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

Blood-derived disease biomarker of Alzheimer’s disease: tell me what you react to and I’ll tell you who you are

In the August 3 online issue of PLoS One (PLoS One. 2011; 6(8): e23112), Eric Nagele and colleagues report the discovery of a potential new diagnostic biomarker for Alzheimer’s disease (AD) based on the detection of serum autoantibodies specific for a unique set of self-proteins.  This work marks a major step forward in the process of realizing the promises of preventive medicine for this devastating disease.  As I wrote in a previous post, the ability to intervene early in the course of AD is considered to be critical to the success of disease modifying therapies currently under development.  By providing an easily deployable means to screen for individual at risks prior to the onset of clinical manifestation of the disease, this simple blood test has the potential to radically change the disease management practices in AD.

The association of autoantibodies with certain diseases is not new.  Antibodies specific for self-proteins are characteristic of rheumatoid diseases and most cases of multiple sclerosis.  These autoantibodies are generally thought to contribute to the pathobiology of these diseases.  In contrast, the association of autoantibodies with non-immunological diseases is rather intriguing.  It is tempting to speculate that this process could be generalized to other degenerative diseases:  disease states characterized by the release in the body of rare and/or usually sequestered proteins that would be recognized by the immune system as potentially foreign (see principles of immune tolerance).  If this generalization turns out to be valid, one could easily imagine a broad application of autoantibody-based disease diagnostics.  While this hypothesis could potentially open the doors to new applications, it could also constitute a potential obstacle.  If auto-antibodies are broadly associated with degenerative diseases, it might be difficult to distinguish between closely related conditions.  Nagele et al. already addressed part of this potential issue by showing that the subset of autoantibodies specific for AD could distinguish with relative accuracy the sera from AD patients from the sera of patients diagnosed with Parkinson’s disease.  Further analysis of this autoantibody-based biomarker in samples derived from patients at different stages of AD and from patients with different forms of dementia (e.g. vascular dementia, dementia with Lewy bodies) should provide the necessary evidences to qualify this biomarker for practical application.

Thierry Sornasse for Integrated Biomarker Strategy

Prognostic biomarkers, preventive medicine, and the aging population challenge

By 2050, the US Census Bureau estimated that the number of US residents 65 or older will double to reach almost 87 million, representing about 21% of the US population (2010 estimated: 40.2 million, 13%).

In keeping with this aging trend of the US population, the Alzheimer’s Association predicts that, based on current estimates of Alzheimer’s disease (AD) prevalence (5.4 million or 13% of people 65 or older), between 11 and 16 million of individuals will suffer from AD by 2050.  Similarly, the number of individuals suffering from Parkinson’s disease (PD) is also expected to increase dramatically: the incidence of PD increases dramatically in people 50 and older (see Incidence of Parkinson’s Disease: Variation by Age, Gender, and Race/Ethnicity for reference).  Considering these figures, the need for efficacious treatment of AD and PD are urgently needed (as of today, there is no preventive or disease modifying treatment for either AD or PD). 

Treatment of AD and PD is particularly challenging because when an individual starts to present the clinical sign of the disease, a great deal of damage has already be made to critical structures of the brain.  Therefore, most specialists in AD and PD believe that early intervention will be critical to successful therapies in these diseases.  Ideally, individuals at risks will be treated prior to the onset of any clinical sign of the disease in a truly preventive manner. But, how do you identify individuals at risk?  Genetic predispositions that could be detected by genetic tests only represent a minor fraction of the individuals at risk of AD or PD.  New brain imaging biomarkers and possibly cerebro-spinal fluid biomarkers currently under development could turn out to be valid prognostic biomarkers. However, in this new era of healthcare cost control, it is difficult to imagine that such sophisticated and/or complex techniques could be practically deployed to assess all individuals 50 - 60 and older.  Therefore, I would argue that one of the major challenges of addressing the rise of neurodegenerative diseases is to develop low cost and easily deployable screening prognostic biomarkers that could be used as a preliminary step to the more complex definitive prognostic tests.  Already, the PD community (See PARS study) has explored the possibility of using a low cost olfaction test (UPSIT) to screen for individuals at potential risk of PD.  Briefly, in Parkinson disease, the decrease in the sense of smell frequently occurs prior to the onset of motor symptoms.  Although the loss of smell (hyposmia and anosmia) is not specific for PD, identifying individuals with abnormally low sense of smell represents a valid first screen to enrich for individuals at potential risk for PD.

Thierry Sornasse for Integrated Biomarker Strategy