Prognostic value of amyloid/tau/neurodegeneration (ATN) classification based on diagnostic cerebrospinal fluid samples for Alzheimer’s disease

Abstract

Objective The primary study objective of this retrospective academic memory clinic-based observational longitudinal study was to investigate the prognostic value of a cerebrospinal fluid (CSF)-based ATN classification for subsequent cognitive decline during the 3 years following lumbar puncture in a clinical, real-life setting. The secondary objective was to investigate the prognostic value of CSF biomarkers as continuous variables. Methods Data from 228 patients (median age 67 (47–85) years), who presented at the Neurology Memory Clinic UZ/KU Leuven between September 2011 and December 2016, were included with a follow-up period of up to 36 months. Patients underwent a CSF AD biomarker test for amyloid-beta 1–42 (Aβ42), hyperphosphorylated tau (p181-tau) and total tau (t-tau) in the clinical work-up for diagnostic reasons. Patients were divided into ATN classes based on CSF biomarkers: Aβ42 for amyloid (A), p181-tau for tau (T), and t-tau as a measure for neurodegeneration (N). Based on retrospective data analysis, cognitive performance was evaluated by Mini Mental State Examination (MMSE) scores every 6 months over a period up to 36 months following the lumbar puncture. The statistical analysis was based on linear mixed-effects modeling (LME). Results The distribution in the current clinical sample was as follows: A−/T−/N− 32.02%, A+/T−/N− 33.33%, A+/T+/N+ 17.11%, A+/T−/N+ 11.84%, A−/T−/N+ 4.39%, A−/T+/N+ 1.32% (3 cases), with no cases in the A−/T+/N− and A+/T+/N− class. Hence, the latter 3 classes were excluded from further analyses. The change of MMSE relative to A−/T−/N− over a 36-month period was significant in all four ATN classes: A+/T+/N+ = − 4.78 points on the MMSE; A−/T−/N+ = − 4.76; A+/T−/N+ = − 2.83; A+/T−/N− = − 1.96. The earliest significant difference was seen in the A+/T+/N+ class at 12 months after baseline. The effect of ATN class on future cognitive decline was confirmed for a different set of CSF thresholds. All individual baseline CSF biomarkers including the Aβ42/t-tau ratio showed a significant correlation with subsequent cognitive decline, with the highest correlation seen for Aβ42/t-tau. Conclusion ATN classification based on CSF biomarkers has a statistically significant and clinically relevant prognostic value for the course of cognitive decline in a 3-year period in a clinical practice setting.

From Cerebrospinal Fluid Neurochemistry to Clinical Diagnosis of Alzheimer’s Disease in the Era of Anti-Amyloid Treatments. Report of Four Patients

“…When incorporated in the AT(N) classification system, CSF biomarkers may be used effectively not only in research but also in clinical practice [36,63]. It should be noted that in patients 2 and 4, CSF levels of Aβ 42 were normal.…”

“…Biomarkers are not stand-alone tools and should always be interpreted along with clinical, neuropsychological, and imaging data. Keeping this in mind, analysis of classical CSF biomarkers, especially when incorporated in a classification/diagnostic system such as the AT(N), may offer a significant diagnostic tool [90,91], with both added [92] and prognostic [36] value, allowing the correct identification of AD during life, especially in cases with atypical or mixed presentations [93]. This is always important for correct therapeutic decisions, and it is of paramount importance currently, due to the recent approval of aducanumab as a disease-modifying treatment.…”

“…Profiles such as A + T − (N) − or A + T − (N) + are compatible with Alzheimer's pathological change (change from normal with the acquisition of amyloid biochemistry/pathology, without or with additional non-AD pathologies), but not Alzheimer's disease (which requires both amyloid plaques and neurofibrillary tangles [1]) [18]. Although the AT(N) system was designed mainly for research purposes, it can be used in clinical practice, even with clinically relevant prognostic value [36] and it may be suitable for in vivo AD verification in patients suitable for aducanumab treatment, especially during the long phase IV trial of aducanumab.…”

Visuospatial memory impairment as a potential neurocognitive marker to predict tau pathology in Alzheimer’s continuum

“…Aβ deposition, pathologic tau, and neurodegeneration have been served as biomarkers to define AD, which lead AT(N) classification system [ 1 ]. Moreover, many studies using cerebrospinal fluid (CSF) demonstrated such classification or combination of the three biomarkers have prognostic utility as well as diagnostic value [ 3 – 5 ]. In addition, ratio between Aβ 1–42 and phosphorylated tau (p-Tau) also showed association with subsequent cognitive decline in cognitively normal (CN) or mild cognitive impairment (MCI) older adults [ 3 , 5 ].…”

“…Moreover, many studies using cerebrospinal fluid (CSF) demonstrated such classification or combination of the three biomarkers have prognostic utility as well as diagnostic value [ 3 – 5 ]. In addition, ratio between Aβ 1–42 and phosphorylated tau (p-Tau) also showed association with subsequent cognitive decline in cognitively normal (CN) or mild cognitive impairment (MCI) older adults [ 3 , 5 ]. Over the past decade, accumulating evidence has suggested that early cognitive changes are more closely associated with tau pathology than Aβ pathology.…”