Impaired hemodynamics and neural activation? A fMRI study of major cerebral artery stenosis

Functional MRI motor mapping was performed in two women with unilateral high-grade stenosis of the middle cerebral artery (MCA) to determine the influence of impaired hemodynamics on the blood oxygenation level dependent (BOLD) response. In both patients no structural lesions were present in primary motor pathways. A redistribution of the motor network to the healthy hemisphere was the main indicator of chronic hemodynamic compromise.     

What are the effects of group cognitive behaviour therapy for voices? A randomised control trial

BACKGROUND: Little evidence exists for the effects of psychological treatment on voices even though it is clear that CBT does affect delusions and symptoms overall. This study tested whether a group based on cognitive behavioural principles could produce beneficial effects on hallucinations. AIM: To test the effectiveness of group CBT on social functioning and severity of hallucinations. METHOD: Participants were included if they had a diagnosis of schizophrenia and experienced distressing auditory hallucinations (rated on the PANSS). They were randomly allocated to group CBT (N = 45) or a control group who received treatment as usual (N = 40). The two main outcomes were social functioning as measured by the Social Behaviour Schedule and the severity of hallucinations as measured by the total score on the Hallucinations Scale of PSYRATS. Assessments were carried out at baseline, 10 weeks (post therapy) and 36 weeks (six months following therapy). RESULTS: Mixed random effects models revealed significant improvement in social functioning (effect size 0.63 six months after the end of therapy). There was no general effect of group CBT on the severity of hallucinations. However, there was a large cluster effect of therapy group on the severity of hallucinations such that they were reduced in some but not all of the therapy groups. Improvement in hallucinations was associated with receiving therapy early in the trial and having very experienced therapists (extensive CBT training which included expert supervision for a series of individual cases for at least a year following initial training). CONCLUSION: Group CBT does improve social functioning but unless therapy is provided by experienced CBT therapists hallucinations are not reduced.     

Observational clinical study in juvenile-adult glycogenosis type 2 patients undergoing enzyme replacement therapy for up to 4?years

The objective of this study was to describe a large Italian cohort of patients with late-onset glycogen storage disease type 2 (GSDII) at various stages of disease progression and to evaluate the clinical effectiveness of alglucosidase alpha enzyme replacement therapy (ERT). Previous studies showed in late-onset patients ERT efficacy against placebo and variable response in uncontrolled studies. Seventy-four juvenile or adult GSDII patients were treated with ERT in a multicenter open label, non-randomized study, from 12 months up to 54 months. Recombinant human alpha glucosidase (rh-GAA) was injected by intravenous route at 20 mg/kg every second week. Patients were divided into three groups according to ERT duration: Group A received treatment for 12-23 months (n = 16), Group B for 24-35 months (n = 14), and Group C for more than 36 months (n = 44). Clinical assessment included a 6-min walk test (6MWT), forced vital capacity (FVC), the Walton and Gardner-Medwin score, the number of hours of ventilation, body mass index, echocardiography and blood creatine kinase (CK). Included in our cohort were 33 males and 41 females (M:F = 0.8:1), with a mean age at first symptoms of 28.3 years (range 2-55 years) and a mean age of 43 years at study entry (range 7-72 years). Seven wheelchair bound patients, as well as 27 patients requiring ventilation support, were included. After treatment we could observe an increase in distance walked on the 6MWT in the large majority of patients (48/58; 83%), with an overall mean increase of 63 m (from 320 ± 161 to 383 ± 178 m). After treatment in the majority of patients FVC was improved or unchanged (45/69; 65%). In ventilated patients we observed an improvement in average number of hours off the ventilator (from 15.6 to 12.1 h). Six patients stopped mechanical ventilation and two others started it. The effect of therapy was not related to ERT duration. Nine of 64 patients (13%) that underwent to echocardiography showed a variable degree of cardiac hypertrophy (left ventriculum or septum), and a positive effect was observed after 36 months of ERT in one adult case. Discontinuation of treatment occurred in four patients: one drop-off case, one patient died for a sepsis after 34 months of treatment and two patients stopped ERT for worsening of general clinical condition. Mild adverse effects were observed in four cases (5%). This study represents the largest cohort of late-onset GSDII patients treated with ERT, and confirm a positive effect of treatment. These results, obtained in a large case series on therapy, indicate a favourable effect of ERT therapy, even in more advanced stage of the disease.     

Risdiplam in types 2 and 3 spinal muscular atrophy: A randomised,placebo-controlled,dose-finding trial followed by 24 months of treatment

Background and purpose

Spinal muscular atrophy (SMA) is caused by reduced levels of survival of motor neuron (SMN) protein due to deletions and/or mutations in the SMN1 gene. Risdiplam is an orally administered molecule that modifies SMN2 pre-mRNA splicing to increase functional SMN protein.

Methods

SUNFISH Part 1 was a dose-finding study conducted in 51 individuals with types 2 and 3 SMA aged 2–25 years. A dose-escalation method was used to identify the appropriate dose for the subsequent pivotal Part 2. Individuals were randomized (2:1) to risdiplam or placebo at escalating dose levels for a minimum 12-week, double-blind, placebo-controlled period, followed by treatment for 24 months. The dose selection for Part 2 was based on safety, tolerability, pharmacokinetic, and pharmacodynamic data. Exploratory efficacy was also measured.

Results

There was no difference in safety findings for all assessed dose levels. A dose-dependent increase in blood SMN protein was observed; a median twofold increase was obtained within 4 weeks of treatment initiation at the highest dose level. The increase in SMN protein was sustained over 24 months of treatment. Exploratory efficacy showed improvement or stabilization in motor function. The pivotal dose selected for Part 2 was 5 mg for patients with a body weight ≥20 kg or 0.25 mg/kg for patients with a body weight <20 kg.

Conclusions

SUNFISH Part 1 demonstrated a twofold increase in SMN protein after treatment with risdiplam. The observed safety profile supported the initiation of the pivotal Part 2 study. The long-term efficacy and safety of risdiplam are being assessed with ongoing treatment.     

Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients

The objective was to determine whether a cannabis-based medicinal extract (CBME) benefits a range of symptoms due to multiple sclerosis (MS). A parallel group, double-blind, randomized, placebo-controlled study was undertaken in three centres, recruiting 160 outpatients with MS experiencing significant problems from at least one of the following: spasticity, spasms, bladder problems, tremor or pain. The interventions were oromucosal sprays of matched placebo, or whole plant CBME containing equal amounts of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) at a dose of 2.5-120 mg of each daily, in divided doses. The primary outcome measure was a Visual Analogue Scale (VAS) score for each patient's most troublesome symptom. Additional measures included VAS scores of other symptoms, and measures of disability, cognition, mood, sleep and fatigue. Following CBME the primary symptom score reduced from mean (SE) 74.36 (11.1) to 48.89 (22.0) following CBME and from 74.31 (12.5) to 54.79 (26.3) following placebo [ns]. Spasticity VAS scores were significantly reduced by CBME (Sativex) in comparison with placebo (P =0.001). There were no significant adverse effects on cognition or mood and intoxication was generally mild.     

Do periodic arm movements during sleep exist in healthy subjects? A polysomnographic study

BackgroundDespite several polysomnographic studies on periodic leg movements (PLM) in healthy sleep, data on the prevalence and characteristics of periodic arm movements (PAM) in normal subjects are lacking. We aimed to investigate PAM and their association with PLM during wakefulness and sleep in healthy subjects.MethodsNinety-one participants underwent video-polysomnography according to American Academy of Sleep Medicine 2007 criteria. In addition to standard electromyographic registration, data for both flexor digitorum superficialis muscles were recorded.ResultsSixty-two subjects (68.1%) had a PAM index during wakefulness >5/h (median PAM index during wakefulness, 8.8/h; range, 0–77). Seven subjects (7.7%) had a PAM index >5/h during sleep (median PAM index during sleep, 0.7/h; range, 0–47.4). In 14% of cases, PAM during wakefulness were coincident with PLM during wakefulness. During sleep, this coincidence was not evident. The correlation between PAM and PLM was weak to moderate (during wakefulness: Spearman's ρ = 0.576, P < 0.001; during sleep: Spearman's ρ = 0.222, P = 0.036).ConclusionIn healthy subjects, PAM occur predominantly during wakefulness with no apparent true periodicity. In contrast to classical PLM, some PAM may not present a true periodic phenomenon, but rather random voluntary movements meeting the wide range of periodicity criteria for PLM.     

Association of postmenopausal hormone replacement therapy with carotid atherosclerosis and soluble thrombomodulin: the vascular aging (EVA) study. Etude du Vieillissement Artériel

Hormone replacement therapy (HRT) may reduce atherosclerosis among postmenopausal women, partly by reducing vascular endothelium damage. We have tested this hypothesis by evaluating the association of HRT with firstly, carotid intima media thickness (IMT) and plaques, and secondly, with endothelial cell damage, indicated by soluble thrombomodulin (sTM). Then, we tested the association between the two markers of atherosclerosis and the levels of sTM. Among 747 postmenopausal women included into the EVA study, we compared 154 HRT users (including 80% transdermal treatment) with 593 never users. Carotid IMT and plaques were measured with B-mode ultrasonography and sTM with ELISA. At least one plaque was detected among 13.6% of HRT users and 27.3% of never users. After adjustment for confounding factors, the odds ratio for the presence of plaque was 0.45 (95% confidence interval, 0.25-0.78, P=0.005) in HRT users in comparison with nonusers. HRT users had a slightly lower crude mean IMT than nonusers, but the difference was not significant. sTM was positively associated with mean IMT (P for trend=0.001) but not with plaques. Finally, estrogen users had a lower sTM level than nonusers (difference 0.14 ng/ml, P=0.03). As HRT was associated with sTM and plaques, but not with IMT, while sTM was only associated with IMT, our hypothesis was not confirmed. This suggests that the possible beneficial effects of HRT on atherosclerosis may not go through the endothelial cell damage assessed by plasma thrombomodulin.     

A pilot psychometric study of aberrant salience state in patients with Parkinson’s disease and its association with dopamine replacement therapy

An overactive striatal dopaminergic neurotransmission is described in psychosis and may be associated with a state of aberrant salience attribution. This pilot psychometric study investigated if features suggestive of an aberrant salience state, a condition of psychosis proneness, are associated with dopamine replacement therapy in patients with early Parkinson’s disease (PD). 77 participants (50 medicated PD patients, 12 newly diagnosed drug-naive PD patients and 15 healthy controls) were enrolled and assessed with the Aberrant Salience Inventory (ASI). Differences between groups were found for ASI scores, and ASI scores correlated with the dopaminergic therapy, in particular levodopa. These findings preliminary suggested that the presence and the degree of an aberrant salience state may be associated with features of the dopaminergic therapy; further studies are needed to investigate which neuropsychiatric complications more common in PD patients may be characterized by an underlying aberrant salience state.     

Longitudinal changes of fractional anisotropy in Alzheimer’s disease patients treated with galantamine: a 12-month randomized, placebo-controlled, double-blinded study

Diffusion tensor imaging (DTI) demonstrates decline of fractional anisotropy (FA) as a marker of fiber tract integrity in Alzheimer's disease (AD). We aimed to assess the longitudinal course of white matter microstructural changes in AD and healthy elderly control (HC) subjects and to evaluate the effects of treatment with the cholinesterase inhibitor galantamine on white matter microstructure in AD patients. We enrolled 28 AD patients and 11 healthy elderly control subjects (HC). AD patients were randomly assigned to 6-month double-blind galantamine treatment or placebo, with a 6-month open-label extension phase. DTI was performed at baseline, as well as at 6 and 12-month follow-up in AD patients. The HC subjects underwent DTI at baseline and 12-month follow-up without treatment. We measured FA in regions of interest covering the posterior cingulate and corpus callosum. At 6-month follow-up, the AD group showed significant FA decline in the left posterior cingulate. FA decline was significantly preserved in the posterior body of the corpus callosum in AD group with treatment compared to placebo. At 12-month follow-up, the AD patients showed no differences in FA decline between initial treatment and placebo groups after the 6-month open-label extension phase. A significant FA decline occurred in the left posterior cingulate across the AD and HC groups without between-group differences. DTI demonstrated FA decline in intracortically projecting fiber tracts in aging and AD over 1 year. Galantamine had limited impact on regional FA decline, which was not preserved after additional 6-month open-label treatment.     

Relationship between trunk muscle strength,reaching ability and balance in children with Down syndrome – A cross-sectional study

BackgroundChildren with Down Syndrome (DS) present with neuromuscular disturbances leading to delayed developmental milestones, poor quality of movement and poor balance. The aim of this study is to discuss the role of trunk muscle strength in the functional performance of children with DS.Methodology28 children were recruited in the study, 14 with DS and 14 age and gender-matched controls. Trunk muscle strength, reaching ability and balance were assessed using a Handheld Dynamometer, Modified Functional Reach test and Pediatric Balance Scale, respectively.ResultsChildren with DS present with poorer trunk muscle strength, reaching ability and balance as compared to typically developing (TD) children. There was a positive correlation between trunk muscle strength and lateral reaching in children with DS. A strong to moderate correlation was observed between the trunk muscle strength and balance in children with DS.DiscussionChildren with DS demonstrated a significantly weak trunk muscle groups. Lateral reaching distance is reduced due to the poor proximal control and they present with near-normal forward reach distance attributed to compensation using the lower trunk muscles. They exhibit poor balance in the components that require a small base of support.ConclusionChildren with DS exhibit weak trunk muscles along with lesser reaching distance and poor balance. Also, trunk muscle strength influences lateral reaching ability. Trunk muscle strength, mainly trunk extensors impacted functional balance in sitting, standing and while performing transfers.     

How many words should we provide in anomia therapy? A meta-analysis and a case series study

Aims: This study investigated whether the number of words provided in naming therapy affects the outcome. A second aim was to investigate whether severity of anomia should be used to determine the number of words provided in therapy.

Methods & Procedures: First a meta-analysis of 21 anomia treatment studies between 1985 and 2006, yielding 109 individual datasets, explored whether the number of items provided and the severity of anomia influenced the success of therapy. The second part was a cross-over case-series study with 13 individuals with aphasia who had varying degrees of anomia. Individuals received two blocks of therapy (each of 10 sessions) where the set size of items to be learned was manipulated: either a small (n?=?20) or large (n?=?60) set in each block. Therapy and control sets were matched for baseline naming ability, frequency, phoneme, and syllable length. Therapy consisted of progressive phonemic and orthographic cues until successful naming was achieved. All word sets (small, large and control) were retested immediately after each therapy block finished (within 1 week) and 5 weeks after the end of each block of therapy.

Outcomes & Results: The meta-analysis showed a large variation in the number of items given to participants to learn (from 5 to 120 items) and very different learning outcomes that were not linked to the number of items given. The current literature contained an unexpected bias in that, across studies, more items were given to those with severe aphasia. Consequently, the meta-analysis could not provide a clear answer to how may items should be given in therapy—thus motivating a direct comparison in a new therapy study. We found significant gains in naming accuracy for both the small (n?=?20) and large (n?=?60) therapy sets immediately and 5 weeks post therapy. Proportionally, there was no difference between the two sets for the group as a whole, although there was individual variation in the overall therapy effect. If expressed as the raw numbers of words learned after therapy, this means that 12 of the 13 participants learned more words when given the large (n?=?60) set. Severity of anomia correlated with learning performance but did not interact with set size.

Conclusions: The empicial study suggested that people with anomia could tolerate more items in therapy and that the severity of anomia should not necessarily determine how many words should be given in therapy.