Dataset Information

Antemortem CSF A?42/A?40 ratio predicts Alzheimer's disease pathology better than A?42 in rapidly progressive dementias.

ABSTRACT:

Objective

Despite the critical importance of pathologically confirmed samples for biomarker validation, only a few studies have correlated CSF A?42 values in vivo with postmortem Alzheimer's disease (AD) pathology, while none evaluated the CSF A?42/A?40 ratio. We compared CSF A?42 and A?42/A?40 ratio as biomarkers predicting AD neuropathological changes in patients with a short interval between lumbar puncture and death.

Methods

We measured CSF A?40 and A?42 and assessed AD pathology in 211 subjects with rapidly progressive dementia (RPD) and a definite postmortem diagnosis of Creutzfeldt-Jakob disease (n = 159), AD (n = 12), dementia with Lewy bodies (DLB, n = 4), AD/DLB mixed pathologies (n = 5), and various other pathologies (n = 31).

Results

The score reflecting the severity of A? pathology showed a better correlation with ln(A?42/A?40) (R ² = 0.506, ? = -0.713, P < 0.001) than with ln(A?42) (R ² = 0.206, ? = -0.458, P < 0.001), which was confirmed after adjusting for covariates. A?42/A?40 ratio showed significantly higher accuracy than A?42 in the distinction between cases with or without AD pathology (AUC 0.818 ± 0.028 vs. 0.643 ± 0.039), especially in patients with A?42 levels ?495 pg/mL (AUC 0.888 ± 0.032 vs. 0.518 ± 0.064). Using a cut-off value of 0.810, the analysis of A?42/A?40 ratio yielded 87.0% sensitivity, 88.2% specificity in the distinction between cases with an intermediate-high level of AD pathology and those with low level or no AD pathology.

Interpretation

The present data support the use of CSF A?42/A?40 ratio as a biomarker of AD pathophysiology and noninvasive screener for A? pathology burden, and its introduction in the research diagnostic criteria for AD.

SUBMITTER: Baiardi S

PROVIDER: S-EPMC6389744 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

Antemortem CSF A<i>β</i>42/A<i>β</i>40 ratio predicts Alzheimer's disease pathology better than A<i>β</i>42 in rapidly progressive dementias.

Baiardi Simone S Abu-Rumeileh Samir S Rossi Marcello M Zenesini Corrado C Bartoletti-Stella Anna A Polischi Barbara B Capellari Sabina S Parchi Piero P

Annals of clinical and translational neurology 20181214 2

<h4>Objective</h4>Despite the critical importance of pathologically confirmed samples for biomarker validation, only a few studies have correlated CSF A<i>β</i>42 values in vivo with postmortem Alzheimer's disease (AD) pathology, while none evaluated the CSF A<i>β</i>42/A<i>β</i>40 ratio. We compared CSF A<i>β</i>42 and A<i>β</i>42/A<i>β</i>40 ratio as biomarkers predicting AD neuropathological changes in patients with a short interval between lumbar puncture and death.<h4>Methods</h4>We measure ...[more]

PMID: 30847359

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Project description:ObjectiveThe diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) must be improved before widespread clinical use. This study aimed to determine whether CSF A?42/A?40 and A?42/A?38 ratios are better diagnostic biomarkers of AD during both predementia and dementia stages in comparison to CSF A?42 alone.MethodsThe study comprised three different cohorts (n = 1182) in whom CSF levels of A?42, A?40, and A?38 were assessed. CSF A?s were quantified using three different immunoassays (Euroimmun, Meso Scale Discovery, Quanterix). As reference standard, we used either amyloid ((18)F-flutemetamol) positron emission tomography (PET) imaging (n = 215) or clinical diagnosis (n = 967) of well-characterized patients.ResultsWhen using three different immunoassays in cases with subjective cognitive decline and mild cognitive impairment, the CSF A?42/A?40 and A?42/A?38 ratios were significantly better predictors of abnormal amyloid PET than CSF A?42. Lower A?42, A?42/A?40, and A?42/A?38 ratios, but not A?40 and A?38, correlated with smaller hippocampal volumes measured by magnetic resonance imaging. However, lower A?38, A?40, and A?42, but not the ratios, correlated with non-AD-specific subcortical changes, that is, larger lateral ventricles and white matter lesions. Further, the A?42/A?40 and A?42/A?38 ratios showed increased accuracy compared to A?42 when distinguishing AD from dementia with Lewy bodies or Parkinson's disease dementia and subcortical vascular dementia, where all A?s (including A?42) were decreased.InterpretationThe CSF A?42/A?40 and A?42/A?38 ratios are significantly better than CSF A?42 to detect brain amyloid deposition in prodromal AD and to differentiate AD dementia from non-AD dementias. The ratios reflect AD-type pathology better, whereas decline in CSF A?42 is also associated with non-AD subcortical pathologies. These findings strongly suggest that the ratios rather than CSF A?42 should be used in the clinical work-up of AD.

Project description:Background Blood-based biomarkers for Alzheimer’s disease (AD) might facilitate identification of participants for clinical trials targeting amyloid beta (Abeta) accumulation, and aid in AD diagnostics. We examined the potential of plasma markers Abeta(1-42/1-40), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) to identify cerebral amyloidosis and/or disease severity. Methods We included individuals with a positive (n?=?176: 63?±?7?years, 87 (49%) females) or negative (n?=?76: 61?±?9?years, 27 (36%) females) amyloid PET status, with syndrome diagnosis subjective cognitive decline (18 PET+, 25 PET?), mild cognitive impairment (26 PET+, 24 PET?), or AD-dementia (132 PET+). Plasma Abeta(1-42/1-40), GFAP, and NfL were measured by Simoa. We applied two-way ANOVA adjusted for age and sex to investigate the associations of the plasma markers with amyloid PET status and syndrome diagnosis; logistic regression analysis with Wald’s backward selection to identify an optimal panel that identifies amyloid PET positivity; age, sex, and education-adjusted linear regression analysis to investigate associations between the plasma markers and neuropsychological test performance; and Spearman’s correlation analysis to investigate associations between the plasma markers and medial temporal lobe atrophy (MTA). Results Abeta(1-42/1-40) and GFAP independently associated with amyloid PET status (p?=?0.009 and p?<?0.001 respectively), and GFAP and NfL independently associated with syndrome diagnosis (p?=?0.001 and p?=?0.048 respectively). The optimal panel identifying a positive amyloid status included Abeta(1-42/1-40) and GFAP, alongside age and APOE (AUC?=?88% (95% CI 83–93%), 82% sensitivity, 86% specificity), while excluding NfL and sex. GFAP and NfL robustly associated with cognitive performance on global cognition and all major cognitive domains (GFAP: range standardized ? (s?)?=???0.40 to ??0.26; NfL: range s??=???0.35 to ??0.18; all: p?<?0.002), whereas Abeta(1-42/1-40) associated with global cognition, memory, attention, and executive functioning (range s??=?0.22 – 0.11; all: p?<?0.05) but not language. GFAP and NfL showed moderate positive correlations with MTA (both: Spearman’s rho>?0.33, p?<?0.001). Abeta(1-42/1-40) showed a moderate negative correlation with MTA (Spearman’s rho?=???0.24, p?=?0.001). Discussion and conclusions Combination of plasma Abeta(1-42/1-40) and GFAP provides a valuable tool for the identification of amyloid PET status. Furthermore, plasma GFAP and NfL associate with various disease severity measures suggesting potential for disease monitoring.