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Psychosomatic Medicine 69:47-53 (2007)
© 2007 American Psychosomatic Society

ORIGINAL ARTICLES

Chronic Distress, Age-Related Neuropathology, and Late-Life Dementia

Robert S. Wilson, PhD, Steven E. Arnold, MD, Julie A. Schneider, MD, Yan Li, PhD and David A. Bennett, MD

From the Rush Alzheimer’s Disease Center (R.S.W., J.A.S., D.A.B.) and Rush Institute for Health Aging (Y.L.), and the Departments of Neurological Sciences (R.S.W., J.A.S., D.A.B.), Psychology (R.S.W.), Pathology (J.A.S.), and Internal Medicine (Y.L.), Rush University Medical Center, Chicago, IL; and the Center for Neurobiology and Behavior, University of Pennsylvania, Philadelphia, PA (S.E.A.).

Address correspondence and reprint requests to Robert S. Wilson, PhD, Rush Alzheimer’s Disease Center, Rush University Medical Center, 600 South Paulina, Suite 1038, Chicago, IL 60612. E-mail: rwilson{at}rush.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Objective: The objective of this study was to test whether common age-related neuropathology could account for the relation of chronic distress to dementia.

Methods: In a selected cohort of more than 1000 older Catholic clergy members undergoing annual clinical evaluations, 326 persons died, of whom 306 (94%) underwent brain autopsy, the results of which were available in 219 (mean age at death = 85.4, standard deviation [SD] = 6.6; mean postmortem interval = 7.6 hours, SD = 6.9). A composite measure of chronic distress was constructed from standard measures of two traits, neuroticism and anxiety proneness, completed at baseline, and of depressive symptoms, completed annually. Dementia was diagnosed according to standard criteria and cognition was assessed with previously established composite measures based on a uniform clinical evaluation that took place a mean of 9.1 months before death (SD = 9.5). On postmortem examination, levels of amyloid-beta and tau-positive neurofibrillary tangles and the presence of Lewy bodies were quantified in six brain regions, and the number and location of chronic cerebral infarctions were noted.

Results: In analyses that controlled for age, sex, education, amyloid, tangles, Lewy bodies, and cerebral infarction, higher level of chronic distress was associated with a higher likelihood of dementia and lower level of cognition proximate to death. Chronic distress was not correlated with any form of neuropathology, including limbic, neocortical, and global indices, and did not modify the association of pathology with cognition.

Conclusions: Chronic psychological distress is associated with late-life dementia but not with its leading causes, suggesting that novel neurodeteriorative mechanisms may be involved.

Key Words: chronic distress • dementia • cognitive function • amyloid beta • neurofibrillary tangles • Lewy bodies

Abbreviations: SD = standard deviation; SE = standard error; OR = odds ratio; CI = confidence interval.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
In old age, the personality trait of neuroticism, an indicator of proneness to experience psychological distress, has been associated with cognitive impairment (1–5), cognitive decline (2,3,5), dementia (2,5,6), and mortality (7–10). Because psychological distress is common and potentially modifiable, understanding the neurobiologic basis of its association with loss of cognition in old age is of great importance. A very basic question is whether the age-related neuropathology commonly associated with late-life dementia (e.g., pathology of Alzheimer disease, stroke, and Parkinson disease) is somehow responsible for the association of distress with dementia. One possibility is that psychological distress in old age is an early manifestation of the neuropathology thought to be contributing to dementia. In this case, level of distress in the last years of life should be correlated with level of pathology in the brain. Alternatively, distress might not be directly related to neuropathology but might modify the correlation of pathology with cognition as previously reported for education (11) and social network size (12). A third possibility is that the association of distress with dementia is independent of the lesions traditionally associated with dementia, implying that chronic distress is associated with changes in the brain that do not leave a pathologic footprint or are not recognizable with currently available methods. Few studies have examined these issues, however (2). As a result, little is known about the relation of chronic distress to common age-related neuropathology or the extent to which the association depends on particular forms of pathology or particular brain regions being affected.

In this article, we examine the associations among chronic psychological distress, dementia, and age-related neuropathology. We used data from the Religious Orders Study, a clinical–pathologic study of aging and Alzheimer disease in older Catholic nuns, priests, and brothers. Participants had annual clinical evaluations, which included assessment of psychological distress, clinical classification of dementia, detailed testing of cognitive function, and brain autopsy at death. On postmortem examination, we quantified amyloid-beta-immunoreactive plaques, tau-immunoreactive neurofibrillary tangles, and alpha synuclein-immunoreactive Lewy bodies in two limbic (entorrhinal cortex, hippocampus) and four neocortical (frontal, temporal, parietal, occipital) sites and the number and location of cerebral infarctions. In analyses, we tested whether these forms of neuropathology were related to chronic distress or could otherwise account for its association with dementia or cognitive impairment.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Participants
All clinical and pathologic data are from persons who participated in the Religious Orders Study (13), died, and underwent a brain autopsy. Participants in the Religious Orders Study are older Catholic nuns, priests, and brothers who agree to annual clinical evaluation and brain autopsy at death. After complete description of the study to participants, written informed consent was obtained. The study was approved by the Institutional Review Board of Rush University Medical Center.

Clinical evaluations began in January 1994 and are continuing. Clinical data for these analyses were collected from 1994 to 2004. At the time of these analyses, 326 study participants had died and 306 (94%) had undergone an autopsy. Of these, data on amyloid-beta plaques and tau neurofibrillary tangles were available from 224 persons. Because we wanted to examine whether distress was related to these pathologic lesions or modified their association with cognitive impairment, we eliminated five persons in whom delirium was thought to be impairing cognition proximate to death. Analyses are based on the remaining 219 people who did not differ from unstudied participants in age at death, sex, education, or last Mini-Mental State Examination score before death. They had a mean age at death of 85.4 (standard deviation [SD] = 6.6), a mean of 18.1 years of education (SD = 3.5), and a mean Mini-Mental State Examination score proximate to death of 21.3 (SD = 9.0); 54.8% were women and 96.3% were white and non-Hispanic. Of these 219 persons, 218 had data on cerebral infarctions and 212 had data on Lewy bodies.

Clinical Evaluation
At the baseline evaluation and annually thereafter, participants had a uniform clinical evaluation that included a medical history, complete neurological examination, and cognitive testing. On the basis of these data and an in-person evaluation of the participant, experienced clinicians classified persons with respect to dementia at each annual evaluation using the criteria of the joint working group of the National Institute of Neurologic and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association (14) as previously described (2,13,15). These require a history of cognitive decline and evidence on examination of impairment in two or more cognitive domains. Clinical classification of dementia proximate to death was rendered after review of clinical data from all annual clinical evaluations blinded to all pathologic data.

Assessment of Chronic Distress
Psychological distress refers to negative emotional states like depression and anxiety. Chronic level of psychological distress can be assessed with a single measurement of relatively stable personality traits associated with the tendency to experience negative emotional states or with repeated measurement of current negative emotional states. We used both approaches. Two trait scales were administered at baseline. On the Neuroticism scale of the NEO Five-Factor Inventory (16), a measure of the tendency to experience psychological distress, participants rated agreement with each of 12 statements on a 5-point scale (0 to 4) with items added to compute the total score (range = 0–48). On a modified version (8) of the Anxiety Trait Scale of the State-Trait Anxiety Inventory (17), a measure of anxiety proneness, persons were read a series of 20 brief statements about anxious feelings; they responded "yes" to statements that indicated how they generally felt and "no" otherwise. We modified the test by using a yes–no response option instead of the original 4-point scale to reduce response burden. The score was the number of questions answered in a direction indicative of anxiety (range = 0–20), which has been associated with mortality in previous research (8).

At baseline and at each follow-up evaluation, the 10-item version (18) of the Center for Epidemiologic Studies Depression Scale (19), a measure of current level of depressive symptomatology, was administered. Persons were asked if they had experienced each of 10 symptoms much of the time in the past week. The number of symptoms reported (0–10) was averaged across evaluations to provide a measure of the enduring tendency to experience depressive symptoms.

Scores on the measure of neuroticism ranged from 0 to 36 (mean = 17.6, SD = 6.5), and anxiety proneness scores ranged from 0 to 20 (mean = 3.4, SD = 3.8) with higher scores indicating a higher level of each trait. Persons reported a mean of 1.5 depressive symptoms (SD = 1.5, range = 0–9) on the Center for Epidemiologic Studies Depression Scale during a mean of 5.3 annual clinical evaluations (SD = 2.7) before death. In a principal components factor analysis, these three indicators of chronic distress loaded on a single factor that accounted for 73.0% of the variance, supporting the idea that the indicators could be summarized in a single measure. Because of this correlational evidence and the need to minimize random variation, we combined the three indicators to form a composite measure of chronic distress. Each indicator was converted to a z score, using the mean and SD from the entire Religious Orders Study cohort, and then averaged to yield the composite.

Assessment of Cognitive Function
Participants underwent uniform annual clinical evaluations, which included administration of a battery of 20 cognitive performance tests. One test, the Mini-Mental State Examination, was used to describe participants but was not used in analyses.

Seven tests assessed episodic memory: Word List Memory, Recall, and Recognition (20) and immediate and delayed recall of the East Boston Story (21) and Story A from Logical Memory (22). Semantic memory was assessed with a 20-item version of the Boston Naming Test (23), Verbal Fluency (20), a 15-item form of Extended Range Vocabulary (24), and a 20-item form of the National Adult Reading Test (25). Working memory was assessed with Digit Span Forward and Digit Span Backward (22), Digit Ordering (26), and Alpha Span (27). The Symbol Digit Modalities Test (28) and Number Comparison (24) were used to assess perceptual speed, and visuospatial ability was assessed with a 15-item form of Judgment of Line Orientation (29) and a 17-item form of Standard Progressive Matrices (30).

Composites of two or more tests were used in analyses to reduce measurement error in general and floor and ceiling artifacts in particular. We used a global measure of cognition based on all 19 tests and specific measures of episodic memory (based on seven tests), semantic memory (four tests), working memory (four tests), perceptual speed (two tests), and visuospatial ability (two tests). We first converted raw scores on individual tests to z scores, using the baseline mean and SD of the entire cohort, and we then averaged the z scores of component tests to get the composite score, in effect weighting individual tests approximately equally. Further information on the tests and on the psychometric properties of these composite measures is published elsewhere (2,13,15,31).

Assessment of Neuropathology
Brains of dead subjects were removed in a standard fashion as described previously (2,32). After weighing, each brain was cut coronally into 1-cm-thick coronal slabs, immersion fixed in 4% paraformaldehyde for 48 to 72 hours, and then placed in graded glycerol/dimethylsulfoxide in phosphate-buffered saline for storage (final dilutions 20% glycerol, 2% dimethylsulfoxide). Tissue from six regions of interest was dissected into 0.5-cm-thick blocks and embedded in paraffin: the entorhinal cortex proper and the CA1/subiculum, the dorsolateral prefrontal cortex or midfrontal gyrus (Brodmann area 46/9), the inferior temporal cortex (Brodmann area 20), the inferior parietal cortex or angular gyrus/supramarginal gyrus (Brodmann area 39/40), and the primary visual cortex or calcarine cortex (Brodmann area 17). Two blocks were obtained from adjacent 1-cm slabs from the neocortex and cut into 20-µm sections. For the hippocampal formation, sections were cut from consecutive 1-cm slabs throughout its length (up to six blocks per case).

Amyloid-beta was labeled with MO0872 (Dako, Carpinteria, CA; 1:100), which identifies both the 1–40 and 1–42 length amyloid-ß fragments as described elsewhere using diaminobenzidine as the reporter with 2.5% nickel sulfate to enhance immunoreaction product contrast (33). All sections were run with identical incubation times on an automated immunohistochemical stainer (Biogenex, San Ramon, CA). Control sections processed without primary antibodies were included in all runs and showed no specific staining. To capture images of amyloid-beta-stained sections for quantitative analysis of plaque deposition, we used a systematic random sampling scheme with a custom algorithm as previously described (34). After camera and illumination calibration, 24-bit color images obtained at each sampling site were converted to eight-bit gray-scale images. The percent area occupied by amyloid-beta-immunoreactive pixels was calculated using the public domain Object-Image 1.62p15 (developed by Norbert Vischer, http://simon.bio.uva.nl/object-image.html). The analysis algorithm segmented each image into labeled and background compartments using one of two histogram-dependent automatic thresholding procedures, iterative self-organizing data analysis or triangulation (35). The percent areas for each section were then averaged for each region of interest. Because these regional indices were highly correlated and we wanted to reduce measurement error, we developed a composite measure of the percent area occupied by amyloid-beta by averaging the values obtained from all six brain regions, as previously reported (33).

Paired helical filament tau was labeled with an antibody specific for phosphorylated tau, AT8 (Innnogenex, San Ramon, CA; 1:800 in 4% horse serum) as previously reported (33,34). All experimental and control (no primary antibody) sections were run using identical incubation times on the automated immunohistochemical stainer.

Neurofibrillary tangles labeled with AT8 have a characteristic appearance and location in the neuronal cell body or as ghost tangles. We quantified tangle density per millimeter squared with a stereologic mapping station, which included a Leica DMRBE microscope and a computer (Millennia Mme; Micron Electronic, Inc. Meridian, ID) equipped with StereoInvestigator software version 5.00 (MicroBrightField, Inc., Colchester, VT). After a region of interest was delimited at low power, a grid of predetermined size was randomly placed over the entire region by the software program. Total magnification was raised to 400x and the program was engaged to direct the motorized stage on the microscope to stop at each intersection point of the grid for sampling. The operator focused through the section depth as the fields were visualized on the video monitor within the superimposed counting frame. All objects within the 150 x 150-µm counting frame that did not touch the exclusion lines of the box (bottom and left sides) were counted. Approximately 50% of the area of a delimited region of interest was quantified. The regional measures of tangle density were strongly correlated, and so we averaged them to form of composite measure of tangle density as previously reported (33).

Lewy bodies were identified with antibodies to alpha synuclein (clone LB509 monoclonal, Zymed, San Francisco, CA; 1:2000), a specific immunohistochemical stain for Lewy bodies. Immunohistochemistry for alpha synuclein was performed as described previously on 6-µm sections of paraformaldehyde fixed tissue and after pretreatment with 90% formic acid with control slides included in each run as previously described (36). All sections from every case were evaluated by light microscopy for intraneuronal Lewy bodies. In analyses, we treated Lewy bodies as a dichotomous variable because they were present in less than 15% of the group.

We uniformly examined the 1-cm slabs from each hemisphere for evidence of cerebral infarctions as reported elsewhere in more detail (37,38). We identified the age, volume, and location of all cerebral infarctions visible to the naked eye, including ischemic lesions with a small amount of hemorrhage. All old cortical and subcortical infarctions affecting gray or white matter were included, whereas microscopic stroke, acute and subacute infarction, and brainstem and cerebellar infarctions were not included. For analyses, persons without infarction were contrasted with two subgroups: those with one infarction and those with more than one infarction.

Data Analysis
Logistic regression models were used to assess the relations of distress and pathology to dementia diagnosis proximate to death. All models included terms for age at death, sex, and education. In an initial analysis, we regressed dementia on distress and then compared R2, computed using Nagelkerke’s modification (39), for this model to R2 from a model with age, sex, and education. We regressed dementia on each pathologic measure. To test for evidence of mediation, we included terms for distress and pathology in the same analyses. The analyses were repeated for individual distress measures. Next, the measures of distress were regressed on each pathologic index in separate linear regression models. The composite distress measure was also regressed on regionally specific pathologic subscores. To test for evidence of a modifying effect, we constructed logistic regression models with dementia as the outcome and terms for distress, a given pathologic index, and their interaction with separate analyses for each pathologic index. We then conducted a similar sequence of linear regression models with level of global cognition proximate to death as the outcome. The initial analysis included a term for distress; to test for evidence of mediation, the initial analysis was repeated with terms added for all four types of pathology; a third set of analyses testing for evidence of a modifying effect included terms for distress, a given pathologic index, and their interaction with separate analyses for each pathologic index. Subsequent analyses used the individual distress scales and the measures of specific cognitive functions. We report the unstandardized regression coefficient from regression analyses. Models were validated graphically and analytically. Programming was done in SAS (40).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
Scores on the composite measure of chronic distress ranged from –1.38 to 4.95 (mean = 0.26, SD = 1.04) with higher scores denoting more distress. Level of chronic distress was not related to age at death (r = –0.04, p = .598), education (r = –0.05, p = .428), or gender (t[217] = 0.95, p = .344).

Distribution of Neuropathology
Table 1 shows the distributions of the four forms of neuropathology. Overall, 98% had at least some evidence of neurofibrillary tangles, 79% had some accumulation of amyloid, 34.9% had one or more chronic cerebral infarctions, and Lewy bodies were detected in 8.1%. Only two persons (1%) were free of all four forms of pathology.


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  		TABLE 1. Distribution of Age-Related Neuropathology on Postmortem Examination

 

Chronic Distress, Neuropathology, and Dementia
A total of 95 persons (43%) met clinical criteria for dementia before death. Those with dementia were older at the time of death than those without dementia, and they had less education and more chronic distress (Table 2). On average, participants in each subgroup were last clinically evaluated approximately 9 months before death with a postmortem interval of 7 to 8 hours.


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  		TABLE 2. Descriptive Characteristics of Persons With Versus Without Dementia Proximate to Death

 

We examined the associations of chronic distress and neuropathology with dementia in a series of logistic regression models. These and all subsequent analyses included terms to control for the effects of age (at death), sex, and education. In an initial model, odds of dementia proximate to death increased by 53% for each point on the composite measure of chronic distress (Table 3, model A) with distress accounting for 3.7% of the variance after adjusting for age, sex, and education. Thus, a person with a high level of distress (score = 1.74, 90th percentile) was twice as likely to have dementia proximate to death as a person with minimal distress (score = –0.70, 10th percentile). In separate subsequent analyses, amyloid, tangles, and multiple infarctions were each associated with higher likelihood of dementia (Table 3, models B, C, and D). We then constructed models that included both the composite measure of chronic distress and the postmortem indices separately (Table 3, models E, F, and G) and together (Table 3, model H). In these analyses, higher level of chronic distress continued to be associated with higher likelihood of dementia. Results were comparable when analyses were repeated controlling for Lewy bodies, but model assumptions were violated because of the virtual absence of Lewy bodies in the subgroup without dementia (0.1% versus 18.2% in dementia subgroup).


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  		TABLE 3. Relation of Chronic Distress and Neuropathology to Odds of Dementia Proximate to Death

 

To see if differences among the components of the chronic distress measure affected findings, we repeated analyses for each of the individual distress measures, and results were similar to those obtained with the composite measure. Thus, neuroticism was related to dementia before (odds ratio [OR] = 1.06; 95% confidence interval [CI] = 1.02–1.12; R2 increase = 1.8%) and after (OR = 1.08; 95% CI = 1.03–1.14) adjusting for amyloid, tangles, and infarctions. Results were similar for trait anxiety (unadjusted OR = 1.13; 95% CI = 1.04–1.22; R2 increase = 3.9%; adjusted OR = 1.19; 95% CI = 1.08–1.30) and the mean level of depressive symptoms across evaluations (unadjusted OR = 1.29; 95% CI = 1.05–1.57; R2 increase = 2.5%; adjusted OR = 1.42; 95% CI = 1.12–1.80).

We next examined whether chronic distress was directly related to any neuropathologic index in a series of linear regression models. In separate analyses, level of chronic distress was not related to amyloid burden ([unstandardized] regression coefficient = 0.01, standard error [SE] = 0.03, p = .791), tangle density (regression coefficient = 0.00, SE = 0.01, p = .635), or the presence of Lewy bodies (regression coefficient = 0.35, SE = 0.41, p = .402) or cerebral infarctions (regression coefficient of one infarction = 0.02, SE = 0.17, p = .890; of more than one infarction = –0.08, SE = 0.16, p = .630). In subsequent analyses, none of the individual measures of distress was related to the neuropathologic measures (data not shown).

Because of the critical role of the limbic system in regulating emotional behavior, we constructed separate limbic (based on entorhinal cortex and CA1/subiculum) and neocortical (based on frontal, temporal, parietal, and occipital cortex) indices of amyloid, tangles, and Lewy bodies to examine whether the relation of neuropathology to chronic distress was regionally specific. In these analyses, the composite measure of chronic distress was not related to limbic measures of amyloid (regression coefficient = 0.03, SE = 0.05, p = .560), tangles (regression coefficient = 0.00, SE = 0.01, p = .771), or Lewy bodies (regression coefficient = 0.39, SE = 0.27, p = .146) or to neocortical measures of amyloid (regression coefficient = 0.00, SE = 0.03, p = .944), tangles (regression coefficient = 0.00, SE = 0.01, p = .921), or Lewy bodies (regression coefficient = 0.88, SE = 0.64, p = .170). There were too few persons with limbic infarctions (n = 7) for analyses.

To test whether distress modified the relation of neuropathology to likelihood of dementia, we constructed separate logistic regression models for each composite neuropathologic index, which included terms for the index, chronic distress, and their interaction. None of these interactions was significant.

Chronic Distress, Neuropathology, and Cognitive Impairment
We constructed a similar series of linear regression models to assess the relations among chronic distress, neuropathology, and level of global cognition proximate to death. The composite measure of global cognition ranged from –4.465 to 1.071 (mean = –0.949, SD = 1.198) at the last evaluation before death with higher scores indicating better cognitive function. In an initial analysis, each point on the summary measure of chronic distress was associated with a 0.236 unit reduction (SE = 0.066, p < .001) in global cognitive score proximate to death, with distress accounting for 3.1% of the variation in global cognition after adjustment for age, sex, and education. When the analysis was repeated with terms added to control for amyloid burden, tangle density, and the presence of Lewy bodies and cerebral infarctions, the inverse association between chronic distress and global cognition persisted (regression coefficient = 0.176, SE = 0.058, p = .003). In separate subsequent analyses, there was no evidence that chronic distress modified the association of neuropathology with global cognition.

Results were comparable in analyses of the individual measures of distress. Neuroticism was inversely related to global cognition proximate to death before (regression coefficient = –0.03, SE = 0.01, p = .015, R2 increase = 3.1%) and after (regression coefficient = –0.02, SE = 0.01, p = .011) adjustment for neuropathology. Results were similar for trait anxiety (unadjusted regression coefficient = –0.06, SE = 0.02, p = .003, R2 increase = 3.1%; adjusted regression coefficient = – 0.04, SE = 0.02, p = .020) and depressive symptomatology (unadjusted regression coefficient = –0.11, SE = 0.05, 0.021, R2 increase = 1.6%; adjusted regression coefficient = –0.12, SE = 0.04, p = .004).

Because cognition is composed of multiple interdependent yet dissociable cognitive systems, we repeated the analyses with summary measures of specific forms of cognition assessed proximate to death in lieu of the measure of global cognition. In analyses that controlled for all four forms of neuropathology (Table 4), higher level of distress was associated with lower level of cognition with effects most robust for working memory, perceptual speed, and visuospatial ability.


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  		TABLE 4. Relation of Chronic Distress Measures to Level of Function in Different Cognitive Domains Proximate to Death

 


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
We previously demonstrated that neuroticism, a stable index of distress proneness, was associated with loss of cognition and development of an Alzheimer disease-like dementia in this (2) and other (3,5,6) cohorts. These results raised the possibility that psychological distress in old age might be an early sign of the pathology of Alzheimer disease or might somehow modify the impact of that pathology on cognitive function. Therefore, we examined the association of neuroticism with Alzheimer pathology identified by traditional staining and rating methods and found no correlation (2). The present study extends our prior research by using more sensitive immunohistochemical methods and a less error-prone sampling approach to quantify Alzheimer disease pathology, by assessing the other two neuropathologic lesions most commonly associated with dementia (i.e., Lewy bodies, cerebral infarctions), and by examining the possibility that distress might be associated with pathology in some brain regions but not others. We found that higher level of chronic distress was associated with higher likelihood of dementia and lower level of cognition proximate to death even after controlling for amyloid-beta deposition, tau neurofibrillary tangles, Lewy bodies, and cerebral infarctions, common neuropathologic lesions thought to account for much of late-life dementia. Chronic distress was not related to global or regional measures of this pathology and did not modify the association of pathology with dementia or cognitive impairment.

How might chronic distress be related to dementia but not to its leading causes? One possibility that cannot be ruled out is that pathology in some brain region not examined in this study is contributing to psychological distress. Brain regions were primarily selected in this study for their role in cognition, not emotion. It will be important to sample a broader range of limbic sites in future research. Level of pathology in such regions would need to be relatively independent of pathology elsewhere in the brain, however, making this possibility somewhat less likely. In addition, distress should be increasing in old age while pathology is accumulating, but longitudinal studies suggest that level of psychological distress is relatively stable (41,42) or decreases slightly (43) in older persons.

Even if chronic distress is not the direct result of the neuropathologic lesions traditionally associated with dementia, distress might become elevated in reaction to declining cognitive ability. According to this view, however, distress still should be correlated with the leading causes of dementia, which these data indicate is not the case, and increasing in old age when cognition is declining.

The absence of a correlation between chronic distress and traditional dementia-related neuropathology observed here might also reflect inadequate measurement of key study constructs or other methodological problems. Yet, the composite measure of chronic psychological distress and each of its components, which included both trait (assessed at baseline) and state (assessed annually) measures, had the hypothesized associations with cognition and dementia; and neuropathological data were systematically sampled from multiple brain regions quantified in a uniform fashion by persons blind to all clinical data and combined into previously established composite measures, which also showed the expected associations with cognition and dementia. Thus, the zero-order correlation between distress and neuropathology observed here is difficult to attribute to inadequate assessment of distress or neuropathology. Also, all analyses were conducted on a single cohort with rates of participation in both follow-up clinical evaluations and brain autopsy exceeding 90%, minimizing the potential of bias from selective attrition and providing clinical data proximate to death. Finally, analyses of the relation of chronic distress to clinical dementia and cognitive function yielded consistent results, making it unlikely that diagnostic imprecision or bias affected results.

If chronic distress is neither an early sign of the pathologies known to be associated with dementia nor a modifier of the association of this pathology with dementia, as these data suggest, we think that the association of chronic distress with dementia is probably mediated by some other neurobiologic mechanisms. In humans, psychiatric disorders like major depression or posttraumatic stress disorder that involve a high level of psychological distress have been associated with reduced volume of the hippocampus and anterior cingulate gyrus (44,45). In animals, chronic exposure to adverse conditions designed to cause distress leads to characteristic changes in the brain, including dendritic atrophy in regions of the hippocampus (46,47) and medial prefrontal cortex (48), synaptic loss in the CA3 region of the hippocampus (47,49), suppression of neurogenesis in the dentate gyrus (50), and downregulation of glucocorticoid receptors in the hippocampus (51,52) accompanied by impairment in forms of learning and memory subserved by these regions (47). Together, these observations support the idea that chronic psychological distress may be associated with structural and neurochemical changes in limbic regions that regulate stress-related behavior and memory. Such changes might contribute to risk of dementia by impairing medial temporal and prefrontal memory systems and to risk of morality by contributing to dysregulation of the hypothalamic–pituitary–adrenal axis. Further clinical–pathologic and clinical–radiologic research is needed to clarify the pathways linking chronic distress to cognitive impairment and dementia, especially because animal research suggests that the deleterious effects of distress on the brain may be modified by antidepressants (53) or activity patterns (54).

These results have important limitations. First, they are based on a selected cohort. Distress has been shown to have a comparable association with dementia (6) and cognition (3) in a community population, however, and obtaining brain autopsy in population-based study poses immense challenges. Indeed, the internal validity that can be achieved in cohort studies like this one is arguably a more important consideration than generalizability, especially when weighed against the potential bias from the low autopsy participation rate expected in a population-based study. Second, we cannot rule out the possibility that pathology in some brain region not examined in this study is contributing to psychological distress. Level of pathology in such a region would need to be relatively independent of pathology elsewhere in the brain, however, making this possibility less likely.

In summary, chronic psychological distress is associated with late-life dementia by mechanisms that appear to be independent of the leading causes of dementia. Because psychological distress is common and because distress and its impact on brain morphology are potentially modifiable, understanding the neurobiologic mechanisms linking chronic distress with late-life dementia is of substantial public health importance.

We greatly appreciate the efforts of the hundreds of Catholic nuns, priests, and brothers who have participated in the Religious Order Study. We also thank Julie Bach, MSW, Tracy Colvin, MPH, and Beth Howard for study coordination; George Dombrowski, MS, and Greg Klein for data management; and Todd Beck, MS, for statistical programming.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 
Received for publication March 7, 2006; revision received August 7, 2006.

This research was supported by National Institute on Aging grants R01 AG024871, R01 AG15819, and P30 AG10161.

DOI:10.1097/01.psy.0000250264.25017.21


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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