Evidence-Based Reviews

Do biomarkers for Alzheimer’s disease have utility in everyday practice?

Current Psychiatry. 2014 June;13(6):57-60

AD remains a clinical diagnosis, but research might change that with specific tests for risk and disease

References

1. Jack CR Jr, Albert MS, Knopman DS, et al. Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011; 7(3):257-262.
2. McKhann GM, Knopman DS. Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging- Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):263-269.
3. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280-292.
4. Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging- Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011; 7(3):270-279.
5. Cummings JL. Biomarkers in Alzheimer’s disease– perspectives for the future. US Neurology. 2010;6(1):23-27.
6. Sperling R, Keith J. Biomarkers of Alzheimer disease: current and future applications to diagnostic criteria. Continuum (Minneap Minn). 2013;19(2 Dementia):325-338.
7. Craig-Shapiro R, Fagan AM, Holtzman DM. Biomarkers of Alzheimer’s disease. Neurobiol Dis. 2009;35(2):128-140.
8. Jack CR Jr, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 2010;9(1):119-128.
9. Foster NL, Heidebrink JL, Clark CM, et al. FDG-PET improves accuracy in distinguishing frontotemporal dementia and Alzheimer’s disease. Brain. 2007;130(pt 10):2616-2635.
10. National Coverage Determination (NCD) for FDG PET for Dementia and Neurodegenerative Diseases (220.6.13). Centers for Medicare and Medicaid Services. http://www. cms.gov/medicare-coverage-database/details/ncd-details. aspx?NCDId=288&ncdver=3&bc=BAABAAAAAAAA&. Accessed May 9, 2014.
11. Small GW, Bookheimer SY, Thompson PM, et al. Current and future uses of neuroimaging for cognitively impaired patients. Lancet Neurol. 2008;7(2):161-172. 12. Clark CM, Schneider JA, Bedell BJ, et al. Use of florbetapir- PET for imaging beta-amyloid pathology. JAMA. 2011;305(3): 275-283.
13. Johnson KA, Minoshima S, Bohnen NI, et al. Update on appropriate use criteria for amyloid PET imaging: dementia experts, mild cognitive impairment, and education. Amyloid Imaging Task Force of the Alzheimer’s Association and Society for Nuclear Medicine and Molecular Imaging. Alzheimers Dement. 2013;9(4):e106-e109.
14. AMYViD [package insert]. Indianapolis, IN: Eli Lilly & Co; 2012.
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16. Zakaib GD. FDA approves Amyvid for clinical use. Alzforum. http://www.alzforum.org/news/research-news/ fda-approves-amyvid-clinical-use. Published April 9, 2012. Accessed May 16, 2014.
17. Skillbäck T, Zetterberg H, Blennow K, et al. Cerebrospinal fluid biomarkers for Alzheimer disease and subcortical axonal damage in 5,542 clinical samples. Alzheimers Res Ther. 2013;5(5):47.
18. Irizarry MC. Biomarkers of Alzheimer disease in plasma. NeuroRx. 2004;1(2):226-234.
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Guidelines for diagnosing Alzheimer’s disease (AD) are undergoing the first major changes since they were developed 30 years ago. The National Institute on Aging (NIA) and the Alzheimer’s Association (AA) have established workgroups to revise guidelines that were written in 1984.¹

One of the major changes to these new guidelines is mention of research on biomarkers for diagnosing and monitoring progression of dementia in AD. This is an exciting and provocative development, but the questions practitioners who diagnose and treat AD should be asking are whether such biomarkers have utility in clinical practice today, or whether their application is a distant promise of continuing research.

Principles put forward in the guidelines
The new AD guidelines set forth in 3 major papers by the workgroups created by the NIA and AA include a change in nomenclature of AD.² The workgroups have sought to define AD with specific stages that include:
• a preclinical/prodromal phase, in which the pathophysiology responsible for future cognitive changes is ongoing but lacks clinical manifestations³ • mild cognitive impairment, now considered a distinct entity from dementia and diagnosed when a person has early signs of AD; manifestations of impaired cognition in early disease are not significant enough to affect daily functioning.⁴

These newly formulated stages of AD rely on clinical judgment, and AD remains a clinical diagnosis. However, the new diagnostic guidelines include the use of biomarkers to measure disease progression.

Biomarkers of normal biologic function and pathology
The Biomarkers Definitions Working Group defines a biomarker as:

… a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.⁵

These characteristics include imaging studies and body fluids, such as serum and cerebrospinal fluid (CSF).

In AD, biomarkers are meant to measure the pathogenic processes of:
• accumulation and deposition of amyloid β _protein (Aβ42) plaques
• neuronal degeneration characterized by an increase in phosphorylated tau protein and neurofibrillary tangles.⁶
The purpose of these biomarkers is to identify ongoing disease and help the clinician stage patients who display a spectrum of symptoms.

Four classes of biomarkers (Table⁷)have been identified for use in the diagnosis of, and research on, AD:
• neuroimaging
• CSF
• serum
• genetic markers.

Neuroimaging
The basic purpose of CT and MRI of the head in the workup of cognitive impairment is to rule out a lesion in the brain, such as a tumor or hemorrhage, as the cause of, or contributor to, the impairment. Several neuroimaging studies are available to aid in diagnosing AD and distinguishing it from other causes of dementia, including:
• Fludeoxyglucose (FDG) positron-emission tomography (PET) scanning
• MRI
• Florbetapir F 18 Injection for PET.

FDG PET identifies areas of the brain in which glucose metabolism is decreased. This finding is thought to represent synaptic dysfunction.⁸ The true clinical utility of FDG PET appears to be as an aid in distinguishing cases of AD from frontotemporal dementia, by identifying regions of metabolic dysfunction.⁹ (Note: Medicare will reimburse for FDG PET only if 1) the patient has met diagnostic criteria for both AD and frontotemporal dementia for at least 6 months and 2) the cause of symptoms is uncertain.¹⁰)

FDG PET also can be useful in patients with mild cognitive impairment by identifying hypometabolism in the temporal and parietal regions of the brain years before clinical AD develops.In addition to FDG, 2 other imaging probes—Pittsburgh compound and 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl) amino]-2-naphthyl}-ethylidene) malononitrile (more commonly, FDDNP)—have been used with PET as research tools to demonstrate evidence of AD.¹¹

MRI has been used to measure hippocampal atrophy and cortical thinning that occurs as a patient progresses from normal cognitive function or mild cognitive impairment to full dementia.⁵ The degree of atrophy has not been well correlated with the degree of functional impairment.

Florbetapir F 18 Injection was approved by the FDA in October 2013, under the brand name AMYViD, for measuring the quantity of Aβ42 deposition in the brain. When injected, this radiopharmaceutical binds to Aβ42 and can be detected on PET.¹² Use criteria for AMYViD PET recently were developed¹³; the technique is indicated as an additional diagnostic tool for ruling out AD.

A negative AMYViD scan indicates sparse or no Aβ42 plaques, and is inconsistent with AD. However, a positive AMYViD scan does not establish a diagnosis of AD or other cognitive disorder.¹⁴ This lack of specificity decreases the potential utility of the scan in clinical practice.

Use of AMYViD PET in general practice also is constrained by cost, which varies by location, based on the fee for the PET scan ($1,000 to $3,000)¹⁵; to that, add the cost of a dose of AMYViD ($1,600, wholesale).¹⁶ The technique is not reimbursable, and the total out-of-pocket expense can be as much as $5,000—making an AMYViD PET prohibitive.

References

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Do biomarkers for Alzheimer’s disease have utility in everyday practice?

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