Volumetric MRI and Neuropathology in the Elderly: a Key Bridging Study

In the October 17^th issue of PLoS One, Robert Dawe and colleagues, from the Illinois Institute of Technology and the Rush Alzheimer’s Disease Center, present the results of a key bridging study of volumetric MRI correlation with normal aging, Alzheimer’s disease (AD), and additional neuropathologies frequently associated with aging (link).

As mentioned in an earlier post (Biomarker Qualification Consortia: The ADNI Success Story), in vivo volumetric MRI of specific region of the brain (i.e. medial temporal lobe à hippocampus) has been shown to be a valuable biomarker of disease progression in AD and mild cognitive impairment (MCI).  While the correlation between reduction in hippocampal volume and histopathologically confirmed AD has been conclusively demonstrated, the effect of other neuropathologies generally associated with aging on hippocampal volume remained ill-defined.

In order to address this gap in knowledge, the authors combined antemortem imaging studies, antemortem cognitive testing, postmortem MRI on isolated brain hemisphere, and histopathology on the brains of 100 elderly subjects from the Rush Memory and Aging Project, and the Religious Order Study (two longitudinal clinical-pathologic studies of aging).  The authors confirmed the strong association between reduced hippocampal volume and the diagnostic of AD (determined prior to death based on cognition test and determined postmortem based on histopathology).  In addition, hippocampal volume was related to multiple cognitive abilities assessed proximate to death, with its strongest association with episodic memory.  Other pathologies such as Lewy bodies, moderate amyloid angiopathy, gross infarcts, and micro infarcts were not significantly associated with reduced hippocampal volume.  In contrast, hippocampal sclerosis (HS) was strongly associated with significant reduction in hippocampal volume independently of the presence or absence of co-occurring AD pathology (of 13 individuals with HS, 9 had also AD pathology and 4 had not other pathology).  In fact, the association of HS and reduced hippocampal volume was more pronounced than that observed in AD.  Shape analysis of the hippocampal surface confirmed prior knowledge namely that hippocampal volume reduction in AD is more pronounced in the head and tail of the hippocampus, and that these changes tend to be more homogeneously distributed in HS.  The authors did not discuss whether shape analysis of the hippocampal surface could be used to distinguish between AD and HS.

Despite some minor limitations: the postmortem MRI performed on isolated brain hemispheres precluded the measurement of cranial volume, this study provides a highly valuable bridge between in vivo volumetric MRI measurements and underlying neuropathology.  


Thierry Sornasse for Integrated Biomarker Strategy

Prognosis of conversion from MCI to AD: of verbal memory, brain volume, and CSF biomarkers

In the September 2011 issue of the Archives of General Psychiatry (reference), Dr. Goldberg and colleagues report the results of the first study that examined the respective predictive values of cognitive measures, brain imaging, and cerebrospinal fluid (CSF) biomarkers in determining the risk of conversion from Mild Cognitive Impairment (MCI) to Alzheimer’s disease (AD).

In contrast with the multiple recent publications derived from the Alzheimer’s Disease Neuroimaging Initiative about biomarkers in AD (ADNI; see earlier post), this work identified measures of delayed verbal memory (Logical Memory delayed recall and Auditory Verbal Learning Test delayed recall) as the most reliable predictors of progression from MCI to AD.  While brain volume assessed by MRI (Left middle temporal lobe thickness) was identified as an additional predictive factor, the levels of Ab42 and Tau in the CSF did not add significant predictive value to their model (systematic stepwise logistic regression).

In commentary provided to Medscape (link), the lead author urged caution in interpreting this finding by stating that “Biomarkers unarguably work. However, cognitive markers, which are less expensive and less invasive, also work and provide strong complementary information”.

In my mind, the question is not so much whether cognitive assessment tools work better than CSF biomarkers but more about the applicability of these findings to the general practice of medicine.  Indeed, while CSF biomarkers are objective measures, the results of even the best cognitive tests are partially subjective: the skills of the person administering the test can have an influence on the results.  Therefore, one can wonder if, in the hands of the average neurologist or neuropsychiatrist, the verbal memory testing would perform as well and would outperform the objective measure provided by CSF biomarkers.

Thierry Sornasse for Integrated Biomarker Strategy

Biomarker Qualification Consortia: The ADNI Success Story

Over the past decade, the rate of biomarker discovery has accelerated considerably thanks to the development of new methods such as advanced mass spectrometry techniques.  However, the effort dedicated to the qualification of these newly discovered biomarkers (i.e. the process of confirming the predictive value of a biomarker candidate) has remained insufficient.  Disease biomarker qualification most often requires access to a large population of patients representing the full spectrum of disease stages encountered in every day medical practice.  While a few large organizations can muster the resources necessary to assemble such large patient samples, most biomarker qualification efforts require close collaboration between multiple stakeholders.  Similarly, the qualification of safety biomarkers, intended to be broadly applicable across the industry, presents an investment that few companies are willing to take on their own.  Hence, the gap in biomarker qualification can only be eliminated by promoting the collaboration between all drug development stakeholders.

The past ten years have seen the emergence of a series of non-competitive biomarker qualification efforts driven by consortia of academic, industrial, and non-profit organizations (see table 1 for examples)

Name	Main Sponsor	Focus
Biomarker Consortium	Foundation for the National Institute of Health	Cancer Immunity/Inflammation Metabolic Disorders Neurosciences
Predictive Safety Testing Consortium	Critical Path Institute	Predictive drug safety
Alzheimer’s Disease Neuroimaging Initiatitive	National Institute on Aging	Alzheimer’s Disease
Parkinson Progression Marker Initiative	Michael J. Fox Foundation	Parkinson’s Disease

Table 1

Among these examples, one effort stands out due its ground-breaking impact on the field of biomarker development.  The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a vast longitudinal study focused on monitoring the evolution of Alzheimer’s disease (AD) patients, Mild Cognitive Impairment (MCI; a common precursor of AD) patients, and age-matched healthy volunteers (see also the article in Lancet of March 2011 about ADNI).  Since its inception in 2004, ADNI enrolled 200 AD patients, 400 MCI patients, and 200 age-matched controls who were followed every 6 months for 2, 4, and 4 years, respectively.  At the onset of the project, the consortium established a set of standardized procedures aimed at monitoring cognition, cerebrospinal fluid (CSF) biomarkers, and brain structure biomarkers.  These standardized procedures have been used uniformly across 57 North-American clinical sites who committed to sharing their results through a common data repository (see also the public presentation by Dr. Michael W. Weiner for more detail about the science).  Over the years, these procedures have been adopted by additional ADNI participants in Europe, Japan, Australia, China, and Korea.  

This treasure trove of inter-connected standardized data has resulted in an amazing number of publications (212 accepted publications as of August 2011; source ADNI.org) which have already have fundamental impact in the field of AD science.  For example, the National Institute on Aging and the Alzheimer’s Association proposed in July 2010 to amend the official diagnosis criteria for AD to reflect the advances in biomarkers of AD.  Also, the work on CSF biomarkers has revealed that the level of amyloid-beta fragment Ab42 is a reliable predictor of conversion from MCI to AD.  Finally, the work on brain structure biomarkers using standardized MRI has demonstrated that changes in key structures of the brain (cortex, ventricles, hippocampus) are much more sensitive than conventional cognitive assessment tools, potentially enabling clinical studies requiring significantly fewer patients.  In 2010, ADNI received additional funding to extend the monitoring of patients already enrolled in the program and to enroll additional volunteers to explore more advanced biomarkers such as high resolution MRI, functional imaging, and amyloid aggregate imaging.

Beyond these remarkable scientific achievements, ADNI has demonstrated beyond doubt that academia, the industry, and non-profit organizations can collaborate efficiently in a non-competitive environment.  Convincing all stakeholders that sharing their data with each other was not an easy task but this proved to be one of the key elements to the success of this project.