Procedural Framework to Facilitate Hospital-Based Informed Consent for Dementia Research.

Improving quality and delivery of care for people with Alzheimer disease and related dementias (ADRD) requires a comprehensive research agenda that encompasses the entire care continuum. Logistical and ethical challenges of informed consent for research participation of persons with ADRD include determination of capacity to consent, surrogate consent when capacity to consent is compromised, timely identification of the legally authorized representative (LAR) providing surrogate consent, and balancing residual autonomy with surrogate consent. Short stays; limited access to patients, caregivers, and LARs; and fluctuating influences of acute illness on capacity determination compound these challenges in the acute care setting. To address these challenges, we worked with the University of Wisconsin Health Sciences Institutional Review Board to develop a procedural framework for obtaining informed consent from hospitalized individuals with ADRD and their caregivers to participate in a minimal risk care intervention. The framework is specially designed for minimal risk situations in which rapid enrollment is a necessity and uses rapid identification of surrogates to consent for patients who lack legal capacity to make medical decisions, indicated by an activated healthcare power of attorney, and individualized formal assent procedures for patients who lack capacity to consent. These methods were proven effective in facilitating hospital-based recruitment in an ongoing randomized controlled trial and provide a basis for increasing access to acute care clinical research for persons with ADRD. Bolstering research participation through more easily used consent procedures during acute illness is critical to fostering improvements in the delivery of high-quality care to persons with ADRD. J Am Geriatr Soc 66:2243-2248, 2018.

The relationship between fasting serum glucose and cerebral glucose metabolism in late-life depression and normal aging.

Evidence exists for late-life depression (LLD) as both a prodrome of and risk factor for Alzheimer׳s disease (AD). The underlying neurobiological mechanisms are poorly understood. Impaired peripheral glucose metabolism may explain the association between depression and AD given the connection between type 2 diabetes mellitus with both depression and AD. Positron emission tomography (PET) measures of cerebral glucose metabolism are sensitive to detecting changes in neural circuitry in LLD and AD. Fasting serum glucose (FSG) in non-diabetic young (YC; n=20) and elderly controls (EC; n=12) and LLD patients (n=16) was correlated with PET scans of cerebral glucose metabolism on a voxel-wise basis. The negative correlations were more extensive in EC versus YC and in LLD patients versus EC. Increased FSG correlated with decreased cerebral glucose metabolism in LLD patients to a greater extent than in EC in heteromodal association cortices involved in mood symptoms and cognitive deficits observed in LLD and dementia. Negative correlations in YC were observed in sensory and motor regions. Understanding the neurobiological consequences of diabetes and associated conditions will have substantial public health significance given that this is a modifiable risk factor for which prevention strategies could have an important impact on lowering dementia risk.

Longitudinal studies of cerebral glucose metabolism in late-life depression and normal aging.

OBJECTIVE: Late-life depression (LLD) has a substantial public health impact and is both a risk factor for and a prodrome of dementia. Positron emission tomography (PET) studies of cerebral glucose metabolism have demonstrated sensitivity in evaluating neural circuitry involved in depression, aging, incipient cognitive decline, and dementia. The present study evaluated the long term effects of a course of antidepressant treatment on glucose metabolism in LLD patients. METHODS: Nine LLD patients and seven non-depressed control subjects underwent clinical and cognitive evaluations as well as brain magnetic resonance imaging and PET studies of cerebral glucose metabolism at baseline, after 8 weeks of treatment with citalopram for a major depressive episode (patients only), and at an approximately 2-year follow-up. RESULTS: The majority of LLD patients were remitted at follow-up (7/9). Neither patients nor controls showed significant cognitive decline. The patients showed greater increases in glucose metabolism than the controls in regions associated with mood symptoms (anterior cingulate and insula). Both groups showed decreases in metabolism in posterior association cortices implicated in dementia. CONCLUSIONS: Longitudinal changes in cerebral glucose metabolism are observed in controls and in LLD patients without significant cognitive decline that are more extensive than the decreases in brain volume. Longer duration follow-up studies and the integration of other molecular imaging methods will have implications for understanding the clinical and neurobiological significance of these metabolic changes.

Serotonin modulation of cerebral glucose metabolism: sex and age effects.

The serotonin system is implicated in a variety of psychiatric disorders whose clinical presentation and response to treatment differ between males and females, as well as with aging. However, human neurobiological studies are limited. Sex differences in the cerebral metabolic response to an increase in serotonin concentrations were measured, as well as the effect of aging, in men compared to women. Thirty-three normal healthy individuals (14 men/19 women, age range 20-79 years) underwent two resting positron emission tomography studies with the radiotracer [18F]-2-deoxy-2-fluoro-D-glucose ([(18)F]-FDG) after placebo and selective serotonin reuptake inhibitor (SSRI, citalopram) infusions on two separate days. Results indicated that women demonstrated widespread areas of increased cortical glucose metabolism with fewer areas of decrease in metabolism in response to citalopram. Men, in contrast, demonstrated several regions of decreased cortical metabolism, but no regions of increased metabolism. Age was associated with greater increases in women and greater decreases in men in most brain regions. These results support prior studies indicating that serotonin function differs in men and women across the lifespan. Future studies aimed at characterizing the influences of age and sex on the serotonin system in patients with psychiatric disorders are needed to elucidate the relationship between sex and age differences in brain chemistry and associated differences in symptom presentation and treatment response.

The relationship between the acute cerebral metabolic response to citalopram and chronic citalopram treatment outcome.

OBJECTIVES: Given the challenges in the clinical management of geriatric depression, research over the past decade has focused on developing early neurobiological markers of antidepressant treatment response. This study tested the hypothesis that lower baseline glucose metabolism and greater acute cerebral metabolic responses to a single, intravenous (IV) dose of the selective serotonin reuptake inhibitor (SSRI) citalopram would be associated with greater improvement of depressive symptoms after 12 weeks of citalopram treatment in geriatric depression. METHODS: sixteen geriatric depressed patients underwent two scans to measure cerebral glucose metabolism after administration of either a saline placebo or citalopram infusion (40 mg, IV). Then, the patients were treated with the oral citalopram medication for 12 weeks. RESULTS: greater improvement of depressive symptoms was associated with lower baseline metabolism in anterior cingulate, superior, middle, and inferior frontal gyri (bilaterally), inferior parietal lobule (bilaterally), precuneus (right), insula (left), parahippocampal gyrus (right), caudate (bilaterally), and putamen (left) regions. Greater improvement of depressive symptoms was associated with greater reductions in metabolism after acute citalopram administration in similar brain regions, including additional posterior cortical regions. CONCLUSIONS: lower baseline cerebral metabolism and greater decreases with acute citalopram administration are associated with better antidepressant response to chronic citalopram treatment. These data are consistent with previous studies of total sleep deprivation and suggest that dynamic, early adaptive changes or normalization of cerebral metabolism may represent early neurobiological markers of chronic SSRI treatment response in geriatric depression.

Distinct functional networks associated with improvement of affective symptoms and cognitive function during citalopram treatment in geriatric depression.

Variability in the affective and cognitive symptom response to antidepressant treatment has been observed in geriatric depression. The underlying neural circuitry is poorly understood. This study evaluated the cerebral glucose metabolic effects of citalopram treatment and applied multivariate, functional connectivity analyses to identify brain networks associated with improvements in affective symptoms and cognitive function. Sixteen geriatric depressed patients underwent resting positron emission tomography (PET) studies of cerebral glucose metabolism and assessment of affective symptoms and cognitive function before and after 8 weeks of selective serotonin reuptake inhibitor treatment (citalopram). Voxel-wise analyses of the normalized glucose metabolic data showed decreased cerebral metabolism during citalopram treatment in the anterior cingulate gyrus, middle temporal gyrus, precuneus, amygdala, and parahippocampal gyrus. Increased metabolism was observed in the putamen, occipital cortex, and cerebellum. Functional connectivity analyses revealed two networks which were uniquely associated with improvement of affective symptoms and cognitive function during treatment. A subcortical-limbic-frontal network was associated with improvement in affect (depression and anxiety), while a medial temporal-parietal-frontal network was associated with improvement in cognition (immediate verbal learning/memory and verbal fluency). The regions that comprise the cognitive network overlap with the regions that are affected in Alzheimer's dementia. Thus, alterations in specific brain networks associated with improvement of affective symptoms and cognitive function are observed during citalopram treatment in geriatric depression.

Serotonin modulation of cerebral glucose metabolism in depressed older adults.

BACKGROUND: Monoamine dysfunction, particularly of the serotonin system, has been the dominant hypothesis guiding research and treatment development in affective disorders. The majority of research has been performed in midlife depressed adults. The importance of understanding the neurobiology of depression in older adults is underscored by increased rates of mortality and completed suicide and an increased risk of Alzheimer's dementia. To evaluate the dynamic response of the serotonin system, the acute effects of citalopram infusion on cerebral glucose metabolism was measured in depressed older adults and control subjects. The hypothesis was tested that smaller decreases in metabolism would be observed in cortical and limbic regions in depressed older adults relative to control subjects. METHODS: Sixteen depressed older adults and 13 control subjects underwent two resting positron emission tomography (PET) studies with the radiotracer [18F]-2-deoxy-2-fluoro-D-glucose after placebo and citalopram infusions. RESULTS: In control subjects compared with depressed older adults, greater citalopram-induced decreases in cerebral metabolism were observed in the right anterior cingulate, middle temporal (bilaterally), left precuneus, and left parahippocampal gyri. Greater decreases in the depressed older adults than control subjects were observed in left superior and left middle frontal gyri and increases in left inferior parietal lobule, left cuneus, left thalamus, and right putamen. CONCLUSIONS: In depressed older adults relative to control subjects, the cerebral metabolic response to citalopram is blunted in cortico-cortical and cortico-limbic pathways and increased in the left hemisphere (greater decrease interiorly and increases posteriorly). These findings suggest both blunted and compensatory cerebral metabolic responses to citalopram in depressed older adults.

Cholinergic modulation of the cerebral metabolic response to citalopram in Alzheimer's disease.

Pre-clinical and human neuropharmacological evidence suggests a role of cholinergic modulation of monoamines as a pathophysiological and therapeutic mechanism in Alzheimer's disease. The present study measured the effects of treatment with the cholinesterase inhibitor and nicotinic receptor modulator, galantamine, on the cerebral metabolic response to the selective serotonin reuptake inhibitor, citalopram. Seven probable Alzheimer's disease patients and seven demographically comparable controls underwent two positron emission tomography (PET) glucose metabolism scans, after administration of a saline placebo infusion (Day 1) and after citalopram (40 mg, IV, Day 2). The scan protocol was repeated in the Alzheimer's disease patients 2 months after titration to a 24 mg galantamine dose. At baseline, cerebral glucose metabolism was reduced in Alzheimer's disease patients relative to controls in right middle temporal, left posterior cingulate and parietal cortices (precuneus and inferior parietal lobule), as expected. Both groups demonstrated acute decreases in cerebral glucose metabolism after citalopram to a greater extent in the Alzheimer's disease patients. In the patients, relative to the controls, citalopram decreased glucose metabolism to a greater extent in middle frontal gyrus (bilaterally), left middle temporal gyrus and right posterior cingulate prior to treatment. Galantamine treatment alone increased metabolism in the right precuneus, right inferior parietal lobule and right middle occipital gyrus. In contrast, during galantamine treatment, citalopram increased metabolism in the right middle frontal gyrus, right post-central gyrus, right superior and middle temporal gyrus and right cerebellum. The combined cerebral metabolic effects of galantamine and citalopram suggest, consistent with preclinical data, a synergistic interaction of cholinergic and serotonergic systems.

Pilot study to test the effectiveness of Healing Touch on agitation in people with dementia.

A pilot study was conducted to investigate the effects of Healing Touch (HT) on agitation in persons with dementia. Because of the restricted availability of patients, the main purpose of the study was to investigate the effectiveness of HT on dementia patients who demonstrated similar high levels of agitation as measured by the Cohen-Mansfield Agitation Inventory. Results indicated that agitation levels were significantly lowered and that HT is worthy of further study.

Acute and chronic effects of citalopram on cerebral glucose metabolism in geriatric depression.

OBJECTIVE: In vivo studies of serotonin function have been limited by the lack of safe and selective pharmacologic agents and availability of suitable radiotracers. In the present study, the authors evaluated the cerebral metabolic effects of acute and continued administration of the selective serotonin reuptake inhibitor citalopram in patients with geriatric depression as a potential marker of serotonin dysfunction. METHODS: Six patients with geriatric depression and five comparison subjects underwent two resting positron emission tomography (PET) studies, performed after administration of a placebo infusion (Day 1) and a citalopram infusion (40 mg, Day 2). The patients were re-scanned after 8 weeks of treatment with the oral medication. RESULTS: The elderly comparison subjects demonstrated greater right-hemisphere cortical decreases than the patients. The depressed patients demonstrated greater left-hemisphere cortical decreases than comparison subjects. The depressed patients demonstrated greater increases in the right putamen and left occipital cortex. After 8 weeks of citalopram treatment, regional decreases and increases in metabolism were observed. CONCLUSION: These findings suggest regional deficits and also compensatory responses in the acute metabolic response to citalopram in the patients. These preliminary results suggest that the cerebral metabolic response to citalopram may be a useful marker of the pathophysiology of serotonin function in geriatric depression.