MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study.

BACKGROUND: Pick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration. METHODS: In this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and ß coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype. FINDINGS: We obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (ß -0·54 [95% CI -1·94 to 0·87], p=0·45) or disease duration (ß 0·05 [-0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (ß 2·66 [0·63 to 4·70], p=0·011), H1i (ß -3·66 [-6·83 to -0·48], p=0·025), and H1u (ß -5·25 [-10·42 to -0·07], p=0·048); and with disease duration for H1x (ß -0·57 [-1·07 to -0·07], p=0·026). INTERPRETATION: The Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies. FUNDING: Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.

EXPRESS: Transfer of cognitive control adjustments within and between speakers.

Congruency effects in conflict tasks are typically larger after congruent compared to incongruent trials. This congruency sequence effect (CSE) indicates that top-down adjustments of cognitive control transfer between processing episodes, at least when controlling for bottom-up memory processes by alternating between stimulus-response (S-R) sets in confound-minimised designs. According to the control-retrieval account, cognitive control is bound to task-irrelevant context features (e.g., stimulus position or modality) and retrieved upon subsequent context feature repetitions. A confound-minimised CSE should therefore be larger when context features repeat rather than change between two trials. The present study tested this prediction for a more abstract contextual stimulus feature, speaker gender. In two preregistered auditory prime-probe task experiments, participants classified colour words spoken by a female or male voice. Across both experiments, we found confound-minimised CSEs that were not reliably affected by whether the speaker gender repeated or changed. This indicates that speaker transitions have virtually no influence on the transfer of control adjustments in the absence of S-R repetitions. By contrast, when allowing for bottom-up memory processes by repeating the S-R set, CSEs were consistently larger when the speaker gender repeated compared to changed. This suggests that speaker transitions can in principle influence transfer between processing episodes. The discrepancy also held true when considering learning and test episodes separated by an intervening episode. Thus, the present findings call for a refinement of the control-retrieval account to accommodate the role of more abstract contextual stimulus features for the maintenance of memory traces in auditory conflict processing.

Reduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase.

Comorbid proteinopathies are observed in many neurodegenerative disorders including Alzheimer's disease (AD), increase with age, and influence clinical outcomes, yet the mechanisms remain ill-defined. Here, we show that reduction of progranulin (PGRN), a lysosomal protein associated with TDP-43 proteinopathy, also increases tau inclusions, causes concomitant accumulation of α-synuclein and worsens mortality and disinhibited behaviors in tauopathy mice. The increased inclusions paradoxically protect against spatial memory deficit and hippocampal neurodegeneration. PGRN reduction in male tauopathy attenuates activity of ß-glucocerebrosidase (GCase), a protein previously associated with synucleinopathy, while increasing glucosylceramide (GlcCer)-positive tau inclusions. In neuronal culture, GCase inhibition enhances tau aggregation induced by AD-tau. Furthermore, purified GlcCer directly promotes tau aggregation in vitro. Neurofibrillary tangles in human tauopathies are also GlcCer-immunoreactive. Thus, in addition to TDP-43, PGRN regulates tau- and synucleinopathies via GCase and GlcCer. A lysosomal PGRN-GCase pathway may be a common therapeutic target for age-related comorbid proteinopathies.

Local structural preferences in shaping tau amyloid polymorphism.

Tauopathies encompass a group of neurodegenerative disorders characterised by diverse tau amyloid fibril structures. The persistence of polymorphism across tauopathies suggests that distinct pathological conditions dictate the adopted polymorph for each disease. However, the extent to which intrinsic structural tendencies of tau amyloid cores contribute to fibril polymorphism remains uncertain. Using a combination of experimental approaches, we here identify a new amyloidogenic motif, PAM4 (Polymorphic Amyloid Motif of Repeat 4), as a significant contributor to tau polymorphism. Calculation of per-residue contributions to the stability of the fibril cores of different pathologic tau structures suggests that PAM4 plays a central role in preserving structural integrity across amyloid polymorphs. Consistent with this, cryo-EM structural analysis of fibrils formed from a synthetic PAM4 peptide shows that the sequence adopts alternative structures that closely correspond to distinct disease-associated tau strains. Furthermore, in-cell experiments revealed that PAM4 deletion hampers the cellular seeding efficiency of tau aggregates extracted from Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy patients, underscoring PAM4's pivotal role in these tauopathies. Together, our results highlight the importance of the intrinsic structural propensity of amyloid core segments to determine the structure of tau in cells, and in propagating amyloid structures in disease.

Truncated TDP-43 proteoforms diagnostic of frontotemporal dementia with TDP-43 pathology.

INTRODUCTION: Biomarkers of TDP-43 pathology are needed to distinguish frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) from phenotypically related disorders. While normal physiological TDP-43 is not a promising biomarker, low-resolution techniques have suggested truncated forms of TDP-43 may be specific to TDP-43 pathology. To advance biomarker efforts for FTLD-TDP, we employed a high-resolution structural technique to characterize TDP-43 post-translational modifications in FTLD-TDP. METHODS: High-resolution mass spectrometry was used to characterize TDP-43 proteoforms in brain tissue from FTLD-TDP, non-TDP-43 dementias and neuropathologically unaffected cases. Findings were then verified in a larger cohort of FTLD-TDP and non-TDP-43 dementias via targeted quantitative mass spectrometry. RESULTS: In the discovery phase, truncated TDP-43 identified FTLD-TDP with 85% sensitivity and 100% specificity. The verification phase revealed similar findings, with 83% sensitivity and 89% specificity. DISCUSSION: The concentration of truncated TDP-43 proteoforms-in particular, in vivo generated C-terminal fragments-have high diagnostic accuracy for FTLD-TDP. HIGHLIGHTS: Discovery: Truncated TDP-43 differentiates FTLD-TDP from related dementias. Verification: Truncated TDP-43 concentration has high accuracy for FTLD-TDP. TDP-43 proteoforms <28 kDa have highest discriminatory power for TDP-43 pathology.

Reactive and proactive control processes in voluntary task choice.

Deciding which task to perform when multiple tasks are available can be influenced by external influences in the environment. In the present study, we demonstrate that such external biases on task-choice behavior reflect reactive control adjustments instead of a failure in control to internally select a task goal. Specifically, in two experiments we delayed the onset of one of two task stimuli by a short (50 ms), medium (300 ms), or long (1,000 ms) stimulus-onset asynchrony (SOA) within blocks while also varying the relative frequencies of short versus long SOAs across blocks (i.e., short SOA frequent vs. long SOA frequent). Participants' task choices were increasingly biased towards selecting the task associated with the first stimulus with increasing SOAs. Critically, both experiments also revealed that the short-to-medium SOA bias was larger in blocks with more frequent long SOAs when participants had limited time to prepare for an upcoming trial. When time to select an upcoming task was extended in Experiment 2, this interaction was not significant, suggesting that the extent to which people rely on reactive control adjustments is additionally modulated by proactive control processes. Thus, the present findings also suggest that voluntary task choices are jointly guided by both proactive and reactive processes, which are likely to adjust the relative activation of different task goals in working memory.

Exploring behavioral adjustments of proportion congruency manipulations in an Eriksen flanker task with visual and auditory distractor modalities.

The present study investigated global behavioral adaptation effects to conflict arising from different distractor modalities. Three experiments were conducted using an Eriksen flanker paradigm with constant visual targets, but randomly varying auditory or visual distractors. In Experiment 1, the proportion of congruent to incongruent trials was varied for both distractor modalities, whereas in Experiments 2A and 2B, this proportion congruency (PC) manipulation was applied to trials with one distractor modality (inducer) to test potential behavioral transfer effects to trials with the other distractor modality (diagnostic). In all experiments, mean proportion congruency effects (PCEs) were present in trials with a PC manipulation, but there was no evidence of transfer to diagnostic trials in Experiments 2A and 2B. Distributional analyses (delta plots) provided further evidence for distractor modality-specific global behavioral adaptations by showing differences in the slope of delta plots with visual but not auditory distractors when increasing the ratio of congruent trials. Thus, it is suggested that distractor modalities constrain global behavioral adaptation effects due to the learning of modality-specific memory traces (e.g., distractor-target associations) and/or the modality-specific cognitive control processes (e.g., suppression of modality-specific distractor-based activation). Moreover, additional analyses revealed partial transfer of the congruency sequence effect across trials with different distractor modalities suggesting that distractor modality may differentially affect local and global behavioral adaptations.

Targeting RACK1 to alleviate TDP-43 and FUS proteinopathy-mediated suppression of protein translation and neurodegeneration.

TAR DNA-binding protein 43 (TDP-43) and Fused in Sarcoma/Translocated in Sarcoma (FUS) are ribonucleoproteins associated with pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Under physiological conditions, TDP-43 and FUS are predominantly localized in the nucleus, where they participate in transcriptional regulation, RNA splicing and metabolism. In disease, however, they are typically mislocalized to the cytoplasm where they form aggregated inclusions. A number of shared cellular pathways have been identified that contribute to TDP-43 and FUS toxicity in neurodegeneration. In the present study, we report a novel pathogenic mechanism shared by these two proteins. We found that pathological FUS co-aggregates with a ribosomal protein, the Receptor for Activated C-Kinase 1 (RACK1), in the cytoplasm of spinal cord motor neurons of ALS, as previously reported for pathological TDP-43. In HEK293T cells transiently transfected with TDP-43 or FUS mutant lacking a functional nuclear localization signal (NLS; TDP-43ΔNLS and FUSΔNLS), cytoplasmic TDP-43 and FUS induced co-aggregation with endogenous RACK1. These co-aggregates sequestered the translational machinery through interaction with the polyribosome, accompanied by a significant reduction of global protein translation. RACK1 knockdown decreased cytoplasmic aggregation of TDP-43ΔNLS or FUSΔNLS and alleviated associated global translational suppression. Surprisingly, RACK1 knockdown also led to partial nuclear localization of TDP-43ΔNLS and FUSΔNLS in some transfected cells, despite the absence of NLS. In vivo, RACK1 knockdown alleviated retinal neuronal degeneration in transgenic Drosophila melanogaster expressing hTDP-43WT or hTDP-43Q331K and improved motor function of hTDP-43WT flies, with no observed adverse effects on neuronal health in control knockdown flies. In conclusion, our results revealed a novel shared mechanism of pathogenesis for misfolded aggregates of TDP-43 and FUS mediated by interference with protein translation in a RACK1-dependent manner. We provide proof-of-concept evidence for targeting RACK1 as a potential therapeutic approach for TDP-43 or FUS proteinopathy associated with ALS and FTLD.

Disseminating cells in human oral tumours possess an EMT cancer stem cell marker profile that is predictive of metastasis in image-based machine learning.

Cancer stem cells (CSCs) undergo epithelial-mesenchymal transition (EMT) to drive metastatic dissemination in experimental cancer models. However, tumour cells undergoing EMT have not been observed disseminating into the tissue surrounding human tumour specimens, leaving the relevance to human cancer uncertain. We have previously identified both EpCAM and CD24 as CSC markers that, alongside the mesenchymal marker Vimentin, identify EMT CSCs in human oral cancer cell lines. This afforded the opportunity to investigate whether the combination of these three markers can identify disseminating EMT CSCs in actual human tumours. Examining disseminating tumour cells in over 12,000 imaging fields from 74 human oral tumours, we see a significant enrichment of EpCAM, CD24 and Vimentin co-stained cells disseminating beyond the tumour body in metastatic specimens. Through training an artificial neural network, these predict metastasis with high accuracy (cross-validated accuracy of 87-89%). In this study, we have observed single disseminating EMT CSCs in human oral cancer specimens, and these are highly predictive of metastatic disease.

When oral cancers metastasise ­ that is, when tumour cells invade other parts of the body ­ they typically do so by first colonizing the lymph nodes present in the neck. As this event significantly reduces chances of survival, oral cancer patients often have their neck lymph nodes removed to prevent the spread of the disease. However, this surgery carries risks and leads to longer hospital stays, stressing the need for better ways to predict which oral tumours will metastasise. Evidence from lab-grown cells and mice studies suggest that, in oral cancer, metastasis occurs when some cells in the original tumour go through a process called the epithelial-mesenchymal transition (EMT for short). This transformation allows the cells to detach from the tumour and become invasive. However, it has so far been difficult to observe this process in actual human tumours; this is partly because cells undergoing EMT stop producing the proteins that scientists rely on to distinguish cancer and healthy cells. To address this knowledge gap, Youssef et al. focused on three proteins: two tumour markers, EpCAM and CD24; and Vimentin, which is produced in greater quantities in the invasive mesenchymal state. Previous work had shown that a specific population of oral tumour cells can continue to express all three proteins even when adopting a mesenchymal identity through EMT. Based on this knowledge, Youssef et al. hypothesised that tracking Vimentin, EpCAM and CD24 using fluorescence microscopy would allow them to identify metastasising cells in human samples. An analysis of over 12,000 images from 74 tumours obtained from surgeries revealed that, in the metastatic samples, the cells detaching from primary tumours were more likely to express these three proteins. Finally, Youssef et al. used these images to train a machine learning algorithm. When applied to data from new oral cancer patients, the programme was able to predict whether their tumours were likely to spread with 89% accuracy. If confirmed by further work, and in particular on larger samples, these findings could in the future help clinicians decide which patients with oral cancer would benefit the most from surgery to remove neck lymph nodes.

Cognitive control in cross-modal contexts: Abstract feature transitions of task-related but not task-unrelated stimuli modulate the congruency sequence effect.

Context information can guide cognitive control, but both the extent and the underlying processes are poorly understood. Previous studies often found that the congruency sequence effect (CSE) is larger when perceptual context features (e.g., modality and format) of task-related distractors and targets repeat compared to change. However, it is unclear whether control adjustments can also be contextualized by more abstract stimulus features and/or by features of task-unrelated stimuli. The present study addressed this issue using a novel context manipulation in a confound-minimized prime-probe task. In Experiment (Exp.) 1, the modality (visual and auditory) of the distractor and target either repeated or changed. Critically, in Exp. 2, the distractor and target modality always switched, but the cross-modal intensity (brightness and loudness) could either repeat (e.g., bright → loud) or change (e.g., bright → soft). A larger CSE for context repeats (vs. changes) was observed in Exps. 1 and 2, indicating that both concrete (modality) and abstract stimulus features (cross-modal intensity) can contextualize control adjustments. Exps. 3 and 4 demonstrated that the CSE was not reliably affected when the context manipulation concerned a prior signal or a simultaneous background stimulus. Thus, task-related, but not task-unrelated, concrete and abstract stimulus features contextualize control adjustments. Moreover, distributional (delta plot) analyses of present and previous data revealed that the confound-minimized CSE and its contextual modulation reflect adjustments in the strength of cognitive control rather than in its timing. Overall, the present study provides new insights into how context information interacts with cognitive control to optimize decision making under conflict. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A Diffusion Model Analysis of Object-Based Selective Attention in the Eriksen Flanker Task.

Selective attention might be space-, feature-, and/or object-based. Clear support for the involvement of an object-based mechanism is rather scarce, possibly because the predictions of models from these different classes often overlap. Yet, only object-based models can account for a larger congruency effect (CE) in the Eriksen flanker task when flankers are more (vs. less) strongly grouped to the target, but spacing and other response-irrelevant features of target and flankers are held constant. Exactly this was observed by Kramer and Jacobson (1991). So far, this theoretically relevant finding has not been replicated closely. We replicated the finding in two web-based experiments. Specifically, CEs were larger when flanker lines were connected to the central target line (vs. to outer neutral lines). We also successfully fitted the Diffusion Model for Conflict tasks (DMC) to the experimental data. Critically, diffusion modeling (DMC) and distributional analyses (delta functions) revealed that object membership primarily affected target processing strength rather than strength or timing of flanker processing. This challenges the prominent attentional spreading (sensory enhancement) account of object-based selective attention and motivates an alternative target attenuation account.

The impact of distractor relevance on the strength and timing of cognitive control: Evidence from delta plots and diffusion model analyses.

In the present study, we examined how the relevance of potentially distracting information modulates the interplay of target and distractor processing in conflict tasks. Specifically, we manipulated the degree to which distracting information is relevant for performing the overall task by varying the proportion of trials in which a response to the distractor(s) (Experiments 1a and 1b: location in a Simon task; Experiment 2: flankers in an Eriksen flanker task) instead of to the target was required. Across all experiments, the congruency effect on mean RT was larger with the increasing relevance of the distractor(s). Critically, the slopes of the delta plot were more strongly increasing when the distractors were potentially relevant (as opposed to completely irrelevant), suggesting that cognitive control affects the timing of suppressing distractor-based activation. In addition, delta plot and diffusion model analyses revealed that the strength of suppressing distractor processing and the efficiency of target processing were enhanced when the distractors were less relevant. Overall, the present study dissociated multiple and time-dependent adjustments of control processes (i.e., target processing enhancement plus timing and strength of distractor suppression) in environments that encourage either a more stable or more flexible processing mode. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Network Connectivity Alterations across the MAPT Mutation Clinical Spectrum.

OBJECTIVE: Microtubule-associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task-free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers. METHODS: We compared cross-sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed-based analyses to examine connectivity within networks associated with the 4 most common MAPT-associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole-brain connectivity analyses. We applied K-means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole-brain connectivity profiles. RESULTS: Symptomatic and presymptomatic carriers had connectivity disruptions within MAPT-syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole-brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline. INTERPRETATION: Network connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023;94:632-646.

Transfer of task-probability-induced biases in parallel dual-task processing occurs in similar, but is constraint in distinct task sets.

Although humans often multitask, little is known about how the processing of concurrent tasks is managed. The present study investigated whether adjustments in parallel processing during multitasking are local (task-specific) or global (task-unspecific). In three experiments, participants performed one of three tasks: a primary task or, if this task did not require a response, one of two background tasks (i.e., prioritized processing paradigm). To manipulate the degree of parallel processing, we presented blocks consisting mainly of primary or background task trials. In Experiment 1, the frequency manipulation was distributed equally across the two background tasks. In Experiments 2 and 3, only one background task was frequency-biased (inducer task). The other background task was presented equally often in all blocks (diagnostic task) and served to test whether processing adjustments transferred. In all experiments, blocks with frequent background tasks yielded stronger interference between primary and background tasks (primary task performance) and improved background task performance. Thus, resource sharing appeared to increase with high background task probabilities even under triple task requirements. Importantly, these adjustments generalized across the background tasks when they were conceptually and visually similar (Experiment 2). Implementing more distinct background tasks limited the transfer: Adjustments were restricted to the inducer task in background task performance and only small transfer was observed in primary task performance (Experiment 3). Overall, the results indicate that the transfer of adjustments in parallel processing is unrestricted for similar, but limited for distinct tasks, suggesting that task similarity affects the generality of resource allocation in multitasking. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Psychotic symptoms in frontotemporal dementia with TDP-43 tend to be associated with type B pathology.

AIMS: Psychotic symptoms are increasingly recognized as a distinguishing clinical feature in patients with dementia due to frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Within this group, carriers of the C9orf72 repeat expansion are particularly prone to develop delusions and hallucinations. METHODS: The present retrospective study sought to provide novel details about the relationship between FTLD-TDP pathology and the presence of psychotic symptoms during life. RESULTS: We found that FTLD-TDP subtype B was more frequent in patients with psychotic symptoms than in those without. This relationship was present even when corrected for the presence of C9orf72 mutation, suggesting that pathophysiological processes leading to the development of subtype B pathology may increase the risk of psychotic symptoms. Within the group of FTLD-TDP cases with subtype B pathology, psychotic symptoms tended to be associated with a greater burden of TDP-43 pathology in the white matter and a lower burden in lower motor neurons. When present, pathological involvement of motor neurons was more likely to be asymptomatic in patients with psychosis. CONCLUSIONS: This work suggests that psychotic symptoms in patients with FTLD-TDP tend to be associated with subtype B pathology. This relationship is not completely explained by the effects of the C9orf72 mutation and raises the possibility of a direct link between psychotic symptoms and this particular pattern of TDP-43 pathology.

Embryonic Stem Cells Can Generate Oral Epithelia under Matrix Instruction.

We aimed to investigate whether molecular clues from the extracellular matrix (ECM) can induce oral epithelial differentiation of pluripotent stem cells. Mouse embryonic stem cells (ESC) of the feeder-independent cell line E14 were used as a model for pluripotent stem cells. They were first grown in 2D on various matrices in media containing vitamin C and without leukemia inhibitory factor (LIF). Matrices investigated were gelatin, laminin, and extracellular matrices (ECM) synthesized by primary normal oral fibroblasts and keratinocytes in culture. Differentiation into epithelial lineages was assessed by light microscopy, immunocytochemistry, and flow cytometry for cytokeratins and stem cell markers. ESC grown in 2D on various matrices were afterwards grown in 3D organotypic cultures with or without oral fibroblasts in the collagen matrix and examined histologically and by immunohistochemistry for epithelial (keratin pairs 1/10 and 4/13 to distinguish epidermal from oral epithelia and keratins 8,18,19 to phenotype simple epithelia) and mesenchymal (vimentin) phenotypes. ECM synthesized by either oral fibroblasts or keratinocytes was able to induce, in 2D cultures, the expression of cytokeratins of the stratified epithelial phenotype. When grown in 3D, all ESC developed into two morphologically distinct cell populations on collagen gels: (i) epithelial-like cells organized in islands with occasional cyst- or duct-like structures and (ii) spindle-shaped cells suggestive of mesenchymal differentiation. The 3D culture on oral fibroblast-populated collagen matrices was necessary for further differentiation into oral epithelia. Only ESC initially grown on 2D keratinocyte or fibroblast-synthesized matrices reached full epithelial maturation. In conclusion, ESC can generate oral epithelia under matrix instruction.

Feasibility and acceptability of remote smartphone cognitive testing in frontotemporal dementia research.

Introduction: Remote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD-mApp). Methods: A diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC-FTLD = 0 [N = 101]; prodromal: 0.5 [N = 49]; symptomatic ≥1 [N = 51]; not measured [N = 13]) were asked to complete ALLFTD-mApp tests on their smartphone three times within 12 days. They completed smartphone familiarity and participation experience surveys. Results: It was feasible for participants to complete the ALLFTD-mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered the time commitment acceptable (98% of respondents). Greater disease severity was associated with poorer performance across several tests. Discussion: These findings suggest that the ALLFTD-mApp study protocol is feasible and acceptable for remote FTD research. HIGHLIGHTS: The ALLFTD Mobile App is a smartphone-based platform for remote, self-administered data collection.The ALLFTD Mobile App consists of a comprehensive battery of surveys and tests of executive functioning, memory, speech and language, and motor abilities.Remote digital data collection using the ALLFTD Mobile App was feasible in a multicenter research consortium that studies FTD. Data was collected in healthy controls and participants with a range of diagnoses, particularly FTD spectrum disorders.Remote digital data collection was well accepted by participants with a variety of diagnoses.

C-terminal TMEM106B fragments in human brain correlate with disease-associated TMEM106B haplotypes.

Transmembrane protein 106B (TMEM106B) is a tightly regulated glycoprotein predominantly localized to endosomes and lysosomes. Genetic studies have implicated TMEM106B haplotypes in the development of multiple neurodegenerative diseases with the strongest effect in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), especially in progranulin (GRN) mutation carriers. Recently, cryo-electron microscopy studies showed that a C-terminal fragment (CTF) of TMEM106B (amino acid residues 120-254) forms amyloid fibrils in the brain of patients with FTLD-TDP, but also in brains with other neurodegenerative conditions and normal ageing brain. The functional implication of these fibrils and their relationship to the disease-associated TMEM106B haplotype remain unknown. We performed immunoblotting using a newly developed antibody to detect TMEM106B CTFs in the sarkosyl-insoluble fraction of post-mortem human brain tissue from patients with different proteinopathies (n = 64) as well as neuropathologically normal individuals (n = 10) and correlated the results with age and TMEM106B haplotype. We further compared the immunoblot results with immunohistochemical analyses performed in the same study population. Immunoblot analysis showed the expected ∼30 kDa band in the sarkosyl-insoluble fraction of frontal cortex tissue in at least some individuals with each of the conditions evaluated. Most patients with GRN mutations showed an intense band representing TMEM106B CTF, whereas in most neurologically normal individuals it was absent or much weaker. In the overall cohort, the presence of TMEM106B CTFs correlated strongly with both age (rs = 0.539, P < 0.001) and the presence of the TMEM106B risk haplotype (rs = 0.469, P < 0.001). Although there was a strong overall correlation between the results of immunoblot and immunohistochemistry (rs = 0.662, P < 0.001), 27 cases (37%) were found to have higher amounts of TMEM106B CTFs detected by immunohistochemistry, including most of the older individuals who were neuropathologically normal and individuals who carried two protective TMEM106B haplotypes. Our findings suggest that the formation of sarkosyl-insoluble TMEM106B CTFs is an age-related feature which is modified by TMEM106B haplotype, potentially underlying its disease-modifying effect. The discrepancies between immunoblot and immunohistochemistry in detecting TMEM106B pathology suggests the existence of multiple species of TMEM106B CTFs with possible biological relevance and disease implications.

The Role of Effector-Specific Task Representations in Voluntary Task Switching.

There has been an increasing interest in uncovering the mechanisms underpinning how people decide which task to perform at a given time. Many studies suggest that task representations are crucial in guiding such voluntary task selection behavior, which is primarily reflected in a bias to select task repetitions over task switches. However, it is not yet clear whether the task-specific motor effectors are also a crucial component of task representations when deciding to switch tasks. Across three experiments using different voluntary task switching (VTS) procedures, we show that a greater overlap in task representations with a task-to-finger mapping than task-to-hand mapping increases participants' switching behavior (Exp. 1 and Exp. 2), but not when they were instructed to randomly select tasks (Exp. 3). Thus, task-specific stimulus-response associations can change the way people mentally represent tasks and influence switching behavior, suggesting that motor effectors should be considered as a component of task representations in biasing cognitive flexibility.