Synarc, the world’s leader in providing medical imaging services for global clinical trials, is also the world’s leader in providing medical imaging services for AD studies. These studies are particularly challenging as rates of brain atrophy in AD are relatively small (e.g. 5-7%/yr), and because the extent to which new treatments slow disease progression is unknown, requiring substantial statistical power. Despite the challenges, it has been repeatedly demonstrated that the statistical power of structural imaging is considerably greater than the power of clinical measures, resulting in a reduction of sample size, or a shortening in the length of the trial.

Neurological disorders overlap in their physiological origins, anatomical sites, diagnostic criteria and prognoses. With rising placebo response rates and increasing number of failed trials, quantitative imaging endpoints can provide critical information to assess therapeutic efficacy, optimize the patient selection process and shorten the length of a clinical trial. Which imaging and molecular endpoints are most applicable depends on the pathophysiology of the disease and mechanism of pharmacological intervention.  

Different neurological disorders are often accompanied by changes in brain morphology. These structural changes vary in location, intensity and temporal evolution. For example, volumes of the hippocampus and entorhinal cortex have each been found to be probable surrogate markers for cognitive decline in Alzheimer’s patients.

Alzheimer’s Disease and Other Neurodegenerative Diseases

Alzheimer’s disease (AD) is by far the most common cause of dementia, and affects almost 50% of the population over the age of 85 years, costing the US economy over $100 billion/year. Several drugs are currently approved by FDA for treatment of AD, but these treatments are thought to be purely symptomatic. These drugs include: Donepezil (Eisai/Pfizer), Galantamine (Janssen J and J), Rivastigmine (Novartis), and Memantine (Forest). As of 2005 there are no treatments available which have been shown to slow the progression of AD. Use of the currently available symptomatic treatments is not widespread because of the generally prevailing view among practicing physicians that they don't help patients that much, and they have no impact on the long term course of the disease. It is clear that treatments that slow the progression of AD pathology are sorely needed.

Advances in the knowledge concerning pathophysiological mechanisms of AD have increased the development of new treatments which may slow disease progression. Numerous clinical trials of various treatments aimed at slowing the progression of AD have been started by the pharmaceutical companies, and many more are expected in the near future. These new treatments are of several types:

1. Drugs which reduce the amount of beta amyloid in the brain
2. Immunotherapy to reduce beta amyloid
3. Drugs which are neuroprotective by reducing oxidative injury, inhibiting necrosis or apoptosis (programmed cell death)
4. Drugs which stimulate growth of new neurons, or promote dendritic sprouting of existing neurons.

All clinical trials involving these treatments will use clinical measures including ADAS-Cog, neuropsychological tests, and activities of daily living as primary endpoints. However, changes in these clinical measures cannot determine if a treatment is modifying disease progression. Imaging, especially structural imaging with MRI, provides a potential measure of disease progression as neurodegeneration is closely associated with brain atrophy. Therefore, quantification of the rates of brain atrophy, including the hippocampus and whole-brain atrophy, are an extremely useful tool to assess the rate of disease progression.

Imaging is playing an increasingly important role in treatment trials for AD because imaging can detect treatment effects. Furthermore, since AD pathology involves neurodegeneration (loss of nerve cells in the brain) and since neurodegeneration is associated with brain shrinkage, simple measurements of brain volume are a sensitive surrogate marker to track progressive AD pathology. Furthermore, imaging has two huge advantages over measurements of cognitive function in AD trials:

1. The test-retest reliability of imaging is much higher than that of cognitive testing. This greatly increases statistical power, leading to either a reduction of sample size, shorter trials or both.
2. Measurements of cognitive function cannot distinguish between the effects of treatments which are purely symptomatic ( i.e., improve cognition) or treatments which slow disease progression. The only way that one can determine if disease progression is slowed with cognitive measures is with a "randomized withdrawal trial" in which treated subjects are washed out of treatment and compared to placebo treated subjects. Such randomized withdrawal studies are lengthy, require large numbers of subjects, have high drop-out rates and are difficult to recruit subjects for. In contrast, imaging appears to be a valid surrogate for neurodegeneration, and any treatment which would slow the rate of brain atrophy would be considered to be slowing disease progression.

For these reasons, quantitative longitudinal measurements of the rate of brain atrophy have become an essential feature of AD trials aimed at slowing disease progression. A major advantage of this approach is that structural MRI is not sensitive to changes in brain function, and therefore can be considered a specific measure of neurodegeneration.
Quantitative methods for measuring progressive brain atrophy using structural MRI are considerably different than routine clinical evaluation of scans by radiologists. Not all imaging sites are suitable for such trials. Specific acquisition sequences should be used. Very specific regions of the brain should be studied, and highly specialized software tools have been developed to analyze brain images in such trials.

There are several approaches to measuring rates of brain atrophy.

1. Measurements of hippocampal volume (see figure below) of the hippocampus is a major "organ of memory" in the brain and is clearly strongly affected by AD pathology. The rate of hippocampal shrinkage has been shown to have high statistical power for AD treatment trials.

		Boundaries of Hippocampus. The image demonstrates the outlines of hippocampus on one slice of a T-1 weighted coronal MRI.

2. Measurements of global atrophy in the brain have also been reported from serial MRI scans and may be a surrogate of Alzheimer’s Disease progression.