Objective: Angiogenin (ANG) is a pro-angiogenic and neurotrophic factor with an important role in stress-induced injury, by promoting neovascularization and neuronal survival. Identification of loss-of-function mutations and evidence of beneficial effect of ANG administration in transgenic SOD1(G93A) mice have linked ANG to the pathogenesis of Amyotrophic Lateral Sclerosis (ALS), stimulating interest in considering circulating ANG levels as an ALS disease biomarker although robust evidence is still lacking. Aim of our study was to assess differences of ANG levels in the cerebrospinal fluid (CSF) of a large cohort of patients with ALS and frontotemporal dementia (FTD) compared to controls and to explore correlations between ANG content and disease-related clinical variables. Methods: ANG levels were measured in CSF samples using a commercially available ELISA kit in 88 patients affected with ALS and/or FTD and 46 unrelated individuals (control group). Results: ANG levels didn't differ significantly between cases and controls. Patients with FTD or ALS-FTD showed significantly increased CSF concentration of ANG compared to ALS patients without dementia and controls in a multivariate regression model (p < 0.001). No correlations were found in ALS/FTD patients between ANG levels and clinical parameters, including age, presence of C9orf72 repeat expansion, body mass index (BMI). Conclusions: our findings highlight a role of ANG as CSF biomarker useful to identify ALS patients with concurrent FTD and suggest that it should be further explored as potential biomarker for FTD.

Poletti, B.1; Lafronza, A.1; Solca, F.1; Raspelli, S.2; Cuzziol, P.3; Cadeo, F.4; Carelli, L.5; Meriggi, P.6; Lombardi, C.7; Bilo, G.8; Revera, M.8; Caldara, G.7; Silani, V.1; Mancia, G.8; Parati, G.8 on behalf of the HIGHCARE-ALPS investigators Author Information

Objective: Exposure to high altitude reduces oxygen supply to the central nervous system and may cause neuropsychological impairment. Aim of our study was to evaluate changes in neuropsychological performances of normal subjects when exposed to high and very high altitude, i.e. to conditions representing an experimental model for investigating cognitive functional changes occurring in clinical conditions characterized by reduced brain oxygen supply, such as obstructive sleep apnea or hypertension-related cerebrovascular damage. Design and Method: Forty-five normal subjects participating in the Himalaya's HIGHCARE expedition underwent an extensive neuropsychological and psychodiagnostic assessment at sea level (SL), at 3500 m and at 5400 m altitudes. Different cognitive domains were investigated with paper and pencil tools as well as with computerized tests (X50 eye-tracking device). Psychological status was assessed by clinical checklists. Results: While classic paper and pencil tests did not detect major changes with altitude, better cognitive performances scores were obtained in normoxia and at 3500 m than at 5400 m for computerized psychomotor (keyboard reaction times, KRT) and eye reaction times (ERT): KRT SL vs 5400 m 0.59 ± 0.15 sec vs 0.67 ± 0.17 sec (p < 0.04); KRT SL vs 3500 m 0.59 ± 0.15 sec vs 0.62 ± 0.17 sec (n.s.); KRT 3500 m vs 5400 m 0.62 ± 0.17 sec vs 0.67 ± 0.17 sec (n.s.). ERT SL vs 5400 m 0.44 ± 0.06 sec vs 0.46 ± 0.04 sec (p < 0.001); ERT SL vs 3500m 0.44 ± 0.06 sec vs 0.42 ± 0.05 sec (p < 0.007); ERT 3500m vs 5400m 0.42 ± 0.05 sec vs 0.46 ± 0.04 sec (p < 0.02). ERT were positively related to respiratory rate (RR) (r = 0.53, P < 0.0007). Gender differences were detected, with women having a better performance than men on psychomotor efficiency (% KRT responses) at 5400 m (p < 0.001). Conclusions: High altitude exposure induces specific alterations in cognitive functions, with significant impairment in cognitive performances at 5400m. Our data suggest that computerized tests used for the assessment could be more sensitive than paper and pencil ones, being able to detect even minimal hypoxia-induced changes in cognitive functions. Thus they might be useful in highlighting mild cognitive changes also in hypertensive patients with increased cerebrovascular risk.