Jorge Navarro

Rehabilitation is a key component of Parkinson’s disease (PD) management, although individual responses differ substantially. Genetic factors involved in neuroplasticity and inflammation may contribute to this variability. We investigated whether selected polymorphisms in inflammation- and neuroplasticity-related genes influence motor outcomes following intensive multidisciplinary rehabilitation in patients with PD. Sixty-six patients with a diagnosis of idiopathic PD were consecutively enrolled and randomly allocated to an intensive multidisciplinary rehabilitation group (EXP-Group, n = 34) or a home-based stretching control group (CTRL-Group, n = 32) for six weeks. MDS-UPDRS III score was assessed at baseline (T0) and post-treatment (T1). SNPs in the TNF, IL6, IL6R, IL1A, IL1B, IL10 and BDNF genes were genotyped. Possible associations between genotype, treatment group and MDS-UPDRS III score at T1 were analyzed using ANCOVA and linear mixed-effects models, adjusting for baseline MDS-UPDRS III score, age, sex, disease duration and levodopa equivalent daily dose (LEDD). A significant treatment group x TNF rs1800629 genotype interaction was observed (p = 0.033). Among EXP-Group patients, GG homozygotes showed lower adjusted MDS-UPDRS III scores than did the A-allele carriers (29.10 vs. 36.11; p = 0.029). Longitudinal analyses revealed a significant time × treatment group × TNF rs1800629 genotype interaction (p = 0.010), with GG homozygotes showing an approximately 10-point reduction in MDS-UPDRS III score (40.87 to 30.87; p < 0.001). These findings suggest that TNF rs1800629 contributes to variability in response to intensive multidisciplinary rehabilitation in PD.

Traumatic brain injury (TBI), a leading cause of mortality and disability, recognizes a primary, immediate injury due to external forces, and a secondary phase that includes inflammation that can lead to complications such as the post-traumatic confusional state (PTCS), potentially impacting long-term neurological recovery. An earlier identification of these complications, including PTCS, upon admission to intensive rehabilitation units (IRU) could possibly allow the design of personalized rehabilitation protocols in the immediate post-acute phase of moderate-to-severe TBI. The present study aims to identify potential biomarkers to distinguish between TBI patients with and without PTCS. We analyzed cellular and molecular mechanisms involved in neuroinflammation (IL-6, IL-1β, IL-10 cytokines), neuroendocrine function (norepinephrine, NE, epinephrine, E, dopamine), and neurogenesis (glial cell line-derived neurotrophic factor, GDNF, insuline-like growth factor 1, IGF-1, nerve growth factor, NGF, brain-derived growth factor, BDNF) using enzyme-linked immunosorbent assay (ELISA), comparing results between 29 TBI patients (17 with PTCS and 12 non-confused) and 34 healthy controls (HC), and correlating results with an actigraphy-derived sleep efficiency parameter. In TBI patients compared to HC, serum concentration of (1) pro-inflammatory IL-1β cytokine was significantly increased while that of anti-inflammatory IL-10 cytokine was significantly decreased; (2) NE, E and DA were significantly increased; (3) GDNF, NGF and IGF-1 were significantly increased while that of BDNF was significantly decreased. Importantly, IL-10 serum concentration was significantly lower in PTCS than in non-confused patients, correlating positively with an improved actigraphy-derived sleep efficiency parameter. An anti-inflammatory environment may be associated with better prognosis after TBI.

Post-traumatic amnesia (PTA), recently conceptualized as part of the broader syndrome known as post-traumatic confusional state (PTCS), marks a critical phase of recovery following moderate-to-severe traumatic brain injury (TBI). Indeed, this state is characterized not only by anterograde memory impairment but also by disorientation, agitation, and attention deficits. Given the phenotypic overlap between PTA/PTCS and delirium—both marked by fluctuating cognitive and attentional disturbances—EEG represents a promising tool for elucidating shared pathophysiological mechanisms. While delirium is typically associated with diffuse EEG slowing and the presence of slow-wave activity (SWA), thought to reflect underlying global cortical disruption, it remains unclear whether PTCS exhibits similar EEG underpinnings. In this prospective longitudinal study, we assessed dynamic EEG correlates of PTCS using the Grand Total EEG (GTE) score. We enrolled 42 consecutive TBI patients, classifying them at baseline into PTA/PTCS or emerged from PTA/PTCS, based on validated clinical assessments. Patients with PTA/PTCS exhibited significantly higher baseline GTE scores compared to TBI controls, reflecting severe EEG abnormalities characterized by diffuse slowing and disrupted rhythmic activity. Longitudinal follow-up revealed significant EEG improvements paralleling clinical recovery, confirming EEG’s sensitivity to dynamic clinical changes. Furthermore, the severity of EEG abnormalities significantly correlated with the duration of PTA/PTCS, underscoring EEG’s potential as an objective biomarker for monitoring recovery trajectories. Notably, these findings were independent of pharmacological confounders, as medication regimens were not significantly different across groups and timepoints. Our results support a reconceptualization of PTA/PTCS as a functional encephalopathy, analogous to delirium, with EEG slowing reflecting widespread yet reversible cortical dysfunction. By capturing these transient yet clinically critical changes, clinical EEG— quantified via GTE scores—offers a novel tool for diagnosing PTA/PTCS, stratifying its severity, and objectively monitoring its evolution in acute and subacute rehabilitation settings.

Background: Inflammasomes regulate the activation of caspases resulting in inflammation; inflammasome activation is dysregulated in Alzheimer’s disease (AD) and plays a role in the pathogenesis of this condition. Glibenclamide, an anti-inflammatory drug, could be an interesting way to down-modulate neuroinflammation. Methods: In this pilot study we verified with ex vivo experiments whether a glibenclamide-loaded nanovector (GNV) could reduce the NLRP3-inflammasome cascade in cells of AD patients. Monocytes isolated from healthy controls (HC) and AD patients were cultured in medium, alone or stimulated with LPS + nigericin in presence/absence of GNV. ASC-speck positive cells and inflammasome-related genes, proteins, and miRNAs expressions were measured. The polymorphisms of ApoE (Apolipoprotein E), specifically rs7412 and rs429358, as well as those of NLRP3, namely rs35829419, rs10733113, and rs4925663, were also investigated. Results: Results showed that ASC-speck+ cells and Caspase-1, IL-1β, and IL-18 production was significantly reduced (p < 0.005 in all cases) by GNV in LPS + nigericin-stimulated cells of both AD and HC. Notably, the NLRP3 rs10733113 AG genotype was associated with excessive inflammasome-related gene and protein expression. GNV significantly down-regulates inflammasome activation in primary monocytes, at least at protein levels, and its efficacy seems to partially depend on the presence of the NLRP3 rs10733113 genotype. Conclusions: All together, these results showed that GNV is able to dampen inflammation and NLRP-3 inflammasome activation in an ex vivo monocyte model, suggesting a possible role for GNV in controlling AD-associated neuroinflammation.

Traumatic brain injury (TBI) affects millions of people worldwide and often results in long-term disabilities. Clinical outcomes vary widely even among patients with similar injury severity, partly due to systemic neuroinflammatory responses mediated by pro- and anti-inflammatory cytokines. Genetic polymorphisms in cytokine-coding genes may influence cytokine expression, thereby affecting rehabilitation and prognosis. We analyzed genetic polymorphisms in the TNF-α, IL-6, IL-6 receptor, IL-1β, and IL-10 genes in 28 subacute TBI patients undergoing rehabilitation. Clinical outcomes were assessed using the Glasgow Outcome Scale Extended (GOSE) and domain-specific scales for cognitive, motor, and functional recovery. Results were correlated with genetic profiles to identify potential predictive biomarkers. The IL-6-174 (GG) and IL-6R 1073 (AA) genotypes correlated with worse GOSE scores (p = 0.02 and p = 0.01, respectively). Co-segregation of IL-6-174 - IL-6R 1073 G-A alleles was linked to poorer outcomes (p = 0.01). Patients with the TNF-α-308 (GA) genotype showed less improvement in Barthel and Mobility scores (p = 0.001 and p = 0.01, respectively) and had a higher incidence of post-traumatic confusional state after rehabilitation (p = 0.03). Overall, the TNF-α-308(GA), IL-6 -174(GG), and IL-6R 1073(AA) genotypes negatively impact rehabilitation outcomes, likely due to their role in enhancing neuroinflammation. Larger studies are needed to develop personalized therapies tailored to genetic profiles, aiming to improve rehabilitation outcomes for TBI patients.

Background/Objectives: Parkinson’s disease (PD) is a neurodegenerative disorder, characterised by cardinal motor features and a multitude of non-motor manifestations. Among them, cognitive impairment in PD has been recognised as a defined clinical entity, and it might lead to an increased risk of developing dementia. Consequently, the present review aimed to ascertain the available interventions for the training of cognitive abilities in persons with PD (PwPD). Methods: PRISMA guidelines were followed to select studies in the following databases: PubMed, PsycINFO, and Web of Science. Two independent reviewers conducted the different phases of the review, and a third expert was called in to address any doubts/conflicts. Randomised controlled trials and randomised clinical trials concerning cognitive training with cognitive outcomes in PwPD were selected. Results: A total of 28 articles were included. The considered studies applied various experimental interventions for the training of cognitive functions in PwPD: computer-based platforms, exergames, paper-and-pencil programmes, dual-task or treadmill training with action observation therapy, motor imagery, and virtual reality components, interventions targeting precise cognitive domain, tele-rehabilitation, transcranial direct current stimulation, structured cognitive training, and multimodal treatments. Cognitive functions were assessed employing neuropsychological tests, self-report questionnaires, and computerised batteries. Conclusions: Overall, the review reported better performances in the experimental groups compared to the control groups, in several cognitive domains. Structured cognitive training emerged as the most effective strategy to enhance cognitive functioning in PwPD. However, further studies are necessary to determine the most appropriate and useful training and to develop interventions that also consider patients’ quality of life.

Although the 6-Minute Walk Test (6MWT) is among the recommended clinical tools to assess gait impairments in individuals with Parkinson’s disease (PD), its standard clinical outcome consists only of the distance walked in 6 min. Integrating a single Inertial Measurement Unit (IMU) could provide additional quantitative and objective information about gait quality complementing standard clinical outcome. This study aims to evaluate the test–retest reliability, validity and discriminant ability of gait parameters obtained by a single IMU during the 6MWT in subjects with mild PD. Twenty-two people with mild PD and ten healthy persons performed the 6MWT wearing an IMU placed on the lower trunk. Features belonging to rhythm and pace, variability, regularity, jerkiness, intensity, dynamic instability and symmetry domains were computed. Test–retest reliability was evaluated through the Intraclass Correlation Coefficient (ICC), while concurrent validity was determined by Spearman’s coefficient. Mann–Whitney U test and the Area Under the receiver operating characteristic Curve (AUC) were then applied to assess the discriminant ability of reliable and valid parameters. Results showed an overall high reliability (ICC ≥ 0.75) and multiple significant correlations with clinical scales in all domains. Several features exhibited significant alterations compared to healthy controls. Our findings suggested that the 6MWT instrumented with a single IMU can provide reliable and valid information about gait features in individuals with PD. This offers objective details about gait quality and the possibility of being integrated into clinical evaluations to better define walking rehabilitation strategies in a quick and easy way.

People with severe acquired brain injury (pwSABI) frequently experience pulmonary complications. Among these, atelectasis can occur as a result of pneumonia, thus increasing the chance of developing acute respiratory failure. Respiratory physiotherapy contribution to the management of atelectasis in pwSABI is yet poorly understood. We conducted a retrospective analysis on 15 non-cooperative pwSABI with tracheostomy and spontaneously breathing, hospitalized and treated with high-frequency percussion physiotherapy between September 2018 and February 2021 at the Neurological Rehabilitation Unit of the IRCCS “S.Maria Nascente - Fondazione Don Gnocchi”, Milan. Our primary aim was to investigate the feasibility of such a physiotherapy intervention method. Then, we assessed changes in respiratory measures (arterial blood gas analysis and peripheral night-time oxygen saturation) and high-resolution computed tomography lung images, evaluated before and after the physiotherapy treatment. The radiological measures were a modified radiological atelectasis score (mRAS) assigned by two radiologists, and an opacity score automatically provided by the software CT Pneumonia Analysis^® that identifies the regions of abnormal lung patterns. Treatment diaries showed that all treatments were completed, and no adverse events during treatment were registered. Among the 15 pwSABI analyzed, 8 were treated with IPV^® and 7 with MetaNeb^®. After a median of 14 (I-III quartile=12.5-14.5) days of treatment, we observed a statistical improvement in various arterial blood gas measures and peripheral night-time oxygen saturation measures. We also found radiological improvement or stability in more than 80% of pwSABI. In conclusion, our physiotherapy approach was feasible, and we observed respiratory parameters and radiological improvements. Using technology to assess abnormal tomographic patterns could be of interest to disentangle the short-term effects of respiratory physiotherapy on non-collaborating people.

Complexity analysis of electroencephalogram (EEG) signals has emerged as a valuable tool for characterizing Parkinson’s disease (PD). Fractal dimension (FD) is a widely employed method for measuring the complexity of shapes with many applications in neurodegenerative disorders. Nevertheless, very little is known on the fractal characteristics of EEG in PD measured by FD. In this study we performed a spatio-temporal analysis of EEG in PD using FD in four dimensions (4DFD). We analyzed 42 resting-state EEG recordings comprising two groups: 27 PD patients without dementia and 15 healthy control subjects (HC). From the original resting-state EEG we derived the cortical activations defined by a source reconstruction at each time sample, generating point clouds in three dimensions. Then, a sliding window of one second (the fourth dimension) was used to compute the value of 4DFD by means of the box-counting algorithm. Our results showed a significantly higher value of 4DFD in the PD group (p < 0.001). Moreover, as a diagnostic classifier of PD, 4DFD obtained an area under curve value of 0.97 for a receiver operating characteristic curve analysis. These results suggest that 4DFD could be a promising method for characterizing the specific changes in the brain dynamics associated with PD.

REM sleep behavior disorder (RBD) has a tighter link with synucleinopathies than other neurodegenerative disorders. Parkinson’s Disease (PD) patients with RBD have a more severe motor and cognitive impairment; biomarkers for RBD are currently unavailable. Synaptic accumulation of α-Syn oligomers and their interaction with SNARE proteins is responsible for synaptic dysfunction in PD. We verified whether oligomeric α-Syn and SNARE components in neural-derived extracellular vesicles (NDEVs) in serum could be biomarkers for RBD. Forty-seven PD patients were enrolled, and the RBD Screening Questionnaire (RBDSQ) was compiled. A cut-off score > 6 to define probable RBD (p-RBD) and probable non-RBD (p non-RBD) was used. NDEVs were isolated from serum by immunocapture, and oligomeric α-Syn and SNARE complex components VAMP-2 and STX-1 were measured by ELISA. NDEVs’ STX-1A resulted in being decreased in p-RBD compared to p non-RBD PD patients. A positive correlation between NDEVs’ oligomeric α-Syn and RBDSQ total score was found (p = 0.032). Regression analysis confirmed a significant association between NDEVs’ oligomeric α-Syn concentration and RBD symptoms (p = 0.033) independent from age, disease duration, and motor impairment severity. Our findings suggest that synuclein-mediated neurodegeneration in PD-RBD is more diffuse. NDEVs’ oligomeric α-Syn and SNARE complex components’ serum concentrations could be regarded as reliable biomarkers for the RBD-specific PD endophenotype.