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Publications in Health Sciences by NOMIS researchers

Cortical thickness across the lifespan in a Colombian cohort with autosomal-dominant Alzheimer’s disease: A cross-sectional study

NOMIS Researcher(s)

Published in

January 1, 2021

Introduction: Cortical thinning is a marker of neurodegeneration in Alzheimer’s disease (AD). We investigated the age-related trajectory of cortical thickness across the lifespan (9-59 years) in a Colombian kindred with autosomal dominant AD (ADAD). Methods: Two hundred eleven participants (105 presenilin-1 [PSEN1] E280A mutation carriers, 16 with cognitive impairment; 106 non-carriers) underwent magnetic resonance imaging. A piecewise linear regression identified change-points in the age-related trajectory of cortical thickness in carriers and non-carriers. Results: Unimpaired carriers exhibited elevated cortical thickness compared to non-carriers, and thickness more negatively correlated with age and cognition in carriers relative to non-carriers. We found increased cortical thickness in child carriers, after which thickness steadied compared to non-carriers prior to a rapid reduction in the decade leading up to the expected age at cognitive impairment in carriers. Discussion: Findings suggest that cortical thickness may fluctuate across the ADAD lifespan, from early-life increased thickness to atrophy proximal to clinical onset.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

DOI
10.1002/dad2.12233

PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer’s disease-causing Presenilin-1 E280A mutation carriers

NOMIS Researcher(s)

Published in

January 1, 2021

Background: In contrast to sporadic Alzheimer’s disease, autosomal dominant Alzheimer’s disease (ADAD) is associated with greater neuropathological evidence of cerebellar amyloid plaque (Aβ) deposition. In this study, we used positron emission tomography (PET) measurements of fibrillar Aβ burden to characterize the presence and age at onset of cerebellar Aβ deposition in cognitively unimpaired (CU) Presenilin-1 (PSEN1) E280A mutation carriers from the world’s largest extended family with ADAD. Methods: 18F florbetapir and 11C Pittsburgh compound B (PiB) PET data from two independent studies – API ADAD Colombia Trial (NCT01998841) and Colombia-Boston (COLBOS) longitudinal biomarker study were included. The tracers were selected independently by the respective sponsors prior to the start of each study and used exclusively throughout. Template-based cerebellar Aβ-SUVR (standard-uptake value ratios) using a known-to-be-spared pons reference region (cerebellar SUVR_pons), to a) compare 28–56-year-old CU carriers and non-carriers; b) estimate the age at which cerebellar SUVR_pons began to differ significantly in carrier and non-carrier groups; and c) characterize in carriers associations with age, cortical SUVR_pons, delayed recall memory, and API ADAD composite score. Results: Florbetapir and PiB cerebellar SUVR_pons were significantly higher in carriers than non-carriers (p < 0.0001). Cerebellar SUVR_pons began to distinguish carriers from non-carriers at age 34, 10 years before the carriers’ estimated age at mild cognitive impairment onset. Florbetapir and PiB cerebellar SUVR_pons in carriers were positively correlated with age (r = 0.44 & 0.69, p < 0.001), cortical SUVR_pons (r = 0.55 & 0.69, p < 0.001), and negatively correlated with delayed recall memory (r = −0.21 & −0.50, p < 0.05, unadjusted for cortical SUVR_pons) and API ADAD composite (r = −0.25, p < 0.01, unadjusted for cortical SUVR_pons in florbetapir API ADAD cohort). Conclusion: This PET study provides evidence of cerebellar Aβ plaque deposition in CU carriers starting about a decade before the clinical onset of ADAD. Additional studies are needed to clarify the impact of using a cerebellar versus pons reference region on the power to detect and track ADAD changes, even in preclinical stages of this disorder.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

DOI
10.1016/j.nicl.2021.102749

Muscleblind acts as a modifier of FUS toxicity by modulating stress granule dynamics and SMN localization

NOMIS Researcher(s)

Published in

January 1, 2021

Mutations in fused in sarcoma (FUS) lead to amyotrophic lateral sclerosis (ALS) with varying ages of onset, progression and severity. This suggests that unknown genetic factors contribute to disease pathogenesis. Here we show the identification of muscleblind as a novel modifier of FUS-mediated neurodegeneration in vivo. Muscleblind regulates cytoplasmic mislocalization of mutant FUS and subsequent accumulation in stress granules, dendritic morphology and toxicity in mammalian neuronal and human iPSC-derived neurons. Interestingly, genetic modulation of endogenous muscleblind was sufficient to restore survival motor neuron (SMN) protein localization in neurons expressing pathogenic mutations in FUS, suggesting a potential mode of suppression of FUS toxicity. Upregulation of SMN suppressed FUS toxicity in Drosophila and primary cortical neurons, indicating a link between FUS and SMN. Our data provide in vivo evidence that muscleblind is a dominant modifier of FUS-mediated neurodegeneration by regulating FUS-mediated ALS pathogenesis.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

DOI
10.1038/s41467-019-13383-z

A Molecular Calcium Integrator Reveals a Striatal Cell Type Driving Aversion

NOMIS Researcher(s)

Published in

December 23, 2020

The ability to record transient cellular events in the DNA or RNA of cells would enable precise, large-scale analysis, selection, and reprogramming of heterogeneous cell populations. Here, we report a molecular technology for stable genetic tagging of cells that exhibit activity-related increases in intracellular calcium concentration (FLiCRE). We used FLiCRE to transcriptionally label activated neural ensembles in the nucleus accumbens of the mouse brain during brief stimulation of aversive inputs. Using single-cell RNA sequencing, we detected FLiCRE transcripts among the endogenous transcriptome, providing simultaneous readout of both cell-type and calcium activation history. We identified a cell type in the nucleus accumbens activated downstream of long-range excitatory projections. Taking advantage of FLiCRE’s modular design, we expressed an optogenetic channel selectively in this cell type and showed that direct recruitment of this otherwise genetically inaccessible population elicits behavioral aversion. The specificity and minute resolution of FLiCRE enables molecularly informed characterization, manipulation, and reprogramming of activated cellular ensembles.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1016/j.cell.2020.11.015

Nuclear Import Receptors Directly Bind to Arginine-Rich Dipeptide Repeat Proteins and Suppress Their Pathological Interactions

NOMIS Researcher(s)

Published in

December 22, 2020

Hutten et al. show that arginine-rich dipeptide repeat proteins (DPRs) associated with the neurodegenerative diseases ALS and FTD bind directly to importins, promote their condensation, and interfere with importin function. Elevated importin levels can shield arginine-rich DPRs and suppress DPR-induced phase separation of TDP-43 and RNA.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1016/j.celrep.2020.108538

Interoceptive Awareness Is Negatively Related to the Exteroceptive Manipulation of Bodily Self-Location

NOMIS Researcher(s)

Published in

December 4, 2020

The perception of being located within one’s body (i.e., bodily self-location) is an essential feature of everyday self-experience. However, by manipulating exteroceptive input, healthy participants can easily be induced to perceive themselves as being spatially dislocated from their physical bodies. It has previously been suggested that interoception, i.e., the processing of inner physiological signals, contributes to the stability of body representations; however, this relationship has not previously been tested for different dimensions of interoception and bodily self-location. In the present study, using an advanced automatized setup, we systematically manipulated participants’ perspective of their own body (first- vs third-person perspective) as well as the synchrony of visuotactile stimulation (synchronous vs asynchronous). The malleability of bodily self-location was assessed using a questionnaire targeting in-body and out-of-body experiences. Participants also performed a heartbeat discrimination task to assess their interoceptive accuracy (behavioral performance), interoceptive sensibility (confidence in their interoceptive abilities), and interoceptive awareness (meta-cognitive representation of interoceptive signals). Bodily self-location was significantly influenced by perspective, with third-person perspective being associated with stronger out-of-body experiences compared to first-person perspective. Furthermore, there was a significant perspective × stimulation interaction, with subsequent analyses showing that participants reported out-of-body experiences particularly under third-person perspective combined with synchronous visuotactile stimulation. Correlation and regression analyses revealed that meta-cognitive interoceptive awareness was specifically and negatively related to the exteroceptively mediated malleability of body experiences. These results indicate that the perception of the self being located within one’s body relies on the interaction of exteroceptive input and higher-order interoceptive abilities. This has implications for theoretical considerations about the bodily self in health as well as for the understanding of disturbed bodily self-processing in clinical contexts.

Research field(s)
Health Sciences, Psychology & Cognitive Sciences, Experimental Psychology

DOI
10.3389/fpsyg.2020.562016

Self-competence increases the willingness to pay for social influence

NOMIS Researcher(s)

Published in

December 1, 2020

Theoretical works in social psychology and neuroscientific evidence have proposed that social rewards have intrinsic value, suggesting that people place a high premium on the ability to influence others. To test this hypothesis, we asked whether, and under what conditions, people are willing to forgo monetary reward for the sake of influencing others’ decisions. In four experiments, online and lab-based participants competed with a rival for influence over a client. The majority of participants sacrificed some of their financial reward to increase their chance of being selected over their rival within the experiment. Willingness to pay was affected by the participant’s current level of influence and performance, as participants were most likely to pay to promote their competence after having given good advice that had been ignored by the client using a situation where monetary incentives fail to explain human motivations, our experiments highlight the intrinsic value of social influence.

Research field(s)
Health Sciences, Psychology & Cognitive Sciences, Social Psychology

DOI
10.1038/s41598-020-74857-5

Effect of perceived interpersonal closeness on the joint Simon effect in adolescents and adults

NOMIS Researcher(s)

Published in

December 1, 2020

Here, we explored the role of perceived interpersonal closeness in joint action using the joint Simon task in adolescents and adults. In a two-choice reaction time task, spatially assigned responses to non-spatial stimulus features are faster when the stimulus and response are in congruent locations than not. This phenomenon is called Simon effect and is absent or strongly attenuated when a participant responds to only one of the stimuli. However, the effect reappears when two participants carry out the same go/no-go tasks cooperatively. This re-emergence of the Simon effect in joint action is called the joint Simon effect (JSE). In this study, we first replicated the standard and joint Simon effects in adolescents (n = 43), as well as adults (n = 39) with similar magnitude of the effects in the two age groups. The magnitude of the JSE was positively correlated with the level of closeness as measured by Inclusion of Other in the Self scale. This correlation was not significantly different in adolescents (n = 73) compared to adults (n = 71). Our findings show that joint action is sensitive to the social factor such as interpersonal closeness, and the underlying mechanisms are already mature by adolescence.

Research field(s)
Health Sciences, Psychology & Cognitive Sciences, Experimental Psychology

DOI
10.1038/s41598-020-74859-3

Glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseases

NOMIS Researcher(s)

Published in

December 1, 2020

Background: In vivo assessment of neuroinflammation by 18-kDa translocator protein positron-emission-tomography (TSPO-PET) ligands receives growing interest in preclinical and clinical research of neurodegenerative disorders. Higher TSPO-PET binding as a surrogate for microglial activation in females has been reported for cognitively normal humans, but such effects have not yet been evaluated in rodent models of neurodegeneration and their controls. Thus, we aimed to investigate the impact of sex on microglial activation in amyloid and tau mouse models and wild-type controls. Methods: TSPO-PET (18F-GE-180) data of C57Bl/6 (wild-type), AppNL-G-F (β-amyloid model), and P301S (tau model) mice was assessed longitudinally between 2 and 12 months of age. The AppNL-G-F group also underwent longitudinal β-amyloid-PET imaging (Aβ-PET; 18F-florbetaben). PET results were confirmed and validated by immunohistochemical investigation of microglial (Iba-1, CD68), astrocytic (GFAP), and tau (AT8) markers. Findings in cerebral cortex were compared by sex using linear mixed models for PET data and analysis of variance for immunohistochemistry. Results: Wild-type mice showed an increased TSPO-PET signal over time (female +23%, male +4%), with a significant sex × age interaction (T = − 4.171, p < 0.001). The Aβ model AppNL-G-F mice also showed a significant sex × age interaction (T = − 2.953, p = 0.0048), where cortical TSPO-PET values increased by 31% in female AppNL-G-F mice, versus only 6% in the male mice group from 2.5 to 10 months of age. Immunohistochemistry for the microglial markers Iba-1 and CD68 confirmed the TSPO-PET findings in male and female mice aged 10 months. Aβ-PET in the same AppNL-G-F mice indicated no significant sex × age interaction (T = 0.425, p = 0.673). The P301S tau model showed strong cortical increases of TSPO-PET from 2 to 8.5 months of age (female + 32%, male + 36%), without any significant sex × age interaction (T = − 0.671, p = 0.504), and no sex differences in Iba-1, CD68, or AT8 immunohistochemistry. Conclusion: Female mice indicate sex-dependent microglia activation in aging and in response to amyloidosis but not in response to tau pathology. This calls for consideration of sex difference in TSPO-PET studies of microglial activation in mouse models of neurodegeneration and by extension in human studies.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

DOI
10.1186/s12974-020-02046-2

Structural determinants and their role in cyanobacterial morphogenesis

NOMIS Researcher(s)

Published in

December 1, 2020

Cells have to erect and sustain an organized and dynamically adaptable structure for an efficient mode of operation that allows drastic morphological changes during cell growth and cell division. These manifold tasks are complied by the so-called cytoskeleton and its associated proteins. In bacteria, FtsZ and MreB, the bacterial homologs to tubulin and actin, respectively, as well as coiled-coil-rich proteins of intermediate filament (IF)-like function to fulfil these tasks. Despite generally being characterized as Gram-negative, cyanobacteria have a remarkably thick peptidoglycan layer and possess Gram-positive-specific cell division proteins such as SepF and DivIVA-like proteins, besides Gram-negative and cyanobacterial-specific cell division proteins like MinE, SepI, ZipN (Ftn2) and ZipS (Ftn6). The diversity of cellular morphologies and cell growth strategies in cyanobacteria could therefore be the result of additional unidentified structural determinants such as cytoskeletal proteins. In this article, we review the current advances in the understanding of the cyanobacterial cell shape, cell division and cell growth.

Research field(s)
Health Sciences, Biomedical Research, Microbiology

DOI
10.3390/life10120355

Aberrant interaction of FUS with the U1 snRNA provides a molecular mechanism of FUS induced amyotrophic lateral sclerosis

NOMIS Researcher(s)

Published in

December 1, 2020

Mutations in the RNA-binding protein Fused in Sarcoma (FUS) cause early-onset amyotrophic lateral sclerosis (ALS). However, a detailed understanding of central RNA targets of FUS and their implications for disease remain elusive. Here, we use a unique blend of crosslinking and immunoprecipitation (CLIP) and NMR spectroscopy to identify and characterise physiological and pathological RNA targets of FUS. We find that U1 snRNA is the primary RNA target of FUS via its interaction with stem-loop 3 and provide atomic details of this RNA-mediated mode of interaction with the U1 snRNP. Furthermore, we show that ALS-associated FUS aberrantly contacts U1 snRNA at the Sm site with its zinc finger and traps snRNP biogenesis intermediates in human and murine motor neurons. Altogether, we present molecular insights into a FUS toxic gain-of-function involving direct and aberrant RNA-binding and strengthen the link between two motor neuron diseases, ALS and spinal muscular atrophy (SMA).

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1038/s41467-020-20191-3

Timed inhibition of CDC7 increases CRISPR-Cas9 mediated templated repair

NOMIS Researcher(s)

Published in

December 1, 2020

Repair of double strand DNA breaks (DSBs) can result in gene disruption or gene modification via homology directed repair (HDR) from donor DNA. Altering cellular responses to DSBs may rebalance editing outcomes towards HDR and away from other repair outcomes. Here, we utilize a pooled CRISPR screen to define host cell involvement in HDR between a Cas9 DSB and a plasmid double stranded donor DNA (dsDonor). We find that the Fanconi Anemia (FA) pathway is required for dsDonor HDR and that other genes act to repress HDR. Small molecule inhibition of one of these repressors, CDC7, by XL413 and other inhibitors increases the efficiency of HDR by up to 3.5 fold in many contexts, including primary T cells. XL413 stimulates HDR during a reversible slowing of S-phase that is unexplored for Cas9-induced HDR. We anticipate that XL413 and other such rationally developed inhibitors will be useful tools for gene modification.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1038/s41467-020-15845-1

Coordinating attention requires coordinated senses

NOMIS Researcher(s)

Published in

December 1, 2020

From playing basketball to ordering at a food counter, we frequently and effortlessly coordinate our attention with others towards a common focus: we look at the ball, or point at a piece of cake. This non-verbal coordination of attention plays a fundamental role in our social lives: it ensures that we refer to the same object, develop a shared language, understand each other’s mental states, and coordinate our actions. Models of joint attention generally attribute this accomplishment to gaze coordination. But are visual attentional mechanisms sufficient to achieve joint attention, in all cases? Besides cases where visual information is missing, we show how combining it with other senses can be helpful, and even necessary to certain uses of joint attention. We explain the two ways in which non-visual cues contribute to joint attention: either as enhancers, when they complement gaze and pointing gestures in order to coordinate joint attention on visible objects, or as modality pointers, when joint attention needs to be shifted away from the whole object to one of its properties, say weight or texture. This multisensory approach to joint attention has important implications for social robotics, clinical diagnostics, pedagogy and theoretical debates on the construction of a shared world.

Research field(s)
Health Sciences, Psychology & Cognitive Sciences, Experimental Psychology

DOI
10.3758/s13423-020-01766-z

Drops and fibers – How biomolecular condensates and cytoskeletal filaments influence each other

NOMIS Researcher(s)

Published in

December 1, 2020

The cellular cytoskeleton self-organizes by specific monomer-monomer interactions resulting in the polymerization of filaments. While we have long thought about the role of polymerization in cytoskeleton formation, we have only begun to consider the role of condensation in cytoskeletal organization. In this review, we highlight how the interplay between polymerization and condensation leads to the formation of the cytoskeleton.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1042/ETLS20190174

The major genetic risk factor for severe COVID-19 is inherited from Neanderthals

NOMIS Researcher(s)

Published in

November 26, 2020

A recent genetic association study1 identified a gene cluster on chromosome 3 as a risk locus for respiratory failure after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A separate study (COVID-19 Host Genetics Initiative)2 comprising 3,199 hospitalized patients with coronavirus disease 2019 (COVID-19) and control individuals showed that this cluster is the major genetic risk factor for severe symptoms after SARS-CoV-2 infection and hospitalization. Here we show that the risk is conferred by a genomic segment of around 50 kilobases in size that is inherited from Neanderthals and is carried by around 50% of people in south Asia and around 16% of people in Europe.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1038/s41586-020-2818-3

Patterns and Drivers of Extracellular Enzyme Activity in New Zealand Glacier-Fed Streams

NOMIS Researcher(s)

Published in

November 19, 2020

Glacier-fed streams (GFSs) exhibit near-freezing temperatures, variable flows, and often high turbidities. Currently, the rapid shrinkage of mountain glaciers is altering the delivery of meltwater, solutes, and particulate matter to GFSs, with unknown consequences for their ecology. Benthic biofilms dominate microbial life in GFSs, and play a major role in their biogeochemical cycling. Mineralization is likely an important process for microbes to meet elemental budgets in these systems due to commonly oligotrophic conditions, and extracellular enzymes retained within the biofilm enable the degradation of organic matter and acquisition of carbon (C), nitrogen (N), and phosphorus (P). The measurement and comparison of these extracellular enzyme activities (EEA) can in turn provide insight into microbial elemental acquisition effort relative to environmental availability. To better understand how benthic biofilm communities meet resource demands, and how this might shift as glaciers vanish under climate change, we investigated biofilm EEA in 20 GFSs varying in glacier influence from New Zealand’s Southern Alps. Using turbidity and distance to the glacier snout normalized for glacier size as proxies for glacier influence, we found that bacterial abundance (BA), chlorophyll a (Chl a), extracellular polymeric substances (EPS), and total EEA per gram of sediment increased with decreasing glacier influence. Yet, when normalized by BA, EPS decreased with decreasing glacier influence, Chl a still increased, and there was no relationship with total EEA. Based on EEA ratios, we found that the majority of GFS microbial communities were N-limited, with a few streams of different underlying bedrock geology exhibiting P-limitation. Cell-specific C-acquiring EEA was positively related to the ratio of Chl a to BA, presumably reflecting the utilization of algal exudates. Meanwhile, cell-specific N-acquiring EEA were positively correlated with the concentration of dissolved inorganic nitrogen (DIN), and both N- and P-acquiring EEA increased with greater cell-specific EPS. Overall, our results reveal greater glacier influence to be negatively related to GFS biofilm biomass parameters, and generally associated with greater microbial N demand. These results help to illuminate the ecology of GFS biofilms, along with their biogeochemical response to a shifting habitat template with ongoing climate change.

Research field(s)
Health Sciences, Biomedical Research, Microbiology

DOI
10.3389/fmicb.2020.591465

A Universal Gut-Microbiome-Derived Signature Predicts Cirrhosis

NOMIS Researcher(s)

Published in

November 3, 2020

Oh et al. identify diagnostic signatures for fibrosis from stool metagenomic and metabolomic profiling that, when combined with serum AST levels, distinguishes cirrhosis in mixed fibrosis cohort. Moreover, this combination signature was validated in racially and geographically independent cohorts.

Research field(s)
Health Sciences, Clinical Medicine, Endocrinology & Metabolism

DOI
10.1016/j.cmet.2020.06.005

Early-phase [18F]PI-2620 tau-PET imaging as a surrogate marker of neuronal injury

NOMIS Researcher(s)

Published in

November 1, 2020

Purpose: Second-generation tau radiotracers for use with positron emission tomography (PET) have been developed for visualization of tau deposits in vivo. For several β-amyloid and first-generation tau-PET radiotracers, it has been shown that early-phase images can be used as a surrogate of neuronal injury. Therefore, we investigated the performance of early acquisitions of the novel tau-PET radiotracer [18F]PI-2620 as a potential substitute for [18F]fluorodeoxyglucose ([18F]FDG). Methods: Twenty-six subjects were referred with suspected tauopathies or overlapping parkinsonian syndromes (Alzheimer’s disease, progressive supranuclear palsy, corticobasal syndrome, multi-system atrophy, Parkinson’s disease, multi-system atrophy, Parkinson’s disease, frontotemporal dementia) and received a dynamic [18F]PI-2620 tau-PET (0–60 min p.i.) and static [18F]FDG-PET (30–50 min p.i.). Regional standardized uptake value ratios of early-phase images (single frame SUVr) and the blood flow estimate (R1) of [18F]PI-2620-PET were correlated with corresponding quantification of [18F]FDG-PET (global mean/cerebellar normalization). Reduced tracer uptake in cortical target regions was also interpreted visually using 3-dimensional stereotactic surface projections by three more and three less experienced readers. Spearman rank correlation coefficients were calculated between early-phase [18F]PI-2620 tau-PET and [18F]FDG-PET images for all cortical regions and frequencies of disagreement between images were compared for both more and less experienced readers. Results: Highest agreement with [18F]FDG-PET quantification was reached for [18F]PI-2620-PET acquisition from 0.5 to 2.5 min p.i. for global mean (lowest R = 0.69) and cerebellar scaling (lowest R = 0.63). Correlation coefficients (summed 0.5–2.5 min SUVr & R1) displayed strong agreement in all cortical target regions for global mean (RSUVr 0.76, RR1 = 0.77) and cerebellar normalization (RSUVr 0.68, RR1 = 0.68). Visual interpretation revealed high regional correlations between early-phase tau-PET and [18F]FDG-PET. There were no relevant differences between more and less experienced readers. Conclusion: Early-phase imaging of [18F]PI-2620 can serve as a surrogate biomarker for neuronal injury. Dynamic imaging or a dual time-point protocol for tau-PET imaging could supersede additional [18F]FDG-PET imaging by indexing both the distribution of tau and the extent of neuronal injury.

Research field(s)
Health Sciences, Clinical Medicine, Nuclear Medicine & Medical Imaging

DOI
10.1007/s00259-020-04788-w

Assessment of 18F-PI-2620 as a Biomarker in Progressive Supranuclear Palsy

NOMIS Researcher(s)

Published in

November 1, 2020

Importance: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis. Objective: To investigate the potential of the novel tau radiotracer 18F-PI-2620 as a biomarker in patients with clinically diagnosed PSP. Design, Setting, and Participants: In this cross-sectional study, participants underwent dynamic 18F-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP-non-RS were excluded from final data analysis owing to incomplete dynamic PET scans. Data were collected from December 2016 to October 2019 and were analyzed from December 2018 to December 2019. Main Outcomes and Measures: Postmortem autoradiography was performed in independent PSP-RS and healthy control samples. By in vivo PET imaging, 18F-PI-2620 distribution volume ratios were obtained in globus pallidus internus and externus, putamen, subthalamic nucleus, substantia nigra, dorsal midbrain, dentate nucleus, dorsolateral, and medial prefrontal cortex. PET data were compared between patients with PSP and control groups and were corrected for center, age, and sex. Results: Of 60 patients with PSP, 40 (66.7%) had RS (22 men [55.0%]; mean [SD] age, 71 [6] years; mean [SD] PSP rating scale score, 38 [15]; score range, 13-71) and 20 (33.3%) had PSP-non-RS (11 men [55.0%]; mean [SD] age, 71 [9] years; mean [SD] PSP rating scale score, 24 [11]; score range, 11-41). Ten healthy controls (2 men; mean [SD] age, 67 [7] years) and 20 controls with disease (of 10 [50.0%] with Parkinson disease and multiple system atrophy, 7 were men; mean [SD] age, 61 [8] years; of 10 [50.0%] with Alzheimer disease, 5 were men; mean [SD] age, 69 [10] years). Postmortem autoradiography showed blockable 18F-PI-2620 binding in patients with PSP and no binding in healthy controls. The in vivo findings from the first large-scale observational study in PSP with 18F-PI-2620 indicated significant elevation of tracer binding in PSP target regions with strongest differences in PSP vs control groups in the globus pallidus internus (mean [SD] distribution volume ratios: PSP-RS, 1.21 [0.10]; PSP-non-RS, 1.12 [0.11]; healthy controls, 1.00 [0.08]; Parkinson disease/multiple system atrophy, 1.03 [0.05]; Alzheimer disease, 1.08 [0.06]). Sensitivity and specificity for detection of PSP-RS vs any control group were 85% and 77%, respectively, when using classification by at least 1 positive target region. Conclusions and Relevance: This multicenter evaluation indicates a value of 18F-PI-2620 to differentiate suspected patients with PSP, potentially facilitating more reliable diagnosis of PSP.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

DOI
10.1001/jamaneurol.2020.2526

Antibody against TDP-43 phosphorylated at serine 375 suggests conformational differences of TDP-43 aggregates among FTLD–TDP subtypes

NOMIS Researcher(s)

Published in

November 1, 2020

Aggregation of hyperphosphorylated TDP-43 is the hallmark pathological feature of the most common molecular form of frontotemporal lobar degeneration (FTLD–TDP) and in the vast majority of cases with amyotrophic lateral sclerosis (ALS–TDP). However, most of the specific phosphorylation sites remain to be determined, and their relevance regarding pathogenicity and clinical and pathological phenotypic diversity in FTLD–TDP and ALS–TDP remains to be identified. Here, we generated a novel antibody raised against TDP-43 phosphorylated at serine 375 (pTDP-43S375) located in the low-complexity domain, and used it to investigate the presence of S375 phosphorylation in a series (n = 44) of FTLD–TDP and ALS–TDP cases. Immunoblot analysis demonstrated phosphorylation of S375 to be a consistent feature of pathological TDP-43 species, including full-length and C-terminal fragments, in all FTLD–TDP subtypes examined (A–C) and in ALS–TDP. Of particular interest, however, detailed immunohistochemical analysis showed striking differences in the immunoreactivity profile of inclusions with the pTDP-43S375 antiserum among pathological subtypes. TDP-43 pathology of ALS–TDP, FTLD–TDP type B (including cases with the C9orf72 mutation), and FTLD–TDP type C all showed strong pTDP-43S375 immunoreactivity that was similar in amount and morphology to that seen with an antibody against TDP-43 phosphorylated at S409/410 used as the gold standard. In stark contrast, TDP-43 pathology in sporadic and genetic forms of FTLD–TDP type A (including cases with GRN and C9orf72 mutations) was found to be almost completely negative by pTDP-43S375 immunohistochemistry. These data suggest a subtype-specific, conformation-dependent binding of pTDP-43S375 antiserum to TDP-43 aggregates, consistent with the idea of distinct structural TDP-43 conformers (i.e., TDP-43 strains) as the molecular basis for the phenotypic diversity in TDP-43 proteinopathies.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

DOI
10.1007/s00401-020-02207-w

Cognitive outcomes in trials of two BACE inhibitors in Alzheimer’s disease

NOMIS Researcher(s)

Published in

November 1, 2020

Introduction: The APECS and AMARANTH trials showed that beta-secretase (BACE) inhibitors verubecestat and lanabecestat failed to slow cognitive and functional decline in individuals with prodromal or early Alzheimer’s disease. Here, the performance on secondary and exploratory cognitive measures in both studies is reported. Methods: APECS (verubecestat) and AMARANTH (lanabecestat) were randomized, double-blind, placebo-controlled, parallel-group, 104-week clinical trials conducted by different sponsors. Measures included the 3-Domain Composite Cognition Score (CCS-3D), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Letter/Category Fluency, and Digit Symbol Coding. Results: Verubecestat showed worsening on the CCS-3D Total Score, Episodic Memory, and Attention/Processing Speed domains. Lanabecestat showed worsening on the RBANS Total Score, Immediate Memory, and Visuospatial/Constructional Indexes. Both BACE inhibitors showed worsening on Digit Symbol Coding and improvements on Letter/Category Fluency. Discussion: In both studies, many measures showed treatment-associated cognitive worsening, whereas verbal fluency tasks showed improvement.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

DOI
10.1002/alz.12164

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