Leif Østergaard’s research while affiliated with Aarhus University and other places

The locus coeruleus (LC) produces most of the brain’s noradrenaline (NA). Among its many roles, NA is often said to be neuroprotective and important for brain upkeep. For this reason, loss of LC integrity is thought to impact brain volume and microstructure as well as plasticity broadly. LC dysfunction is also a suspected driver in the development of neurodegenerative diseases. Nevertheless, the impact of LC dysfunction on the gross structure and microstructure of normal brains is not well-studied. We employed high-field ex vivo magnetic resonance imaging (MRI) to investigate brain volumetrics and microstructure in control (CON) mice and mice with LC ablation (LCA) at two ages, representing the developing brain and the fully matured brain. These whole-brain methods are known to be capable of detecting subtle morphological changes and brain microstructural remodeling. We found mice behavior consistent with histologically confirmed LC ablation. However, MRI showed no difference between CON and LCA groups with regard to brain size, relative regional volumes, or regional microstructural indices. Our findings suggest that LC-NA is not needed for postnatal brain maturation and growth in mice. Nor is it required for maintenance in the normal adult mouse brain, as no atrophy or microstructural aberration is detected after weeks of LC dysfunction. This adds clarity to the often-encountered notion that LC-NA is important for brain “trophic support” as it shows that such effects are likely most relevant to mechanisms related to brain plasticity and neuroprotection in the (pre)diseased brain.

Awake mouse MRI and spectroscopy (MRS) are valuable techniques for studying biological questions without the confounding effects of anaesthesia. Currently, no off-the-shelf solution exists for awake mouse MRI/S. To address this, we present a Mouse Cradle Suspension System (MCSS) for awake mouse MRI/S. Our design is freely available and offers a low-cost 3D-printed setup compatible with a Bruker Biospec 94/20 scanner and commercially available 1H/³¹P surface- and volume-coils, such as coils from Bruker Biospin (T20025V3) and Rapid (O-XL-HL-094). While the focus here is measurements in awake mouse brain, the coils and the presented setup is suitable for both mouse and rat brain, and studies of mouse body organs. Moreover, the design is easily modifiable to suit other applications and hardware configurations. The MCSS reduces gradient-induced coil vibrations and supports cross-coil setups. It features an inner and outer rail system for easy insertion of the coil and customized mouse cradle into the scanner. The cradle is suitable for both anaesthetized and awake mouse scans and existing habituation protocols for awake mouse MRI/S. This MCSS design ensures a smooth workflow for awake mouse MRI/S. The cost is approximately 200€, achieved using 3D-printed and off-the-shelf components.

Conventional MRI is crucial for diagnosing multiple sclerosis (MS) but lacks precision, leading to the clinico-radiological paradox and misdiagnosis risk, especially when confronted with unspecific lesions not related to MS. Advancements in perfusion-weighted imaging (PWI) with an algorithm designed for diseases with anticipated contrast agent extravasation offer insight into microvascular impairment and flow heterogeneity. Our study aimed to assess these factors in MS patients and their association with clinically relevant white matter injury and disease course. We evaluated 60 adults with white matter lesions (WML), including 50 diagnosed with MS or MS syndromes and 10 non-diseased symptomatic controls (SC) with unspecific WML. MRI included conventional three-dimensional (3D) T2-weighted fluid-attenuated inversion recovery (T2-FLAIR), 3D magnetization-prepared two rapid acquisition gradient-echo (MP2RAGE), post-contrast 3D T1-weighted (T1) images, and Dynamic Susceptibility Contrast (DSC) PWI at 3T. WML masks of “unspecific T2-FLAIR lesions”, “MS T2-FLAIR lesions”, and “MS T1-lesions” were manually outlined and validated by a neuroradiologist. DSC-derived parameters were analyzed in WML masks and healthy-appearing tissue. MS T2-FLAIR lesions showed increased flow heterogeneity and vasodilation compared to unspecific T2-FLAIR lesions in SC, as well as compared to unspecific T2-FLAIR lesions within the MS group. MS T1-lesions exhibited more homogenized flow. Our findings suggest that DSC-PWI, combined with lesion delineation, can provide clinically relevant differentiation of MS lesions from unspecific WML, highlighting potential microvascular pathology previously overlooked in MS.

APOE-ɛ4 is a genetic risk factor for Alzheimer's disease (AD). AD is associated with reduced cerebral blood flow (CBF) and with microvascular changes that limit the transport of oxygen from blood into brain tissue: reduced microvascular cerebral blood volume and high relative transit time heterogeneity (RTH). Healthy APOE-ɛ4 carriers reveal brain regions with elevated CBF compared with carriers of the common ɛ3 allele. Such asymptomatic hyperemia may reflect microvascular dysfunction: a vascular disease entity characterized by suboptimal tissue oxygen uptake, rather than limited blood flow per se. Here, we used perfusion MRI to show that elevated regional CBF is accompanied by reduced capillary blood volume in healthy APOE-ɛ4 carriers (carriers) aged 30–70 years compared with similarly aged APOE-ɛ3 carriers (noncarriers). Younger carriers have elevated hippocampal RTH and more extreme RTH values throughout both white matter (WM) and cortical gray matter (GM) compared with noncarriers. Older carriers have reduced WM CBF and more extreme GM RTH values than noncarriers. Across all groups, lower WM and hippocampal RTH correlate with higher educational attainment, which is associated with lower AD risk. Three days of dietary nitrate supplementation increased carriers' WM CBF but caused older carriers to score worse on two of six aggregate neuropsychological scores. The intervention improved late recall in younger carriers and in noncarriers. The APOE-ɛ4 gene is associated with microvascular changes that may impair tissue oxygen extraction. We speculate that vascular risk factor control is particularly important for APOE-ɛ4 carriers' healthy aging.

INTRODUCTION Disturbances in microvascular flow dynamics are hypothesized to precede the symptomatic phase of Alzheimer’s disease (AD). However, evidence in presymptomatic AD remains elusive, underscoring the need for therapies targeting these early vascular changes. METHODS We employed a multimodal approach, combining in vivo optical imaging, molecular techniques, and ex vivo MRI, to investigate early capillary dysfunction in Tg-SwDI mice without memory impairment. We also assessed the efficacy of carbonic anhydrase inhibitors (CAIs) in preventing capillary flow disturbances. RESULTS Our study revealed capillary flow disturbances associated with alterations in capillary morphology, adhesion molecule expression, and Amyloid-β (Aβ) load in 9–10-month-old Tg-SwDI mice without memory impairment. CAI treatment ameliorated these capillary flow disturbances, enhanced oxygen availability, and reduced Aβ load. DISCUSSION These findings underscore the importance of capillary flow disturbances as early biomarkers in presymptomatic AD and highlight the potential of CAIs for preserving vascular integrity in the early stages of AD.

Hypoparathyroidism (HypoPT) is a disease with no/or inadequate production/secretion of parathyroid hormone (PTH) from the parathyroid glands. Low levels of PTH result in hypocalcemia, which is often treated with calcium supplementation and active vitamin-D analogs. However, increasing evidence suggests that HypoPT has a profound impact on several organ systems. Quality of life (QOL) is reduced in patients with HypoPT, partly due to symptoms related to the central nervous system—including subjective feelings of confusion, a reduced ability to focus and think clearly(i.e., “brain fog”). However, the extent to which these complex symptoms relate to quantifiable changes in patients’ cognitive performance as determined by neuropsychological tests remains unclear. The brains of HypoPT patients may reveal tissue calcifications, but the extent to which long-term brain exposure to low PTH levels and/or changing calcium levels affects brain structure is unknown. In a cross-sectional study, we investigated PTH levels, QOL, cognitive impairment, and brain structure in well-treated post-surgical and non-surgical hypoparathyroid patients compared with healthy controls. QOL was quantified by the SF36v2, WHO-5 wellbeing Index, and two disease-specific questionnaires—the HPQ28 and Hypoparathyroidism Symptom Diary. Cognitive functions were tested using comprehensive neuropsychological. Brain structure was quantified by morphological analyses of MRI images. We found reduced QOL and cognitive functioning in terms of processing speed, executive functions, visual memory, and auditory memory in HypoPT. Furthermore, HypoPT revealed a reduced volume of the hippocampus—and the size of the thalamus in postsurgical patients was associated with the disease duration. Importantly, patients reporting severe brain fog had a smaller hippocampus than those with less brainfog. HypoPT is associated with quantifiable cognitive deficits and changes in brain structure that align with patient symptoms. Our exploratory study warrants further studies of the neurobiological impact of PTH and of the impact of PTH replacements therapy on patients’ cognitive functioning.