Microglia are the resident immune cells of the central nervous system. They constantly survey the brain parenchyma for redundant synapses, debris, or dying cells, which they remove through phagocytosis. Microglial ramification, motility, and cytokine release are regulated by tonically active THIK-1 K+ channels on the microglial plasma membrane. Here, we examined whether these channels also play a role in phagocytosis. Using pharmacological blockers and THIK-1 knockout (KO) mice, we found that a lack of THIK-1 activity approximately halved both microglial phagocytosis and marker levels for the lysosomes that degrade phagocytically removed material. These changes may reflect a decrease of intracellular [Ca2+]i activity, which was observed when THIK-1 activity was reduced, since buffering [Ca2+]i reduced phagocytosis. Less phagocytosis is expected to result in impaired pruning of synapses. In the hippocampus, mice lacking THIK-1 expression had an increased number of anatomically and electrophysiologically defined glutamatergic synapses during development. This resulted from an increased number of presynaptic terminals, caused by impaired removal by THIK-1 KO microglia. The dependence of synapse number on THIK-1 K+ channels, which control microglial surveillance and phagocytic ability, implies that changes in the THIK-1 expression level in disease states may contribute to altering neural circuit function.
IntroductionDespite major advances in the field of neuroscience over the last three decades, the quality of assessments available to patients with memory problems in later life has barely changed. At the same time, a large proportion of dementia biomarker research is conducted in selected research samples that often poorly reflect the demographics of the population of patients who present to memory clinics. The Oxford Brain Health Clinic (BHC) is a newly developed clinical assessment service with embedded research in which all patients are offered high quality clinical and research assessments, including MRI, as standard.Methods and analysisHere we describe the BHC protocol, including aligning our MRI scans with those collected in the UK Biobank. We evaluate rates of research consent for the first 108 patients (data collection ongoing) and the ability of typical Psychiatry-led NHS memory-clinic patients to tolerate both clinical and research assessments.Ethics and disseminationOur ethics and consenting process enables patients to choose the level of research participation that suits them. This generates high rates of consent, enabling us to populate a research database with high quality data that will be disseminated through a national platform (the Dementias Platform UK data portal).ARTICLE SUMMARYThe Oxford Brain Health Clinic embeds high-quality assessments into routine clinical care for typical patients with memory problems.The BHC MRI protocol is aligned with the UK Biobank providing a unique opportunity to link the power of big-data and individual patients at the clinical interface.The BHC ethics and consenting process, designed in partnership with an active PPI advisory group, enables patients to choose the level of research participation that suits them.The BHC research database and associated information governance will facilitate research use of real-world clinical information where consent is given.The Oxford BHC pilot required that patients were not contraindicated for MRI. Future work to expand the model will remove this constraint.
The Oxford Brain Health Clinic (BHC) is a joint clinical-research service that provides memory clinic patients and clinicians access to high-quality assessments not routinely available, including brain MRI aligned with the UK Biobank imaging study (UKB). In this work we present how we 1) adapted the UKB MRI acquisition protocol to be suitable for memory clinic patients, 2) modified the imaging analysis pipeline to extract measures that are in line with radiology reports and 3) compared measures from BHC patients to the largest brain MRI study in the world (ultimately 100,000 participants). Adaptations of the UKB acquisition protocol for BHC patients include dividing the scan into core and optional sequences (i.e., additional imaging modalities) to improve patients' tolerance for the MRI assessment. We adapted the UKB structural MRI analysis pipeline to take into account the characteristics of a memory clinic population (e.g., high amount of white matter hyperintensities and hippocampal atrophy). We then compared the imaging derived phenotypes (IDPs) extracted from the structural scans to visual ratings from radiology reports, non-imaging factors (age, cognition) and to reference distributions derived from UKB data. Of the first 108 BHC attendees (August 2020-November 2021), 92.5% completed the clinical scans, 88.0% consented to use of data for research, and 48.1% completed at least one additional research sequence, demonstrating that the protocol is well tolerated. The high rates of consent to research makes this a unique real-world quality research dataset routinely captured in a clinical service. Modified tissue-type segmentation with lesion masking greatly improved grey matter volume estimation. CSF-masking marginally improved hippocampal segmentation. The IDPs were in line with radiology reports and showed significant associations with age and cognitive performance, in line with the literature. Due to the age difference between memory clinic patients of the BHC (age range 65-101 years, average 78.3 years) and UKB participants (44-82 years, average 64 years), additional scans on elderly healthy controls are needed to improve reference distributions. Current and future work aims to integrate automated quantitative measures in the radiology reports and evaluate their clinical utility.
IntroductionDespite major advances in the field of neuroscience over the last three decades, the quality of assessments available to patients with memory problems in later life has barely changed. At the same time, a large proportion of dementia biomarker research is conducted in selected research samples that often poorly reflect the demographics of the population of patients who present to memory clinics. The Oxford Brain Health Clinic (BHC) is a newly developed clinical assessment service with embedded research in which all patients are offered high-quality clinical and research assessments, including MRI, as standard.Methods and analysisHere we describe the BHC protocol, including aligning our MRI scans with those collected in the UK Biobank. We evaluate rates of research consent for the first 108 patients (data collection ongoing) and the ability of typical psychiatry-led NHS memory-clinic patients to tolerate both clinical and research assessments.Ethics and disseminationOur ethics and consenting process enables patients to choose the level of research participation that suits them. This generates high rates of consent, enabling us to populate a research database with high-quality data that will be disseminated through a national platform (the Dementias Platform UK data portal).
BackgroundThe Oxford Brain Health Centre (BHC) provides real‐world research data, aligned with the UK Biobank imaging study (UKB), routinely captured in a clinical service from patients under‐represented in dementia research. In this work we present how we 1) adapted the UKB MRI acquisition protocol to be suitable for memory clinic patients, 2) modified the imaging analysis pipeline to extract measures that are in line with radiology reports and 3) compare measures from BHC patients to the biggest brain MRI study in the world (ultimately 100,000 participants).MethodAdaptations of the UKB acquisition protocol for BHC patients include dividing the scan into core and optional sequences to improve patients’ tolerance. We adapted the UKB structural MRI analysis pipeline to extract quantitative measures from the scans, taking into account the characteristics of a memory clinic population (e.g. high level of white matter hyperintensities, WMH, causing misclassifications in tissue‐type segmentation). We compared the measurements extracted from the scans to visual ratings from radiology reports and to reference distributions derived from UKB data.ResultOf the 108 BHC attendees since August 2020 (average age 78.5 years, range 65‐101 years, 50.9% female), 100 (92.6%) completed the clinical scans, 100 (92.6%) consented to use of data for research, and 69 (63.9%) consented to additional research sequences, demonstrating that the protocol is well tolerated. Modified tissue‐type segmentation improved grey matter volume estimation, which showed stronger correlation with visual ratings of global atrophy after correction (r=‐0.34; p=0.001) than with the original analysis pipeline (r=‐0.31; p=0.002). Correlations between hippocampal volumes and MTA scale (r(L)=‐0.59, r(R)=‐0.71) and between WMH volume and Fazekas scale (r=0.78) were also significant (p<0.001). Because UKB participants are younger than memory clinic patients, additional scans on elderly healthy controls are planned to improve reference distributions to detect pathological deviations. Measures from BHC patients within UKB age range are comparable to those from UKB participants, with several patients falling in the lower percentiles.ConclusionWe adapted UKB research imaging for clinical practice. Current and future work aims to integrate automated quantitative measures in the radiology reports and evaluate their clinical utility.
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