Objective To assess progression of semantic loss in early stages of cognitive decline using semantic and letter fluency performance, and its relation with Alzheimer's disease (AD)‐specific neurodegeneration using longitudinal multimodal neuroimaging measures. Methods Change in verbal fluency was analyzed among 2261 non‐demented individuals with a follow‐up diagnosis of no mild cognitive impairment (MCI), amnestic MCI (aMCI), non‐amnestic MCI (naMCI), or incident dementia, using linear mixed models across 4 years of follow‐up, and relations with magnetic resonance imaging (MRI; n = 1536) and 18 F‐fluorodeoxyglucose brain positron emission tomography ( 18 F‐FDG‐PET) imaging (n = 756) using linear regression models across 2 years of follow‐up. Results Semantic fluency declined—fastest in those at higher risk for AD (apolipoprotein E [APOE] e4 carriers, Clinical Dementia Rating score of .5, aMCI, or incident dementia)—while letter fluency did not except for those with incident dementia. Lower baseline semantic fluency was associated with an increase in white matter hyperintensities and total mean cortical thinning over time, and regionally with less hippocampal volume as well as more cortical thinning and reduced 18 F‐FDG‐PET uptake in the inferior parietal lobule, entorhinal cortex, isthmus cingulate, and precuneus–posterior cingulate area. In contrast, baseline letter fluency was not associated with change in total nor regional neurodegeneration. Whole‐brain neurodegeneration over time was associated with faster decline in both fluencies, while AD‐specific regions were associated with a faster rate of decline in semantic but not letter fluency. Interpretation This study provides strong evidence of distinctive degeneration of semantic abilities early on in relation to both cognitive decline and AD‐specific neurodegeneration.

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder affecting both upper and lower motor neurons. Despite much research and effort, no clear insights into a unifying hypothesis for the pathogenesis has so far emerged for this disease. Areas covered: We review the main pathophysiological hypotheses and the potential therapeutic targets in ALS, as well as the management of these patients (in order to improve their survival and quality of life). Expert commentary: ALS is a complex neurodegenerative disease, these days considered as a multisystem disorder with predominant motor symptoms (and various clinical forms). Further comprehension of the pathophysiology of this disease is required, although pathophysiological mechanisms (such as TDP-43) show promise in the search for new therapies. There is still no curative treatment for ALS, but the emergence of multidisciplinary specialized ALS clinics has increased both the quality of life and the survival of these patients.

Amyotrophic lateral sclerosis (ALS), identified as a distinct clinical entity by Charcot since the end of the nineteenth century, is a devastating and fatal neurodegenerative disorder that affects motor neurons in the brain, brainstem and spinal cord. Survival of patients with ALS is associated with several factors such as clinical phenotype, age at onset, gender, early presence of respiratory failure, weight loss and treatment with Riluzole (the only disease-modifying drug approved for this disease). Nowadays, there is still no curative treatment for ALS: palliative care and symptomatic treatment are therefore essential components in the management of these patients. Nevertheless, the scientific knowledge in the field of ALS motor neuron degeneration is growing, with the prospect of new treatments. Based on this physiopathological knowledge, several new therapeutic targets are being studied, involving various mechanisms such as excitotoxicity, neuroinflammation, mitochondrial dysfunction, oxidative stress, RNA metabolism and other attractive concepts. Moreover, it is also important to identify reliable biomarkers that will be essential components for future therapeutic development and study design in ALS. In this review, we present the main recent advances and promising therapeutics and biomarkers in the field of ALS.