Jessica Alber

Brief Wakeful Resting Boosts New Memories Over the Long Term

A brief wakeful rest after new verbal learning enhances memory for several minutes. In the research reported here, we explored the possibility of extending this rest-induced memory enhancement over much longer periods. Participants were presented with two stories; one story was followed by a 10-min period of wakeful resting, and the other was followed by a 10-min period during which participants played a spot-the-difference game. In Experiment 1, wakeful resting led to significant enhancement of memory after a 15- to 30-min period and also after 7 days. In Experiment 2, this striking enhancement of memory 7 days after learning was demonstrated even when no retrievals were imposed in the interim. The degree to which people can remember prose after 7 days is significantly affected by the cognitive activity that they engage in shortly after new learning takes place. We propose that wakeful resting after new learning allows new memory traces to be consolidated better and hence to be retained for much longer.

Pathophysiologic relationship between Alzheimer's disease, cerebrovascular disease, and cardiovascular risk: A review and synthesis

As the population ages due to demographic trends and gains in life expectancy, the incidence and prevalence of dementia increases, and the need to understand the etiology and pathogenesis of dementia becomes ever more urgent. Alzheimers disease (AD), the most common form of dementia, is a complex disease, the mechanisms of which are poorly understood. The more we learn about AD, the more questions are raised about our current conceptual models of disease. In the absence of a cure or the means by which to slow disease progress, it may be prudent to apply our current knowledge of the intersection between AD, cardiovascular disease, and cerebrovascular disease to foster efforts to delay or slow the onset of AD. This review discusses our current understanding of the epidemiology, genetics, and pathophysiology of AD, the intersection between AD and vascular causes of dementia, and proposes future directions for research and prevention.

Boosting Long-Term Memory via Wakeful Rest: Intentional Rehearsal Is Not Necessary, Consolidation Is Sufficient

People perform better on tests of delayed free recall if learning is followed immediately by a short wakeful rest than by a short period of sensory stimulation. Animal and human work suggests that wakeful resting provides optimal conditions for the consolidation of recently acquired memories. However, an alternative account cannot be ruled out, namely that wakeful resting provides optimal conditions for intentional rehearsal of recently acquired memories, thus driving superior memory. Here we utilised non-recallable words to examine whether wakeful rest boosts long-term memory, even when new memories could not be rehearsed intentionally during the wakeful rest delay. The probing of non-recallable words requires a recognition paradigm. Therefore, we first established, via Experiment 1, that the rest-induced boost in memory observed via free recall can be replicated in a recognition paradigm, using concrete nouns. In Experiment 2, participants heard 30 non-recallable non-words, presented as ‘foreign names in a bridge club abroad’ and then either rested wakefully or played a visual spot-the-difference game for 10 minutes. Retention was probed via recognition at two time points, 15 minutes and 7 days after presentation. As in Experiment 1, wakeful rest boosted recognition significantly, and this boost was maintained for at least 7 days. Our results indicate that the enhancement of memory via wakeful rest is not dependent upon intentional rehearsal of learned material during the rest period. We thus conclude that consolidation is sufficient for this rest-induced memory boost to emerge. We propose that wakeful resting allows for superior memory consolidation, resulting in stronger and/or more veridical representations of experienced events which can be detected via tests of free recall and recognition.

Minimizing Interference With Early Consolidation Boosts 7-Day Retention in Amnesic Patients

OBJECTIVE A short wakeful rest immediately after learning boosts memory retention in amnesic patients over several minutes. Here we investigated whether a short wakeful rest could boost memory retention in amnesic patients over a much longer period. METHOD The authors tested 15 patients with amnesia associated with amnestic mild cognitive impairment (MCI)/mild Alzheimers disease (AD) and 15 age- and-education-matched controls. All participants learned 2 prose passages, 1 followed by a 10-min wakeful rest (minimal sensory stimulation), and the other by a 10-min visual spot the difference game. Participants were given a surprise delayed recall test for both prose passages after 15-30 min and after 7 days. RESULTS Wakeful resting boosted memory substantially in the patients over 15-30 min and 7 days: After 7 days all 15 patients retained >30% of the prose that had been learned prior to wakeful resting. In contrast, after 7 days, only 4 patients retained >30% of the prose that had been learned prior to playing the spot the difference game. CONCLUSIONS This striking 7-day memory boost via wakeful resting is remarkable, given that amnesic patients often struggle to remember new information over just a few minutes. Our novel findings indicate that there is substantial capacity for longer-term retention in patients with amnestic MCI/mild AD, and bolster the hypothesis that wakeful resting boosts memory by protecting the compromised memory consolidation system from interfering incoming information.

Nonvascular retinal imaging markers of preclinical Alzheimer's disease

In patients with Alzheimers disease (AD) and mild cognitive impairment, structural changes in the retina (i.e., reduced thicknesses of the ganglion cell and retinal nerve fiber layers and inclusion bodies that appear to contain beta‐amyloid protein [Ab]) have been previously reported. We sought to explore whether anatomic retinal changes are detectable in the preclinical stage of AD.

Use of Eflornithine (DFMO) in the Treatment of Early Alzheimer's Disease: A Compassionate Use, Single-Case Study

Background: Recent genome-wide association screening (GWAS) studies have linked Alzheimers disease (AD) neuropathology to gene networks that regulate immune function. Kan et al. recently reported that Arg1 (an anti-inflammatory gene that codes for arginase-1) is expressed in parts of the brain associated with amyloidosis prior to the onset of neuronal loss, suggesting that chronic brain arginine deprivation promotes AD-related neuropathology. They blocked arginine catabolism in their mouse AD model by administration of eflornithine (DFMO) to juvenile animals, effectively blocking the expression of AD-related amyloid pathology as the mice aged. We report results from a single-case study in which DFMO was administered, for the first time, in an attempt to slow progression of AD in a single woman with multi-domain, amnestic MCI who was unable to tolerate an acetylcholinesterase inhibitor. Methods: Patient C.S. is a 74-year old female with a 5-year history of cognitive decline who was placed on DFMO (500 mg b.i.d.) for 12 months, with amyloid PET scans (baseline and 12-months), APOE genotyping and neuropsychological exams at baseline, 3, 9, and 12 months. Results: C.S. suffered continued cognitive decline over 12 months, including progressive worsening of orientation, social functions and ability to engage in IADLs. She also showed progressive decline on measures of episodic memory and executive function. Florbetapir PET imaging yielded elevated total neocortical SUVr scores at both baseline (SUVr = 1.55) and at 12 months (SUVr = 1.69). Conclusions: We report a first attempt at using DFMO to slow AD progression. This 12-month single-case trial did not halt continued amyloidosis nor cognitive decline. Although this trial was predicated on data reported by Kan et al. (2015) showing that DFMO administered to juvenile AD-prone mice led to diminished amyloid aggregation, this attempt to treat an older mild AD patient may not be a fair test of Kan et al.s model and results. A future trial might seek to block amyloidosis in young adults who are autosomal gene carriers for early onset AD, or perhaps in adults who are very clearly in the pre-clinical disease stage. Trial Registration: This trial was registered as a Compassionate Use IND #128888 with the United States Food and Drug Administration (FDA).

DISRUPTION OF CHOLINERGIC NEUROTRANSMISSION, WITHIN A COGNITIVE CHALLENGE PARADIGM, PREDICTS Aβ-RELATED COGNITIVE IMPAIRMENT IN PRECLINICAL ALZHEIMER’S DISEASE AFTER A 27-MONTH DELAY INTERVAL

Figure 1. Performance on the International Shopping List (ISLT) Delayed Recall Task, by participants who either failed the scopolamine challenge test (SCT) at baseline (N 1⁄4 28, at end of study) vs. those who passed the SCTat baseline (N1⁄4 30, at end of study), modeled over all four study visits. Dark lines indicate group mean scores at each visit, with SE bars provided. Both betweenand within-subject variation is represented in each group, by displaying individual subject change over time, with each case yoked to the group baseline mean score. Danielle Goldfarb, Peter J. Snyder, Paul Maruff, Cl audia Y. Santos, Brian R. Ott, Stephen Salloway, Don C. Yoo, Richard B. Noto, Jessica Alber, Louisa I. Thompson, Alex Song, Alpert Medical School of Brown University, Providence, RI, USA; University of Rhode Island, Kingston, RI, USA; The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia; Cogstate Ltd., Melbourne, Australia; Lifespan, Providence, RI, USA; Butler Hospital, Providence, RI, USA; Brown University, Providence, RI, USA. Contact e-mail: dagoldfarb9@gmail.com

THE EFFECTS OF SUBJECTIVE COGNITIVE DECLINE ON APOE GENOTYPE DISCLOSURE IN THE BUTLER ALZHEIMER’S PREVENTION REGISTRY

Background:Alzheimer’s disease (AD) prevention trial recruitment targets healthy older adults at high risk for AD. Common risk measures include the presence of subjective cognitive decline (SCD) or the apolipoprotein (APOE) 34 allele. Understanding the relationship between SCD and the impact of APOE disclosure has implications for the psychological well-being and health behaviors of trial volunteers. This study investigates how SCD associates with other participant characteristics and whether SCD interacts with APOE genotype to effect emotional impact of APOE disclosure over time.Methods:67 healthy adults (aged 59-77) from the Butler Hospital Alzheimer’s Prevention Registry completed a pre-APOE genotyping assessment (psychological interview, Montreal Cognitive Assessment (MoCA)), genetic disclosure, and two follow-ups (3 days, 6 weeks). Baseline variables of interest included education, first-degree family dementia history, psychiatric history, and perceived risk of AD. Mood measures included self-reported depression, anxiety, and impact of events scales (IES). All variables were compared across 3 groups at baseline: no SCD (no cognitive concerns, n1⁄430), SCD (cognitive concerns, MoCA 26, n1⁄422), and mildly impaired (MoCA<26, n1⁄415). The interaction effect between SCD (no SCD, SCD, mildly impaired) and APOE genotype ( 34-carriers, non-carriers) on mood measures and perceived risk of AD over time were computed using a mixed model RMANOVA design. Results:The three groups showed no difference in baseline characteristics or mood measures, with the exception of relatively lower education in the mildly impaired group (p<0.05), which was controlled for in subsequent analyses. Following APOE disclosure, there was a significant SCD by APOE genotype interaction on IES (p<0.05), such that ε4-carriers with SCD and non-carriers with mild impairment scored higher on IES than other groups. However, this difference dissipated with all groups reporting low IES at both follow-ups. There were no significant interaction effects on other measures. Conclusions: These findings suggest that baseline SCD heightened the acute emotional impact of APOE disclosure for 34-carriers. Interestingly, individuals with mild impairment on cognitive screening showed stronger emotional reaction to the disclosure of non34 vs. 34 status, possibly due to a dissonant effect. As good clinical practice, the presence of SCD should be taken into consideration when disclosing APOE risk to prevention trial candidates.

USE OF EFLORNITHINE (DFMO) IN THE TREATMENT OF MILD ALZHEIMER’S DISEASE: A COMPASSIONATE USE SINGLE-CASE STUDY

predicted using two methods: simulations (which accounted for inter-individual variability and parameter uncertainty) and a less conservative, bias-corrected 90% confidence interval approach. Results: A small, positive relationship between azeliragon plasma concentration and QTcF was noted with a slope of 0.059 msec/ng/mL. Simulations predicted mean (90% prediction interval) changes in QTcF of 0.733 msec (0.32-1.66 msec) with the Phase 3 dose (5 mg QD stead state, predicted Cmax 11.0 ng/mL (5.24-23.7 ng/mL)) and 4.32 msec (1.78.74 msec) at supra-therapeutic doses (20 mg QD steady state or 60 mg QD x 6d, predicted Cmax 66.0 ng/mL (26.5-122.9 ng/mL)). Bias-corrected upper 90% confidence intervals for therapeutic and supra-therapeutic doses are 0.88 msec and 5.01 msec, respectively. Conclusions:The model-based analysis shows a small, non-clinically meaningful, positive relationship between azeliragon plasma concentration and QTcF with a slope close to zero. Neither the prediction interval nor the upper bound of the 90% confidence interval reach 10 msec, thus demonstrating no clinically meaningful (i.e. >5 msec prolongation) drug-related effect on QTcF at expected therapeutic and supratherapeutic doses of azeliragon.