Ilaria Cani

Heterogeneity in sporadic Parkinson’s Disease (PD) is a critical problem that drives variable rates of progression and treatment response and complicates clinical trials. Access to large PD datasets that may help in clustering this heterogeneity is restricted by privacy and regulatory constraints. Simulated patients or digital twins may offer a solution. We developed a large language model (LLM)-framework to generate high-fidelity synthetic PD patients from the Parkinson’s Progression Markers Initiative (PPMI) dataset based on the open-source Qwen3-8B-Base model. Using a relational, tree-structured representation and domain-specific fine-tuning, the model produces patient-level records with longitudinal clinical, imaging, and biomarker data. Fidelity was assessed through distributional similarity, correlation structure, and neurologist review. Utility was tested by training diagnostic classifiers, reproducing a published pharmacometric disease progression model applied to in silico trials, and by extracting a stringent dopamine–motor impairment relationship at early PD stages. Privacy was evaluated via identical match share, distance-to-closest-record, and membership inference attacks. These findings support the use of a dedicated LLM framework for patient simulation, contributing to the foundations of digital twins for PD in silico trials.

Neuronal migration is a vital process that positions billions of neurons to create a functional brain. To navigate the constrained microenvironments within the cortex, precise control over the nuclear mechanics in migrating neurons is indispensable. Here, we show that Lamin B1 (LB1) regulates neuronal migration by modulating nuclear deformability. Excess LB1 in neurons halted migration without altering laminar identity or overall gene expressions in vivo , while in vitro, it elevated nuclear stiffness and impaired neuronal motility in confined spaces. Moreover, mispositioned neurons resulted in electrophysiological defects in the brain. Computational modeling predicted a temporal relationship between nuclear deformation and enhanced migration velocity, which was validated experimentally through live imaging. Notably, cerebral organoid assays using iPS cells established from patients with LMNB1 duplication exhibited impaired neuronal migration in a human model. Collectively, these findings demonstrate that LB1 is a critical regulator of nuclear mechanics, ensuring the accurate spatiotemporal positioning of neurons.

Background: Early stridor onset (≤ 3 years from disease onset) is a predictor of shorter survival in Multiple System Atrophy (MSA), but its role on disease progression is not yet established. In MSA, previous studies on trajectories of disease did not include stridor and REM sleep behavior disorder (RBD) as clinical variable. The aims of the study were: (1) to investigate disease progression in MSA patients with early stridor onset and with early stridor and/or RBD onset; (2) to assess cerebrospinal fluid (CSF) levels of neurofilament light chain protein (NfL) in MSA patients with early onset sleep disorders. Methods: This is a retrospective and prospective cohort study including 208 (120 males) MSA patients. Occurrence of symptoms/signs, milestones of disease progression, and their latency from disease onset were collected. RBD and stridor were video-polysomnography (VPSG)-confirmed. CSF NfL levels were analyzed. Survival data and predictors of mortality were calculated. Results: Out of 208 MSA patients (157 deceased), 91 were diagnosed with stridor and 160 with VPSG-confirmed RBD. Patients with early stridor onset (n = 41) and with early stridor and/or RBD onset (n = 132) showed an early autonomic involvement, developed a more progressive and severe disease and presented higher CSF NfL than those with late stridor and RBD onset. Early stridor and early RBD were independent risk factors on MSA survival. Conclusions: The evidence of a more rapid and severe disease progression and of high CSF NfL levels in patients who early developed sleep disorders could define a different MSA phenotype with a widespread impairment of central-brainstem circuits.

Objective. Recent innovative neurostimulators allow recording local field potentials (LFPs) while performing motor tasks monitored by wearable sensors. Inertial sensors can provide quantitative measures of motor impairment in people with subthalamic nucleus deep brain stimulation. To the best of our knowledge, there is no validated method to synchronize inertial sensors and neurostimulators without an additional device. This study aims to define a new synchronization method to analyze disease-related brain activity patterns during specific motor tasks and evaluate how LFPs are affected by stimulation and medication. Approach. Fourteen male subjects treated with subthalamic nucleus deep brain stimulation were recruited to perform motor tasks in four different medication and stimulation conditions. In each condition, a synchronization protocol was performed consisting of taps on the implanted neurostimulator, which produces artifacts in the LFPs that a nearby inertial sensor can simultaneously record. Main results. In 64% of the recruited subjects, induced artifacts were detected at least in one condition. Among those subjects, 83% of the recordings could be synchronized offline analyzing LFPs and wearables data. The remaining recordings were synchronized by video analysis. Significance. The proposed synchronization method does not require an external system (e.g., TENS electrodes) and can be easily integrated into clinical practice. The procedure is simple and can be carried out in a short time. A proper and simple synchronization will also be useful to analyze subthalamic neural activity in the presence of specific events (e.g., freezing of gait events) to identify predictive biomarkers.

Hereditary transthyretin amyloidosis (hATTR) is a multisystemic, rare, inherited, progressive and adult-onset disease, affecting the sensory-motor nerves, heart, autonomic function, and other organs. There are over 130 mutations known in the TTR gene. The His90Asn mutation has been previously reported in several reports, but its pathogenetic role is still debated. We report two sporadic cases of adult women with a heterozygous His90Asn mutation in TTR gene and neurological involvement extensively investigated. A typical Congo red-positive pathologic deposition of amyloid fibrils in the salivary glands was documented in one subject. Patients were successfully treated with patisiran with a good clinical outcome. These data support a pathogenetic role of His90Asn mutation in hATTR, and suggest early treatment in symptomatic carriers of His90Asn mutation.

Background: Blood pressure control in Parkinson's disease (PD) under subthalamic deep brain stimulation (STN‐DBS) is influenced by several intertwined aspects, including autonomic failure and levodopa treatment. Objective: To evaluate the effect of chronic STN‐DBS, levodopa, and their combination on cardiovascular autonomic functions in PD. Methods: We performed cardiovascular reflex tests (CRTs) before and 6‐months after STN‐DBS surgery in 20 PD patients (pre‐DBS vs. post‐DBS). CRTs were executed without and with medication (med‐OFF vs. med‐ON). Results: CRT results and occurrence of neurogenic orthostatic hypotension (OH) did not differ between pre‐ and post‐DBS studies in med‐OFF condition. After levodopa intake, the BP decrease during HUTT was significantly greater compared to med‐OFF, both at pre‐DBS and post‐DBS evaluation. Levodopa‐induced OH was documented in 25% and 5% of patients in pre‐DBS/med‐ON and post‐DBS/med‐ON study. Conclusion: Chronic stimulation did not influence cardiovascular responses, while levodopa exerts a relevant hypotensive effect. The proportion of patients presenting levodopa‐induced OH decreases after STN‐DBS surgery.