Narrative Review of Sensory Changes as a Biomarker for Alzheimer's Disease.

Early recognition of Alzheimer's disease (AD) in the prodromal period has not been robust yet will be necessary if effective disease-modifying drugs are to be useful in preventing or delaying the condition. The objective of this narrative review was to describe the current, evidenced based understanding of alterations in sensory data as potential biomarkers for AD. Review of empirical studies that tested senses as biomarkers for AD and were published in English within the past 50 years was completed. Eighteen empirical studies were identified that met the strict criteria for inclusion, with 12 of these studies being related to the olfactory system. Two studies examined auditory, two examined vision, one examined proprioception, and one examined taste. Thus, only olfaction has been studied to any extent, leaving a clear gap in the literature for the use of other senses. A promising area of research has begun to be reported concerning differences in responses to pain stimuli in AD relative to cognitively normal subjects. Pain is not a single sense like the others but integrates several senses and may allow for use as an early biomarker for AD, as it integrates several brain areas and pathways. Unlike the other senses, simple devices can be used to measure changes in pain perception in cognitively normal adults with genetic predispositions for possible AD, making this potentially useful for clinicians in the future.

Could Altered Evoked Pain Responsiveness Be a Phenotypic Biomarker for Alzheimer's Disease Risk? A Cross-Sectional Analysis of Cognitively Healthy Individuals.

BACKGROUND: This study evaluated whether the apolipoprotein ɛ4 (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 ɛ4 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.

An integrative review of system-level factors influencing dementia detection in primary care.

BACKGROUND AND PURPOSE: The incidence of Alzheimer disease (AD) is increasing in the United States, yet more than half of the people with AD are diagnosed late in the course of the disease. Most are identified outside primary care. New approaches to prevention and treatment mean that early detection of AD may improve the quality of life of those affected by the disease. Nurse practitioners (NPs) have an important role in increasing early diagnosis of AD.The purpose of this systematic literature review is to identify health care system factors that contribute to missed or delayed diagnosis of dementia by primary care providers. METHODS: Articles were identified through a systematic electronic search of the following databases: MEDLINE, the Cochrane Central Register of Controlled Trials, CINAHL, and PsycINFO. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Results indicate considerable variation in the diagnostic accuracy of dementia by primary care providers. Missed or underdiagnosis of dementia results from organizational, provider, and patient factors. New treatments are under investigation that may slow the progression of AD much better than current therapy, emphasizing the need to improve early detection by clinicians, especially primary care NPs.

Sex Differences in Associations of Cognitive Function with Perceptions of Pain in Older Adults.

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.

A Mutual Self- and Informant-Report of Cognitive Complaint Correlates with Neuropathological Outcomes in Mild Cognitive Impairment.

BACKGROUND: This study examines whether different sources of cognitive complaint (i.e., self and informant) predict Alzheimer's disease (AD) neuropathology in elders with mild cognitive impairment (MCI). METHODS: Data were drawn from the National Alzheimer's Coordinating Center Uniform and Neuropathology Datasets (observational studies) for participants with a clinical diagnosis of MCI and postmortem examination (n = 1843, 74±8 years, 52% female). Cognitive complaint (0.9±0.5 years prior to autopsy) was classified into four mutually exclusive groups: no complaint, self-only, informant-only, or mutual (both self and informant) complaint. Postmortem neuropathological outcomes included amyloid plaques and neurofibrillary tangles. Proportional odds regression related complaint to neuropathology, adjusting for age, sex, race, education, depressed mood, cognition, APOE4 status, and last clinical visit to death interval. RESULTS: Mutual complaint related to increased likelihood of meeting NIA/Reagan Institute (OR = 6.58, p = 0.004) and Consortium to Establish a Registry for Alzheimer's Disease criteria (OR = 5.82, p = 0.03), and increased neurofibrillary tangles (OR = 3.70, p = 0.03), neuritic plaques (OR = 3.52, p = 0.03), and diffuse plaques (OR = 4.35, p = 0.02). Informant-only and self-only complaint was not associated with any neuropathological outcome (all p-values>0.12). CONCLUSIONS: In MCI, mutual cognitive complaint relates to AD pathology whereas self-only or informant-only complaint shows no relation to pathology. Findings support cognitive complaint as a marker of unhealthy brain aging and highlight the importance of obtaining informant corroboration to increase confidence of underlying pathological processes.

Associations between Verbal Learning Slope and Neuroimaging Markers across the Cognitive Aging Spectrum.

A symptom of mild cognitive impairment (MCI) and Alzheimer's disease (AD) is a flat learning profile. Learning slope calculation methods vary, and the optimal method for capturing neuroanatomical changes associated with MCI and early AD pathology is unclear. This study cross-sectionally compared four different learning slope measures from the Rey Auditory Verbal Learning Test (simple slope, regression-based slope, two-slope method, peak slope) to structural neuroimaging markers of early AD neurodegeneration (hippocampal volume, cortical thickness in parahippocampal gyrus, precuneus, and lateral prefrontal cortex) across the cognitive aging spectrum [normal control (NC); (n=198; age=76±5), MCI (n=370; age=75±7), and AD (n=171; age=76±7)] in ADNI. Within diagnostic group, general linear models related slope methods individually to neuroimaging variables, adjusting for age, sex, education, and APOE4 status. Among MCI, better learning performance on simple slope, regression-based slope, and late slope (Trial 2-5) from the two-slope method related to larger parahippocampal thickness (all p-values<.01) and hippocampal volume (p<.01). Better regression-based slope (p<.01) and late slope (p<.01) were related to larger ventrolateral prefrontal cortex in MCI. No significant associations emerged between any slope and neuroimaging variables for NC (p-values ≥.05) or AD (p-values ≥.02). Better learning performances related to larger medial temporal lobe (i.e., hippocampal volume, parahippocampal gyrus thickness) and ventrolateral prefrontal cortex in MCI only. Regression-based and late slope were most highly correlated with neuroimaging markers and explained more variance above and beyond other common memory indices, such as total learning. Simple slope may offer an acceptable alternative given its ease of calculation.

An intervention to enhance Alzheimer's disease clinical research participation among older African Americans.

BACKGROUND: Alzheimer's disease (AD) rates are higher among African Americans than in other racial or ethnic groups. However, Black elders participate in research at lower rates than Whites. OBJECTIVE: The present study aimed to: (1) implement an informational protocol for African Americans elders and their loved ones about the benefits of clinical research and brain donation program participation in AD, and (2) quantitatively assess changes in knowledge, attitudes, and trust. METHODS: Participants included 52 African American participants from the Boston University Alzheimer's Disease Center research registry (74 ± 8 years, 83% female) and 11 loved ones. Registry participants completed a pre- and post-group survey assessing brain donation knowledge, factors influencing brain donation, attitudes about medical research, and trust in medical researchers. RESULTS: There were no significant changes in mean scores between the pre- and post-group surveys. However, post-group outcomes revealed that 69% of participants shared details from the protocol with loved ones, 27% expressed an interest in joining Center-sponsored studies, and 10% indicated an interest in changing their brain donation status. CONCLUSION: The informational protocol implemented in this study is an effective method to encourage family discussions about brain donation and increase interest in other AD research studies. Longitudinal follow-up is necessary to assess the long-term implications of these groups on participation in a brain donation program.