Cerebrospinal Fluid Concentration of Neurogranin in Hip Fracture Patients with Delirium

BACKGROUND: Delirium is associated with an increased risk of incident dementia and accelerated progression of existing cognitive symptoms. Reciprocally, dementia increases the risk of delirium. Cerebrospinal fluid (CSF) concentration of the dendritic protein neurogranin has been shown to increase in early Alzheimer's disease (AD), likely reflecting synaptic dysfunction and/or degeneration. OBJECTIVE: To elucidate the involvement of synaptic dysfunction in delirium pathophysiology, we tested the association between CSF neurogranin concentration and delirium in hip fracture patients with different AD-biomarker profiles, while comparing them to cognitively unimpaired older adults (CUA) and AD patients. METHODS: The cohort included hip fracture patients with (n = 70) and without delirium (n = 58), CUA undergoing elective surgery (n = 127), and AD patients (n = 46). CSF was collected preoperatively and diagnostically in surgery and AD patients respectively. CSF neurogranin concentrations were analyzed in all samples with an in-house ELISA. Delirium was assessed pre-and postoperatively in hip fracture patients by trained investigators using the Confusion Assessment Method. Hip fracture patients were further stratified based on pre-fracture dementia status, delirium subtype, and AD fluid biomarkers. RESULTS: No association was found between delirium and CSF neurogranin concentration (main analysis: delirium versus no delirium, p = 0.68). Hip fracture patients had lower CSF neurogranin concentration than AD patients (p = 0.001) and CUA (p = 0.035) in age-adjusted sensitivity analyses. CONCLUSION: The findings suggest that delirium is not associated with increased CSF neurogranin concentration in hip fracture patients, possibly due to advanced neurodegenerative disease and age and/or because synaptic degeneration is not an important pathophysiological process in delirium

Relationship between cerebrospinal fluid neurodegeneration biomarkers and temporal brain atrophy in cognitively healthy older adults

It is unclear whether cerebrospinal fluid (CSF) biomarkers of neurodegeneration predict brain atrophy in cognitively healthy older adults, whether these associations can be explained by phosphorylated tau181 (p-tau) and the 42 amino acid form of amyloid-ꞵ (Aꞵ42) biomarkers, and which neural substrates may drive these associations. We addressed these questions in two samples of cognitively healthy older adults who underwent longitudinal structural MRI up to 7 years and had baseline CSF levels of heart-type fatty-acid binding protein [FABP3], total-tau, neurogranin, and neurofilament light [NFL] (n=189, scans=721). The results showed that NFL, total-tau, and FABP3 predicted entorhinal thinning and hippocampal atrophy. Brain atrophy was not moderated by Aꞵ42 and the associations between NFL and FABP3 with brain atrophy were independent of p-tau. The spatial pattern of cortical atrophy associated with the biomarkers overlapped with neurogenetic profiles associated with expression in the axonal (total-tau, NFL) and dendritic (neurogranin) components. CSF biomarkers of neurodegeneration are useful for predicting specific features of brain atrophy in older adults, independently of amyloid and tau pathology biomarkers

Neurofilament Light in Serum and Cerebrospinal Fluid of Hip Fracture Patients with Delirium

BACKGROUND: Delirium is associated with new-onset dementia, suggesting that delirium pathophysiology involves neuronal injury. Neurofilament light (NFL) is a sensitive biomarker for neuroaxonal injury. METHODS: NFL was measured in cerebrospinal fluid (CSF) (n = 130), preoperative serum (n = 192), and postoperative serum (n = 280) in hip fracture patients, and in CSF (n = 123) and preoperative serum (n = 134) in cognitively normal older adults undergoing elective surgery. Delirium was diagnosed with the Confusion Assessment Method. RESULTS: Median serum NFL (pg/mL) was elevated in delirium in hip fracture patients (94 vs. 54 pre- and 135 vs. 92 postoperatively, both p < 0.001). Median CSF NFL tended to be higher in hip fracture patients with delirium (1,804 vs. 1,636, p = 0.074). Serum and CSF NFL were positively correlated (ρ = 0.56, p < 0.001). CONCLUSION: Our findings support an association between neuroaxonal injury and delirium. The correlation between serum and CSF NFL supports the use of NFL as a blood biomarker in future delirium studies

Increased leptin concentrations correlate with increased concentrations of inflammatory markers in morbidly obese individuals

OBJECTIVE: To study whether an increase of plasma leptin concentrations, as observed in the case of increased body weight, is associated with an inflammatory state. SUBJECTS: Sixty-three healthy subjects with body mass index (BMI) ranging from 20 to 61 kg/m2. MEASUREMENTS: Plasma concentrations of leptin, the inflammatory parameter soluble TNF-alpha receptors (TNFR55 and TNFR75), the acute phase proteins lipopolysaccharide binding protein (LBP), serum amyloid A (SAA), alpha-acid glycoprotein (AGP), C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1) and the anti-inflammatory soluble Interleukin-1 decoy receptor (sIL-1RII) were measured. RESULTS: As expected, BMI correlated significantly with leptin (r=0.823, P <0.001), but also with all acute phase proteins, both soluble TNF receptors and PAI concentrations. After correction for BMI and sex, no significant correlation between leptin and the acute phase proteins was seen. Interestingly, however, leptin strongly correlated with both TNF receptors (r=0.523, P <0.001 for TNFR55 and r=0.438, P <0.001 for TNFR75). CONCLUSIONS: This study shows the development of a pro-inflammatory state with increasing body weight. The BMI independent relationship between leptin and both soluble TNF-receptors is consistent with a regulatory role for leptin in the inflammatory state in morbidly obese subject