Proteinopathy and neuroinflammation are two main hallmarks of neurodegenerative diseases. They also represent rare common events in an exceptionally broad landscape of genetic, environmental, neuropathologic, and clinical heterogeneity present in patients. Here, we aim to recount the emerging trends in amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) spectrum disorder. Our review will predominantly focus on neuroinflammation and systemic immune imbalance in ALS and FTD, which have recently been highlighted as novel therapeutic targets. A common mechanism of most ALS and ~50% of FTD patients is dysregulation of TAR DNA-binding protein 43 (TDP-43), an RNA/DNA-binding protein, which becomes depleted from the nucleus and forms cytoplasmic aggregates in neurons and glia. This, in turn, via both gain and loss of function events, alters a variety of TDP-43-mediated cellular events. Experimental attempts to target TDP-43 aggregates or manipulate crosstalk in the context of inflammation will be discussed. Targeting inflammation, and the immune system in general, is of particular interest because of the high plasticity of immune cells compared to neurons.

Background: Differentiation between primary (PLS) and amyotrophic lateral sclerosis (ALS) entails relevant consequences for prognosis and management but is mostly unreliable at early stages. The objectives of the study are: i) to determine the features at onset that could help to differentiate between PLS and ALS; ii) to evaluate the diagnostic performance of an integrated serum biomarker panel; iii) to identify the prognostic factors for patients presenting with an upper motor neuron (UMN)-syndrome. Methods: We selected and retrospectively analyzed the clinical data of patients presenting with UMN-syndrome. At the first evaluation, when available, serum biomarkers were measured using ultrasensitive single molecule array. Results: Study population included 55 PLS and 50 ALS patients. PLS patients presented a longer time to first neurological evaluation (PLS: 35.0 months, IQR: 17.0-38.0; ALS: 12.5 months, IQR: 7.0-21.3; p<0.01) and lower levels of neurofilament light chain (NfL) (PLS: 81.8 pg/mL, IQR: 38.4-111.1; ALS: 155.9 pg/mL, IQR: 85.1-366.4; p=0.01). Two PLS and three ALS patients carried the C9orf72 expansion. NfL resulted an independent predictor of final diagnosis (OR: 1.01, 95%CI: 1.00-1.02; p=0.04) and an independent prognostic factor (HR: 1.01, 95%CI: 1.00-1.01; p<0.01). Conclusions: NfL might help to differentiate PLS from ALS patients and to predict prognosis in patients with an UMN-syndrome.

Background and ObjectivesThere is currently no validated disease-stage biomarker for amyotrophic lateral sclerosis (ALS). The identification of quantitative and reproducible markers of disease stratification in ALS is fundamental for study design ...

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with variable phenotypic expressions which has been associated with autonomic dysfunction. The cardiovascular system seems to be affected especially in the context of bulbar involvement. We describe four new cases of Tako-Tsubo syndrome (TTS) in ALS patients with an appraisal of the literature. We present a late-stage ALS patient with prominent bulbar involvement that presented TTS during hospitalization. We then retrospectively identify three additional ALS–TTS cases reporting relevant clinical findings. TTS cardiomyopathy has been observed in different acute neurological conditions, and the co-occurrence of ALS and TTS has already been reported. Cardiovascular autonomic dysfunctions have been described in ALS, especially in the context of an advanced diseases and with bulbar involvement. Noradrenergic hyperfunction linked to sympathetic denervation and ventilatory deficits coupled in different instances with a trigger event could play a synergistic role in the development of TTS in ALS. Sympathetic hyperfunctioning and ventilatory deficits in conjunction with cardiac autonomic nerves impairment may play a role in the development of TTS in a context of ALS.