Comparison of three rating scales as outcome measures for treatment trials of depression in Alzheimer disease: findings from DIADS

CONTEXT: Major depression affects about 25% of patients with Alzheimer's disease (AD) and has serious adverse consequences for patients as well as caregivers. Studies of treatments for depression in AD, like most treatment studies, depend on the ability of the scales used to measure outcome to detect a difference between the effects of treatment and control, particularly in trials conducted over waves. OBJECTIVE: To compare the ability of three depression scales, and some of their subscales, to detect the difference in the effects of drug (treatment) and placebo (control). DESIGN: Comparison of three scales of depression in terms of percent variance explained as indicated by the adjusted or partial eta-squared for the effect of drug versus placebo, controlling for baseline depression, in a randomized, placebo-controlled, parallel, 12-week, clinical trial of sertraline for the treatment of depression with AD. SETTING: University outpatient clinic. PARTICIPANTS: Forty-four patients with probable Alzheimer's disease and Major Depressive Episode. OUTCOME MEASURES: The Cornell Scale for Depression in Dementia (CSDD), the Hamilton Depression Rating Scale (HDRS), and the Neuropsychiatric-Inventory Mood Domains (NPI-M). RESULTS: Examination of the treatment effects as indicated by the partial eta-squared's for each scale at each wave, revealed a slight, but not significant, advantage for the use of the CSDD over the HDRS, and a significant advantage for the use of either of these over the NPI-M. Treatment effects, as reflected in the partial eta-squared's computed for the subscales at each wave, were significant for all four subscales, and were largest for the CSDD 'mood' subscale although they were not significantly greater than for the other subscales. CONCLUSIONS: The CSDD, and particularly its mood subscale, appears to be more sensitive than the HDRS, it's subscales or the NPI-M, for comparing drug to placebo in treating major depression in AD patients. Treatment effects as reflected in the partial eta-squared's were largest on the CSDD mood subscale and increased over time. The pattern for the other subscales was non-monotonic over waves and resembled the pattern for the entire scale. Perhaps combining the CSDD two subscales obscures the treatment effects for the separate subscales.     

Prognosis and histopathologic features in papillary tumors of the pineal region: a retrospective multicenter study of 31 cases

Papillary tumor of the pineal region (PTPR) is a recently described tumor entity thought to arise from the specialized ependyma of the subcommissural organ. Whereas histologic features of PTPR are well defined, data on the prognostic value of PTPR remain scarce. We therefore investigated clinicopathologic features, including data on progression-free survival and overall survival, in a retrospective series of 31 PTPR. The age of the 14 males and 17 females ranged from 5 to 66 years (median age, 29 years). Histologically, all tumors were characterized by an epithelial-like growth pattern in which the vessels were covered by layers of columnar or cuboidal tumor cells forming perivascular pseudorosettes. Most of the tumor cells showed strong expression of neuron-specific enolase, cytokeratins (particularly CK18), S-100 protein, and vimentin. Most PTPRs examined also expressed microtubule-associated protein-2. Expression of synaptophysin, epithelial membrane antigen, transthyretin, neural cell adhesion molecule, and nestin was encountered in some tumors. Gross total resection could be achieved in 21 of 31 cases; 15 patients received radiotherapy on resection of the primary tumor. Nevertheless, the majority of patients experienced recurrences; 5-year estimates for overall survival and progression-free survival were 73% and 27%, respectively. To conclude, the clinical course of PTPR is characterized by frequent local recurrence, and the value of radiotherapy on disease progression will need to be investigated in future prospective trials.     

Fukutin gene mutations in steroid-responsive limb girdle muscular dystrophy

OBJECTIVE: Defects in glycosylation of alpha-dystroglycan are associated with several forms of muscular dystrophy, often characterized by congenital onset and severe structural brain involvement, collectively known as dystroglycanopathies. Six causative genes have been identified in these disorders including fukutin. Mutations in fukutin cause Fukuyama congenital muscular dystrophy. This is the second most common form of muscular dystrophy in Japan and is invariably associated with mental retardation and structural brain defects. The aim of this study was to determine the genetic defect in two white families with a dystroglycanopathy. METHODS: The six genes responsible for dystroglycanopathies were studied in three children with a severe reduction of alpha-dystroglycan in skeletal muscle. RESULTS: We identified pathogenic fukutin mutations in these two families. Affected children had normal intelligence and brain structure and shared a limb girdle muscular dystrophy (LGMD) phenotype, had marked elevation of serum creatine kinase, and were all ambulant with remarkable steroid responsiveness. INTERPRETATION: Our data suggest that fukutin mutations occur outside Japan and can be associated with much milder phenotypes than Fukuyama congenital muscular dystrophy. These findings significantly expand the spectrum of phenotypes associated with fukutin mutations to include this novel form of limb girdle muscular dystrophy that we propose to name LGMD2L.     

Saccadic adaptation in Chiari type II malformation

BACKGROUND: Saccadic adaptation corrects errors in saccadic amplitude. Experimentally-induced saccadic adaptation provides a method for studying motor learning. The cerebellum is a major participant in saccadic adaptation. Chiari type II malformation (CII) is a developmental deformity of the cerebellum and brainstem that is associated with spina bifida. We investigated the effects of CII on saccadic adaptation. METHOD: We measured eye movements using an infrared eye tracker in 21 subjects with CII (CII group) and 39 typically developing children (control group), aged 8-19 years. Saccadic adaptation was induced experimentally using targets that stepped horizontally 120 to the right and then stepped backward 3 degrees during saccades. RESULTS: Saccadic adaptation was achieved at the end of the adaptation phase in participants in each group. Saccadic amplitude gain decreased by 6.9% in the CII group and 9.3% in the control group. The groups did not differ significantly (p = 0.27). Amplitude gain reduction was significantly less in the CII participants who had multiple shunt revisions. Regression analyses revealed no effects of spinal lesion level, presence of nystagmus, or cerebellar vermis dysmorphology on saccadic adaptation. CONCLUSION: The neural circuits involved in saccadic adaptation appear to be functionally intact in CII.     

Central periodic breathing observed on hospital admission is associated with an adverse prognosis in conscious acute stroke patients

BACKGROUND: Central periodic breathing (CPB) is common following acute stroke, but its prognostic significance is uncertain. We determined the frequency of CPB on admission with stroke and assessed whether it was related to outcome. METHODS: We measured arterial oxygen saturation (SaO2), chest wall movements and nasal airflow continually with portable monitoring equipment in a large cohort of acute stroke patients, from arrival at hospital through acute assessment to reaching the ward. Baseline neurological examination and 3-month outcome (modified Rankin scale, MRS) were assessed blind to recordings. CPB was defined as cyclical rises and falls in ventilation, with intermittent reduced respiratory airflow or total apnoea. RESULTS: CPB was common in acute stroke (33/138, 24%), but was poorly recognised by clinical staff. Patients with CPB were more likely to have a total anterior circulation syndrome and higher National Institutes of Health Stroke Scale scores than those without (both p<0.01). Patients with CPB had significantly higher median SaO2 than those without (p<0.01), unrelated to whether they received oxygen or not. At 3-month follow-up: 91% of patients with CPB were dead or dependent (MRS>or=3) compared with 53% of those without (OR 8.8; 95% CI 2.5-30.5); the association remained statistically significant after adjusting for covariates (OR 5.9; 95% CI 1.4-25.4). CONCLUSION: CPB is independently associated with poor outcome after stroke, but is not by association with hypoxia. Further work is required to identify causes, effects and interventions that might improve effects of CPB.     

International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson's disease: the NMSQuest study.

Nonmotor symptoms (NMS) of Parkinson's disease (PD) are not well recognized in clinical practice, either in primary or in secondary care, and are frequently missed during routine consultations. There is no single instrument (questionnaire or scale) that enables a comprehensive assessment of the range of NMS in PD both for the identification of problems and for the measurement of outcome. Against this background, a multidisciplinary group of experts, including patient group representatives, has developed an NMS screening questionnaire comprising 30 items. This instrument does not provide an overall score of disability and is not a graded or rating instrument. Instead, it is a screening tool designed to draw attention to the presence of NMS and initiate further investigation. In this article, we present the results from an international pilot study assessing feasibility, validity, and acceptability of a nonmotor questionnaire (NMSQuest). Data from 123 PD patients and 96 controls were analyzed. NMS were highly significantly more prevalent in PD compared to controls (PD NMS, median = 9.0, mean = 9.5 vs. control NMS, median = 5.5, mean = 4.0; Mann-Whitney, Kruskal-Wallis, and t test, P < 0.0001), with PD patients reporting at least 10 different NMS on average per patient. In PD, NMS were highly significantly more prevalent across all disease stages and the number of symptoms correlated significantly with advancing disease and duration of disease. Furthermore, frequently, problems such as diplopia, dribbling, apathy, blues, taste and smell problems were never previously disclosed to the health professionals.     

Characterization of epidermal neural crest stem cell (EPI-NCSC) grafts in the lesioned spinal cord

We have characterized in the contusion-lesioned murine spinal cord the behavior of acutely implanted epidermal neural crest stem cells (EPI-NCSC, formerly eNCSC). EPI-NCSC, a novel type of multipotent adult stem cell, are remnants of the embryonic neural crest. They reside in the bulge of hair follicles and have the ability to differentiate into all major neural crest derivatives (Sieber-Blum, M., Grim, M., Hu, Y.F., Szeder, V., 2004. Pluripotent neural crest stem cells in the adult hair follicle. Dev. Dyn. 231, 258-269). Grafted EPI-NCSC survived, integrated, and intermingled with host neurites in the lesioned spinal cord. EPI-NCSC were non-migratory. They did not proliferate and did not form tumors. Significant subsets expressed neuron-specific beta-III tubulin, the GABAergic marker glutamate decarboxylase 67 (GAD67), the oligodendrocyte marker, RIP, or myelin basic protein (MBP). Close physical association of non-neuronal EPI-NCSC with host neurites was observed. Glial fibrillary acidic protein (GFAP) immunofluorescence was not detected. Collectively, our data indicate that intraspinal EPI-NCSC demonstrate several desirable characteristics that may include local neural replacement and re-myelination.     

Taurine reverses neurological and neurovascular deficits in Zucker diabetic fatty rats

Increased oxidative stress is implicated in the pathogenesis of diabetic peripheral neuropathy (DPN). However, the efficacy of antioxidant therapy on DPN complicating type 2 diabetes remains unexplored. We therefore determined the ability of the antioxidant taurine to reverse deficits of hind limb sciatic motor and digital sensory nerve conduction velocity (NCV), nerve blood flow (NBF), and sensory thresholds in hyperglycemic Zucker diabetic fatty (ZDF) rats. Experimental groups comprised lean nondiabetic (ND), ND treated with taurine (ND + T), untreated ZDF diabetic (D), and D rats treated with taurine (D + T). Compared to ND rats, 23%, 15% and 56% deficits of motor NCV, sensory NCV and NBF, respectively as well as thermal and mechanical hyperalgesia were reversed by taurine. An 84% deficit of dorsal root ganglion neuron calcitonin gene-related peptide in D rats was prevented by taurine. In summary, the antioxidant taurine reverses neurological and neurovascular deficits in experimental type 2 diabetes.     

Central fatigue in continuous and intermittent contractions of triceps brachii

Conflicting results have been found across studies concerning the effect of rest periods on the development of central fatigue during prolonged muscle activity. Thus, the aim of the present study was to assess differences in the development of central fatigue between continuous and intermittent elbow extension fatigue tasks in the same subjects. Force and electromyographic data were collected on eight healthy volunteers. The ability to maximally activate the triceps brachii muscle was assessed by delivering trains of electrical stimulation during maximal voluntary efforts. This was done before, during, and after three fatigue tasks involving a maximal contraction in elbow extension. One short-duration ( approximately 55-s) and two long-duration (3-min) fatigue tasks were performed by all subjects on separate sessions. One 3-min task was intermittent (5-s rests every 30 s) and the other was continuous. The main findings were that the development and extent of central fatigue were task-dependent, with a greater decrease in the ability to maximally activate triceps brachii observed for the 3-min continuous task. Also, the voluntary activation (VA) ratio was found to be a more sensitive index of central fatigue than the central activation ratio (CAR). These results suggest that, when assessing central fatigue in patients, conclusions may vary depending on the continuous/intermittent nature of the task performed and the estimate of voluntary activation used.