Neurocognition, Cerebellar Functions and Psychiatric Features in Spinocerebellar Ataxia Type 34: a case series

Maurizio Cundari^1,2,3*Lena Kirchhoff⁴Susanna Vestberg⁴Danielle Van Westen^5,6Sigurd Dobloug^7,8Karin Markenroth Bloch⁹Markus Nilsson¹⁰Linda Wennberg^10,8Boel Hansson^10,8Nikolaos Priovoulos^11,12Anders Rasmussen¹³Sorina Gorcenco⁸

• ¹Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden
• ²Unit of Neurology, Hospital of Helsingborg, Helsingborg, Sweden
• ³Unit of Neuropsychiatry, Hospital of Helsingborg, Helsingborg, Sweden
• ⁴Department of Psychology, Faculty of Social Science, Lund University, Lund, Sweden
• ⁵Institution for Clinical Sciences Lund, Lund University, Lund, Sweden
• ⁶Image and Function, Skane University Hospital, Lund, Sweden
• ⁷Unif of Neurology, Hospital of Helsingborg, Helsingborg, Sweden
• ⁸Lund University, Skane University Hospital, Department for Clinical Sciences Lund, Neurology, Lund, Sweden
• ⁹Lund University Bioimaging Centre, Lund University, Lund, Sweden
• ¹⁰Department of Clinical Sciences Lund, Radiology, Lund University, Lund, Sweden
• ¹¹Oxford University Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
• ¹²Spinoza Centre for Neuroimaging, Royal Netherlands Academy for Arts and Sciences, Amsterdam, Netherlands
• ¹³Lund University, Lund, Sweden

Objective:This study primarily aimed to comprehensively characterize the neurological, neuroradiological and neurocognitive profiles, as well psychiatric features of individuals with Spinocerebellar Ataxia Type 34(SCA34)associated with pathogenic variants in theELOVL4gene. Secondarily, we investigated the relationship between neurocognitive functions and cerebellar morphology in individuals withSCA34by correlating structural changes to cognitive performance. Given involvement of the cerebellum inSCA34, our findings will contribute to a broader understanding of the role of the cerebellum in cognition. Methods:Fourindividuals(52f,72m,76m,76 f)underwentDNAtesting usingNext-GenerationSequencing and detailed assessment of neurocognitive functions.The test battery evaluated all six cognitive domains:verbal functions,executive functions,attention and processing speed,learning and memory,visuospatial perception and abilities,and social cognition. In addition, cerebellar and motor functions were evaluated using FingerTapping,PrismAdaptation, and the Motor Speed subtest of theD-KEFS.Test results were compared with each individual's estimated premorbid cognitive level,determined from their highest educational attainment or occupational status prior to disease onset.Psychiatric symptoms related to anxiety, depression, and sleep were reported using clinical scales.The Scale for the Assessment and Rating of Ataxia(SARA) was used to assess ataxia severity.Two individuals and one matched control underwent high-resolution7TMRI to characterize cerebellar morphology.Results: Neurocognitive assessments identified cognitive and motor dysfunction across all individuals, including distinct neurocognitive impairments consistent with cerebellar cognitive-affective syndrome(CCAS), along with additional deficits in learning, visual and verbal episodic memory, emotion recognition—a component of social cognition. Anxiety and sleep disturbance, but not depression, were observed in both female participants. High-resolution7TMRI revealed structural cerebellar alterations, with moderate to severe bilateral cerebellar atrophy, including the vermis and multiple lobules(CrusII,VIIb,VIIIa,VIIIb,IX), as well as atrophy of the middle and superior cerebellar peduncles, accompanied by mild pontine atrophy. Genetic analyses confirmed the involvement ofELOVL4-related disruptions in long-chain fatty acid biosynthesis, offering insight into the molecular underpinnings of cerebellar degeneration inSCA34. Conclusion: Individuals withSCA34 show cerebellar degeneration accompanied by cognitive, motor, and social-affective impairments consistent with CCAS. Atrophy of the vermis, multiple lobules, and cerebellar peduncles align with these deficits, highlighting the cerebellum's key role in cognition. ELOVL4-related disruptions in fatty acid biosynthesis provides insight into the molecular basis of SCA34. Together, these findings advance our understanding of how cerebellar pathology contributes to complex neurocognitive and psychiatric symptoms in genetic ataxias.