Katheryn A Q Cousins1, Jeffrey S Phillips1, David J Irwin1, Edward B Lee2, David A Wolk2, Leslie M Shaw2, Henrik Zetterberg3,4,5,6, Kaj Blennow3,4, Sarah E Burke1, Nikolas G Kinney1, Garrett S Gibbons2, Corey T McMillan1, John Q Trojanowski2, Murray Grossman1. 1. Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 2. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 3. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 4. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. 5. Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK. 6. UK Dementia Research Institute, University College London, London, UK.
Abstract
INTRODUCTION: The ATN framework provides an in vivo diagnosis of Alzheimer's disease (AD) using cerebrospinal fluid (CSF) biomarkers of pathologic amyloid plaques (A), tangles (T), and neurodegeneration (N). ATN is rarely evaluated in pathologically confirmed patients and its poor sensitivity to suspected non-Alzheimer's pathophysiologies (SNAP), including frontotemporal lobar degeneration (FTLD), leads to misdiagnoses. We compared accuracy of ATN (ATNTAU ) using CSF total tau (t-tau) to a modified strategy (ATNNfL ) using CSF neurofilament light chain (NfL) in an autopsy cohort. METHODS: ATNTAU and ATNNfL were trained in an independent sample and validated in autopsy-confirmed AD (n = 67) and FTLD (n = 27). RESULTS: ATNNfL more accurately identified FTLD as SNAP (sensitivity = 0.93, specificity = 0.94) than ATNTAU (sensitivity = 0.44, specificity = 0.97), even in cases with co-occurring AD and FTLD. ATNNfL misclassified fewer AD and FTLD as "Normal" (2%) than ATNTAU (14%). DISCUSSION: ATNNfL is a promising diagnostic strategy that may accurately identify both AD and FTLD, even when pathologies co-occur.
INTRODUCTION: The ATN framework provides an in vivo diagnosis of Alzheimer's disease (AD) using cerebrospinal fluid (CSF) biomarkers of pathologic amyloid plaques (A), tangles (T), and neurodegeneration (N). ATN is rarely evaluated in pathologically confirmed patients and its poor sensitivity to suspected non-Alzheimer's pathophysiologies (SNAP), including frontotemporal lobar degeneration (FTLD), leads to misdiagnoses. We compared accuracy of ATN (ATNTAU ) using CSF total tau (t-tau) to a modified strategy (ATNNfL ) using CSF neurofilament light chain (NfL) in an autopsy cohort. METHODS: ATNTAU and ATNNfL were trained in an independent sample and validated in autopsy-confirmed AD (n = 67) and FTLD (n = 27). RESULTS: ATNNfL more accurately identified FTLD as SNAP (sensitivity = 0.93, specificity = 0.94) than ATNTAU (sensitivity = 0.44, specificity = 0.97), even in cases with co-occurring AD and FTLD. ATNNfL misclassified fewer AD and FTLD as "Normal" (2%) than ATNTAU (14%). DISCUSSION: ATNNfL is a promising diagnostic strategy that may accurately identify both AD and FTLD, even when pathologies co-occur.
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