Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease. While genetics and other factors contribute to ALS pathogenesis, critical knowledge is still missing and ...validated biomarkers for monitoring the disease activity have not yet been identified. To address those aspects we carried out this study with the primary aim of identifying possible miRNAs/mRNAs dysregulation associated with the sporadic form of the disease (sALS). Additionally, we explored miRNAs as modulating factors of the observed clinical features. Study included 56 sALS and 20 healthy controls (HCs). We analyzed the peripheral blood samples of sALS patients and HCs with a high-throughput next-generation sequencing followed by an integrated bioinformatics/biostatistics analysis. Results showed that 38 miRNAs (let-7a-5p, let-7d-5p, let-7f-5p, let-7g-5p, let-7i-5p, miR-103a-3p, miR-106b-3p, miR-128-3p, miR-130a-3p, miR-130b-3p, miR-144-5p, miR-148a-3p, miR-148b-3p, miR-15a-5p, miR-15b-5p, miR-151a-5p, miR-151b, miR-16-5p, miR-182-5p, miR-183-5p, miR-186-5p, miR-22-3p, miR-221-3p, miR-223-3p, miR-23a-3p, miR-26a-5p, miR-26b-5p, miR-27b-3p, miR-28-3p, miR-30b-5p, miR-30c-5p, miR-342-3p, miR-425-5p, miR-451a, miR-532-5p, miR-550a-3p, miR-584-5p, miR-93-5p) were significantly downregulated in sALS. We also found that different miRNAs profiles characterized the bulbar/spinal onset and the progression rate. This observation supports the hypothesis that miRNAs may impact the phenotypic expression of the disease. Genes known to be associated with ALS (e.g.,
) were confirmed to be dysregulated in our study. We also identified other potential candidate genes like
(implicated in neuroinflammation) and
(activated in mitochondrial-induced apoptosis). Some of the downregulated genes are involved in molecular bindings to ions (i.e., metals, zinc, magnesium) and in ions-related functions. The genes that we found upregulated were involved in the immune response, oxidation-reduction, and apoptosis. These findings may have important implication for the monitoring, e.g., of sALS progression and therefore represent a significant advance in the elucidation of the disease's underlying molecular mechanisms. The extensive multidisciplinary approach we applied in this study was critically important for its success, especially in complex disorders such as sALS, wherein access to genetic background is a major limitation.
Recent evidence suggests that intermediate-length polyglutamine (PolyQ) expansions in the ataxin-2 (ATXN-2) gene are a risk factor for amyotrophic lateral sclerosis (ALS). This work was undertaken ...with the aim to investigate the frequency of ataxin-1 (ATXN-1) and ATXN-2 PolyQ expansions in a cohort of patients with sporadic ALS (sALS) and patients with familial ALS (fALS) from southern Italy.
We assessed the PolyQ lengths of ATXN-1 and ATXN-2 in 405 patients with sALS, 13 patients with fALS, and 296 unrelated controls without history of neurodegenerative disorders.
We found significantly higher intermediate PolyQ expansions ≥ 32 for ATXN-1 alleles and ≥ 28 for ATXN-2 alleles in the sALS cohort (ATXN-1: ALS, 7.07% vs controls, 2.38%; p = 0.0001; ATXN-2: ALS, 2.72% vs controls, 0.5%; p = 0.001). ATXN-1 CAT and ATXN-2 CAA interruptions were detected in patients with ALS only. Age at onset, site of onset, and sex were not significantly related to the ATXN-1 or ATXN-2 PolyQ repeat length expansions.
Both ATXN-1 and ATXN-2 PolyQ intermediate expansions are independently associated with an increased risk for ALS.
In amyotrophic lateral sclerosis (ALS), memory deficits may be primary or secondary to executive dysfunction. We assessed episodic memory and executive function of nondemented ALS patients, comparing ...episodic memory profiles and learning rates of ALS patients with those of mild cognitive impairment (MCI) subjects and cognitively healthy controls (HC). In a multidisciplinary tertiary centre for motor neuron disease, 72 nondemented ALS patients, 57 amnestic MCI (aMCI), 89 single non amnestic MCI with compromised executive functions (dysexecutive MCI), and 190 HC were enrolled. They were screened using the Frontal Assessment Battery and Mini Mental State Examination. Episodic memory performances and learning rates were tested using the Rey Auditory Verbal Learning Test (RAVLT). Episodic memory dysfunction (immediate recall) was found in 14 ALS patients (19.4%). The ALS group had lower performance than HC on immediate recall, without differences in learning rate, and better performance than aMCI subjects on all RAVLT measures. Compared to dysexecutive MCI subjects, ALS patients had only better verbal learning abilities. ALS patients with executive dysfunction had a lower score on immediate and delayed recalls, verbal learning, and primacy effect than ALS patients without executive dysfunction. The immediate recall among couples of diagnostic groups differed in a statistically significant way except for the ALS/dysexecutive MCI groups. In ALS patients, episodic memory performances and learning rates appeared to be better than in aMCI subjects and similar to those with dysexecutive MCI, suggesting also a secondary functional damage due to executive impairment.
Forced vital capacity (FVC) shows limitations in detecting respiratory failure in the early phase of amyotrophic lateral sclerosis (ALS). In fact, mild-to-moderate respiratory muscle weakness may be ...present even when FVC is normal, and ALS patients with bulbar involvement might not be able to perform correctly the spirometry test. Sniff nasal inspiratory pressure (SNIP) is correlated with transdiaphragmatic strength. We evaluated SNIP at baseline as a prognostic factor of tracheostomy or death in patients with ALS. In a multidisciplinary tertiary care center for motorneuron disease, we enrolled 100 patients with ALS diagnosed with El Escorial criteria in the period between January 2006 and December 2010. Main outcome measures were tracheostomy or death. RECursive Partitioning and AMalgamation (RECPAM) analysis was also used to identify subgroups at different risks for the tracheostomy or death. Twenty-nine patients with ALS reached the outcome (12 died and 17 had tracheostomy). Using a multivariate model SNIP correctly classified the risk of the composite event within 1 year of follow-up with a continuous Net Reclassification Improvement cNRI of 0.58 (
p
= 0.03). Sex, Amyotrophic Lateral Sclerosis Functional Rating Scale revisited, site of onset, and FVC did not improve the classification of prognostic classes. SNIP ≤18 cmH
2
O identified the RECPAM class with the highest risk (Class 1, hazard ratio = 9.85, 95 % confidence interval: 2.67–36.29,
p
< 0.001). SNIP measured at baseline identified patients with ALS with initial respiratory failure. Finally, using only ALS patients with spinal onset of the disease, our findings were mostly overlapping with those reported in the models including the whole sample. At baseline, SNIP appeared to be the best predictor of death or tracheostomy within 1 year of follow-up. The measurement of SNIP in the early phase of the disease may contribute to identify patients with high risk of mortality or intubation. SNIP may also provide an additional tool for baseline stratification of patients with ALS in clinical trials.
Abstract
Our objective was to assess the effects of acetyl-L-carnitine (ALC) with riluzole on disability and mortality of amyotrophic lateral sclerosis (ALS). Definite/probable ALS patients, 40−70 ...years of age, duration 6−24 months, self-sufficient (i.e. able to swallow, cut food/handle utensils, and walk), and with forced vital capacity (FVC) > 80% entered a pilot double-blind, placebo-controlled, parallel group trial and were followed for 48 weeks. ALC or placebo 3 g/day was added to riluzole 100 mg/day. Primary endpoint: number of patients no longer self-sufficient. Secondary endpoints: changes in ALSFRS-R, MRC, FVC and McGill Quality of Life (QoL) scores. Analysis was made in the intention-to-treat (ITT) and per-protocol (PP) population, completers and completers/compliers (i.e. taking > 75% of study drug). Forty-two patients received ALC and 40 placebo. In the ITT population, 34 (80.9%) patients receiving ALC and 39 (97.5%) receiving placebo became non-self-sufficient (p = 0.0296). In the PP analysis, percentages were 84.4 and 100.0% (p = 0.0538), respectively. Mean ALSFRS-R scores at 48 weeks were 33.6 (SD 10.4) and 27.6 (9.9) (p = 0.0388), respectively, and mean FVC scores 90.3 (32.6) and 58.6 (31.2) (p = 0.0158), respectively. Median survival was 45 months (ALC) and 22 months (placebo) (p = 0.0176). MRC, QoL and adverse events were similar. In conclusion, ALC may be effective, well-tolerated and safe in ALS. A pivotal phase III trial is needed.
Percutaneous endoscopic gastrostomy (PEG) is the standard procedure for feeding severely dysphagic patients with amyotrophic lateral sclerosis (ALS). It is associated with prolonged survival and ...improvement in quality of life. Nasal inspiratory pressure during a sniff (SNIP) is a respiratory test used extensively in ALS for the assessment of inspiratory muscle strength. In this study, we aimed to investigate the role of SNIP at baseline to predict PEG placement in ALS. Data from a clinical incident cohort of 179 ALS cases attending the multidisciplinary ALS unit of the University of Bari between April 2006 and December 2012 were retrospectively analysed. At baseline, patients underwent detailed neurological, nutritional and respiratory assessments, including measurements of SNIP and forced vital capacity (FVC). Patients were therefore followed up approximately every three to six months until they were able to attend the centre. The censoring date for the survival analysis was 15 April 2014, with PEG placement as the main outcome. Cox proportional hazard regression models were used to examine the association between SNIP and PEG placement, adjusted for possible confounders. During the follow-up period, 75 participants (42%) received PEG implant. PEG placement was more frequent (57% vs. 31%; p = 0.001) and earlier (after 11.6 ± 14.0 months from the first visit, vs. 23.3 ± 15.5 months; p < 0.0001) in the group of patients with baseline SNIP ≤ 40 cm H2O. Baseline SNIP was a predictor of PEG placement even after correction for multiple potential confounders (HR 0.98; 95% CI: 0.96–0.99; p = 0.02). To conclude, the present study showed that SNIP at baseline is an early indicator of disease progression and therefore of the need for enteral nutrition in ALS.
This article reports a patient with a de novo ∼ 9.32 Mb duplication at 16p13.3 and a ∼ 71 Kb deletion at 22q13.33. The patient was followed from 1 month old to 3 years and 8 months of age and ...presented typical features of the 16p13.3 duplication syndrome. In addition, the patient presents a portal cavernoma, an alteration rarely reported in this condition. Renal agenesis was detected as additional developmental defect. After genomic array and FISH analysis, the karyotype was 46,XX,ins(22;16)(q13;p13.2p13.3). ish ins(22;16)(RP11-35P16+, RP11-27M24+). arr16p13.2p13.3(85,880-9,413,353)×3 dn arr22q13.33 (51,140,789-51,197,838)×1 dn. The authors provide a comprehensive review of the literature. This approach shed light on the genotype-phenotype correlation.
IMPORTANCE: Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for ...neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date. OBJECTIVES: To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions. DATA SOURCES: PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC. STUDY SELECTION: Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex. DATA EXTRACTION AND SYNTHESIS: Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept. MAIN OUTCOME AND MEASURE: The cNfL levels adjusted for age and sex across diagnoses. RESULTS: Data were collected for 10 059 individuals (mean SD age, 59.7 18.8 years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes. CONCLUSIONS AND RELEVANCE: These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
Eye-tracking communication devices and brain-computer interfaces are the two resources available to help people with advanced amyotrophic lateral sclerosis (ALS) avoid isolation and passivity.
This ...study was aimed at assessing a technology-aided program (i.e., a third possible resource) for five patients with advanced ALS who needed support for communication and leisure activities.
The participants were exposed to baseline and intervention conditions. The technology-aided program, which was used during the intervention, (a) included the communication and leisure options that each participant considered important for him or her (e.g., music, videos, statements/requests, and text messaging) and (b) allowed the participant to access those options with minimal responses (e.g., finger movement or eyelid closure) monitored via microswitches.
The participants started leisure and communication engagement independently only during the intervention (i.e., when the program was used). The mean percentages of session time spent in those forms of engagement were between about 60 and 80. Preference checks and brief interviews indicated that participants and families liked the program.
The program might be viewed as an additional approach/resource for patients with advanced ALS.
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