Reliability and factor structure of the Short Problem Behaviors Assessment for Huntington's disease (PBA-s) in the TRACK-HD and REGISTRY studies.

The authors report the inter-rater reliability and factor structure of the Short Problem Behaviors Assessment (PBA-s), a semistructured interview to measure severity and frequency of behavioral problems in Huntington's disease. Video recordings of 410 PBA-s interviews were rescored by an independent rater, and Cohen's kappa calculated to assess inter-rater reliability. The mean kappa was 0.74 for severity and 0.76 for frequency scores, whereas weighted kappa (allowing scores to differ by 1 point) was 0.94 for severity and 0.92 for frequency scores. The results of factor analysis were consistent with previous studies using other measures. The authors conclude that the PBA-s is a reliable measure.

Evaluation of longitudinal 12 and 24 month cognitive outcomes in premanifest and early Huntington's disease.

BACKGROUND: Deterioration of cognitive functioning is a debilitating symptom in many neurodegenerative diseases, such as Huntington's disease (HD). To date, there are no effective treatments for the cognitive problems associated with HD. Cognitive assessment outcomes will have a central role in the efforts to develop treatments to delay onset or slow the progression of the disease. The TRACK-HD study was designed to build a rational basis for the selection of cognitive outcomes for HD clinical trials. METHODS: There were a total of 349 participants, including controls (n=116), premanifest HD (n=117) and early HD (n=116). A standardised cognitive assessment battery (including nine cognitive tests comprising 12 outcome measures) was administered at baseline, and at 12 and 24 months, and consisted of a combination of paper and pencil and computerised tasks selected to be sensitive to cortical-striatal damage or HD. Each cognitive outcome was analysed separately using a generalised least squares regression model. Results are expressed as effect sizes to permit comparisons between tasks. RESULTS: 10 of the 12 cognitive outcomes showed evidence of deterioration in the early HD group, relative to controls, over 24 months, with greatest sensitivity in Symbol Digit, Circle Tracing direct and indirect, and Stroop word reading. In contrast, there was very little evidence of deterioration in the premanifest HD group relative to controls. CONCLUSIONS: The findings describe tests that are sensitive to longitudinal cognitive change in HD and elucidate important considerations for selecting cognitive outcomes for clinical trials of compounds aimed at ameliorating cognitive decline in HD.

Prevention of depressive behaviour in the YAC128 mouse model of Huntington disease by mutation at residue 586 of huntingtin.

Huntington disease is a neurodegenerative disorder caused by an expanded CAG repeat in the Huntington disease gene. The symptomatic phase of the disease is defined by the onset of motor symptoms. However, psychiatric disturbances, including depression, are common features of Huntington disease and recent studies indicate that depression can occur long before the manifestation of motor symptoms. The aetiology of depression in Huntington disease is not fully understood and psychosocial factors such as the knowledge of carrying a mutation for an incurable disease or adverse social circumstances may contribute to its presentation. Due to the difficulties in discriminating between social and biological factors as contributors to depression in clinical Huntington disease, we chose to assess whether a model for Huntington disease not subject to environmental stressors, namely the YAC mouse model of Huntington disease, displays a depressive phenotype. Indeed, the YAC transgenic mice recapitulate the early depressive phenotype of Huntington disease as assessed by the Porsolt forced swim test as well as the sucrose intake test as a measure of anhedonia. The YAC model mirrors clinical Huntington disease in that there were no effects of CAG repeat length or disease duration on the depressive phenotype. The depressive phenotype was completely rescued in YAC transgenic animals expressing a variant of mutant huntingtin that is resistant to cleavage at amino acid 586 suggesting that therapies aimed towards inhibition of huntingtin cleavage are also likely to have beneficial effects on this aspect of the disease. In conclusion, our study provides strong support for a primary neurobiological basis for depression in Huntington disease.

The safety and performance of a maxillary sinus ostium self-dilation device: a pilot study.

BACKGROUND: Balloon dilation is now commonly used to open sinus ostia while preserving mucosa and minimizing trauma. A new maxillary sinus ostium (MSO) self-dilation device that functions on the principle of osmosis, absorbing a small amount of fluid from the surrounding tissues, can be placed into the MSO under endoscopic visualization and slowly enlarge its outer diameter. The slower dilation may further minimize tissue damage and scarring compared to the currently available balloon dilation systems. The MSO self-dilating expansion device has never been studied before in clinical trials; the purpose of this pilot study is to determine the safety and performance of the device in human subjects. METHODS: Twelve chronic rhinosinusitis (CRS) patients presenting with maxillary sinus inflammation requiring FESS were enrolled. The device was inserted into the MSO at the start of surgery and removed after 60 minutes. Endoscopic evaluation for patency was performed immediately after removal, and at 1 week, 1 month, and 3 months. Adverse events were recorded intraoperatively and at each subsequent visit. RESULTS: The device was successfully inserted in 100% of cases attempted (19/19 MSOs, 12 patients). Seventeen (89%) devices remained in the MSO for 60 minutes and dilated to a mean diameter of 4.8 ± 0.5 mm. One patient was withdrawn from the study. No adverse events occurred during insertion or removal of the device. At 3 months postinsertion 14 of 15 MSO dilated (93%) were confirmed patent. CONCLUSION: Placement of an osmotic self-dilating expansion device in human MSO is safe, achievable and effective at dilating the ostia.

The safety and efficacy of short-term budesonide delivered via mucosal atomization device for chronic rhinosinusitis without nasal polyposis.

BACKGROUND: Budesonide is a potent corticosteroid commonly prescribed for management of inflammation in chronic rhinosinusitis (CRS). The standard for prescribing budesonide is via impregnated nasal saline irrigation (INSI), although recently the mucosal atomization device (MAD) has emerged as a theoretically superior method of distributing medication into the sinuses. The MAD atomizes medication into small droplets and this is thought to enhance absorption and improve bioavailability. However, no studies have shown whether enhanced absorption and improved bioavailability of budesonide via MAD causes adrenal suppression. The objective of this study is to determine whether budesonide via MAD affects the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: Twenty CRS patients were recruited from a tertiary rhinology clinic and randomized to take budesonide (1 mg) via MAD or via INSI twice a day for 60 days. The adrenocorticotropic hormone (ACTH) stimulation test and 22-item Sinonasal Outcomes Test (SNOT-22) questionnaire were administered on days 1, 30, and 60 of the study. Plasma budesonide and cortisol levels were simultaneously quantified using a high-performance liquid chromatography-tandem mass spectrometry technique. RESULTS: There was no indication of adrenal suppression in either group (n = 20) based on ACTH stimulation test results nor was there significant plasma budesonide levels detected in either group. Quality of life, as indicated by SNOT-22, did not differ between groups at 60 days (p = 0.404; 95% confidence interval [CI], -37.2 to 15.9), but SNOT-22 scores for patients using MAD did show statistically significant improvement at 60 days compared to baseline (p = 0.02). CONCLUSION: The MAD is likely a safe and effective method of delivering budesonide to the sinuses in the short term.