Arianna Palmieri

Spinal and bulbar muscular atrophy: Skeletal muscle pathology in male patients and heterozygous females

Spinal and bulbar muscular atrophy (SBMA) is an adult form of X-linked motor neuron disease caused by an expansion of a CAG repeat sequence in the first exon of the androgen receptor (AR) gene. Nuclear accumulation of mutant AR with expanded polyglutamines in motor neurons is a major pathogenic mechanism. To characterize muscle involvement in SBMA the skeletal muscle biopsies of 8 SBMA patients and 3 female carriers were studied. Six of 8 SBMA patients showed myogenic changes together with the neurogenic atrophy in their muscle biopsy. Myopathic abnormalities did not correlate with disease duration and were more prominent in the muscle of patients with an higher degree of disability. In all patients plasma CK levels were more elevated than what usually occurs in denervative diseases. Both neurogenic and myopathic changes were also observed in female carriers. Here we suggest that myopathic changes in SBMA muscle are not only related to denervation and that muscle satellite cells may have a role in the pathogenesis of muscle damage.

Survival and quality of life after tracheostomy for acute respiratory failure in patients with amyotrophic lateral sclerosis

BACKGROUND Acute respiratory failure (ARF) is a common event in the advanced stage of amyotrophic lateral sclerosis (ALS) and may be rarely a presenting symptom. Frequently, such patients require intubation and mechanical ventilation (MV) and, in a large proportion, receive tracheostomy, as a consequence of weaning failure. In our study, we investigated postdischarge survival and quality of life (QoL) after tracheostomy for ARF in patients with ALS. METHODS DESIGN This study is a retrospective chart review combined with prospective evaluation of QoL and degree of depression. SETTING The study was conducted in an adult, respiratory intensive care unit in a university hospital. PATIENTS Amyotrophic lateral sclerosis patients with tracheostomy for ARF between January 1, 1995 and April 30, 2008 were investigated. INTERVENTION AND MEASUREMENTS (a) A retrospective chart review was used and (b) prospective administration of the 11-item short-form Life Satisfaction Index (LSI-11) and Beck Depression Inventory (BDI) questionnaires to survivors, at least 1 month after discharge from hospital, was performed. RESULTS Sixty patients were studied retrospectively. None of the patients died in the hospital after tracheostomy. Forty-two patients (70%) were discharged completely MV dependent, and 17 patients (28.3%) were partially MV dependent. One patient (1.6%) was liberated from MV. The median survival after tracheostomy was 21 months (range, 0-155 months). The survival rate was 65% by 1 year and 45% by 2 years after tracheostomy. Survival was significantly shorter in patients older than 60 years at tracheostomy, with a hazard ratio of dying of 2.1 (95% confidence interval, 1.1-3.9). All 13 survivors completed the LSI-11 and BDI. The mean (SD) cumulative score on the LSI-11 was 9.3 (3.6; range, 0-22; higher values indicating better QoL), similar to that obtained from a control group consisting of individuals with ALS who had not received tracheostomy (9.3 ± 4.3) and to that reported for persons in the general population. Only 15% of the tracheostomized patients (2/13) were severely depressed, according to BDI; 11 of 13 patients reported a positive view of tracheostomy and said that they would want to undergo this procedure if they could make the decision again. CONCLUSIONS Patients with ALS have a high chance of long-term survival after tracheostomy for ARF. Although administered at the time of a respiratory crisis without being discussed in advance, tracheostomy shows good acceptance and results in acceptable QoL.

Brain involvement in myotonic dystrophies: neuroimaging and neuropsychological comparative study in DM1 and DM2

The objective of this study was to determine the degree of brain involvement in a cohort of myotonic dystrophy type 1 and type 2 (DM1, DM2) patients by brain studies and functional tests and to compare the results of the two groups. DM1, DM2 are multisystemic disorders due to polynucleotide expansions. Previous studies on brain involvement by neuroimaging and functional methods have led to contradictory results. Fifty molecularly defined DM1 patients and 14 DM2 patients, were recruited for the study. Age at recruitment, age at disease onset, disease duration and educational level were recorded. Neuromuscular assessment was done by MIRS. An extensive neuropsychological battery was performed in 48/50 DM1 and in a control group of 44 healthy matched subjects. Forty six of 50 DM1 and 12/14 DM2 underwent brain MRI; 21/50 DM1 and 9/14 DM2 underwent brain perfusion SPECT, with semiquantitative analysis of the results. MRI images were classified by ARWMC (age-related white matter changes) score, in order to quantify recurrence, localization and patterns of distribution of white matter hyperintense lesions (WMHLs) in our two cohorts. MRI results were matched to SPECT and to neuropsychological results. Thirty-seven of 46 DM1 and 10/12 DM2 had abnormal MRI imaging, showing scattered supratentorial, bilateral, symmetrical focal or diffuse WMHLs. A typical temporo-insular diffuse subcortical pattern was seen in DM1 subjects only, with no correlation with cognitive involvement. Major cognitive involvement was seen in the case of diffuse frontal lesions. A relationship with CTG expansion size was documented for DM1 subjects. SPECT showed minimal hypoperfusion in the posterior cortex planes in DM1 and, to a lesser extent, in DM2. Very mild degrees of involvement in the DM2 cohort were seen. Neuroimaging and functional investigations confirmed a more severe involvement of the brain in DM1 compared to DM2. A temporo-insular diffuse lesional pattern, specific for DM1, was found on MRI. This confirms greater expansion size as a risk factor for more extensive brain involvement in DM1.

Neural Correlates of Psychotherapy in Anxiety and Depression: A Meta-Analysis

Several studies have used neuroimaging methods to identify neural change in brain networks associated to emotion regulation after psychotherapy of depression and anxiety. In the present work we adopted a meta-analytic technique specific to neuroimaging data to evaluate the consistence of empirical findings and assess models of therapy that have been proposed in the literature. Meta-analyses were conducted with the Activation Likelihood Estimation technique, which evaluates the overlap between foci of activation across studies. The analysis included 16 studies found in Pubmed (200 foci of activation and 193 patients). Separate meta-analyses were conducted on studies of 1) depression, post-traumatic stress disorder and panic disorder investigated with rest state metabolism (6 studies, 70 patients); 2) depression, post-traumatic stress disorder and panic disorder investigated with task-related activation studies (5 studies, 65 patients); 3) the previous studies considered jointly; and 4) phobias investigated with studies on exposure-related activation (5 studies, 57 patients). Studies on anxiety and depression gave partially consistent results for changes in the dorsomedial prefrontal cortex and in the posterior cingulated gyrus/precuneus. Several areas of change in the temporal lobes were also observed. Studies on the therapy of phobia were consistent with a reduction of activity in medial temporal areas. The cluster of change in the prefrontal cortex may refer to increased recruitment of control processes, as hypothesized by influential models of emotion regulation changes due to psychotherapy. However, not all areas associated with controlled emotion regulation were detected in the meta-analysis, while involvement of midline structures suggested changes in self-related information processing. Changes in phobia were consistent with reduced reactivity to phobic stimuli.

Right hemisphere dysfunction and emotional processing in ALS: an fMRI study.

Emotional processing may be abnormal in amyotrophic lateral sclerosis (ALS). Our aim was to explore functional anatomical correlates in the processing of aversive information in ALS patients. We examined the performance of nine non-demented ALS patients and 10 healthy controls on two functional MRI (fMRI) tasks, consisting of an emotional attribution task and a memory recognition task of unpleasant versus neutral stimuli. During the emotional decision task, subjects were asked to select one of three unpleasant or neutral words. During the memory task, subjects were asked to recognize words presented during the previous task. Controls showed, as expected, greater activation in the right middle frontal gyrus during selection of unpleasant than neutral words, and a greater activation mainly in right-sided cerebral areas during the emotional recognition task. Conversely, patients showed a general increase in activation of the left hemisphere, and reduced activation in right hemisphere in both emotional tasks. Such findings may suggest extra-motor neurodegeneration involving key circuits of emotions, mostly negative, commonly involved in FTD.

Epidemiology of ALS in Padova district, Italy, from 1992 to 2005

Background and purpose:  Several studies have reported an increase in ALS incidence in recent years but population‐based studies in Europe do not confirm this trend. To analyze ALS incidence over time we conducted a retrospective incidence study in the Padova district of Italy (1992 to 2005). We had previously conducted a survey in the same area in the years 1980–1991.

Natural history of upper motor neuron-dominant ALS

Abstract A new amyotrophic lateral sclerosis (ALS) category named ‘UMN-dominant ALS’ and defined as ‘due predominantly to UMN signs but with minor electromyogram (EMG) denervation or LMN signs on examination’ has been proposed. The clinical and laboratory features of 20 patients with UMN-dominant ALS are described here, their disease course is analysed longitudinally according to their disability progression, and all these parameters are compared with those of typical ALS patients. Ten women and 10 men diagnosed with UMN-dominant ALS were evaluated. Their mean age at disease onset was 58.6 years. At the most recent evaluation, after a mean disease duration of 7.7 years, all patients progressed to a tetrapyramidal syndrome with pseudobulbar features of varying degree. No patient had respiratory problems. Cognitive impairment was observed in eight patients. The differences in disease progression between the UMN-dominant ALS and typical ALS patients proved significant (p <0.02) both with regard to the total ALSFRS-R score at six months and to each single region subscore at 12 months. Our findings suggest that there is both a different pattern of disability and longer survival in UMN-dominant ALS compared to classic ALS patients.

Working Memory in Amyotrophic Lateral Sclerosis: Auditory Event-related Potentials and Neuropsychological Evidence

Aim of this study is to investigate working memory functions in nondemented patients with amyotrophic lateral sclerosis (ALS) using neuropsychological testing and auditory event-related potentials. Twenty-four patients with ALS and 17 age- and education-matched controls underwent a comprehensive neuropsychological assessment, with particular emphasis on working memory functions. Event-related potentials were assessed with an active auditory oddball paradigm. In a subsample (67%) of patients with ALS, the neuropsychological assessment revealed impaired performance on working memory tests (semantic and letter verbal fluency, modified card sorting test, trail making test, digit span, Corsi blocks tapping test, and prose memory). The analysis of event-related potentials showed a significant delay of the N100, P200, and N200 latency in ALS compared with controls. Correlation analysis showed a relation between clinical parameters (disease duration and functional rating scale) and neuropsychological test results (letter fluency and trail making test) and between disease duration and P300 amplitude. The neuropsychological and event-related potentials profile of patients with ALS at an average is consistent with a mild dysfunction of the central executive component of working memory. In conclusion, the results support previously published reports that indicate the involvement of the extramotor functions in a significant subsample of ALS.

Psychopathological features and suicidal ideation in amyotrophic lateral sclerosis patients.

Psychopathological diagnosis has become increasingly important in amyotrophic lateral sclerosis (ALS), since the recent emphasis on the comprehensive management and end-of-life decisions. Rorschach test is the third most commonly used psychological instrument worldwide and can offer a different approach from self-reporting questionnaires, mainly providing information on issues of which individuals may be unaware or unwilling to admit to. Forty-two ALS patients underwent a psychopathological assessment with the Rorschach test. Psychopathological data were also correlated with skeletal muscle strength as measured by MRC scale and functional evaluation as ALSFRSr and FVC values. Psychopathological features, including suicidial ideation, were more frequent in the recently diagnosed ALS patients. These features were observed to be different according to the kind of functional impairment. Rorschach test may be an useful tool to assess psychopathological features in ALS. Results of our study highlight the need of an early psychopathological diagnosis and specific psychotherapeutic treatment in patients with ALS.

Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy

Protein-o-mannosyl transferase 1 (POMT1) is a glycosyltransferase involved in α-dystroglycan (α-DG) glycosylation. Clinical phenotype in POMT1-mutated patients ranges from congenital muscular dystrophy (CMD) with structural brain abnormalities, to limb-girdle muscular dystrophy (LGMD) with microcephaly and mental retardation, to mild LGMD. No cardiac involvement has until now been reported in POMT1-mutated patients. We report three patients who harbored compound heterozygous POMT1 mutations and showed left ventricular (LV) dilation and/or decrease in myocardial contractile force: two had a LGMD phenotype with a normal or close-to-normal cognitive profile and one had CMD with mental retardation and normal brain MRI. Reduced or absent α-DG immunolabeling in muscle biopsies were identified in all three patients. Bioinformatic tools were used to study the potential effect of POMT1-detected mutations. All the detected POMT1 mutations were predicted in silico to interfere with protein folding and/or glycosyltransferase function. The report on the patients described here has widened the clinical spectrum associated with POMT1 mutations to include cardiomyopathy. The functional impact of known and novel POMT1 mutations was predicted with a bioinformatics approach, and results were compared with previous in vitro studies of protein-o-mannosylase function.