In summary, the formation of inclusions in clonal striatal cells corresponds to that seen in the HD brain and is separable from events that regulate cell death. N-terminal cleavage may be linked to mutant huntingtin's role in cell death.

Neurons in Huntington's disease exhibit selective morphological and subcellular alterations in the striatum and cortex. The link between these neuronal changes and behavioral abnormalities is unclear. We investigated relationships between essential neuronal changes that predict motor impairment and possible involvement of the corticostriatal pathway in developing behavioral phenotypes. We therefore generated heterozygote mice expressing the N-terminal one-third of huntingtin with normal (CT18) or expanded (HD46, HD100) glutamine repeats. The HD mice exhibited motor deficits between 3 and 10 months. The age of onset depended on an expanded polyglutamine length; phenotype severity correlated with increasing age. Neuronal changes in the striatum (nuclear inclusions) preceded the onset of phenotype, whereas cortical changes, especially the accumulation of huntingtin in the nucleus and cytoplasm and the appearance of dysmorphic dendrites, predicted the onset and severity of behavioral deficits. Striatal neurons in the HD mice displayed altered responses to cortical stimulation and to activation by the excitotoxic agent NMDA. Application of NMDA increased intracellular Ca(2+) levels in HD100 neurons compared with wild-type neurons. Results suggest that motor deficits in Huntington's disease arise from cumulative morphological and physiological changes in neurons that impair corticostriatal circuitry.

In the current study, divalproex sodium extended-release did not differentiate from placebo in the prophylactic treatment of migraine headaches but was generally well-tolerated in adolescents aged 12 to 17 years.

Model-based statistical approaches were used to compare the ability of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), cerebrospinal fluid (CSF), fluorodeoxyglucose positron emission tomography and volumetric magnetic resonance imaging (MRI) markers to predict 12-month progression from mild cognitive impairment (MCI) to Alzheimer disease (AD). Using the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set, properties of the 11-item ADAS-cog (ADAS.11), the 13-item ADAS-cog (ADAS.All) and novel composite scores were compared, using weighting schemes derived from the Random Forests (RF) tree-based multivariate model. Weighting subscores using the RF model of ADAS.All enhanced discrimination between elderly controls, MCI and AD patients. The ability of the RF-weighted ADAS-cog composite and individual scores, along with neuroimaging or biochemical biomarkers to predict MCI to AD conversion over 12 months was also assessed. Although originally optimized to discriminate across diagnostic categories, the ADAS. All, weighted according to the RF model, did nearly as well or better than individual or composite baseline neuroimaging or CSF biomarkers in prediction of 12-month conversion from MCI to AD. These suggest that a modified subscore weighting scheme applied to the 13-item ADAS-cog is comparable to imaging or CSF markers in prediction of conversion from MCI to AD at 12 months.