TEST CATALOG ORDERING & RESULTS SPECIMEN HANDLING CUSTOMER SERVICE EDUCATION & INSIGHTS
Test Catalog

Test ID: ADEVL    
Alzheimer Disease Evaluation, Spinal Fluid

Useful For Suggests clinical disorders or settings where the test may be helpful

Assessment of adults with cognitive impairment being evaluated for Alzheimer disease (AD) and other causes of cognitive impairment

 

These assays should not be used to predict the development of dementia or other neurologic conditions or to monitor response to therapies.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Currently the diagnosis of probable Alzheimer disease (AD) is made based on clinical symptoms, largely by the exclusion of other causes of dementia, with postmortem evidence of AD pathology required to confirm the diagnosis. Two common neuropathologic features found in the brain of patients with AD dementia are the presence of plaques composed of beta-amyloid (Abeta) peptides and intracellular neurofibrillary tangles containing hyperphosphorylated Tau (tubulin-associated unit) proteins. These 2 groups of molecules are the most established biomarkers of the disease used in clinical and research practice. Positron emission tomography (PET) imaging using FDA-approved amyloid radiotracer to visualize the presence of amyloid lesions in the cerebral cortex is available in some specialized centers. Measuring Abeta peptides and Tau proteins in cerebrospinal fluid (CSF) is being proposed as an alternative/adjunct to imaging studies to assess AD pathology. Recently the use of these biomarkers has been included in the new consensus research diagnostic criteria for AD, mild cognitive impairment (MCI), and preclinical AD, proposed by the National Institute on Aging and Alzheimer's Association (NIA-AA) Research Framework.

 

The CSF assays included in this evaluation are beta-amyloid (1-42; Abeta42), total-Tau (t-Tau) and phosphorylated-Tau (p-Tau181).

 

Abeta42 is approximately 4 kDa protein of 42 amino acids that is formed following proteolytic cleavage of a transmembrane protein known as amyloid precursor protein (APP). Due to its hydrophobic nature, Abeta42 has the propensity to form aggregates and oligomers. Oligomers form fibrils that accumulate into amyloid plaques. These pathological changes in Abeta42 are reflected by the decrease in the CSF concentrations of Abeta42 and/or by the increase in the brain uptake of specific tracers during beta-amyloid PET.

 

Tau is present as six isoforms in human brain tissue. These isoforms are generated by alternative splicing of the pre-mRNA. The t-Tau assay measures all these isoforms. The most common post-translational modification of Tau proteins is phosphorylation. During neurodegeneration, abnormal phosphorylation leads to the formation of intracellular neurofibrillary tangles composed of the Tau protein that has undergone hyper-phosphorylation and developed aggregates of hyper-phosphorylated Tau proteins called p-Tau. The p-Tau assay detects phosphorylated Tau at threonine 181 (p-Tau181).

 

Pathological changes associated with AD are reflected by an increase in the CSF concentrations of t-Tau and p-Tau. Increases in CSF t-Tau reflect the intensity of the neuronal and axonal damage and degeneration and is associated with a faster progression from MCI to AD. Increases in CSF p-Tau concentrations are also associated with a faster progression from MCI to AD with more rapid cognitive decline in AD patients and in mild AD dementia cases.

 

The Alzheimer's Association has developed an appropriate use criterion (AUC), in order to guide safe and optimal use of CSF testing for AD pathology detection in the diagnostic process. The use of CSF biomarker testing may be indicated for the following patient groups:

1) Patients with subjective cognitive decline (SCD) who are considered to be at increased risk for AD

2) Patients with MCI that is persistent, progressing, and unexplained

3) Patients with symptoms that suggest possible AD

4) MCI or dementia with an onset at an early age (less than 65)

5) Patients meeting core clinical criteria for probable AD with typical age of onset

6) Patients whose dominant symptom is a change in behavior (eg, Capgras syndrome, paranoid delusions, unexplained delirium, combative symptoms, and depression) and where AD diagnosis is being considered.

Ultimately, the decision to initiate CSF testing for the evaluation of suspected AD is also based on the clinical judgment of expert providers and the patient's individual presentation.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

Abeta42: >1026 pg/mL

Total-Tau: < or =238 pg/mL

Phospho-Tau 181: < or =21.7 pg/mL

p-Tau/Abeta42: < or =0.023

Interpretation Provides information to assist in interpretation of the test results

A beta-amyloid (1-42; Abeta42) result greater than 1026 pg/mL is consistent with a negative amyloid positron emission tomography (PET) scan. A negative amyloid PET scan indicates the presence of no or sparse neuritic plaques and is inconsistent with a neuropathological diagnosis of Alzheimer disease (AD). An Abeta42 result greater than 1026 pg/mL is associated with a reduced likelihood that a patient's cognitive impairment is due to AD. Total Tau (t-Tau) and phosphorylated Tau (p-Tau181) cerebrospinal fluid (CSF) concentrations increase approximately 2 to 3-times as much in patients with mild-moderate AD as compared to age-matched controls. A t-Tau and/or p-Tau181 concentration of less than or equal to 238 pg/mL and less than or equal to 21.7 pg/mL, respectively, reduces the likelihood that a patient's cognitive impairment is due to AD.

 

The use of p-Tau181/Abeta42 ratio provides better concordance with amyloid PET scan when compared to Abeta42, p-Tau181 and t-Tau individually. A cut-off of 0.023 provides optimal balance between NPA (negative % agreement) and PPA (positive % agreement) when compared to amyloid PET results. A p-Tau181/Abeta42 ratio of less than or equal to 0.023 has a 92% NPA with normal amyloid PET. A ratio of greater than 0.023 has a 92% PPA with abnormal amyloid PET.

 

High CSF t-Tau protein concentrations are found in other neurodegenerative diseases such as prion disease or Creutzfeldt-Jakob disease (CJD). In this situation, an elevated t-Tau concentration and an increased t-Tau to p-Tau ratio has a very high specificity for differential diagnoses of CJD.

 

Abnormal (+)/Normal (-)

Individual comments for AD reporting values

Abeta42 (-)

phospho Tau (-)

total Tau (-)

Normal concentrations of Abeta42, phospho-Tau, and total-Tau concentrations are present in CSF. These results are not consistent with the presence of pathological changes associated with Alzheimer's disease.

Abeta42 (+)

phospho-Tau (-)

total-Tau (-)

Abnormal Abeta42 concentrations are present in CSF.

Phospho-Tau and total-Tau concentrations are normal.

These results may be consistent with Alzheimer's related pathologic change. 

Abeta42 (+)

phospho-Tau (+)

total-Tau (-)

Abnormal Abeta42 and phospho-Tau concentrations are present in CSF.

The total-Tau concentration is normal.

These results are consistent with the presence of Alzheimer's disease.

Abeta42 (+)

phospho Tau (+)

total Tau (+)

Abnormal Abeta42, phospho-Tau and total-Tau concentrations are present in CSF. These results are consistent with the presence of Alzheimer's disease.

Abeta42 (+)

phospho Tau (-)

total Tau (+)

Abnormal Abeta42, and total-Tau concentrations are present in CSF.

The phospho-Tau concentration is normal.

These results may be consistent with Alzheimer's related pathologic change.

Abeta42 (-)

phospho-Tau (+)

total-Tau (-)

Abnormal phospho-Tau concentrations are present in CSF.

Abeta42 and total-Tau concentrations are normal.

These results are not consistent with the presence of pathological changes associated with Alzheimer's disease. 

Abeta42 (-)

phospho tau (-)

total-Tau (+)

Abnormal total-Tau concentrations are present in CSF.

The Abeta42 and phospho-Tau concentrations are normal.

These results are not consistent with the presence of pathological changes associated with Alzheimer's disease.

Abeta42 (-)

phospho-Tau (+)

total-Tau (+)

Abnormal phospho-Tau and total-Tau concentrations are present in CSF.

The Abeta42 concentration is normal.

These results are not consistent with the presence of pathological changes associated with Alzheimer's disease. 

 

This table and interpretations are based on the National Institute on Aging and Alzheimer's Association research framework diagnostic recommendations.(1)

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

A positive cerebrospinal fluid (CSF) beta-amyloid 42 (Abeta42), total Tau (t-Tau), or phosphorylated Tau (p-Tau181) result, or p-Tau181/Abeta42 ratio does not establish a diagnosis of Alzheimer disease (AD) or other cognitive disorder. These results should be interpreted in combination with other clinical diagnostic and radiologic evaluations.

 

An abnormal p-Tau181/Abeta42 ratio in the context of a normal Abeta42 may be observed in some individuals. In some situations, interindividual differences in overall concentration of Abeta peptide production and/or in p-Tau elevation stemming from other neurodegenerative disease may result in an abnormal p-Tau181/Abeta42 ratio.

 

To achieve the best clinical performance (ie, keep patient misclassification rate at a minimum), it is important that the recommended pre-analytical protocol for sample collection is followed. Based on the Alzheimer's Association international guidelines for consensus handling of CSF for clinical measurements of Abeta42 and Tau, CSF should be collected using the drip method and directly collected into a low bind polypropylene tube. The low bind polypropylene tube should be filled to at least 80% of the tube volume capacity. Failure to adhere to this sample collection recommendation may impact to the measured Abeta42 concentration and may influence the interpretation relation to the laboratory used cut-offs.

 

Improper specimen handling or interindividual differences in overall concentration of Abeta peptide production may yield an abnormally low Abeta42 in the context of a normal p-Tau181/Abeta42 ratio. Results should be interpreted in concordance with other clinical information.

 

Exposure of CSF to polystyrene tubes can reduce concentrations of the amyloid Abeta42 by as much as 20% to 50% due to adherence of the sticky amyloid protein to polystyrene tube surface material, potentially altering clinical interpretation, including the p-Tau181/Abeta 42 ratio. p-Tau181 and t-Tau protein do not substantially adhere to polystyrene collection tubes.

 

Failure to adhere to the specimen collection instructions provided may result in falsely low Abeta42 concentrations and potential misdiagnosis of AD.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1 Jack CR Jr, Bennett DA, Blennow K, et al: NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018 Apr;14(4):535-562

2. Lifke V, Kollmorgen G, Manuilova E, et al: Elecsys Total-Tau and Phospho-Tau (181P) CSF assays: Analytical performance of the novel, fully automated immunoassays for quantification of tau proteins in human cerebrospinal fluid. Clin Biochem. 2019 Oct;72:30-38

3. Willemse EAJ, van Maurik IS, Tijms BM, et al: Diagnostic performance of Elecsys immunoassays for cerebrospinal fluid Alzheimer's disease biomarkers in a nonacademic, multicenter memory clinic cohort: The ABIDE project. Alzheimers Dement (Amst). 2018 Sep 12;10:563-572

4. Hansson O, Seibyl J, Stomrud E et al: CSF biomarkers of Alzheimer's disease concord with amyloid-beta PET and predict clinical progression: A study of fully automated immunoassays in BioFINDER and ADNI cohorts. Alzheimers Dement. 2018 Nov;14(11):1470-1481

5. Schindler SE, Gray JD, Gordon BA, et al: Cerebrospinal fluid biomarkers measured by Elecsys assays compared to amyloid imaging. Alzheimers Dement. 2018 Nov;14(11):1460-1469

6. Shaw LM, Arias J, Blennow K, et al: Appropriate use criteria for lumbar puncture and cerebrospinal fluid testing in the diagnosis of Alzheimer's disease. Alzheimers Dement. 2018; 14(11):1505-1521

7. Hansson O, Batrla R, Brix B, et al: The Alzheimer's Association international guidelines for handling of cerebrospinal fluid for routine clinical measurements of amyloid beta and tau. Alzheimers Dement. 2021 Mar 31. doi: 10.1002/alz.12316. Epub ahead of print