Protocol for the Brain Health Support Program Study of the Canadian Therapeutic Platform Trial for Multidomain Interventions to Prevent Dementia (CAN-THUMBS UP): A Prospective 12-Month Intervention Study.

BACKGROUND/OBJECTIVES: CAN-THUMBS UP is designed as a comprehensive and innovative fully remote program to 1) develop an interactive and compelling online Brain Health Support Program intervention, with potential to positively influence dementia literacy, self-efficacy and lifestyle risk factors; 2) enroll and retain a community-dwelling Platform Trial Cohort of individuals at risk of dementia who will participate in the intervention; 3) support an open platform trial to test a variety of multidomain interventions that might further benefit individuals at risk of dementia. This manuscript presents the Brain Health Support Program Study protocol. DESIGN/SETTING: Twelve-month prospective multi-center longitudinal study to evaluate a fully remote web-based educational intervention. Participants will subsequently be part of a Platform Trial Cohort and may be eligible to participate in further dementia prevention clinical trials. PARTICIPANTS: Three hundred fifty older adults who are cognitively unimpaired or have mild cognitive impairment, with at least 1 well established dementia risk factor. INTERVENTION: Participants engage in the Brain Health Support Program intervention for 45-weeks and complete pre/post intervention measures. This intervention is designed to convey best available evidence for dementia prevention, consists of 181 chapters within 8 modules that are progressively delivered, and is available online in English and French. The program has been developed as a collaborative effort by investigators with recognized expertise in the program's content areas, along with input from older-adult citizen advisors. MEASUREMENTS: This study utilizes adapted remote assessments with accessible technologies (e.g. videoconferencing, cognitive testing via computer and mobile phone, wearable devices to track physical activity and sleep, self-administered saliva sample collection). The primary outcome is change in dementia literacy, as measured by the Alzheimer's Disease Knowledge Scale. Secondary outcomes include change in self-efficacy; engagement using the online program; user satisfaction ratings; and evaluation of usability and acceptance. Exploratory outcomes include changes in attitudes toward dementia, modifiable risk factors, performance on the Neuropsychological Test Battery, performance on self-administered online cognitive assessments, and levels of physical activity and sleep; success of the national recruitment plan; and the distribution of age adjusted polygenic hazard scores. CONCLUSIONS: This fully remote study provides an accessible approach to research with all study activities being completed in the participants' home environment. This approach may reduce barriers to participation, provide an easier and less demanding participant experience, and reach a broader geography with recruitment from all regions of Canada. CAN-THUMBS UP represents a Canadian contribution to the global World-Wide FINGERS program (alz.org/wwfingers).

Feasibility and preliminary efficacy of the LEAD trial: a cluster randomized controlled lifestyle intervention to improve hippocampal volume in older adults at-risk for dementia.

BACKGROUND: Healthy diet and exercise are associated with reduced risk of dementia in older adults. The impact of diet and exercise interventions on brain health is less consistent, especially with dietary interventions which rely on varying approaches. Our objective was to evaluate the feasibility and preliminary efficacy of a 6-month intervention combining exercise with a novel dietary counseling approach to improve hippocampal volume among older adults at-risk for dementia. METHODS: Participants with vascular risk factors and subjective cognitive decline or early mild cognitive impairment were cluster randomized in groups of 3-4 to the diet intervention (DIET) or control education (ED) group. All participants engaged in 1 h of supervised exercise per week and additional exercise at home. DIET involved 1 h per week of group-based dietary counseling comprising education, goal setting, and strategy training. ED involved 1 h per week of group-based brain health education classes. Our primary outcome was change in hippocampal volume from baseline to 6 months. Secondary outcomes included changes in cognitive function, blood biomarkers, diet, and fitness. Recruitment challenges and early discontinuation of the trial due to COVID-19 necessitated a revised focus on feasibility and preliminary efficacy. RESULTS: Of 190 older adults contacted, 14 (7%) were eligible and enrolled, constituting 21% of our recruitment target. All participants completed the intervention and attended 90% of exercise and DIET/ED sessions on average. All 6-month assessments prior to COVID-19 were completed but disruptions to in-person testing resulted in incomplete data collection. No serious adverse events occurred and all participants expressed positive feedback about the study. Preliminary findings did not identify any significant changes in hippocampal volume; however, substantial improvements in diet and HbA1c were observed with DIET compared to ED (d = 1.75 and 1.07, respectively). CONCLUSIONS: High adherence and retention rates were observed among participants and preliminary findings illustrate improvements in diet quality and HbA1c. These results indicate that a larger trial is feasible if difficulties surrounding recruitment can be mitigated. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03056508 .

Rationale and protocol of the ENGAGE study: a double-blind randomized controlled preference trial using a comprehensive cohort design to measure the effect of a cognitive and leisure-based intervention in older adults with a memory complaint.

BACKGROUND: Leisure activities can be both enjoyable and cognitively stimulating, and participation in such activities has been associated with reduced age-related cognitive decline. Thus, integrating stimulating leisure activities in cognitive training programs may represent a powerful and innovative approach to promote cognition in older adults at risk of dementia. The ENGAGE study is a randomized controlled, double-blind preference trial with a comprehensive cohort design that will test the efficacy and long-term impact of an intervention that combines cognitive training and cognitively stimulating leisure activities. METHODS: One hundred and forty-four older adults with a memory complaint will be recruited in Montreal and Toronto. A particular effort will be made to reach persons with low cognitive reserve. Participants will be randomly assigned to one of two conditions: cognitive + leisure training (ENGAGE-MUSIC/SPANISH) or active control (ENGAGE-DISCOVERY). The ENGAGE-MUSIC/SPANISH training will include teaching of mnemonic and attentional control strategies, casual videogames selected to train attention, and classes in music or Spanish as a second language. The ENGAGE-DISCOVERY condition will comprise psychoeducation on cognition and the brain, low-stimulating casual videogames and documentary viewing with discussions. To retain the leisure aspect of the activities, participants will be allowed to exclude either music or Spanish at study entry if they strongly dislike one of these activities. Participants randomized to ENGAGE-MUSIC/SPANISH who did not exclude any activity will be assigned to music or Spanish based on a second random assignment. Training will be provided in 24 2-h sessions over 4 months. Outcomes will be measured at baseline, at 4-month follow-up, and at 24-month follow-up. The primary outcome will be cognitive performance on a composite measure of episodic memory (delayed recall scores for words and face-name associations) measured at baseline and at the 4-month follow-up. Secondary outcomes will include a composite measure of attention (speed of processing, inhibition, dual tasking, and shifting), psychological health, activities of daily living, and brain structure and function and long-term maintenance measured at the 24-month follow-up. Information on cognitive reserve proxies (education and lifestyle questionnaires), sex and genotype (apolipoprotein (Apo)E4, brain-derived neurotrophic factor (BDNF), and catechol-O-methyltransferase (COMT)) will be collected and considered as moderators of training efficacy. DISCUSSION: This study will test whether a program combining cognitive training with stimulating leisure activities can increase cognition and reduce cognitive decline in persons at risk of dementia. TRIAL REGISTRATION: NCT03271190 . Registered on 5 September 2017.

Asymmetry between encoding and retrieval processes: evidence from divided attention and a calibration analysis.

Two experiments provide further information on the effects of divided attention (DA) on encoding and retrieval processes. The first experiment examined the effects of decision and motor difficulty of a concurrent reaction time task. A calibration analysis was used in the second experiment to test the hypothesis that shifting attentional emphasis away from encoding to the secondary task reduces the level of processing the to-be-remembered items receive. Overall, the results confirm and extend the conclusions of Craik, Govoni, Naveh-Benjamin, and Anderson (1996) and Naveh-Benjamin, Craik, Guez, and Dori (1998), by pointing to clear differences between encoding and retrieval processes: Encoding is affected by simultaneous task demands, especially those associated with "central" resources involved in conscious decision making, whereas retrieval is obligatory in that it is largely immune to the effects of simultaneous demands. The results of the calibration analysis suggest that one reason for the poorer memory performance as a result of DA at encoding is a qualitative shift to less deep, elaborative strategies.

The effects of divided attention on encoding- and retrieval-related brain activity: A PET study of younger and older adults.

Divided attention (DA) disrupts episodic encoding, but has little effect on episodic retrieval. Furthermore, normal aging is associated with episodic memory impairments, and when young adults are made to encode information under DA conditions, their memory performance is reduced and resembles that of old adults working under full attention (FA) conditions. Together, these results suggest a common neurocognitive mechanism by which aging and DA during encoding disrupt memory performance. In the current study, we used PET to investigate younger and older adults' brain activity during encoding and retrieval under FA and DA conditions. In FA conditions, the old adults showed reduced activity in prefrontal regions that younger adults activated preferentially during encoding or retrieval, as well as increased activity in prefrontal regions young adults did not activate. These results indicate that prefrontal functional specificity of episodic memory is reduced by aging. During encoding, DA reduced memory performance, and reduced brain activity in left-prefrontal and medial-temporal lobe regions for both age groups, indicating that DA during encoding interferes with encoding processes that lead to better memory performance. During retrieval, memory performance and retrieval-related brain activity were relatively immune to DA for both age groups, suggesting that DA during retrieval does not interfere with the brain systems necessary for successful retrieval. Finally, left inferior prefrontal activity was reduced similarly by aging and by DA during encoding, suggesting that the behavioral correspondence between these effects is the result of a reduced ability to engage in elaborate encoding operations.

The effect of divided attention on encoding and retrieval in episodic memory revealed by positron emission tomography.

The effects of divided attention (DA) on episodic memory encoding and retrieval were investigated in 12 normal young subjects by positron emission tomography (PET). Cerebral blood flow was measured while subjects were concurrently performing a memory task (encoding and retrieval of visually presented word pairs) and an auditory tone-discrimination task. The PET data were analyzed using multivariate Partial Least Squares (PLS), and the results revealed three sets of neural correlates related to specific task contrasts. Brain activity, relatively greater under conditions of full attention (FA) than DA, was identified in the occipital-temporal, medial, and ventral-frontal areas, whereas areas showing relatively more activity under DA than FA were found in the cerebellum, temporo-parietal, left anterior-cingulate gyrus, and bilateral dorsolateral-prefrontal areas. Regions more active during encoding than during retrieval were located in the hippocampus, temporal and the prefrontal cortex of the left hemisphere, and regions more active during retrieval than during encoding included areas in the medial and right-prefrontal cortex, basal ganglia, thalamus, and cuneus. DA at encoding was associated with specific decreases in rCBF in the left-prefrontal areas, whereas DA at retrieval was associated with decreased rCBF in a relatively small region in the right-prefrontal cortex. These different patterns of activity are related to the behavioral results, which showed a substantial decrease in memory performance when the DA task was performed at encoding, but no change in memory levels when the DA task was performed at retrieval.

Age-related differences in neural activity during item and temporal-order memory retrieval: a positron emission tomography study.

Positron emission tomography (PET) was used to investigate the hypothesis that older adults' difficulties with temporal-order memory are related to deficits in frontal function. Young (mean 24.7 years) and old (mean 68.6 years) participants studied a list of words, and were then scanned while retrieving information about what words were in the list (item retrieval) or when they occurred within the list (temporal-order retrieval). There were three main results. First, whereas the younger adults engaged right prefrontal regions more during temporal-order retrieval than during item retrieval, the older adults did not. This result is consistent with the hypothesis that context memory deficits in older adults are due to frontal dysfunction. Second, ventromedial temporal activity during item memory was relatively unaffected by aging. This finding concurs with evidence that item memory is relatively preserved in old adults and with the notion that medial temporal regions are involved in automatic retrieval operations. Finally, replicating the result of a previous study (Cabeza, R., Grady, C. L., Nyberg, L., McIntosh, A. R. , Tulving, E., Kapur, S., Jennings, J. M., Houle, S., and Craik, F. I. M., 1997), the old adults showed weaker activations than the young adults in the right prefrontal cortex but stronger activations in the left prefrontal cortex. The age-related increase in left prefrontal activity may be interpreted as compensatory. Taken together, the results suggest that age-related changes in brain activity are rather process- and region-specific, and that they involve increases as well as decreases in neural activity.

Divided attention during encoding and retrieval: differential control effects?

Previous studies have shown that divided attention (DA) during retrieval has little effect on recall of episodic memories, although DA during encoding has a large detrimental effect. One possible reason for this asymmetry is that stimulus presentation at encoding is under experimenter control, whereas retrieval operations and responses are under participant control. This experiment tested this possibility by presenting paired-associate word lists for learning and recall, either at a fixed 4-s rate or at a rate controlled by the participant. The results showed that the higher recall levels for DA at retrieval than for DA at encoding held under all combinations of experimenter and participant control. The implications of these results for a fuller understanding of encoding and retrieval processes are discussed.

Imaging spectrum of extracapsular silicone: correlation of US, MR imaging, mammographic, and histopathologic findings.

The appearance of free silicone at mammography, ultrasonography (US), and magnetic resonance (MR) imaging is variable. The classic appearance is dense areas of opacity on mammograms, a highly echogenic pattern with or without hypoechoic masses on US images, and foci of low signal intensity on fat-suppressed T1-weighted MR images or high signal intensity on water-suppressed T2-weighted MR images. Mammography is a reliable, cost-effective, and readily available means of demonstrating silicone. The major disadvantage of US is that its accuracy depends on the capability of the operator to recognize the abnormality. Although MR imaging outperforms US or mammography in detection of implant rupture, it is not clear that MR imaging is superior in detection of free or residual silicone. The sequelae of noncontained silicone include granuloma formation, fibrosis, and migration. After extrusion from an implant, silicone migrates primarily to local sites, such as the ipsilateral chest wall and axillary nodes. Migration of silicone into the axilla can involve the brachial plexus, resulting in neuropathy. Silicone can also migrate into more distal regions, including the arm and subcutaneous tissues of the abdominal wall. Whatever the source, silicone in breast tissue interferes with the interpretation of mammographic findings.

The attentional demands of encoding and retrieval in younger and older adults: 2. Evidence from secondary task reaction time distributions.

Three studies examined the effects of encoding or retrieval on properties of secondary task reaction time (RT) distributions in younger and older adults. Relative to full attention conditions, encoding and retrieval increased secondary task RT medians and standard deviations more for older adults than for younger adults, and the age-related RT increase was most pronounced among the slowest RTs. Hierarchical regression analyses revealed two age-related mechanisms underlying these effects, which were interpreted as cognitive slowing and reductions in attentional resources. Cognitive slowing affects the entire RT distribution regardless of the memory task. By contrast, reduced attentional resources result in very long RTs, especially when the tasks require self-initiated encoding or retrieval operations.

The attentional demands of encoding and retrieval in younger and older adults: 1. Evidence from divided attention costs.

Four studies examined the effects of divided attention in younger and older adults. Attention was divided at encoding or retrieval in free recall (Experiment 1), cued recall (Experiments 2 and 3), and recognition (Experiment 4). Dividing attention at encoding disrupted memory performance equally for the two age groups; by contrast, for both age groups, dividing attention at retrieval had little or no effect on memory performance. Secondary task reaction times (RTs) were slowed to a greater extent for the older adults than for the younger adults, especially at retrieval. Age-related differences in RT costs at retrieval were largest in free recall, smaller in cued recall, and smallest in recognition. These results provide evidence for an age-related increase in the attentional demands of encoding and retrieval.

The effects of divided attention on encoding and retrieval processes in human memory.

The authors examined the effects of divided attention (DA) at encoding and retrieval in free recall, cued recall, and recognition memory in 4 experiments. Lists of words or word pairs were presented auditorily and recalled orally; the secondary task was a visual continuous reaction-time (RT) task with manual responses. At encoding, DA was associated with large reductions in memory performance, but small increases in RT; trade-offs between memory and RT were under conscious control. In contrast, DA at retrieval resulted in small or no reductions in memory, but in comparatively larger increases in RT, especially in free recall. Memory performance was sensitive to changes in task emphasis at encoding but not at retrieval. The results are discussed in terms of controlled and automatic processes and speculatively linked to underlying neuropsychological mechanisms.

Single- and double- lumen silicone breast implant integrity: prospective evaluation of MR and US criteria.

PURPOSE: To evaluate the accuracy of magnetic resonance (MR) and ultrasound (US) criteria for breast implant integrity. MATERIALS AND METHODS: One hundred twenty-two single-lumen silicone breast implants and 22 bilumen implants were evaluated with surface coil MR imaging and US and surgically removed. MR criteria for implant failure were a collapsed implant shell ("linguine sign"), foci of silicone outside the shell ("noose sign"), and extracapsular gel, US criteria were collapsed shell, low-level echoes within the gel, and "snowstorm" echoes of extracapsular silicone. RESULTS: Among single-lumen implants, MR imaging depicted 39 of 40 ruptures, 14 of 28 with minimal leakage; 49 of 54 intact implants were correctly interpreted. US depicted 26 of 40 ruptured implants, four of 28 with minimal leakage, and 30 of 54 intact implants. Among bilumen implants, MR imaging depicted four of five implants with rupture of both lumina and nine of 10 as intact; US depicted one rupture and helped identify two of 10 as intact. Mammography accurately depicted the status of 29 of 30 bilumen implants with MR imaging correlation. CONCLUSION: MR imaging depicts implant integrity more accurately than US; neither method reliably depicts minimal leakage with shell collapse. Mammography is useful in screening bilumen implant integrity.

MR imaging of the breast in patients with silicone breast implants: normal postoperative variants and diagnostic pitfalls.

Because of the wide variety of types of silicone breast implants, modifications, and surgical procedures, a number of normal variants and potentially misleading appearances can be encountered on MR images of breast implants. Familiarity with these findings is essential to proper interpretation of these images. The purpose of this essay is to illustrate the overlap in appearances of MR images in different clinical scenarios. When confusing findings are present, confirmation of the surgical history can usually clarify the matter.

Breast implant rupture: diagnosis with US.

PURPOSE: To characterize sonographic criteria for the detection of implant rupture. MATERIALS AND METHODS: One hundred nineteen symptomatic women (221 silicone implants) were evaluated with ultrasound (US) over 11 months to detect implant rupture. Fifty-nine breast prostheses in 31 women were surgically removed. RESULTS: Five sonographic findings associated with rupture were identified: echogenic noise, low-level homogeneous echoes within the implant, echogenic lines coursing within the implant, a contour bulge of the implant, and peri-implant fluid accumulations. The most useful finding in the detection of implant rupture was low-level homogeneous echoes, which were associated with 55% of ruptured implants and 16% of intact implants. This was statistically significant, achieving a 55% sensitivity and 84% specificity for the detection of implant rupture. Nine of 22 ruptured implants (41%) displayed none of the described criteria. CONCLUSION: US may be useful to detect implant rupture; however, a larger prospective study is necessary for adequate evaluation.

Diagnosing breast implant rupture with MR imaging, US, and mammography.

A total of 135 symptomatic women with 262 breast implants were examined with magnetic resonance (MR) imaging performed with a body coil, ultrasound (US), or both to determine imaging features of implant rupture. Surgical proof was available for 33 women with 62 implants; 24 were ruptured and 38 were intact. Complicated internal structure was the most reliable predictor of implant rupture: Diffuse low-level echoes were seen on sonograms in 56% of ruptured implants; internal membranes (which correspond to the collapsed implant shell) were seen on MR images in 58% of ruptured implants. Fluid droplets were seen within the silicone in 26% of ruptured implants on MR images. Irregular implant contour can be a sign of rupture but is unreliable. Fluid collections around silicone implants are not a sign of rupture. At present, neither US nor conventional MR imaging with a body coil is sufficiently reliable to advocate routine screening of asymptomatic women with breast implants. Evaluation with MR imaging performed with a surface coil is more reliable.

Stereospecific chemoattraction of lymphoblastic cells by gradients of lysophosphatidylcholine.

Human plasma contains chemoattractant activity for cultured cells from the mouse thymic lymphoma 6C3HED and also for lymphoblasts from concanavalin A-stimulated mouse spleen cells. A major portion of the attractant activity for both cell types could be attributed to plasma lysophosphatidylcholine. Studies on synthetic lysophosphatides showed that polar head group structure, acyl chain length, and stereochemical configuration are important determinants for attractant activity.