Mapping Motor Cortical Network Excitability and Connectivity Changes in De Novo Parkinson's Disease.

BACKGROUND: Transcranial magnetic stimulation-electroencephalography (TMS-EEG) has demonstrated decreased excitability in the primary motor cortex (M1) and increased excitability in the pre-supplementary motor area (pre-SMA) in moderate-advanced Parkinson's disease (PD). OBJECTIVES: The aim was to investigate whether these abnormalities are evident from the early stages of the disease, their behavioral correlates, and relationship to cortico-subcortical connections. METHODS: Twenty-eight early, drug-naive (de novo) PD patients and 28 healthy controls (HCs) underwent TMS-EEG to record TMS-evoked potentials (TEPs) from the primary motor cortex (M1) and the pre-SMA, kinematic recording of finger-tapping movements, and a 3T-MRI (magnetic resonance imaging) scan to obtain diffusion tensor imaging (DTI) reconstruction of white matter (WM) tracts connecting M1 to the ventral lateral anterior thalamic nucleus and pre-SMA to the anterior putamen. RESULTS: We found reduced M1 TEP P30 amplitude in de novo PD patients compared to HCs and similar pre-SMA TEP N40 amplitude between groups. PD patients exhibited smaller amplitude and slower velocity in finger-tapping movements and altered structural integrity in WM tracts of interest, although these changes did not correlate with TEPs. CONCLUSIONS: M1 hypoexcitability is a characteristic of PD from early phases and may be a marker of the parkinsonian state. Pre-SMA hyperexcitability is not evident in early PD and possibly emerges at later stages of the disease. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Evaluating the Diagnostic Potential of Combined Salivary and Skin Biomarkers in Parkinson's Disease.

Oligomeric alpha-synuclein (α-syn) in saliva and phosphorylated α-syn deposits in the skin have emerged as promising diagnostic biomarkers for Parkinson's disease (PD). This study aimed to assess and compare the diagnostic value of these biomarkers in discriminating between 38 PD patients and 24 healthy subjects (HSs) using easily accessible biological samples. Additionally, the study sought to determine the diagnostic potential of combining these biomarkers and to explore their correlations with clinical features. Salivary oligomeric α-syn levels were quantified using competitive ELISA, while skin biopsies were analyzed through immunofluorescence to detect phosphorylated α-syn at Ser129 (p-S129). Both biomarkers individually were accurate in discriminating PD patients from HSs, with a modest agreement between them. The combined positivity of salivary α-syn oligomers and skin p-S129 aggregates differentiated PD patients from HSs with an excellent discriminative ability with an AUC of 0.9095. The modest agreement observed between salivary and skin biomarkers individually suggests that they may reflect different aspects of PD pathology, thus providing complementary information when combined. This study's results highlight the potential of utilizing a multimodal biomarker approach to enhance diagnostic accuracy in PD.

Exploring miRNAs' Based Modeling Approach for Predicting PIRA in Multiple Sclerosis: A Comprehensive Analysis.

The current hypothesis on the pathophysiology of multiple sclerosis (MS) suggests the involvement of both inflammatory and neurodegenerative mechanisms. Disease Modifying Therapies (DMTs) effectively decrease relapse rates, thus reducing relapse-associated disability in people with MS. In some patients, disability progression, however, is not solely linked to new lesions and clinical relapses but can manifest independently. Progression Independent of Relapse Activity (PIRA) significantly contributes to long-term disability, stressing the urge to unveil biomarkers to forecast disease progression. Twenty-five adult patients with relapsing-remitting multiple sclerosis (RRMS) were enrolled in a cohort study, according to the latest McDonald criteria, and tested before and after high-efficacy Disease Modifying Therapies (DMTs) (6-24 months). Through Agilent microarrays, we analyzed miRNA profiles from peripheral blood mononuclear cells. Multivariate logistic and linear models with interactions were generated. Robustness was assessed by randomization tests in R. A subset of miRNAs, correlated with PIRA, and the Expanded Disability Status Scale (EDSS), was selected. To refine the patient stratification connected to the disease trajectory, we computed a robust logistic classification model derived from baseline miRNA expression to predict PIRA status (AUC = 0.971). We built an optimal multilinear model by selecting four other miRNA predictors to describe EDSS changes compared to baseline. Multivariate modeling offers a promising avenue to uncover potential biomarkers essential for accurate prediction of disability progression in early MS stages. These models can provide valuable insights into developing personalized and effective treatment strategies.

Resting-state electroencephalography microstates as a marker of photosensitivity in juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy is an idiopathic generalized epilepsy syndrome associated with photosensitivity in approximately 30-40% of cases. Microstates consist of a brief period of time during which the topography of the whole resting-state electroencephalography signal is characterized by a specific configuration. Previous neurophysiological and neuroimaging studies have suggested that Microstate B may represent activity within the visual network. In this case-control study, we aimed to investigate whether anatomical and functional alterations in the visual network observed in individuals with photosensitivity could lead to changes in Microstate B dynamics in photosensitive patients with juvenile myoclonic epilepsy. Resting-state electroencephalography microstate analysis was performed on 28 patients with juvenile myoclonic epilepsy. Of these, 15 patients exhibited photosensitivity, while the remaining 13 served as non-photosensitive controls. The two groups were carefully matched in terms of age, sex, seizure control and anti-seizure medications. Multivariate analysis of variance and repeated-measures analysis of variance were performed to assess significant differences in microstate metrics and syntax between the photosensitive and the non-photosensitive group. Post hoc false discovery rate adjusted unpaired t-tests were used to determine differences in specific microstate classes between the two groups. The four classical microstates (Classes A, B, C and D) accounted for 72.8% of the total electroencephalography signal variance in the photosensitive group and 75.64% in the non-photosensitive group. Multivariate analysis of variance revealed a statistically significant class-group interaction on microstate temporal metrics (P = 0.021). False discovery rate adjusted univariate analyses of variance indicated a significant class-group interaction for both mean occurrence (P = 0.002) and coverage (P = 0.03), but not for mean duration (P = 0.14). Post hoc false discovery rate adjusted unpaired t-tests showed significantly higher coverage (P = 0.02) and occurrence (P = 0.04) of Microstate B in photosensitive patients compared with non-photosensitive participants, along with an increased probability of transitioning from Microstates C (P = 0.04) and D (P = 0.02) to Microstate B. No significant differences were found concerning the other microstate classes between the two groups. Our study provides novel insights on resting-state electroencephalography microstate dynamics underlying photosensitivity in patients with juvenile myoclonic epilepsy. The increased representation of Microstate B in these patients might reflect the resting-state overactivation of the visual system underlying photosensitivity. Further research is warranted to investigate microstate dynamics in other photosensitive epilepsy syndromes.

A systematic review of salivary biomarkers in Parkinson's disease.

The search for reliable and easily accessible biomarkers in Parkinson's disease is receiving a growing emphasis, to detect neurodegeneration from the prodromal phase and to enforce disease-modifying therapies. Despite the need for non-invasively accessible biomarkers, the majority of the studies have pointed to cerebrospinal fluid or peripheral biopsies biomarkers, which require invasive collection procedures. Saliva represents an easily accessible biofluid and an incredibly wide source of molecular biomarkers. In the present study, after presenting the morphological and biological bases for looking at saliva in the search of biomarkers for Parkinson's disease, we systematically reviewed the results achieved so far in the saliva of different cohorts of Parkinson's disease patients. A comprehensive literature search on PubMed and SCOPUS led to the discovery of 289 articles. After screening and exclusion, 34 relevant articles were derived for systematic review. Alpha-synuclein, the histopathological hallmark of Parkinson's disease, has been the most investigated Parkinson's disease biomarker in saliva, with oligomeric alpha-synuclein consistently found increased in Parkinson's disease patients in comparison to healthy controls, while conflicting results have been reported regarding the levels of total alpha-synuclein and phosphorylated alpha-synuclein, and few studies described an increased oligomeric alpha-synuclein/total alpha-synuclein ratio in Parkinson's disease. Beyond alpha-synuclein, other biomarkers targeting different molecular pathways have been explored in the saliva of Parkinson's disease patients: total tau, phosphorylated tau, amyloid-ß1-42 (pathological protein aggregation biomarkers); DJ-1, heme-oxygenase-1, metabolites (altered energy homeostasis biomarkers); MAPLC-3beta (aberrant proteostasis biomarker); cortisol, tumor necrosis factor-alpha (inflammation biomarkers); DNA methylation, miRNA (DNA/RNA defects biomarkers); acetylcholinesterase activity (synaptic and neuronal network dysfunction biomarkers); Raman spectra, proteome, and caffeine. Despite a few studies investigating biomarkers targeting molecular pathways different from alpha-synuclein in Parkinson's disease, these results should be replicated and observed in studies on larger cohorts, considering the potential role of these biomarkers in determining the molecular variance among Parkinson's disease subtypes. Although the need for standardization in sample collection and processing, salivary-based biomarkers studies have reported encouraging results, calling for large-scale longitudinal studies and multicentric assessments, given the great molecular potentials and the non-invasive accessibility of saliva.

Insight into motor fatigue mechanisms in natalizumab treated multiple sclerosis patients with wearing off.

Motor fatigue in Multiple Sclerosis (MS) is due to reduced motor cortex (M1) output and altered sensorimotor network (SMN) modulation. Natalizumab, a disease-modifying therapy, reduces neuroinflammation and improves fatigue. However, some patients treated with natalizumab experience fatigue recurrence ('wearing-off') before subsequent infusions. Wearing-off provides a valuable window into MS-related motor fatigue mechanisms in a controlled, clinically stable, setting. This study investigates whether wearing-off is associated with worsening motor fatigue and its neurophysiological mechanisms and assesses natalizumab's effect on MS-related fatigue. Forty-five relapsing-remitting MS patients with wearing-off symptoms were evaluated pre- and post-natalizumab infusion. Assessments included evaluating disability levels, depressive symptoms, and the impact of fatigue symptoms on cognitive, physical, and psychosocial functioning. The motor fatigue index was computed through the number of blocks completed during a fatiguing task and peripheral, central, and supraspinal fatigue (M1 output) were evaluated by measuring the superimposed twitches evoked by peripheral nerve and transcranial magnetic stimulation of M1. Transcranial magnetic stimulation-electroencephalography assessed M1 effective connectivity by measuring TMS-evoked potentials (TEPs) within the SMN before- and after the task. We found that wearing-off was associated with increased motor fatigue index, increased central and supraspinal fatigue, and diminished task-related modulation of TEPs compared to post-natalizumab infusion. Wearing-off was also associated with worsened fatigue impact and depression symptom scores. We conclude that the wearing-off phenomenon is associated with worsening motor fatigue due to altered M1 output and modulation of the SMN. Motor fatigue in MS may reflect reversible, inflammation-related changes in the SMN that natalizumab can modulate. Our findings apply primarily to MS patients receiving natalizumab, emphasizing the need for further research on other treatments with wearing-off.

Pain in Parkinson's disease: a neuroanatomy-based approach.

Parkinson's disease is a progressive neurodegenerative disorder characterized by the deposition of misfolded alpha-synuclein in different regions of the central and peripheral nervous system. Motor impairment represents the signature clinical expression of Parkinson's disease. Nevertheless, non-motor symptoms are invariably present at different stages of the disease and constitute an important therapeutic challenge with a high impact for the patients' quality of life. Among non-motor symptoms, pain is frequently experienced by patients, being present in a range of 24-85% of Parkinson's disease population. Moreover, in more than 5% of patients, pain represents the first clinical manifestation, preceding by decades the exordium of motor symptoms. Pain implies a complex biopsychosocial experience with a downstream complex anatomical network involved in pain perception, modulation, and processing. Interestingly, all the anatomical areas involved in pain network can be affected by a-synuclein pathology, suggesting that pathophysiology of pain in Parkinson's disease encompasses a 'pain spectrum', involving different anatomical and neurochemical substrates. Here the various anatomical sites recruited in pain perception, modulation and processing are discussed, highlighting the consequences of their possible degeneration in course of Parkinson's disease. Starting from peripheral small fibres neuropathy and pathological alterations at the level of the posterior laminae of the spinal cord, we then describe the multifaceted role of noradrenaline and dopamine loss in driving dysregulated pain perception. Finally, we focus on the possible role of the intertwined circuits between amygdala, nucleus accumbens and habenula in determining the psycho-emotional, autonomic and cognitive experience of pain in Parkinson's disease. This narrative review provides the first anatomically driven comprehension of pain in Parkinson's disease, aiming at fostering new insights for personalized clinical diagnosis and therapeutic interventions.

Exploring the Central Mechanisms of Botulinum Toxin in Parkinson's Disease: A Systematic Review from Animal Models to Human Evidence.

Botulinum toxin (BoNT) is an effective and safe therapy for the symptomatic treatment of several neurological disturbances. An important line of research has provided numerous pieces of evidence about the mechanisms of action of BoNT in the central nervous system, especially in the context of dystonia and spasticity. However, only a few studies focused on the possible central effects of BoNT in Parkinson's disease (PD). We performed a systematic review to describe and discuss the evidence from studies focused on possible central effects of BoNT in PD animal models and PD patients. To this aim, a literature search in PubMed and SCOPUS was performed in May 2023. The records were screened according to title and abstract by two independent reviewers and relevant articles were selected for full-text review. Most of the papers highlighted by our review report that the intrastriatal administration of BoNT, through local anticholinergic action and the remodulation of striatal compensatory mechanisms secondary to dopaminergic denervation, induces an improvement in motor and non-motor symptoms in the absence of neuronal loss in animal models of PD. In human subjects, the data are scarce: a single neurophysiological study in tremulous PD patients found that the change in tremor severity after peripheral BoNT administration was associated with improved sensory-motor integration and intracortical inhibition measures. Further clinical, neurophysiological, and neuroimaging studies are necessary to clarify the possible central effects of BoNT in PD.