Alzheimer's & Dementia: The Journal of the Alzheimer's Association
Volume 2, Issue 1 , Pages 33-35, January 2006

Commentary on “The NIH Cognitive and Emotional Health Project. Report of the Critical Evaluation Study Committee”

  • Lewis H. Kuller

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: 412-383-1895; Fax: 412-383-1856

Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA

Article Outline

 

Cognitive and emotional health, especially of older individuals, has become increasingly important because of the increasing life expectancy and the growing population of older individuals.

The report is a comprehensive review of primarily studies of determinants of cognitive and emotional or mental health changes through older ages. The report documents many studies and a large number of potential risk factors. The report has a major flaw in that it fails to attempt to synthesize the information into a coherent picture that would be suitable for hypothesis testing. Human population, especially epidemiologic, studies are a relatively weak tool for measuring normality or average distribution of change because of substantial within-individual variability and selective loss to follow-up [1].

The committee makes several recommendations for studying brain aging including the secondary analysis and continued follow-up of large cohorts. Such an approach is useful and cost effective but only if there are specific hypotheses that can be tested. Secondary analysis of data, just because they are available, often is of little or no value.

A second recommendation is for better access to data. Collaboration among investigators to test important hypotheses has always been, and continues to be, an important component of successful research. Whether new and potentially cumbersome mechanisms are necessary to obtain access to data from a variety of studies is unsubstantiated and has created an unneeded bureaucracy.

The third recommendation is to create a consortium to pool data from a variety of sources to increase the power of analysis in identifying specific or new risk factors. Obviously, it is hard to fault such a recommendation, but, again, it must be driven by specific testable hypotheses and not just a collection of bigger data sets.

A fourth recommendation, that the National Institutes of Health (NIH) consider a support structure, much like the Alzheimer’s Disease Center program for supporting collaboration among longitudinal studies and supporting cognitive and emotional aging, is, I believe, one of the most important recommendations. There is, unfortunately, an overemphasis at the present time on studying end-stage disease (i.e., patients who already have Alzheimer’s disease) or severe depression and for short-term quick results (i.e., testing drugs or evaluating new imaging techniques) in individuals who already have extensive disease.

It is almost certain that only a refocus on etiologic hypothesis testing and then, in subsequent clinical trials, on prevention, are likely to have any major impact on both cognitive aging and the prevention of dementia and improved emotional health.

A second group of recommendations related to standardized questions to measure cognitive and emotional health may have some merit. However, there is often a tendency to “rediscover the wheel” and to spend an inordinate amount of time and money on classification and quantification rather than focusing on hypothesis testing. There is a huge battery of cognitive testing instruments already available, and it is unlikely that the absence of a battery of cognitive testing is a rate-limiting factor in understanding cognitive aging or mental health, or the development of Alzheimer’s and other diseases.

There is a high probability that further development of batteries of cognitive tests and their evaluation in different populations will slow, rather than enhance, good research to understand cognitive aging and dementia. Certainly, panels of tests are currently being used in many of the large studies and could be provided to other investigators [2], [3], [4].

The next recommendation is the use of biomarkers. Unfortunately, this remains a major stumbling block in studying brain aging, dementia, and depression. The biochemical changes which may be occurring in the brain cannot be measured adequately in the peripheral circulation. Certainly, systemic diseases are related to brain aging, cognition, and, likely, risk of dementia. It is unlikely, at least in the United States, that spinal fluid analysis will be available for follow-up of large normal populations. Hopefully, specific unique biochemical markers in the peripheral circulation that reflect changes in biochemistry in the brain will be available in the future [5].

Imaging of the brain clearly represents the greatest potential for further hypothesis testing and, perhaps, in understanding brain and emotional aging and their inter-relationships. The improvement not only in structural magnetic resonance imaging (MRI), but also in positron emission tomography (PET) scanning, as well as blood flow and metabolism studies, offer unique opportunities to study brain aging [6].

Currently, there are 3 major areas of interest that can generate important hypotheses. First is whether small vessel vascular disease, probably secondary to vascular stiffness; hypertension (especially systolic hypertension) leads to changes in white matter in the brain and, secondarily, to loss of neurons and grey matter disease, a primary determinant of brain aging and dementia [7], [8], [9], [10], [11], [12]. Such changes may be global or focal and may be associated with inflammation and, perhaps, increasing production of β-amyloid, as well as damage to the blood–brain barrier. A second hypothesis is whether there is a gradual loss of neurons with aging, possibly secondary to oxidative stress and inflammation or loss of neurotropic factors with increasing age [13], [14], [15]. This is measurable by the increasing size of the ventricles and measures of brain size with age and association with cognitive decline, mental health, and dementia. It is possible that the number of neurons or the size of the brain at earlier ages (i.e., brain reserve) and the rate of decline over time, contribute to cognitive aging in a similar manner as peak bone mass and bone loss contribute to osteopenia and osteoporosis. Some of the determinants of this “brain aging” could potentially be related to exposure to toxic chemicals in the environment, infectious agents, nutritional factors, and, obviously, genetic susceptibility. An important question would be to try to determine whether global brain atrophy, as measured, varies across populations that are exposed to very different lifestyles, especially earlier in life, and whether such differences are related to cognitive and emotional function. The identification of such differences across populations, especially at both older and middle ages, would provide, perhaps, the most important insight into etiologic hypothesis and, I believe, should have one of the highest priorities.

The third issue is whether the variations in cognitive aging are a function of the extent of β-amyloid deposition, protein abnormalities, and neural fibrillary tangles over time (i.e., a continuum of normative aging to Alzheimer’s disease) [16], [17], [18], [19], [20]. The availability of new imaging techniques using PET scanning will make it possible in vivo to potentially evaluate the extent of amyloid deposition. As these approaches become more available, especially in combination with structural and functional MRI and cognitive measurements across populations, the answer may be provided as to whether cognitive aging and Alzheimer’s disease are part of a continuum of disease or distinct from each other.

I would suggest that until we have a better understanding of the distribution of brain abnormalities (as described above) across and within populations, the likelihood of major insights into cognitive or emotional aging is remote. Similarly, expending extraordinary resources to improve measurements on the MRI without their proper application in population studies testing specific hypotheses is probably of little value. There is a need to combine measures of cognition and mental health with imaging techniques in well-defined populations that can test definitive hypotheses of etiology and natural history. The tools are becoming available. Their application lags behind.

It will be very important, once some of these techniques for studying cognitive and mental health aging are available, to further link them to measures of systemic aging, especially vascular and neurohumeral and genetic variations. Is brain aging unique, consistent with general system aging or, possibly, does the systemic diseases associated with “aging” determine the brain and mental health aging? In other words, should brain or mental health aging be studied in isolation or as part of an overall aging process? The report identifies a major need for research. The application of the report requires planned testing of specific hypotheses in a stepwise manner that is likely to lead to improved prevention of cognitive and mental dysfunction with aging and the prevention of specific diseases (such as Alzheimer’s disease and vascular dementia).

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PII: S1552-5260(05)00523-6

doi:10.1016/j.jalz.2005.12.005

Alzheimer's & Dementia: The Journal of the Alzheimer's Association
Volume 2, Issue 1 , Pages 33-35, January 2006

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