Biology subjects

Vandenbulcke, M.

Publications and source records attributed to Vandenbulcke, M..

6 recordsLinked to original sources

bioRxiv2026

Targeted single-nucleus sequencing of 39,800 neurons reveals extensive low-frequency somatic variants

Recent evidence implicates somatic mutations in disease-associated genes across multiple neurodegenerative disorders, including the identification of two somatic TARDBP variants as a putative cause of frontotemporal lobar degeneration with TDP-43 pathology type C (FTLD-TDP type C). However, these findings remain anecdotal. We performed single-nucleus amplicon sequencing of 39,800 neurons from the superior temporal gyrus of sporadic FTLD-TDP type C patients (34,738 neurons, 52 individuals) and non-demented controls (5,062 neurons, 26 individuals) using the Mission Bio Tapestri platform and investigated somatic variants in TARDBP and other FTLD-TDP-associated genes in a case-control setting. We uncovered an extensive landscape of ultra-low-frequency (<1%) somatic mutations across all analysed genes, including TARDBP. Rare somatic occurrences of known ALS/FTD-associated germline TARDBP variants, including p.N267S and p.M337V, were identified exclusively in patients. Among all targeted genes, TARDBP had the highest proportion of neurons harbouring a somatic variant, and this mutational burden was lower in individuals who died at an older age. Strikingly, the C-terminal domain of TDP-43, where most ALS/FTD germline pathogenic variants reside, exhibited a lower neuronal mutational burden than its other domains. This suggests that neurons harbouring damaging mutations may undergoprogressive loss prior to autopsy, leaving only rare survivors at frequencies too low to detect by bulk or small-scale single-cell approaches. Together, our findings provide an unprecedented resolution into the somatic mutational landscape of post-mitotic neurons in FTLD-TDP type C and reveal a gene-specific layer of neuronal mosaicism that current single-cell WGS studies fail to detect.

genetics↗

bioRxiv2026

Epicranial electrical stimulation improves non-navigational spatial memory in macaque monkeys

BackgroundThe hippocampus and medial temporal lobe are crucial for spatial memory, and their dysfunction is linked to Alzheimers disease (AD), with changes detectable even in preclinical stages. Recently, neuromodulation has gained interest as a potential treatment due to its beneficial effects on AD pathology and cognitive performance. However, outcomes vary significantly based on stimulation parameters and study conditions, and evidence from large animal models remains limited. ObjectiveTo assess whether epicranial current stimulation (ECS) at 40 Hz can improve non-navigational spatial memory and hippocampal activations. MethodsThree rhesus macaques were implanted with spiral platinum electrodes bilaterally on the skull and were trained in a non-navigational spatial memory task. ECS was applied at 40 Hz or at 10 Hz and performance across multiple sessions was evaluated. We further performed ECS during fMRI to examine the spread of activations caused by ECS across the brain in a block-design experiment. ResultsECS at 40 Hz improved performance in a non-navigational spatial memory task, while 10 Hz ECS had minimal or negative effects. Concurrent ECS-fMRI showed extensive brain activations at 40 Hz, including significant hippocampal activations, which was not observed at 10 Hz. ConclusionsOur results show that ECS could be a minimally-invasive and effective approach to improve memory performance and activate the hippocampus. ECS could represent a potential treatment for patients suffering from memory impairment.

neuroscience↗

bioRxiv2025

Alzheimer's disease and its co-pathologies: implications for hippocampal degeneration, cognitive decline, and the role of APOE ϵ4

INTRODUCTIONIn neurodegenerative dementias, the co-occurrence and interaction of A{beta}, tau, and other pathological lesions confound their individual contributions to neurodegeneration and their modulation by risk factors. METHODSWe analyzed 480 post-mortem human brains (ages 50-99) using regression and structural equation models to assess the relationships among A{beta}, tau, LATE-NC, -synuclein, other age-related lesions, and APOE {varepsilon}4, as well as their effects on CA1 neuronal density, brain weight, and cognitive status. RESULTSA{beta}, tau, LATE-NC, and amygdala-predominant -synuclein pathology were highly interconnected. Tau was the strongest predictor of global neurodegeneration, while LATE-NC primarily, but not exclusively, affected hippocampal neuron loss. Small vessel disease correlated with both LATE-NC and -synuclein, while APOE {varepsilon}4 was mainly associated with extracellular and capillary A{beta}. DISCUSSIONAlthough Alzheimers pathology plays a central role in brain degeneration, coexisting pathologies can both exacerbate and independently contribute to it. These factors should be considered in patient stratification.

neuroscience↗

bioRxiv2024

Amygdala-predominant α-synuclein pathology exacerbates hippocampal neuron loss in Alzheimer's disease

Misfolded -synuclein (Syn) protein accumulates in 43-63% of individuals with symptomatic Alzheimers disease (AD). Two main patterns of co-morbid Syn pathology have been identified: caudo-rostral and amygdala-predominant, with the latter being more common in AD. Syn pathology has been shown to interact with DNA-binding protein 43 (TDP-43) and abnormally phosphorylated Tau protein (pTau). These proteins tend to accumulate in the amygdala, yet the specific role of amygdala-predominant Syn pathology in the progression of AD and hippocampal degeneration remains unclear. In this cross-sectional study, we analyzed 291 autopsy brains from both demented and non-demented elderly individuals neuropathologically. Neuronal density in the CA1 region of the hippocampus was assessed using hematoxylin-stained sections for all cases. We semi-quantitatively evaluated Syn pathology severity in six brain regions and stratified the cases into the two spreading patterns. In 99 AD cases, we assessed limbic-predominant age-related TDP-43 neuropathological changes (LATE-NC), CA1 pTau density, and cerebral amyloid angiopathy (CAA). Structural equation modeling analysis was conducted based on the assessed pathological parameters in AD patients. We identified an association between the amygdala-predominant Syn pathology pattern and decreased neuronal density in the CA1 region. AD patients with an amygdala-predominant Syn pattern exhibited the most severe pTDP-43 pathology among all groups, while those with the caudo-rostral pattern had the lowest severity of AD-related pathological changes including CAA type 1. Our model revealed that the relationship between Syn pathology and CA1 neuron loss is mediated through pTau and LATE-NC. Our results indicate that amygdala-predominant Syn pathology, in contrast to Syn pathology with a caudo-rostral pattern, significantly contributes to hippocampal neuron loss, potentially by accelerating TDP-43 and pTau pathologies. This finding, along with observed neuropathological differences between AD patients with these two Syn spreading patterns, underscores the need for precise stratification of patients. The stratification should consider not only the molecular and morphological identity of co-pathologies but also the distribution pattern of the respective co-pathologies.

neuroscience↗

bioRxiv2021

An atlas of white matter anatomy, its variability, and reproducibility based on Constrained Spherical Deconvolution of diffusion MRI

Virtual dissection of white matter (WM) using diffusion MRI tractography is confounded by its poor reproducibility. Despite the increased adoption of advanced reconstruction models, early region-of-interest driven protocols based on diffusion tensor imaging (DTI) remain the dominant reference for virtual dissection protocols. Here we bridge this gap by providing a comprehensive description of typical WM anatomy reconstructed using a reproducible automated subject-specific parcellation-based approach based on probabilistic constrained-spherical deconvolution (CSD) tractography. We complement this with a WM template in MNI space comprising 68 bundles, including all associated anatomical tract selection labels and associated automated workflows. Additionally, we demonstrate bundle inter- and intra-subject variability using 40 (20 test-retest) datasets from the human connectome project (HCP) and 5 sessions with varying b-values and number of b-shells from the single-subject Multiple Acquisitions for Standardization of Structural Imaging Validation and Evaluation (MASSIVE) dataset. The most reliably reconstructed bundles were the whole pyramidal tracts, primary corticospinal tracts, whole superior longitudinal fasciculi, frontal, parietal and occipital segments of the corpus callosum and middle cerebellar peduncles. More variability was found in less dense bundles, e.g., the first segment of the superior longitudinal fasciculus, fornix, dentato-rubro-thalamic tract (DRTT), and premotor pyramidal tract. Using the DRTT as an example, we show that this variability can be reduced by using a higher number of seeding attempts. Overall inter-session similarity was high for HCP test-retest data (median weighted-dice = 0.963, stdev = 0.201 and IQR = 0.099). Compared to the HCP-template bundles there was a high level of agreement for the HCP test-retest data (median weighted-dice = 0.747, stdev = 0.220 and IQR = 0.277) and for the MASSIVE data (median weighted-dice = 0.767, stdev = 0.255 and IQR = 0.338). In summary, this WM atlas provides an overview of the capabilities and limitations of automated subject-specific probabilistic CSD tractography for mapping white matter fasciculi in healthy adults. It will be most useful in applications requiring a highly reproducible parcellation-based dissection protocol, as well as being an educational resource for applied neuroimaging and clinical professionals. O_FIG O_LINKSMALLFIG WIDTH=182 HEIGHT=200 SRC="FIGDIR/small/464139v2_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@18e7c79org.highwire.dtl.DTLVardef@18e2213org.highwire.dtl.DTLVardef@5f124borg.highwire.dtl.DTLVardef@1aa242c_HPS_FORMAT_FIGEXP M_FIG Graphical abstract(Top) shows the FWT pipeline for both CSTs, AF, and motor CC bundles. (Left to right) show the required input structural parcellation maps and a priori atlases for FWT and the resulting virtual dissection include/exclude VOIs. FWT provides two approaches to virtual dissection: (1) is a bundle-specific approach where streamlines are only seeded for the bundle of interest, (2) is a whole brain tractography followed by streamlines segmentation, (top right) shows output tractograms. (Middle) Group-averaged T1 and fODF images are generated from the HCP test-retest data, and FWT is applied to generate the HCP-atlas using the bundle-specific approach (1*). FWTs whole brain tracking and segmentation approach (2*) was applied to the HCP and MASSIVE dataset (right and left) and conducted model-based, and pair-wise similarity analyses and generated voxel-wise cumulative maps per bundle. FWT= Fun With Tracts, FS= FreeSurfer, MSBP= MultiScaleBrainParcellator, PD25= NIST Parkinsons histological, JHU= Johns Hopkins university, Juelich= Juelich university histological atlas, AC/PC= anterior commissure/posterior commissure) UKBB= UK Biobank, SUIT (spatially unbiased cerebellar atlas template), dMRI= diffusion magnetic resonance imaging, CSD= constrained spherical deconvolution, fODF= fiber orientation distribution function, CST= corticospinal tract, AF= arcuate fasciculus, CC= corpus callosum, HCP= human connectome project, MASSIVE= Multiple acquisitions for standardization of structural imaging validation and evaluation. C_FIG

neuroscience↗

bioRxiv2021

Neural excitation/inhibition imbalance and the treatment of severe depression

An influential hypothesis holds that depression is related to a neural excitation/inhibition imbalance, but its role in the treatment of depression remains unclear. Here, we show that unmedicated patients with severe depression demonstrated reduced inhibition of brain-wide resting-state networks relative to healthy controls. Patients using antidepressants showed inhibition that was higher than unmedicated patients and comparable to controls, but they still suffered from severe depression. Subsequent treatment with electroconvulsive therapy (ECT) reduced depressive symptoms, but its effectiveness did not depend on changes in network inhibition. Concomitant pharmacotherapy increased the effectiveness of ECT, but only when the strength of neural inhibition before ECT was within the normal range and not when inhibition was excessive. These findings suggest that reversing the excitation/inhibition imbalance may not be sufficient nor necessary for the effective treatment of severe depression, and that brain-state informed pharmacotherapy management may enhance the effectiveness of ECT.

neuroscience↗