Cristina Agliardi

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.

The glymphatic system is a glial-dependent network responsible for the clearance of waste products from the brain through cerebrospinal fluid (CSF) circulation. This process, which involves astrocytes and the water channel AQP4, facilitates the removal of harmful proteins like β-amyloid and tau, making it crucial in neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD). AQP4 dysfunction has been linked to the accumulation of these proteins and related pathologies. This study aimed to investigate the association between AQP4 gene polymorphisms (rs2075575, rs162009, and rs335929) and PD in an Italian cohort, consisting of 380 individuals with PD enrolled in a rehabilitation protocol and 461 healthy controls. The analysis found no significant correlation between the selected AQP4 single nucleotide polymorphisms (SNPs) and PD risk. However, the rs162009 AA genotype was associated with a lower risk of developing REM sleep behavior disorder (RBD) symptoms in PD patients, while rs2075575 was linked to hallucinations in these individuals. These findings suggest a potential role for AQP4 polymorphisms in sleep disturbances and psychotic symptoms in PD, but further research is needed to confirm these results and understand the complex interactions between the glymphatic system and PD pathophysiology.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting more than 10 million people worldwide

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that affects young adults with different clinical phenotypes: relapsing–remitting MS (RR-MS), secondary progressive MS (SP-MS), and primary progressive MS (PP-MS). Aquaporin 4 (AQP4), a protein found in astrocytes, plays a crucial role in CNS functions. We investigated the possible association of three AQP4 gene single-nucleotide polymorphisms (SNPs), rs2075575, rs162009, and rs335929, with MS risk and rehabilitation outcomes. SNPs were genotyped in 237 people with MS (pwMS), spanning all disease forms and enrolled in an intensive, multidisciplinary rehabilitation program, and 461 healthy controls (HCs). The AQP4 rs2075575 GG genotype was significantly less frequent in male pwRR-MS compared to HCs (15.4% vs. 29.1%, p = 0.033, OR = 0.44), suggesting a protective role. Haplotype analysis identified the rs2075575(A)-rs162009(A)-rs335929(C) (A-A-C) haplotype as an MS risk factor, particularly in males (p = 0.001, OR = 2.70). Finally, the rs335929 SNP was significantly associated with EDSS improvement after rehabilitation (p = 0.011), with the CC genotype showing the highest mean ΔEDSS in pwRR-MS (p = 0.009), especially in males (p = 0.003). AQP4 gene SNPs may influence both MS susceptibility and rehabilitation outcomes, with sex-specific effects. Further studies are needed to understand the mechanisms behind these associations and their potential for personalized treatment strategies in MS.

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.

A significant proportion of children with Autism spectrum disorder (ASD) experience sleep issues, such as insomnia and other disorders, as assessed by the Sleep Disturbance Scale for Children. Our study investigated the link between six single nucleotide polymorphisms (SNPs) in the melatonin receptor genes MT1 and MT2 and ASD susceptibility, clinical severity and associated sleep problems. A total of 139 ASD children, 82 siblings, and 53 unrelated healthy controls, all of Sardinian ancestry, were studied; among them, 38 children with co-occurring sleep issues were assessed for the outcomes of a rehabilitative program, including behavioral therapy and sleep hygiene. The MT2 rs10830963 G allele is more prevalent in ASD children and their siblings compared to the healthy controls, while rs2119882 (MT1) and rs1562444 (MT2) are associated with DIMS, DA, and SHY. ASD Children carrying the rs2119882 T allele have higher scores for DIMS and DA compared to C allele carriers, and those carrying rs1562444 A allele have higher scores for SHY than G allele carriers. After rehabilitative treatment, homozygous TT carriers of rs2119882 showed less improvement in DIMS symptoms compared to CT and CC carriers. A similar result was observed for AA carriers of SNP rs1562444 about SHY. We may suggest that the MT1 and MT2 variants may serve as useful predictive genetic markers for the severity of sleep disorders in children with ASD, potentially informing the design of more targeted rehabilitative treatments.

Blood-based biomarkers are minimally invasive tools to detect the pathological changes of Alzheimer’s Disease (AD). This meta-analysis aims to investigate the use of blood-derived p-tau isoforms (181, 217, 231) to predict conversion from mild cognitive impairment (MCI) to AD dementia (ADD). Studies involving MCI patients with data on blood p-tau isoforms at baseline and clinical diagnosis at follow-up (≥1 year) were included. Twelve studies on p-tau 181 (4340 MCI, conversion rate 20.6%), four on p-tau 217 (913 MCI, conversion rate 33.4%), and one on p-tau 231 (135 MCI, conversion rate 33%) were included. For p-tau 181, the pooled area under the receiver operating characteristic curve (AUC) was 0.73 (95% CI = 0.68–0.78), and for p-tau 217 was 0.85 (95% CI = 0.75–0.91). Plasma levels of p-tau 181 had good discriminatory power to identify MCI patients who will convert to ADD. Although only four studies on p-tau 217 have been included in the meta-analysis, in the last year the predictive power of p-tau 217 is emerging as superior to that of other isoforms. However, given the high heterogeneity detected in the p-tau 217 studies included in this meta-analysis, additional supportive evidence is needed. Insufficient results were available for p-tau 231. These findings support the prognostic utility of p-tau 181 and p-tau 217 measured in blood to predict progression to ADD in MCI and encourage its future implementation in clinical practice.

Autism Spectrum disorders (ASD) are diagnosed more often in males than in females, by a ratio of about 3:1; this is likely to be due to a difference in risk burden between the sexes and/or to “compensatory skills” in females, that may delay the diagnosis of ASD. Identifying specific risk factors for ASD in females may be important in facilitating early diagnosis. We investigated whether HLA- class I: -A, -B, -C and class II -DRB1 alleles, which have been suggested to play a role in the development of ASD, can be considered as sex-related risk/protective markers towards the ASD. We performed HLA allele genotyping in 178 Italian children with ASD, 94 healthy siblings, and their parents. HLA allele distribution was compared between children with ASD, sex-matched healthy siblings, and a cohort of healthy controls (HC) enrolled in the Italian bone marrow donor registry. Allele transmission from parents to children with ASD and their siblings was also assessed. Our findings suggest that HLA-A*02, B*38, and C*12 alleles are more frequently carried by females with ASD compared to both HC and healthy female siblings, indicating these alleles as potential risk factors for ASD in females. Conversely, the HLA-A*03 allele was more commonly transmitted to healthy female siblings, suggesting it might have a protective effect. Additionally, the HLA-B*44 allele was found to be more prevalent in boys with ASD, indicating it is a potential risk factor for male patients. This is the first Italian study of sex-related HLA association with ASD. If confirmed, these results could facilitate early ASD diagnosis in female patients, allowing earlier interventions, which are crucial in the management of neurodevelopmental disorders.

Parkinson’s disease (PD) is a neurodegenerative disorder affecting about 10 million people worldwide with a prevalence of about 2% in the over-80 population. The disease brings in also a huge annual economic burden, recently estimated by the Michael J Fox Foundation for Parkinson’s Research to be USD 52 billion in the United States alone. Currently, no effective cure exists, but available PD medical treatments are based on symptomatic prescriptions that include drugs, surgical approaches and rehabilitation treatment. Due to the complex biology of a PD brain, the design of clinical trials and the personalization of treatment strategies require the identification of accessible and measurable biomarkers to monitor the events induced by treatment and disease progression and to predict patients’ responsiveness. In the present review, we strive to briefly summarize current knowledge about PD biomarkers, focusing on the role of extracellular vesicles as active or involuntary carriers of disease-associated proteins, with particular attention to those research works that envision possible clinical applications.

Autism spectrum disorders (ASD) can present with different onset and timing of symptom development; children may manifest symptoms early in their first year of life, i.e., early onset (EO-ASD), or may lose already achieved skills during their second year of life, thus showing a regressive-type onset (RO-ASD). It is still controversial whether regression represents a neurobiological subtype of ASD, resulting from distinct genetic and environmental causes. We focused this study on the 25 kD synaptosomal-associated protein (SNAP-25) gene involved in both post-synaptic formation and adhesion and considered a key player in the pathogenesis of ASD. To this end, four single nucleotide polymorphisms (SNPs) of the SNAP-25 gene, rs363050, rs363039, rs363043, and rs1051312, already known to be involved in neurodevelopmental and psychiatric disorders, were analyzed in a cohort of 69 children with EO-ASD and 58 children with RO-ASD. Both the rs363039 G allele and GG genotype were significantly more frequently carried by patients with EO-ASD than those with RO-ASD and healthy controls (HC). On the contrary, the rs1051312 T allele and TT genotype were more frequent in individuals with RO-ASD than those with EO-ASD and HC. Thus, two different SNAP-25 alleles/genotypes seem to discriminate between EO-ASD and RO-ASD. Notably, rs1051312 is located in the 3′ untranslated region (UTR) of the gene and is the target of microRNA (miRNA) regulation, suggesting a possible epigenetic role in the onset of regressive autism. These SNPs, by discriminating two different onset patterns, may represent diagnostic biomarkers of ASD and may provide insight into the different biological mechanisms towards the development of better tailored therapeutic and rehabilitative approaches.