Frontotemporal dementia associated with intrathecal antibodies against axon initial segments

A recent publication by del Campo and colleagues (2022) summarized the current evidence of cerebrospinal fluid (CSF) biomarkers in frontotemporal dementia (FTD).1 In addition to the established CSF biomarkers of neurodegeneration,1 autoimmune mechanisms could be associated with FTD.2, 3 Underlying autoimmune encephalitis or autoimmune psychosis can be treated with immunotherapies.3, 4 The present article illustrates a paradigmatic case study in which routine diagnostic findings revealed the presence of neurodegenerative FTD5 and novel neuronal autoantibodies leading to the conclusion of possibly autoimmune-modulated neurodegenerative FTD. The 57-year-old male developed cognitive deficits, including substantial memory impairment, over 5 months, followed by a first acute severe psychotic decompensation, including auditory hallucinations, disorganized thinking, and suicidality due to the stress of hearing his own thoughts. His productive psychotic symptomatology regressed under treatment with aripiprazole (15 mg). Mirtazapine (30 mg) led to normalization of his sleep disturbances. However, the patient still suffered from concentration deficits, memory problems, anxiety, flat affect, and reduced energy levels. Neuropsychological testing revealed deficits in reaction time with or without sound and deficits in verbal learning and memory abilities. Further diagnostic work-up resulted in findings reminiscent of neurodegenerative FTD. Magnetic resonance imaging (MRI) demonstrated right-sided anterior temporal lobe atrophy. [18F]Fluorodeoxyglucose positron emission tomography (FDG-PET) of the brain revealed right-ward asymmetric temporal polar hypometabolism compatible with right temporal variant of FTD (rtvFTD).6 CSF showed blood–CSF barrier disturbance and tauopathy. All well-characterized neuronal autoantibodies were negative. However, in tissue-based assays,7 a strong autoantibody staining against axon initial segments (AIS) was identified in the CSF (+++) and also weaker in serum. The binding pattern was reminiscent of anti-tripartite motif-containing protein 46 (TRIM46) autoantibodies, a marker of paraneoplastic neurological syndromes.8 However, testing for TRIM46 autoantibodies remained negative using a cell-based assay. Therefore, novel autoantibodies against another AIS antigen can be assumed to exist. After a multidisciplinary case discussion, immunotherapy with plasmapheresis (five sessions across 5 days) followed by azathioprine (up to 150 mg per day) was initiated. After plasmapheresis, mood and concentration improved (the patient felt “more receptive”), and anxiety disappeared. Neuropsychological follow-up after 3 months showed improvements, and the patient returned to work. Glutamate levels (measured using MR spectroscopy) in the right insula were decreasing parallel to the clinical improvement. Affective flattening and partially reduced energy persisted. The FDG-PET follow-up showed no relevant change (Figure 1). This case presentation suggests that future studies on FTD should include screening for novel neural autoantibodies from CSF. Such an approach could expand the current arsenal of CSF biomarkers in FTD1 and optimally improve treatment approaches in similar patients. D.E., K.N., K.R., N.V., H.P., and L.T.vE. were involved in the treatment of the patient. K.N. was responsible for the vision tests. K.R. performed the olfactory tests and a lumbar puncture. A.S. performed the neuropsychological testing. K.D. critically revised the manuscript. H.U. and T.L. performed the MRI measurements and interpreted the findings. N.V. was responsible for the immunological co-assessment. J.B. and P.T.M. performed the FDG-PET measurements and interpreted the findings. H.P. performed the tissue-based assays. H.P. and B.B. were responsible for the neurological co-assessment. All authors were critically involved theoretical discussion and composition of the manuscript. All authors read and approved the final version of the manuscript. Open access funding enabled and organized by Projekt DEAL. Author disclosures are available in the supporting information. The article processing charge was funded by the Baden-Wuerttemberg Ministry of Science, Research and Art and the University of Freiburg in the funding programme Open Access Publishing. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.