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

Figures & data

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).

Table 1. Overview of pre-analytical confounders and current recommendations in the CSF analysis of AD biomarkers.

Confounder	Recommendation
Sample withdrawal volume	12 ml
Type of needle	25G atraumatic needle
Location of LP	Intervertebral space L3-L5
Traumatic LP	Discard blood-contaminated CSF until sample is clear, followed by immediate centrifugation at 2,000 × g for 10 min at RT
Erythrocyte count	<500 erythrocytes/µl
Sample collection tube	PP tube, but preferably copolymer PP-PE tube
Sample storage tube	PP tube, but preferably copolymer PP-PE tube
Sample storage volume	1–2 ml, preferably filled to 75% of its capacity
Sample centrifugation	Not essential, only when CSF sample is blood-contaminated
Sample storage temperature	As soon as possible at –80 °C
Delayed freezing of samples	<4 h
Long-term stability	Up to 10 years at –80 °C
Freeze-thaw cycles	Maximum of two cycles

CSF: cerebrospinal fluid; LP: lumbar puncture; PP: polypropylene; PE: polyethylene; RT: room temperature.

Table 2. Performance of the analytical methods for CSF β-amyloid (Aβ42) in the Alzheimer’s Association Quality Control (QC) programme during 2014–2016.

Assay name	INNOTEST^®	EuroImmune/ADx	AlzBio3	Meso Scale	Elecsys	Lumipulse
	β-amyloid (1–42)	β-amyloid (1–42)	β-amyloid (1–42)	Human Aβ42	β-amyloid (1–42)	β-amyloid (1–42)
	Fujirebio		Fujirebio		Roche Diagnostics	Fujirebio
Technique	ELISA	ELISA	Luminex	V-PLEX	Fully automated	Fully automated
Round
2014-14A	18		16	low n	2.9
2014-14B	21		19	low n	4.4
2014-15A	15		7.1	12	4.6
2014-15B	17		14	12	3.4
2104-16A	27	57	40	13	3
2014-16B	17	19	30	11	2.5
2015-17A	19	6.5	17	21	1.9
2015-17B	14	8.2	15	20	3.2
2015-18A	13	22	25	10	7.2
2015-18B	13	16	13	9.4	4.7
2015-19A	13	13	40	10	3
2015-19B	13	13	15	13	1.5
2016-20A	17.4	18	ND	10.5	2
2015-20B	21.1	15.4	ND	14	Out of range
2016-21A	15	18	22	8.1	10	6.3
2016-21B	11	15	29	7.4	5.2	4
MEAN	16.5	18.4	21.6	12.2	4.0	5.2

Values indicate between-laboratory CV (%).

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+.

Box 1. Evidence supporting a role for CSF biomarkers in clinical trials in AD.

CSF biomarkers for inclusion/selection

• In previous AD clinical trials, only half of participants selected by clinical criteria had biological evidence of AD.  • Aβ1–42 alone or in combination with total tau has been the most widely used biomarker to enrich the selection of participants in clinical trials.

CSF biomarkers as a measure of target engagement

• Several trials with β-secretase inhibitors have detected a reduction in CSF levels of Aβ1–42, Aβ1–40, sAPPβ or other subproducts of APP. Other fragments, such as Aβ5-42, Aβ5-X or sAPPα, have been found increased in CSF, suggesting an enhanced alternative processing of APP after β-secretase inhibition.  • In trials with γ-secretase inhibitors and modulators, the changes in CSF levels of Aβ1–42, Aβ1–40 have not been consistent.  • None of the trials with the active immunisation compounds showed changes in the levels of amyloid-derived CSF biomarkers.  • Patients treated with solanezumab showed an increase of total Aβ1–40 and Aβ1–42 levels in CSF following treatment, perhaps reflecting a change in the balance between fibrillar and soluble Aβ.

CSF biomarkers as a measure of disease modification

• Total Tau and pTau levels have been investigated as markers of the downstream effects in anti-amyloid treatments.  • The active Aβ immunisation study AN1792 (but not CAD106) showed that antibody responders had a reduction in CSF total Tau levels compared to those patients who received placebo.  • Treatment with bapineuzumab (but not solanezumab) was associated with a decrease in CSF pTau levels.

Lewczuk P, Matzen A, Blennow K, Parnetti L, Molinuevo JL, Eusebi P, Kornhuber J, Morris JC, Fagan AM. 2017. Cerebrospinal fluid Abeta42/40 corresponds better than Abeta42 to amyloid PET in Alzheimer’s disease. J Alzheimer’s Dis. 55:813–822.

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