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Prognostic value of complementary biomarkers of neurodegeneration in a mixed memory clinic cohort.

ABSTRACT: Background:Biomarkers of neurodegeneration, e.g. MRI brain atrophy and [18F]FDG-PET hypometabolism, are often evaluated in patients suspected of neurodegenerative disease. Objective:Our primary objective was to investigate prognostic properties of atrophy and hypometabolism. Methods:From March 2015-June 2016, 149 patients referred to a university hospital memory clinic were included. The primary outcome was progression/stable disease course as assessed by a clinician at 12 months follow-up. Intracohort defined z-scores of baseline MRI automatic quantified volume and [18F]FDG-PET standardized uptake value ratios were calculated for all unilaterally defined brain lobes and dichotomized as pronounced atrophy (+A)/ pronounced hypometabolism (+H) at z-score <0. A logistic regression model with progression status as the outcome was carried out with number of lobes with the patterns +A/-H, -A/+H, +A/+H respectively as predictors. The model was mutually adjusted along with adjustment for age and sex. A sensitivity analysis with a z-score dichotomization at -0.1 and -0.5 and dichotomization regarding number of lobes affected at one and three lobes was done. Results:Median follow-up time was 420 days [IQR: 387-461 days] and 50 patients progressed. Patients with two or more lobes affected by the pattern +A/+H compared to patients with 0-1 lobes affected had a statistically significant increased risk of progression (odds ratio, 95 % confidence interval: 4.33, 1.90-9.86) in a multivariable model. The model was partially robust to the applied sensitivity analysis. Conclusion:Combined atrophy and hypometabolism as assessed by MRI and [18F]FDG-PET in patients under suspicion of neurodegenerative disease predicts progression over 1 year.

SUBMITTER: Gramkow MH

PROVIDER: S-EPMC7354835 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Prognostic value of complementary biomarkers of neurodegeneration in a mixed memory clinic cohort.

Gramkow Mathias Holsey MH Gjerum Le L Koikkalainen Juha J Lötjönen Jyrki J Law Ian I Hasselbalch Steen Gregers SG Waldemar Gunhild G Frederiksen Kristian Steen KS

PeerJ 20200709

<h4>Background</h4>Biomarkers of neurodegeneration, e.g. MRI brain atrophy and [<sup>18</sup>F]FDG-PET hypometabolism, are often evaluated in patients suspected of neurodegenerative disease.<h4>Objective</h4>Our primary objective was to investigate prognostic properties of atrophy and hypometabolism.<h4>Methods</h4>From March 2015-June 2016, 149 patients referred to a university hospital memory clinic were included. The primary outcome was progression/stable disease course as assessed by a clini ...[more]

PMID: 32714664

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Project description:Background and objectivesBlood-based biomarkers have emerged as minimally invasive options for evaluating cognitive impairment. Most studies to date have assessed them in research cohorts, limiting their generalization to everyday clinical practice. We evaluated their diagnostic performance and clinical applicability in a prospective, real-world, memory clinic cohort.MethodsAll patients referred with suspected cognitive impairment between July 2019 and June 2021 were prospectively invited to participate. Five plasma biomarkers (tau phosphorylated at threonine 181 [p-tau181], glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL], total tau [t-tau], and ubiquitin C-terminal hydrolase L1 [UCH-L1]) were determined with single-molecule array. Performance was assessed in comparison to clinical diagnosis (blinded to plasma results) and amyloid status (CSF/PET). A group of cognitively unimpaired (CU) controls was also included.ResultsThree hundred forty-nine participants (mean age 68, SD 8.3 years) and 36 CU controls (mean age 61.7, SD 8.2 years) were included. In the subcohort with available Alzheimer disease (AD) biomarkers (n = 268), plasma p-tau181 and GFAP had a high diagnostic accuracy to differentiate AD from non-neurodegenerative causes (area under the receiver operating characteristic curve 0.94 and 0.92, respectively), with p-tau181 systematically outperforming GFAP. Plasma p-tau181 levels predicted amyloid status (85% sensitivity and specificity) with accurate individual prediction in approximately 60% of the patients. Plasma NfL differentiated frontotemporal dementia (FTD) syndromes from CU (0.90) and non-neurodegenerative causes (0.93), whereas the discriminative capacity with AD and between all neurodegenerative and non-neurodegenerative causes was less accurate. A combination of p-tau181 and NfL identified FTD with 82% sensitivity and 85% specificity and had a negative predictive value for neurodegenerative diagnosis of 86%, ruling out half of the non-neurodegenerative diagnoses. In the subcohort without AD biomarkers, similar results were obtained. T-tau and UCH-L1 did not offer added diagnostic value.DiscussionPlasma p-tau181 predicted amyloid status with high accuracy and could have potentially avoided CSF/amyloid PET testing in approximately 60% of subjects in a memory clinic setting. NfL was useful for identifying FTD from non-neurodegenerative causes but behaved worse than p-tau181 in all other comparisons. Combining p-tau181 and NfL improved diagnostic performance for FTD and non-neurodegenerative diagnoses. However, the 14% false-negative results suggest that further improvement is needed before implementation outside memory clinics.Classification of evidenceThis study provides Class I evidence that plasma p-tau181 correlates with the presence or absence of AD and a combination of plasma p-tau181 and NfL correlates moderately well with a diagnosis of FTD.

Project description:Neurodegeneration occurs during the early stages of multiple sclerosis. It is an essential, devastating part of the pathophysiology. Tools for measuring the degree of neurodegeneration could improve diagnostics and patient characterization.This study aimed to determine the diagnostic value of biomarkers of degeneration in patients with recent clinical onset of suspected multiple sclerosis, and to evaluate these biomarkers for characterizing disease course.This cross-sectional study included 271 patients with clinical features of suspected multiple sclerosis onset and was the baseline of a prospective study. After diagnostic investigations, the patients were classified into the following disease groups: patients with clinically isolated syndrome (n = 4) or early relapsing remitting multiple sclerosis (early RRMS; n = 93); patients with relapsing remitting multiple sclerosis with disease durations ?2 years (established RRMS; n = 39); patients without multiple sclerosis, but showing symptoms (symptomatic controls; n = 89); and patients diagnosed with other diseases (n = 46). In addition, we included healthy controls (n = 51) and patients with progressive multiple sclerosis (n = 23). We analyzed six biomarkers of neurodegeneration: cerebrospinal fluid neurofilament light chain levels; cerebral spinal fluid glial fibrillary acidic protein; cerebral spinal fluid tau; retinal nerve fiber layer thickness; macula volume; and the brain parenchymal fraction.Except for increased cerebral spinal fluid neurofilament light chain levels, median 670 ng/L (IQR 400-2110), we could not find signs of early degeneration in the early disease group with recent clinical onset. However, the intrathecal immunoglobin G production and cerebral spinal fluid neurofilament light chain levels showed diagnostic value. Moreover, elevated levels of cerebral spinal fluid glial fibrillary acidic protein, thin retinal nerve fiber layers, and low brain parenchymal fractions were associated with progressive disease, but not with the other phenotypes. Thin retinal nerve fiber layers and low brain parenchymal fractions, which indicated neurodegeneration, were associated with longer disease duration.In clinically suspected multiple sclerosis, intrathecal immunoglobin G production and neurofilament light chain levels had diagnostic value. Therefore, these biomarkers could be included in diagnostic work-ups for multiple sclerosis. We found that the thickness of the retinal nerve fiber layer and the brain parenchymal fraction were not different between individuals that were healthy, symptomatic, or newly diagnosed with multiple sclerosis. This finding suggested that neurodegeneration had not reached a significant magnitude in patients with a recent clinical onset of multiple sclerosis.

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Prognostic value of complementary biomarkers of neurodegeneration in a mixed memory clinic cohort.

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Prognostic value of complementary biomarkers of neurodegeneration in a mixed memory clinic cohort.

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