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How to do it

CSF biomarkers for dementia

Ashvini Keshavan ‍ ‍ ,1 Frankie O’Shea,1 Miles D Chapman,2,3
Melanie S Hart,2,3 Michael PT Lunn ‍ ‍ ,2,4 Ross W Paterson ‍ ‍ ,1
Jonathan D Rohrer ‍ ‍ ,5 Catherine J Mummery,6 Nick C Fox ‍ ‍ ,1
Henrik Zetterberg ‍ ‍ ,7,8 Jonathan M Schott ‍ ‍ 1

For numbered affiliations see Abstract AD dementia is classically associated

end of article.
Although cerebrospinal fluid (CSF) biomarker with a CSF profile of a reduced amyloid-β
Correspondence to testing is incorporated into some current 1–42/1–40 ratio (Aβ42/40), increased
Professor Jonathan M guidelines for the diagnosis of dementia (such p-­tau and increased total tau (t-­ tau)
Schott, Dementia Research as England's National Institute for Health and compared with cognitively normal indi-
Centre, Department of
Neurodegenerative Disease, Care Excellence (NICE)), it is not widely accessible viduals.1 However, in clinical practice, it
UCL Queen Square Institute of for most patients for whom biomarkers could is more important to be able to distinguish
Neurology, London WC1N 3BG, potentially change management. Here we share those with AD dementia from other types
UK; ​j.​schott@u​ cl.​ac.​uk
our experience of running a clinical cognitive of slowly progressive dementia, particu-
Accepted 18 February 2022 CSF service and discuss recent developments larly as the phenotypical manifestations
Published Online First in laboratory testing including the use of the of the dementias often overlap. A recently
17 March 2022
CSF amyloid-β 42/40 ratio and automated updated meta-­analysis2 shows that low
assay platforms. We highlight the importance Aβ42, increased p-­tau181 and increased
of collaborative working between clinicians t-­
tau can differentiate clinically defined
and laboratory staff, of preanalytical sample AD dementia from many conditions

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handling, and discuss the various factors that may present to the memory clinic,
influencing interpretation of the results in including frontotemporal, vascular and
appropriate clinical contexts. We advocate for Lewy body dementias (table 1). Combi-
broadening access to CSF biomarkers by sharing nations of these classical biomarkers can
clinical expertise, protocols and interpretation also discriminate neuropathologically
with colleagues working in psychiatry and elderly confirmed AD from frontotemporal
care, especially when access to CSF may be part lobar degeneration, with areas under the
of a pathway to disease-­modifying treatments receiver operating characteristic curve of
for Alzheimer’s disease and other forms of 0.94–0.98.3 4
dementia. Some limitations of lumbar punctures
(LPs) are that they are more invasive
than amyloid PET; they require caution
in people with coagulopathies; and they
Introduction carry a risk of low CSF pressure headache
While cerebrospinal fluid (CSF) has been (about 1 in 10 using atraumatic needles).5
used in the investigation of dementia for However, CSF testing allows for a single
many years, the context of its use has sample to be assayed for several proteins
changed recently from excluding ‘treat- of interest and is cheaper than amyloid
able conditions’ (eg, neuroinflamma- PET. The 2018 NICE guideline NG97
tion) to detecting the core pathologies for dementia6 recommends testing if the
underlying specific forms of dementia diagnosis of dementia is uncertain, and
using biomarkers. There is a particular knowing the dementia subtype would
emphasis on Alzheimer’s disease (AD), both be useful and change manage-
where CSF can be used to demonstrate its ment. The Alzheimer’s Association has
© Author(s) (or their three main pathologies—β-amyloid depo- published some appropriate use criteria
employer(s)) 2022. No sition, hyperphosphorylated tau (p-­ tau) for CSF AD biomarker testing7 (table 2);
commercial re-­use. See rights accumulation and neurodegeneration— conditions considered appropriate for
and permissions. Published
by BMJ. all of which can also be evaluated using CSF testing include both typical and atyp-
imaging techniques like amyloid and tau ical presentations of AD dementia, mild
To cite: Keshavan A,
O’Shea F, Chapman MD, et al. positron emission tomography (PET) or cognitive impairment and some presen-
Pract Neurol 2022;22:285– MRI for assessing brain volumes/atrophy tations of subjective cognitive decline at
294. (figure 1). high risk of AD.

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How to do it

Figure 1  Biomarker correlates of pathologies of amyloid, tau and neurodegeneration in AD. (A) Immunostaining for amyloid-β
(clone 6F3D, DAKI, M0872) shows frequent parenchymal deposits in the neocortex, including many plaques with central amyloid
cores (black arrows). (B) Immunostaining for hyperphosphorylated tau (clone AT8, Thermo MN1020) shows a dense meshwork of
neuropil threads in the neocortex with neuritic plaques (white arrow) and frequent neurofibrillary tangles (black arrow). (C) Coronal
section at the level of the lateral geniculate nucleus from a patient with no known neurological disease shows mild dilation of the
frontal and temporal horns of the lateral ventricle but no other macroscopically visible pathology. (D) Coronal section from a patient
with AD shows prominent dilatation of the frontal and temporal horns of the lateral ventricle and enlarged insular space (black
asterisks). Cortical ribbon shows widespread thinning and blurred outlines between the cortical grey and white matter. The white
matter volume is significantly reduced and the corpus callosum is thin (white asterisks). The hippocampus is severely atrophic (black
arrow). AD, Alzheimer’s disease; CSF, cerebrospinal fluid; NfL, neurofilament light chain; PET, positron emission tomography.

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Another context for CSF testing is to evaluate methods; RT-­ QuIC takes several hours to days to
rapidly progressive dementia, where prion disease is perform11 but has significantly greater specificity and
a consideration. Non-­specific biomarkers of neuronal slightly better sensitivity for sporadic CJD than these
damage, such as 14-­ 3-­
3, neurone-­ specific enolase other proteins.11 12 In a recent multicentre validation
and S100B proteins, are elevated in CSF from people of the revised diagnostic criteria for sporadic CJD,
with sporadic Creutzfeldt-­Jakob disease (CJD).8 The CSF RT-­QuIC on its own had 91.6% sensitivity and
combination of a very high CSF t-­ tau (>1400 ng/ 100% specificity for neuropathologically confirmed
mL on INNOTEST assays) and a high t-­tau to p-­tau cases, outperforming MRI signs of cortical ribboning
ratio (>25) has >99% specificity for sporadic CJD in (67.9% sensitivity and 86.5% specificity) and basal
relation to both AD and other dementias,9 and high ganglial hyperintensity (58.7% sensitivity and 91.9%
CSF t-­tau is also seen in variant CJD.10 However, specificity).13
the use of real-­ time quaking-­ induced conversion CSF biomarkers are also useful in considering
(RT-­QuIC) for prion protein has superseded these whether there is evidence for neurodegeneration

Table 1  Heatmap showing the ability of CSF Alzheimer’s biomarkers to discriminate AD dementia from other types of dementia
Effect size/fold change compared with AD (95% CI)
CSF biomarker Aβ42 p-t­ au181 t-­tau
Frontotemporal dementia 1.66 (1.57 to 1.75) 0.52 (0.48 to 0.56) 0.52 (0.49 to 0.56)
Progressive supranuclear palsy 1.48 (1.35 to 1.62) 0.43 (0.38 to 0.48) 0.37 (0.33 to 0.41)
Parkinson’s disease 1.68 (1.22 to 1.55) 0.46 (0.42 to 0.50) 0.35 (0.32 to 0.39)
Dementia with Lewy bodies 1.16 (1.10 to 1.22) 0.56 (0.52 to 0.60) 0.49 (0.46 to 0.53)
Parkinson’s disease dementia 1.37 (1.22 to 1.55) 0.53 (0.46 to 0.60) 0.43 (0.39 to 0.47)
Multiple system atrophy 1.55 (1.45 to 1.65) 0.41 (0.37 to 0.46) 0.39 (0.33 to 0.46)
Normal pressure hydrocephalus 1.37 (1.20 to 1.57) 0.35 (0.29 to 0.42) 0.35 (0.27 to 0.46)
Vascular dementia 1.31 (1.23 to 1.39) 0.55 (0.49 to 0.61) 0.40 (0.53 to 0.67)
Data are adapted from the Alzbiomarker database V.3.0 (July 2021).2
Orange indicates a higher level of the biomarker in the non-­AD dementia compared with AD dementia. Cyan indicates a lower level of the biomarker in
the non-­AD dementia. All fold changes are significant at the p<0.0001 level.
AD, Alzheimer’s disease; CSF, cerebrospinal fluid.

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How to do it

Table 2  Clinical indications for appropriate use of lumbar puncture and cerebrospinal fluid testing in the diagnosis of AD, as detailed by the
Alzheimer’s Association’s appropriate use criteria
Alzheimer’s Association’s
Clinical indication appropriate use criteria
Meeting core clinical criteria for probable AD dementia with typical age of onset Appropriate
Symptoms suggesting possible AD dementia*
Dementia with onset age below 65 years*
Mild cognitive impairment with onset age below 65 years
Persistent, progressing or unexplained mild cognitive impairment
Subjective cognitive decline but considered to be at high risk of AD (persistent decline in memory rather than other
cognitive domains; onset in the last 5 years, age at onset >60 years, worries associated with subjective cognitive
decline, feeling of worse performance than others of the same age group, confirmation of cognitive decline by an
informant; carriage of APOE ‍ ‍4)
Dominant symptom of change in behaviour, where AD diagnosis is being considered*
Determining disease severity in patients who have already received a diagnosis of AD Inappropriate
Subjective cognitive decline not considered to be at high risk of AD
Symptoms of rapid eye movement sleep behaviour disorder
Carriers of autosomal dominant AD mutations, with or without symptoms
In lieu of genotyping for suspected carriers of autosomal dominant AD mutations
Carriers of APOE ‍ ‍4 with no cognitive impairment
Cognitively unimpaired on objective testing and no subjective cognitive decline but considered as high risk due to
family history of AD
Cognitively unimpaired on objective testing, no subjective cognitive decline, no expressed concern about developing
AD and no condition suggesting high risk

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Reproduced with minor reformatting from Shaw et al7 with the publisher’s permission.
*Indications that would be considered appropriate according to the current NICE guideline.6
AD, Alzheimer’s disease; APOE, apolipoprotein E gene; NICE, National Institute for Health and Care Excellence.

of any form. In a wide range of processes involving has not been shown to improve outcomes, so we offer
either acute or chronic neuronal damage, neurofila- an opportunity for seated rest. Although the consensus
ment light chain (NfL) concentrations are elevated in recommendation is to use ≤25 G atraumatic needles
CSF. Pronounced CSF NfL elevation occurs in prion in the lateral decubitus position, a multicentre feasi-
disease.14 Compared with AD dementia (where there bility study did not show a significant benefit of using
is an average 1.9-­fold change relative to cognitively smaller gauge needles,5 and so we use 22 G needles
normal controls), there are greater elevations in CSF and allow for collection in the seated position. This
NfL in certain non-­AD dementias such as some types improves the speed of collection especially when larger
of frontotemporal dementia (fold change 3.9 rela- volumes (eg, 20 mL) are routinely taken, where the
tive to healthy controls) and HIV-­ associated cogni- patient has additionally consented to research sample
tive impairment (fold change 21.4).15 However, it is collection, and where measurement of CSF opening
important to note that CIs are wide, and a normal CSF pressure is not of clinical concern.
NfL concentration does not exclude the presence of Since 2018, an advanced nurse practitioner (FO’S)
neurodegeneration. has been performing the LPs at the NHNN cognitive
CSF clinic following the development of a local clin-
CSF sampling ical guideline on nurse-­ performed LP (available on
We have had a dedicated cognitive CSF clinic at request) and appropriate competency-­based training.
London’s National Hospital for Neurology and The advanced nurse practitioner now runs the clinic
Neurosurgery (NHNN) since 2013. Diagnostic LPs independently, with back-­up support from a rota of
are undertaken in a day care setting with an option trainee doctors if technical difficulties are encoun-
for research sample donation. Box 1 summarises the tered, and research staff where research samples are
standard operating procedure for this clinic, which also taken.
is broadly in line with the recommendations of a
consensus guideline for LP in patients with neuro- Preanalytical handling
logical diseases.16 Key recommendations to minimise We exclusively collect CSF in standardised polypro-
post-­
LP complications include adequate counselling pylene tubes, as polystyrene (the material in standard
of patients to allay fears beforehand, using atraumatic universal containers) results in artefactual lowering of
needles, limiting the number of attempts to four or the measured Aβ peptide concentrations by up to 30%
fewer, and using passive (drip) CSF collection. Bed rest and of t-­tau by up to 15%.17 We also avoid collecting

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How to do it

Box 1  Standard operating procedure for cognitive Box 1  Continued

CSF clinic at NHNN, including clinical and research
sampling of CSF and blood ►► Intervertebral space between L2/L3 and L5/S1 located
by palpation.
Referral information ►► Skin preparation as per local clinical guidelines (with
►► Demographic and contact details. chlorhexidine 2%/ethanol 70%, allowed to dry fully
►► Need for coordination with other tests. before proceeding).
►► Not likely to require radiological guidance for LP. ►► Technique: aseptic (sterile gloves, standard personal
►► Specify whether CSF opening pressure is needed (not protective equipment including plastic apron).
routinely done). ►► Local anaesthesia: lignocaine 2%, maximum 3 mg/kg.
►► Arrangements for antiplatelet and anticoagulant ►► Spinal needle: atraumatic 22 G, no more than four
medication cessation if relevant. passes.
►► Full blood count and coagulation profile not ►► Method of collection: drip without suction.
required unless the patient has known history of ►► If manometer is used, contents are emptied into routine
thrombocytopenia or coagulopathy. CSF analysis container and manometer is removed
before collection for AD CSF biomarkers.
Preclinic telephone call (if not already addressed ►► Primary containers for clinical CSF collection:
in clinic from which patient was referred/if patient polypropylene screw top yellow cap 25 mL (Sarstedt
requests additional call) 63.9922.254).
►► Address concerns/questions. ►► Volume collected for clinical sample, each into different
►► Ask if willing to receive research information. tubes: routine tests (cell counts, protein, glucose,
►► Arrange to send LP information leaflet by post/email, microscopy culture and sensitivities) 1 mL; AD CSF
along with research information leaflet if relevant. biomarkers 2 mL, virology (if needed) 1 mL, cytology (if
►► Participant not instructed to fast but to drink copious needed) 5 mL.
fluids on the day if not contraindicated. ►► Primary containers for research CSF collection:

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►► Confirm not on antiplatelets or anticoagulants for the polypropylene screw top clear cap 10 mL (Sarstedt
proposed appointment date or has a plan for cessation 62.610.018).
and recommencement (following the Association of ►► Volume collected for research sample (if relevant):
British Neurologists 2018 guideline).38 maximum 15 mL.
Clinic day ►► Needle bevel reinserted before withdrawal.
History and investigation review ►► Dry adhesive dressing applied to site.
►► Review of recent neuroimaging (within the last 6 ►► Patient assisted to supine position.
months) to confirm no contraindications (tonsillar Paired venous blood sample
descent/large mass lesion) OR ►► Taken immediately after LP, tourniquet used.
confirm no history of features of raised intracranial ►► Venepuncture location: upper limb peripheral vein.
pressure and no papilloedema on funduscopy. ►► Needle: 21 G or 23 G butterfly needle with BD
►► Confirm no allergies (latex, plasters and lignocaine). Vacutainer adaptor.
►► Blood collection tubes (clinical), BD Vacutainer: 1×SST
Consent serum (gold top) 4 mL, 1×fluoride oxalate (grey top)
►► Formal written consent on hospital’s general procedure 2 mL.
consent form 1, or if patient is deemed to lack capacity ►► Blood collection tubes (research), BD Vacutainer: up
to consent, document consultee discussion on consent to 1×lithium heparin plasma 6 mL, up to 4×SST serum
form 4. 5 mL, up to 4×K2 EDTA plasma 6 mL.
►► Indication: diagnostic. ►► Dry adhesive plaster applied to site.
►► Risks: common—headache (10%) and back pain (25%); After-­care
rare—failure of procedure, bleeding, infection and ►► Patient transfers to reclining chair, is offered a beverage
nerve damage; very rare—hearing loss, double vision, and rests for 1 hour before going home; advised
need for a blood patch to treat prolonged post LP to avoid bending/straining for the rest of the day;
headache (<1 in 500). plaster removed on the following day. Offer patient-­
►► Separate consent for research sample donation (CSF initiated telephone follow-­up post-­LP: document any
and blood). symptoms and arrange further follow-­up if needed
LP (eg, to monitor post-­LP headache and arrange blood
►► Second member of staff acts as an assistant/chaperone. patch if persistent); organise radiologically guided LP if
►► CSF collected between 08:00 and 12:00. procedure failed.
►► Patient in either lateral decubitus position or seated
AD, Alzheimer’s dsease; CSF, cerebrospinal fluid; K2 EDTA, dipo-
with lumbar forward flexion (when CSF opening
tassium ethylenediaminetetraacetic acid; LP, lumbar puncture;
pressure is not required). NHNN, National Hospital for Neurology and Neurosurgery.
Continued

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How to do it

AD biomarker samples through manometers, as they somewhat arbitrary and depends on the diagnostic
may reduce measured Aβ peptide concentrations by up aim, so it is important for the clinician to bear in mind.
to 5%.18 We undertook a validation of CSF Aβ42/40 ratio
CSF AD biomarker testing in the UK is currently testing on the Lumipulse platform in relation to both
carried out at a single UK Accreditation Service-­ the INNOTEST platform and to amyloid PET data,
accredited laboratory (the Neuroimmunology and resulting in a cut-­point of 0.065 for this ratio, which
CSF Laboratory (NICL) at the Queen Square Insti- gives 95% sensitivity and 89% specificity for identi-
tute of Neurology). We recommend that all external fying symptomatic individuals previously defined as
samples that may incur a transport delay of >2 hours having AD-­like CSF on INNOTEST, and 85% sensi-
after LP are first processed in the referring hospital’s tivity but up to 96% specificity for identifying asymp-
laboratory. This involves centrifugation of CSF for tomatic amyloid PET-­positive individuals using 18 F
5 min at room temperature at 1750 g (3000 rpm) and florbetapir PET scans.23 The t-­tau and p-­tau assay cut-­
aliquoting into 2  mL polypropylene aliquot tubes, points we use are from the manufacturer but also vali-
ensuring a minimum volume of 0.5 mL per tube. The dated in local samples.
aliquots must then be frozen directly at minus 80°C
on the same day of the LP and transported on dry Cerebrospinal fluid neurofilament light
ice to the NICL. Information about the tests offered, chain
sample requirements, costs and turnaround times can Since 2019, the NICL has offered CSF NfL testing
be found in the NICL’s user handbook.19 using the CE-­ marked UmanDiagnostics NF-­ light
ELISA, which allows measurement of CSF NfL over
a wide range of values encountered in normal phys-
CSF AD biomarker assays iology and pathological states (100–10 000  pg/mL
Until recently, we used Conformité Européenne in CSF, although the assay’s dilution linearity allows
(CE-­marked) INNOTEST ELISAs for Aβ 1–42, t-­tau higher values to be quantified reliably if needed).
and tau phosphorylated at serine 181 (p-­ tau181). Figure 2 shows the values obtained by measuring CSF

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However, we switched to the automated Lumi- NfL at the NHNN lab in the first 300 CSF samples
pulse platform (Fujirebio) in July 2020 to allow for since the assay was adopted; as NfL increases with age,
testing of Aβ1–42, Aβ1–40, t-­tau and p-­tau181 using the normal ranges we use are age-­specific (by decade),
CE-­marked assays, the main advantages including taken from a group of >350 normal controls in an
►► Improved diagnostic accuracy: the CSF Aβ42/40 international multicentre study.24
ratio improves the classification of clinical AD versus
non-­AD dementias and improves detection of cerebral Interpreting biomarker results
fibrillar amyloid deposition (as defined by amyloid The National Institute on Aging—Alzheimer's
PET) compared with CSF Aβ42 alone.20 This is prob- Association (NIA-­
AA) research framework for AD
ably because use of CSF Aβ40 concentration corrects
for interindividual variability in the overall rate of Aβ
peptide production.
►► Reduced susceptibility of results to variations in prea-
nalytical handling: normalising to Aβ40 concentrations
at least partly mitigates against the artificial lowering
of Aβ42 through adsorption to sample tube surfaces,17
across multiple freeze–thaw cycles21 and through
repeated tube transfers.22
►► Fewer possible pipetting errors when performing manual
ELISAs.
►► Increased throughput and reduced turnaround time
(results may be obtained in 10 or fewer days, as opposed
to 25 days).
►► Potential for harmonisation of cut-­points or interpreta-
tion with other centres using the same automated plat-
form calibrated against certified reference material. Figure 2  Results from the first 300 samples measured for CSF
It is not straightforward to determine cut points NfL at the Neuroimmunology and CSF laboratory of the Queen
for clinical use. Some of the challenges include accu- Square Institute of Neurology. Where available, age-­adjusted
rate definitions of case–control status (noting that norms (black horizontal lines) are shown from an independent
some healthy people will have preclinical disease) cohort of 359 healthy controls from Yilmaz et al24 . Note:
usually, the upper limit of quantification is 10 000 pg/mL;
and balancing sensitivity (favouring minimising false however, where CSF NfL has been quantified as >10 000 pg/
negatives) with specificity (minimising false positives). mL, the sample has been retested after further dilution. CSF,
The trade-­ off between sensitivity and specificity is cerebrospinal fluid; NfL, neurofilament light chain.

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How to do it

biomarkers conceptualises a spectrum of amyloid, tau issues of classifying people with evidence of AD along
and neurodegeneration (A/T/N) biomarkers on which with other pathologies.
everyone may be defined independently of clinical In our own practice, after having first requested
status; for example, an individual with A+T−N− the test only in the appropriate clinical context
would be classified as having ‘Alzheimer’s pathological (see the Introduction section and table 2), we use a
change’, even if they were asymptomatic. However, staged approach as shown in figure 3. Here, a low
in routine clinical practice, and as advocated by the CSF Aβ42/40 ratio is required, but not sufficient, for
latest International Working Group consensus on making a diagnosis of clinical AD. This is because a
clinical diagnosis of AD,25 we believe it is essential to proportion of people with normal cognition will have
interpret AD CSF biomarkers in the clinical context. amyloid deposition as defined by CSF (about 18% at
Biomarkers should be used to lend support for, or age 50 years, 25% at age 60 years, 33% at age 70 years
against, a clinical formulation of the patient’s presen- and 43% at age 80 years).26 We therefore interpret a
tation and not on their own to make a diagnosis of normal Aβ42/40 ratio to mean that AD is unlikely to be
dementia or any subtype. This is because currently the cause for an individual’s cognitive concerns at any
available biomarkers do not reliably predict clinical age, but because AD pathology may be coincidental
progression in an individual, and there are problems rather than causal at older ages, the positive predic-
of interpreting values near to binary cut-­points, and tive value of a low Aβ42/40 ratio for AD reduces with

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Figure 3  Flow diagram for interpretation of CSF AD biomarkers requested in the context of a possible AD phenotype. AD,
Alzheimer’s disease; CSF, cerebrospinal fluid; NfL, neurofilament light chain.

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How to do it

increasing age. We currently do not routinely request

Box 2  Case studies
t-­tau, as in the AD context it gives similar information
to p-­tau. However, in situations where prion disease is Patient 1
a consideration, a very high t-­tau (eg, above the upper ►► A 61-­year-­old woman presented with a 4-­year
limit of quantification of the assay) with an elevated history of cognitive decline starting with reduced
t-­tau to p-­tau ratio would support a diagnosis of prion motivation, followed by word finding difficulty and
disease that could then later be confirmed with other mispronunciation. There were no ritualistic/obsessive
more specific biomarkers like CSF RTQuIC for prion behaviours and memory was not a significant
protein or characteristic diffusion-­ weighted MRI complaint. She had a history of depression and anxiety
changes. but denied feeling low or anxious currently. She took
Box 2 discusses some illustrative case studies in mirtazapine, propranolol and folic acid. Her mother
which CSF contributed to the clinical diagnosis, with had been diagnosed with AD in her 50s and had died
accompanying figure 4. a few years later. She retired before symptom onset,
The setting of cut-­ points for interpreting CSF and drove a car on familiar routes with no concerns
biomarkers, and harmonising reporting to patients from family. She was an ex-­smoker and drank minimal
and clinicians, is a topic of active work. Currently alcohol.
the NICL participates in the Alzheimer’s Associa- ► ► On examination, she turned frequently to her
tion’s external quality control programme27 for CSF son for reassurance. She was not orientated
Aβ42, Aβ40, t-­tau, p-­tau181 and NfL. This allows to time (day, date, month or year) or location
for monitoring of performance relative to other (town or country). She could register three
laboratories performing these tests globally, and for items but could not recall after a delay. Her
assessing drift of results over time. Certified refer- reading was slow with frequent pauses and some
ence materials and methods28–30 are available for mispronunciations. Spontaneous speech was
CSF Aβ42 and are being developed for Aβ40, t-­tau, fluent but with word-­f inding pauses.
p-­tau181 and NfL. ►► On neuropsychological testing, single-­word and phrase

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A recent survey of 40 laboratories across 15 coun- repetition was satisfactory; naming was impaired.
tries31 indicated that cut-­points are more similar across Single-­word comprehension was intact, but sentence
centres (but still not exactly the same) when automated comprehension was impaired. Visuoperceptual
assays are used, and this may in part relate to differ- processing was impaired, but simple visual detection
ences in preanalytical conditions but also to differ- was intact. Speed was very slow and there was
ences in the populations served. This study proposed executive dysfunction.
a harmonisation of reporting of CSF AD biomarkers ►► MR scan of the brain (figure 4A) did not show
according to the eight different combinations that significant atrophy or vascular burden, but a
may be derived when the axes of amyloid, t-­tau and fluorodeoxyglucose (FDG) PET scan (figure 4B) showed
p-­tau are interpreted using centre-­specific binary cut-­ hypometabolism in the temporoparietal region
points. Other methods of reporting used mostly in with involvement of the precuneus bilaterally, more
Europe include the Paris-­North, Lille and Montpellier pronounced on the left side, and also minimal FDG
score,32 derived simply as the number of these three hypometabolism in the left frontal lobe.
biomarkers that is abnormal, and the Erlangen score, ►► CSF showed white cell count of 1/µL (0–5), red cells
which incorporates the concept of border zones to 1/µL, protein 0.24 g/L (0.13–0.45), albumin quotient
account for the possible influence of assay imprecision 3.02 (<7.2), glucose 3.3 mM (2.2–4.2), plasma glucose
on the interpretation.33 34 5.2 mM (3.9–5.8), oligoclonal bands negative in CSF
and serum.
Future ►► CSF dementia biomarkers were Aβ42/40 ratio 0.036
Most patients assessed in ‘memory clinics’ or dementia (≥0.065), p-­tau181 216 pg/mL (≤57), t-­tau 1041 pg/
services in the UK are under the care of psychiatrists or mL (146-­595) and NfL 2892 pg/mL (<1781); this profile
geriatricians. A recent report by Alzheimer’s Research was considered typical of AD.
UK and the Royal College of Psychiatrists35 detailed ►► She was given a diagnosis of AD dementia (logopenic
the many barriers that need to be overcome for these variant) and advised that she would need to stop
services to be ready to deliver disease-­modifying treat- driving and inform the Driver and Vehicle Licensing
ments. Such treatments have become particularly Agency of her diagnosis. She was offered treatment
topical, given the US Food and Drug Administration’s with a cholinesterase inhibitor, referred for speech and
recent accelerated approval of one anti-­Aβ antibody language therapy and, in view of her family history,
for therapeutic use in mild cognitive impairment AD offered genetic testing for rare monogenetic causes of
or mild AD dementia and the pending applications for AD.
approval of other similar agents in the USA and Europe.
Deployment of molecular biomarkers such as CSF Continued
testing at scale in these services currently is limited by

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How to do it

Box 2  Continued Box 2  Continued

Patient 2 ►► CSF showed white cell count of 1 /µL (0–5), red cells
►► A 68-­year-­old woman presented with a 2-­year history 2 /µL, protein 0.48 g/L (0.13–0.45), albumin quotient
of deteriorating driving ability, vision problems, 7.35 (<7.2), glucose 3.2 mM (2.2–4.2), plasma glucose
emotional blunting, reduced social interaction, 5.0 mM (3.9–5.8), oligoclonal bands negative in CSF
increased eating, word-­finding problems and frequent and serum.
falls. Her mood had become low since failing a road ►► CSF dementia biomarkers were Aβ42/40 ratio 0.054
driving test that identified problems with attention, (≥0.065), p-­tau181 46 pg/mL (≤57) and NfL 4318 pg/
information processing and vehicle placement. Her mL (<1781). Despite the low Aβ42/40 ratio, the
medical history included hypercholesterolaemia and normal p-­tau181 did not support AD as the cause of
urinary urgency and she took a statin, omeprazole, symptoms.
calcium-­vitamin D supplements and mirabegron. She ►► She was diagnosed with progressive supranuclear
lived alone and was independent in daily activities, palsy–frontotemporal dementia and given
as well as being a carer for her mother who had been speech therapy input with an 8-­week course in
diagnosed with dementia at age 84. Her father had communication partner training, as well as signposted
late-­onset ataxia and had died at age 81. She had two to Rare Dementia Support and the PSP Association.
siblings and two daughters who were all well. She was
Normal ranges for CSF biomarkers are shown in brackets.
an ex-­smoker of 40 pack years and drank 1 bottle of
Aβ42/40, amyloid-β 1–42/1–40 ratio; AD, Alzheimer’s
wine per week.
disease; CSF, cerebrospinal fluid.
►► On examination, she was intermittently tearful and had
frequent pauses in spontaneous speech. She scored
27/30 on the Mini-­Mental State Examination, losing physical infrastructure, availability of clinical expertise
two marks for orientation and one for recall. Bedside and clinical commissioning. Through better multidisci-
cognitive testing showed impaired letter fluency (9 plinary working, neurologists and allied professionals

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‘C’ words in 1 min) but intact naming, repetition and in neurology services will have a role in supporting our
comprehension. There was patchy difficulty with colleagues in these areas of significant unmet need, by
memory and arithmetic. She gave concrete explanations
for proverbs and had mild difficulty with the Stroop
test. Physical examination showed square wave jerks
in primary gaze, and ‘round the houses’ vertical eye
movements. There was left arm bradykinesia with no
rigidity, ataxia or tremor, and reflexes were symmetrical
with down-­going plantars.
►► On neuropsychological testing, expressive language
was slightly lacking in grammar but she could
use sentences. She made occasional semantic
and phonemic errors, but single-­word and phrase
repetitions were intact. Single-­word comprehension
was good for concrete but poor for abstract nouns
and also for grammar. Tests of executive function
showed significantly impaired response inhibition
(Stroop), impaired letter and category fluency, and
inflated cognitive estimates, with mildly slowed
processing speed. Visuoperceptual functions were
acceptable, but visuospatial processing (Adult Memory
and Information Processing Battery figure copy <5th
centile) was impaired.
►► MR scan of brain showed mild generalised
parenchymal volume loss without lobar preference or
asymmetry. The choroidal fissures were prominent but
Figure 4  MRI brain scans from the two patient case studies.
hippocampal volumes appeared preserved (Figure 4C– (A) Patient 1, MR T1 coronal multiplanar reconstruction at
E). A mild burden of white matter microangiopathy mid-­hippocampal level. (B) Patient 1, FDG PET axial fused.
was noted without evidence of recent infarct (C) Patient 2, MR T1 coronal multiplanar reconstruction at
(figure 4F). orbitofrontal level. (D) Patient 2, MR T1 coronal multiplanar
reconstruction at mid-­hippocampal level. (E) Patient 2, MR T1
Continued
sagittal multiplanar reconstruction at midbrain level. (F) Patient
2, MR fluid-­attenuated inversion recovery coronal.

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How to do it

sharing our clinical experience and our pathways to of disease, it would be ideal to be able to predict
accessing these investigations. individualised risks for conversion to dementia. In
Blood measurement of NfL on the Simoa plat- research cohorts outside the UK, algorithms have been
form is set to enter the clinical testing schedule in the derived incorporating CSF biomarkers36 or plasma
UK soon via the NICL, and this will be followed by biomarkers37 with demographic factors, cognitive
technical validation and application of plasma phos- testing and imaging findings to predict conversion of
pho-­tau. While blood biomarkers may in due course mild cognitive impairment to AD dementia. Further
have sufficient sensitivity and specificity to be used work is needed to validate this type of approach in the
alone, currently the most likely scenario is for these to UK National Health Service.
be used to prescreen individuals before proceeding to Efforts are ongoing to discover and validate molec-
CSF examination or amyloid PET. ular biomarkers for other dementias and related disor-
As clinical trials move into earlier stages including ders, such as specific tau strains in non-­AD tauopathies,
the preclinical and mild cognitive impairment stages such as progressive supranuclear palsy, ‍ ‍-­synculein in
dementia with Lewy bodies, and TAR DNA-­binding
protein 43 in frontotemporal dementias. In time, it
may become possible to index the relative contribu-
Key points
tions of different coexisting molecular pathologies to
►► Current guidelines/appropriate use criteria for a patient’s symptoms or likelihood of progression to
cerebrospinal fluid (CSF) testing in dementia indicate dementia, and provide evidence for targeted therapies
it should be carried out where knowing the molecular in a more personalised way.
diagnosis will change management.
►► The typical CSF profile of Alzheimer’s disease is a low Author affiliations
1
Dementia Research Centre, Department of Neurodegenerative Disease, UCL
amyloid-β 1–42/1–40 ratio, elevated p-­tau181 and Queen Square Institute of Neurology, London, UK
t-­tau. 2
Neuroimmunology and CSF Laboratory, National Hospital for Neurology and
►► An elevated CSF neurofilament light chain

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Neurosurgery, London, UK
3
concentration may occur in a wide variety of Department of Neuroinflammation, UCL Queen Square Institute of Neurology,
London, UK
conditions involving either acute or chronic neuronal 4
MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of
damage. Neurology, London, UK
►► Services incorporating CSF neurodegeneration 5
Dementia Research Centre, Department of Neurodegenerative Disease,
biomarker testing should incorporate the relevant University College London Institute of Neurology, London, UK
6
Dementia Research Centre, Department of Neurodegenerative Disease,
clinical expertise in procedures, logistical requirements National Hospital for Neurology and Neurosurgery, London, UK
for sample transport and processing, robust processes 7
Fluid Biomarkers Laboratory, UK DRI at University College London, UK
for interpreting and feeding back of results to Dementia Research Institute, London, UK
8
requesting clinicians and patients, and improved Clinical Neurochemistry Laboratory, Department of Psychiatry and
Neurochemistry, Institute of Neuroscience and Physiology, University of
access to testing for patients cared for in neurology, Gothenburg Sahlgrenska Academy, Goteborg, Sweden
psychiatry and elderly care services.
Twitter Ashvini Keshavan @AshviniKeshavan, Michael PT
Lunn @mike_the_nerve, Jonathan D Rohrer @ftdtalk and
Recommended reading Jonathan M Schott @jmschott
Acknowledgements  We are grateful to Dr Zane Jaunmuktane
1. Olsson B, Lautner R, Andreasson U, et al. CSF and for providing the images in figure 1. The UCL Dementia
blood biomarkers for the diagnosis of Alzheimer’s Research Centre is supported by the Alzheimer’s Society,
disease: a systematic review and meta-­analysis. The Alzheimer's Research UK, Brain Research UK and the Wolfson
Lancet Neurology 2016;15(7):673–84. Foundation.
2. Duits FH, Martinez-­Lage P, Paquet C, et al. Contributors  AK and JMS conceived of and drafted the main
Performance and complications of lumbar puncture manuscript. All authors contributed significantly to the content
of the manuscript and reviewed the drafts and provided
in memory clinics: Results of the multicenter lumbar feedback.
puncture feasibility study. Alzheimers Dement
Funding  AK is supported by a Weston Brain Institute and
2016;12(2):154–63. Selfridges Group Foundation award (UB170045). RWP is
3. NICE. Dementia: assessment, management and supported by an Alzheimer’s Association Clinician Scientist
support for people living with dementia and their Fellowship and the UK Dementia Research Institute. JDR is
carers. NICE Guideline 97. London, 2018 (available at supported by the Miriam Marks Brain Research UK Senior
Fellowship and has received funding from an MRC Clinician
https://www.nice.org.uk/guidance/ng97) Scientist Fellowship (MR/M008525/1) and the NIHR Rare
4. Shaw LM, Arias J, Blennow K, et al. Appropriate Disease Translational Research Collaboration (BRC149/NS/
use criteria for lumbar puncture and cerebrospinal MH). HZ is a Wallenberg Scholar supported by grants from
fluid testing in the diagnosis of Alzheimer’s disease. the Swedish Research Council (#2018-­02532), the European
Alzheimers Dement 2018;14(11):1505–21. Research Council (#681712), Swedish State Support for
Clinical Research (#ALFGBG-­720931), the Alzheimer Drug

Keshavan A, et al. Pract Neurol 2022;22:285–294. doi:10.1136/practneurol-2021-003310 9 of 11

 Pract Neurol: first published as 10.1136/practneurol-2021-003310 on 17 March 2022. Downloaded from http://pn.bmj.com/ on September 6, 2022 at EVES-Escola Valenciana d'Estudis de la
How to do it
Discovery Foundation (ADDF), USA (#201809-­2016862), 2 Alzbiomarker database, version 3.0: Alzforum, 2021.
the AD Strategic Fund and the Alzheimer's Association Available: http://www.alzforum.org/alzbiomarker [Accessed 9
(#ADSF-­21-­831376-­C, #ADSF-­21-­831381-­C and #ADSF-­ Feb 2022].
21-­831377-­C), the Olav Thon Foundation, the Erling-­ 3 Goossens J, Bjerke M, Van Mossevelde S, et al. Diagnostic
Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor,
value of cerebrospinal fluid tau, neurofilament, and
Hjärnfonden, Sweden (#FO2019-­0228), the European
Union’s Horizon 2020 research and innovation programme progranulin in definite frontotemporal lobar degeneration.
under the Marie Skłodowska-­Curie grant agreement No Alzheimers Res Ther 2018;10:31.
860197 (MIRIADE) and the European Union Joint Program 4 Lleó A, Irwin DJ, Illán-­Gala I, et al. A 2-­step cerebrospinal
for Neurodegenerative Disorders (JPND2021-­00694). algorithm for the selection of frontotemporal lobar
JMS is supported by Engineering and Physical Sciences degeneration subtypes. JAMA Neurol 2018;75:738–45.
Research Council (EP/J020990/1), British Heart Foundation 5 Duits FH, Martinez-­Lage P, Paquet C, et al. Performance and
(PG/17/90/33415) and EU’s Horizon 2020 research and
complications of lumbar puncture in memory clinics: results of
innovation programme (666992). NCF and HZ are supported
by UK Dementia Research Institute at University College the multicenter lumbar puncture feasibility study. Alzheimers
London. MSH, MPTL, RWP, JDR, CJM, NCF and JMS are Dement 2016;12:154–63.
supported by the National Institute for Health Research 6 NICE. Dementia: assessment, management and support for
University College London Hospitals Biomedical Research people living with dementia and their carers. London: NICE
Centre. Guideline 97, 2018.
Competing interests  RWP is codirector of the NfL 7 Shaw LM, Arias J, Blennow K, et al. Appropriate use
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Wave Life Sciences and Prevail Therapeutics, and had 8 Beaudry P, Cohen P, Brandel JP, et al. 14-­3-­3 protein, neuron-­
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on the international steering committee for aducanumab,
and has lectured for Biogen. NCF’s research group has 9 Skillbäck T, Rosén C, Asztely F, et al. Diagnostic performance
received payment for consultancy or for conducting studies of cerebrospinal fluid total tau and phosphorylated tau in

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from Biogen, Eli Lilly Research Laboratories, Ionis and Creutzfeldt-­Jakob disease: results from the Swedish mortality
Roche. NCF received no personal compensation for the registry. JAMA Neurol 2014;71:476–83.
aforementioned activities. NCF also serves on a Data 10 Green AJE, Thompson EJ, Stewart GE. Use of 14-­3-­3 and
Safety Monitoring Board for Biogen. JMS has received
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wholly owned subsidiary of Eli Lilly), has consulted for Creutzfeldt-­Jakob disease. J Neurol Neurosurg Psychiatry
Roche Pharmaceuticals, Biogen, Merck, and Eli Lilly, given 2001;70:744–8.
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sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and
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Gothenburg AB, which is a part of the GU Ventures Incubator JAMA Netw Open 2022;5:e2146319–e19.
Programme. 14 Steinacker P, Blennow K, Halbgebauer S, et al.
Patient consent for publication  Not applicable. Neurofilaments in blood and CSF for diagnosis and
prediction of onset in Creutzfeldt-­Jakob disease. Sci Rep
Ethics approval  This study does not involve human
participants. 2016;6:38737.
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Provenance and peer review  Commissioned; externally
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neurology: a systematic review and meta-­analysis. JAMA Neurol
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Jonathan D Rohrer http://orcid.org/0000-0002-6155-8417 diseases. Alzheimers Dement 2017;8:111–26.
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Jonathan M Schott http://orcid.org/0000-0003-2059-024X of tau proteins and amyloid beta peptides. Clin Chem
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