Disentangling the heterogeneity of multiple sclerosis through identification of independent neuropathological dimensions.

Multiple sclerosis (MS) is a heterogeneous neurological disorder with regards to clinical presentation and pathophysiology. Here, we investigated the heterogeneity of MS by performing an exploratory factor analysis on quantitative and qualitative neuropathology data collected for 226 MS donors in the Netherlands Brain Bank autopsy cohort. Three promising dimensions were identified and subsequently validated with clinical, neuropathological, and genetic data. Dimension 1 ranged from a predominance of remyelinated and inactive lesions to extensive pathological changes, higher proportions of active and mixed lesions, and foamy microglia morphology. This pattern was positively correlated with more severe disease, the presence of B and T cells, and neuroaxonal damage. Scoring high on dimension 2 was associated with active lesions, reactive sites, and the presence of nodules. These donors had less severe disease, a specific pattern of cortical lesions, and MS risk variants in the human leukocyte antigen region, the latter indicating a connection between disease onset and this neuropathological dimension. Donors scoring high on dimension 3 showed increased lesional pathology with relatively more mixed and inactive lesions and ramified microglia morphology. This pattern was associated with longer disease duration, subpial cortical lesions, less involvement of the adaptive immune system, and less axonal damage. Taken together, the three dimensions may represent (1) demyelination and immune cell activity associated with pathological and clinical progression, (2) microglia (re)activity and possibly lesion initiation, and (3) loss of lesion activity and scar formation. Our findings highlight that a thorough understanding of the interplay between multiple pathological characteristics is crucial to understand the heterogeneity of MS pathology, as well as its association with genetic predictors and disease outcomes. The scores of donors on the dimensions can serve as an important starting point for further disentanglement of MS heterogeneity and translation into observations and interventions in living cohorts with MS.

Three-Verb Clusters in Interference Frisian: A Stochastic Model over Sequential Syntactic Input.

Abstract Interference Frisian (IF) is a variety of Frisian, spoken by mostly younger speakers, which is heavily influenced by Dutch. IF exhibits all six logically possible word orders in a cluster of three verbs. This phenomenon has been researched by Koeneman and Postma (2006), who argue for a parameter theory, which leaves frequency differences between various orders unexplained. Rejecting Koeneman and Postma's parameter theory, but accepting their conclusion that Dutch (and Frisian) data are input for the grammar of IF, we will argue that the word order preferences of speakers of IF are determined by frequency and similarity. More specifically, three-verb clusters in IF are sensitive to: their linear left-to-right similarity to two-verb clusters and three-verb clusters in Frisian and in Dutch; the (estimated) frequency of two- and three-verb clusters in Frisian and Dutch. The model will be shown to work best if Dutch and Frisian, and two- and three-verb clusters, have equal impact factors. If different impact factors are taken, the model's predictions do not change substantially, testifying to its robustness. This analysis is in line with recent ideas that the sequential nature of human speech is more important to syntactic processes than commonly assumed, and that less burden need be put on the hierarchical dimension of syntactic structure.

Identification of clinical disease trajectories in neurodegenerative disorders with natural language processing.

Neurodegenerative disorders exhibit considerable clinical heterogeneity and are frequently misdiagnosed. This heterogeneity is often neglected and difficult to study. Therefore, innovative data-driven approaches utilizing substantial autopsy cohorts are needed to address this complexity and improve diagnosis, prognosis and fundamental research. We present clinical disease trajectories from 3,042 Netherlands Brain Bank donors, encompassing 84 neuropsychiatric signs and symptoms identified through natural language processing. This unique resource provides valuable new insights into neurodegenerative disorder symptomatology. To illustrate, we identified signs and symptoms that differed between frequently misdiagnosed disorders. In addition, we performed predictive modeling and identified clinical subtypes of various brain disorders, indicative of neural substructures being differently affected. Finally, integrating clinical diagnosis information revealed a substantial proportion of inaccurately diagnosed donors that masquerade as another disorder. The unique datasets allow researchers to study the clinical manifestation of signs and symptoms across neurodegenerative disorders, and identify associated molecular and cellular features.

The Minimal and Short-Lived Effects of Minority Language Exposure on the Executive Functions of Frisian-Dutch Bilingual Children.

Various studies have shown that bilingual children need a certain degree of proficiency in both languages before their bilingual experiences enhance their executive functioning (EF). In the current study, we investigated if degree of bilingualism in Frisian-Dutch children influenced EF and if this effect was sustained over a 3-year period. To this end, longitudinal data were analyzed from 120 Frisian-Dutch bilingual children who were 5- or 6-years-old at the first time of testing. EF was measured with two attention and two working memory tasks. Degree of bilingualism was defined as language balance based on receptive vocabulary and expressive morphology scores in both languages. In a context with a minority and a majority language, such as the Frisian-Dutch context, chances for becoming proficient in both languages are best for children who speak the minority language at home. Therefore, in a subsequent analysis, we examined whether minority language exposure predicted language balance and whether there was a relationship between minority language exposure and EF, mediated by language balance. The results showed that intensity of exposure to Frisian at home, mediated by language balance, had an impact on one of the attention tasks only. It predicted performance on this task at time 1, but not at time 2 and 3. This partially confirms previous evidence that the cognitive effects of bilingualism are moderated by degree of bilingualism and furthermore reveals that substantial minority language exposure at home indirectly affects bilingual children's cognitive development, namely through mediation with degree of bilingualism. However, the findings also demonstrate that the effect of bilingualism on EF is limited and unstable.

Verbal Working Memory Is Related to the Acquisition of Cross-Linguistic Phonological Regularities.

Closely related languages share cross-linguistic phonological regularities, such as Frisian -âld [Í»:t] and Dutch -oud [ʱut], as in the cognate pairs kâld [kÍ»:t] - koud [kʱut] 'cold' and wâld [wÍ»:t] - woud [wʱut] 'forest'. Within Bybee's (1995, 2001, 2008, 2010) network model, these regularities are, just like grammatical rules within a language, generalizations that emerge from schemas of phonologically and semantically related words. Previous research has shown that verbal working memory is related to the acquisition of grammar, but not vocabulary. This suggests that verbal working memory supports the acquisition of linguistic regularities. In order to test this hypothesis we investigated whether verbal working memory is also related to the acquisition of cross-linguistic phonological regularities. For three consecutive years, 5- to 8-year-old Frisian-Dutch bilingual children (n = 120) were tested annually on verbal working memory and a Frisian receptive vocabulary task that comprised four cognate categories: (1) identical cognates, (2) non-identical cognates that either do or (3) do not exhibit a phonological regularity between Frisian and Dutch, and (4) non-cognates. The results showed that verbal working memory had a significantly stronger effect on cognate category (2) than on the other three cognate categories. This suggests that verbal working memory is related to the acquisition of cross-linguistic phonological regularities. More generally, it confirms the hypothesis that verbal working memory plays a role in the acquisition of linguistic regularities.