Testing the 2018 NIA-AA research framework in a retrospective large cohort of patients with cognitive impairment: from biological biomarkers to clinical syndromes

Abstract

Background According to the 2018 NIA-AA research framework, Alzheimer’s disease (AD) is not defined by the clinical consequences of the disease, but by its underlying pathology, measured by biomarkers. Evidence of both amyloid-β (Aβ) and phosphorylated tau protein (p-tau) deposition—assessed interchangeably with amyloid-positron emission tomography (PET) and/or cerebrospinal fluid (CSF) analysis—is needed to diagnose AD in a living person. Our aim was to test the new NIA-AA research framework in a large cohort of cognitively impaired patients to evaluate correspondence between the clinical syndromes and the underlying pathologic process testified by biomarkers. Methods We retrospectively analysed 628 subjects referred to our centre in suspicion of dementia, who underwent CSF analysis, together with neuropsychological assessment and neuroimaging, and were diagnosed with different neurodegenerative dementias according to current criteria, or as cognitively unimpaired. Subjects were classified considering CSF biomarkers, and the prevalence of normal, AD-continuum and non-AD profiles in each clinical syndrome was calculated. The positivity threshold of each CSF biomarker was first assessed by receiver operating characteristic analysis, using Aβ-positive/negative status as determined by amyloid-PET visual reads. The agreement between CSF and amyloid-PET data was also evaluated. Results Among patients with a clinical diagnosis of AD, 94.1% were in the AD-continuum, whereas 5.5% were classified as non-AD and 0.4% were normal. The AD-continuum profile was found also in 26.2% of frontotemporal dementia, 48.6% of Lewy body dementia, 25% of atypical parkinsonism and 44.7% of vascular dementia. Biomarkers’ profile did not differ in amnestic and not amnestic mild cognitive impairment. CSF Aβ levels and amyloid-PET tracer binding negatively correlated, and the concordance between the two Aβ biomarkers was 89%. Conclusions The examination of the 2018 NIA-AA research framework in our clinical setting revealed a good, but incomplete, correspondence between the clinical syndromes and the underlying pathologic process measured by CSF biomarkers. The AD-continuum profile resulted to be a sensitive, but non-specific biomarker with regard to the clinical AD diagnosis. CSF and PET Aβ biomarkers were found to be not perfectly interchangeable to quantify the Aβ burden, possibly because they measure different aspects of AD pathology.

The Amyloid, Tau, and Neurodegeneration (A/T/N) Classification Applied to a Clinical Research Cohort with Long-Term Follow-Up

“…The prevalence of suspected non-Alzheimer disease pathophysiology (SNAP) at baseline was relatively consistent across clinical groups (controls 13%, amnestic MCI 9%, and AD dementia 5%) and correlates well with other studies [22,23]. These individuals had tau pathology (T+) and/or neurodegeneration (N+), but lacked amyloid deposition (A-), thereby distinguishing them from the typical biomarker profile of AD [24].…”

Discordant Alzheimer's neurodegenerative biomarkers and their clinical outcomes

“…5,[12][13][14][15] Researchers have compared the prevalence of biologically defined AD with clinically defined probable AD, 29 and evaluated the correspondence between clinical syndromes and biological biomarkers as well as between CSF tau and tau-PET. 30,31 Likewise, they obtained similar but not equivalent results, revealing the importance of recognizing the discordant status. Some mechanisms were possibly helpful in explaining the discordant states.…”

“…Neurodegenerative pathology can be reliably measured in vivo with neuroimaging technology, CSF assessments, or blood tests, 28 but substantial discordance exists when utilizing different methods to evaluate the “N” biomarkers in the same person 5,12–15 . Researchers have compared the prevalence of biologically defined AD with clinically defined probable AD, 29 and evaluated the correspondence between clinical syndromes and biological biomarkers as well as between CSF tau and tau‐PET 30,31 . Likewise, they obtained similar but not equivalent results, revealing the importance of recognizing the discordant status.…”

Optimal Combinations of AT(N) Biomarkers to Determine Longitudinal Cognition in the Alzheimer's Disease

“…First, the difference in the composition of AT(N) categories between CU and CI individuals is not surprising. Categories representing the AD continuum were the most common in CI participants, while more subjects with non-AD pathological changes were observed in the CU group (Rami et al, 2011;Jack et al, 2018;Knopman et al, 2018;Carandini et al, 2019). Moreover, different AT(N) variants resulted in considerable differences in prevalence, such as a lower prevalence of T+ when using tau PET in all groups and a higher prevalence of N+ when using fluid biomarkers in the CU group.…”