Assessing behavioural changes in ALS: cross-validation of ALS-specific measures

Objective: The Beaumont Behavioural Inventory (BBI) is a behavioural proxy report for the assessment of behavioural changes in ALS. This tool has been validated against the FrSBe, a non-ALS specific behavioural assessment, and further comparison of the BBI against a disease-specific tool was considered. This study cross-validates the BBI against the ALS-FTD-Q. Methods: 60 ALS patients, 8% also meeting criteria for FTD, were recruited. All patients were evaluated using the BBI and the ALS-FTD-Q, completed by a carer. Correlational analysis was performed to assess construct validity. Precision, sensitivity, specificity and overall accuracy of the BBI, when compared to the ALS-FTD-Q, were obtained. Results: The mean score of the whole sample on the BBI was 11.45±13.06. ALS-FTD patients scored significantly higher than non-demented ALS patients (31.6±14.64, 9.62±11.38; p<.0001). A significant large positive correlation between the BBI and the ALS-FTD-Q was observed (r=.807, p<.0001), and no significant correlations between the BBI and other clinical/demographic characteristics, indicating good convergent and discriminant validity, respectively. 72% of overall concordance was observed. Precision, sensitivity and specificity for the classification of severely impaired patients were adequate. However, lower concordance in the classification of mild behavioural changes was observed, with higher sensitivity using the BBI, most likely secondary to BBI items which endorsed behavioural aspects not measured by the ALS-FTD-Q. Discussion: Good construct validity has been further confirmed when the BBI is compared to an ALS-specific tool. Furthermore, the BBI is a more comprehensive behavioural assessment for ALS, as it measures the whole behavioural spectrum in this condition

A qualitative evaluation of the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) by the patient community: a web-based cross-sectional survey

Objective: The revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) is the most commonly used outcome measure in ALS studies. The aim of this study was to identify potential limitations of the ALSFRS-R from the perspective of people living with ALS and their caregivers. Methods: A web-based survey was developed by investigators, people living with ALS, and their caregivers, and shared across social media. For each item, participants were asked, “Can you think of a situation where you might not be able to answer this item accurately or that your answer might not reflect your abilities?” Responses were divided into two categories: criticisms that could be addressed in a manual or issues with the items/responses that would require measure modification. Results: 57 participants (72% participants with ALS, 28% caregivers) responded to at least one item question, of which 71.9% expressed concern about at least one item. The most frequently identified items were speech, walking, and cutting food. Common criticisms were: language used is of a medical literacy level too high; item is situational; difficult to distinguish the difference between response choices; and the structure and/or underlying assumptions of the item makes it difficult to answer. Conclusions: Several items of the ALSFRS-R were considered to inaccurately reflect the abilities of patients with ALS. The ALSFRS-R may need a revision to address these issues, preferably in co-development with people living with ALS and their caregivers, and/or alternate outcome measures should be considered for patients with ALS

Apraxia and motor dysfunction in corticobasal syndrome

Background: Corticobasal syndrome (CBS) is characterized by multifaceted motor system dysfunction and cognitive disturbance; distinctive clinical features include limb apraxia and visuospatial dysfunction. Transcranial magnetic stimulation (TMS) has been used to study motor system dysfunction in CBS, but the relationship of TMS parameters to clinical features has not been studied. The present study explored several hypotheses; firstly, that limb apraxia may be partly due to visuospatial impairment in CBS. Secondly, that motor system dysfunction can be demonstrated in CBS, using threshold-tracking TMS, and is linked to limb apraxia. Finally, that atrophy of the primary motor cortex, studied using voxel-based morphometry analysis (VBM), is associated with motor system dysfunction and limb apraxia in CBS.   Methods: Imitation of meaningful and meaningless hand gestures was graded to assess limb apraxia, while cognitive performance was assessed using the Addenbrooke's Cognitive Examination - Revised (ACE-R), with particular emphasis placed on the visuospatial subtask. Patients underwent TMS, to assess cortical function, and VBM.   Results: In total, 17 patients with CBS (7 male, 10 female; mean age 64.4+/2 6.6 years) were studied and compared to 17 matched control subjects. Of the CBS patients, 23.5% had a relatively inexcitable motor cortex, with evidence of cortical dysfunction in the remaining 76.5% patients. Reduced resting motor threshold, and visuospatial performance, correlated with limb apraxia. Patients with a resting motor threshold <50% performed significantly worse on the visuospatial sub-task of the ACE-R than other CBS patients. Cortical function correlated with atrophy of the primary and pre-motor cortices, and the thalamus, while apraxia correlated with atrophy of the pre-motor and parietal cortices.   Conclusions: Cortical dysfunction appears to underlie the core clinical features of CBS, and is associated with atrophy of the primary motor and pre-motor cortices, as well as the thalamus, while apraxia correlates with pre-motor and parietal atrophy

Evaluation of very high- and very low-dose intravitreal aflibercept in patients with neovascular age-related macular degeneration.

PURPOSE: To determine bioactivity and duration of effect of intravitreal aflibercept injection (also known as vascular endothelial growth factor Trap-Eye) for neovascular age-related macular degeneration (AMD). METHODS: In this double-masked, phase 1 study, 28 patients with lesions ≤12 disc areas, ≥50% active choroidal neovascularization (CNV), and best corrected visual acuity (BCVA) ≤20/40 were randomized 1:1 to a single intravitreal injection of aflibercept 0.15 or 4 mg. The primary end point was the change from baseline in central retinal/lesion thickness (CR/LT) at week-8. Secondary outcomes were the change from baseline BCVA, the change in CNV lesion size and area of leakage, and proportion of patients requiring repeat injection at 8 weeks. RESULTS: Mean percent decrease in CR/LT for the 4-mg and 0.15-mg groups was, respectively, 34.2 versus 13.3 at week 4 (P=0.0065), 23.8 versus 5.9 at week 6 (P=0.0380), and 25.2% versus 11.3% at week 8 (P=0.150). The 4-mg group gained a mean of 4.5 letters in BCVA (6/14 patients gaining ≥10 letters) versus 1.1 letters in 0.15-mg group (1/14 gaining ≥10 letters) at week 8. Fewer patients needed retreatment in the 4-mg group at week 8. No serious adverse event or ocular inflammation was reported in either group. CONCLUSIONS: Intravitreal aflibercept 4 mg had a safety profile similar to that of the very low dose 0.15 mg, and was well-tolerated. The 4-mg dose significantly reduced foveal thickening at weeks 4 and 6, significantly improved BCVA at weeks 6, and reduced the need for repeat injection after 8 weeks compared with intravitreal aflibercept 0.15 mg in neovascular AMD patients

Cerebellar Integrity in the Amyotrophic Lateral Sclerosis - Frontotemporal Dementia Continuum

Amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD) are multisystem neurodegenerative disorders that manifest overlapping cognitive, neuropsychiatric and motor features. The cerebellum has long been known to be crucial for intact motor function although emerging evidence over the past decade has attributed cognitive and neuropsychiatric processes to this structure. The current study set out i) to establish the integrity of cerebellar subregions in the amyotrophic lateral sclerosis-behavioural variant frontotemporal dementia spectrum (ALS-bvFTD) and ii) determine whether specific cerebellar atrophy regions are associated with cognitive, neuropsychiatric and motor symptoms in the patients. Seventy-eight patients diagnosed with ALS, ALS-bvFTD, behavioural variant frontotemporal dementia (bvFTD), most without C9ORF72 gene abnormalities, and healthy controls were investigated. Participants underwent cognitive, neuropsychiatric and functional evaluation as well as structural imaging using voxel-based morphometry (VBM) to examine the grey matter subregions of the cerebellar lobules, vermis and crus. VBM analyses revealed: i) significant grey matter atrophy in the cerebellum across the whole ALS-bvFTD continuum; ii) atrophy predominantly of the superior cerebellum and crus in bvFTD patients, atrophy of the inferior cerebellum and vermis in ALS patients, while ALS-bvFTD patients had both patterns of atrophy. Post-hoc covariance analyses revealed that cognitive and neuropsychiatric symptoms were particularly associated with atrophy of the crus and superior lobule, while motor symptoms were more associated with atrophy of the inferior lobules. Taken together, these findings indicate an important role of the cerebellum in the ALS-bvFTD disease spectrum, with all three clinical phenotypes demonstrating specific patterns of subregional atrophy that associated with different symptomology

Biomarkers of Sarcopenia in Clinical Trials—Recommendations from the International Working Group on Sarcopenia

Sarcopenia, the age-related skeletal muscle decline, is associated with relevant clinical and socioeconomic negative outcomes in older persons. The study of this phenomenon and the development of preventive/therapeutic strategies represent public health priorities. The present document reports the results of a recent meeting of the International Working Group on Sarcopenia (a task force consisting of geriatricians and scientists from academia and industry) held on June 7–8, 2011 in Toulouse (France). The meeting was specifically focused at gaining knowledge on the currently available biomarkers (functional, biological, or imaging-related) that could be utilized in clinical trials of sarcopenia and considered the most reliable and promising to evaluate age-related modifications of skeletal muscle. Specific recommendations about the assessment of aging skeletal muscle in older people and the optimal methodological design of studies on sarcopenia were also discussed and finalized. Although the study of skeletal muscle decline is still in a very preliminary phase, the potential great benefits derived from a better understanding and treatment of this condition should encourage research on sarcopenia. However, the reasonable uncertainties (derived from exploring a novel field and the exponential acceleration of scientific progress) require the adoption of a cautious and comprehensive approach to the subject