Neuroinflammation in Lyme neuroborreliosis affects amyloid metabolism

<p>Abstract</p> <p>Background</p> <p>The metabolism of amyloid precursor protein (APP) and β-amyloid (Aβ) is widely studied in Alzheimer's disease, where Aβ deposition and plaque development are essential components of the pathogenesis. However, the physiological role of amyloid in the adult nervous system remains largely unknown. We have previously found altered cerebral amyloid metabolism in other neuroinflammatory conditions. To further elucidate this, we investigated amyloid metabolism in patients with Lyme neuroborreliosis (LNB).</p> <p>Methods</p> <p>The first part of the study was a cross-sectional cohort study in 61 patients with acute facial palsy (19 with LNB and 42 with idiopathic facial paresis, Bell's palsy) and 22 healthy controls. CSF was analysed for the β-amyloid peptides Aβ38, Aβ40 and Aβ42, and the amyloid precursor protein (APP) isoforms α-sAPP and β-sAPP. CSF total-tau (T-tau), phosphorylated tau (P-tau) and neurofilament protein (NFL) were measured to monitor neural cell damage. The second part of the study was a prospective cohort-study in 26 LNB patients undergoing consecutive lumbar punctures before and after antibiotic treatment to study time-dependent dynamics of the biomarkers.</p> <p>Results</p> <p>In the cross-sectional study, LNB patients had lower levels of CSF α-sAPP, β-sAPP and P-tau, and higher levels of CSF NFL than healthy controls and patients with Bell's palsy. In the prospective study, LNB patients had low levels of CSF α-sAPP, β-sAPP and P-tau at baseline, which all increased towards normal at follow-up.</p> <p>Conclusions</p> <p>Amyloid metabolism is altered in LNB. CSF levels of α-sAPP, β-sAPP and P-tau are decreased in acute infection and increase after treatment. In combination with earlier findings in multiple sclerosis, cerebral SLE and HIV with cerebral engagement, this points to an influence of neuroinflammation on amyloid metabolism.</p

Correction to: Relevance of biomarkers across different neurodegenerative diseases

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Associations among amyloid status, age, and longitudinal regional brain atrophy in cognitively unimpaired older adults.

The goal of this study was to compare regional brain atrophy patterns in cognitively unimpaired (CU) older adults with and without brain accumulation of amyloid-β (Aβ) to elucidate contributions of Aβ, age, and other variables to atrophy rates. In 80 CU participants from the Alzheimer's Disease Neuroimaging Initiative, we determined effects of Aβ and age on longitudinal, regional atrophy rates, while accounting for confounding variables including sex, APOE ε4 genotype, white matter lesions, and cerebrospinal fluid total and phosphorylated tau levels. We not only found overlapping patterns of atrophy in Aβ+ versus Aβ- participants but also identified regions where atrophy pattern differed between the 2 groups. Higher Aβ load was associated with increased longitudinal atrophy in the entorhinal cortex, amygdala, and hippocampus, even when accounting for age and other variables. Age was associated with atrophy in insula, fusiform gyrus, and isthmus cingulate, even when accounting for Aβ. We found age by Aβ interactions in the postcentral gyrus and lateral orbitofrontal cortex. These results elucidate the separate and related effects of age, Aβ, and other important variables on longitudinal brain atrophy rates in CU older adults

Serum but not cerebrospinal fluid levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) are increased in Alzheimer's disease

Background: Although insulin-like growth factor-I (IGF-I) is of importance for the adult function of the central nervous system (CNS), little is known of the significance of IGF-I in cerebrospinal fluid (CSF) in relation to Alzheimer's disease (AD). Methods: A cross-sectional study of 60 consecutive patients under primary evaluation of cognitive impairment and 20 healthy controls. The patients had AD dementia or mild cognitive impairment (MCI) diagnosed with AD dementia upon follow-up (n = 32), stable MCI (SMCI, n = 13), or other dementias (n = 15). IGF-I, IGF-binding protein-3 (IGFBP-3), and insulin were measured in serum and CSF. Results: Serum IGF-I level was increased in AD patients and in patients with other dementias compared to healthy controls (P = 0.01 and P < 0.05, respectively). Serum IGFBP-3 concentration was increased in AD and SMCI patients compared to controls (P = 0.001 and P < 0.05, respectively). CSF levels of IGF-I and IGFBP-3 as well as serum and CSF levels of insulin were similar in all study groups. In the total study population (n = 80), serum levels of IGF-I and IGFBP-3 correlated negatively with CSF beta-amyloid(1-42) (A beta(1-42)) level (r = -0.29, P = 0.01 and r = -0.27, P = 0.02, respectively) and in the AD patients (n = 32), the increased CSF/serum IGF-I ratio correlated positively with the CSF level of phosphorylated tau protein (P-tau; r = 0.42, P = 0.02). Conclusion: Patients with AD as well as other dementias had high levels of IGF-I in serum but not in CSF. In AD patients, the IGF-I system was associated with biomarkers of AD disease status. (C) 2013 Elsevier Ltd. All rights reserved

Ex vivo 18O-labeling mass spectrometry identifies a peripheral amyloid β clearance pathway

Background: Proteolytic degradation of amyloid β (Aβ) peptides has been intensely studied due to the central role of Aβ in Alzheimer’s disease (AD) pathogenesis. While several enzymes have been shown to degrade Aβ peptides, the main pathway of Aβ degradation in vivo is unknown. Cerebrospinal fluid (CSF) Aβ42 is reduced in AD, reflecting aggregation and deposition in the brain, but low CSF Aβ42 is, for unknown reasons, also found in some inflammatory brain disorders such as bacterial meningitis. Method: Using 18O-labeling mass spectrometry and immune-affinity purification, we examined endogenous proteolytic processing of Aβ in human CSF. Results: The Aβ peptide profile was stable in CSF samples from healthy controls but in CSF samples from patients with bacterial meningitis, showing increased leukocyte cell count, 18O-labeling mass spectrometry identified proteolytic activities degrading Aβ into several short fragments, including abundant Aβ1-19 and 1-20. After antibiotic treatment, no degradation of Aβ was detected. In vitro experiments located the source of the proteolytic activity to blood components, including leukocytes and erythrocytes, with insulin-degrading enzyme as the likely protease. A recombinant version of the mid-domain anti-Aβ antibody solanezumab was found to inhibit insulin-degrading enzyme-mediated Aβ degradation. Conclusion: 18O labeling-mass spectrometry can be used to detect endogenous proteolytic activity in human CSF. Using this technique, we found an enzymatic activity that was identified as insulin-degrading enzyme that cleaves Aβ in the mid-domain of the peptide, and could be inhibited by a recombinant version of the mid-domain anti-Aβ antibody solanezumab

Cerebrospinal fluid CXCL13 in Lyme neuroborreliosis and asymptomatic HIV infection

<p>Abstract</p> <p>Background</p> <p>It has been suggested that cerebrospinal fluid (CSF) CXCL13 is a diagnostic marker of Lyme neuroborreliosis (LNB), as its levels have been shown to be significantly higher in LNB than in several other CNS infections. Levels have also been shown to decline after treatment with intravenous ceftriaxone, but levels after treatment with oral doxycycline have previously not been studied. Like <it>Borrelia burgdorferi</it>, HIV also has neurotropic properties. Elevated serum CXCL13 concentrations have been reported in HIV patients, but data on CSF levels are limited.</p> <p>Methods</p> <p>We longitudinally analysed CSF CXCL13 concentrations in 25 LNB patients before and after oral doxycycline treatment. Furthermore, we analysed CSF CXCL13 concentrations in 16 untreated LNB patients, 27 asymptomatic untreated HIV-1 infected patients and 39 controls with no signs of infectious or inflammatory disease.</p> <p>Results</p> <p>In the longitudinal LNB study, initially high CSF CXCL13 levels declined significantly after doxycycline treatment, which correlated to a decreased CSF mononuclear cell count. In the cross-sectional study, all the LNB patients had CSF CXCL13 levels elevated above the lowest standard point of the assay (7.8 pg/mL), with a median concentration of 500 pg/mL (range 34–11,678). Of the HIV patients, 52% had elevated CSF CXCL13 levels (median 10 pg/mL, range 0–498). There was a clear overlap in CSF CXCL13 concentrations between LNB patients and asymptomatic HIV patients. All but one of the 39 controls had CSF CXCL13 levels below 7.8 pg/mL.</p> <p>Conclusions</p> <p>We confirm previous reports of highly elevated CSF CXCL13 levels in LNB patients and that these levels decline after oral doxycycline treatment. The same pattern is seen for CSF mononuclear cells. CSF CXCL13 levels are elevated in neurologically asymptomatic HIV patients and the levels overlap those of LNB patients. The diagnostic value of CSF CXCL13 in LNB remains to be established.</p

Comparing ATN-T designation by tau PET visual reads, tau PET quantification, and CSF PTau181 across three cohorts.

PurposeTo compare rates of tau biomarker positivity (T-status) per the 2018 Alzheimer's Disease (AD) Research Framework derived from [18F]flortaucipir (FTP) PET visual assessment, FTP quantification, and cerebrospinal fluid (CSF) phosphorylated Tau-181 (PTau181).MethodsWe included 351 subjects with varying clinical diagnoses from three cohorts with available FTP PET and CSF PTau181 within 18&nbsp;months. T-status was derived from (1) FTP visual assessment by two blinded raters; (2) FTP standardized uptake value ratio (SUVR) quantification from a temporal meta-ROI (threshold: SUVR ≥1.27); and (3) Elecsys® Phospho-Tau (181P) CSF (Roche Diagnostics) concentrations (threshold: PTau181 ≥ 24.5&nbsp;pg/mL).ResultsFTP visual reads yielded the highest rates of T+, while T+ by SUVR increased progressively from cognitively normal (CN) through mild cognitive impairment (MCI) and AD dementia. T+ designation by CSF PTau181 was intermediate between FTP visual reads and SUVR values in CN, similar to SUVR in MCI, and lower in AD dementia. Concordance in T-status between modality pairs ranged from 68 to 76% and varied by clinical diagnosis, being highest in patients with AD dementia. In discriminating Aβ + MCI and AD subjects from healthy controls and non-AD participants, FTP visual assessment was most sensitive (0.96) but least specific (0.60). Specificity was highest with FTP SUVR (0.91) with sensitivity of 0.89. Sensitivity (0.73) and specificity (0.72) were balanced for PTau181.ConclusionThe choice of tau biomarker may differ by disease stage and research goals that seek to maximize sensitivity or specificity. Visual interpretations of tau PET enhance sensitivity compared to quantification alone, particularly in early disease stages

Relevance of biomarkers across different neurodegenerative diseases

Abstract: Background: The panel of fluid- and imaging-based biomarkers available for neurodegenerative disease research is growing and has the potential to close important gaps in research and the clinic. With this growth and increasing use, appropriate implementation and interpretation are paramount. Various biomarkers feature nuanced differences in strengths, limitations, and biases that must be considered when investigating disease etiology and clinical utility. For example, neuropathological investigations of Alzheimer’s disease pathogenesis can fall in disagreement with conclusions reached by biomarker-based investigations. Considering the varied strengths, limitations, and biases of different research methodologies and approaches may help harmonize disciplines within the neurodegenerative disease field. Purpose of review: Along with separate review articles covering fluid and imaging biomarkers in this issue of Alzheimer’s Research and Therapy, we present the result of a discussion from the 2019 Biomarkers in Neurodegenerative Diseases course at the University College London. Here, we discuss themes of biomarker use in neurodegenerative disease research, commenting on appropriate use, interpretation, and considerations for implementation across different neurodegenerative diseases. We also draw attention to areas where biomarker use can be combined with other disciplines to understand issues of pathophysiology and etiology underlying dementia. Lastly, we highlight novel modalities that have been proposed in the landscape of neurodegenerative disease research and care