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@ARTICLE{Pontillo:285633,
      author       = {Pontillo, Giuseppe and Penna, Simone and Arrigoni, Filippo
                      and Bender, Benjamin and Boesch, Sylvia and Brunetti, Arturo
                      and Cendes, Fernando and Chopra, Sidhant and Corben, Louise
                      A and Deistung, Andreas and Delatycki, Martin B and
                      Diciotti, Stefano and Dogan, Imis and Egan, Gary F and
                      França, Marcondes C and Georgiou-Karistianis, Nellie and
                      Göricke, Sophia L and Henry, Pierre-Gilles and
                      Hernandez-Castillo, Carlos R and Hutter, Diane and Joers,
                      James M and Lenglet, Christophe and Lindig, Tobias and Lodi,
                      Raffaele and Manners, David N and Martinez, Alberto R M and
                      Martinuzzi, Andrea and Marzi, Chiara and Mascalchi, Mario
                      and Nachbauer, Wolfgang and Pane, Chiara and Peruzzo, Denis
                      and Pishardy, Pramod K and Reetz, Kathrin and Rezende,
                      Thiago J R and Romanzetti, Sandro and Saccà, Francesco and
                      Schoels, Ludger and Schulz, Jorg B and Stefani, Ambra and
                      Synofzik, Matthis and Thomopoulos, Sophia I and Thompson,
                      Paul M and Timmann, Dagmar and Tonon, Caterina and Vavla,
                      Marinela and Harding, Ian H and Cocozza, Sirio},
      title        = {{I}dentification of {B}iological {S}ubtypes of {F}riedreich
                      {A}taxia with {S}tructural {MRI}-based {M}achine
                      {L}earning.},
      journal      = {Radiology},
      volume       = {318},
      number       = {3},
      issn         = {0033-8419},
      address      = {Oak Brook, Ill.},
      publisher    = {Soc.},
      reportid     = {DZNE-2026-00272},
      pages        = {e251386},
      year         = {2026},
      abstract     = {Background Friedreich ataxia (FRDA) is an inherited,
                      progressive neurodegenerative disease. Interindividual
                      heterogeneity in the rate and phenotypic profile of disease
                      progression indicates a biologic variability in the pattern
                      and spatial evolution of underlying changes, but the
                      occurrence of possible FRDA subgroups, which could aid in
                      clinical trial design and treatment, are still unknown.
                      Purpose To obtain a structural MRI-based stratification of
                      participants with FRDA using the Subtype and Stage Inference
                      (SuStaIn) algorithm and determine whether these subgroups
                      are biologically meaningful and clinically relevant.
                      Materials and Methods This multicenter secondary analysis of
                      prospectively acquired data included structural MRI and
                      clinical-demographic data from participants from the
                      ENIGMA-Ataxia working group. MRI biomarkers were analyzed
                      using the SuStaIn algorithm to identify subgroups with
                      distinct patterns and disease stages. The clinical and
                      genetic relevance of these subgroups were assessed within a
                      linear model framework. Results This study included 565
                      participants (mean age, 32 years ± 13.1 [SD]; 286 women;
                      275 participants with FRDA and 290 healthy controls).
                      SuStaIn identified three subtypes: (a) a classical subtype
                      $(66.5\%$ [183 of 275 participants]), characterized by an
                      ascending gradient of damage from brainstem to cerebellar
                      cortex to cerebrum; (b) an early cerebral subtype $(25.8\%$
                      [71 of 275 participants]) with cerebral atrophy preceding
                      the involvement of cerebellar cortex; and (c) and an early
                      cerebellar subtype $(7.64\%$ [21 of 275 participants])
                      showing cerebellar lobule atrophy before upper brainstem or
                      cerebral involvement. More advanced disease stages
                      (MRI-based SuStaIn stages) correlated with greater symptom
                      duration (unstandardized coefficient B = 0.422, standard
                      error = 0.065, P < .001) and severity (B = 1.404, standard
                      error = 0.201, P < .001), and these relationships were
                      moderated by subtype, with biologic stage progression in the
                      early cerebral subtype mapping less strongly to clinical
                      variables relative to the others (interaction term early
                      cerebral subtype × stage: B = -0.925, standard error =
                      0.410, P = .02). Conclusion Using the SuStaIn algorithm,
                      three distinct structural MRI-based subtypes of FRDA were
                      identified, with different patterns of brain degeneration
                      and associations with clinical severity. © RSNA, 2026
                      Supplemental material is available for this article.},
      keywords     = {Humans / Friedreich Ataxia: diagnostic imaging / Friedreich
                      Ataxia: classification / Friedreich Ataxia: pathology /
                      Magnetic Resonance Imaging: methods / Female / Male / Adult
                      / Machine Learning / Prospective Studies / Brain: diagnostic
                      imaging / Brain: pathology / Middle Aged / Disease
                      Progression / Young Adult},
      cin          = {AG Schöls / AG Gasser},
      ddc          = {610},
      cid          = {I:(DE-2719)5000005 / I:(DE-2719)1210000},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41805414},
      doi          = {10.1148/radiol.251386},
      url          = {https://pub.dzne.de/record/285633},
}