Effect of 1 Night of Total Sleep Deprivation on Cerebrospinal Fluid β-Amyloid 42 in Healthy Middle-Aged Men A Randomized Clinical Trial

Importance  Increasing evidence suggests a relationship between poor sleep and the risk of developing Alzheimer disease. A previous study found an effect of sleep on β-amyloid (Aβ), which is a key protein in Alzheimer disease pathology.

Objective  To determine the effect of 1 night of total sleep deprivation on cerebrospinal fluid Aβ42 protein levels in healthy middle-aged men.

Design, Setting, and Participants  The Alzheimer, Wakefulness, and Amyloid Kinetics (AWAKE) study at the Radboud Alzheimer Center, a randomized clinical trial that took place between June 1, 2012, and October 1, 2012. Participants were cognitively normal middle-aged men (40-60 years of age) with normal sleep (n = 26) recruited from the local population.

Interventions  Participants were randomized to 1 night with unrestricted sleep (n = 13) or 1 night of total sleep deprivation (24 hours of wakefulness) (n = 13).

Main Outcomes and Measures  Sleep was monitored using continuous polysomnographic recording from 3 pm until 10 am. Cerebrospinal fluid samples were collected using an intrathecal catheter at defined times to compare cerebral Aβ42 concentrations between evening and morning.

Results  A night of unrestricted sleep led to a 6% decrease in Aβ42 levels of 25.3 pg/mL (95% CI [0.94, 49.6], P = .04), whereas sleep deprivation counteracted this decrease. When accounting for the individual trajectories of Aβ42 over time, a difference of 75.8 pg/mL of Aβ42 was shown between the unrestricted sleep and sleep deprivation group (95% CI [3.4, 148.4], P = .04). The individual trajectories of evening and morning Aβ42 concentrations differed between the unrestricted sleep and sleep deprivation groups (P = .04) in contrast to stable Aβ40, tau, and total protein levels.

Conclusions and Relevance  Sleep deprivation, or prolonged wakefulness, interferes with a physiological morning decrease in Aβ42. We hypothesize that chronic sleep deprivation increases cerebral Aβ42 levels, which elevates the risk of Alzheimer disease

JAMA Neurology 2014

Body Mass Index and Death by Stroke No Obesity Paradox

Importance  Reports of an obesity paradox have led to uncertainty about secondary prevention in obese patients with stroke. The paradox is disputed and has been claimed to be an artifact due to selection bias.

Objective  To determine whether the obesity paradox in stroke is real or an artificial finding due to selection bias.

Design, Setting, and Participants  We studied survival after stroke in relation to body mass index (BMI, calculated as weight in kilograms divided by height in meters squared). To overcome selection bias, we studied only deaths caused by the index stroke on the assumption that death by stroke reported on a death certificate was due to the index stroke if death occurred within the first month poststroke. We used the Danish Stroke Register, containing information on all hospital admissions for stroke in Denmark from 2003 to 2012, and the Danish Registry of Causes of Death. The study included all registered Danes (n = 71 617) for whom information was available on BMI (n = 53 812), age, sex, civil status, stroke severity, stroke subtype, a predefined cardiovascular profile, and socioeconomic status.

Main Outcomes and Measures  The independent relation between BMI and death by the index stroke within the first week or month by calculating hazard ratios in multivariate Cox regression analysis and multiple imputation for cases for whom information on BMI was missing.

Results  Of the 71 617 patients, 7878 (11%) had died within the first month; of these, stroke was the cause of death of 5512 (70%). Of the patients for whom information on BMI was available, 9.7% were underweight, 39.0% were of normal weight, 34.5% were overweight, and 16.8% were obese. Body mass index was inversely related to mean age at stroke onset (P < .001). There was no difference in the risk for death by stroke in the first month among patients who were normal weight (reference), overweight (hazard ratio, 0.96; 95% CI, 0.88-1.04), and obese (hazard ratio, 1.0; 95% CI, 0.88-1.13). Analysis of deaths within 1 week gave similar results.

Conclusions and Relevance  We found no evidence of an obesity paradox in patients with stroke. Stroke occurred at a significantly younger age in patients with higher BMI. Hence, obese patients with stroke should continue to aim for normal weight.

JAMA Neurology 2014

The Preclinical Alzheimer Cognitive Composite Measuring Amyloid-Related Decline

Importance  As Alzheimer disease (AD) research moves to intervene in presymptomatic phases of the disease, we must develop outcome measures sensitive to the earliest disease-related changes.

Objective  To demonstrate the feasibility of a cognitive composite outcome for clinically normal elderly participants with evidence of AD pathology using the ADCS Preclinical Alzheimer Cognitive Composite (ADCS-PACC). The ADCS-PACC combines tests that assess episodic memory, timed executive function, and global cognition. The ADCS-PACC is the primary outcome measure for the first clinical trial in preclinical AD (ie, the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study).

Design, Setting, and Participants  With the ADCS-PACC, we derive pilot estimates of amyloid-related decline using data from 2 observational studies conducted in North America and another conducted in Australia. The participants analyzed had normal cognition and mean ages of 75.81, 71.37, and 79.42 years across the 3 studies.

Main Outcomes and Measures  For the 2 studies that collected data on Aβ levels (ADNI and AIBL), we estimate decline in a preclinical AD “Aβ-positive” placebo group and compare them with an “Aβ-negative” group. For the study that did not include data on Aβ levels (the ADCS Prevention Instrument [ADCS-PI] study), we grouped participants by the presence of APOE-ε4 and by clinical progression.

Results  In ADNI, Aβ-positive participants showed more decline than did Aβ-negative participants with regard to the ADCS-PACC score at 24 months (mean [SE] difference, −1.239 [0.522] [95% CI, −2.263 to −0.215]; P = .02). In AIBL, the mean (SE) difference is significant at both 18 months (−1.009 [0.406] [95% CI, −1.805 to −0.213]; P = .01) and 36 months (−1.404 [0.452] [95% CI, −2.290 to −0.519]; P = .002). In the ADCS-PI study, APOE-ε4 allele carriers performed significantly worse on the ADCS-PACC at 24 months (mean [SE] score, −0.742 [0.294] [95% CI, −1.318 to −0.165]; P = .01) and 36 months (−1.531 [0.469] [95% CI, −2.450 to −0.612]; P = .001). In the ADCS-PI study, cognitively normal participants who progress from a global Clinical Dementia Rating score of 0 are significantly worse on the ADCS-PACC than cognitively normal participants who are stable with a global Clinical Dementia Rating score of 0 at months 12, 24, and 36 (mean [SE] ADCS-PACC score, −4.471 [0.702] [95% CI, −5.848 to −3.094]; P < .001). Using pilot estimates of variance and assuming 500 participants per group with 30% attrition and a 5% α level, we project 80% power to detect effects in the range of Δ = 0.467 to 0.733 on the ADCS-PACC.

Conclusions and Relevance  Analyses of at-risk cognitively normal populations suggest that we can reliably measure the first signs of cognitive decline with the ADCS-PACC. These analyses also suggest the feasibility of secondary prevention trials.

JAMA Neurology 2014

Targeting impulsivity in Parkinson’s disease using atomoxetine

Noradrenergic dysfunction may play a significant role in cognition in Parkinson’s disease due to the early degeneration of the locus coeruleus. Converging evidence from patient and animal studies points to the role of noradrenaline in dopaminergically insensitive aspects of the parkinsonian dysexecutive syndrome, yet the direct effects of noradrenergic enhancement have not to date been addressed. Our aim was to directly investigate these, focusing on impulsivity during response inhibition and decision making. To this end, we administered 40 mg atomoxetine, a selective noradrenaline re-uptake inhibitor to 25 patients with Parkinson’s disease (12 female /13 male; 64.4 ± 6.9 years old) in a double blind, randomized, placebo controlled design. Patients completed an extensive battery of neuropsychological tests addressing response inhibition, decision-making, attention, planning and verbal short term memory. Atomoxetine improved stopping accuracy on the Stop Signal Task [F(1,19) = 4.51, P = 0.047] and reduced reflection impulsivity [F(1,9) = 7.86, P =0.02] and risk taking [F(1,9) = 9.2, P = 0.01] in the context of gambling. The drug also conferred effects on performance as a function of its measured blood plasma concentration: it reduced reflection impulsivity during information sampling [adjusted R² = 0.23, F(1,16) = 5.83, P =0.03] and improved problem solving on the One Touch Stockings of Cambridge [adjusted R² = 0.29, F(1,17) = 8.34, P = 0.01]. It also enhanced target sensitivity during sustained attention [F(1,9) = 5.33, P =0.046]. The results of this exploratory study represent the basis of specific predictions in future investigations on the effects of atomoxetine in Parkinson’s disease and support the hypothesis that targeting noradrenergic dysfunction may represent a new parallel avenue of therapy in some of the cognitive and behavioural deficits seen in the disorder.

Brain 2014

Joint effect of mid- and late-life blood pressure on the brain

Objective: We hypothesized that in participants with a history of hypertension, lower late-life blood pressure (BP) will be associated with more brain pathology.

Methods: Participants are 4,057 older men and women without dementia with midlife (mean age 50 ± 6 years) and late-life (mean age 76 ± 5 years) vascular screening, cognitive function, and brain structures on MRI ascertained as part of the Age, Gene/Environment Susceptibility (AGES)–Reykjavik Study.

Results: The association of late-life BP to brain measures depended on midlife hypertension history. Higher late-life systolic and diastolic BP (DBP) was associated with an increased risk of white matter lesions and cerebral microbleeds, and this was most pronounced in participants without a history of midlife hypertension. In contrast, in participants with a history of midlife hypertension, lower late-life DBP was associated with smaller total brain and gray matter volumes. This finding was reflected back in cognitive performance; in participants with midlife hypertension, lower DBP was associated with lower memory scores.

Conclusion: In this large population-based cohort, late-life BP differentially affects brain pathology and cognitive performance, depending on the history of midlife hypertension. Our study suggests history of hypertension is critical to understand how late-life BP affects brain structure and function.

Neurology 2014

Long-term safety and effectiveness of natalizumab redosing and treatment in the STRATA MS Study

Objectives: Report long-term safety and effectiveness of natalizumab over 240 weeks in the prospective, observational, open-label Safety of TYSABRI Re-dosing and Treatment (STRATA) Study.

Methods: Patients (N = 1,094) previously enrolled in natalizumab multiple sclerosis clinical trials received natalizumab 300 mg IV every 4 weeks, up to 240 weeks. Serious adverse events, Expanded Disability Status Scale (EDSS) scores, and annualized relapse rates were analyzed.

Results: At data cutoff (February 9, 2012), natalizumab exposure was 3,460 patient-years; a median of 56 (range 1–70) infusions were received. Serious adverse events, including progressive multifocal leukoencephalopathy, were consistent with natalizumab's known profile. Upon natalizumab re-exposure, rates of anti-natalizumab antibodies and hypersensitivity reactions were 3% and 5% overall, and 40% and 24% among patients with 1 to 2 prior natalizumab doses. Patients originally randomized to placebo/another disease-modifying therapy vs natalizumab in previous studies had significantly higher EDSS scores at STRATA baseline; this difference persisted over 240 weeks. EDSS scores generally remained stable. Patients initially randomized to natalizumab had lower annualized relapse rates over 240 weeks.

Conclusions: Serious adverse events were consistent with natalizumab's known safety profile; short exposure with a gap before redosing was associated with higher incidences of anti-natalizumab antibodies and hypersensitivity reactions. Stability of EDSS scores and consistently low relapse rates over 5 years of natalizumab treatment are consistent with its known efficacy profile.

Classification of evidence: This study provides Class III evidence that in patients with relapsing-remitting multiple sclerosis, natalizumab stabilizes EDSS scores, decreases relapse rates, and is associated with an increased risk of progressive multifocal leukoencephalopathy.

Neurology 2014

Antiretroviral penetration into the CNS and incidence of AIDS-defining neurologic conditions

Objective: The link between CNS penetration of antiretrovirals and AIDS-defining neurologic disorders remains largely unknown.

Methods: HIV-infected, antiretroviral therapy–naive individuals in the HIV-CAUSAL Collaboration who started an antiretroviral regimen were classified according to the CNS Penetration Effectiveness (CPE) score of their initial regimen into low (<8), medium (8–9), or high (>9) CPE score. We estimated “intention-to-treat” hazard ratios of 4 neuroAIDS conditions for baseline regimens with high and medium CPE scores compared with regimens with a low score. We used inverse probability weighting to adjust for potential bias due to infrequent follow-up.

Results: A total of 61,938 individuals were followed for a median (interquartile range) of 37 (18, 70) months. During follow-up, there were 235 cases of HIV dementia, 169 cases of toxoplasmosis, 128 cases of cryptococcal meningitis, and 141 cases of progressive multifocal leukoencephalopathy. The hazard ratio (95% confidence interval) for initiating a combined antiretroviral therapy regimen with a high vs low CPE score was 1.74 (1.15, 2.65) for HIV dementia, 0.90 (0.50, 1.62) for toxoplasmosis, 1.13 (0.61, 2.11) for cryptococcal meningitis, and 1.32 (0.71, 2.47) for progressive multifocal leukoencephalopathy. The respective hazard ratios (95% confidence intervals) for a medium vs low CPE score were 1.01 (0.73, 1.39), 0.80 (0.56, 1.15), 1.08 (0.73, 1.62), and 1.08 (0.73, 1.58).

Conclusions: We estimated that initiation of a combined antiretroviral therapy regimen with a high CPE score increases the risk of HIV dementia, but not of other neuroAIDS conditions.

Neurology 2014