Sensory aspects of restless legs syndrome: Clinical, neurophysiological and neuroimaging prospectives.

Restless Legs Syndrome (RLS) is a complex sensorimotor disorder, classified among the sleep-related movement disorders. Although sensory symptoms appear as key features of the disorder, they are still poorly characterized from a clinical perspective and conceptualized from a pathophysiological point of view. In this review, we aim to describe the clinical and functional substrates of RLS, focusing mainly on its sensory symptoms and on their neurophysiological and anatomical correlates. Knowledge of both subjective sensory symptoms and objective sensory signs are still controversial. Current data also indicate that the sensory component of RLS seems to be subserved by anomalies of sensorimotor integration and by mechanism of central sensitization. Overall, electrophysiological findings highlight the involvement of multiple generators in the pathogenesis of RLS, eventually resulting in an increased nervous system excitability and/or alterations in inhibition within the somatosensory and nociceptive pathways. Structural and functional neuroimaging data show the involvement of several crucial areas and circuits, among which the thalamus appears to play a pivotal role. A holistic approach looking at brain connectivity, structural or functional abnormalities, and their interplay with molecular vulnerability and neurotransmitter alterations is warranted to disentangle the complex framework of RLS.

Targeting the adenosinergic system in restless legs syndrome: A pilot, "proof-of-concept" placebo-controlled TMS-based protocol.

Restless Legs Syndrome (RLS) is a common sleep disorder characterized by an urge to move the legs that is responsive to movement (particularly during rest), periodic leg movements during sleep, and hyperarousal. Recent evidence suggests that the involvement of the adenosine system may establish a connection between dopamine and glutamate dysfunction in RLS. Transcranial magnetic stimulation (TMS) is a non-invasive electrophysiological technique widely applied to explore brain electrophysiology and neurochemistry under different experimental conditions. In this pilot study protocol, we aim to investigate the effects of dipyridamole (a well-known enhancer of adenosinergic transmission) and caffeine (an adenosine receptor antagonist) on measures of cortical excitation and inhibition in response to TMS in patients with primary RLS. Initially, we will assess cortical excitability using both single- and paired-pulse TMS in patients with RLS. Then, based on the measures obtained, we will explore the effects of dipyridamole and caffeine, in comparison to placebo, on various TMS parameters related to cortical excitation and inhibition. Finally, we will evaluate the psycho-cognitive performance of RLS patients to screen them for cognitive impairment and/or mood-behavioral dysfunction, thus aiming to correlate psycho-cognitive findings with TMS data. Overall, this study protocol will be the first to shed lights on the neurophysiological mechanisms of RLS involving the modulation of the adenosine system, thus potentially providing a foundation for innovative "pharmaco-TMS"-based treatments. The distinctive TMS profile observed in RLS holds indeed the potential utility for both diagnosis and treatment, as well as for patient monitoring. As such, it can be considered a target for both novel pharmacological (i.e., drug) and non-pharmacological (e.g., neuromodulatory), "TMS-guided", interventions.

Large Muscle Group Movements during Sleep in Restless Leg Syndrome: Neurophysiological and Clinical Implications.

STUDY OBJECTIVES: Recently, criteria have been drawn up for Large Muscle group Movements during sleep (LMM), defined as movements lasting for 3-45 seconds in adults, which are often accompanied by changes in sleep stage, arousals, and increases in heart rate. The aim of this study was to characterize LMM in RLS, in order to better evaluate their impact on the neurophysiology of the disorder and, therefore, the possible clinical implications. METHODS: Consecutive, drug-free patients diagnosed with RLS and controls, aged 18 years or more, were retrospectively enrolled. Leg movement activity - short-interval (SILMS), periodic (PLMS) and isolated (ISOLMS) leg movements during sleep - and LMM were detected and scored. RESULTS: One-hundred patients and 67 controls were recruited. All movement measures were significantly higher in RLS. A significant positive correlation was found between LMM and ISOLMS index but not PLMS index in both groups. LMM index showed a significant negative correlation with total sleep time, sleep efficiency, and percentage of sleep stages N3 and R, as well as a significant positive correlation with number of awakenings, and percentage of sleep stages N1 and N2 only in patients with RLS. No significant correlation was found for either LMM or PLMS index and RLS severity. CONCLUSIONS: Different types of movements, including SILMS, ISOLMS, and LMM, play somewhat distinct roles in sleep neurophysiology in RLS. Notably, LMM, a newly recognized category of movements, demonstrate associations with sleep architecture instability and fragmentation, arousals, and awakenings, suggesting potential clinical implications.

A survey-based approach on restless legs syndrome: practices and perspectives among Italian neurologists.

INTRODUCTION: Restless Legs Syndrome (RLS) is a widely prevalent and complex neurological disorder. Despite notable advancements in managing RLS, the disorder continues to face challenges related to its recognition and management. OBJECTIVE: This study seeks to gain comprehensive insights into the knowledge and clinical practices among Italian neurologists regarding RLS diagnosis, management, and treatment, comparing approaches among general neurologists, movement disorder specialists, and sleep experts. METHODS: Members of the Italian Society of Neurology, the Italian Society of Parkinson and Movement Disorders, and the Italian Association of Sleep Medicine were invited to participate in a 19-question online survey. RESULTS: Among the 343 surveyed neurologists, 60% categorized RLS as a "sleep-related movement disorder." Forty% indicated managing 5-15 RLS patients annually, with sleep specialists handling the highest patient volume. Of note, only 34% adhered strictly to all five essential diagnostic criteria. The majority (69%) favored low-dosage dopamine agonists as their first-line treatment, with movement disorder specialists predominantly endorsing this approach, while sleep experts preferred iron supplementation. Regular screening for iron levels was widespread (91%), with supplementation typically guided by serum iron alterations. In cases of ineffective initial treatments, escalating dopamine agonist dosage was the preferred strategy (40%). CONCLUSIONS: These findings underscore a lack of a clear conceptualization of RLS, with a widespread misconception of the disorder as solely a movement disorder significantly influencing treatment approaches. Disparities in RLS understanding across neurology subspecialties underscore the necessity for improved diagnostic accuracy, targeted educational initiatives, and management guidelines to ensure consistent and effective RLS management.

Unveiling the pathophysiology of restless legs syndrome through transcriptome analysis.

The aim of this study was to analyze signaling pathways associated with differentially expressed messenger RNAs in people with restless legs syndrome (RLS). Seventeen RLS patients and 18 controls were enrolled. Coding RNA expression profiling of 12,857 gene transcripts by next-generation sequencing was performed. Enrichment analysis by pathfindR tool was carried-out, with p-adjusted ≤0.001 and fold-change ≥2.5. Nine main different network groups were significantly dysregulated in RLS: infections, inflammation, immunology, neurodegeneration, cancer, neurotransmission and biological, blood and metabolic mechanisms. Genetic predisposition plays a key role in RLS and evidence indicates its inflammatory nature; the high involvement of mainly neurotropic viruses and the TORCH complex might trigger inflammatory/immune reactions in genetically predisposed subjects and activate a series of biological pathways-especially IL-17, receptor potential channels, nuclear factor kappa-light-chain-enhancer of activated B cells, NOD-like receptor, mitogen-activated protein kinase, p53, mitophagy, and ferroptosis-involved in neurotransmitter mechanisms, synaptic plasticity, axon guidance, neurodegeneration, carcinogenesis, and metabolism.

Setting research priorities for global pandemic preparedness: An international consensus and comparison with ChatGPT's output.

Background: In this priority-setting exercise, we sought to identify leading research priorities needed for strengthening future pandemic preparedness and response across countries. Methods: The International Society of Global Health (ISoGH) used the Child Health and Nutrition Research Initiative (CHNRI) method to identify research priorities for future pandemic preparedness. Eighty experts in global health, translational and clinical research identified 163 research ideas, of which 42 experts then scored based on five pre-defined criteria. We calculated intermediate criterion-specific scores and overall research priority scores from the mean of individual scores for each research idea. We used a bootstrap (n = 1000) to compute the 95% confidence intervals. Results: Key priorities included strengthening health systems, rapid vaccine and treatment production, improving international cooperation, and enhancing surveillance efficiency. Other priorities included learning from the coronavirus disease 2019 (COVID-19) pandemic, managing supply chains, identifying planning gaps, and promoting equitable interventions. We compared this CHNRI-based outcome with the 14 research priorities generated and ranked by ChatGPT, encountering both striking similarities and clear differences. Conclusions: Priority setting processes based on human crowdsourcing - such as the CHNRI method - and the output provided by ChatGPT are both valuable, as they complement and strengthen each other. The priorities identified by ChatGPT were more grounded in theory, while those identified by CHNRI were guided by recent practical experiences. Addressing these priorities, along with improvements in health planning, equitable community-based interventions, and the capacity of primary health care, is vital for better pandemic preparedness and response in many settings.

Polysomnographic features associated with clonazepam and melatonin treatment in isolated REM sleep behavior disorder: Time for new therapeutic approaches?

AIMS: Although clonazepam (CLO) and melatonin (MLT) are the most frequently used treatments for REM sleep behavior disorder, the polysomnographic features associated with their use are little known. The aim of this study was to evaluate polysomnographic and clinical parameters of patients with idiopathic/isolated REM sleep behavior disorder (iRBD) treated chronically with CLO, sustained-release MLT, alone or in combination, and in a group of drug-free iRBD patients. METHODS: A total of 96 patients were enrolled: 43 drug-free, 21 with CLO (0.5-2 mg), 20 with sustained-release MLT (1-4 mg), and 12 taking a combination of them (same doses). Clinical variables and polysomnography were collected. RESULTS: Although clinical improvement was reported in all groups, MLT impacted sleep architecture more than the other treatments, with significant and large increase in N3 stage, moderate reduction in N2 and REM sleep, and moderate increase in REM latency. CLO moderately increased the percentage of both REM sleep and especially N2, while reducing N1 and wakefulness. Patients treated with both CLO and MLT did not show major changes in sleep architecture. CONCLUSION: These results suggest that the administration of MLT or CLO impacts (positively) on sleep parameters of iRBD patients. However, there is a need to better stratify patients, in order to treat them in a targeted manner, depending on the patient's individual sleep architecture and expected differential effects of these agents.

Current opinions and practices in post-stroke movement disorders: Survey of movement disorders society members.

BACKGROUND: Post-stroke movement disorders (PSMD) encompass a wide array of presentations, which vary in mode of onset, phenomenology, response to treatment, and natural history. There are no evidence-based guidelines on the diagnosis and treatment of PSMD. OBJECTIVES: To survey current opinions and practices on the diagnosis and treatment of PSMD. METHODS: A survey was developed by the PSMD Study Group, commissioned by the International Parkinson's and Movement Disorders Society (MDS). The survey, distributed to all members, yielded a total of 529 responses, 395 (74.7%) of which came from clinicians with experience with PSMD. RESULTS: Parkinsonism (68%), hemiballismus/hemichorea (61%), tremor (58%), and dystonia (54%) were by far the most commonly endorsed presentation of PSMD, although this varied by region. Basal ganglia stroke (76% of responders), symptoms contralateral to stroke (75%), and a temporal relationship (59%) were considered important factors for the diagnosis of PSMD. Oral medication use depended on the phenomenology of the PSMD. Almost 50% of respondents considered deep brain stimulation and ablative surgeries as options for treatment. The lack of guidelines for the diagnosis and treatment was considered the most important gap to address. CONCLUSIONS: Regionally varying opinions and practices on PSMD highlight gaps in (and mistranslation of) epidemiologic and therapeutic knowledge. Multicenter registries and prospective community-based studies are needed for the creation of evidence-based guidelines to inform the diagnosis and treatment of patients with PSMD.

Efficacy and safety of ketamine and esketamine for unipolar and bipolar depression: an overview of systematic reviews with meta-analysis.

Background: Unipolar and bipolar depression present treatment challenges, with patients sometimes showing limited or no response to standard medications. Ketamine and its enantiomer, esketamine, offer promising alternative treatments that can quickly relieve suicidal thoughts. This Overview of Reviews (OoR) analyzed and synthesized systematic reviews (SRs) with meta-analysis on randomized clinical trials (RCTs) involving ketamine in various formulations (intravenous, intramuscular, intranasal, subcutaneous) for patients with unipolar or bipolar depression. We evaluated the efficacy and safety of ketamine and esketamine in treating major depressive episodes across various forms, including unipolar, bipolar, treatment-resistant, and non-resistant depression, in patient populations with and without suicidal ideation, aiming to comprehensively assess their therapeutic potential and safety profile. Methods: Following PRIOR guidelines, this OoR's protocol was registered on Implasy (ID:202150049). Searches in PubMed, Scopus, Cochrane Library, and Epistemonikos focused on English-language meta-analyses of RCTs of ketamine or esketamine, as monotherapy or add-on, evaluating outcomes like suicide risk, depressive symptoms, relapse, response rates, and side effects. We included studies involving both suicidal and non-suicidal patients; all routes and formulations of administration (intravenous, intramuscular, intranasal) were considered, as well as all available comparisons with control interventions. We excluded meta-analysis in which the intervention was used as anesthesia for electroconvulsive therapy or with a randomized ascending dose design. The selection, data extraction, and quality assessment of studies were carried out by pairs of reviewers in a blinded manner. Data on efficacy, acceptability, and tolerability were extracted. Results: Our analysis included 26 SRs and 44 RCTs, with 3,316 subjects. The intervention is effective and well-tolerated, although the quality of the included SRs and original studies is poor, resulting in low certainty of evidence. Limitations: This study is limited by poor-quality SRs and original studies, resulting in low certainty of the evidence. Additionally, insufficient available data prevents differentiation between the effects of ketamine and esketamine in unipolar and bipolar depression. Conclusion: While ketamine and esketamine show promising therapeutic potential, the current evidence suffers from low study quality. Enhanced methodological rigor in future research will allow for a more informed application of these interventions within the treatment guidelines for unipolar and bipolar depression. Systematic review registration: [https://inplasy.com/inplasy-2021-5-0049/], identifier (INPLASY202150049).

A narrative review on insomnia and hypersomnolence within Major Depressive Disorder and bipolar disorder: A proposal for a novel psychometric protocol.

Sleep disorders have become increasingly prevalent, with many adults worldwide reporting sleep dissatisfaction. Major Depressive Disorder (MDD) and Bipolar Disorder (BD) are common conditions associated with disrupted sleep patterns such as insomnia and hypersomnolence. These sleep disorders significantly affect the progression, severity, treatment, and outcome of unipolar and bipolar depression. While there is evidence of a connection between sleep disorders and depression, it remains unclear if sleep features differ between MDD and BD. In light of this, this narrative review aims to: (1) summarize findings on common sleep disorders like insomnia and hypersomnolence, strongly linked to MDD and BD; (2) propose a novel psychometric approach to assess sleep in individuals with depressive disorders. Despite insomnia seems to be more influent in unipolar depression, while hypersomnolence in bipolar one, there is no common agreement. So, it is essential adopting a comprehensive psychometric protocol for try to fill this gap. Understanding the relationship between sleep and MDD and BD disorders are crucial for effective management and better quality of life for those affected.

Changes in time structure of periodic leg movements during sleep in restless legs syndrome: Effects of sex and age.

BACKGROUND: The objective of this study was to check the hypothesis that in women with restless legs syndrome (RLS) different changes occur in periodic leg movements during sleep (PLMS) during the post-menopausal period (using >50 years as a proxy) than in men of the same age. METHODS: We recruited 36 untreated patients aged 18-50 years (19 men, median age 40 years, and 17 women, median age 37 years) while the remaining 67 were >50 years old (24 men, median age 66.6 years, and 43 women, median age 60.0 years). Leg movement activity during sleep was analyzed by means of an approach utilizing indexes especially suitable to assess leg movement periodicity. RESULTS: No significant difference was seen between men in the two age groups; conversely, in women, a clear and significant increase in Periodicity Index was observed in the older group, along with a decrease in isolated leg movements. In women, a clear age-related enhancement of PLMS was found in the intermovement interval graphs, especially in the 16-22 s range, which was more evident than that observed in men. The results remained unchanged also when they were replicated by selecting only subjects aged 18-45 years vs. those aged >55 years. CONCLUSIONS: Our findings indicate that assessing PLMS in women after menopause is clinically relevant because they are probably connected with the hormonal fluctuations of this period of life. Translationally, identifying and addressing PLMS in post-menopausal women is crucial for optimizing their sleep health and addressing potential health risks associated with sleep disturbances.

Gene Expression Profiling of Post Mortem Midbrain of Parkinson's Disease Patients and Healthy Controls.

Parkinson's disease (PD) stands as the most prevalent degenerative movement disorder, marked by the degeneration of dopaminergic neurons in the substantia nigra of the midbrain. In this study, we conducted a transcriptome analysis utilizing post mortem mRNA extracted from the substantia nigra of both PD patients and healthy control (CTRL) individuals. Specifically, we acquired eight samples from individuals with PD and six samples from CTRL individuals, with no discernible pathology detected in the latter group. RNA sequencing was conducted using the TapeStation 4200 system from Agilent Technologies. A total of 16,148 transcripts were identified, with 92 mRNAs displaying differential expression between the PD and control groups. Specifically, 33 mRNAs were significantly up-regulated, while 59 mRNAs were down-regulated in PD compared to the controls. The identification of statistically significant signaling pathways, with an adjusted p-value threshold of 0.05, unveiled noteworthy insights. Specifically, the enriched categories included cardiac muscle contraction (involving genes such as ATPase Na+/K+ transporting subunit beta 2 (ATP1B2), solute carrier family 8 member A1 (SLC8A1), and cytochrome c oxidase subunit II (COX2)), GABAergic synapse (involving GABA type A receptor-associated protein-like 1 (GABARAPL1), G protein subunit beta 5 (GNB5), and solute carrier family 38 member 2 (SLC38A2), autophagy (involving GABARAPL1 and tumor protein p53-inducible nuclear protein 2 (TP53INP2)), and Fc gamma receptor (FcγR) mediated phagocytosis (involving amphiphysin (AMPH)). These findings uncover new pathophysiological dimensions underlying PD, implicating genes associated with heart muscle contraction. This knowledge enhances diagnostic accuracy and contributes to the advancement of targeted therapies.

Pain-Free Alpha-Synuclein Detection by Low-Cost Hierarchical Nanowire Based Electrode.

Analytical methods for the early detection of the neurodegenerative biomarker for Parkinson's disease (PD), α-synuclein, are time-consuming and invasive, and require skilled personnel and sophisticated and expensive equipment. Thus, a pain-free, prompt and simple α-synuclein biosensor for detection in plasma is highly demanded. In this paper, an α-synuclein electrochemical biosensor based on hierarchical polyglutamic acid/ZnO nanowires decorated by gold nanoparticles, assembled as nanostars (NSs), for the determination of α-synuclein in human plasma is proposed. ZnO NSs were prepared by chemical bath deposition (CBD) and decorated with electrodeposited Au nanoparticles (Au NPs). Then, electro-polymerized glutamic acid was grown and functionalized with anti-α-synuclein. A synergistic enhancement of electrode sensitivity was observed when Au NPs were embedded into ZnO NSs. The analytical performance of the biosensor was evaluated by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), using the Fe(II)(CN)64-/Fe(III)(CN)63- probe. The charge transfer resistance after α-synuclein recognition was found to be linear, with a concentration in the range of 0.5 pg·mL-1 to 10 pg·mL-1, a limit of detection of 0.08 pg·mL-1, and good reproducibility (5% variation) and stability (90%). The biosensor was also shown to reliably discriminate between healthy plasma and PD plasma. These results suggest that the proposed biosensor provides a rapid, quantitative and high-sensitivity result of the α-synuclein content in plasma, and represents a feasible tool capable of accelerating the early and non-invasive identification of Parkinson's disease.

Mediterranean Diet and Sleep Features: A Systematic Review of Current Evidence.

The prevalence of sleep disorders, characterized by issues with quality, timing, and sleep duration is increasing globally. Among modifiable risk factors, diet quality has been suggested to influence sleep features. The Mediterranean diet is considered a landmark dietary pattern in terms of quality and effects on human health. However, dietary habits characterized by this cultural heritage should also be considered in the context of overall lifestyle behaviors, including sleep habits. This study aimed to systematically revise the literature relating to adherence to the Mediterranean diet and sleep features in observational studies. The systematic review comprised 23 reports describing the relation between adherence to the Mediterranean diet and different sleep features, including sleep quality, sleep duration, daytime sleepiness, and insomnia symptoms. The majority of the included studies were conducted in the Mediterranean basin and reported a significant association between a higher adherence to the Mediterranean diet and a lower likelihood of having poor sleep quality, inadequate sleep duration, excessive daytime sleepiness or symptoms of insomnia. Interestingly, additional studies conducted outside the Mediterranean basin showed a relationship between the adoption of a Mediterranean-type diet and sleep quality, suggesting that biological mechanisms sustaining such an association may exist. In conclusion, current evidence suggests a relationship between adhering to the Mediterranean diet and overall sleep quality and different sleep parameters. The plausible bidirectional association should be further investigated to understand whether the promotion of a healthy diet could be used as a tool to improve sleep quality.

Neuroanatomical findings in isolated REM sleep behavior disorder and early Parkinson's disease: a Voxel-based morphometry study.

Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is a parasomnia characterized by loss of physiological atonia of skeletal muscles with abnormal behaviors arising during REM sleep. RBD is often the early manifestation of neurodegenerative diseases, particularly alpha-synucleinopathies, such as Parkinson's disease (PD). Both structural and functional neuroimaging studies suggest that iRBD might share, or even precede, some of the features commonly found in PD, although without a definitive conclusion. Aim of the study is to evaluate the presence of structural abnormalities involving cortical and subcortical areas in PD patients with RBD and iRBD. Patients with video-polysomnographic (VPSG)-confirmed iRBD, and patients with a diagnosis of PD were recruited. In all PD patients, the presence of probable RBD was assessed during the follow-up visits (PD/pRBD). A group of healthy controls (HC) subjects was also recruited. Each subject underwent a structural brain MRI using a 3-D T1-weighted spoiled gradient echo sequence. Twenty-three patients with iRBD, 24 PD/pRBD, and 26 HC were enrolled. Voxel-based morphometry-AnCOVA analysis revealed clusters of grey matter changes in iRBD and PD/pRBD compared to HC in several regions, involving mainly the frontal and temporal regions. The involvement of cortical brain structures associated to the control of sleep cycle and REM stage both in PD/pRBD and iRBD might suggest the presence of a common structural platform linking iRBD and PD, although this pattern may not underlie exclusively RBD-related features. Further longitudinal studies are needed to clarify the patterns of changes occurring at different time points of RBD-related neurodegeneration.

A Next-Generation Sequencing Study in a Cohort of Sicilian Patients with Parkinson's Disease.

Parkinson's disease (PD) is a multisystem and multifactorial disorder and, therefore, the application of modern genetic techniques may assist in unraveling its complex pathophysiology. We conducted a clinical-demographic evaluation of 126 patients with PD, all of whom were Caucasian and of Sicilian ancestry. DNA was extracted from the peripheral blood for each patient, followed by sequencing using a Next-Generation Sequencing system. This system was based on a custom gene panel comprising 162 genes. The sample underwent further filtering, taking into account the allele frequencies of genetic variants, their presence in the Human Gene Mutation Database, and their association in the literature with PD or other movement/neurodegenerative disorders. The largest number of variants was identified in the leucine-rich repeat kinase 2 (LRRK2) gene. However, variants in other genes, such as acid beta-glucosidase (GBA), DNA polymerase gamma catalytic subunit (POLG), and parkin RBR E3 ubiquitin protein ligase (PRKN), were also discovered. Interestingly, some of these variants had not been previously associated with PD. Enhancing our understanding of the genetic basis of PD and identifying new variants possibly linked to the disease will contribute to improved diagnostic accuracy, therapeutic developments, and prognostic insights for affected individuals.

Interdisciplinary Multidimensional Assessment of Transthyretin Amyloidosis before and after Tafamidis.

BACKGROUND: Clinically, there is considerable heterogeneity in the presentation of transthyretin amyloidosis (ATTR), which ranges from primarily cardiac and primarily neurologic to mixed disease, among other manifestations. Because of this complex presentation, the diagnosis and management of patients with ATTR are often challenging and should be performed in interdisciplinary centers specialized in amyloidosis. Here, we aimed to increase awareness of ATTR detection and pathophysiology through a multidimensional multiorgan approach. CASE REPORT: We reported on a 60-year-old man with wild-type ATTR who underwent a number of both basic and advanced cardiological and neurological investigations at baseline and after a treatment period with the TTR tetramer stabilizer, tafamidis. Several findings are provided here, some of which might be considered instrumental correlates of the patient's clinical improvement after therapy. CONCLUSIONS: Adequate awareness and prompt recognition of ATTR support early diagnosis and faster access to therapies, thereby slowing the progression and improving the prognosis. The need for a multidisciplinary alliance between specialists and the opportunity to perform, at least in selected cases, a set of specific examinations for a detailed assessment of ATTR patients can also provide valuable insights into the physiopathology and response to therapy of a disease as complex and intriguing as ATTR.

"Mind" versus "Body" in Mild Cognitive Impairment Rehabilitation: Does a Multicomponent Physical Exercise Program Have a Dichotomous Effect on Cognitive Functions and Physical Performance?

In the relevant study by Boulares and colleagues, the importance of a multicomponent physical activity program in improving balance skills and leading to falling risk and fear reduction in older adults with mild cognitive impairment (MCI) is highlighted, despite the lack of cognitive effects. Given this apparent discrepancy between "body" and "mind" in MCI rehabilitation, the present commentary faces and discusses these findings within the existing literature and poses the question whether there were actually no cognitive results or if the program design and evaluation tool used were not sensitive enough to detect them, at least at this stage.