Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘Cognitive Function’

It’s a fact of human life that we lose physical and mental function as we get older. In the information age that we currently live in, this translates into a decline in our ability to function and perform the activities of daily living. Can we halt or delay age-related memory loss?

Min Wang and colleagues from Yale University School of Medicine in the August 11 issue of Nature, have published some elegant research that suggests we may be able to, at some point in the future.

It’s important to distinguish the cognitive loss associated with normal ageing from that associated with dementias such as Alzheimer’s disease where major changes to the brain structure and function occur. The Yale researchers accomplished this by using aged monkeys that have a highly developed prefrontal cortex (PFC), the part of the brain associated with working memory. Monkeys, unlike humans, do not develop age-related dementias!

Working memory that allows you to keep things “in mind” e.g. where you put the car keys down, relies on a network of pyramidal neurons in the dorsolateral PFC that excite each other.

The strength of this excitatory network depends on the neurochemical environment e.g. elevated cAMP signaling reduces nerve firing. Wang and colleagues reversed the age-related decline in PFC activity by restoring an optimal neurochemical environment. Through a series of experiments they found that:

The memory-related firing of aged DELAY neurons was partially restored to more youthful levels by inhibiting cAMP signalling, or by blocking HCN or KCNQ channels.

These findings reveal the cellular basis of age-related cognitive decline in dorsolateral PFC, and demonstrate that physiological integrity can be rescued by addressing the molecular needs of PFC circuits.

This research, although preliminary and based on animal models, is promising. It offers the hope that in the future we may be able to reverse or slow-down the age-related memory loss and cognitive defects we would otherwise experience.

Many biotechnology and pharmaceutical companies are focusing on Alzheimer’s disease as a target. What this research suggests is that developing therapies that may delay or slow-down age-related memory decline could also be a valid target for drug development, with a significant market opportunity.

ResearchBlogging.orgWang, M., Gamo, N., Yang, Y., Jin, L., Wang, X., Laubach, M., Mazer, J., Lee, D., & Arnsten, A. (2011). Neuronal basis of age-related working memory decline Nature, 476 (7359), 210-213 DOI: 10.1038/nature10243

Changes in brain structure, function and molecular processes occur several years before clinical symptoms of Alzheimer’s disease (AD) become apparent.

The big question then, is can you detect patients who are cognitively normal, but will go on to develop AD before they show symptoms, i.e. pre-symptomatic patients?  The answer is “Yes” according to results published in the April 19, 2011 issue of Neurology by Brad Dickerson and colleagues.

In this small study, the team of researchers from two centers (Massachusetts General Hospital and Rush University in Chicago) followed a small sample of cognitively normal (CN) subjects over time with magnetic resonance imaging (MRI) and then sought to identify what structural changes had taken place in those subjects who were initially cognitively normal, but went on to develop AD, on average 11.1 years later.

The researchers found that changes in brain cortical thickness were associated with AD:

AD-signature cortical thinning in CN-AD converters in both samples was remarkably similar, about 0.2 mm (p < 0.05)

They concluded that:

By focusing on cortical regions known to be affected in AD dementia, subtle but reliable atrophy is identifiable in asymptomatic individuals nearly a decade before dementia, making this measure a potentially important imaging biomarker of early neurodegeneration.

Some of the limitations of this research and questions that come to mind are:

  • Small sample size: only 8 individuals who developed AD and 25 in the cognitively normal control group.
  • Reproducibility: the 0.2mm difference seen is small and the extent to which other centers may be able to reproduce this measurement is uncertain
  • Accuracy of detection: in any screening tool the issue of false positives and negatives arises i.e. in a larger sample size will there be a margin for error that results in some people being included in the pre-symptomatic AD group, when they may be normal?  Also will the proposed measurement remain valid in a large population of patients with other disease symptoms and chronic illnesses?
  • Validity of biomarker: are the changes in cortical thickness causally linked to AD or just an incidental correlation i.e. is this a valid biomarker?

Brad Dickerson in the excellent Neurology podcast available with this publication clearly sees this currently as a research tool, especially given the requirement for considerable computer power to make these types of cortical measurements in the brain.  The podcast interview is well worth listening to.

The MRI biomarker proposed by Dickerson is therefore not something that is really applicable to screen the general population at the moment.

However, the promise from this and other biomarker research is that at some point in the not too distant future we will be able to detect those at risk of developing AD. Those patients could then be given neuroprotective drugs that may delay the onset of the clinical symptoms of AD such as memory loss and cognitive impairment.

Biomarkers that identify those at risk of developing AD will also be useful as inclusion and screening tools for clinical trials of drugs aimed at slowing disease progression in pre-symptomatic patients.

Alzheimer’s disease has been called “The challenge of the Second Century,” we still have a long way to go before this is overcome.

Story Source:  BBC Health

ResearchBlogging.orgDickerson, B., Stoub, T., Shah, R., Sperling, R., Killiany, R., Albert, M., Hyman, B., Blacker, D., & deToledo-Morrell, L. (2011). Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults Neurology, 76 (16), 1395-1402 DOI: 10.1212/WNL.0b013e3182166e96

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