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Authors: Romano, Raymond R. | Carter, Michael A. | Dietrich, Mary S. | Cowan, Ronald L. | Bruehl, Stephen P. | Monroe, Todd B.

Article Type: Research Article

Abstract: Background: This study evaluated whether the apolipoprotein ɛ 4 (APOE4 ) allele, a genetic marker associated with increased risk of developing late-onset Alzheimer’s disease (AD), was associated with differences in evoked pain responsiveness in cognitively healthy subjects. Objective: The aim was to determine whether individuals at increased risk of late-onset AD based on APOE allele genotype differ phenotypically in their response to experimentally-induced painful stimuli compared to those who do not have at least one copy of the ɛ 4 allele. Methods: Forty-nine cognitively healthy subjects aged 30–89 years old with the APOE4 allele (n  = 12) and without (n  = 37) …were assessed for group differences in pain thresholds and affective (unpleasantness) responses to experimentally-induced thermal pain stimuli. Results: Statistically significant main effects of APOE4 status were observed for both the temperature at which three different pain intensity percepts were reached (p  = 0.040) and the level of unpleasantness associated with each (p  = 0.014). APOE4 positive participants displayed lower overall pain sensitivity than those who were APOE4 negative and also greater overall levels of pain unpleasantness regardless of intensity level. Conclusion: Cognitively healthy APOE4 carriers at increased risk of late-onset AD demonstrated reduced thermal pain sensitivity but greater unpleasantness to thermal pain stimuli relative to individuals at lower risk of late-onset AD. These results suggest that altered evoked pain perception could potentially be used as a phenotypic biomarker of late-onset AD risk prior to disease onset. Additional studies of this issue may be warranted. Show more

Keywords: Alzheimer’s disease, APOE, biomarker, nociception, pain

DOI: 10.3233/JAD-201293

Citation: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 1227-1233, 2021

Authors: Romano, Raymond R. | Anderson, Alison R. | Failla, Michelle D. | Dietrich, Mary S. | Atalla, Sebastian | Carter, Michael A. | Monroe, Todd B.

Article Type: Research Article

Abstract: Background: Sex differences in pain have been shown to exist in older adults with normal cognition and people with Alzheimer’s disease. It is unknown if sex differences in pain in older adults exist in a range of communicative older adults with varying cognitive ability from no impairment to moderately severe cognitive impairment. Objective: This study proposes to compare the association between psychophysical responses to experimental thermal pain between males and females to determine if sex differences in pain exist across the cognitive spectrum. Methods: We conducted a secondary analysis of data from an age- and sex-matched between-groups cross-sectional study examining …the psychophysical response to contact heat in people with and without dementia. Results: Median age of males (n  = 38) and females (n  = 38) was 73 (range: 68–87) with similar distributions of Mini-Mental State Examination (MMSE) scores (range: 11–30). Findings revealed inverse statistically significant associations with the threshold temperature of warmth (females: r  = –0.41, p  = 0.010; males: r  = –0.33, p  = 0.044). There was an apparent divergent pattern of MMSE associations with unpleasantness ratings between the groups. At the moderate pain threshold, that difference became statistically significant (p  = 0.033). Females demonstrated a positive association of MMSE with unpleasantness (r  = 0.30, p  = 0.072), while males demonstrated an inverse association at that respective threshold (r  = –0.20, p  = 0.221). Conclusions: Between-group findings suggest that patterns of responses to thermal stimulus intensity may differ between males and females with worsening cognition with females reporting significantly less unpleasantness with the percept of moderate pain and males reporting significantly higher unpleasantness with moderate pain perception. Show more

Keywords: Cognition, dementia, pain, sex differences

DOI: 10.3233/JAD-190142

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 715-722, 2019

Authors: Cowan, Ronald L. | Beach, Paul A. | Atalla, Sebastian W. | Dietrich, Mary S. | Bruehl, Stephen P. | Deng, Jie | Wang, Jinjiao | Newhouse, Paul A. | Gore, John C. | Monroe, Todd B.

Article Type: Research Article

Abstract: Background: People with Alzheimer’s disease (AD) report pain less frequently and receive less pain medication than people without AD. Recent studies have begun to elucidate how pain may be altered in those with AD. However, potential sex differences in pain responsiveness have never been explored in these patients. It is unclear whether sex differences found in prior studies of healthy young and older individuals extend to people with AD. Objective: The purpose of this study was to examine sex differences in the psychophysical response to experimental thermal pain in people with AD. Methods: Cross-sectional analysis of 14 male and 14 …female age-matched (≥65 years of age, median = 74) and AD severity-matched (Mini-Mental State Exam score <24, median = 16) communicative people who completed thermal psychophysics. Results: There was a statistically significant main effect of sex for both temperature and unpleasantness ratings that persisted after controlling for average and current pain (mixed-effects general liner model: temperature: p  = 0.004, unpleasantness: p  < 0.001). Females reported sensing mild pain and moderate pain percepts at markedly lower temperatures than did males (mild: Cohen ’s d  = 0.72, p  = 0.051, moderate: Cohen ’s d  = 0.80, p  = 0.036). By contrast, males rated mild and moderate thermal pain stimuli as more unpleasant than did females (mild: Cohen ’s d  = 0.80, p  = 0.072, moderate: Cohen ’s d  = 1.32, p  = 0.006). There were no statistically significant correlations of temperature with perceived unpleasantness for mild or moderate pain (rs  = 0.29 and rs  = 0.20 respectively, p  > 0.05). Conclusions: Results suggest experimental pain-related sex differences persist in older adults with AD in a different manner than those previously demonstrated in cognitively intact older adults. These findings could potentially aid in developing targeted pain management approaches in this vulnerable population. Further studies are warranted to replicate the findings from this pilot work. Show more

Keywords: Alzheimer’s disease, dementia, pain, pain threshold, perception, sex differences

DOI: 10.3233/JAD-170532

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1633-1640, 2017

Authors: Monroe, Todd B. | Beach, Paul A. | Bruehl, Stephen P. | Dietrich, Mary S. | Rogers, Baxter P. | Gore, John C. | Atalla, Sebastian W. | Cowan, Ronald L.

Article Type: Research Article

Abstract: Background: It is currently unknown why people with Alzheimer’s disease (AD) receive less pain medication and report pain less frequently. Objective: The purpose of this study was to determine the impact of AD on thermal psychophysics and resting-state functional connectivity (RSFC) among sensory, affective, descending modulatory, and default mode structures. Methods: Controls (n  = 23, 13 = female) and age-matched people with AD (n  = 23, 13 = females) underwent psychophysical testing to rate perceptions of warmth, mild, and moderate pain and then completed resting-state fMRI. Between groups analysis in psychophysics and RSFC were conducted among pre-defined regions of interest implicated in sensory and affective dimensions …of pain, descending pain modulation, and the default mode network. Results: People with AD displayed higher thermal thresholds for warmth and mild pain but similar moderate pain thresholds to controls. No between-group differences were found for unpleasantness at any percept. Relative to controls, people with AD demonstrated reduced RSFC between the right posterior insula and left anterior cingulate and also between right amygdala and right secondary somatosensory cortex. Moderate pain unpleasantness reports were associated with increased RSFC between right dorsolateral prefrontal cortex and left ACC in controls only. Conclusions: While AD had little effect on unpleasantness, people with AD had increased thermal thresholds, altered RSFC, and no association of psychophysics with RSFC in pain regions. Findings begin to elucidate that in people with AD, altered integration of pain sensation, affect, and descending modulation may, in part, contribute to decreased verbal pain reports and thus decreased analgesic administration. Show more

Keywords: Acute pain, Alzheimer’s disease, brain mapping, dementia, experimental thermal pain, functional connectivity, neurobiology, neuroimaging, pain perception, pain threshold, psychophysics

DOI: 10.3233/JAD-161187

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 71-83, 2017