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In this issue of Alzheimer's & Dementia, Mashour et al. propose the intriguing hypothesis that some manifestations of late-stage dementia are reversible, albeit transiently. Calling this phenomenon paradoxical lucidity, their paper follows a 2018 workshop sponsored by the National Institute on Aging that assessed the state of knowledge on lucidity in dementia and identified areas ripe for further study. The National Institute on Aging has since released two funding opportunity announcements (RFA-AG-20-016 and RFA-AG-20-017) to establish the building blocks of such a research program. The potential challenges of conducting such studies are matched by the potential opportunities to open a novel window onto our understanding of dementia. Initial findings from this research may eventually lead to studies that uncover novel mechanisms underlying cognitive decline, identify potential preventive or therapeutic approaches for individuals with dementia, offer more effective strategies for caregivers, and perhaps even expand our understanding of the nature of personhood and consciousness.

In September 2010, the Cancer and Aging Research Group, in collaboration with the National Cancer Institute and the National Institute on Aging, conducted the first of three planned conferences to discuss research methodology to generate the highest quality research in older adults with cancer and then disseminate these findings among those working in the fields of cancer and aging. Conference speakers discussed the current level of research evidence in geriatric oncology, outlined the current knowledge gaps, and put forth principles for research designs and strategies that would address these gaps within the next 10 years. It was agreed that future oncology research trials that enroll older adults should include: (1) improved standardized geriatric assessment of older oncology patients, (2) substantially enhanced biological assessment of older oncology patients, (3) specific trials for the most vulnerable and/or those older than 75 years, and (4) research infrastructure that specifically targets older adults and substantially strengthened geriatrics and oncology research collaborations. This initial conference laid the foundation for the next two meetings, which will address the research designs and collaborations needed to enhance therapeutic and intervention trials in older adults with cancer.

Objective. There has been a growing recognition of the need for better pharmacologic management of chronic pain among older adults. To address this need, the National Institutes of Health Pain Consortium sponsored an “Expert Panel Discussion on the Pharmacological Management of Chronic Pain in Older Adults” conference in September 2010 to identify research gaps and strategies to address them. Specific emphasis was placed on ascertaining gaps regarding use of opioid and nonsteroidal anti-inflammatory medications because of continued uncertainties regarding their risks and benefits. Design. Eighteen panel members provided oral presentations; each was followed by a multidisciplinary panel discussion. Meeting transcripts and panelists' slide presentations were reviewed to identify the gaps and the types of studies and research methods panelists suggested could best address them. Results. Fifteen gaps were identified in the areas of treatment (e.g., uncertainty regarding the long-term safety and efficacy of commonly prescribed analgesics), epidemiology (e.g., lack of knowledge regarding the course of common pain syndromes), and implementation (e.g., limited understanding of optimal strategies to translate evidence-based pain treatments into practice). Analyses of data from electronic health care databases, observational cohort studies, and ongoing cohort studies (augmented with pain and other relevant outcomes measures) were felt to be practical methods for building an age-appropriate evidence base to improve the pharmacologic management of pain in later life. Conclusion. Addressing the gaps presented in the current report was judged by the panel to have substantial potential to improve the health and well-being of older adults with chronic pain.

Aging kidneys undergo structural and functional changes that decrease autoregulatory capacity and increase susceptibility to acute injury. Acute kidney injury associates with duration and location of hospitalization, mortality risk, progression to chronic kidney disease, and functional status in daily living. Definition and diagnosis of acute kidney injury are based on changes in creatinine, which is an inadequate marker and might identify patients when it is too late. The incidence of acute kidney injury is rising and increases with advancing age, yet clinical studies have been slow to address geriatric issues or the heterogeneity in etiologies, outcomes, or patient preferences among the elderly. Here we examine some of the current literature, identify knowledge gaps, and suggest potential research questions regarding acute kidney injury in older adults. Answering these questions will facilitate the integration of geriatric issues into future mechanistic and clinical studies that affect management and care of acute kidney injury.

This case report describes successful treatment of autoimmune autonomic ganglionopathy (AAG) in a 74-year-old woman by total plasma exchanges (PLEX) and rituximab. Two series of PLEX temporarily, but dramatically improved orthostatic intolerance and hypotension and baroreflex function, in a manner inversely related to ganglionic neuronal nicotinic receptor antibody titer. After rituximab treatment, the antibody titer was decreased modestly but persistently, and the patient had symptomatic and clinical laboratory evidence of continued benefit for at least 10 months, supporting the autoimmune pathogenesis of AAG.

Diseases characterized by neurogenic orthostatic hypotension (NOH), such as Parkinson disease (PD) and pure autonomic failure (PAF), are associated with cardiac sympathetic denervation, as reflected by low myocardial concentrations of 6-[(18)F]fluorodopamine-derived radioactivity. We studied the impact of such denervation on cardiac chronotropic and inotropic function.Cardiac inotropic function was assessed by the pre-ejection period index and the systolic time ratio index in response to the directly acting beta-adrenoceptor agonist, isoproterenol, and to the indirectly acting sympathomimetic amine, tyramine, in patients with PD+NOH or PAF (PD+NOH/PAF group, N=13). We compared the results to those in patients with multiple system atrophy, which usually entails NOH with normal cardiac sympathetic innervation (MSA, N=15), and in normal control subjects (N=5).The innervated and denervated groups did not differ in baseline mean pre-ejection period index or systolic time ratio index. Tyramine increased cardiac contractility in the MSA patients and controls but not in the PD+NOH/PAF group. For similar heart rate responses, the PD+NOH/PAF group required less isoproterenol (p0.01) and had lower plasma isoproterenol levels (p0.01) than did the MSA group.Among patients with NOH those with cardiac sympathetic denervation have an impaired inotropic response to tyramine and exaggerated responses to isoproterenol. This pattern suggests that cardiac denervation is associated with decreased ability to release endogenous norepinephrine from sympathetic nerves and with supersensitivity of cardiac beta-adrenoreceptors.

Stress is a well-known factor affecting cardiac contractility through the cardiac sympathetic nerves. A positive inotropic effect of the cardiac sympathetic nerves on the myocardium is reflected by pre-ejection period (PEP) shortening. Patients with Parkinson disease (PD) and neurogenic orthostatic hypotension (NOH) (PD + NOH) or with pure autonomic failure (PAF) have markedly decreased myocardial 6-[ 18 F]Fluorodopamine-derived radioactivity, reflecting cardiac sympathetic denervation. The functional effects of the cardiac sympathetic denervation have been unknown. We measured PEP and heart rate-corrected PEP (PEPI) responses to i.v. tyramine (1 mg/min) in 13 patients (9 PD + NOH and 4 PAF) with low 6-[ 18 F]Fluorodopamine-derived radioactivity and in subjects with normal radioactivity (15 multiple system atrophy with NOS patients (MSA + NOS). Baseline PEP and PEPI did not differ between the groups. By 10 min after initiation of tyramine infusion, PEP and PEPI were significantly lower (P < 0.01) in MSA + NOS, compared to base line, whereas PEP and PEPI remained unchanged in the PD + NOH/PAF group. The PEP and PEPI decrease was larger in the MSA + NOS group than in the PD + NOH/PAF group (P < 0.05). One of the functional consequences of cardiac sympathetic denervation is failure to increase contractility in response to stimuli that depend on endogenous norepinephrine release.

Biomarkers are increasingly important to diagnose and test treatments of neurodegenerative diseases such as Parkinson disease (PD). This study compared neuroimaging, neurochemical, and olfactory potential biomarkers to detect central dopamine (DA) deficiency and distinguish PD from multiple system atrophy (MSA).In 77 PD, 57 MSA, and 87 control subjects, radioactivity concentrations in the putamen (PUT), caudate (CAU), occipital cortex (OCC), and substantia nigra (SN) were measured 2h after 6-[18F]fluorodopa injection, septal myocardial radioactivity measured 8min after 6-[18F]fluorodopamine injection, CSF and plasma catechols assayed, or olfaction tested (University of Pennsylvania Smell Identification Test (UPSIT)). Receiver operating characteristic curves were constructed, showing test sensitivities at given specificities.PUT:OCC, CAU:OCC, and SN:OCC ratios of 6-[18F]fluorodopa-derived radioactivity were similarly low in PD and MSA (p0.0001, p0.0001, p=0.003 compared to controls), as were CSF dihydroxyphenylacetic acid (DOPAC) and DOPA concentrations (p0.0001, each). PUT:SN and PUT:CAU ratios were lower in PD than in MSA (p=0.004; p=0.005). CSF DOPAC correlated positively with PUT:OCC ratios (r=0.61, p0.0001). Myocardial 6-[18F]fluorodopamine-derived radioactivity distinguished PD from MSA (83% sensitivity at 80% specificity, 100% sensitivity among patients with neurogenic orthostatic hypotension). Only PD patients were anosmic; only MSA patients had normal olfaction (61% sensitivity at 80% specificity).PD and MSA feature low PUT:OCC ratios of 6-[18F]fluorodopa-derived radioactivity and low CSF DOPAC and DOPA concentrations, cross-validating the neuroimaging and neurochemical approaches but not distinguishing the diseases. PUT:SN and PUT:CAU ratios of 6-[18F]fluorodopa-derived radioactivity, cardiac 6-[18F]fluorodopamine-derived radioactivity, and olfactory testing separate PD from MSA.

Familial dysautonomia (FD) involves incomplete development of the sympathetic nervous system. Whether such loss extends to sympathetic innervation of the heart has been unknown. This study used 6-[(18)F]fluorodopamine neuroimaging to assess cardiac sympathetic innervation and function in FD.Six adult FD patients underwent thoracic PET scanning for 30 minutes after i.v. 6-[(18)F]fluorodopamine injection, as did healthy volunteers without (N = 21) or with (N = 10) pre-treatment by desipramine, which interferes with neuronal uptake and thereby simulates effects of noradrenergic denervation. Effective rate constants for uptake and loss were calculated using a single compartment pharmacokinetic model.FD patients had decreased uptake and accelerated loss of 6-[(18)F]fluorodopamine-derived radioactivity in the interventricular myocardial septum (P = 0.009, P = 0.05) and ventricular free wall (P = 0.007, P0.001), compared to untreated controls. Desipramine-treated subjects had decreased uptake but normal loss of 6-[(18)F]fluorodopamine-derived radioactivity.FD involves cardiac noradrenergic hypo-innervation. Since accelerated loss of 6-[(18)F]fluorodopamine-derived radioactivity cannot be explained by decreased neuronal uptake alone, FD may also involve augmented NE loss from extant terminals.

Identifying knowledge gaps and research opportunities in cancer and aging research was the focus of a three-part conference series led by the Cancer and Aging Research Group from 2010 to 2015. The third meeting, featured representatives from the NIA, NCI, ACS and PCORI each of whom discussed research priorities and funding opportunities in cancer and aging at their respective agencies. This manuscript reports on the proceedings of that conference with a specific focus on funding priorities for interventions to improve the quality of life and survivorship of older adults with cancer. Helpful tips from each funder regarding writing a scientifically strong research proposal are presented.

In patients with neurocardiogenic syncope, head-up tilt often evokes acute loss of consciousness accompanied by vasodilatation, increased plasma adrenaline and systemic hypotension. Since hypotension increases adrenaline levels and adrenaline can produce skeletal muscle vasodilatation by activating β2 receptors, adrenaline might induce a positive feedback loop precipitating circulatory collapse. We hypothesized that propranolol, a non-selective β-blocker, would prevent adrenaline-induced vasodilatation and thereby prevent syncope. Eight subjects with recurrent neurocardiogenic syncope and previously documented tilt-induced syncope with elevated plasma adrenaline levels participated in the present study. Subjects underwent tilt table testing after receiving oral propranolol or placebo in a double-blind randomized crossover fashion. Haemodynamic and neurochemical variables were measured using intra-arterial monitoring, impedance cardiography, arterial blood sampling and tracer kinetics of simultaneously infused [3H]noradrenaline and [3H]adrenaline. The occurrence of tilt-induced neurally mediated hypotension and syncope, duration of tilt tolerance, extent of the decrease in SVRI (systemic vascular resistance index) and magnitude of plasma adrenaline increases did not differ between the propranolol and placebo treatment phases. SVRI was inversely associated with fractional increase in plasma adrenaline during both phases. One subject did not faint when on propranolol; this subject's response is discussed in the context of central effects of propranolol. In this small, but tightly controlled, study, propranolol did not prevent tilt-induced vasodilatation, syncope or elevated plasma adrenaline.

Background— Chronic orthostatic intolerance (COI) occurs in postural tachycardia syndrome (POTS) and in some individuals with repeated neurocardiogenic syncope/presyncope (NCS), without POTS. This study addressed whether patients with COI and POTS or NCS have neurocirculatory abnormalities during supine rest. Methods and Results— Adult patients referred for COI who had POTS (n=90, mean±SEM age 40±1 years, 86% women) or NCS (n=36, 41±2 years old, 78% women) underwent measurements of plasma levels of catecholamines and forearm hemodynamics. Comparison data were obtained from 32 age- and gender-matched normal volunteers (39±2 years old, 81% women). The POTS group had a relatively fast mean heart rate (79±2 bpm) during supine rest compared with the NCS group (69±1.6 bpm, P =0.03) and normal volunteers (66±3 bpm, P =0.0004). The POTS group also had higher mean arterial norepinephrine (1.61±0.11 nmol/L, n=37) and epinephrine (0.39±0.03 nmol/L, n=37) concentrations than the NCS group (1.03±0.12 nmol/L, n=20, P =0.0012; 0.21±0.03 nmol/L, n=20, P =0.0005) and normal volunteers (1.13±0.11 nmol/L, n=20, P =0.006; 0.17±0.03 nmol/L, n=15, P =0.0001). The NCS group had higher mean forearm vascular resistance (52±6 U) than the POTS group (36±2 U, P =0.003). Conclusions— Overall, POTS features increased heart rate and sympathetic nervous and adrenomedullary hormonal system outflows during supine rest. Increased sympathetic outflow may contribute to the relative tachycardia in POTS. NCS features forearm vasoconstriction during supine rest but not sympathoneural or adrenomedullary activation.

Supine hypertension occurs commonly in primary chronic autonomic failure. This study explored whether supine hypertension in this setting is associated with orthostatic hypotension (OH), and if so, what mechanisms might underlie this association. Supine and upright blood pressures, hemodynamic responses to the Valsalva maneuver, baroreflex-cardiovagal gain, and plasma norepinephrine (NE) levels were measured in pure autonomic failure (PAF), multiple-system atrophy (MSA) with or without OH, and Parkinson’s disease (PD) with or without OH. Controls included age-matched, healthy volunteers and patients with essential hypertension or those referred for dysautonomia. Baroreflex-cardiovagal gain was calculated from the relation between the interbeat interval and systolic pressure during the Valsalva maneuver. PAF, MSA with OH, and PD with OH all featured supine hypertension, which was equivalent in severity to that in essential hypertension, regardless of fludrocortisone treatment. Among patients with PD or MSA, those with OH had higher mean arterial pressure during supine rest (109±3 mm Hg) than did those lacking OH (96±3 mm Hg, P =0.002). Baroreflex-cardiovagal gain and orthostatic increments in plasma NE levels were markedly decreased in all 3 groups with OH. Among patients with PD or MSA, those with OH had much lower mean baroreflex-cardiovagal gain (0.74±0.10 ms/mm Hg) than did those lacking OH (3.13±0.72 ms/mm Hg, P =0.0002). In PAF, supine hypertension is linked to both OH and low baroreflex-cardiovagal gain. The finding of lower plasma NE levels in patients with than without supine hypertension suggests involvement of pressor mechanisms independent of the sympathetic nervous system.

Idiopathic pulmonary fibrosis (IPF), a heterogeneous disease with respect to clinical presentation and rates of progression, disproportionately affects older adults. The diagnosis of IPF is descriptive, based on clinical, radiologic, and histopathologic examination, and definitive diagnosis is hampered by poor interobserver agreement and lack of a consensus definition. There are no effective treatments. Cellular, molecular, genetic, and environmental risk factors have been identified for IPF, but the initiating event and the characteristics of preclinical stages are not known. IPF is predominantly a disease of older adults, and the processes underlying normal aging might significantly influence the development of IPF. Yet, the biology of aging and the principles of medical care for this population have been typically ignored in basic, translational, or clinical IPF research. In August 2009, the Association of Specialty Professors, in collaboration with the American College of Chest Physicians, the American Geriatrics Society, the National Institute on Aging, and the National Heart, Lung, and Blood Institute, held a workshop, summarized herein, to review what is known, to identify research gaps at the interface of aging and IPF, and to suggest priority areas for future research. Efforts to answer the questions identified will require the integration of geriatrics, gerontology, and pulmonary research, but these efforts have great potential to improve care for patients with IPF.

IN older adults, fatigue is a commonly reported symptom. Different definitions have sought to represent fatigue (1,2), and for use in the present study, it is conceptualized as “the awareness of a decreased capacity for physical and/or mental activity due to an imbalance in the availability, utilization, and/or restoration of resources needed to perform activity” (3). Typically, fatigue is studied in patient populations with an index condition such as cancer, HIV infection, or multiple sclerosis. Indeed, a review of symptoms associated with cancer, AIDS, heart disease, chronic obstructive pulmonary disease, and renal disease found that between 32% and 90% of patients report fatigue (4). However, although fatigue is often attributed to underlying disease, in a large study of the general population only about one third of all fatigue cases could be explained by a diagnosed medical condition (5). The prevalence of fatigue in nondisease–specific community-dwelling older adults has not been well established. General population surveys indicate that fatigue increases with advancing age (6,7), although not consistently (8). In those studies, it was difficult to identify the prevalence of fatigue specifically for older individuals. However, in a sample of 199 older ambulatory residents of a long-term care facility, 47% reported moderate and severe fatigue (9). Furthermore, in a primary care sample of 124 older adults the prevalence of fatigue was 27% (10). Although functional consequences of fatigue have not been well characterized, studies in older adults have shown that fatigue is associated with restricted activity and disability. In a study of 754 nondisabled community-dwelling older adults, Gill and colleagues (11) showed that fatigue was the leading reason for restricted activity. In fact, among 24 prespecified reasons, 65.5 episodes of fatigue per 100 person-months of restricted activity were reported, whereas “pain or stiffness in joints” was the second leading cause associated with about half the rate (35.7 episodes per 100 person-months of restricted activity) (11). In addition, Avlund and colleagues (12) found that “tiredness” predicted adverse events such as the onset of disability, future hospitalization, and use of home care help (13) in an older nondisabled population. However, tiredness in these studies was evaluated in relation to task-specific activities of daily living (ADL), and the functional consequences of nontask-specific tiredness or fatigue are unclear. The present study used a measure of general fatigue to examine its distribution in a representative sample of older adults and to investigate the association of fatigue with measures of physical function and disability. Those classified as fatigued reported feeling that they could not get going and/or that everything was an effort on 3 or more days during a week (see the Methods section). Different measures of physical function were examined to understand whether fatigue was associated with each stage of the disablement process. In the framework of the disablement process (14–16), pathology is proposed as the first step in the model leading to impairments (e.g., low strength), functional limitation (e.g., slow walking speed), and ultimately, disability (e.g., inability to perform ADL). Typically, age-associated diseases are used to measure pathology, but markers of inflammation and thyroid function were examined as well in the current study to assess the subclinical disease that might be associated with fatigue and physical function (17–20).

Power spectral analysis of heart rate variability (HRV) has been used to indicate cardiac autonomic function. High-frequency power relates to respiratory sinus arrhythmia and therefore to parasympathetic cardiovagal tone; however, the relationship of low-frequency (LF) power to cardiac sympathetic innervation and function has been controversial. Alternatively, LF power might reflect baro reflexive modulation of autonomic outflows.We studied normal volunteers and chronic autonomic failure syndrome patients with and without loss of cardiac noradrenergic nerves to examine the relationships of LF power with cardiac sympathetic innervation and baroreflex function.We compared LF power of HRV in patients with cardiac sympathetic denervation, as indicated by low myocardial concentrations of 6-[(18)F]fluorodopamine-derived radioactivity or low rates of norepinephrine entry into coronary sinus plasma (cardiac norepinephrine spillover) to values in patients with intact innervation, at baseline, during infusion of yohimbine, which increases exocytotic norepinephrine release from sympathetic nerves, or during infusion of tyramine, which increases non-exocytotic release. Baroreflex-cardiovagal slope (BRS) was calculated from the cardiac interbeat interval and systolic pressure during the Valsalva maneuver. Results. LF power was unrelated to myocardial 6-[(18)F]fluorodopamine-derived radioactivity or cardiac norepinephrine spillover. In contrast, the log of LF power correlated positively with the log of BRS (r = 0.72, P0.0001). Patients with a low BRS (/=3 msec/mm Hg) had low LF power, regardless of cardiac innervation. Tyramine and yohimbine increased LF power in subjects with normal BRS but not in those with low BRS. BRS at baseline predicted LF responses to tyramine and yohimbine.LF power reflects baroreflex function, not cardiac sympathetic innervation.

Patient groups with chronic autonomic failure and neuroimaging evidence of intact or absent cardiac sympathetic innervation had similar mean values for myocardial perfusion. Cardiac sympathetic outflow does not seem to contribute to coronary vascular resistance.

Background Upper thoracic sympathectomy is used to treat several disorders. Sympathetic nerve fibers emanating from thoracic ganglia innervate the heart. Whether unilateral or bilateral upper thoracic sympathectomy affects cardiac sympathetic innervation in humans in vivo has been unclear. Objectives The purpose of this study was to assess whether thoracic sympathectomy decreases cardiac sympathetic innervation, as indicated by positron emission tomographic scanning after intravenous injection of the sympathoneural imaging agent 6-[ 18 F]fluorodopamine. Methods Nine patients with previous upper thoracic sympathectomies (four right-sided, one left-sided, four bilateral) underwent thoracic 6-[ 18 F]fluorodopamine scanning between 1 and 2 hours after injection of the imaging agent. In each case, a low rate of entry of norepinephrine into the arm venous drainage (norepinephrine spillover) verified upper limb sympathectomy. Data were compared with those from the interventricular septum of patients with cardiac sympathetic denervation associated with pure autonomic failure and from normal volunteers. Results All four patients with bilateral sympathectomy had low septal myocardial 6-[ 18 F]fluorodopamine-derived radioactivity (2,673 ± 92 nCi-kg/cc-mCi at an average of 89 minutes after injection) compared with normal volunteers (3,634 ± 311 nCi-kg/cc-mCi at 83 minutes, N=22, P = .007) and higher radioactivity than in patients with pure autonomic failure (1,320 ± 300 nCi-kg/cc-mCi at 83 minutes, N=7, P = .003). Patients with unilateral sympathectomy had normal 6-[ 18 F]fluorodopamine-derived radioactivity (3,971 ± 337 nCi-kg/cc-mCi at 87 minutes). Conclusions Bilateral upper thoracic sympathectomy partly decreases cardiac sympathetic innervation density.

Neuronal reuptake (uptake-1) constitutes the main route of inactivation of the sympathetic neurotransmitter norepinephrine in the heart and therefore contributes importantly to cardiac sympathetic neuroeffector function. In laboratory animals and in vitro preparations, half saturation of the transporter occurs at norepinephrine concentrations of 0.1 to 1 μmol/L. This study addressed whether endogenous norepinephrine can attain high enough plasma concentrations in humans to inhibit cardiac uptake-1. Patients with increased plasma norepinephrine levels due to pheochromocytoma were assessed by 6-[ 18 F]fluorodopamine positron emission tomography. Above an antecubital venous plasma concentration of 3 nmol/L (≈500 pg/mL), left ventricular myocardial 6-[ 18 F]fluorodopamine-derived radioactivity varied inversely with the logarithm of the plasma norepinephrine concentration ( r =−0.77, P 18 F]fluorodopamine-derived radioactivity. At sufficiently high plasma concentrations, endogenous norepinephrine can compete with sympathetic imaging agents for uptake-1. The results call for caution in drawing quantitative conclusions about uptake-1 in the setting of high circulating concentrations of endogenous norepinephrine.

Uptake-1, mediated by the cell membrane norepinephrine transporter (NET), constitutes the main route of inactivation of norepinephrine at sympathetic nerve terminals. In vitro, the NET can be saturated with a KM between 0.1 and 1 μmol/L. This study addressed whether endogenous norepinephrine levels can attain high enough plasma concentrations in humans to inhibit cardiac uptake-1. patients with pheochromocytoma, a catecholamine-secreting tumor, were imaged by 6-[18F]fluorodopamine positron emission tomography. Above 3 nmol/L (about 500 pg/ml) in antecubital venous plasma, left ventricular myocardial 6-[18F]fluorodopamine-derived radioactivity varied inversely with the logarithm of plasma norepinephrine concentration (R = −0.77, P