Anatomic and Clinical Pathology of Cognitive Impairment and Dementia

Abstract

Progressive cognitive impairment and its clinical culmination in dementia loom as a major public health problem in the coming generation of older adults, and this fact compels investigation to develop interventions that prevent, delay, or cure. The tools of anatomic pathology have provided key insights into the complex convergence of multiple diseases that commonly contribute to the dementia syndrome and its prodrome in the community setting, and they have suggested some exposures that may modulate disease burden. The tools of clinical pathology, in combination with neuroimaging, have revolutionized the approach to clinical investigation of Alzheimer's disease and are now doing the same with Lewy body disease and vascular brain injury. The tools of anatomic and clinical pathology will continue to contribute to our understanding of these diseases as we advance toward effective interventions for the diseases that commonly cause cognitive impairment and dementia in older adults.

INTRODUCTION

Progressive cognitive impairment and dementia among older individuals is a major public health issue that looms as a catastrophe that will cause untold suffering to patients and their loved ones, and is poised to undermine the financing of health care systems around the globe. Very painful choices await the coming generation of older adults, their care givers, and families, and very difficult decisions will face healthcare policymakers, unless effective interventions are developed that at least slow the progression if not cure the diseases that cause cognitive impairment and dementia.

Dementia is a syndrome, a common clinical constellation of signs and symptoms that derives from multiple different disease processes. Dementia culminates from one or more chronic diseases. These two statements are critical to developing strategies for detection and treatment of diseases that can cause dementia. Here we review some of our work that has used the tools of anatomic and clinical pathology to investigate the chronic diseases that contribute to the dementia syndrome.

ANATOMIC PATHOLOGY

The tools of anatomic pathology applied to diseases that cause dementia are restricted largely to brain autopsy. There are clear limitations to brain autopsy, like exclusively cross-sectional design; but there also are unique strengths, the major one being the comprehensiveness of evaluation that cannot yet be matched by neuroimaging or clinical laboratory testing. Most clinico-pathologic correlations of diseases that cause dementia have been performed within clinical research centers. While this focus brings a depth of experience with the illness that is the focus of research, it alohas the potential to skew the representation of diseases from how they may exist in the community [1]. This is an important point because ultimately any therapeutic intervention devised by researchers will need to be effectively applied in the community setting.

Several studies around the world have attempted to address this limitation by organizing a population-or community-based sample of older individuals who agree to undergo evaluation of cognitive performance over the remainder of their lives and who agree to donate their brains for research [2]. One such study of brain aging and dementia with brain autopsy end-point is the Adult Changes in Thought (ACT) study in the Seattle metropolitan area [3]. ACT is significant in comparison to other studies that are restricted to a particular ethnic group, men, or Catholic religious because it enrolls cognitively normal men adwomen at age 65 years or older who are members of the Group Health Cooperative, a large managed care organization in the Seattle area, and it is not restricted by ethnicity or religion. Our investigations of the ACT brain autopsy cohort have shown that the population-attributable risk from dementia in the group is approximately 45% for Alzheimer's disease, 33%for small caliber vessel-mediated damage to brain, a process we call microscopic vascular brain injury (VBI), 10% for neocortical Lewy body disease, and 12% remains unclassified [4]. Other similar studies also have identified an equivalent fraction of cases of dementia that are not classifiable, and much has been speculated about these cases. It is important to stress that all community subjects with dementia show some evidence of at least one of these diseases, but not at levels expected to be sufficient to cause dementia[5]. Possibly explanations for this group include some individuals being especially vulnerable to lower levels of disease or that other disease process(es) contributing to dementia without yielding structural changes recognized by neuropathologists.

A strength of the ACT is the extensive pharmacy database available for subjects that goes back to the 1970's. Using this resource, we have tested the hypothesis that some commonly used medications, supplements, or cigarette smoking may modulate the risk of these common diseases that cause dementia as defined by tools of anatomic pathology. Our studies have suggested that use of statins, especially at certain ages, may be associated with reduced burden of neurofibrillary tangles, but not neuritic plaque bur-den or VBI [6]. We have examined several other exposures including non-steroidal anti-inflammatory drugs (associated with increased burden of neuritic plaques [7]), antioxidant supplements (no significant effect on histopathologic endpoints of these three diseases [8]), and cigarette smoking (strongly associated with reduced burden of Lewy bodies[9]).

While the population-attributable risk is a useful statistical estimate of the burden of disease, it does not convey the complexity of co-morbidity among diseases that cause dementia. Indeed, a recent collaborative study among many of the community- or population-based studies of brain aging and dementia demonstrated that co-morbidity among Alzheimer's disease, VBI, and Lewy body disease is the rule, rather than the exception, in older individuals at all clinical stages (vide infra) [5]. Finally, while it is important to concentrate on the three diseases that most commonly cause dementia, it also is important to recognize that the tools of anatomic pathology still are unveiling new or less common diseases and disease variants. One example of this is collaborative work among several groups that described the co-morbidity betweenTDP-43 proteinopathy and Lewy body disease[10].

CLINICAL PATHOLOGY

As mentioned, the tools of anatomic pathology continue to provide insight into common, unusual, and even previously unrecognized diseases that contribute to cognitive impairment and dementia in older individuals. The major limitation of using these tools to study disease is that it is restricted to cross-sectional design and to pathologic data collection after the sub-ject has died. In contrast, the tools of clinical pathology can be used during life to identify and quantify specific pathologic processes that are related to certain diseases and to follow them longitudinally. Such clinical laboratory tests, often called biomarkers, are measures of a molecule or molecules that are associated with a disease but are not a direct measure of the disease. As an example, consider measurement of serum prostate-specific antigen as a biomarker of carcinoma of the prostate.

Following the pioneering work in the mid 1990's that focused on cerebrospinal fluid concentrations of A42 and tau species in subjects with Alzheimer's disease dementia [11, 12], many translational and clinical research studies have been undertaken in the last20 years to develop biomarkers for Alzheimer's disease. Indeed, cerebrospinal fluid concentration of A42 and tau species has been demonstrated repeatedly to discriminate Alzheimer's disease dementia or its prodrome from cognitively normal controls. We [13], along with colleagues from Washington University in St. Louis [14], were among the first to demonstrate that measurement of these proteins in cerebrospinal fluid also can be used to detect latent, also called preclinical or antecedent, Alzheimer's disease, a finding that now has been replicated by several other groups and consortia. These now-many studies strongly suggest that we have a clinical laboratory tool to assess early stage Alzheimer's disease, even before its initial mild clinical expression. This new tool already is being used in organizing clinical research and trials for early stage Alzheimer's disease, and it likely will become important in medical management once disease-modifying therapies are developed.

Cerebrospinal fluid Aβ42 and tau species were pursued as targeted biomarkers for Alzheimer's disease based on knowledge from anatomic pathology studies. Several groups have attempted non-targeted approaches to cerebrospinal fluid biomarkers for Alzheimer's disease and other common neurodegenerative diseases using a variety of analytical platforms. Our group has contributed to this discovery effort using stable isotope dilution techniques coupled with tan-dem mass spectrometry in a non-targeted approach to cerebrospinal fluid protein biomarkers. Our work has led to the discovery of over two thousand proteins in human cerebrospinal fluid, and a panel of proteins whose concentration is substantially different between groups of subjects with Alzheimer's disease and controls [15]. We next adapted the most discriminating of these candidates identified by non-targeted proteomics to a multiplexed antibody-based assay and validated the ability to discriminate not only between controls and Alzheimer's disease but also among these two groups and Parkinson's disease [16]. Indeed, using a comparison to expert clinical diagnosis, an optimal 8-member multianalyte profile correctly classified 95% of controls, 75% of Alzheimer's disease, and 95% of Parkinson's disease.

CONCLUSION

The tools of anatomic pathology have provided key insights into the complex convergence of multiple diseases that commonly contribute to the dementia syndrome in the community setting, and they have suggested some exposures that may modulate disease burden. The tools of clinical pathology, in combination with neuroimaging, have revolutionized the approach to clinical investigation of Alzheimer's disease and are now doing the same with Lewy body disease and vascular brain injury. These tools of anatomic and clinical pathology will continue to contribute to our understanding of diseases that can cause cognitive impairment and dementia as we advance toward effective interventions that will prevent, delay, or cure.