The use of biomarkers for the etiologic diagnosis of MCI in Europe: An EADC survey

The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it “always/frequently”) followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as “moderate”. Seventy-nine percent of responders felt “very/extremely” comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.

DOI: http://dx.doi.org/10.1016/j.jalz.2014.06.006

Amyloid imaging

Biomarkers can predict risk for Alzheimer’s several years before symptoms appear

Brain imaging and spinal-fluid testing can help predict which cognitively normal older people will develop Alzheimer’s disease as many as 7.5 years before symptoms appear, according to a new study supported in part by the NIA. The findings confirm the power of biomarkers as predictors of disease risk in the earliest, symptom-free stages of Alzheimer’s disease. These biomarkers may prove to be valuable tools in testing promising treatments in future studies. While not typically used in clinical practice, investigators worldwide are studying, refining, and standardizing biomarkers aimed at identifying who is at risk for developing Alzheimer’s, the most common form of dementia in older adults. The biomarkers in this study, published May 7 in Neurology, included positron emission tomography (PET) scans of the brain to detect deposits of the telltale protein beta-amyloid, as well as levels of beta-amyloid and another protein, tau, found in cerebrospinal fluid. The research team, at Washington University School of Medicine in St. Louis, tracked the cognition of 201 dementia-free volunteers, ages 45 to 88, at the school’s Alzheimer’s Disease Research Center.
The researchers found that abnormal levels of biomarkers identified in PET scans and lumbar punctures could predict who would develop cognitive impairment among the volunteers who were followed for an average of 3.7 years, but in some cases as long as 7.5 years. Some 28 volunteers (14 percent) of the group developed memory loss and other signs of cognitive impairment. Abnormal levels of all biomarkers predicted the development of Alzheimer’s dementia equally well, the study found. Older participants, men, and African Americans who developed dementia did so faster than those who were younger, female, and white, the researchers report. In a few cases, participants with abnormal biomarker levels remained cognitively normal, perhaps because of “cognitive reserve,” the ability of some brains to cope with or stave off decline.
Reference: Roe CM, et al. Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later.

Reference: Roe CM, et al. Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later. Neurology 2013;80(19):1784-91.

Association of plasma and cortical amyloid beta is modulated by APOE ε4 status

Background

Apolipoprotein E (APOE) ε4 allele's role as a modulator of the relationship between soluble plasma amyloid beta (Aβ) and fibrillar brain Aβ measured by Pittsburgh compound B positron emission tomography ([¹¹C]PiB PET) has not been assessed.

Methods

Ninety-six Alzheimer's Disease Neuroimaging Initiative participants with [¹¹C]PiB scans and plasma Aβ_1–40 and Aβ_1–42 measurements at the time of PET scanning were included. Regional and voxelwise analyses of [¹¹C]PiB data were used to determine the influence of APOE ε4 allele on association of plasma Aβ_1–40, Aβ_1–42, and Aβ_1–40/Aβ_1–42 with [¹¹C]PiB uptake.

Results

In APOE ε4− but not ε4+ participants, positive relationships between plasma Aβ_1–40/Aβ_1–42 and [¹¹C]PiB uptake were observed. Modeling the interaction of APOE and plasma Aβ_1–40/Aβ_1–42 improved the explained variance in [¹¹C]PiB binding compared with using APOE and plasma Aβ_1–40/Aβ_1–42 as separate terms.

Conclusions

The results suggest that plasma Aβ is a potential Alzheimer's disease biomarker and highlight the importance of genetic variation in interpretation of plasma Aβ levels.

Fig. 1. (A–D) Scatterplots of plasma Aβ_1–40/Aβ_1–42 vs average regional [¹¹C]PiB uptake from the (Average regional [¹¹C]PiB uptake = Plasma Aβ_1–40/Aβ_1–42 + APOE ε4 status + [Plasma Aβ_1–40/Aβ_1–42 × APOE ε4 status]) model (A and B), and plasma Aβ_1–40/Aβ_1–42 vs mean [¹¹C]PiB uptake from the cluster identified in the (Voxel [¹¹C]PiB uptake = Plasma Aβ_1–40/Aβ_1–42 + APOE ε4 status + [Plasma Aβ_1–40/Aβ_1–42 × APOE ε4 status]) model (C and D). Aβ, amyloid beta; PiB, Pittsburgh compound B; APOE, apolipoprotein E.

Figure options

Fig. 2. Brain regions (R, right; L, left) identified in the (Voxel [¹¹C]PiB uptake = Plasma Aβ_1–40/Aβ_1–42 + APOE ε4 status + [Plasma Aβ_1–40/Aβ_1–42 × APOE ε4 status]) model (voxel-level threshold of P < .005 [uncorrected], cluster size ≥ 200 voxels). The red-to-yellow scale indicates increasing statistical significance of association. PiB, Pittsburgh compound B; Aβ, amyloid beta; APOE, apolipoprotein E.

Biomarker Changes Precede Symptoms by 20 Years

Click on image to play movie

Amyloid accumulation. Cross-sectional analysis using florbetapir PET shows that brain amyloid deposits ramp up steeply in AD mutation carriers between the ages of 28 and 38, several years before clinical symptoms appear. Movie courtesy of Adam Fleisher and Lancet Neurology

Evidence keeps building that the first signs of Alzheimer’s disease appear decades before symptoms. In two companion papers in the November 6 Lancet Neurology, theAlzheimer’s Prevention Initiative (API) formally published cross-sectional biomarker data from young adults who carry a presenilin 1 mutation and are destined to develop AD. Researchers led by Eric Reiman at Banner Alzheimer’s Institute, Phoenix, Arizona, and Francisco Lopera, University of Antioquia, Medellin, Colombia, report that mutation carriers show structural and functional brain abnormalities characteristic of AD more than two decades before they are expected to develop cognitive symptoms of the disease. Notably, the changes occur in the presence of high levels of Aβ42, but before there is evidence of amyloid accumulation in the brain. Although it is not yet proven that these results will generalize to late-onset AD, researchers noted the changes are consistent with brain imaging findings in young adults at increased risk for sporadic AD, suggesting the two forms of the disease progress similarly. The researchers saw the first evidence of amyloid deposits about 16 years before the expected symptom onset, in agreement with findings from the Dominantly Inherited Alzheimer Network (DIAN) cohort. Much of these data were previously presented at conferences.

Preclinical Alzheimer disease: identification of cases at risk among cognitively intact older individuals

Hypothetical model of preclinical Alzheimer's disease (AD). According to the proposed model, the group currently defined as 'preclinical AD' is heterogeneous and comprises two subpopulations. Firstly, there is the group of individuals at different stages of preclinical AD defined by the biomarkers indicated in the lower panel of the figure. All of these individuals will progress to dementia, and we call this phase 'presymptomatic AD'. The second group comprises individuals who are positive for amyloid markers and neuronal injury markers, and fall into one of the stages of preclinical AD, based on the current classification. However, this population has efficient active compensatory mechanisms, and remains resistant to dementia (stable asymptomatic cerebral amyloidosis).

Since the first description of the case of Auguste Deter, presented in Tübingen in 1906 by Alois Alzheimer, there has been an exponential increase in our knowledge of the neuropathological, cellular, and molecular foundation of Alzheimer's disease (AD). The concept of AD pathogenesis has evolved from a static, binary view discriminating cognitive normality from dementia, towards a dynamic view that considers AD pathology as a long-lasting morbid process that takes place progressively over years, or even decades, before the first symptoms become apparent, and thus operating in a continuum between the two aforementioned extreme states. Several biomarkers have been proposed to predict AD-related cognitive decline, initially in cases with mild cognitive impairment, and more recently in cognitively intact individuals. These early markers define at-risk individuals thought to be in the preclinical phase of AD. However, the clinical relevance of this preclinical phase remains controversial. The fate of such individuals, who are cognitively intact, but positive for some early AD biomarkers, is currently uncertain at best. In this report, we advocate the point of view that although most of these preclinical cases will evolve to clinically overt AD, some appear to have efficient compensatory mechanisms and virtually never develop dementia. We critically review the currently available early AD markers, discuss their clinical relevance, and propose a novel classification of preclinical AD, designating these non-progressing cases as 'stable asymptomatic cerebral amyloidosis'.

BMC Medicine 2012, 10:127 doi:10.1186/1741-7015-10-127 © 2012 Lazarczyk et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Movie showing the accumulation of amyloid plaques in carriers of autosomal dominant AD mutations over time

Using Pittsburgh compound B based PET imaging, the following movie shows the accumulation of amyloid plaques in carriers of autosomal dominant AD mutations. The movie starts 25 years before, and ends 10 years after, the expected onset of clinical symptoms.

Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD

OBJECTIVE:

To compare the diagnostic performance of PET with the amyloid ligand Pittsburgh compound B (PiB-PET) to fluorodeoxyglucose (FDG-PET) in discriminating between Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD).

METHODS:

Patients meeting clinical criteria for AD (n = 62) and FTLD (n = 45) underwent PiB and FDG-PET. PiB scans were classified as positive or negative by 2 visual raters blinded to clinical diagnosis, and using a quantitative threshold derived from controls (n = 25). FDG scans were visually rated as consistent with AD or FTLD, and quantitatively classified based on the region of lowest metabolism relative to controls.

RESULTS:

PiB visual reads had a higher sensitivity for AD (89.5% average between raters) than FDG visual reads (77.5%) with similar specificity (PiB 83%, FDG 84%). When scans were classified quantitatively, PiB had higher sensitivity (89% vs 73%) while FDG had higher specificity (83% vs 98%). On receiver operating characteristic analysis, areas under the curve for PiB (0.888) and FDG (0.910) were similar. Interrater agreement was higher for PiB (κ = 0.96) than FDG (κ = 0.72), as was agreement between visual and quantitative classification (PiB κ = 0.88-0.92; FDG κ = 0.64-0.68). In patients with known histopathology, overall classification accuracy (2 visual and 1 quantitative classification per patient) was 97% for PiB (n = 12 patients) and 87% for FDG (n = 10).

CONCLUSIONS:

PiB and FDG showed similar accuracy in discriminating AD and FTLD. PiB was more sensitive when interpreted qualitatively or quantitatively. FDG was more specific, but only when scans were classified quantitatively. PiB slightly outperformed FDG in patients with known histopathology.

 Neurology. 2011 Dec 6;77(23):2034-42