Circulating endocannabinoidome signatures of disease activity in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Preclinical studies of amyotrophic lateral sclerosis (ALS) have shown altered endocannabinoid (eCB) signalling that may contribute to the disease. Results from human studies are sparse and inconclusive. The aim of this study was to determine the association between serum levels of eCBs or their congeners, the so-called endocannabinoidome, and disease status and activity in ALS patients. METHODS: Serum concentrations of 2-arachidonoylglycerol and N-arachidonoylethanolamine (AEA), and AEA congeners palmitoylethanolamide (PEA), oleoylethanolamide (OEA), eicosapentaenoylethanolamide (EPEA), 2-docosahexaenoylglycerol (2-DHG) and docosahexaenoylethanolamide (DHEA) were measured in samples from 65 ALS patients, 32 healthy controls (HCs) and 16 neurological disease controls (NALS). A subset of 46 ALS patients underwent a longitudinal study. Disease activity and progression were correlated with eCB and congener levels. RESULTS: Most circulating mediators were higher in ALS than HCs (all p < 0.001), but not NALS. Across clinical stages, ALS patients showed increased levels of PEA, OEA and EPEA (all p < 0.02), which were confirmed by the longitudinal study (all p < 0.03). Serum PEA and OEA levels were independent predictors of survival and OEA levels were higher in patients complaining of appetite loss. Cluster analysis revealed two distinct profiles of circulating mediators associated with corresponding patterns of disease activity (severe vs. mild). Patients belonging to the 'severe' cluster showed significantly higher levels of OEA and PEA and lower levels of 2-DHG compared to NALS and HCs. CONCLUSION: Circulating endocannabinoidome profiles are indicative of disease activity, thus possibly paving the way to a personalized, rather than a 'one-fits-all', therapeutic approach targeting the endocannabinoidome.

Voice signals database of ALS patients with different dysarthria severity and healthy controls.

This paper describes a new publicly-available database of VOiCe signals acquired in Amyotrophic Lateral Sclerosis (ALS) patients (VOC-ALS) and healthy controls performing different speech tasks. This dataset consists of 1224 voice signals recorded from 153 participants: 51 healthy controls (32 males and 19 females) and 102 ALS patients (65 males and 37 females) with different severity of dysarthria. Each subject's voice was recorded using a smartphone application (Vox4Health) while performing several vocal tasks, including a sustained phonation of the vowels /a/, /e/, /i/, /o/, /u/ and /pa/, /ta/, /ka/ syllable repetition. Basic derived speech metrics such as harmonics-to-noise ratio, mean and standard deviation of fundamental frequency (F0), jitter and shimmer were calculated. The F0 standard deviation of vowels and syllables showed an excellent ability to identify people with ALS and to discriminate the different severity of dysarthria. These data represent the most comprehensive database of voice signals in ALS and form a solid basis for research on the recognition of voice impairment in ALS patients for use in clinical applications.

Exploring the relation between reserve and fatigue in multiple sclerosis.

INTRODUCTION: Intellectual enrichment and brain reserve modulate the expression of cognitive and motor disability in multiple sclerosis (MS). Their association with fatigue, one of the most debilitating and common symptoms of MS, has never been explored. MATERIALS AND METHODS: Forty-eight MS patients underwent clinical and MRI examination at baseline and after 1 year. Physical and cognitive MS-related fatigue were evaluated via Modified Fatigue Impact subscales (MFIS-P and MFIS-C). Differences in reserve indexes between fatigued and non-fatigued patients were tested. The relationship between clinico-demographic features, global brain structural damage, indexes of reserve (age-adjusted intracranial volume and cognitive reserve index) and fatigue were tested via correlations and hierarchical linear/binary logistic regression, to predict MFIS-P and MFIS-C (at baseline) or new-onset fatigue and meaningful worsening in MFIS (at follow-up). RESULTS: At baseline, although a significant difference was identified for cognitive reserve questionnaire between fatigued and non-fatigued patients (18.19 ± 4.76 versus 15.15 ± 3.56, p = 0.015), only depression accounted for significant variance in MFIS-P and MFIS-C (R2=0.248, p = 0.002; R2=0.252, p<0.001). MFIS-T, MFIS-P and MFIS-C changes over time were associated to depression changes over time (r = 0.56, r = 0.55, and r = 0.57, respectively; all p<0.001). Indexes of reserve did not differ between non-fatigued patients and patients developing new-onset fatigue at follow-up. None of the baseline features was able to predict the new-onset fatigue or meaningful worsening in MFIS at follow-up. CONCLUSIONS: Among the explored features, only depression was strongly associated to both physical and cognitive fatigue. Intellectual enrichment and brain reserve did not seem to affect fatigue symptoms in MS patients.

Retrospective observational study on the use of acetyl-L-carnitine in ALS.

ALCAR (Acetyl-L-carnitine) is a donor of acetyl groups and increases the intracellular levels of carnitine, the primary transporter of fatty acids across the mitochondrial membranes. In vivo studies showed that ALCAR decrease oxidative stress markers and pro-inflammatory cytokines. In a previous double-blind placebo-controlled phase II trial showed positive effects on self-sufficiency (defined as a score of 3+ on the ALSFRS-R items for swallowing, cutting food and handling utensils, and walking) ALSFRS-R total score and FVC. We conducted an observational, retrospective, multicentre, case-control study to provide additional data on the effects of ALCAR in subjects with ALS in Italy. Subjects treated with ALCAR 1.5 g/day or 3 g/day were included and matched with not treated subjects by sex, age at diagnosis, site of onset, and time from diagnosis to baseline, (45 subjects per group). ALCAR 3 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 23 (51.1%) treated subjects (adj. OR 1.18, 95% CI 0.46-3.02). No statistically significant differences were detected in ALSFRS nor FVC nor self-sufficiency. ALCAR 1.5 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 32 (71.1%) treated subjects (adj. OR 0.27, 95% CI 0.10-0.71). For ALSFRS-R, a mean slope of - 1.0 was observed in treated subjects compared to - 1.4 in those not treated (p = 0.0575). No statistically significant difference was detected in the FVC nor self-sufficiency. Additional evidence should be provided to confirm the efficacy of the drug and provide a rationale for the dosage.

Cognitive impairment is associated with gait variability and fall risk in amyotrophic lateral sclerosis.

BACKGROUND: In amyotrophic lateral sclerosis (ALS), gait abnormalities contribute to poor mobility and represent a relevant risk for falls. To date, gait studies in ALS patients have focused on the motor dimension of the disease, underestimating the cognitive aspects. METHODS: Using a wearable gait analysis device, we compared gait patterns in ambulatory ALS patients with mild cognitive impairment (ALS MCI+; n = 18), and without MCI (ALS MCI-; n = 24), and healthy subjects (HS; n = 16) under two conditions: (1) normal gait (single task) and (2) walking while counting backward (dual task). Finally, we examined if the occurrence and number of falls in the 3 months following the baseline test were related to cognition. RESULTS: In the single task condition, ALS patients, regardless of cognition, displayed higher gait variability than HS, especially for stance and swing time (p < 0.001). The dual task condition revealed additional differences in gait variability parameters between ALS MCI+ and ALS MCI- for cadence (p = 0.005), stance time (p = 0.04), swing time (p = 0.04) and stability index (p = 0.02). Moreover, ALS MCI+ showed a higher occurrence (p = 0.001) and number of falls (p < 0.001) at the follow-up. Regression analyses demonstrated that MCI condition predicted the occurrence of future falls (ß = 3.649; p = 0.01) and, together with executive dysfunction, was associated with the number of falls (cognitive impairment: ß = 0.63; p < 0.001; executive dysfunction: ß = 0.39; p = 0.03), regardless of motor impairment at clinical examination. CONCLUSION: In ALS, MCI is associated with exaggerated gait variability and predicts the occurrence and number of short-term falls.

Correlation between Retinal Vascularization and Disease Aggressiveness in Amyotrophic Lateral Sclerosis.

Abnormalities in retinal vascularization and neural density have been found in many neurodegenerative diseases; however, conflicting results are described in Amyotrophic Lateral Sclerosis (ALS). The aim of the present study was, therefore, to systematically analyze retinal layers and vascularization by means of spectral-domain (SD-OCT) and optical coherence tomography angiography (OCT-A) in ALS patients. We enrolled 48 ALS patients and 45 healthy controls. ALS patients were divided into three groups: slow progressors (n = 10), intermediate progressors (n = 24) and fast progressors (n = 14), according to the disease progression rate. For SD-OCT, we evaluated the Subfoveal choroidal thickness (SFCT), ganglion cell complex (GCC) and retinal nerve fiber layer (RNFL). Regarding the OCT-A, we assessed the vessel density (VD) in superficial and deep capillary plexuses, radial peripapillary capillary plexus, choriocapillary and the foveal avascular zone (FAZ) area. SD-OCT exam did not show any significant differences in GCC and RNFL thickness between patients and controls and among the three ALS groups. The SFCT was statistically greater in patients compared with controls (357.95 ± 55.15 µm vs. 301.3 ± 55.80 µm, p < 0.001); interestingly, the SFCT was thicker in patients with slow and intermediate disease progression than in those with fast disease progression (394.45 ± 53.73 µm vs. 393.09 ± 42.17 µm vs. 267.71 ± 56.24 µm, p < 0.001). OCT-A did not reveal any significant results. Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-r) and disease duration did not correlate with any of the OCT parameters, except for SFCT with ALSFRS-r (r = 0.753, p = 0.024). This study demonstrated the possible association between choroidal thickness and disease activity in ALS. OCT could be a useful biomarker in the management of the disease.