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We investigated whether the C9orf72 repeat expansion is associated with specific clinical features, comorbidities, and prognosis in patients with amyotrophic lateral sclerosis (ALS). A cohort of 1417 ALS patients, diagnosed between January 1, 2009 and December 31, 2013 by 13 Italian ALS Referral Centers, was screened for the C9orf72 repeat expansion, and the analyses were performed comparing patients carrying this expansion (ALS-C9Pos) to those negative for this and other explored ALS-related mutations (ALS without genetic mutations, ALSwoGM). Compared to the ALSwoGM group, ALS-C9Pos patients (n = 84) were younger at disease onset, at the first clinical observation and at diagnosis (p < 0.001). After correcting for these differences, we found that ALS-C9Pos patients had higher odds of bulbar onset, diagnosis of frontotemporal dementia (FTD) and family history of ALS, FTD, and Alzheimer's disease and had lower odds of spinal onset, non-invasive ventilation, hypertension and psychiatric diseases than ALSwoGM patients. Among these variables, those related to shorter survival time were: bulbar onset, presence of FTD, hypertension, psychiatric disease, and family history of ALS (p < 0.05). Cox proportional hazards regression multivariate analysis suggested that carrying the C9orf72 repeat expansion was an independent factor negatively impacting on survival time in men (HR 1.58, 95% CI 1.07–2.33, p = 0.021), but not in women (p > 0.05) as well as in the whole sample (p > 0.05). When compared to ALSwoGM, ALS-C9Pos showed an earlier disease onset, no significant diagnostic delay and a higher odds of bulbar onset, FTD and family history of ALS and dementia. Moreover, male sex drove the negative effect of expanded variant on survival, confirming the hypothesis that sex is likely to be a crucial factor in the biology of C9orf72-related disease.

Amyotrophic lateral sclerosis (ALS) is a fatal progressive motor neuron disease, for which there are still no diagnostic/prognostic test and therapy. Specific molecular biomarkers are urgently needed to facilitate clinical studies and speed up the development of effective treatments.We used a two-dimensional difference in gel electrophoresis approach to identify in easily accessible clinical samples, peripheral blood mononuclear cells (PBMC), a panel of protein biomarkers that are closely associated with ALS. Validations and a longitudinal study were performed by immunoassays on a selected number of proteins. The same proteins were also measured in PBMC and spinal cord of a G93A SOD1 transgenic rat model. We identified combinations of protein biomarkers that can distinguish, with high discriminatory power, ALS patients from healthy controls (98%), and from patients with neurological disorders that may resemble ALS (91%), between two levels of disease severity (90%), and a number of translational biomarkers, that link responses between human and animal model. We demonstrated that TDP-43, cyclophilin A and ERp57 associate with disease progression in a longitudinal study. Moreover, the protein profile changes detected in peripheral blood mononuclear cells of ALS patients are suggestive of possible intracellular pathogenic mechanisms such as endoplasmic reticulum stress, nitrative stress, disturbances in redox regulation and RNA processing.Our results indicate that PBMC multiprotein biomarkers could contribute to determine amyotrophic lateral sclerosis diagnosis, differential diagnosis, disease severity and progression, and may help to elucidate pathogenic mechanisms.

Background: The sympathetic baroreflex (sBR) adjusts muscle sympathetic nerve activity (MSNA) in response to arterial pressure changes but the relevance of assessing sBR control complexity is unclear. Objective: We propose a method for the evaluation of sBR control complexity. Approach: The approach comprises the quantification of complexity of the sBR latency regulation and the assessment of complexity of the relationship linking MSNA burst to R-wave peak regardless of the variability of the sBR latency. The Shannon entropy (SE) of the sBR latency distribution is taken as an estimate of complexity of the sBR latency regulation. The conditional entropy (CE) of the beat-to-beat binary series obtained by coding the presence/absence of the MSNA burst after an R-wave peak is taken as an estimate of complexity of the sBR control regardless of the sBR latency variability. Surrogate analysis was utilized to set the level of inactive or impaired sBR. The approach was applied to 10 young healthy subjects undergoing head-up tilt (HUT) followed by lower body negative pressure to evoke presyncope (preSYNC) before and after 21 d head-down bed rest (HDBR), and to five amyotrophic lateral sclerosis (ALS) patients undergoing HUT. Main results: In healthy subjects the surrogate analysis suggested that HUT and preSYNC significantly activated the sBR control but its response was weakened after 21 d HDBR. During preSYNC sBR latency increased significantly only after 21 d HDBR. In ALS patients the complexity of the sBR latency regulation was close to the level set by surrogate analysis and HUT did not trigger any sBR control response. Significance: The proposed method for sBR control complexity quantification was useful in detecting the impairment of the sBR control after 21 d HDBR in healthy subjects and the dysfunction of the sBR regulation in ALS patients. [ABSTRACT FROM AUTHOR]

Although the clinical hallmark of amyotrophic lateral sclerosis (ALS) is a progressive motor weakness, different combinations of autonomic nervous system (ANS) dysfunction have been described. No clear correlation between ANS abnormalities and ALS clinical characteristics has been found so far. We investigated the cardiovascular neural regulation in ALS with a non-invasive methodology, using spectral and complexity analysis of heart rate variability (HRV) and systolic arterial pressure (SAP) variability. In all patients, we found low RR variance and an altered response to orthostasis, witnessed by the indices derived from both spectral and complexity analysis of HRV and SAP variability. Besides, we identified two groups with distinct autonomic profiles at rest, those with higher, and those with lower cardiac sympathetic activity. In both groups the cardiovascular response to tilting was impaired. Our study outlined that ANS is invariably impaired in ALS, and patients can present with different baseline patterns. Our findings suggest important pathophysiological, clinical and prognostic insights. The presence of different autonomic profiles at rest supports the new concept of ALS as a multisystem disorder with phenotypic heterogeneity. Our results are also relevant in clinical practice. They can help to improve patients’ management, and to identify prognostic factors. [ABSTRACT FROM AUTHOR]