A verb-naming test accurately detects cognitive changes in ALS.

Verb-naming tests were proposed for detecting cognitive impairment in ALS, although statistical evidence on their clinical usefulness is still lacking. A total of 29 ALS patients and 29 demographic-matched healthy controls (HCs) were administered the Action-Verb-Naming Test (AVNT), a standardized picture-naming task of actions. Patients were also administered the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), and classified according to Strong et al. (Amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD): revised diagnostic criteria. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18:153-4) criteria. The AVNT discriminated ALS patients from HCs (p = 0.026) and yielded high accuracy in detecting cognitive impairments among ALS patients (88% of accuracy; sensitivity = 1; specificity = 0.84; PPV = 0.5; NPV = 1; LR+ = 3.83; LR- = 0), as well as a below-cutoff performance on the ECAS (AUC = 0.74). The AVNT was unrelated to other clinical variables, despite being strongly associated with ECAS total, ALS-specific, Language and Executive scores (rs = 0.65-0.75). These findings show that verb naming is an accurate test to detect domain-specific cognitive changes in ALS patients, regardless of their disease phenotype.

Cognition and motor phenotypes in ALS: a retrospective study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is phenotypically heterogeneous in motor manifestations, and the extent of upper vs. lower motor neuron involvement is a widespread descriptor. This study aimed to examine cognition across different ALS motor phenotypes. METHODS: ALS patients (N = 124) were classified as classical (N = 66), bulbar (N = 13), predominant-upper motor neuron (PUMN; N = 19), and predominant-lower motor neuron (PLMN; N = 26) phenotypes. Cognition was assessed with the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and function with the ALS Functional Rating Scale-Revised (ALSFRS-R). Revised ALS-FTD consensus criteria were applied for cognitive/behavioral phenotyping. RESULTS: Defective ECAS-total scores were detected in all groups - bulbar: 15.4%, classical: 30.3%, PLMN: 23.1%, and PUMN: 36.8%. Classical and PUMN ALS patients performed worse than PLMN ones on ECAS-total, ALS-specific, Fluency, and Executive measures. No other difference was detected. Worse ASLFRS-R scores correlated with poorer ECAS-total scores in classical ALS patients. CONCLUSIONS: Frontotemporal cognitive deficits are more prevalent in PUMN and classical ALS and linked to disease severity in the latter, but occur also in PLMN phenotypes.

Comparison between K-nearest-neighbor approaches for conditional entropy estimation: Application to the assessment of the cardiac control in amyotrophic lateral sclerosis patients.

The study evaluates the k-nearest-neighbor (KNN) strategy for the assessment of complexity of the cardiac neural control from spontaneous fluctuations of heart period (HP). Two different procedures were assessed: i) the KNN estimation of the conditional entropy (CE) proposed by Porta et al; ii) the KNN estimation of mutual information proposed by Kozachenko-Leonenko, refined by Kraskov-Stögbauer-Grassberger and here adapted for the CE estimation. The two procedures were compared over HP variability recordings obtained at rest in supine position and during head-up tilt (HUT) in amyotrophic lateral sclerosis patients and healthy subjects. We found that the indexes derived from the two procedures were significantly correlated and both methods were able to detect the effect of HUT on HP complexity within the same group and distinguish the two populations within the same experimental condition. We recommend the use of the KNN strategy to quantify the dynamical complexity of cardiac neural control in addition to more traditional approaches.

Cardiovascular neural regulation is impaired in amyotrophic lateral sclerosis patients. A study by spectral and complexity analysis of cardiovascular oscillations.

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.

Exposure to perfluorinated compounds: in vitro study on thyroid cells.

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are widely used perfluorinated chemicals (PFCs). Previous studies detected PFOA and PFOS in human tissues including the thyroid gland. There are no studies on the in vitro effects of PFOA and PFOS on thyroid cells. Our study was aimed at evaluating the effect of the in vitro exposure to PFOA and PFOS on thyroid cell proliferation and viability. These objectives were investigated using Fisher rat thyroid line-5 (FRTL-5) cells. FRTL-5 cells cultured in the presence of PFOA and PFOS at concentrations up to 10(4) nM do not display changes in their viability and proliferation rate, while at a concentration of 10(5) nM of either PFCs, a significant inhibition of cell proliferation, mainly due to increased cell death, was found. PFOA and PFOS were detected in FRTL-5 cell pellets after 72 h of incubation with PFCs but not in control cultures. When FRTL-5 were incubated with PFCs then washed in PBS and re-cultured for 72 h without PFCs in the medium, no detectable concentrations of PFOA and PFOS were measured in the cell pellet. This indicates that PFOA and PFOS enter thyroid cells by a gradient-based passive diffusion mechanism. Future studies are required to evaluate the potential toxic effect resulting from prolonged in vivo exposure to even lower concentrations of PFCs.

Amyotrophic lateral sclerosis outcome measures and the role of albumin and creatinine: a population-based study.

IMPORTANCE: There is an urgent need to identify reliable biomarkers of amyotrophic lateral sclerosis (ALS) progression for clinical practice and pharmacological trials. OBJECTIVES: To correlate several hematological markers evaluated at diagnosis with ALS outcome in a population-based series of patients (discovery cohort) and replicate the findings in an independent validation cohort from an ALS tertiary center. DESIGN, SETTING, AND PARTICIPANTS: The discovery cohort included 712 patients with ALS from the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis from January 1, 2007, to December 31, 2011. The validation cohort comprised 122 patients with ALS at different stages of disease consecutively seen at an ALS tertiary center between January 1, 2007, and January 1, 2009. MAIN OUTCOMES AND MEASURES: The following hematological factors were investigated and correlated with survival: total leukocytes, neutrophils, lymphocytes, monocytes, glucose, creatinine, uric acid, albumin, bilirubin, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, creatine kinase, thyroid-stimulating hormones, and erythrocyte sedimentation rate; all analyses were performed separately by sex. The patient of the validation cohort also underwent bioelectrical impedance analysis for the calculation of fat-free mass. RESULT: Of the 712 patients in the examined period in Piemonte and Valle d'Aosta, 638 (89.6%) were included in the study. Only serum albumin (men: ≤ 4.3 vs >4.3 mg/dL, P < .001; women: ≤ 4.3 vs >4.3 mg/dL, P < .001) and creatinine levels (men: ≤ 0.82 vs >0.82 mg/dL, P = .004; women: ≤ 0.65 vs >0.05 mg/dL, P = .004) and lymphocyte count (men: ≤ 1700 vs >1700/µL, P = .04; women: ≤ 1700 vs >1700/µL, P = .02) were significantly associated with ALS outcome in both sexes with a dose-response effect (better survival with increasing levels). These findings were confirmed in the validation cohort. Multivariable analysis showed that serum albumin (men: hazard ratio [HR], 1.39; 95% CI, 1.05-1.90; P = .02; women: HR, 1.73; 95 % CI, 1.35-2.39; P = .001) and creatinine (men: HR, 1.47; 95% CI, 1.11-1.95; P = .007; women: HR, 1.49; 95% CI, 1.07-2.05; P = .02) were independent predictors of survival in both sexes; no other hematological factor was retained in the model. In patients with ALS, serum albumin was correlated with markers of inflammatory state while serum creatinine was correlated with fat-free mass, which is a marker of muscle mass. CONCLUSIONS AND RELEVANCE: In ALS, serum albumin and creatinine are independent markers of outcome in both sexes. Creatinine reflects the muscle waste whereas albumin is connected with inflammatory state. Both creatinine and albumin are reliable markers of the severity of clinical status in patients with ALS and can be used in defining prognosis at the time of diagnosis.

Severe disability in patients with relapsing-remitting multiple sclerosis is associated with profound changes in the regulation of leptin secretion.

OBJECTIVES: Experimental evidences indicate that leptin is involved in the neuroinflammatory process sustaining multiple sclerosis (MS). However, the relationship between leptin and body fat, as assessed by body mass index (BMI), in MS was not previously evaluated. It was the aim of this study to compare serum leptin levels between patients with MS and healthy controls and to evaluate the possible relationship between circulating leptin levels and disease severity. PATIENTS AND METHODS: Eighty-four MS patients and 57 sex-matched healthy volunteers were enrolled. Serum leptin levels were measured in all patients and controls. MS patients were stratified in 3 groups according to their degree of disability as assessed by the Expanded Disability Status Scale (EDSS). Patients were classified as having low (33 patients with an EDSS score <1.5), intermediate (28 patients with an EDSS score from 2 to 3) and high disability (23 patients with an EDSS score ≥3.5). RESULTS: No significant differences in serum leptin levels and BMI were observed between patients and controls. In patients with MS, serum leptin levels were significantly correlated with BMI in those patients with low (R(2) = 0.363; p < 0.001) and intermediate disability (R(2) = 0.408; p < 0.001), but not in patients with a higher disability score (R(2) = 0.064; p = 0.256). CONCLUSION: BMI, the major determinant of leptin level in physiological conditions, has a minor role in determining the serum levels of leptin in MS patients with a high EDSS score. Future longitudinal studies will be required in order to provide further insights into the regulation of leptin secretion in patients with MS.

Type I and type II interferons inhibit both basal and tumor necrosis factor-α-induced CXCL8 secretion in primary cultures of human thyrocytes.

Interferons (IFNs) and tumor necrosis factor-α (TNF-α) cooperate in activating several inflammation-related genes, which sustain chronic inflammation in autoimmune thyroid disease (AITD). Much is known about the positive signaling of IFNs to activate gene expression in AITD, while the mechanisms by which IFNs negatively regulate genes remain less studied. While IFNs inhibit CXCL8 secretion in several human cell types, their effects on thyroid cells were not evaluated. Our aim was to study the interplay between TNF-α and type I or type II IFNs on CXCL8 secretion by human thyroid cells. CXCL8 was measured in supernatants of primary cultures of thyroid cells basally and after a 24-h incubation with TNF-α. CXCL8 was detected in thyroid cell supernatants in basal conditions (96.2±23.5 pg/mL) being significantly increased (784.7±217.3 pg/mL; P<0.0001 vs. basal) by TNF-α. Twenty-four hour incubation with IFN-γ or IFN-ß or IFN-α dose dependently and significantly inhibited both basal and TNF-α-induced CXCL8 secretion. The degree of the inhibitory effect was IFN-γ>IFN-ß>IFN-α. This study demonstrates that type I and type II IFNs downregulate both basal and TNF-α-induced CXCL8 secretion by human thyrocytes, IFN-γ being the most powerful inhibitor. Future studies aimed at a better comprehension of the interplay between CXCL8 and thyroid diseases appear worthwhile.

Interferon-γ and tumor necrosis factor-α sustain secretion of specific CXC chemokines in human thyrocytes: a first step toward a differentiation between autoimmune and tumor-related inflammation?

CONTEXT: Chemokines are chemotactic cytokines responsible for the attraction and recruitment of different cell types during leukocyte infiltration, the histopathological hallmark of autoimmunity. Previous data demonstrate that thyrocytes secrete CXC chemokines, particularly CXCL8 and CXCL10. However, the physiopathological significance of such secretion and the effects of a combination of proinflammatory stimuli in terms of preferential CXCL8 and CXCL10 release remain unclear. OBJECTIVE: The aim of this study was to investigate whether the secretion of chemokines by human thyrocytes is a generalized inflammatory response or whether it is dependent upon specific proinflammatory stimuli. METHODS: CXCL8 and CXCL10 were measured in supernatants of human thyrocytes in primary cultures basally and after 24 h stimulation with interferon-γ (IFNγ) (1000 U/ml) and TNFα (10 ng/ml), alone or in combination. RESULTS: CXCL8 but not CXCL10 was detected in basal conditions. The two chemokines showed differences in their response to proinflammatory cytokines. Indeed, significant secretion of CXCL10 was induced by IFNγ (P < 0.01) and not TNFα, whereas CXCL8 was secreted in response to TNFα (P < 0.01) being inhibited by IFNγ (P < 0.01). The combination of TNFα plus IFNγ synergistically increased the IFNγ-induced CXCL10 secretion (P < 0.01) and reversed the TNFα-induced CXCL8 secretion (P < 0.01). CONCLUSIONS: These results confirm that human thyrocytes secrete CXC chemokines and demonstrate that the secretion of CXCL8 and CXCL10 is sustained by specific proinflammatory cytokines or their combination, which ultimately determines the nature of the infiltrating lymphocytes in human thyroid diseases. These results indirectly support a major role for CXCL10 in thyroid autoimmunity whereas CXCL8 might be involved in tumor-related inflammation.