Blood-based biomarkers in Alzheimer's disease: a mini-review.

Alzheimer's disease (AD) is the most common cause of dementia and has far reaching consequences for patients and their caregivers. Early detection and treatment are key factors in limiting the impact of the disease. However, a definitive diagnosis of AD requires an examination of brain tissue during an autopsy. Although a plethora of biomarkers such as neuroimaging, electrophysiological, and cerebrospinal fluid (CSF) biomarkers are available, their utility is limited to research due to their poor reach and prohibitive cost. In order for biomarkers to be widely used, they need to be accessible, affordable, and conducive for the patient population or disease stage. Blood-based biomarkers may not only be less expensive and more accessible compared to neuroimaging or CSF tests, but they are also preferred by patients with AD as they are much less invasive. In this mini-review article, we expand on the rationale for the use of blood-based biomarkers, review currently available biomarkers and discuss the need for the standardization of these biomarkers. We contrast the blood-based biomarkers with other available biomarkers and discuss the advantages of using a panel of blood-based biomarkers to strengthen their accuracy.

Estradiol treatment in young postmenopausal women with self-reported cognitive complaints: Effects on cholinergic-mediated cognitive performance.

OBJECTIVE: Older women are at increased risk of developing Alzheimer's disease compared to men. One proposed reason is that following menopause there is a decline in estrogens. Estrogens are important for cholinergic functioning and attenuate the impact of cholinergic antagonists on cognitive performance in postmenopausal women. Self-reported or subjective cognitive complaints in middle or older age may represent a harbinger of cognitive decline and those who endorse cognitive complaints appear more likely to develop future cognitive impairment. However, the response of individuals with cognitive complaints after menopause to estrogen and the relationship to cholinergic functioning has not been investigated. This study investigated the effect of estrogen treatment using 17ß-estradiol on cognitive performance following anticholinergic blockade in postmenopausal women and the relationship of this interaction with the level of self-reported (subjective) postmenopausal cognitive complaints. METHODS: Forty postmenopausal women (aged 50-60 years) completed a 3-month treatment regimen of either 1 mg oral estradiol or placebo. Participants then completed four challenge days in which they completed cognitive and behavioral tasks after one of four cholinergic antagonist drug conditions (oral mecamylamine (MECA), intravenous scopolamine, combined MECA and scopolamine, or PLC). RESULTS: Compared to PLC, the estradiol treated group performed worse on attention tasks under cholinergic challenge including the choice reaction time task and the critical flicker fusion task. In addition, participants who endorsed greater cognitive complaints showed reduced performance on the N-back working memory task, regardless of whether they received estradiol treatment. CONCLUSIONS: The findings of this study indicate that estradiol treatment was unable to mitigate anticholinergic blockade in postmenopausal women with subjective cognitive complaints, and worsened performance on attention tasks. Moreover, the present study suggests that greater levels of cognitive complaints following menopause may be associated with an underlying decline in cholinergic function that may manifest as an inability to compensate during working memory tasks.

SAR-Connect: A Socially Assistive Robotic System to Support Activity and Social Engagement of Older Adults.

Multi-domain activities that incorporate physical, cognitive, and social stimuli can enhance older adults' overall health and quality of life. Several robotic platforms have been developed to provide these therapies in a quantifiable manner to complement healthcare personnel in resource-strapped long-term care settings. However, these platforms are primarily limited to one-to-one human robot interaction (HRI) and thus do not enhance social interaction. In this paper, we present a novel HRI framework and a realized platform called SAR-Connect to foster robot-mediated social interaction among older adults through carefully designed tasks that also incorporate physical and cognitive stimuli. SAR-Connect seamlessly integrates a humanoid robot with a virtual reality-based activity platform and a multimodal data acquisition module including game interaction, audio, visual and electroencephalography responses of the participants. Results from a laboratory-based user study with older adults indicates the potential of SAR-Connect that showed this system could 1) involve one or multiple older adults to perform multi-domain activities and provide dynamic guidance, 2) engage them in the robot-mediated task and foster human-human interaction, and 3) quantify their social and activity engagement from multiple sensory modalities.

Preliminary Evidence That Cortical Amyloid Burden Predicts Poor Response to Antidepressant Medication Treatment in Cognitively Intact Individuals With Late-Life Depression.

OBJECTIVE: Amyloid accumulation, the pathological hallmark of Alzheimer's disease, may predispose some older adults to depression and cognitive decline. Deposition of amyloid also occurs prior to the development of cognitive decline. It is unclear whether amyloid influences antidepressant outcomes in cognitively intact depressed elders. DESIGN: A pharmacoimaging trial utilizing florbetapir (18F) PET scanning followed by 2 sequential 8-week antidepressant medication trials. PARTICIPANTS: Twenty-seven depressed elders who were cognitively intact on screening. MEASUREMENTS AND INTERVENTIONS: After screening, diagnostic testing, assessment of depression severity and neuropsychological assessment, participants completed florbetapir (18F) PET scanning. They were then randomized to receive escitalopram or placebo for 8 weeks in a double-blinded two-to-one allocation rate. Individuals who did not respond to initial treatment transitioned to a second open-label trial of bupropion for another 8 weeks. RESULTS: Compared with 22 amyloid-negative participants, 5 amyloid-positive participants exhibited significantly less change in depression severity and a lower likelihood of remission. In the initial blinded trial, 4 of 5 amyloid-positive participants were nonremitters (80%), while only 18% (4 of 22) of amyloid-negative participants did not remit (p = 0.017; Fisher's Exact test). In separate models adjusting for key covariates, both positive amyloid status (t = 3.07, 21 df, p = 0.003) and higher cortical amyloid binding by standard uptake value ratio (t = 2.62, 21 df, p = 0.010) were associated with less improvement in depression severity. Similar findings were observed when examining change in depression status across both antidepressant trials. CONCLUSIONS: In this preliminary study, amyloid status predicted poor antidepressant response to sequential antidepressant treatment. Alternative treatment approaches may be needed for amyloid-positive depressed elders.

Estrogen, Stress, and Depression: Cognitive and Biological Interactions.

This article reviews the interactions of estrogen changes and psychosocial stress in contributing to vulnerability to major depressive disorder (MDD) in women. Estrogen modulates brain networks and processes related to changes in stress response, cognition, and emotional dysregulation that are core characteristics of MDD. Synergistic effects of estrogen on cognitive and emotional function, particularly during psychosocial stress, may underlie the association of ovarian hormone fluctuation and depression in women. We propose a model of estrogen effects on multiple brain systems that interface with stress-related emotional and cognitive processes implicated in MDD and discuss possible mechanisms through which reproductive events and changes in estrogen may contribute to MDD risk in women with other concurrent risk factors.

Self-reported chemotherapy-related cognitive impairment compared with cognitive complaints following menopause.

OBJECTIVE: Cancer-related cognitive impairment (CRCI) is commonly reported following the administration of cancer treatment. Current longitudinal studies, primarily in women with breast cancer, suggest that up to 35% to 60% of patients exhibit persistent CRCI (pCRCI) following completion of chemotherapy. Complaints of subjective cognitive decline (SCD) are also commonly reported by women during and following the menopause transition in noncancer patients. Although the majority of evidence for cognitive difficulties in cancer patients and survivors is attributed to chemotherapy, there is growing evidence to suggest that menopausal status can also influence cognitive function in cancer patients. METHODS: Given that menopausal status may be contributing to pCRCI, we compared a group of primarily postmenopausal women with pCRCI to 2 groups of postmenopausal women: women who endorse menopause-associated SCD (maSCD+) and women who do not (maSCD-) to explore the similarities/differences between maSCD and pCRCI and the potential role of menopause in pCRCI. RESULTS: Persistent CRCI participants report more severe SCD symptoms than women after natural menopause, despite being on average 2.5-year postchemotherapy, supporting previous findings that CRCI can persist for months to years after completing treatment. Persistent CRCI participants not only endorsed greater SCD but also exhibited objective performance differences. In addition, pCRCI participants endorsed significantly greater menopausal symptoms compared with either maSCD group. Results were not related to menopausal status prior to chemotherapy or current endocrine therapy use. CONCLUSIONS: These results suggest that while menopausal symptoms may contribute to SCD experienced by cancer patients after chemotherapy, they do not fully account for pCRCI.

Cognitive Effects of Chemotherapy and Cancer-Related Treatments in Older Adults.

Advances in cancer treatment are producing a growing number of cancer survivors; therefore, issues surrounding quality of life during and following cancer treatment have become increasingly important. Chemotherapy-related cognitive impairment (CRCI) is a problem that is commonly reported following the administration of chemotherapy treatment in patients with cancer. Research suggests that CRCI can persist for months to years after completing treatment, which has implications for the trajectory of normal and pathologic cognitive aging for the growing number of long-term cancer survivors. These problems are particularly relevant for older individuals, given that cancer is largely a disease of older age, and the number of patients with cancer who are aged 65 years or older will increase dramatically over the coming decades. This review will briefly summarize empirical findings related to CRCI, discuss CRCI in older patients with cancer, propose potential causative hypotheses, and provide a canonical patient case to illustrate how CRCI presents clinically. Finally, potential intervention strategies for CRCI will be highlighted and issues to consider when evaluating older patients with a history of cancer will be discussed.

CADASIL as a Useful Medical Model and Genetic Form of Vascular Depression.

OBJECTIVE: The main magnetic resonance imaging (MRI) findings of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are white matter hyperintensities (WMHs), lacunar infarctions, and cerebral microbleeds (CMBs). The purpose of this study was to investigate the effects of these three neuroimaging markers of CADASIL on depression to determine whether CADASIL is a useful medical model supporting the vascular depression hypothesis. METHODS: Eighty-four subjects with CADASIL, aged 34-86 years, participated in this study. They underwent comprehensive clinical evaluation, including 3T MRI and genotyping of NOTCH3. The effects of WMH, lacunar infarctions, and CMBs were analyzed by path analyses and multivariate logistic regression analyses. RESULTS: Patients with CADASIL exhibited frequencies of 17.9% for major depressive disorder (MDD) and 10.7% for minor depressive disorder. The frequency of MDD increased from 5.0% to 46.2% as WMH volume increased from first quartile to fourth quartile. WMH volume (OR: 1.03, 95% CI: 1.003-1.06) in patients with CADASIL was associated with the current depressive disorder. Path analyses demonstrated that only WMH volume was associated with the Korean version of the short form Geriatric Depression Scale score, Center for Epidemiologic Studies Depression Scale score, and 17-item Hamilton depression scale score. The effects of lacunar infarctions and CMBs on depression were not significant in path analyses and multivariate logistic regression analyses. CONCLUSIONS: This study demonstrates that WMHs are closely associated with depression in patients with CADASIL. This supports that CADASIL might be a useful medical model and genetic form of vascular depression.

Socially Assistive Robots: Measuring Older Adults' Perceptions.

To address manpower shortages, health care leaders recommend technology, including robots, to facilitate and augment processes for delivery of efficient, safe care. Little is known regarding older adults' perceptions of socially assistive robots (SARs). Using the Unified Theory of Acceptance and Use Technology framework, a survey was developed and tested for capturing older adults' likelihood to use SARs. The Robot Acceptance Survey (RAS) comprises three subscales: Performance Expectancy, Effort Expectancy, and Attitude. Older adults completed the RAS pre- and post-experimental procedure with a SAR. Cronbach's alpha coefficients for the subscales ranged from 0.77 to 0.89. Subscales were sensitive to change, with more positive reactions after exposure to SAR activities. Future studies must identify robotic programming capable of providing cognitive, physical, and social assistance, as well as person-, activity-, situation-, and robot-specific factors that will influence older adults' acceptance of SARs. [Journal of Gerontological Nursing, 43(12), 35-43.].

Impaired working memory in geriatric depression: an FMRI study.

OBJECTIVE: Older adults with major depressive disorder (MDD) experience poor cognitive and behavioral outcomes as MDD occurs in the context of other age-related brain changes. Patients with depression often have impairments on measures of frontal lobe functioning such as working memory. Understanding the effects of depression on cognitive functioning in older adults is important for the development of treatment strategies that focus on cognitive changes as well as mood. METHODS: Eleven older adults with current MDD and 12 nondepressed comparison participants (all aged 60 years and older) performed the N-back test of working memory during fMRI. RESULTS: Depressed older adults performed worse than nondepressed participants on the N-back task. Depressed older adults had decreased lateral frontal and parietal activation during the most difficult working memory load condition on the N-back compared with nondepressed older adults. CONCLUSION: Cognitive dysfunction in geriatric depression may be related to reorganization of brain networks involved in working memory.

Specific Physician Orders Improve Pain Detection and Pain Reports in Nursing Home Residents: Preliminary Data.

Despite evidence that many nursing home residents' pain is poorly managed, reasons for this poor management remain unanswered. The aim of this study was to determine if specific order sets related to pain assessment would improve pain management in nursing home (NH) residents. Outcomes included observed nurse pain assessment queries and resident reports of pain. The pretest/post-test study was performed in a 240-bed for-profit nursing home in the mid-southern region of the United States and participants were 43 nursing home residents capable of self-consent. Medical chart abstraction was performed during a 2-week (14-day) period before the implementation of specific order sets for pain assessment (intervention) and a 2-week (14-day) period after the intervention. Trained research assistants observed medication administration passes and performed participant interviews after each medication pass. One month after intervention implementation, 1 additional day of observations was conducted to determine data reliability. Nurses were observed to ask residents about pain more frequently, and nurses continued to ask about pain at higher rates 1 month after the intervention was discontinued. The proportion of residents who reported pain also significantly increased in response to increased nurse queries (e.g., "Do you have any pain right now?"), which underscores the importance of nurses directly asking residents about pain. Notably 70% of this long-stay NH population only told the nurses about their pain symptoms when asked directly. Findings uncover that using specific pain order sets seems to improve the detection of pain, which should be a routine part of nursing assessment.

Mild cognitive impairment: diagnosis, longitudinal course, and emerging treatments.

Mild cognitive impairment (MCI) is widely regarded as the intermediate stage of cognitive impairment between the changes seen in normal cognitive aging and those associated with dementia. Elderly patients with MCI constitute a high-risk population for developing dementia, in particular Alzheimer's disease (AD). Although the core clinical criteria for MCI have remained largely unchanged, the operational definition of MCI has undergone several revisions over the course of the last decade and remains an evolving diagnosis. Prognostic implications of this diagnosis are becoming clearer with regard to the risk of progressive cognitive deterioration. Although patients with MCI may represent an optimal target population for pharmacological and non-pharmacological interventions, results from clinical trials have been mixed and an effective treatment remains elusive. This article provides a brief overview of the evolution of the concept of MCI and reviews current diagnostic criteria, the longitudinal course of the disorder, and current and emerging treatments for MCI.

Cholinergic System Structure and Function Changes in Individuals with Down Syndrome During the Development of Alzheimer's Disease.

Adults with Down syndrome represent the population with the highest risk of developing Alzheimer's disease worldwide. The cholinergic system is known to decline in Alzheimer's disease, with this decline responsible for many of the cognitive deficits that develop. The integrity of the cholinergic system across the lifespan in individuals with Down syndrome is not well characterized. Small fetal and infant post-mortem studies suggest an intact cholinergic projection system with a potential reduction in cholinergic receptors, while post-mortem studies in adults with Down syndrome reveal an age-related decrease in cholinergic integrity. Advances in magnetic resonance imaging (MRI) and positron emission tomography (PET) over the last 20 years have allowed for studies investigating the changes in cholinergic integrity across aging and during the development of Alzheimer's disease. One large cross-sectional study demonstrated reduced cholinergic basal forebrain volume measured by MRI associated with increasing Alzheimer's disease pathology. In a small cohort of adults with Down syndrome, we have recently reported that PET measures of cholinergic integrity negatively correlated with amyloid accumulation. New disease-modifying treatments for Alzheimer's disease and treatments under development for Alzheimer's disease in Down syndrome have the potential to preserve the cholinergic system, while treatments targeting the cholinergic system directly may be used in conjunction with disease-modifying therapies to improve cognitive function further. A greater understanding of cholinergic neuronal and receptor integrity across the lifespan in individuals with Down syndrome will provide insights as to when targeting the cholinergic system is an appropriate therapeutic option and, in the future, maybe a valuable screening tool to identify individuals that would most benefit from cholinergic interventions.

Effect of estradiol with or without micronized progesterone on cholinergic-related cognitive performance in postmenopausal women.

Introduction: Women are at a higher risk of developing Alzheimer's disease (AD), and the decline in estrogens post-menopause is thought of as a factor increasing this risk. Estradiol (E2) is important in supporting cholinergic neuronal integrity, and cholinergic functioning may be negatively impacted following the loss of E2 post-menopause. The use of exogenous E2 has been observed to enhance cholinergically mediated cognitive performance in healthy post-menopausal women, which indicates a potentially protective mechanism. However, E2 is often co-administered with progestin or progesterone to prevent endometrial proliferation. Progesterone/progestins have previously been shown to have a detrimental effect on E2-mediated biological and cognitive effects mediated by cholinergic systems in preclinical models, therefore the present study aimed to assess whether progesterone would modify the effect of E2 to influence cognition during cholinergic blockade. Methods: Twenty participants completed 3-months of oral E2 treatment with micronized progesterone (mPRO) or with placebo (PLC) in a repeated-measures within-subjects crossover design, in which they also completed five anticholinergic challenge days per hormone treatment condition. During the challenge participants were administered low or high doses of the nicotinic cholinergic antagonist mecamylamine, the muscarinic cholinergic antagonist scopolamine, or placebo. Following drug administration participants performed cognitive tests sensitive to cholinergic tone, assessing attention, episodic memory, and working memory. Results: Significant decrements were found on some tasks when participants were taking E2+mPRO compared to E2 alone. Specifically, under more challenging task conditions and larger anticholinergic doses, participants showed poorer performance on the Critical Flicker Fusion task and the Stroop test and responded more conservatively on the N-back working memory task. Other tasks showed no differences between treatments under cholinergic blockade. Discussion: The findings show that mPRO when taken in concert with E2, was detrimental to effortful cognitive performance, in the presence of cholinergic blockade. These results are important for assessing the impact of combined postmenopausal hormone treatment on cognitive performance that is dependent on cholinergic functioning after menopause.

Use of focused computerized cognitive training (Neuroflex) to improve symptoms in women with persistent chemotherapy-related cognitive impairment.

Purpose: Chemotherapy-related cognitive impairment (CRCI) is a distressing and increasingly recognized long-term sequela reported by breast cancer patients following cancer treatment. There is an urgent but unmet clinical need for treatments that improve CRCI. In this context, we proposed the use of a novel cognitive enhancement strategy called Neuroflex to target CRCI experienced by breast cancer survivors. Methods: The primary aim of this pilot study was to evaluate the feasibility and acceptability of Neuroflex, a novel digital cognitive enhancement strategy, in breast and gynecologic cancer survivors with CRCI. Secondary analyses focused on whether improvements in performance on Neuroflex were associated with improvement in subjective cognitive complaints and objective cognitive performance measures. Results: Participants (N = 21) completed an average of 7.42 hours of Neuroflex training per week, an average of 44.5 (±1.01) hours total, and had a 100% completion rate. Participants exhibited significant improvement in self-reported cognitive function as well as significant improvement on tasks of verbal learning and memory and auditory working memory. Participants also exhibited improvement in mood, as well as improvement on a disability assessment. Conclusions: Results demonstrate feasibility and that breast cancer survivors are capable of completing a lengthy and challenging cognitive training program. Secondly, Neuroflex may confer specific cognitive benefits to both self-reported and objective performance. Results strongly support further investigation of Neuroflex in a larger controlled trial to establish efficacy for CRCI symptoms. Further studies may also result in optimization of this digital intervention for women with CRCI.

Brain gray matter reduction and premature brain aging after breast cancer chemotherapy: a longitudinal multicenter data pooling analysis.

Brain gray matter (GM) reductions have been reported after breast cancer chemotherapy, typically in small and/or cross-sectional cohorts, most commonly using voxel-based morphometry (VBM). There has been little examination of approaches such as deformation-based morphometry (DBM), machine-learning-based brain aging metrics, or the relationship of clinical and demographic risk factors to GM reduction. This international data pooling study begins to address these questions. Participants included breast cancer patients treated with (CT+, n = 183) and without (CT-, n = 155) chemotherapy and noncancer controls (NC, n = 145), scanned pre- and post-chemotherapy or comparable intervals. VBM and DBM examined GM volume. Estimated brain aging was compared to chronological aging. Correlation analyses examined associations between VBM, DBM, and brain age, and between neuroimaging outcomes, baseline age, and time since chemotherapy completion. CT+ showed longitudinal GM volume reductions, primarily in frontal regions, with a broader spatial extent on DBM than VBM. CT- showed smaller clusters of GM reduction using both methods. Predicted brain aging was significantly greater in CT+ than NC, and older baseline age correlated with greater brain aging. Time since chemotherapy negatively correlated with brain aging and annual GM loss. This large-scale data pooling analysis confirmed findings of frontal lobe GM reduction after breast cancer chemotherapy. Milder changes were evident in patients not receiving chemotherapy. CT+ also demonstrated premature brain aging relative to NC, particularly at older age, but showed evidence for at least partial GM recovery over time. When validated in future studies, such knowledge could assist in weighing the risks and benefits of treatment strategies.

Estradiol treatment altered anticholinergic-related brain activation during working memory in postmenopausal women.

Estradiol has been shown to affect cholinergic modulation of cognition in human and nonhuman animal models. This study examined the brain-based interaction of estradiol treatment and anticholinergic challenge in postmenopausal women during the performance of a working memory task and functional MRI. Twenty-four postmenopausal women were randomly and blindly placed on 1mg oral 17-ß estradiol or matching placebo pills for three months after which they participated in three anticholinergic challenge sessions. During the challenge sessions, subjects were administered the antimuscarinic drug scopolamine, the antinicotinic drug mecamylamine, or placebo. After drug administration, subjects completed an fMRI session during which time they performed a visual verbal N-back test of working memory. Results showed that scopolamine increased activation in the left medial frontal gyrus (BA 10) and mecamylamine increased activation in the left inferior frontal gyrus (BA 46). Estradiol treatment compared to placebo treatment significantly reduced the activation in this left medial frontal region during scopolamine challenge. Estradiol treatment also increased activation in the precuneus (BA 31) during mecamylamine challenge. These data are the first to show that estradiol modulated antimuscarinic- and anitnicotinic-induced brain activity and suggest that estradiol affected cholinergic system regulation of cognition-related brain activation in humans.