ObjectiveTo retrospectively determine the frequency of N-Methyl-D-Aspartate (NMDA) receptor (NMDAR) autoantibodies in patients with different forms of dementia.MethodsClinical characterization of 660 patients with dementia, neurodegenerative disease without dementia, other neurological disorders and age-matched healthy controls combined with retrospective analysis of serum or cerebrospinal fluid (CSF) for the presence of NMDAR antibodies. Antibody binding to receptor mutants and the effect of immunotherapy were determined in a subgroup of patients.ResultsSerum NMDAR antibodies of IgM, IgA, or IgG subtypes were detected in 16.1% of 286 dementia patients (9.5% IgM, 4.9% IgA, and 1.7% IgG) and in 2.8% of 217 cognitively healthy controls (1.9% IgM and 0.9% IgA). Antibodies were rarely found in CSF. The highest prevalence of serum antibodies was detected in patients with “unclassified dementia” followed by progressive supranuclear palsy, corticobasal syndrome, Parkinson’s disease-related dementia, and primary progressive aphasia. Among the unclassified dementia group, 60% of 20 patients had NMDAR antibodies, accompanied by higher frequency of CSF abnormalities, and subacute or fluctuating disease progression. Immunotherapy in selected prospective cases resulted in clinical stabilization, loss of antibodies, and improvement of functional imaging parameters. Epitope mapping showed varied determinants in patients with NMDAR IgA-associated cognitive decline.InterpretationSerum IgA/IgM NMDAR antibodies occur in a significant number of patients with dementia. Whether these antibodies result from or contribute to the neurodegenerative disorder remains unknown, but our findings reveal a subgroup of patients with high antibody levels who can potentially benefit from immunotherapy.

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Background: Gait variability is an established marker of gait function that can be assessed using sensor-based approaches. In clinical settings, spatial constraints and patient condition impede the execution of longer distance walks for the recording of gait parameters. Turning paradigms are often used to overcome these constraints and commercial gait analysis systems algorithmically exclude turns for gait parameters calculations. We investigated the effect of turns in sensor-based assessment of gait variability.Methods: Continuous recordings from 31 patients with movement disorders (ataxia, essential tremor and Parkinson’s disease) and 162 healthy elderly (HE) performing level walks including 180° turns were obtained using an inertial sensor system. Accuracy of the manufacturer’s algorithm of turn-detection was verified by plotting stride time series. Strides before and after turn events were extracted and compared to respective average of all strides. Coefficient of variation (CoV) of stride length and stride time was calculated for entire set of strides, segments between turns and as cumulative values. Their variance and congruency was used to estimate the number of strides required to reliably assess the magnitude of stride variability.Results: Non-detection of turns in 5.8% of HE lead to falsely increased CoV for these individuals. Even after exclusion of these, strides before/after turns tended to be spatially shorter and temporally longer in all groups, contributing to an increase of CoV at group level and widening of confidence margins with increasing numbers of strides. This could be attenuated by a more generous turn excision as an alternative approach. Correlation analyses revealed excellent consistency for CoVs after at most 20 strides in all groups. Respective stride counts were even lower in patients using a more generous turn excision.Conclusion: Including turns to increase continuous walking distance in spatially confined settings does not necessarily improve the validity and reliability of gait variability measures. Specifically with gait pathology, perturbations of stride characteristics before/after algorithmically excised turns were observed that may increase gait variability with this paradigm. We conclude that shorter distance walks of around 15 strides suffice for reliable and valid recordings of gait variability in the groups studied here.