Leader: Angelo Antonini (UNIPD); Other collaborator(s): Benedetta Nacmias (UNIFI); Stefano Salvioli (UNIBO); Carlo Pappone, Patrizia Rovere-Querini (UniSR); Licia Iacoviello (NEUROMED); Maria Benedetta Donati (NEUROMED); RTDA PNRR TBA (UNICATT); Emanuele Marzetti (UNICATT)
The general objective is that of the identification of markers (imaging and soluble markers) to monitor: 1. longevity mechanisms in cognitive health; 2. early, preclinical diagnosis of neurodegenerative diseases that cause cognitive disorders; 3. therapy success; 4. the improvement of the complex clinical management of the affected people and therefore to improve the significant social, welfare and economic that these pathologies bring to society.5. aging trajectories and their association with mortality and neurodegenerative diseases.
Brief description of the activities and of the intermediate results: Partner UNIPD team continued its collection and analysis of key biomarkers— NfL, GFAP, and pTau181—in the Parkinson’s disease (PD) population. These plasma/serum biomarkers, identified jointly with the other partner (UNIFI), are deemed highly relevant in the neurodegenerative context. Partner UNIPD has conducted serum analyses for NfL, GFAP, and pTau181 in 92 PD patients, along with 20 age-, education-, and sex-matched healthy controls (HC). Additionally, a subgroup of PD patients (n=65) underwent a comprehensive neuropsychological assessment, with 44 categorized as PD with normal cognition (PD-NC) and 21 with mild cognitive deficits (PD-MCI). Biomarker concentrations were measured using commercially available Simoa kits. Their preliminary findings indicate higher levels of neurodegeneration biomarkers in PD compared to HC, with NfL and GFAP potentially serving as indicators for distinguishing PD patients with MCI. Specifically, elevated NfL levels were associated with poorer performance in the attentional domain. By contrast, the role of pTau181 in PD and its relationship with cognition require further elucidation. These initial results will be presented orally at the national congress "10th Congress of the Italian Parkinson's Disease and Movement Disorders Society/LIMPE-DISMOV."
Furthermore, UNIPD conducted preliminary analyses in a subgroup of PD patients who underwent MRI and an extensive neuropsychological assessment. The main aim was to explore cortical and subcortical differences between PD patients with vs. without cognitive deficits (n=14 PD vs 34, respectively) and their association with neurodegenerative biomarkers (NfL, GFAP, pTau181). Although these results are highly preliminary (p<0.05, without FDR/FEW correction), they observed significant involvement of numerous subcortical regions. The sample size needs to be expanded to potentially identify stronger differences, given the substantial variability between the two PD-subgroups.
Partner UNIFI (Prof Nacmias) has studied the usefulness of GFAP, NfL and pTau 181 for the early detection of dementia before the onset of clinical stages. The results are reported in a recently accepted paper (Ingannato et al., in press).
Research products of the reported period related to this Task:
Main policy, industrial and scientific implications: Data Analysis and drafting article on the role of HL in the dyad caregiver/older person
Partner UNIPD has expanded the numerosity for the preliminary analyses in PD patient sample to explore the relation between biofluid biomarkers (NFl, GFAP, pTau181) and brain imaging (structural MRI). New results are expected by the end of the October. A paper titled “The role of cerebellum in physical and functional impairment of older adults with mild cognitive impairment” has been submitted.
In the framework of task 3.2, UNIPD focused on three subtasks involving the analysis, data interpretation and writing of the following works:
1) The role of serum biomarkers in Parkinsonian disorders, Alzheimer’s disease and Frontotemporal dementia. In this study, we analyzed and discussed the role of GFAP, NfL, and pTau181 in a cohort of 179 participants, comprising: 120 Parkinson’s disease (PD) patients, 88 with Alzheimer’s disease (AD), 16 with Frontotemporal dementia (FTD), 11 with multiple system atrophy (MSA) and 14 with progressive supranuclear palsy (PSP) patients. We compared them with 30 sex and age-matched healthy individuals (HC). The serum biomarkers were analyzed with the SIMOA technique.
2) Serum GFAP and NFL Correlates of Brain Morphometry and Cognitive Dysfunction in Parkinson's Disease. This work examined the relationship between blood biomarkers, brain volumes, and cognitive state in a cohort of 58 PD patients. Patients were stratified in 37 PD with no cognitive impairment (PD-NC) and 21 PD with cognitive impairment (PD-CI), for each patient one T1-weighted and one T2-weighted FLAIR image was acquired on a Philps 3T scanner. The serum biomarkers were analyzed with the SIMOA technique. Key findings revealed that the GFAP-NFL ratio showed the largest and most widespread inverse correlations with brain volumes, particularly in the anterior cingulate region. These correlations remained significant after adjusting for age, gender, intracranial volume, and education. Additionally, brain volume differences between PD-NC and PD-CI groups were significant.
3) Plasma pTau217 as a Marker for Alzheimer’s Co-Pathology in Parkinson’s Spectrum Disorders. Here, we evaluate the utility of plasma pTau217 for detecting AD co-pathology in parkinsonian disorders and its association with cognitive impairment. The PADUA-CESNE cohort included 170 participants: 57 with PD, 4 with dementia with Lewy bodies (DLB), 28 with PSP, 4 with corticobasal syndrome (CBS) patients, 51 HC and 26 with mild cognitive deficits (MCI). Plasma pTau217 was measured using a research-use-only Lumipulse G1200 assay (Fujirebio, Japan). We found that pTau217 is elevated in PD patients with cognitive impairment, particularly PDD/DLB, but not in cognitively normal PD. It may serve as a reliable marker of AD co-pathology, warranting further validation with PET imaging.
During this trimester, UNIPD promoted a third mission activity as part of the SOPRANO dissemination project. Two events were organized to promote healthy aging: “Orchestra Asclepio in Concerto – Quando la musica diventa cura”. “La musica del cervello”.
Additionally, a poster was presented at the Autumn Meeting of the SINP (Bologna, December 13, 2024). The poster, titled “Optimal MMSE and MoCA Cutoffs for Cognitive Diagnoses in Parkinson’s Disease: A Data-Driven Decision Tree Model,” showcased our latest findings on cognitive diagnostic thresholds in PD.
Devita, M., Debiasi, G., … Cauzzo, S, … Anglani, M. et al. The Role of Cognitive Reserve in Protecting Cerebellar Volumes of Older Adults with mild Cognitive Impairment. Cerebellum 23, 1966–1974 (2024). https://doi.org/10.1007/s12311-024-01695-w
Neurogenetic Laboratory of UNIFI, coordinated by Prof. Nacmias, collected final data regarding the completed analysis of the plasma NfL (Neurofilament light Chain) of 185 patients included in the study, affected by SCD (Subjective cognitive decline), MCI (Mild cognitive impairment) and AD (Alzheimer’s Disease). The Neurogenetic laboratory is running statistical analysis of clinical and biological data and evaluating the results of the task.
Moreover, The Neurogenetic laboratory extended the previous analysis of the neurodegenerative biomarker P-TAU217 in a new group of plasma samples of patients with different levels of cognitive decline included in the study, in particular SCD and MCI.
Neurogenetic Laboratory of UNIFI contributed to the paper “Multi-pathway blood biomarkers to target and monitor multidimensional prevention of cognitive and functional decline (nested in the IN-TeMPO study framed within the World-Wide FINGERS network)” by Gessica Sala, Luca Cuffaro, Federico Emanuele Pozzi, Simona Andreoni, Chiara Bazzini, Elisa Conti, Chiara Paola Zoia, Simone Beretta, Lucio Tremolizzo, Giuseppe Bellelli, Chukwuma Okoye, Maria Cristina Ferrara, Annamaria De Luca, Roberta Lenti, Paola Mantuano, Paola Pontrelli, Alessandra Stasi, Giovanni Defazio, Vincenzo Solfrizzi, Lucilla Crudele, Cristina Airoldi, Ferdinando Chiaradonna, Maria Pia Longhese, Giovanni Messina, Antonino Natalello, Ivan Orlandi, Alessandra Aloisi, Simonetta Capone, Assunta Ingannato, Benedetta Nacmias, Daniela Capello, Francesca Mangialasche and Carlo Ferrarese, recently accepted for the publication on the Journal “Frontiers in Aging Neuroscience, section Alzheimer's Disease and Related Dementias”. The In-TeMPO study involved different spokes of the AGE-IT project (Spoke 8, Spoke3 – Unifi, Spoke 9).
The Neurogenetic laboratory is also preparing an abstract to submit to the CALL FOR PAPERS for the participation to the Second General Meeting di Age-IT, that will be held in Naples on Oct 29th-31st 2025.
In this semester, the UNIPD activity focused on the following three research lines:
1) Plasma pTau217 as a Marker of Alzheimer’s Co-Pathology in Parkinsonian Disorders
We investigated the utility of plasma phosphorylated Tau 217 (pTau217) as a biomarker for Alzheimer's disease (AD) co-pathology in a cohort of 170 participants, including individuals diagnosed with Parkinson’s disease (PD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB). Following comprehensive data analysis, we prepared and submitted a manuscript titled "Plasma pTau217 as a Marker for Alzheimer’s Co-Pathology in Parkinson’s Spectrum Disorders."
2) Serum Biomarkers Across Neurodegenerative Disorders
We analyzed serum levels of GFAP, neurofilament light (NfL), and pTau181 in a cohort of 179 participants, including 120 PD patients, 88 with AD, 16 with frontotemporal dementia (FTD), 11 with multiple system atrophy (MSA), and 14 with PSP. These were compared with 30 age- and sex-matched healthy controls (HCs). Biomarker measurements were conducted using the SIMOA platform. Based on the findings, we submitted a manuscript entitled "The Role of Blood-Based Biomarkers in Parkinsonian Disorders, Alzheimer’s Disease, and Frontotemporal Dementia."
3) Associations Between Blood Biomarkers, Brain Volume, and Cognition in PD
We explored the relationship between serum biomarkers, brain imaging, and cognitive status in 58 PD patients, divided into 37 cognitively unimpaired (PD-NC) and 21 cognitively impaired (PD-CI) individuals. Each participant underwent T1-weighted and T2-weighted FLAIR MRI scans using a Philips 3T scanner. Serum biomarkers were again analyzed via the SIMOA method. A manuscript based on this study is currently in preparation.