Lasse Melvaer Giil

Autoantibodies Toward the Angiotensin 2 Type 1 Receptor: A Novel Autoantibody in Alzheimer's Disease

BACKGROUND Autoantibodies with agonist function are described in cardiovascular disorders. Since vascular risk factors are associated with an increased risk for Alzheimers disease (AD), we investigated a potential association between antibodies to the angiotensin 2 type 1 receptor (anti-AT1R) and AD. OBJECTIVE The primary objective of this study was to investigate the association between anti-AT1R and AD. The secondary objective was to investigate the association between clinical or biomarker features of AD and anti-AT1R. METHODS Samples from patients with mild AD participating in a longitudinal study in Western Norway (n = 92, 65 [71%] females, mean age 74.8 [range 50-89]) and age- and gender-matched healthy controls (n = 102) were included. Cerebrospinal fluid (CSF) AD biomarkers were assessed in a subgroup of patients. Patients were examined annually, including Mini-Mental State Examination. ELISA was used to measure anti-AT1R in serum. Non-parametric tests were used for statistical calculations and a p <  0.05 was considered significant. RESULTS AD patients had significantly higher levels of anti-AT1R compared with healthy controls (10.2 U/mL versus 8.1 U/mL, p = 0.04). This difference was found only in patients without hypertension and diabetes. Anti-AT1R levels correlated with CSF total tau (p = 0.03) and phosphorylated tau (p = 0.03) levels, and inversely with blood pressure in AD (Spearman R -0.277, p = 0.008). DISCUSSION AD is associated with increased levels of anti-AT1R, and the antibodies correlated with CSF total, and phosphorylated tau levels. Further research is needed to understand the blood pressure response in AD without hypertension and a potential link between tau and anti-AT1R in AD.

Antibodies to receptors are associated with biomarkers of inflammation and myocardial damage in heart failure

INTRODUCTION Naturally occurring antibodies are linked to inflammation, tissue injury and apoptosis, processes also linked to heart failure. Associations between antibodies, inflammation and myocardial damage, have not been elucidated in heart failure. OBJECTIVE We investigated if 25 antibodies to receptors expressed in the cardiovascular system were associated with troponin-T, biomarkers of inflammation and clinical measures of disease severity, in patients with heart failure. METHODS Antibodies in sera from patients (n=191) with ischemic (n=155) or non-ischemic (n=36) heart failure were measured with full-receptor sandwich enzyme-linked immunosorbent assays. All patients underwent coronary angiography with determination of left ventricular ejection fraction (LVEF) and left ventricular end-diastolic pressure (LVEDP). Measured biomarkers included troponin-T, C-reactive protein, erythrocyte sedimentation rate, fibrinogen and neopterin. RESULTS Stabilin-1-antibodies correlated with troponin-T (β 0.23 p=0.008), soluble endoglin-antibodies with erythrocyte sedimentation rate (β 0.19, p=0.007) and fibrinogen (β 0.28, p<0.001). Platelet-derived growth factor subunit β-antibodies were associated with neopterin (β 0.17, p=0.002). All antibodies were correlated (R 0.26 to 0.91) and formed 4 principal components (PCs). Patients with high CRP and high PC2 had higher NYHA class and patients with high troponin-T and high PC1 had lower LVEDP (interactions, all p<0.05). CONCLUSION Antibodies to receptors are correlated and are associated with biomarkers of inflammation and myocardial damage, which further modifies their association with disease severity in heart failure. Their functional activity and immunological function, remain undecided.

Antibodies to Signaling Molecules and Receptors in Alzheimer’s Disease are Associated with Psychomotor Slowing, Depression, and Poor Visuospatial Function

BACKGROUND Alzheimers disease (AD) is associated with several antibodies as well as signaling molecules and receptors. These may be detrimental in the presence of a disrupted blood-brain barrier (BBB). OBJECTIVE To investigate whether the levels of antibodies toward 33 signaling molecules involved in neurotransmitter, vascular, and immune functions were associated with AD and, within the AD group; cognitive function and mood. METHODS Antibodies in sera from patients with mild AD [(n = 91) defined as a Mini-Mental State Examination ≥ 20 or a Clinical Dementia Rating Scale≤1] and healthy controls (n = 102) were measured with enzyme-linked immunosorbent assays. Levels in AD and controls were compared by Mann-Whitney test. In the AD group, associations between antibodies and psychometric test scores were analyzed by robust regression. The false discovery threshold was set to 0.05. RESULTS Antibodies to serotonin receptors [5-HT2AR (effect size (r) = 0.21, p = 0.004), 5-HT2CR (r = 0.25, p = 0.0005) and 5-HT7R (r = 0.21, p = 0.003)], vascular endothelial growth factor receptor 1 [VEGFR1 (r = 0.29, p < 0.001)] and immune-receptors (Stabilin-1 (r = 0.23, p = 0.001) and C5aR1 (r = 0.21, p = 0.004) were higher in AD. Psychomotor speed was associated with D1R-abs (β 0.49, p < 0.001), depression with ETAR-abs (β 0.31, p < 0.001), and visuospatial function with 5-HT1AR-abs (β 0.27, p = 0.004) despite similar antibody levels compared to controls. CONCLUSIONS Antibody levels to VEGFR1, serotonergic receptors, and receptors in the immune system were increased in AD. Antibodies at similar levels as in controls were associated cognitive dysfunction and depression in AD.

Severe extremity amputations in surviving Palestinian civilians caused by explosives fired from drones during the Gaza War

BACKGROUND During four separate Israeli military attacks on Gaza (2006, 2009, 2012, and 2014), about 4000 Palestinians were killed and more than 17 000 injured (412 killed and 1264 injured in 2006; 1383 killed and more than 5300 injured in 2009; 130 killed and 1399 injured in 2012; and 2251 killed and 11 231 injured in 2014). An unknown number of people had traumatic amputations of one or more extremities. Use of unmanned Israeli drones for surveillance and armed attacks on Gaza was evident, but exact figures on numbers of drone strikes on Gaza are not available. The aim of this study was to explore the medical consequences of strikes on Gaza with different weapons, including drones. METHODS We studied a cohort of civilians in the Gaza Strip who had one of more traumatic limb amputation during the Israeli military attacks between 2006 and 2016. The study was done at The Artificial Limb and Polio Center (ALPC) in the Gaza Strip where most patients are treated and trained after amputation. We used standardised forms and validated instruments to record date and mechanism of injury, self-assessed health, socioeconomic status, anatomical location and length of amputation, comorbidity, and the results of a detailed clinical examination. FINDINGS The studied cohort consisted of 254 Paletinian civilians (234 [92%] men, 20 [8%] women, and 43 [17%] children aged 18 years and younger) with traumatic amputations caused by different weapons. 216 (85%) people had amputations proximal to wrist or ankle, 131 (52%) patients had more than one major amputation or an amputation above the knee, or both, and 136 (54%) people were injured in attacks with Israeli drones, including eight (40%) of the women. The most severe amputations were caused by drone attacks (p=0·0001). Extremity injuries after drone attacks led to immediate amputation more often than with other weapons (p=0·014). Patients injured during cease-fire periods were younger than patients injured during periods of declared Israeli military operations (p=0·0001). INTERPRETATION Weapons fired on the Gaza Strip from Israeli drones caused severe injuries in surviving Palestinian civilians. Drone-fired missiles resulted in major amputations in almost all victims who had limb losses. Substantially more severe injuries were inflicted by the drone-launched explosives than by other weapons used during the Gaza War. Traumatic amputations caused by drones were often immediately complete. One limitation of our study is that it does not elucidate injury patterns in victims with fatal injuries. FUNDING None.

Reduced Walking Speed in Subjective and Mild Cognitive Impairment: A Cross-sectional Study

Supplemental Digital Content is Available in the Text. Background and Purpose: Walking speed is reduced in people with dementia, but less is known about predementia conditions. We, therefore, studied the relationship between walking speed, cognition, and cerebrospinal fluid biomarkers in persons with subjective (SCI) and mild cognitive impairment (MCI). Methods: We conducted a cross-sectional study of 22 healthy controls, 30 SCI and 17 MCI (N = 69). Walking speed was measured by a 10-m gait test at usual and fast pace. We analyzed the association between walking speed and the ordered categories of controls, SCI, and MCI in a generalized proportional odds model. Neuropsychological tests, Consortium to Establish a Registry for Alzheimers Disease (delayed recall), and Trail Making (TMT) A and B, were analyzed by negative binomial, linear, and robust regression for association with walking speed. Results: Walking speed at usual pace was slower moving from controls to SCI (odds ratio: 0.46, P = 0.031) and MCI (odds ratio: 0.44, P = .019) on an ordinal scale. In MCI, walking speed was reduced at fast speed (odds ratio: 0.46, P = 0.04). There were significant associations between walking speeds and neuropsychological test performance. Usual walking speed was associated with slower test performance on TMT-A (β: −.02, P = .04) and fast pace with slower performance on TMT-B (β: −.01, P = .03). There were no associations between cerebrospinal fluid biomarkers and walking speeds. Conclusion: Usual walking speed is reduced in a graded fashion with the early symptoms of cognitive impairment. Our results suggest that reduced walking speed at both usual and fast speed is associated with impaired cognitive function, and that walking speed could be affected at very early stages of neurodegeneration.

Course of neuropsychiatric symptoms in dementia: 5-year longitudinal study

Neuropsychiatric symptoms (NPS) in dementia are frequent and challenging for patients, carers, and the health care system, but few long‐term studies exist. We analyse the longitudinal course of NPS in patients with mild dementia.

Reduced glucose transporter-1 in brain derived circulating endothelial cells in mild Alzheimer’s disease patients

Patients with Alzheimers disease (AD) have blood-brain barrier (BBB) dysfunction. Methods to study cells of the BBB in vivo would facilitate analyses of neurovascular damage in early AD. Thus, we conducted a pilot study to investigate if brain-derived endothelial cells (BDCECs) could be identified from a cell population of circulating endothelial cells (CECs). Peripheral blood was sampled from early AD patients (n = 9), patients with vascular diseases (myocardial infarction (n = 8) and ischemic stroke (n = 8)), and healthy controls (n = 8). We enumerated CD34+/CD146+/CD45- cells (CECs) and Glucose transporter-1 (Glut1+ CECs (BDCECs)) by flow cytometry. We found that BDCECs formed a separate, aggregate cell population. Glut1 expression on BDCECs, measured by the median fluorescence intensity, was significantly decreased in patients with AD compared to both the healthy controls and patients with myocardial infarction ((p < .05, Kruskal-Wallis, Dunns post hoc test). We found no significant differences in cell numbers. Our study shows that isolation of BDCECs offers a promising non-invasive tool to investigate cells derived from the BBB. Downregulation of Glut1 at the mild stages of AD suggests that agents that increase Glut1 levels may be therapeutic candidates to improve energy availability to the brain.

VASCULAR AUTOANTIBODIES IN ALZHEIMER'S DISEASE: AN UNEXPLORED DISEASE MEDIATOR?

Background: From a clinical and public health perspective there is an urgency to identify blood based biomarkers for Alzheimer’s disease(AD). A recent study by Mapstone et al. (Nature Medicine 2014) identified 8 metabolites associated to AD/amnestic Mild Cognitive Impairment (aMCI) in blood plasma and 10 metabolites that predicted development of amnestic mild cognitive impairment with over 90% accuracy. A question that remains to be answered is whether these lipids are associated to the genes implicated in AD.Methods: The study was conducted in the Erasmus Rucphen Family (ERF) Study, a family based population not selected based on AD or any other disease. Subjects were extensively phenotyped using three metabolite platforms; the AbsoluteIDQTM p150 Kit of Biocrates Life Sciences AG (N1⁄4992), nuclear magnetic resonance spectroscopy(N1⁄42416) and liquid chromatography-mass spectrometry(N1⁄42592). We associated 15 out of 18 metabolites reported by Mapstone et al. with the 23 common and relatively rare genetic variants implicated in AD. We used linear-mixed models to adjust for familial relations, age and gender. Bonferroni adjustment was performed to adjust for multiple testing. Results: Carriers of the APOE-ε4 variant had lower levels of lysine(p-value1⁄44.25310 -3). Also acylcarnitine C7 levels in blood cluster with APOE-ε4 and lysine. These findings are line with that of Mapstone et al. and others reporting significant alterations in the lysine pathway in plasma of MCI/AD patients. Lysine is required for the synthesis of L-carnitine, the transporter of fatty acids to mitochondria. Decreased levels of L-carnitine have been found in CSF from AD patients. In our ERF samples, in linewith that ofMapstone et al. plasma proline levels were significantly lower in carriers of the PLD3(Val232Met) variant, which like APOE-ε4 is associated with a substantial increased AD risk. PLD3(Val232Met) was further associated with various phosphatidylcholines. Proline has been proposed to stabilize cell membranes by interacting with phospholipids in membranes. Conclusions: Our findings indicate that various metabolites associated to AD are determined in part by AD genes that convey a substantial increase risk in AD. Our findings suggest that blood-based biomarkers may represent etiological pathways relevant to AD and may in the future be useful for risk prediction and monitoring of treatment.