Empirically Defining Trajectories of Late-Life Cognitive and Functional Decline

Background: Alzheimer’s disease (AD) is associated with variable cognitive and functional decline, and it is difficult to predict who will develop the disease and how they will progress. Objective: This exploratory study aimed to define latent classes from participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database who had similar growth patterns of both cognitive and functional change using Growth Mixture Modeling (GMM), identify characteristics associated with those trajectories, and develop a decision tree using clinical predictors to determine which trajectory, as determined by GMM, individuals will most likely follow. Methods: We used ADNI early mild cognitive impairment (EMCI), late MCI (LMCI), AD dementia, and healthy control (HC) participants with known amyloid-β status and follow-up assessments on the Alzheimer’s Disease Assessment Scale - Cognitive Subscale or the Functional Activities Questionnaire (FAQ) up to 24 months postbaseline. GMM defined trajectories. Classification and Regression Tree (CART) used certain baseline variables to predict likely trajectory path. Results: GMM identified three trajectory classes (C): C1 (n = 162, 13.6%) highest baseline impairment and steepest pattern of cognitive/functional decline; C3 (n = 819, 68.7%) lowest baseline impairment and minimal change on both; C2 (n = 211, 17.7%) intermediate pattern, worsening on both, but less steep than C1. C3 had fewer amyloid- or apolipoprotein-E ɛ4 (APOE4) positive and more healthy controls (HC) or EMCI cases. CART analysis identified two decision nodes using the FAQ to predict likely class with 82.3% estimated accuracy. Conclusions: Cognitive/functional change followed three trajectories with greater baseline impairment and amyloid and APOE4 positivity associated with greater progression. FAQ may predict trajectory class

Emerging pharmacotherapy for cancer patients with cognitive dysfunction

Advances in the diagnosis and multi-modality treatment of cancer have increased survival rates for many cancer types leading to an increasing load of long-term sequelae of therapy, including that of cognitive dysfunction. The cytotoxic nature of chemotherapeutic agents may also reduce neurogenesis, a key component of the physiology of memory and cognition, with ramifications for the patient's mood and other cognition disorders. Similarly radiotherapy employed as a therapeutic or prophylactic tool in the treatment of primary or metastatic disease may significantly affect cognition. A number of emerging pharmacotherapies are under investigation for the treatment of cognitive dysfunction experienced by cancer patients. Recent data from clinical trials is reviewed involving the stimulants modafinil and methylphenidate, mood stabiliser lithium, anti-Alzheimer's drugs memantine and donepezil, as well as other agents which are currently being explored within dementia, animal, and cell culture models to evaluate their use in treating cognitive dysfunction

Amyloid and tau pathology associations with personality traits, neuropsychiatric symptoms, and cognitive lifestyle in the preclinical phases of sporadic and autosomal dominant Alzheimer’s disease

Background Major prevention trials for Alzheimer’s disease (AD) are now focusing on multidomain lifestyle interventions. However, the exact combination of behavioral factors related to AD pathology remains unclear. In 2 cohorts of cognitively unimpaired individuals at risk of AD, we examined which combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle (years of education or lifetime cognitive activity) related to the pathological hallmarks of AD, amyloid-β, and tau deposits. Methods A total of 115 older adults with a parental or multiple-sibling family history of sporadic AD (PREVENT-AD [PRe-symptomatic EValuation of Experimental or Novel Treatments for AD] cohort) underwent amyloid and tau positron emission tomography and answered several questionnaires related to behavioral attributes. Separately, we studied 117 mutation carriers from the DIAN (Dominant Inherited Alzheimer Network) study group cohort with amyloid positron emission tomography and behavioral data. Using partial least squares analysis, we identified latent variables relating amyloid or tau pathology with combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle. Results In PREVENT-AD, lower neuroticism, neuropsychiatric burden, and higher education were associated with less amyloid deposition (p = .014). Lower neuroticism and neuropsychiatric features, along with higher measures of openness and extraversion, were related to less tau deposition (p = .006). In DIAN, lower neuropsychiatric burden and higher education were also associated with less amyloid (p = .005). The combination of these factors accounted for up to 14% of AD pathology. Conclusions In the preclinical phase of both sporadic and autosomal dominant AD, multiple behavioral features were associated with AD pathology. These results may suggest potential pathways by which multidomain interventions might help delay AD onset or progression

Purinergic signalling and immune cells

This review article provides a historical perspective on the role of purinergic signalling in the regulation of various subsets of immune cells from early discoveries to current understanding. It is now recognised that adenosine 5'-triphosphate (ATP) and other nucleotides are released from cells following stress or injury. They can act on virtually all subsets of immune cells through a spectrum of P2X ligand-gated ion channels and G protein-coupled P2Y receptors. Furthermore, ATP is rapidly degraded into adenosine by ectonucleotidases such as CD39 and CD73, and adenosine exerts additional regulatory effects through its own receptors. The resulting effect ranges from stimulation to tolerance depending on the amount and time courses of nucleotides released, and the balance between ATP and adenosine. This review identifies the various receptors involved in the different subsets of immune cells and their effects on the function of these cells

Validation of a Wireless, Self-Application, Ambulatory Electroencephalographic Sleep Monitoring Device in Healthy Volunteers.

Study objectivesTo evaluate the validity of an ambulatory electroencephalographic (EEG) monitor for the estimation of sleep continuity and architecture in healthy adults.MethodsHealthy, good sleeping participants (n = 14) were fit with both an ambulatory EEG monitor (Sleep Profiler) and a full polysomnography (PSG) montage. EEG recordings were gathered from both devices on the same night, during which sleep was permitted uninterrupted for eight hours. The study was set in an inpatient clinical research suite. PSG and Sleep Profiler records were scored by a neurologist board certified in sleep medicine, blinded to record identification. Agreement between the scored PSG record, the physician-scored Sleep Profiler record, and the Sleep Profiler record scored by an automatic algorithm was evaluated for each sleep stage, with the PSG record serving as the reference.ResultsResults indicated strong percent agreement across stages. Kappa was strongest for Stage N3 and REM. Specificity was high for all stages; sensitivity was low for Wake and Stage N1, and high for Stage N2, Stage N3, and REM. Agreement indices improved for the manually scored Sleep Profiler record relative to the autoscore record.ConclusionsOverall, the Sleep Profiler yields an EEG record with comparable sleep architecture estimates to PSG. Future studies should evaluate agreement between devices with a clinical sample that has greater periods of wake in order to better understand utility of this device for estimating sleep continuity indices, such as sleep onset latency and wake after sleep onset

Validation of a Wireless, Self-Application, Ambulatory Electroencephalographic Sleep Monitoring Device in Healthy Volunteers

STUDY OBJECTIVES: To evaluate the validity of an ambulatory electroencephalographic (EEG) monitor for the estimation of sleep continuity and architecture in healthy adults. METHODS: Healthy, good sleeping participants (n = 14) were fit with both an ambulatory EEG monitor (Sleep Profiler) and a full polysomnography (PSG) montage. EEG recordings were gathered from both devices on the same night, during which sleep was permitted uninterrupted for eight hours. The study was set in an inpatient clinical research suite. PSG and Sleep Profiler records were scored by a neurologist board certified in sleep medicine, blinded to record identification. Agreement between the scored PSG record, the physician-scored Sleep Profiler record, and the Sleep Profiler record scored by an automatic algorithm was evaluated for each sleep stage, with the PSG record serving as the reference. RESULTS: Results indicated strong percent agreement across stages. Kappa was strongest for Stage N3 and REM. Specificity was high for all stages; sensitivity was low for Wake and Stage N1, and high for Stage N2, Stage N3, and REM. Agreement indices improved for the manually scored Sleep Profiler record relative to the autoscore record. CONCLUSIONS: Overall, the Sleep Profiler yields an EEG record with comparable sleep architecture estimates to PSG. Future studies should evaluate agreement between devices with a clinical sample that has greater periods of wake in order to better understand utility of this device for estimating sleep continuity indices, such as sleep onset latency and wake after sleep onset. CITATION: Finan PH, Richards JM, Gamaldo CE, Han D, Leoutsakos JM, Salas R, Irwin MR, Smith MT. Validation of a wireless, self-application, ambulatory electroencephalographic sleep monitoring device in healthy volunteers. J Clin Sleep Med 2016;12(11):1443–1451

Neuropsychiatric Symptoms as Risk Factors for Cognitive Decline in Clinically Normal Older Adults: The Cache County Study.

INTRODUCTION: There has been considerable progress in identifying early cognitive and biomarker predictors of Alzheimer\u27s disease (AD). Neuropsychiatric symptoms (NPS) are common in AD and appear to predict progression after the onset of mild cognitive impairment or dementia. OBJECTIVES: The objective of the study is to examine the relationship between NPS in clinically normal older adults and subsequent cognitive decline in a population-based sample. METHODS: The Cache County Study on Memory in Aging consists of a population-based sample of 5,092 older adults. We identified 470 clinically normal adults who were followed for an average period of 5.73 years. NPS were evaluated at the baseline clinical assessment using the Neuropsychiatric Inventory (NPI). NPI domain scores were quantified as the product of frequency X severity in individual NPI domains, and then summed for the NPI-Total. Neuropsychological measures were collected at baseline and at each subsequent follow-up wave. Linear mixed-effects models assessed the association of NPI-Total, NPI-Depression, and NPI-Anxiety scores (obtained at baseline) on longitudinal change in neuropsychological performance, controlling for age, sex, and education. RESULTS: Baseline NPI-Total score was associated with a more rapid rate of decline in word list memory, praxis recall, and animal fluency. Baseline NPI-Depression was not associated with later decline on any of the cognitive tests, while baseline NPI-Anxiety was associated with decline in Symbol Digit Modality. CONCLUSION: In conclusion, among clinically normal older adults derived from this population-based study, total burden of NPS was associated with longitudinal cognitive decline. These results add to the evidence that NPS are risk factors for or clinical indicators of preclinical dementia syndrome. Our study was an exploratory study and we did not control for multiple comparisons

Near Mission Operations: Demonstrated Strengths and Weaknesses of a Faster, Better, Cheaper Program

The Near Earth Asteroid Rendezvous (NEAR) Mission was successfully launched on February 17, 1996 from Cape Canaveral Air Force Base. A small mission operations team of 8 to 12 people have controlled the NEAR spacecraft from the JHU/APL campus in Maryland since then, using Deep Space Network ground stations and NASCOM circuitry, a Commercial Off The Shelf (COTS) ground computer system, and a unique streamlined concept of operations. The primary science data gathering portion of the mission will not begin until rendezvous with the asteroid EROS in January 1999, but 3 exciting bonus science observations have already occurred: visible images of the Earth\u27s Moon were taken on mission day 4, passive momentum dumping was demonstrated using solar pressure and small attitude offsets held for long periods of time, and visible images of the comet Hyakutake were taken from 1 million kilometers range on mission day 37. These bonus science observations were made possible by the less-formal concept of operations coupled with a very experienced senior group of people running operations. In the arena of mission operations, the mantra faster, better, cheaper should be discarded and replaced with faster, cheaper, increased risk . No significant failures have occurred in any flight or ground subsystem, and that is fortunate because short-term operational risk was uncomfortably high in the area of contingency readiness. Contingency readiness was limited in scope due to lack of schedule time ( faster ) and man-hours ( cheaper ). No long-term operational risks are expected, but there was a sobering amount of team cross training and software tool development which remained unfinished 30 days after launch. The NEAR mission three year cruise period provides ample time to complete this work: early mission experience with simultaneous operations and software tool development will be discussed