2 Minute Medicine Rewind July 6, 2020

Association of Early-Life Cognitive Enrichment With Alzheimer’s Disease Pathological Changes and Cognitive Decline

1. Early-life cognitive enrichment was associated with decreased Alzheimer’s disease pathology and cognitive decline in late-life.

Evidence Rating Level: 2 (Good)

Factors such as educational performance and childhood socioeconomic status impact cognitive decline and Alzheimer’s disease- (AD) related pathology later in life. While these are components of early-life cognitive enrichment (ECLE), ECLE has not been examined as a specific outcome in AD research. The Rush Memory and Aging Project (MAP), an ongoing community-based cohort study, aimed to assess ELCE and AD pathology through a mean summary score of neuritic and diffuse plaques and neurofibrillary tangles visualized by a modified Bielschowsky silver stain. Between January 1997 and June 2019, 1,018 MAP participants had passed away. A total of 813 of these participants had undergone brain autopsy, neuropathological examination, and complete ELCE data (M [SD] age = 90.1 [6.3] years, 69% female). Higher levels of ELCE were associated with lower global AD pathology scores (estimate -0.057, standard error [SE] 0.022, p = 0.01), amyloid-β (estimate -0.136, SE 0.066, p = 0.04), and tau (estimate -0.188, SE, 0.076, p = 0.01). Comparisons of ELCE and age at death estimates were utilized to contextualize effect size (estimate 0.007, SE 0.002, p = 0.003). Specifically, a one-unit increase in ELCE equated to an effect size associated with being eight years younger. The association between ELCE and AD pathology scores persisted when models included vascular risk factors (estimate 0.052, SE 0.022, p =0.02), vascular diseases (estimate -0.052, SE 0.022, p = 0.02), socioeconomic status (estimate -0.089, SE 0.035, p = 0.01), and cognitive activity (estimate -0.060, SE 0.022, p = 0.007). Less cognitive decline was associated with high levels of ELCE (mean [SD] = -0.13 [0.19] units per year, range -1.74 to 0.85). AD pathological changes indirectly accounted for 20% of the association between ELCE and rate of cognitive decline in later life, with 80% being a direct association. Overall, this study highlights the importance of early development and enriched environments in preventing late-life cognitive decline and AD pathology. Therefore, programs and policies that optimize early educational stimulation may reduce future healthcare burden mediated by neurodegenerative processes.


Assessment of Racial Differences in Rates of Autopsy In the US, 2008-2017

1. Autopsy rates have significantly declined over time, though the rates of autopsy among Black persons was significantly higher than those among White persons.

2. Among several possibilities, this may illustrate racial health disparities related to precision and extent of diagnostic workups prior to death.

Evidence Rating Level: 2 (Good)

Clinical autopsy rates have declined over time, potentially due to overconfidence in antemortem diagnostic improvements and financial constraints. However, autopsy rates between racial groups have not been fully examined to determine whether or not health disparities are at play. This retrospective cohort study included individuals 18 years of age or older between 2008 and 2017 with data from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database. Those excluded were deaths from suicide, homicide, accidents, and those with unknown autopsy status. A total of 23,670,006 decedents were eligible for analysis following exclusions (73.9% aged > 65 years, 49.6% female, 85.7% White). With an overall autopsy rate of 7.9%, the rate was higher among Black persons (12.7%, 95% CI 12.7 to 12.8) compared to their White counterparts (7.3%, 95% CI 5.4 to 5.5). These rates were also higher in deaths related to cirrhosis (6.7%) and cardiovascular disease (7.6%) compared to kidney disease (1.5%) and cancer (0.9%). Across all available conditions, Black persons had significantly higher autopsy rates compared with White persons (difference 0.9% for cancer, 5.6% for cardiovascular disease). Autopsies for all causes of death, except for diabetes-related deaths, declined across the study period (p < 0.01). Overall, this study suggests that several factors may be influencing this decline in autopsies, including the fact that they are expensive and rarely reimbursed. Further, this may reflect racial health disparities, resulting from less aggressive diagnostic workups among Black patients and, thus, questionable causes of death.


Attitudes and Psychological Factors Associated With New Monitoring, Social Distancing, Disinfecting, and Hoarding Behaviors Among US Adolescents During the Coronavirus Disease 2019 Pandemic

1. Adolescents who perceived COVID-19 as more severe were more likely to engage in news monitoring, social distancing, disinfecting, and hoarding behaviors compared to those viewing it as less severe.

Evidence Rating Level: 3 (Average)

A vast body of literature is being produced on the psychological impacts of coronavirus disease 2019 (COVID-19). Adolescents, specifically, are less likely to experience severe consequences from COVID-19, yet they may still contribute to its spread and, thus, indirectly affect their behaviors during this time. This self-reported survey recruited a population-based sample of adolescents via social media (Twitter, Facebook, Instagram, Reddit) and was conducted for two days in March 2020. The survey was comprised of 31 items and approximately 10 minutes in duration, including demographics, COVID-19 experiences, social distancing, disinfecting behaviors, hoarding behaviors, news monitoring, COVID-19 attitudes, and community attachment. A total of 770 adolescents completed the survey (mean [SD] age = 16.3 [1.1] years, 74.7% female). Daily disinfecting (87.8%) and news-monitoring (89.4%) were reported more commonly than pure social distancing (68.6%). Approximately 19.7% reported hoarding behaviors. Greater severity of perceptions of COVID-19 were associated with more news monitoring (β = 0.26, 95% CI 0.18 to 0.33), social distancing (β = 0.18, 95% CI 0.10 to 0.25), disinfecting (β = 0.16, 95% CI 0.08 to 0.23), and hoarding (β = 0.08, 95% CI 0.01 to 0.16). Increased social responsibility was associated with greater news monitoring (β = 0.14, 95% CI 0.07 to 0.22) and disinfecting (β = 0.24, 0.17 to 0.32) but decreased hoarding (β = -0.07, 95% CI -0.14 to -0.01). Greater social trust was associated with less hoarding (β = -0.09, 95% CI -0.16 to -0.02) while higher self-interest values were associated with greater hoarding (β = 0.008, 95% CI 0.01 to 0.15) and less social distancing (β = 0.08, -0.15 to -0.01). Study findings emphasize the importance of portraying public health crises appropriately as the perception of severity drives subsequent behaviours of public safety.


Cortical Proteins Associated With Cognitive Resilience in Community-Dwelling Older Persons

1. This protein-wide association study found that eight specific proteins were associated with cognitive resilience in older adults, pointing toward targets for novel therapies.

Evidence Rating Level: 2 (Good)

Many primary causes of dementia occur among older adults present without commonly recognized neuropathological signatures. Proteomics can be useful in identifying proteins that are associated with cognitive decline, resulting in novel drug targets to curb this decline in the absence of neuropathological signatures. This proteome-wide association study of the human dorsolateral prefrontal cortex (DLPFC) aimed to identify proteins associated with cognitive decline using data from the Religious Orders Study and Rush Memory and Aging Project. These studies began enrollment in January 1994 and September 1997, respectively, with data collected and analyzed through October 2019. Data included annual clinical examinations, postmortem evaluations, and tandem mass tag proteomic analyses. Cognitive resilience was defined by this study as longitudinal change in cognition after controlling for age-related neuropathology, including Lewy bodies, Alzheimer’s disease (AD), transactive response DNA-binding protein 43, infarcts, hippocampal sclerosis, and vessel diseases. More than 8,000 high-abundance proteins were quantified from DLPFC tissue using tandem mass tag and liquid chromatography-mass spectrometry. A total of 391 participants were included in the analyses (mean [SD] age = 79.7 [6.7] years at baseline; 89.2 [6.5] years at death). A total of 59.6% of participants had a pathologic diagnosis of AD at autopsy, as well as cerebrovascular diseases such as macroscopic infarcts (32.0%). Cognitive resilience was associated with eight cortical proteins, including higher levels of SH3GL1 (estimate 0.179, SE 0.039, p = 4.21×10-6), CPLX1 (estimate 0.136, SE 0.029, p = 4.06×10-6), SGTB (estimate 0.211, SE 0.045, p = 3.28×10-6), RPH3A (estimate 0.148, SE 0.031, p = 2.58×10-6), EPHX4 (estimate 0.198, 0.042, p = 2.13×10-6), ACTN4 (estimate 0.321, SE 0.065, p = 9.94×10-7), and NRN1 (estimate 0.140, SE 0.024, p = 7.35×10-9), along with lower levels of UBA1 (estimate -0.366, SE 0.076, p = 1.43×10-6). Overall, this study suggests that maintenance of these proteins may improve cognitive resilience in later life, particularly in the context of NRN1, due to neuritin’s role in axonal regeneration, extension, and neuritic arborization.



Carotid Atherosclerosis Evolution when Targeting a Low-Density Lipoprotein Cholesterol Concentration < 70 mg/dL after an Ischemic Stroke of Atherosclerotic Origin

1. Targeting a lower LDL does not impact carotid plaque incidence but does increase the rate of regression of pre-existing atherosclerotic lesions among patients who have experienced an ischemic stroke.

Evidence Rating Level: 2 (Good)

Low-density lipoprotein (LDL) is a lipid molecule that has been implicated in the development of atherosclerotic lesions. The Treat Stroke to Target (TST) trial showed that a target LDL of <70 mg/dL compared to a target of 90 to 110 mg/dL reduced the risk of major cardiovascular events among patients who have experienced an ischemic stroke as a result of atherosclerotic cerebral vasculature. This nested, parallel study of the TST trial sought to explore whether targeting an LDL <70 mg/dL had a positive impact on carotid atherosclerosis progression. Carotid ultrasounds from 201 patients (M [SD] age = 67.2 [11.8] years, 66.2% male) with a target LDL of <70 mg/dL were compared to ultrasounds from 212 patients (M [SD] age = 67.5 [11.7] years, 66.5% male) with a target LDL of 90 to 110 mg/dL. The primary outcome was new plaque formation on the carotid bifurcation or the internal carotid artery; common carotid artery intima-media thickness (CCA-IMT) was measured as a secondary outcome. CCA-IMT has been recognized as a predictor of future cardiovascular and cerebrovascular events. Mean LDL was 64 mg/dL in the lower-target group and 106 mg/dL in the higher-target group. 46 of 201 patients (22.9%) in the lower-target group developed new carotid plaques, which did not differ significantly from the 45 of 212 patients (21.2%) in the higher-target group who also developed new carotid plaques (HR 1.03, 95% CI 0.68 to 1.56, p = 0.88). This finding was significant even after controlling for time since stroke, age, and sex. Conversely, CCA-IMT change among patients in the lower-target group was -10.53 μm/year (95% CI -14.21 to -6.85) while it was -2.69 μm/year (95% CI -6.55 to 1.18) among patients in the higher-target group (absolute difference -7.84 μm, 95% CI -13.18 to -2.51, p = 0.004). Again, the results remained significant after adjustment. Overall, this study showed that targeting a lower LDL among post-ischemic stroke patients does not affect the incidence of new carotid plaque formation but does impact the rate of regression of pre-existing atherosclerotic lesions as measured by CCA-IMT. These data lend further evidence to the benefit of titrating lipid-lowering drugs such as statins to target lower LDL levels among select patients.

Image: PD

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