Phase II - IV Clinical

Imaging Methods for Alzheimer’s Disease

Modern, non-invasive imaging techniques serve two key purposes in the study of Alzheimer’s disease (AD): to support early diagnosis, and to document treatment-related morphological and functional changes.

Magnetic Resonance Imaging (MRI)

Magnetic resonance imaging is advantageous in that it is available in practically every large hospital and allows a detailed analysis of morphological changes in the brain. Typical features of AD, such as ventricular widening or degeneration of the hippocampus, entorhinal cortex or temporal cortex, can be qualitatively and quantitatively evaluated. The measurement of hippocampal changes has been assessed (Scheltens score) as an early diagnostic tool and may predict the risk for patients with mild forms of dementia to convert to full-blown AD. Figure 1 shows typical magnetic resonance images from patients at the various stages of AD.

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The temporal course of brain atrophy in AD is well known; structural imaging analysis techniques allow precise evaluation of tissue loss over time, in the whole brain and in defined small areas such as those mentioned above. Manual, semi-automatic and automatic segmentation techniques can be applied for rapid and reliable quantification of disease-specific changes. Several published papers have demonstrated that a study design based on brain volumetry could significantly reduce the number of patients needed to detect drug effects, assuming that there is a 25 to 30 % effect by the candidate drug on neurodegeneration.

On-going multinational efforts, like the Alzheimer’s Disease Neuroimaging Initiative (ADNI), are helping to collect huge amounts of standard brain imaging data, which will elucidate the time course of disease progression at different stages of AD. This understanding can then form a reliable basis for assessing the effects of disease-modifying drugs. Other new methods have arisen, such as quantitative susceptibility mapping (QSM), which allows the sensitive detection of iron in the brain. Hopefully, this technique will also enable MRI use for quantification of amyloid plaques, which often accumulate bound iron. In addition, this method can detect paramagnetic material associated with micro bleeds. QSM is an absolutely new technology which so far has not been used widely in routine clinical applications, but carries the potential to become a valuable diagnostic tool.

Another new MRI application is the true inversion recovery sequence, which allows the sensitive detection of hippocampal atrophy (Figure 2).

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The next image (Figure 3) shows another useful application of MRI: when it is co-registered with Positron emission tomography (PET) images, functional changes can be attributed to an exact brain structure.

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Important advantages of MRI are its availability, its extremely high morphological resolution, and its exclusion of radioactive materials, permitting repeated use throughout a long-term clinical trial.

Positron Emission Tomography (PET).

PET measures the specific retention time of radioactively labelled compounds in the body. A very early application was the measurement of glucose metabolism in the brain, which shows typical hypo-metabolism in brain areas most afflicted by Alzheimer’s disease. These metabolic changes are seen before cognitive deficits can be detected. There is a close correlation between changes in FDG-PET and disease progression. The possibility of imaging aggregations of the toxic amyloid protein in the brain is a current area of interest. Specific stains that bind to amyloid structures can be used to evaluate pathological changes in the brain at very early stages, and this imaging technique has supported the suspicion that AD pathology is in progress decades before the first symptoms are detected. It even seems that the amyloid levels are already at a plateau when the first memory deficits are reported.

These findings advocate for early intervention in Alzheimer's disease and are the basis for prevention studies. Again, huge amounts of data collected from international studies indicate that positive amyloid imaging is a predictor for conversion to the disease within a predefined timeframe. For the first time, using these modern imaging technologies, it is possible to diagnose Alzheimer's disease in pre-symptomatic patients, enabling the selection of such populations for clinical trials of new, disease-modifying treatment approaches, such as immunotherapy. Recent clinical trials with monoclonal antibodies have strongly confirmed initial assumptions that this treatment is helpful only very early in the disease. Hence, the introduction of amyloid imaging has opened a new era in the diagnosis of Alzheimer's disease. Furthermore, several studies have been already published demonstrating that this technique can also register treatment effects (Figure 4).

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In some of the immunotherapy studies, reduction of brain amyloid was demonstratedin vivo. Studies involving small molecules with anti-amyloid effects have also been published.

Clearly, structural and molecular imaging is of extreme clinical value in Alzheimer's disease, as it not only allows early detection and diagnosis of the disease, but also chronicles disease progression. In addition, these imaging studies aid in differential diagnosis. For drug development purposes, they allow stratification of patients for drug trials, most likely reducing variability in outcome measures. Finally, imaging facilitates the study of drug effects on brain pathology, and disease modification. The development of new 18F-labelled imaging compounds will now allow a more frequent use of these techniques, because due to the longer half-life of this isotope, studies can even be performed in centers without direct access to a cyclotron. Look for further information on imaging methods for neurological disorders in the next QPS newsletter.

Services provided by QPS:
  • Development of imaging protocols for mono- and multicenter clinical studies
  • Specification of the most suitable imaging sequences
  • Standardization of imaging data quality across sites
  • Quality Control of MRI images
  • Centralized MRI reading
    • Allows chemical leads to be rank-ordered to optimize PK properties
    • Allows chemical leads to be rank-ordered to optimize PK properties
  • Safe Data Storage
  • Manual, Semi-Automatic and Automatic Segmentation
    • Hippocampal volume
    • Entorhinal cortical volume
    • Brain Volumetry
    • Complete Evaluation of Imaging data
    • Statistics and Report Writing
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