Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry

Abstract

In the 12 years since the publication of the first Consensus Paper of the WFSBP on biomarkers of neurodegenerative dementias, enormous advancement has taken place in the field, and the Task Force takes now the opportunity to extend and update the original paper. New concepts of Alzheimer's disease (AD) and the conceptual interactions between AD and dementia due to AD were developed, resulting in two sets for diagnostic/research criteria. Procedures for pre-analytical sample handling, biobanking, analyses and post-analytical interpretation of the results were intensively studied and optimised. A global quality control project was introduced to evaluate and monitor the inter-centre variability in measurements with the goal of harmonisation of results. Contexts of use and how to approach candidate biomarkers in biological specimens other than cerebrospinal fluid (CSF), e.g. blood, were precisely defined. Important development was achieved in neuroimaging techniques, including studies comparing amyloid-β positron emission tomography results to fluid-based modalities. Similarly, development in research laboratory technologies, such as ultra-sensitive methods, raises our hopes to further improve analytical and diagnostic accuracy of classic and novel candidate biomarkers. Synergistically, advancement in clinical trials of anti-dementia therapies energises and motivates the efforts to find and optimise the most reliable early diagnostic modalities. Finally, the first studies were published addressing the potential of cost-effectiveness of the biomarkers-based diagnosis of neurodegenerative disorders.

Keywords: Alzheimer’s disease; biomarkers; cerebrospinal fluid; consensus; dementia.

Figure 1

Erlangen Score. Erlangen Score is the sum of the scores for Aβ biomarkers (0, normal; 1, borderline pathological; 2, pathological) and Tau/pTau biomarkers (0, normal; 1, borderline pathological; 2, pathological), always in relation to a given laboratory’s cut-offs. Depending on the total score, NDD is interpreted as: 0, neurochemically normal; 1, AD neurochemically improbable; 2–3, AD neurochemically possible; 4, AD neurochemically probable. The original algorithm was modified by excluding cases with very high Tau concentrations, which points at rapidly progressing neurodegeneration (for example, CJD).

Figure 2

Conceptual overview of multi-stage neurodiagnostic process beginning with blood screen in primary care setting.

Figure 3

Histological lesions in Alzheimer’s disease. Neurofibrillary tangles, neuropil threads, neuritic plaques (lower left) and amyloid angiopathy (upper left insert).

Figure 4

Dementia with Lewy bodies. Diffuse brain atrophy (upper left), degeneration of substantia nigra (lower left), multiple Lewy bodies and Lewy neurites in brainstem and cerebral cortex (right).

Figure 5

Amyloid deposition (upper panel, white arrows) and glucose hypometabolism (lower panel, red arrows) in an AD patient. Images from [¹¹C]PIB-PET and [¹⁸F]FDG-PET, respectively. SUVR, standardised uptake value ratio, presented as ratios to cerebellum).

Figure 6

Scatterplots of cortical amyloid PET load using [¹¹C]PiB and Aβ1–42 concentrations (A) and Aβ42/40 ratio (B). Vertical line represents dichotomous cut-off for PiB positivity. Horizontal lines represent the best-performing cut-offs of the respective CSF biomarkers calculated in the present study. Green areas comprise CSF/PET concordant results (either CSF−/PET− or CSF+/PET+), yellow areas comprise discordant results with normal CSF and abnormal PET (CSF−/PET+), and red areas include results with abnormal CSF and normal PET (CSF+/PET−). Note: (a) better concordance between Aβ42/40 and PET compared to Aβ1–42 and PET, and (b) significantly more CSF+/PET− than CSF−/PET +discordant cases for both CSF biomarkers. Reprinted slightly modified from (Lewczuk et al. 2017) with kind permission from IOS Press. The publication is available at IOS Press through http://dx.doi.org/10.3233/JAD-160722.

Figure 7

Tau PET and MRI in an A−T + N+ SNAP subject. Clinically normal 81-year-old male participant in the Mayo Clinic Study of Aging. Abnormal Tau PET uptake (AV1451) is present in the medial, basal, lateral temporal lobes bilaterally (left panel). Non-specific AV1451 uptake is present in the basal ganglia bilaterally. This participant also has medial temporal lobe atrophy (right panel) and a normal amyloid PET scan (PIB, not shown). This individual’s ATN profile was A−T+N+.