Clinical reporting following the quantification of cerebrospinal fluid biomarkers in Alzheimer's disease: An international overview

Abstract

BackgroundThe quantification of cerebrospinal fluid (CSF) biomarkers (Amyloid beta peptides [Aß1‐40 and Aß1‐42], t‐tau and p‐tau(181)) is progressively implemented in specialized laboratories as an aid for the multidisciplinary diagnosis of Alzheimer’s disease (AD). There is however a diversity of practices between centers related to pre‐analytical and analytical conditions, the calculation of ratios between analytes, the applied cut‐off, or the use of interpretation scales. Finally, for the same biochemical profile, the interpretation and reporting of results may differ from one center to another, which may raise questions about the commutability of the tests. So far, no consensus has been reached between the different laboratories involved to define the most appropriate conclusions/comments based on the profile of the quantified biomarkers.This work is an essential step towards a consensual harmonization of clinical reporting after CSF analysis in the context of AD diagnosis, as advocated by the "Biofluid Based Biomarkers PIA" working group of the Alzheimer's Association.MethodWe obtained, by means of a questionnaire, a description of the pre‐analytical and analytical protocols and examples of reporting from 40 centers located in 15 countries, i.e. in the majority of countries that have implemented clinical CSF tests for the diagnosis of AD. We then adopted a consensus approach to propose harmonized comments corresponding to different AD CSF biomarker profiles observed in patients.ResultPre‐analytical procedures were very similar, among the centers. Regarding the analytical part, more than 88% of the laboratories use automatized immunoassays and more than 83% measure Aß1‐40 and compute the Aß1‐42/Aß1‐40 ratio, in addition to the three core biomarkers (Aß1‐42, t‐tau and p‐tau(181)). The cut‐off values of biomarkers used by the different laboratories are widely dispersed. Delay before sending back the results is lower than 1 week in more than 34% of the laboratories.ConclusionOur results highlight the state of the art in terms of clinical CSF analysis in the context of AD. Harmonization of clinical reporting between different centers could benefit AD care, prevention and treatment strategies, as a common terminology will allow a better assessment of the prevalence of AD and the contribution of biochemical biomarkers to its diagnosis.

Biomarkers for the Diagnosis of Alzheimer’s Disease in Clinical Practice: The Role of CSF Biomarkers during the Evolution of Diagnostic Criteria

“…The application of CSF biomarkers in routine clinical practice allows for detection of the disease at a very early, asymptomatic (preclinical) stage through the prodromal phase (MCI—mild cognitive impairment) to full-blown, symptomatic AD [ 3 , 6 , 15 , 53 ]. Other consensus and research groups (e.g., IWG) have proposed diagnosing AD as a clinical and biological entity based on in vivo biomarkers [ 6 , 16 , 17 , 18 , 20 , 21 ]. Some of these criteria are still in research and development for later clinical use (yellow dots in Figure 1 ) [ 6 , 15 , 18 , 53 , 54 , 57 ].…”

“…An accurate diagnosis of AD commonly involves an interdisciplinary approach to evaluating the clinical signs and symptoms of this multifactorial disease and the biochemical changes [ 1 , 4 , 15 ]. Diagnostic criteria, recommendations, scoring systems and scales for in vivo biomarkers improve early diagnosis and monitoring of disease progression [ 6 , 16 , 17 , 18 , 19 , 20 ]. Scientists continue to search for the main and earliest triggers underlying the neurodegenerative changes associated with AD dementia [ 16 ].…”

“…Middle-stage and later symptoms include disorientation, confusion, behavioral changes and problems with speech or language [ 6 , 16 , 17 ]. These symptoms also have a neurobiological basis and can be monitored based on the assessment of biological substances reflecting pathological changes in human fluids decades before disease onset [ 4 , 20 ]. It is postulated that, in addition to obtaining the patient’s medical history, several tests should be performed to assess decline of cognitive function related to AD, including neuropsychological tests, neuroimaging tests and assessment of biochemical markers [ 1 , 6 ].…”

“…CSF biomarkers are widely discussed in working groups and included in international guidelines for clinical practice [ 4 , 6 , 15 , 18 , 21 , 22 ]. Clinicians may encounter a number of challenges in diagnosing AD [ 20 ] due to mixed pathologies related to cerebrovascular disease or Lewy body dementia (LBD). Furthermore, the diagnostic process may be complicated because of the use of different diagnostic techniques or presence of other, pre-analytical factors [ 8 , 11 , 19 , 20 , 23 , 24 , 25 ].…”

“…Clinicians may encounter a number of challenges in diagnosing AD [ 20 ] due to mixed pathologies related to cerebrovascular disease or Lewy body dementia (LBD). Furthermore, the diagnostic process may be complicated because of the use of different diagnostic techniques or presence of other, pre-analytical factors [ 8 , 11 , 19 , 20 , 23 , 24 , 25 ]. Therefore, proper recognition of pre-analytical conditions will result in improved reproducibility and quality of CSF measurements.…”