Memory support training and lifestyle modifications to promote healthy aging in persons at risk for Alzheimer's disease: a digital application supported intervention (Brain Boosters).

BACKGROUND: Evidence-based interventions to protect against cognitive decline among older adults at risk for Alzheimer's disease and related dementias (ADRD) are urgently needed. Rehabilitation approaches to support memory and behavioral/lifestyle interventions are recognized as promising strategies for preserving or improving cognitive health, although few previous interventions have combined both approaches. This paper describes the protocol of the Brain Boosters intervention, which synergistically combines training in compensatory and healthy lifestyle behaviors and supports implementation and tracking of new behaviors with a digital application. METHODS: The study utilizes a single-site, single-blinded, randomized controlled design to compare a structured lifestyle and compensatory aid intervention to an education-only self-guided intervention. We plan to enroll 225 community-dwelling adults (25% from underrepresented groups) aged 65 + who endorse subjective cognitive decline (SCD) and low baseline levels of healthy lifestyle behaviors. Both interventions will be administered in group format, consisting of 15 two-hour classes that occur weekly for ten weeks and taper to bi-monthly and monthly, for an intervention duration of 6 months. Participants in both interventions will receive education about a variety of memory support strategies and healthy lifestyle behaviors, focusing on physical and cognitive activity and stress management. The structured intervention will also receive support in adopting new behaviors and tracking set goals aided by the Electronic Memory and Management Aid (EMMA) digital application. Primary outcomes include global cognition (composite of memory, attention, and executive function tests) and everyday function (Everyday Cognition Questionnaire). Data will be collected at baseline and outcome visits, at approximately 6, 12, and 18 months. Qualitative interviews, self-report surveys (e.g., indicators of self-determination, health literacy) and EMMA data metrics will also be used to identify what components of the intervention are most effective and for whom they work. DISCUSSION: Successful project completion will provide valuable information about how individuals with SCD respond to a compensation and preventative lifestyle intervention assisted by a digital application, including an understanding of factors that may impact outcomes, treatment uptake, and adherence. The work will also inform development, scaling, and personalization of future interventions that can delay disability in individuals at risk for ADRD. TRIAL REGISTRATION: ClinicalTrials.gov. (NCT05027789, posted 8/30/2021).

Assessing the quality of activities in a smart environment.

OBJECTIVES: Pervasive computing technology can provide valuable health monitoring and assistance technology to help individuals live independent lives in their own homes. As a critical part of this technology, our objective is to design software algorithms that recognize and assess the consistency of activities of daily living that individuals perform in their own homes. METHODS: We have designed algorithms that automatically learn Markov models for each class of activity. These models are used to recognize activities that are performed in a smart home and to identify errors and inconsistencies in the performed activity. RESULTS: We validate our approach using data collected from 60 volunteers who performed a series of activities in our smart apartment testbed. The results indicate that the algorithms correctly label the activities and successfully assess the completeness and consistency of the performed task. CONCLUSIONS: Our results indicate that activity recognition and assessment can be automated using machine learning algorithms and smart home technology. These algorithms will be useful for automating remote health monitoring and interventions.

Acquisition of skilled visual search performance following severe closed-head injury.

This study used a semantic-category visual search task to investigate skill acquisition and automatic process development in a severe closed-head injured (CHI) population. Eighteen severe CHI participants (> I year post injury) and 18 matched controls completed over 3600 trials of training in both consistent mapping (CM) and varied mapping (VM) training situations. Transfer conditions were also used to test for development of an automatic attention response (AAR) that was independent of general, task-related learning. For both the severe CHI and control group, CM training, where individuals always responded in the same way to a specific class of stimuli, resulted in dramatic performance improvements and the development of an AAR. In the VM training condition, where individuals could not respond in the same way to a class of stimuli from one stimulus exposure to the next, there was little performance improvement and continued reliance on controlled processes. The visual search rates of the CHI participants also remained slower than those of controls following extended VM but not extended CM practice. These results indicate that skill acquisition training guidelines can be used to teach severe CHI patients to develop a new automatic skill.

Effects of divided attention on automatic and controlled components of memory after severe closed-head injury.

The relation between attention available at encoding and automatic and consciously controlled aspects of memory was investigated using the process-dissociation procedure. Twenty-four severely closed-head injured (CHI) participants (> 1 year postinjury) and 24 matched controls studied word lists in full- and divided-attention conditions. Recall cued with word stems was tested. In contrast to consciously controlled memory, the CHI group did not perform more poorly than the controls in estimates of automatic memory. Furthermore, for both groups, the divided-attention manipulation reduced the controlled estimates of memory, whereas automatic influences remained invariant. These results suggest that automatic memory processes may remain partially immune to the deleterious effects of severe CHI or show recovery by 1 year postinjury. They also indicate that automatic memory processes do not require additional attentional resources following severe CHI.

Intactness of inhibitory attentional mechanisms following severe closed-head injury.

Attentional problems are a common sequelae of closed-head injury (CHI). Research in the area of selective attention has pointed to the role of inhibitory mechanisms in the suppression of irrelevant information. In the current study, a negative priming paradigm was used to assess the inhibitory mechanisms of individuals suffering from a severe CHI. Twenty participants with severe CHIs (greater than 1 year postinjury) and 20 matched controls completed a negative priming task, as well as several other standardized tests of cognitive functioning. Within the negative priming task, 2 conditions were used to elicit information regarding facilitation by attended and ignored information and 1 condition was used to elicit inhibition of ignored information, as compared with a neutral control condition. Despite poorer performances on several tests of attention, there were no significant differences in the amount of inhibition displayed by the CHI participants as compared with the controls. Findings suggest that inhibitory processing deficits may not underlie the selective attention difficulties commonly seen following a severe CHI.

Aging and word-finding: a comparison of spontaneous and constrained naming tests.

This study compared the word-finding abilities of 26 young adults (ages 18-22 years), 26 young-old adults (ages 58-74 years), and 26 old-old adults (ages 75-93 years) on a confrontational naming test (Boston Naming Test) and a more spontaneous discourse test. The groups were matched in terms of gender (7 male, 19 female) and estimated IQ (M = 114). When participants were asked to narrate what they perceived in pictures (discourse test), the older adult groups committed significantly more word-retrieval errors than the younger adults. In contrast, results from the picture-naming test surprisingly revealed higher naming accuracy by the older adult groups. Subsequent examination of the picture-naming items revealed that four items appeared to be influenced by generational familiarity with the item. These results suggest that selection of cohort-free items for picture-naming tests is important when comparing across age-groups, and that tests of discourse may be better measures for assessing everyday word-finding difficulties in healthy older adults.

Diadenosine polyphosphates and the control of cyclic AMP concentrations in isolated rat liver cells.

Extracellular diadenosine polyphosphates (Ap(n)A), through their interactions with appropriate P(2) receptors, influence a diverse range of intracellular activities. In particular, Ap(4)A stimulates alterations in intracellular calcium homeostasis and subsequent activation of glycogen breakdown in isolated liver cells. Here we show that, like ATP, Ap(4)A and other naturally occurring diadenosine polyphosphates attenuate glucagon-stimulated accumulation of cyclic AMP in isolated rat liver cells. The characteristics of Ap(4)A- and ATP-dependent modulation of glucagon-stimulated cyclic AMP accumulation are similar. These results are discussed in the context of the repertoire of intracellular signalling processes modulated by extracellular nucleotides.

Effects of divided attention and time course on automatic and controlled components of memory in older adults.

The relation between attention available at encoding and automatic and consciously controlled aspects of memory was investigated within a single task using the process-dissociation procedure (L. L. Jacoby, 1991). Sixty-four older adults and 64 young adults studied a word list in either a full or a divided attention condition. Recall cued with word stems was tested immediately and at 20-minute and 60-minute delays. In contrast to consciously controlled influences of memory, automatic influences of memory (a) showed generally no reliable age differences, (b) remained invariant across the manipulation of attention, and (c) remained relatively invariant across the 60-minute time course. Furthermore, age did not interact with the attentional manipulation or the time course factor.

Effects of divided attention on perceptual and conceptual memory tests: an analysis using a process-dissociation approach.

In two experiments, the nature of the relation between attention available at learning and subsequent automatic and controlled influences of memory was explored. Participants studied word lists in full and divided encoding conditions. Memory for the word lists was then tested with a perceptually driven task (stem completion) in Experiment 1 and with a conceptually driven task (category association) in Experiment 2. For recall cued with word stems, automatic influences of memory derived using the process-dissociation procedure remained invariant across a manipulation of attention that substantially reduced conscious recollection for the learning episode. In contrast, for recall cued with category names, dividing attention at learning significantly reduced the parameter estimates representing both controlled and automatic memory processes. These findings were similar to those obtained using indirect test instructions. The results suggest that, in contrast to perceptual priming, conceptual priming may be enhanced by semantic processing, and this effect is not an artifact of contamination from conscious retrieval processes.

Diadenosine polyphosphate-mediated activation of phospholipase D in isolated rat liver cells.

Diadenosine polyphosphates (ApnAs) can, through interaction with appropriate purinoceptors, affect a range of cellular activities. Ap4A, the most prominent naturally occurring diadenosine polyphosphate, stimulates alterations in intracellular calcium homeostasis and subsequent activation of glycogen breakdown in isolated liver cells. Here we show that Ap4A, and other naturally occurring diadenosine polyphosphates, also stimulates phospholipase D (PLD) activity in isolated rat liver cells. The characteristics of Ap4A-mediated activation of PLD are similar to those for the activation of PLD by extracellular ATP. These results are discussed in the context of the relation between diadenosine polyphosphate- and adenine mononucleotide-mediated cellular signalling processes.

Visual selective attention after severe closed head injury.

This study investigated the nature of selective attention deficits after severe closed head injury (CHI). Twenty participants with severe CHI (greater than 1 year postinjury) and 20 matched controls completed search and nonsearch visual selective attention tasks under conditions of low (Experiment 1) and high (Experiment 2) target-distractor similarity. In the search situations, participants searched visual displays that contained 1, 4, or 8 items for the targets. In the nonsearch situations, the location of the targets was visually cued with a peripheral arrow. The results revealed that in both the low and high target-distractor similarity search conditions. CHI participants required a longer time than controls to locate and identify the target. In contrast, in the nonsearch condition, CHI participants were able to successfully ignore irrelevant task information when target-distractor similarity was low. However, when target-distractor similarity was high, CHI participants had more difficulty than controls ignoring the irrelevant information. These results suggest that, in comparison to controls, CHI participants may be at a disadvantage in selective attention situations when visual search is required and when the discriminability between targets and distractors is difficult.

Ecological validity of neuropsychological tests: focus on the California Verbal Learning Test and the Wisconsin Card Sorting Test.

To date, few studies have assessed the ecological validity of current measures of memory and executive functioning, particularly the California Verbal Learning Test (CVLT) and the Wisconsin Card Sorting Test (WCST). A battery of tests, including the CVLT and the WCST, was administered to 28 severely head-injured adults who were 1 year or more postinjury. Hierarchical linear regression was performed to assess the relationship between these cognitive tests and work functioning while statistically controlling for physical disability, emotional distress, and memory compensation strategies utilized by the participants. Results suggest that the CVLT was best at predicting performance on the job; however, the CVLT and the WCST were about equally predictive of the type of position held by a participant. Hence, this study demonstrates the ecological validity of measures of memory and executive functioning for predicting work-related skills.

Diadenosine polyphosphate-stimulated gluconeogenesis in isolated rat proximal tubules.

Diadenosine polyphosphates released into the extracellular environment influence a variety of metabolic and other cellular activities in a wide range of target tissues. Here we have studied the impact of these novel nucleotides on gluconeogenesis in isolated rat proximal tubules. Gluconeogenesis was stimulated following exposure of isolated proximal tubules to a range of adenine-containing nucleotides including ADP, ATP, Ap3A, Ap4A, Ap5A and Ap6A. The concentration-dependence of ATP-, Ap3A- and Ap4A-mediated stimulation of gluconeogenesis was similar and was consistent with a role for these agents in the physiological control of renal metabolism. Nucleotide-stimulated gluconeogenesis was diminished in the presence of agents that interfere with phospholipase C activation or intracellular Ca2+ metabolism, indicative of a role for polyphosphoinositide-mediated Ca2+ mobilization in the mechanism of action of ATP, Ap3A and Ap4A. The characteristics of binding of [2-3H]Ap4A to renal plasma-membrane preparations suggest that Ap4A mediates its effects on proximal tubule gluconeogenesis via interaction with P2y-like purinoceptor(s) also recognized by extracellular ATP.

Automatic process development following severe closed head injury.

Automatic process development was investigated in a closed head injury (CHI) population. Ten severe CHI participants (> 1 year postinjury) and 10 matched controls completed consistent mapping (CM) and varied mapping (VM) semantic-category memory search tasks. In VM search, despite a similar pattern of serial memory search, the CHI participants responded slower than controls and exhibited slower memory search rates throughout practice (1,800 trials). In CM search, after extensive practice (1,800 trials) both groups showed the performance characteristics indicative of automatic process development, that is, near-zero slopes and large reductions in response times. However, the CHI participants were slower to automatize the task. These results indicate that for memory-based search tasks the effects of a CHI may slow down the speed with which automatic processes develop but that CHI participants can acquire and use automatic processes in task performance.

Extracellular matrix proteins induce changes in intracellular calcium and cyclic AMP signalling systems in cultured human keratinocytes.

The purpose of this study was to investigate whether extracellular matrix proteins which influence human keratinocyte behaviour are capable of altering intracellular signalling systems in these cells. The effects of extracellular matrix proteins on two major signal transduction pathways, intracellular calcium and cyclic adenosine monophosphate (cyclic AMP), were investigated. The extracellular matrix proteins examined were the basement membrane preparation matrigel, collagens type I and IV, vitronectin and its active tripeptide component Arg-Gly-Asp (RGD). Acute additions of matrigel, vitronectin and RGD caused rapid transient increases in intracellular calcium and, together with collagen type I, also caused sustained elevations in basal calcium when cells were grown on these substrates. Cyclic AMP production was unaffected by acute exposure to these extracellular matrix proteins. Culture of cells on matrigel, collagen type I or IV, however, significantly reduced basal cyclic AMP accumulation and increased the response of the cells to the receptor-independent agonist forskolin. It is concluded that in vitro some extracellular matrix proteins can initiate both acute and sustained changes in intracellular signalling in human keratinocytes.

Characterization of the binding of diadenosine 5',5'''-P1,P4-tetraphosphate (Ap4A) to rat liver cell membranes.

Diadenosine polyphosphates present in the extracellular environment can, through interaction with appropriate purinoceptors, influence a range of cellular activities. Here we have investigated the nature of the ligand:receptor interactions involved in diadenosine 5',5'''-P1, P4-tetraphosphate (Ap4A)-mediated stimulation of glycogen breakdown in isolated rat liver cells. [2-3H]Ap4A showed specific binding to both intact isolated liver cells and plasma membrane fractions prepared from isolated liver cells. HPLC analysis confirmed that binding was mediated by intact Ap4A and not by potential breakdown products (e.g. ATP, adenosine, etc.). Binding of [2-3H]Ap4A, to isolated liver cell plasma membrane preparations, was successfully displaced by a range of both naturally occurring and synthetic diadenosine polyphospates with the rank order potency Ap4A > or = Ap5A > Ap6A > Ap3A > Ap2A. [2-3H]Ap4A binding was not displaced by P1 effectors but was successfully displaced by a range of P2 effectors with the rank order potency 2-methylthio-ATP > ATP > ATP > or = adenosine 5'-[alpha beta-methylene]triphosphate > adenosine 5'-[beta gamma-methylene]triphospate. These findings are consistent with the interaction of Ap4A with a P2y-like subclass of purinoceptor and are discussed in relation to (1) the known purinoceptor populations in liver cell plasma membranes and (2) observations concerning the binding of diadenosine polyphosphates to purinoceptors in other tissues.

The effects of divided attention on implicit and explicit memory performance.

This study explored the nature of the relationship between attention available at learning and subsequent implicit and explicit memory performance. One hundred neurologically normal subjects rated their liking of target words on a five-point scale. Half of the subjects completed the word-rating task in a full attention condition and the other half performed the task in a divided attention condition. Following administration of the word-rating task, all subjects completed five memory tests, three implicit (category association, tachistoscopic identification, and perceptual clarification) and two explicit (semantic-cued recall and graphemic-cued recall), each bearing on a different subset of the list of previously presented target words. The results revealed that subjects in the divided attention condition performed significantly more poorly than subjects in the full attention condition on the explicit memory measures. In contrast, there were no significant group differences in performance on the implicit memory measures. These findings suggest that the attention to an episode that is necessary to produce later explicit memory may differ from that necessary to produce unconscious influences. The relationship between implicit memory, neurologic injury and automatic processes is discussed.

Memory remediation after severe closed head injury: notebook training versus supportive therapy.

This study evaluated the effectiveness of a 9-week memory notebook treatment for closed-head-injured (CHI) participants with documented memory deficits. Eight participants who had sustained a severe CHI more than 2 years earlier were allocated to receive either notebook training or supportive therapy. Memory outcome indicators, which differed in sensitivity to detect everyday memory failures (EMFs), were administered before treatment, immediately after treatment, and at a 6-month follow-up. At posttreatment, the notebook training group reported significantly fewer observed EMFs on a daily checklist measure than the supportive therapy group. Although in the same direction, this finding no longer reached significance at follow-up. No significant treatment effects were found for the laboratory-based memory measures at posttreatment or follow-up. Although the present results are to be considered preliminary because of the small sample size, they suggest that notebook training has the potential to help individuals compensate for everyday memory problems and that the methods used to measure training efficacy are important.

Calcium plays a complex role in the regulation of melanogenesis in murine B16 melanoma cells.

To learn more of the role of calcium in the regulation of melanogenesis, we have used direct manipulation of medium calcium and pharmacological modulation of intracellular calcium to examine the consequences on unstimulated and cyclic AMP elevated tyrosinase activity and melanin synthesis and distribution in B16 melanoma cells. In unstimulated cells, calcium is clearly inhibitory to tyrosinase activity. However, in cells stimulated with cAMP-elevating agents the requirement for extracellular calcium was changed such that cells required a minimum of 0.4-0.6 mmol medium calcium for maximum tyrosinase response to these agents. Paradoxically, pharmacologically increasing intracellular calcium in cAMP-stimulated cells with ionophore inhibited tyrosinase activity, and the calcium-lowering agent TMB8 and the calcium channel blocker verapamil both stimulated tyrosinase activity. When melanin synthesis was measured in cAMP-stimulated cells, TMB8 was found to significantly increase the sensitivity and the maximum melanogenic response to alpha-MSH, suggesting the presence of at least one level of endogenous calcium inhibitory control operative in these cells. In addition, TMB8 changed the distribution of melanin between the cell and the medium such that, in the presence of alpha-MSH and TMB8, significantly more melanin was secreted into the medium. These data suggest that calcium is required for several steps in melanogenesis, having an apparently inhibitory effect on pre-tyrosinase activity in unstimulated cells, but also showing evidence of a positive role in cyclic AMP-stimulated tyrosinase activity, as well as a further possible inhibitory role in melanin movement or secretion.

Platelet-Platelet Contact is Required to Observe Guanylate Cyclase Activation in Stimulated Platelets.

Increases in [cyclic-3',5'-GMP] in aspirin-treated platelet-rich plasma and washed platelet preparations resulted from stimulation by all excitatory agonists tested, and by other agents which induced aggregate formation. The maximal increase observed was approximately 4-fold above the resting level. The increase in [cyclic-3',5'-GMP] correlated closely in both time-, and agonist dose-dependence with aggregation as measured by an increase in light transmittance. It was delayed in time, and occurred at a higher agonist concentration, than the initial phase of aggregation as measured by loss of single platelets. The extent of increase in [cyclic-3',5'-GMP] was independent of the signal transduction pathway used by the agonist/agent. Inhibition of aggregation by removal of Ca(2+), failure to induce contact, addition of antibodies or antagonists to the glycoprotein IIb/IIIa complex or the presence of an inhibitory agonist such as PGI(2) prevented the increase in [cyclic-3',5'-GMP]. Contact with collagen fibrils causing adhesion to this matrix, or aggregate formation induced by ristocetin or by certain lectins also caused an increase in [cyclic-3',5'-GMP]. Contact of platelets either with other platelets or with a matrix therefore results in stimulation of guanylate cyclase. The mechanism responsible for such stimulation remains unclear but does not appear simply to be attributable to activation of nitric oxide synthase by Ca(2+).