Overview
The goal of this observational study is to study whether major surgery is linked to changes in the brain that are typical of Alzheimer's disease.
The study is a prospective observational study that will be carried out in Uppsala University Hospital. Adults aged 55-75 years who are healthy otherwise American Society of Anesthesiologists (ASA) 1-2 having a hip or knee replacement under spinal anesthesia, and a comparison group of people of the same age and sex with hip or knee arthrosis who are not having surgery will be included.
The main questions it aims to answer are:
- Does the amount of the protein tau in the brain increase in the two years after surgery?
- Are changes in tau linked to inflammation in the blood and spinal fluid, and to changes in memory and thinking?
Participants will:
- Have brain scans with positron emission tomography (PET) and magnetic resonance imaging (MRI) scans before surgery and 12 and 24 months later
- Give small samples of spinal fluid and blood
- Complete memory and thinking tests at the same time points
Researchers will compare the surgery group with the non-surgery group to see whether surgery is associated with more tau in the brain and with changes in memory and thinking.
Description
Background: Postoperative neurocognitive decline is common in older surgical patients and has been associated with an increased risk of later dementia. Experimental studies show that surgery and anesthesia can trigger neuroinflammation, tau phosphorylation and tau aggregation, and clinical studies have shown acute increases in cerebrospinal fluid (CSF) and blood markers of neuronal injury (tau, neurofilament light) after surgery. Whether surgery leads to increased tau pathology in the human brain is unknown.
Aims: To translate preclinical findings of surgery-induced tau pathology to surgical patients by (A) mapping individual brain tau trajectories, cognitive function and biomarkers of neurodegeneration and brain injury during 24 months after surgery compared with matched non-surgical controls, and (B) linking individual patterns of inflammatory and neurodegenerative biomarkers and immune cell phenotypes to tau pathology and neurocognitive outcomes using pattern-recognition analysis.
Design: Prospective, longitudinal observational cohort study at Uppsala University Hospital, Sweden. A surgical cohort (n=20) undergoing elective hip or knee arthroplasty under spinal anesthesia is compared with a non-surgical control cohort (n=10) with hip or knee arthrosis, matched by age and sex. Participants are aged 55-75 years, ASA physical status 1-2, with MMSE score of 23 or higher.
Methods: All assessments are performed at baseline (before surgery), and at 12 and 24 months after surgery, with corresponding time points in the control cohort.
- Tau PET imaging with the second-generation tracer \[18F\]RO948 on a simultaneous PET-MR camera. Tau burden is quantified as binding potential in automatically delineated cortical regions (FreeSurfer), with cerebellar cortex as reference region.
- Cognitive assessment with the Neuropsychological Test Battery (NTB; composite z-score and the domains memory, psychomotor speed and executive function) and the Clinical Dementia Rating scale (CDR).
- CSF (4 mL) collected by spinal puncture; at baseline this is done in connection with the spinal anesthesia, before injection of the anesthetic.
- Venous blood samples (25 mL) for plasma, serum and immune cell phenotyping by flow cytometry.
- Biomarkers: Neurofilament light chain (NfL), tau and Glial fibrillary acidic protein (GFAP) by Simoa, and broad inflammatory and glial protein panels by proximity extension assay (Olink).
Analysis: Mixed models and multivariate methods (e.g. principal component analysis) will be used to relate individual biomarker and immune cell trajectories to changes in brain tau burden and cognitive outcomes, and to compare the surgical and control cohorts.
Eligibility
Inclusion Criteria:
Surgical cohort:
- Age 55 to 75 years
- ASA physical status class 1 or 2
- Scheduled for hip or knee arthroplasty under regional (spinal) anesthesia at Uppsala University Hospital
- Written informed consent
Non-surgical control cohort:
- Age 55 to 75 years
- ASA physical status class 1 or 2
- Hip or knee osteoarthritis, recruited from the orthopedic outpatient clinic at Uppsala University Hospital
- Not scheduled for surgery
- Written informed consent
Exclusion Criteria:
Exclusion Criteria (both cohorts):
- Mini-Mental State Examination (MMSE) score below 23
- History of systemic inflammatory disorder
- Advanced cardiopulmonary disease
