Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criteria for Alzheimer’s disease

Background

The promise of Alzheimer’s disease (AD) biomarkers has led to their incorporation in new diagnostic criteria and in therapeutic trials; however, significant barriers exist to widespread use. Chief among these is the lack of internationally accepted standards for quantitative metrics. Hippocampal volumetry is the most widely studied quantitative magnetic resonance imaging (MRI) measure in AD and thus represents the most rational target for an initial effort at standardization.

Methods and Results

The authors of this position paper propose a path toward this goal. The steps include: 1) Establish and empower an oversight board to manage and assess the effort, 2) Adopt the standardized definition of anatomic hippocampal boundaries on MRI arising from the EADC-ADNI hippocampal harmonization effort as a Reference Standard, 3) Establish a scientifically appropriate, publicly available Reference Standard Dataset based on manual delineation of the hippocampus in an appropriate sample of subjects (ADNI), and 4) Define minimum technical and prognostic performance metrics for validation of new measurement techniques using the Reference Standard Dataset as a benchmark.

Conclusions

Although manual delineation of the hippocampus is the best available reference standard, practical application of hippocampal volumetry will require automated methods. Our intent is to establish a mechanism for credentialing automated software applications to achieve internationally recognized accuracy and prognostic performance standards that lead to the systematic evaluation and then widespread acceptance and use of hippocampal volumetry. The standardization and assay validation process outlined for hippocampal volumetry is envisioned as a template that could be applied to other imaging biomarkers.

Very early brain changes detected in children with genetic predisposition to Alzheimer's

A very interesting study found that infant ε4 carriers had lower MWF and GMV measurements than noncarriers in precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions, areas preferentially affected by AD, and greater MWF and GMV measurements in extensive frontal regions and measurements were also significant in the subset of 2- to 6-month-old infants (MWF differences, P<.05, after correction for multiple comparisons; GMV differences, P<.001,uncorrected fo rmultiple comparisons). Infant ε4 carriers also exhibited an attenuated relationship between MWF and age in posterior white matter regions.

This study raises new questions about the role of APOE in normal human brain development, the extent to which these processes are related to subsequent AD pathology, and whether they could be targeted by AD prevention therapies.

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Neuroimaging and Biomarkers: How Early Can We Diagnose Alzheimer's?

Dementia: role of MRI

This review is based on a presentation given by Frederik Barkhof at the Neuroradiology teaching course for the Dutch Radiology Society and was adapted for the Radiology Assistant by Robin Smithuis.
First publication: 1-3-2007.
Updated version: 9-1-2012.

This presentation will focus on the role of MRI in the diagnosis of dementia and related diseases.

We will discuss the following subjects:

• Systematic assessment of MR in dementia
• MR protocol for dementia
• Typical findings in the most common dementia syndromes
  • Alzheimer's disease (AD)
  • Vascular Dementia (VaD)
  • Frontotemporal lobe dementia (FTLD)
• Short overview of neurodegenerative disorders which may be associated with dementia

Going to Biomarker Extremes to Find Rare Alzheimer’s Variants

Researchers have identified potential Alzheimer’s mutations by focusing their attention on people whose biomarkers reach extreme ends of the spectrum. As reported in the August 22 PLoS Genetics, scientists from Washington University in St. Louis, Missouri, found variants both known and novel when they sequenced major AD genes in people with very high or very low amounts of tau and amyloid β in their cerebrospinal fluid (CSF). Led by senior author Carlos Cruchaga, the researchers were surprised to find one of the risk variants was a polymorphism in presenilin 1 (PS1) that had previously been deemed non-pathogenic. When they considered this variant in the context of ApoE4, they found it conferred as much risk as a second copy of that allele. Someone carrying a single copy of both the PS1 variant and ApoE4 has 10 times the risk of someone with wild-type presenilin and no ApoE4, the researchers calculated. As scientists hunt for rare variants, it is important to consider that mutations may still be risk factors even if they exist in people without AD, Cruchaga said.

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.

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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.