Acute brain ischemia causes changes in several neural networks and related cortico-subcortical excitability, both in the affected area and in the apparently spared contralateral hemisphere. The modulation of these processes through modern techniques of noninvasive brain stimulation, namely repetitive transcranial magnetic stimulation (rTMS), has been proposed as a viable intervention that could promote post-stroke clinical recovery and functional independence. This review provides a comprehensive summary of the current evidence from the literature on the efficacy of rTMS applied to different clinical and rehabilitative aspects of stroke patients. A total of 32 meta-analyses published until July 2019 were selected, focusing on the effects on motor function, manual dexterity, walking and balance, spasticity, dysphagia, aphasia, unilateral neglect, depression, and cognitive function after a stroke. Only conventional rTMS protocols were considered in this review, and meta-analyses focusing on theta burst stimulation only were excluded. Overall, both HF-rTMS and LF-rTMS have been shown to be safe and well-tolerated. In addition, the current literature converges on the positive effect of rTMS in the rehabilitation of all clinical manifestations of stroke, except for spasticity and cognitive impairment, where definitive evidence of efficacy cannot be drawn. However, routine use of a specific paradigm of stimulation cannot be recommended yet due to a significant level of heterogeneity of the studies in terms of protocols to be set and outcome measures that have to be used. Future studies need to preliminarily evaluate the most promising protocols before going on to multicenter studies with large cohorts of patients in order to achieve a definitive translation into daily clinical practice.

Cognitive impairment, also known as cognitive decline, can occur gradually or suddenly and can be temporary or more permanent. It represents an increasingly important public health problem and can depend on normal aging or be linked to different neurodegenerative disorders, including Alzheimer’s disease (AD). It is now well-established that lifestyle factors including dietary patterns play an important role in healthy aging as well as in the prevention of cognitive decline in later life. Among the natural compounds, dietary polyphenols including phenolic acids have been recently the focus of major attention, with their supplementation being associated with better cognitive status and prevention of cognitive decline. Despite their therapeutic potential, human studies investigating the relation between phenolic acids intake and cognitive outcomes are rather scarce. In this review, we provide preclinical evidence that different dietary polyphenols such as rosmarinic acid, ellagic acid, and cinnamic aldehyde can exert neuroprotective and pro-cognitive activities through different molecular mechanisms including the modulation of pro-oxidant and antioxidant machinery as well as inflammatory status. Future and more numerous in vivo studies are needed to strengthen the promising results obtained at the preclinical level. Despite the excellent pharmacokinetic properties of phenolic acids, which are able to be accumulated in the brain at pharmacologically relevant levels, future studies should also identify which among the different metabolites produced as a consequence of phenolic acids’ consumption may be responsible for the potential neuroprotective effects of this subgroup of polyphenols.

The neurodegenerative synucleinopathies, including Parkinson’s disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson’s disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson’s disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson’s disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials.