B04
In the first funding period, we demonstrated that in the medial temporal lobe (MTL) an augmented vascular supply and smaller distances of surrounding vessels to the hippocampus are associated with better cognitive performance and higher MTL regional volumes in older adults including individuals with cerebral small vessel disease (CSVD). The entorhinal cortex (ERC) gives major input to the hippocampus via the perforant path and this circuit is highly vulnerable to age-related pathology such as MTL tau accumulations. It is still unclear which neural resources mediate the beneficial effect of vascularisation on cognition and on MTL volume integrity. Furthermore, it remains unclear whether microvascular and neural plasticity and improved memory performance can be induced by non-invasive brain stimulation such as low-intensity transcranial focused ultrasound (TUS). In the current project, we aim to understand the interplay between MTL vascularisation, synaptic integrity as neural resource and tau accumulation, and how this relationship contributes to entorhinal-hippocampal network function in old age. In close collaboration with the University Clinic Leipzig, we will establish synaptic density PET that will be also used in other subprojects. We will further investigate whether we can induce microvascular plasticity and MTL network changes by targeted TUS in the ERC to promote cognitive resilience.
Principal Investigators
Prof. Dr. Henryk Barthel
Prof. Dr. Anne Maass
Prof. Dr. med. Stefanie Schreiber
Co-Workers
Joseph Höpker-Fernandes
Jonas Marquardt
Mahima Rebello
Niklas Vockert
Why focus on the medial temporal lobe?
The medial temporal lobe (MTL) contains, among other brain regions, the hippocampus and the adjacent entorhinal cortex. These two areas form a neuronal circuit, which is significantly involved in the formation of episodic memory and spatial navigation. At the same time, the MTL is particularly affected by both normative and pathological age-related changes. Alzheimer’s disease-related tau protein accumulation in the MTL, independent of atrophy or beta-amyloid accumulation, explains approximately 20% of the variance concerning episodic memory performance in healthy elderly subjects (Maass et al., 2018). One major question is which neural resources contribute to the preservation and/or vulnerability of this circuit in age-related degeneration. The term neural resource generally refers to structures and/or processes in the brain (e.g. higher blood flow, synaptic density, volume, or myelin) that can affect cognition and vary between individuals.
One promising factor:
the vascularization of the hippocampus
The hippocampus can be supplied by both the anterior choroidal artery and the posterior cerebral artery (Erdem et al., 1993, Marinkovic et al., 1992). Some individuals have an augmented hippocampal supply (both arteries), whereas others only have a basic supply (only supplied by the posterior cerebral artery), which has been confirmed using high-resolution imaging in vivo (Perosa et al., 2020; Spallazzi et al., 2019). We previously found that that an augmented supply is associated with several benefits, including better cognitive performance and higher anterior hippocampal and entorhinal volume (Perosa et al., 2020, Vockert et al., 2021).
We further established a novel methodology, namely Vessel Distance Mapping (VDM) (together with Z02) to assess vascularisation as a continuous metric beyond binary classification. Based on vessel segmentation, VDM computes for each voxel the distance to its closest vessel, and hence, allows data-driven analysis for proxies of vessel density and vessel pattern (Garcia-Garcia*, Mattern* et al., 2023). Different metrics can be derived from VDM, such as “Global VDM” and “Center of mass distance”. VDM revealed, that in the presence of pathology, i.e. CSVD, larger distances of the hippocampal arteries and their branches to the hippocampus were related to worse cognition (Garcia-Garcia*, Mattern* et al. 2023). VDM has been applied in different associated projects that aimed to understand the role of brain vascularisation in cognitive and brain vascular health (together with Z02; see for example Morton*, Arndt* et al., 2023; Schreiber*, Bernal*, Arndt* et al., 2023). In the second funding period, we will apply VDM based on automatic vessel segmentation to assess how vascularization is linked to tau pathology, synaptic density and circuit function of the MTL in older adults including “SuperAgers”.
In vivo imaging of synaptic density
Until recently, synaptic density could, in humans, only be assessed post mortem. With the advent of PET tracers like [18F]SynVesT-1 which bind to the synaptic vesicle glycoprotein 2A , we can now measure the synaptic density in the living brain. SV2A is expressed ubiquitously at (presynaptic) nerve terminals throughout the brain and plays a crucial role in normal synaptic functioning. In Alzheimer’s Disease, synaptic density PET imaging so far revealed, amongst other findings, reduced MTL and hippocampal binding readouts in early disease stages (Mecca et al., 2020). Furthermore, reduced synaptic density as determined by PET imaging has been related to higher tau burden (Mecca et al., 2022), to reduced functional and structural connectivity (Zhang et al., 2023), and to reduced grey matter diffusivity (Silva-Rudberg et al., 2024). Interestingly, Mecca and colleagues (Mecca et al., 2020) showed that higher ERC tau burden related to lower synaptic density in the hippocampus, which receives strong projections from ERC via the perforant path. While these and also previous post mortem studies are cross-sectional, the main hypothesis is that tau drives synaptic density loss. However, the association between regional synaptic density and tau burden is probably region- and disease state-specific in a way in which, in early states, regions with higher synaptic density show more tau burden, while over time tau-induced toxicity relates to synapse loss (Holland et al., 2022), followed by neurodegeneration and disconnection. It is still unknown how synaptic density in the MTL relates to local network function and vascularization. In the current project, we aim to establish synaptic density PET imaging in cognitively normal older adults and SuperAgers.
The aims of our project
In a group of cognitively normal older adults (Z03 cohort) with known MTL tau pathology status, including SuperAgers, we will first investigate the association between MTL vascularisation, synaptic density and tau burden. We hypothesise that better vascularisation is associated with higher synaptic density/integrity, and that both are linked to preserved MTL network function. To this end we will apply ultra-high-field vascular, functional and structural 7T MRI by means of the novel 7T Connectome scanner. In addition, we will establish [18F]SynVesT-1 PET to quantify MTL synaptic density.
Together with subproject B02 in a shared cohort of mild cognitive impairment (MCI) patients characterised for Tau/Abeta pathology, we will further assess microvascular changes induced by TUS that is unilaterally applied to targeting the MTL and fusiform gyrus (within B02). By doing so we will assess whether TUS can promote microvascular plasticity, such as increased perfusion and angiogenesis, and whether these changes promote MTL functional network changes that favour better memory performance. For this purpose, we will quantify MTL connectivity, MTL vessel density, and perfusion/cerebrovascular reactivity before and after the intervention using the 7T Connectome scanner. Our study will lay the ground for the discovery of vascular and neural resilience mechanisms in the MTL. It will further understand how TUS of the MTL could stimulate these mechanisms, potentially serving as an intervention to unlock cognitive resilience in the face of age-related pathologies.
Our key questions
- Is synaptic density/integrity a key neural resource for SuperAging and what is the relationship between this parameter, vascularisation, tau burden in the MTL?
- How do MTL vascularisation and synaptic density/integrity affect MTL network activity? Are tau load and deteriorated vascularisation directly linked or do they have additive effects on synapse loss and network failure (of the entorhinal-hippocampal pathway)?
- Can focused TUS induce MTL vascular plasticity and does this relationship depend on MTL vascularisation? Does TUS-induced MTL vascular plasticity relate to TUS-induced MTL network changes?
MTL vascularisation, synaptic density and tau accumulation in old age and SuperAging
We will make use of simultaneous synaptic density PET/MRI to investigate how MTL synaptic density and vascularisation are related to one another and to superior memory performance in very old age. Vascularisation provides energy and metabolic supply, and is thus a pivotal factor for synaptic plasticity and function. Specifically, we aim to compare MTL synaptic density/integrity and vascularisation between SuperAgers and typical agers.
We will perform simultaneous [18F]SynVesT-1 PET/MRI in an existing cohort (Z03) of older adults including SuperAgers (age > 79.5 years), typical Agers (age > 79.5 years) and cognitively normal older adults aged 60-79 years. This is performed in close collaboration with the University Clinic Leipzig (Prof. Osama Sabri and PI Henryk Barthel), where the tracer is produced. During the PET scan, 3T-MR data will be acquired to assess MTL perfusion and MTL cerebrovascular reactivity (by resting-state fMRI). MTL VDM metrics will be derived from additional ultra-high field 7T ToF MRA. To estimate cerebrovascular reactivity, an intermittent respiratory modulation task is used to induce respiratory fluctuations during the resting-state fMRI.
MTL network connectivity in old age and SuperAging
We will further zoom into the MTL via ultra high-resolution MR imaging at 7 Tesla. Here, we will focus on the entorhinal-hippocampal pathway that is critical for episodic memory performance. Particularly, the superficial layers II and III of the ERC give rise to input to the outer molecular layer of the dentate gyrus and the molecular layer (stratum lacunosum-moleculare) of the hippocampal CA fields. This pathway seems to deteriorate in Alzheimer’s disease in relation to tau pathology, which might be related to loss of synaptic density in the hippocampus and likely translates to regional network dysfunction. Animal studies further suggest that the perforant pathway is also vulnerable to aging and hippocampal hyperactivity (Wilson et al., 2006). We will study SuperAgers and typical agers by means of ultra-high field 7T MRI at the Connectome scanner including ToF MRA for assessment of MTL vascularisation, and high-resolution resting-state fMRI to assess subfield and layer-specific functional connectivity (<1mm isotropic resolution) in the MTL. In addition, we will perform ultra-high resolution microstructural DTI to assess structural connectivity in the MTL (with Z02). Our major questions here are the following: Do SuperAgers have preserved ERC-hippocampal functional and structural connectivity compared to typical agers? Is increased tau and reduced synaptic density in the hippocampus associated with reduced ERC-hippocampal connectivity?
Future outlook
Prospectively, we aim to bring the techniques into the clinic and apply them to larger patient cohorts with, e.g. microvascular disease or Amyloid positivity, and transfer the knowledge on MTL alterations to other disorders, e.g. diabetes, epilepsy, or autoimmune encephalopathies. We will try to implement measures on MTL vascular parameters into clinical MRI scanning (downscaling to 3T MRI, for example, and establishment of user-oriented pipelines for imaging analysis). In case, focused TUS will prove to be successful, we will consider its application in a larger clinical trial.
