Lewy body disease (LBD) and Alzheimer’s disease (AD) are the most common causes of cognitive decline and dementia and are associated with characteristic alterations in resting-state electroencephalographic (rsEEG) activity. This multicenter exploratory study investigated periodic and aperiodic rsEEG features in patients with cognitive decline due to Lewy body disease (LBCD) and Alzheimer’s disease (ADCD), compared with cognitively unimpaired older adults (Nold), and examined the clinical relevance of these markers in LBCD. A total of 140 LBCD, 135 ADCD, and 118 Nold datasets from the PDWAVES archive underwent spectral parameterization to decompose rsEEG power spectra (1–30 Hz) into periodic peaks and aperiodic background activity. Both clinical groups showed a significant slowing of the individual alpha frequency (IAF), more pronounced in LBCD, along with reduced periodic alpha and beta power reflected in a lower vigilance index. The aperiodic exponent was elevated in both groups, and the aperiodic offset was also higher in LBCD, suggesting steeper spectral profiles consistent with increased inhibitory cortical tone. Within the LBCD group, poorer cognition was associated with higher low-frequency alpha power, whereas better cognition was predicted by higher high-frequency alpha power. A reduced vigilance index was associated with the presence of visual hallucinations, while no associations emerged for other symptoms. These findings suggest that combined periodic and aperiodic rsEEG features may provide relevant markers of altered vigilance regulation in LBCD. Future studies should evaluate whether these EEG markers can inform targeted interventions, such as neuromodulatory or audiovisual stimulation, to stabilize quiet-vigilance states and improve clinical outcomes. Panel A shows the spectral parameterization of rsEEG activity into periodic and aperiodic components. Panel B summarizes the main group differences in key rsEEG markers across LBCD, ADCD, and Nold participants. Panel C shows the topographical associations between the vigilance index and cognition and visual hallucinations in LBCD; colors reflect the direction and strength of the associations. For the visual hallucinations map, negative log-odds indicate lower odds of hallucinations for higher vigilance index values, whereas positive log-odds indicate higher odds; values around ± 1.5 correspond approximately to odds ratios of 0.22 and 4.5, respectively. Abbreviations: rsEEG, resting-state electroencephalography; LBCD, cognitive decline due to Lewy body disease; ADCD, cognitive decline due to Alzheimer’s disease; Nold, cognitively unimpaired older adults; IAF, individual alpha frequency; MMSE, Mini-Mental State Examination; p, standardized regression coefficient; log-odds, logistic regression coefficient.

Despite the technological advancements in modern genetic diagnosis, customized genetic panels are still frequently employed for diagnostic purposes due to their rapid, efficient, and cost-effective ability to detect genetic variants. In this study, we utilized a customized genetic panel designed to identify genetic variants associated with neurodegenerative disorders. The panel consisted of 61 genes and was applied to a cohort of 186 unrelated individuals diagnosed with different degenerative cognitive and movement disorders. The identified variants were filtered for a minor allele frequency of less than 1% and classified according to the American College of Medical Genetics (ACMG) guidelines. Our results showed that 20.97% of individuals carried at least one likely pathogenic or pathogenic variant, with 35% of those individuals diagnosed with Alzheimer's disease (AD). The positive diagnostic yield of the panel was 16.67%, calculated based on variant zygosity, inheritance pattern, and concordance with the clinical phenotype. Furthermore, 34.41% of the individuals carried variants of uncertain significance (VUS), and 44.62% carried benign variants. Variants have been found only in 58 genes. Among these, 24.14% showed benign variants, 48.28% had VUS, and 27.59% carried pathogenic or likely pathogenic variants. Principal component analysis analysis based on the variables "age at onset" in addition to the phenotypic scores "MMSE" (global cognitive screening test), "IADL" (instrumental activities of daily living), and "ADL" (basic activities of daily living) distributed the individuals associated with the specific disease and variant in the plot. Notably, the individuals showed AD exhibited an average age at onset of 68 ± 12.5 years and were differentiated in the plot. GBA gene exhibited the highest number of pathogenic variants (9) linked to AD, Parkinson's disease, early onset parkinsonism with epilepsy, fronto-temporal dementia, and mild cognitive impairment. The results highlighted a broad phenotypic heterogeneity associated with genes previously linked to only a limited number of neurodegenerative conditions, underscoring the value of the genetic testing performed. Translationally, although clinical exome sequencing has enabled novel gene discovery in neurodegenerative disorders, targeted genetic panels remain a cost-effective and clinically valuable approach for routine diagnostics. In this context, our study highlights the "real-world" utility and clinical impact of a focused panel-based strategy.

INTRODUCTION:We evaluated whether the brain glymphatic drainage function estimated by the diffusion tensor imaging along the perivascular space (DTI-ALPS) index relates to white matter (WM) integrity, Alzheimer's disease (AD) neuropathology, resting-state electroencephalogram (rsEEG) alpha rhythms underpinning quiet vigilance, and cognitive decline in mild cognitive impairment (MCI). METHODS:Clinical, neuroimaging, and rsEEG data were analyzed in matched mild cognitive impairment due to AD (ADMCI) and MCI not due to AD (noADMCI) participants. DTI-ALPS index and aperiodic and periodic components of the rsEEG power spectra were calculated following standard pipelines. RESULTS:Lower DTI-ALPS index was associated with higher AD neuropathology and WM lesions, lower periodic rsEEG alpha rhythms, and worse cognition in patients with ADMCI and noADMCI as a whole population, with the ADMCI (over noADMCI) group showing lower DTI-ALPS index, greater AD neuropathology, and lower periodic rsEEG alpha rhythms. CONCLUSIONS:The DTI-ALPS index may capture glymphatic system impairment linked to AD neuropathology, vigilance dysfunction, and cognitive decline in MCI.

Abstract Introduction REM sleep behavior disorder (RBD) is classically considered a prodromal marker of α-synucleinopathies, yet it also occurs in association with other neurological disorders and with antidepressant use. Whether these forms represent clinically and biologically distinct entities remains insufficiently explored. This study aimed to compare multidimensional clinical profiles of idiopathic, antidepressant-associated, and tauopathy-associated RBD. Methods We retrospectively reviewed clinical and video-polysomnographic data of patients hospitalized between 2018 and 2023 with polysomnography-confirmed RBD, excluding individuals with Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy. Patients were classified as idiopathic RBD (iRBD), antidepressant-associated RBD, or tauopathy-associated RBD. Demographic variables, disease duration, sleep-related comorbidities, cognitive status (including Mini-Mental State Examination), depressive symptoms, and neuroimaging findings (vascular damage and cerebral atrophy) were compared across groups using non-parametric statistics. Results Eighty-four patients were included (iRBD n = 45; antidepressant-associated RBD n = 27; tauopathy-associated RBD n = 12). Age at diagnosis did not differ between groups. Male predominance and longer disease duration characterized iRBD. Sleep-related comorbidities, including obstructive sleep apnea and periodic leg movements, were similarly prevalent across groups. Tauopathy-associated RBD showed a markedly higher prevalence of cognitive impairment or dementia, significantly lower MMSE scores, and more frequent and severe cerebral atrophy. Depressive symptoms were most prevalent in antidepressant-associated RBD, whereas vascular neuroimaging findings did not differ among groups. Conclusion RBD encompasses etiologically distinct clinical profiles. Stratification by underlying context reveals meaningful differences in cognitive, psychiatric, and neuroimaging features, with important implications for diagnosis, risk assessment, and clinical management. Support (if any) No specific external funding was received.

To compare clinical and polysomnographic features of patients with isolated REM sleep behavior disorder (iRBD) and patients with clinically reported dream-enactment behaviors (DEB) occurring in the absence of REM sleep without atonia (RSWA), and to clarify the clinical significance of DEB without RSWA. We retrospectively reviewed clinical records and polysomnography of consecutive patients referred to a tertiary sleep and neurology center. Twenty-six patients with polysomnography-confirmed iRBD, 21 patients with DEB without RSWA, and 24 control subjects were included. Clinical features related to prodromal neurodegeneration, neuroimaging findings, sleep architecture, REM atonia indices, limb movements, and respiratory parameters were analyzed using age-adjusted comparisons with effect size estimation. Compared with DEB patients, iRBD patients were older and showed a higher prevalence of subtle extrapyramidal signs, lower cognitive performance, and a greater burden of vascular neuroimaging abnormalities. Clinically reported hyposmia and depression were infrequent and did not differ between groups. Both clinical groups exhibited increased sleep fragmentation and instability, most pronounced in iRBD, with DEB patients showing intermediate values. REM atonia robustly differentiated groups, whereas periodic limb movements during sleep and respiratory disturbance did not differ significantly after age adjustment. DEB occurring without RSWA are associated with a clinical and polysomnographic profile distinct from iRBD, characterized by preserved REM atonia and a lower burden of markers linked to prodromal neurodegeneration. These findings highlight the heterogeneity of DEB and support characterization beyond conventional RBD diagnostic criteria. Current knowledge/study rationale: Isolated REM sleep behavior disorder (iRBD) is defined by dream-enactment behaviors (DEB) with REM sleep without atonia (RSWA), whereas clinically reported DEB without RSWA presents a diagnostic challenge and unclear significance in relation to prodromal neurodegeneration. Study impact: In this retrospective tertiary-center cohort, iRBD patients had more extrapyramidal signs, lower cognitive performance, and greater vascular imaging abnormalities compared with DEB without RSWA, whereas both groups showed increased sleep instability. These findings highlight that DEB without RSWA has a distinct clinical and polysomnographic profile, supporting the need for characterization beyond conventional RBD diagnostic criteria.

BACKGROUND:REM sleep behavior disorder (RBD) is increasingly recognized as a heterogeneous condition that may arise in different etiological contexts, including an isolated form that is often a prodromal synucleinopathy, antidepressant exposure, and RBD occurring in the context of clinically diagnosed tau-spectrum neurodegenerative syndromes. The aim of this study was to compare clinical, cognitive, neuroimaging, and polysomnographic features of isolated RBD (iRBD), antidepressant-associated RBD (iatroRBD), and tauopathy-associated RBD (tauRBD) associated with Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, or frontotemporal dementia, within a single cohort. METHODS:We conducted a retrospective analysis of patients with polysomnographically confirmed RBD evaluated at a tertiary sleep center, excluding individuals with established synucleinopathies. Patients were classified as iRBD (n = 26), iatroRBD (n = 16), or tauRBD (n = 6) based on the current criteria. Demographics, non-motor symptoms, Mini-Mental State Examination (MMSE) scores, neuroimaging reports, and detailed polysomnographic parameters were compared using non-parametric statistics and effect sizes. RESULTS:Age, age at onset, and disease duration did not differ across groups. Sex distribution showed a significant male predominance in iRBD, with a more balanced distribution in iatroRBD and tauRBD. Cognitive performance differed markedly, with tauRBD patients showing significantly lower MMSE scores than both iRBD and iatroRBD, whereas cognition was largely preserved in the latter groups. Non-motor symptoms, including hyposmia and depressive symptoms, showed limited discriminatory value. Polysomnography revealed selective differences in REM sleep architecture, including reduced REM sleep percentage in tauRBD and prolonged REM sleep latency in iatroRBD, while REM atonia, limb movements, and respiratory parameters were broadly similar. CONCLUSIONS:RBD appears to be a shared motor phenotype that can arise in different etiological contexts. In this cohort, cognitive status, sex distribution, and selected REM sleep features were the most informative contextual markers, whereas history-derived non-motor features available in this retrospective dataset (hyposmia and depressive symptoms) and routine PSG metrics showed limited discrimination.

STUDY OBJECTIVES:To characterize nocturnal motor activity across isolated REM sleep behavior disorder (iRBD), Parkinson's disease with REM sleep behavior disorder (PD+RBD), PD without RBD (PD-RBD), and healthy controls, with particular focus on large muscle group movements (LMMs) during sleep. MATERIALS AND METHODS:We included 109 participants: controls (n = 25; 13F/12M, age 67.6 ± 6.70 years), iRBD (n = 25; 4F/21M, 70.7 ± 8.42 years), PD+RBD (n = 31; 10F/21M, age 71.1 ± 7.30), and PD-RBD (n = 28; 9F/19M, age 67.9 ± 8.05 years). Conventional sleep architecture, REM atonia index (RAI), leg-movement subtypes, and LMM indices and duration across total sleep time (TST), NREM sleep, and REM sleep were analyzed. RESULTS:As expected, RAI showed the clearest group separation, with reduced values in iRBD and PD+RBD. Sleep instability, reflected by increased stage shifts, was greater in iRBD and PD+RBD than in controls. Among leg-movement measures, only isolated leg movement index remained significantly increased after correction, specifically in PD+RBD. LMM provided the most distinctive additional signal: total LMM index differed across TST, NREM, and REM sleep, with lower values in PD-RBD and higher polysomnography (PSG)-defined REM-related LMM activity in iRBD and PD+RBD. LMM duration was longer in all clinical groups than in controls, whereas LMM associated with arousal or wake did not differ significantly across groups. CONCLUSIONS:Quantitative assessment of LMM, together with refined leg-movement phenotyping and REM atonia measures, may improve characterization of nocturnal motor dysregulation across the synucleinopathy spectrum. LMM may represent a PSG-derived marker of sleep-state instability and REM-related motor activation, with potential relevance for iRBD progression and PD phenotyping. Statement of Significance This study suggests that the nocturnal motor phenotype of synucleinopathy is broader than REM sleep without atonia and conventional PLMS measures alone. By showing that LMM and isolated leg movements help distinguish iRBD, PD+RBD, and PD-RBD, the findings support a more refined polysomnographic framework for capturing disease-related motor disorganization during sleep. The contrasting profile of PD-RBD, with fewer but longer LMM, also points to nocturnal hypokinesia as a potentially distinct motor signature. If confirmed longitudinally, these measures could improve phenotypic stratification and help identify clinically meaningful pathways linked to progression, cognition, autonomic dysfunction, and future targeted treatments.

OBJECTIVES:This exploratory study tested the hypothesis that Huntington's disease (HD) is characterized by distinct abnormalities in resting-state electroencephalographic (rsEEG) rhythms compared to Alzheimer's disease (AD). METHODS:Clinical and rsEEG data were collected from 35 patients with HD, 81 patients with AD, and 102 healthy controls (HC). The rsEEG cortical source activations from 30 electrodes were estimated using eLORETA and were harmonized across clinical sites. RESULTS:Compared to the HC group, both the HD and AD groups showed widespread increases in rsEEG delta source activation and decreases in alpha source activation, with the HD patients exhibiting the most pronounced frontal effects. In patients with HD, those abnormal rsEEG source activations were associated with cognitive, motor, and functional deficits. CONCLUSIONS:Patients with HD were characterized by a particular slowing of frontal rsEEG rhythms associated with clinically relevant variables. SIGNIFICANCE:A topographically widespread slowing of cortical oscillatory activity was observed in both HD and AD groups, with a particularly pronounced frontal effect in HD, which may predict a greater impact on the sleep-wake cycle. These observations should be considered exploratory and need validation in future studies with enhanced vigilance monitoring during longer rsEEG recordings.

Alzheimer's disease (AD) dementia is associated with marked disruptions in resting-state eyes-closed electroencephalographic (rsEEG) rhythms, particularly in the periodic alpha band (8-12 Hz), suggesting impaired vigilance regulation. In contrast, the aperiodic rsEEG component, reflecting global cortical arousal, has been reported to remain unchanged. This exploratory study examined periodic and aperiodic EEG activity in patients with mild cognitive impairment due to AD (ADMCI) during transitions from quiet wakefulness to light sleep. EEG datasets (∼30 min) from 19 ADMCI patients and 18 matched cognitively unimpaired older adults (control) were analyzed. Vigilance stages were scored using a reduced version of Hori's system, distinguishing the alpha-dominant wakefulness stage and the theta-dominant light sleep (ripples) stage. EEG spectra were parameterized using the specparam algorithm. ADMCI participants showed reduced reactivity of individual alpha power between the wakefulness and ripples stages compared to the control group. Conversely, both groups exhibited comparable increases in fronto-central theta power and steepening of the aperiodic slope and offset. No group differences emerged in aperiodic exponent and offset, although statistical power was limited by modest sample size. Overall, EEG alpha rhythms reflecting vigilance regulation are disrupted in prodromal AD, while periodic and aperiodic signatures of sleep onset are relatively preserved, suggesting selective vulnerability of attentional thalamocortical systems.

Patients with mild cognitive impairment due to Alzheimer’s disease (ADMCI) typically show abnormally high delta (<4 Hz) and low alpha (8–12 Hz) rhythms measured from resting-state eyes-closed electroencephalographic (rsEEG) activity. Here, we hypothesized that the abnormalities in rsEEG activity may be greater in ADMCI patients than in those with MCI not due to AD (noADMCI). Furthermore, they may be associated with the diagnostic cerebrospinal fluid (CSF) amyloid–tau biomarkers in ADMCI patients. An international database provided clinical–demographic–rsEEG datasets for cognitively unimpaired older (Healthy; N = 45), ADMCI (N = 70), and noADMCI (N = 45) participants. The rsEEG rhythms spanned individual delta, theta, and alpha frequency bands. The eLORETA freeware estimated cortical rsEEG sources. Posterior rsEEG alpha source activities were reduced in the ADMCI group compared not only to the Healthy group but also to the noADMCI group (p < 0.001). Negative associations between the CSF phospho-tau and total tau levels and posterior rsEEG alpha source activities were observed in the ADMCI group (p < 0.001), whereas those with CSF amyloid beta 42 levels were marginal. These results suggest that neurophysiological brain neural oscillatory synchronization mechanisms regulating cortical arousal and vigilance through rsEEG alpha rhythms are mainly affected by brain tauopathy in ADMCI patients.

Here, we investigated whether educational attainment influences the neurophysiological mechanisms underlying vigilance regulation, as reflected in resting-state eyes-closed electroencephalographic (rsEEG) rhythms, in patients with dementia due to Parkinson's (PDD) and Lewy body disease (DLB). Clinical, demographic, and rsEEG data were obtained from an international database, including PDD patients (N = 75), DLB patients (N = 50), and cognitively unimpaired older controls (Healthy; N = 54). Each group was partitioned into low (Edu-) and high (Edu+) educational attainment subgroups, matched for age, sex, and cognitive-motor status. We analyzed rsEEG rhythms across the individual delta, theta, and alpha frequency bands. Cortical rsEEG source topography was estimated using eLORETA freeware. In the Healthy group, Edu+ participants exhibited significantly greater widespread rsEEG alpha source activities compared to Edu- participants, possibly reflecting neuroprotective neurophysiological mechanisms. Conversely, in the PDD group, Edu+ patients showed lower widespread rsEEG alpha source activities than Edu- patients, possibly indicating compensatory mechanisms. No significant differences in rsEEG source activities were observed between DLB-Edu+ and DLB-Edu- patients. Educational attainment may be associated with compensatory mechanisms that counteract the abnormal neurophysiological processes underlying rsEEG alpha rhythms and vigilance regulation in PDD patients, but not in DLB patients. Future studies combining rsEEG and neuroimaging techniques should investigate the metabolic and functional connectivity correlates of these putative compensatory mechanisms in the PDD brain. Early education may be a key investment for national governments, especially in low-income countries, to prevent the cognitive deficits of Parkinson's disease along aging, thereby reducing the unbearable social and economic burden.

BACKGROUND:Clinical predictors of treatment-resistant depression could improve treatment strategies. Depressive symptom profiles at baseline are potential outcome predictors, but little evidence is available, and sex-specific profiles have been scarcely investigated. METHODS:Baseline symptom scores of 1294 patients with major depressive disorder were assessed by the Montgomery-Åsberg depression rating scale (MADRS) as part of a multicenter study by the "Group for the Studies of Resistant Depression". Treatment outcomes were assessed according to the MADRS after ≥4 weeks of naturalistic treatment. We tested if individual MADRS item scores at baseline were associated with treatment outcome in the whole sample and in sex-stratified subgroups. RESULTS:A specific baseline symptom profile was associated with non-response in the whole sample. In particular, apparent and reported sadness, reduced sleep, lassitude, inability to feel, and pessimistic thoughts were the only MADRS items that scored higher at baseline in patients with subsequent lack of response. In the sex-stratified analysis, females showed a similar profile overall, however they showed higher baseline levels of inner tension, inability to feel, and pessimistic thoughts compared to males, and these symptoms were associated with lack of response in females but not in males. Neurovegetative symptoms were poorly predictive. Overall baseline severity related to poor response. LIMITATIONS:This is a post-hoc analysis. The naturalistic design of the study with a retrospective assessment is potential limitations. CONCLUSION:A specific baseline symptom profile characterized by higher sadness, reduced sleep and anhedonic features may be indicative of poor treatment outcome. Females showed a distinctive baseline profile associated with poor response.

The relationship between major depressive disorder (MDD) and mild motor signs (MMS) remains to be elucidated. The present study aims to assess the association between neurological symptoms and medications and treatment response. Neurological signs in 790 patients with MDD were correlated with treatment outcome. Three hundred ten (39.2%) were responders and 480 (60.8%) were non-responders. 342 (43.3%) presented neurological signs. In the whole sample negative associations between dystonia and rigidity and various medications was observed. Non-response was associated with dystonia, rigidity, and hypokinesia independent from age and medications. This study highlighted an association between MMS and specific medications. Moreover, MMS were associated with non-response to treatment, regardless of medication use. This may suggest that a subgroup of patients with MDD may respond less to therapy because of an underlying still undetected neurological disorder.

Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are more prevalent in males than females. Furthermore, they typically showed abnormally high delta (< 4 Hz) and low alpha (8-10 Hz) rhythms from resting-state electroencephalographic (rsEEG) activity. Here, we hypothesized that those abnormalities may depend on the patient's sex. An international database provided clinical-demographic-rsEEG datasets for cognitively unimpaired older (Healthy; N = 49; 24 females), PDD (N = 39; 13 females), and DLB (N = 38; 15 females) participants. Each group was stratified into matched female and male subgroups. The rsEEG rhythms were investigated across the individual rsEEG delta, theta, and alpha frequency bands based on the individual alpha frequency peak. The eLORETA freeware was used to estimate cortical rsEEG sources. In the Healthy group, widespread rsEEG alpha source activities were greater in the females than in the males. In the PDD group, widespread rsEEG delta source activities were lower and widespread rsEEG alpha source activities were greater in the females than in the males. In the DLB group, central-parietal rsEEG delta source activities were lower, and posterior rsEEG alpha source activities were greater in the females than in the males. These results suggest sex-dependent hormonal modulation of neuroprotective-compensatory neurophysiological mechanisms in PDD and DLB patients underlying the generation of rsEEG delta and alpha rhythms, which should be considered in the treatment of vigilance dysregulation in those patients.

Restless Legs Syndrome (RLS) and its associated motor manifestations, such as periodic leg movements during sleep (PLMS), exhibit significant sex-related differences in prevalence, progression, and treatment response. Epidemiological studies suggest a higher prevalence of RLS in women, but the underlying mechanisms remain unclear. This presentation combines two studies to explore: (1) sex differences in PLMS patterns across various age groups and hormonal stages, and (2) sex-specific responses to dopamine agonists (DA), pramipexole and ropinirole, in adult RLS patients. In the first study, a retrospective analysis of 184 drug-free RLS patients (95 females, 89 males, ages 2–83 years) evaluated PLMS index and periodicity index via polysomnographic (PSG) recordings, stratified by age. The second study analyzed 41 drug-free adult RLS patients (26 treated with pramipexole, 15 with ropinirole) using baseline and post-treatment PSG. Treatment efficacy was assessed through changes in sleep parameters, movement indices, and a Visual Analogue Scale (VAS) for symptom severity. The first study revealed distinct age-related PLMS trends: women experienced a rapid PLMS increase before age 10, plateauing until menopause, followed by a sharp rise post-55 years. Men showed a more gradual PLMS increase, peaking after age 75. Periodicity index increased progressively in both sexes but remained slightly higher in women during midlife. These patterns aligned with hormonal shifts and autonomic nervous system modulation. In the second study, DA treatment reduced total leg movements, PLMS, and periodicity index in all patients, with greater reductions in women. Women exhibited higher sleep efficiency and lower wakefulness after sleep onset compared to men. The VAS scores improved across both sexes, though no sex differences were observed. These findings underscore the complex interplay between sex, age, and neurophysiological factors in RLS. Hormonal changes and differential D3 receptor expression likely contribute to the observed disparities in PLMS progression and DA response. The results highlight the need for personalized, sex-specific approaches in RLS management, considering both lifespan dynamics and pharmacological nuances. Future guidelines should integrate these insights to optimize treatment efficacy and improve sleep outcomes for diverse demographic groups.

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.

Background Restless legs syndrome (RLS) and periodic leg movements during sleep (PLMS) are prevalent sleep disorders with significant implications for health and well-being. While previous research has highlighted sex-related disparities in RLS and PLMS prevalence, comprehensive understanding of these differences across the lifespan remains limited. This study aims to explore sex differences in RLS and PLMS across diverse age groups, spanning ages 2 to over 80 years, and to investigate the underlying mechanisms influenced by sex hormones. Methods A retrospective analysis was conducted on drug-free patients diagnosed with RLS, including 95 females (age range: 2-83.2 years) and 89 males (age range: 2-79.5 years). Polysomnographic recordings were analyzed to assess leg movement activity, including PLMS index and Periodicity index. Results A more rapid increase in PLMS index was observed in women starting before age 10, plateauing lower than men until around age 55. An increase in women occurred after 55, lasting over a decade, while in men, PLMS index continued to rise after 75. Conversely, Periodicity index displayed a simpler pattern, increasing progressively from prepuberty to around 35 in males and 45-50 in females. Females maintained a slightly higher Periodicity index than males for over a decade after this age. Conclusion These findings underscore the complex interplay between sex hormones, age, and sleep disorders, highlighting the need for tailored approaches to diagnosis and management across diverse demographic cohorts. Further research is warranted to elucidate the underlying mechanisms and develop targeted interventions to optimize sleep health outcomes.