Biology subjects

van Eimeren, T.

Publications and source records attributed to van Eimeren, T..

7 recordsLinked to original sources

bioRxiv2024

The speed limits for tau pathology progression in Alzheimer's disease

ObjectiveTo examine interactive effects of modifiable factors, genetic determinants and load-dependent pathology effects on tau pathology progression. MethodsData of 162 amyloid-positive individuals were included, for whom longitudinal [18F]AV-1451-PET scans, baseline information on global amyloid load, ApoE4 status, body-mass-index (BMI), hypertension, education, neuropsychiatric symptom severity and demographic information were available in ADNI. All [18F]AV-1451 PETs were intensity-standardized (reference: inferior cerebellum), z-transformed (control sample: 147 amyloid-negative subjects) and subsequently thresholded (z-score > 1.96) and converted to volume-maps. Based on these volume-maps, tau-changes over time were assessed in terms of 1) tau-speed (i.e. newly affected volume at follow-up), and 2) tau-level-rise (i.e. tau increase in previously affected volume). These two measures were entered as dependent variables in separate linear mixed effects models including four baseline risk factors (BMI, education, hypertension, neuropsychiatric symptom severity), baseline amyloid, tau-volume or tau burden, ApoE4 status, clinical stage, sex, and age as predictors. Next, we tested the interactive effects between baseline amyloid or tau burden with the four modifiable factors on either tau-speed or tau-level-rise, respectively. ResultsFaster tau-speed was linked to higher BMI, female sex, ApoE4-status, and baseline tau-volume. The effect of baseline tau-volume on tau-speed was driven by greater global amyloid burden. In terms of tau-level-rise, we observed that lower hypertension and BMI were linked to a slower increase in tau burden. A load-dependent effect of baseline amyloid and tau burden was found. Higher amyloid and BMI as well as lower education and higher tau burden were linked to greater tau-level-rise. ConclusionEducation, BMI and hypertension differentially influence tau speed and level rise by its interaction with initial pathological burden. Timely modification of these factors may overall slow taus progression.

neuroscience↗

bioRxiv2024

Dopamine and temporal discounting: revisiting pharmacology and individual differences

Disorders characterised by changes in dopamine (DA) neurotransmission are often linked to changes in the temporal discounting of future rewards. Likewise, pharmacological manipulations of DA neuro-transmission in healthy individuals modulate temporal discounting, but there is considerable variability in the directionality of reported pharmacological effects, as enhancements and reductions of DA signalling have been linked to both increases and reductions of temporal discounting. This may be due to meaningful individual differences in drug effects and/or false positive findings in small samples. To resolve these inconsistencies, we 1) revisited pharmacological effects of the DA precursor L-DOPA on temporal discounting in a large sample of N = 76 healthy participants (n = 44 male) and 2) examined several putative proxy measures for DA to revisit the role of individual differences in a randomised, double-blind placebo-controlled pre-registered study (https://osf.io/a4k9j/). Replicating previous findings, higher rewards were discounted less (magnitude effect). Computational modelling using hierarchical Bayesian parameter estimation confirmed that the data in both drug conditions were best accounted for by a non-linear temporal discounting drift diffusion model. In line with recent animal and human work, L-DOPA reliably reduced the discount rate with a small effect size, challenging earlier findings in substantially smaller samples. We found no credible evidence for linear or quadratic effects of putative DA proxy measures on model parameters, calling into question the role of these measures in accounting for individual differences in DA drug effects.

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bioRxiv2024

Neuronal and oligodendroglial but not astroglial tau translates to in vivo tau-PET signals in primary tauopathies

Tau-PET receives growing interest as an imaging biomarker for the 4-repeat tauopathy progressive supranuclear palsy (PSP). However, the translation of in vitro 4R-tau binding to in vivo tau-PET signals is still unclear. Therefore, we conducted a longitudinal [18F]PI-2620 PET/MRI study in a 4-repeat-tau mouse model (PS19) and found elevated [18F]PI-2620 PET signal in the presence of high neuronal tau. Cell sorting after radiotracer injection in vivo revealed higher tracer uptake in single neurons compared to astrocytes of PS19 mice. Regional [18F]PI-2620 tau-PET signals during lifetime correlated with abundance of fibrillary tau in subsequent autopsy samples of PSP patients and disease controls. In autoradiography, tau-positive neurons and oligodendrocytes with high AT8 density but not tau-positive astrocytes were the driver of [18F]PI-2620 autoradiography signals in PSP. In summary, neuronal and oligodendroglial tau constitutes the dominant source of tau-PET radiotracer binding in 4-repeat-tauopathies, yielding the capacity to translate to an in vivo signal.

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bioRxiv2024

Putaminal dopamine modulates movement motivation in Parkinson's disease

The relative inability to produce effortful movements (akinesia) is the most specific motor sign of Parkinsons disease. The motor motivation hypothesis suggests that akinesia may not reflect a deficiency in motor control per se, but a deficiency in cost-benefit considerations for motor effort. For the first time, we investigated the quantitative effect of dopamine depletion on the motivation of motor effort in Parkinsons disease. A total of 21 patients with Parkinsons disease and 26 healthy controls were included. An incentivized force task was used to capture the amount of effort participants were willing to invest for different monetary incentive levels and dopamine transporter depletion in the bilateral putamen was assessed. Our results demonstrate that patients with Parkinsons disease applied significantly less grip force than healthy controls, especially for low incentive levels. Congruously, decrease of motor effort with greater loss of putaminal dopaminergic terminals was most pronounced for low incentive levels. This signifies that putaminal dopamine is most critical to motor effort when the trade-off with the benefit is poor. Taken together, we provide direct evidence that the reduction of effortful movements in Parkinsons disease depends on motivation and that this effect is associated with putaminal dopaminergic degeneration.

neuroscience↗

bioRxiv2024

Dynamic properties in functional connectivity changes and striatal dopamine deficiency in Parkinson's disease

IntroductionRecent studies in Parkinsons disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in separate PD cohorts, indexing dopamine-dependent changes in large-scale brain network dynamics and its implications in clinical features. MethodsWe pooled data from two cohorts reflecting early PD. From the Parkinsons Progression Marker Initiative (PPMI) cohort, resting-state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) SPECT were available for 63 PD patients and 16 age- and sex-matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age- and sex-matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent 18F-DOPA-PET imaging. The striatal synthesis capacity of 18F-DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre-processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44s window) and a subsequent k-means clustering were conducted separately for each cohort to derive dFC states (reemerging intra- and interindividual connectivity patterns). From these states we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. ResultsIn both cohorts, dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state (X2(1, N=79) = 5.82, p= 0.016) and a lower number of transitions (U(N=79) = 337.5, z = -2.06 p= .039) than controls. Significantly, worse motor scores (UPDRS-III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state (UPDRS-III: {tau}b(N=63) = -.281; p =.003, DaT putamen: {tau}b(N=63)=.213, p= .023, DaT caudate: {tau}b(N=63)=.209, p= .025) and a low total number of transitions (UPDRS-III: {tau}b(N=63)= -.308; p = .001, DaT putamen: {tau}b(N=63)=.350, p<.001, DaT caudate: {tau}b(N=63)=.251, p=.007). Additionally, worse motor performance was associated with a low number of bi-directional transitions between the GI and the lesser connected (LC) state ({tau}b(N=63)= -.237; p =.019). These results could not be reproduced in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity or clinical measure were observed. ConclusionIn early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large-scale network dynamics seem to depend on striatal dopamine availability. Notably, we obtained these results in only one cohort, but not in a replication sample. Key pointsO_LIExploring dopamines role in brain network dynamics in two Parkinsons disease (PD) cohorts, we unraveled PD-specific changes in dynamic functional connectivity (dFC). C_LIO_LIIn the discovery cohort, results suggest striatal dopamine availability influences large-scale network dynamics that are relevant in motor control. C_LIO_LIIn the confirmation cohort, these findings were not replicated, indicating PD-specific dFC changes are dependent on unrecognized cohort features. C_LI

neuroscience↗

bioRxiv2024

The long distance relationship of regional amyloid burden and tau pathology spread

IntroductionConsistent with the amyloid-cascade-hypothesis, we tested whether regional amyloid burden is associated with tau pathology increases in spatially independent brain regions and whether functional connectivity serves as a mediator bridging the observed spatial gap between these pathologies. MethodsData of 98 amyloid-positive and 35 amyloid-negative subjects with baseline amyloid (18F-AV45) and longitudinal tau (18F-AV1451) PET were selected from ADNI. Annual tau change maps were computed. All images were z-transformed using the amyloid-negative subjects as reference. Z-maps of baseline amyloid and annual tau change were submitted to a parallel independent component analysis in GIFT, yielding six component pairs linking spatial patterns of baseline amyloid to longitudinal tau increase. Next, we used the region of maximum coefficient per component as seeds for functional connectivity analyses in a healthy control dataset. This resulted in six pairs of amyloid and tau seed-based networks (SBN). The spatial overlap between these SBNs and components (amyloid OR tau change) and the combined component pairs (amyloid AND tau change) were quantified. ResultsAmyloid SBNs presented greater spatial overlap with their respective amyloid components (24%-54%) than tau SBNs with the respective tau change components (16%-40%). However, the spatial combination of amyloid and tau component pairs showed highest spatial overlap with the amyloid SBNs (up to 62% vs. 39% for the tau SBNs). ConclusionMechanistically, regional associations of amyloid and tau pathology may be driven by underlying large-scale functional networks. Functional connections may thereby transmit soluble amyloid to remote brain regions within the same network, likely triggering tau aggregation.

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bioRxiv2023

Pharmacological enhancement of dopamine neurotransmission does not affect illusory pattern perception

Psychotic symptoms and delusional belief have been linked to dopamine transmission in both healthy and clinical samples and are assumed to result at least in part from perceiving illusory patterns in noise. However, the existing literature on the role of dopamine in detecting patterns in noise is inconclusive. To address this issue, we assessed the effect of manipulating dopaminergic neurotransmission on illusory pattern perception in healthy individuals (n = 48, n = 19 female) in a double-blind placebo-controlled within-subjects design (see preregistration at https://osf.io/a4k9j/). We predicted individuals on vs. off L-DOPA to be more likely to perceive illusory patterns, specifically objects in images containing only noise. Using a signal detection model, however, we found no credible evidence that L-DOPA compared to placebo increased false alarm rates. Further, L-DOPA did not modulate measures of accuracy, discrimination sensitivity and response bias. In all cases, Bayesian statistics revealed strong evidence in favour of the null hypothesis Future studies should address possible dose-dependent effects and differential effects in healthy vs. clinical samples.

neuroscience↗