Abstract
ObjectiveThe 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.MethodsData 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).ResultsThe 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.ConclusionATN 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.
Highlights
Alzheimer’s disease (AD) is the most frequent cause of dementia, with a prevalence of approximately 0.2–0.9% in the age group of 60–64 years old, with an exponential increase to 10.7–13.1% in the age group of 80–84 years old [1].Originally, for clinical diagnosis, the NINCDS-ADRDA diagnostic criteria [2] were used, with only a “probable” diagnosis based on the clinical presentation during life, as histopathological confirmation was essential for a “definitive” diagnosis
For clinical diagnosis, the NINCDS-ADRDA diagnostic criteria [2] were used, with only a “probable” diagnosis based on the clinical presentation during life, as histopathological confirmation was essential for a “definitive” diagnosis
To enhance homogeneity of the sample, we eliminated samples requested by external physicians or by other internal physicians who are not part of the Neurology Memory Clinic UZ/KU Leuven, so that a total of 410 samples remained. Medical records of these 410 patients were retrospectively analyzed for the Mini Mental State Examination (MMSE) scale (/30) [13] in a period of 6 months before the lumbar puncture (i.e., MMSE at time 0) and for every 6month period up to a maximum of 3 years after the lumbar puncture (i.e., MMSE at time 6 for the period till 6 months after the lumbar puncture, time 12 for the period from 6 till 12 months, time 18 for the period from 12 till 18 months and so on until time 36, which corresponds to the period from 30 till 36 months after the lumbar puncture)
Summary
Alzheimer’s disease (AD) is the most frequent cause of dementia, with a prevalence of approximately 0.2–0.9% in the age group of 60–64 years old, with an exponential increase to 10.7–13.1% in the age group of 80–84 years old [1].Originally, for clinical diagnosis, the NINCDS-ADRDA diagnostic criteria [2] were used, with only a “probable” diagnosis based on the clinical presentation during life, as histopathological confirmation was essential for a “definitive” diagnosis. In 2016, Jack et al [7] proposed a new classification scheme based on biomarkers, for three dimensions: A/ T/N In this scheme, “A” stands for amyloid and is tested for by CSF amyloid-beta 1–42 (Aβ42) and/or amyloid positron emission tomography (amyloid-PET); “T” stands for tau and is tested for by CSF hyperphosphorylated tau (p181-tau) and/or a tau-PET; and “N” stands for neurodegeneration and is tested for by CSF total tau (ttau), temporoparietal hypometabolism on [18F]fluodeoxyglucose PET ([18F]FDG-PET) or atrophy on magnetic resonance imaging (MRI). “A” stands for amyloid and is tested for by CSF amyloid-beta 1–42 (Aβ42) and/or amyloid positron emission tomography (amyloid-PET); “T” stands for tau and is tested for by CSF hyperphosphorylated tau (p181-tau) and/or a tau-PET; and “N” stands for neurodegeneration and is tested for by CSF total tau (ttau), temporoparietal hypometabolism on [18F]fluodeoxyglucose PET ([18F]FDG-PET) or atrophy on magnetic resonance imaging (MRI) This ATN classification scheme is an unbiased descriptive system which can be applied to all patients, without being coupled to a specific diagnosis. It was intended for use in a research context, here we examine the prognostic value of this classification scheme in a clinical practice setting
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