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. 2025 Feb 12;272(3):203.
doi: 10.1007/s00415-024-12836-w.

Motor and nonmotor features of p.A53T alpha-synuclein PD vs idiopathic PD: longitudinal data from the PPMI study

Athina Maria Simitsi  1 , Evangelos Sfikas  2 , Christos Koros  2 , Nikolaos Papagiannakis  2 , Ion Beratis  2 , Dimitra Papadimitriou  3 , Roubina Antonellou  2 , Styliani Fragiadaki  2 , Dionysia Kontaxopoulou  2 , Marina Picillo  4 , Ioanna Pachi  2   5 , Ioanna Alefanti  2 , Maria Stamelou  6   7 , Paolo Barone  4 , Leonidas Stefanis  2   8
Affiliations

Motor and nonmotor features of p.A53T alpha-synuclein PD vs idiopathic PD: longitudinal data from the PPMI study

Athina Maria Simitsi et al. J Neurol. .

Abstract

Background and objectives: The phenotype of p.A53T-α-synuclein (SNCA) mutation carriers with Parkinson's disease (A53T-PD) appears more severe compared to idiopathic PD (iPD), however, information is limited. Here we conducted a comprehensive longitudinal study to investigate the progression of motor and nonmotor features of Α53Τ-PD compared to iPD.

Methods: Detailed longitudinal 3-year data, concerning both motor and non-motor features, of 16 p.A53T-PD and 48 iPD, matched for age (51-53 years) and disease duration (approximately 4 years) at baseline, were downloaded from the Parkinson's Progression Markers Initiative (PPMI) database and compared between the two groups. Additionally, a cognitive composite score was generated by five cognitive tests, focused more on executive/visuospatial function.

Results: At baseline, global cognitive function, as assessed by the Montreal Cognitive Assessment (MOCA), was not significantly different between the two groups, in contrast to tests evaluating executive/visuospatial function, including the composite score, which were worse in A53T-PD. There was a significant decline over time in all neuropsychological tests in A53T-PD, while iPD remained stable. A similar pattern was revealed for motor status and function, as well as autonomic function, which were similar between the two groups at baseline, but deteriorated significantly only in A53T-PD over time.

Discussion: A53T-PD patients present an accelerated decline in both motor and non-motor parameters, with an impairment in executive-visuospatial function occurring early in the disease process. Such data may set the stage for targeted disease-modifying therapies in this particular subtype, while generated data may be widely applicable to iPD, which is largely a sporadic synucleinopathy.

Keywords: Longitudinal; Motor; Non-motor; Parkinson’s disease; p.A53T-α-synuclein mutation.

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Conflict of interest statement

Declarations: The author(s) would like to disclose the following: Athina Maria Simitsi received funding from the Michael J Fox Foundation for her participation in PPMI; Evangelos Sfikas has no disclosures; Christos Koros received funding from the Michael J Fox Foundation for his participation in PPMI; Nikolaos Papagiannakis received funding from the Michael J Fox Foundation for his participation in PPMI; Ion Beratis received funding from the Michael J Fox Foundation for his participation in PPMI; Dimitra Papadimitriou has no disclosures; Roubina Antonelou received funding from by the National Network for Research of Neurodegenerative Diseases on the basis of Medical Precision (Grant 2018E01300001), funded by the General Secretariat of Research and Innovation (GSRI), and by Brain Precision(TAEDR-0535850), funded by the GSRI, through funds provided by the European Union (Next Generation EU)to the National Recovery and Resilience Plan; Stella Fragkiadaki received funding from the Michael J Fox Foundation for her participation in PPMI; Dionysia Kontaxopoulou received funding from the Michael J Fox Foundation for her participation in PPMI; Marina Picillo received funding from the Italian Ministry of Health, the Italian Ministry of University and Fondazione della Società Italiana di Neurologia; Ioanna Pachi has no disclosures; Ioanna Alefanti has no disclosures; Maria Stamelou has no disclosures; Paolo Barone Prof Paolo Barone received consultancies as a member of the advisory board for Zambon, Lundbeck, UCB, Chiesi, Abbvie and Acorda; Leonidas Stefanis over the past year has received the following grants: PPMI2(supported by the Michael J. Fox Foundation), IMPRIND-IMI2 Number 116060 (EU, H2020), "Transferring autonomous and non-autonomous cell degeneration 3D models between EU and USA for development of effective therapies for neurodegenerative diseases (ND)—CROSS NEUROD" (H2020-EU 1.3.3., GrantNumber778003), «Chaperone-Mediated Autophagy in Neurodegeneration» (Hellenic Foundation for Research and Innovation Grant HFRI-FM17-3013), "ALAMEDA" (H2020-EU, Grant Agreement 101017558),"Next-generation antisense molecules for Parkinson's disease therapy (THERASYN)" (Greek Secretariat of Research and Technology (GSRT), Collaborator), "Brain Precision" (GSRT), and "CMA as a Means to Counteract alpha-Synuclein Pathology in Non-Human Primates" (by the Michael J. Fox Foundation(Collaborator)). He has served on Advisory Boards for Abbvie, Innovis Pharma, ITF Hellas and Biogen and has received honoraria from ITF Hellas, Innovis Pharma and Abbvie.

Figures

Fig. 1
Fig. 1
Longitudinal cognitive Tests in A53T-PD vs. iPD. a a significant reduction was observed in the MOCA score in the group of A53T-PD at time “3”(year number 2) vs time “1” (baseline), as well at time “4” (year number 3) comparing to times “1” (baseline) and “2” (year number 1). The two groups differed at all time points, except baseline, with p-values < 0.01 indicating lower MOCA values in the group of A53T-PD. b A significant reduction in the SDMT score was observed in the group of A53T-PD at times “2”, “3” and “4” vs time “1”. The two groups differed at all time points, indicating lower SDMT values in the group of A53T-PD. c In Semantic Fluency, differences were found between groups but also across time for the group of A53T-PD. Specifically a significant reduction was observed in the group of A53T-PD at time “4” vs time “1”. The two groups differed at all time points, except baseline, indicating lower SEMANTIC F values in the group of A53T-PD. d A composite cognitive score was generated (COMPOSITE), constituted of 5 cognitive domains: MOCA score, Semantic fluency, Letter Number Sequencing Test, BENTON and Symbol Digit Modality Test [COMPOSITE = (MOCA + Semantic.F + LNST + BENTON + SDMT)/5]. A significant reduction was observed in the COMPOSITE score in the group of A53T-PD at time “2”(year number 1) vs time “1” (baseline), at time “3” (year number 2) vs time “1” (baseline), as well at “4” (year number 3) vs time “1”. The two groups differed at all time points, with p-values < 0.001, indicating significant cognitive decline in the sum of these domains in the group of A53T-PD related to iPD
Fig. 2
Fig. 2
Longitudinal Non-Motor Tests in A53T-PD vs. iPD. a SCOPA-AUT: a significant increase was observed in the group of A53T-PD at times “3” vs time “1” and “2”, as well at time “4” comparing to time “2”. The two groups differed at time points “3” and “4”, indicating higher SCOPA-AUT values in the group of A53T-PD. b MDS-UPDRS IA: 1.1 Cognition (UPDRS.1COG): A significant increase was observed in the group of A53T-PD at times “3” and “4” vs time “1” and at times “3” and “4” vs time “2” The two groups differed at all time points except baseline, with p-values ≤ 0.04, indicating higher values in the group of A53T-PD. c MDS-UPDRS IA: 1.2 Hallucinations and psychosis (UPDRS.1HAL): Cognition (UPDRS.1COG): A significant increase was observed in the group of A53T-PD at times “3” and “4” vs time “1” and at times “3” and “4” vs time “2”. The two groups differed at time points “3” and “4”, with p-values < 0.001, indicating higher values in the group of A53T-PD
Fig. 3
Fig. 3
Longitudinal Motor Tests in A53T-PD vs. iPD. (a) MDS-UPDRS-III in the ON state: a significant increase was observed in the group of A53T-PD at times “3” vs “1” and “2”, as well at time “4” comparing to times “1” and “2”. The two groups differed at time points “3” and “4”, indicating higher UPDRS.III.ON values in the group of A53T-PD. b H&Y scale in the ON state: a significant increase was observed in A53T-PD at time “4” vs “1”, “2” and “3”. The two groups differed at time points “3” and “4”, indicating higher H & Y. ON values in the group of A53T-PD. c MDS-UPDRS II: For the group of A53T-PD all values were significantly different, gradually increasing, except for time “3” vs “4”. A statistically significant increase is observed between baseline and time “4” for the iPD group as well (p = 0.005). The two groups differed at time points “2”, “3” and “4”, indicating higher UPDRS.II values in the group of A53T-PD. d S&E: a significant reduction was observed in the group of A53T-PD at time “3” vs time “1”, as well as at time “4” comparing to times “1” and “2”. The two groups differed at all time points, indicating lower S &E values in the group of A53T-PD
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