domenica 29 ottobre 2017
NEWS FROM THE WORLD- Peripheral nerve involvement in multiple sclerosis: Demonstration by magnetic resonance neurography
NEWS FROM THE WORLD- Comprehension of an Elevated Amyloid Positron Emission Tomography Biomarker Result by Cognitively Normal Older Adults
Importance The goal of Alzheimer disease (AD) prevention together with advances in understanding the pathophysiology of AD have led to clinical trials testing drugs in cognitively unimpaired persons who show evidence of AD biomarkers. Data are needed to inform the processes of describing AD biomarkers to cognitively normal adults and assessing their understanding of this knowledge.
Objective To determine the comprehension of an elevated amyloid positron emission tomographic (PET) biomarker result by cognitively unimpaired adults.
Design, Setting, and Participants The Study of Knowledge and Reactions to Amyloid Testing, a substudy of an AD prevention trial, involved 2 semistructured telephone interviews with 80 participants recruited from 9 study sites: 50 received elevated and 30 received not elevated amyloid PET scan results. Interviews were conducted 4 to 12 weeks after result disclosure and again 1 year later. Data presented here were collected from November 5, 2014, through December 10, 2015. The 50 participants included in this study were cognitively normal, aged 65 to 85 years, evenly distributed by gender, and had elevated amyloid PET results. Subsequent reports will examine persons with “not elevated” results and compare the influence of the different results.
Main Outcomes and Measures Participant comprehension of an elevated amyloid result was assessed by analyzing their responses to the following questions: “What was the result of your amyloid PET scan?” (followed by “Can you tell me in your own words what that means?” or “How would you explain it to a friend?”), “Was it the result you expected?” and “Did the result teach you anything or clarify anything for you?”
Results Of the 50 participants aged 65 to 85 years, 49 (98%) were white, 40 (80%) reported a family history of AD, and 30 (60%) had a postgraduate educational level. Most participants (31 [62%]) understood that elevated amyloid conferred an increased but uncertain risk of developing AD. Some desired understanding of the term elevated other than its being a categorical result enabling trial entry eligibility; they wanted information regarding how elevated their amyloid was, how close to the study threshold they were, or percentages, numbers, or a scale to help them make sense of the result.
Conclusions and Relevance Including an explanation of how and why a dimensional biomarker is converted to a categorical classification would enhance future AD biomarker clinical trials and educational materials.
JAMA Neurology 2017
NEWS FROM THE WORLD- Kinetics of Human Mutant Tau Prion Formation in the Brains of 2 Transgenic Mouse Lines
Importance Accumulation of the protein tau is a defining characteristic of several neurodegenerative diseases. Thorough assessment of transgenic (Tg) mouse lines that replicate this process is critical for establishing the models used for testing anti-tau therapeutics in vivo.
Objective To define a consistent mouse model of disease for use in future compound efficacy studies.
Design, Setting, and Participants In this time course study, cohorts of Tg and control mice were euthanized at defined intervals. Collected brains were bisected down the midline. One half was frozen and used to measure the tau prion content, while the other half was fixed for immunostaining with anti-tau antibodies. All mice were maintained at the Hunters Point Animal Facility at the University of California, San Francisco, and all experiments were performed at the Mission Bay Campus of the University of California, San Francisco. Study animals were PS19, homozygous and hemizygous Tg(MAPT*P301S), and B6/J mice. The study dates were August 9, 2010, to October 3, 2016.
Main Outcomes and Measures Tau prions were measured using a cell-based assay. Neuropathology was measured by determining the percentage area positive for immunostaining in defined brain regions. A separate cohort of mice was aged until each mouse developed neurological signs as determined by trained animal technicians to assess mortality.
Results A total of 1035 mice were used in this time course study. These included PS19 mice (51.2% [126 of 246] male and 48.8% [120 of 246] female), Tg(MAPT*P301S+/+) mice (52.3% [216 of 413] male, 43.8% [181 of 413] female, and 3.9% [16 of 413] undetermined), Tg(MAPT*P301S+/−) mice (51.8% [101 of 195] male and 48.2% [94 of 195] female), and B6/J mice (49.7% [90 of 181] male and 50.3% [91 of 181] female). While considerable interanimal variability in neuropathology, disease onset, and tau prion formation in the PS19 mice was observed, all 3 measures of disease were more uniform in the Tg(MAPT*P301S+/+) mice. Comparing tau prion formation in Tg(MAPT*P301S+/+) mice with B6/J controls, the 95% CIs for the 2 mouse lines diverged before age 5 weeks, and significant (P < .05) neuropathology in the hindbrain of 24-week-old mice was quantifiable.
Conclusions and Relevance The assessment of disease progression using 3 criteria showed that disease onset in PS19 mice is too variable to obtain reliable measurements for drug discovery research. However, the reproducibility of tau prion formation in young Tg(MAPT*P301S+/+) mice establishes a rapid assay for compound efficacy in vivo.
JAMA Neurology 2017
NEWS FROM THE WORLD- Disability Trajectories Before and After Stroke and Myocardial Infarction The Cardiovascular Health Study
Importance Ischemic strokes may accelerate long-term functional decline apart from their acute effects on neurologic function.
Objective To test whether the increase in long-term disability is steeper after than before the event for ischemic stroke but not myocardial infarction (MI).
Design, Settings, and Participants In the population-based, prospective cohort Cardiovascular Health Study (1989-2013), longitudinal follow-up was conducted for a mean (SD) of 13 (6.2) years. Follow-up data were used until September 1, 2013; data analysis was performed from August 1, 2013, to June 1, 2016. Models based on generalized estimating equations adjusted for baseline covariates and included a test for different slopes of disability before and after the event. Participants included 5888 Medicare-eligible individuals 65 years or older who were not institutionalized, expected to reside in the area for 3 or more years, and able to provide informed consent. Exclusions were needing a wheelchair, receiving hospice care, and undergoing radiotherapy or chemotherapy.
Exposures Ischemic stroke and MI.
Main Outcomes and Measures Annual assessments with a disability scale (measuring activities of daily living [ADLs] and instrumental ADLs). The number of ADLs and instrumental ADLs (range, 0-12) that the participant could not perform was analyzed continuously.
Results The mean (SD) age of the entire cohort (n = 5888) was 72.8 (5.6) years; 2495 (42.4%) were male. During follow-up, 382 (6.5%) participants had ischemic stroke and 395 (6.7%) had MI with 1 or more disability assessment after the event. There was a mean of 3.7 (2.4) visits before stroke and 3.7 (2.3) visits after stroke; there was a mean of 3.8 (2.5) visits before MI and 3.8 (2.4) visits after MI. The increase in disability near the time of the event was greater for stroke (0.88 points on the disability scale; 95% CI, 0.57 to 1.20; P < .001) than MI (0.20 points on the disability scale; 95% CI, 0.06 to 0.35; P = .006). The annual increase in disability before stroke (0.06 points per year; 95% CI, 0.002 to 0.12; P = .04) more than tripled after stroke (0.15 additional points per year; 95% CI, 0.004 to 0.30; P = .04). The annual increase in disability before MI (0.04 points per year; 95% CI, 0.004 to 0.08; P = .03) did not change significantly after MI (0.02 additional points per year; 95% CI, −0.07 to 0.11; P = .69).
Conclusions and Relevance In this large, population-based study, a trajectory of increasing disability became significantly steeper after stroke but not after MI. Thus, in addition to the acute brain injury and consequent impairment, ischemic stroke may also be associated with potentially treatable long-term adverse effects on the brain that lead to accelerated functional decline.
JAMA Neurology 2017