Omonigho Michael Bubu

Obstructive sleep apnea severity affects amyloid burden in cognitively normal elderly a longitudinal study

Rationale: Recent evidence suggests that obstructive sleep apnea (OSA) may be a risk factor for developing mild cognitive impairment and Alzheimers disease. However, how sleep apnea affects longitudinal risk for Alzheimers disease is less well understood. Objectives: To test the hypothesis that there is an association between severity of OSA and longitudinal increase in amyloid burden in cognitively normal elderly. Methods: Data were derived from a 2‐year prospective longitudinal study that sampled community‐dwelling healthy cognitively normal elderly. Subjects were healthy volunteers between the ages of 55 and 90, were nondepressed, and had a consensus clinical diagnosis of cognitively normal. Cerebrospinal fluid amyloid &bgr; was measured using ELISA. Subjects received Pittsburgh compound B positron emission tomography scans following standardized procedures. Monitoring of OSA was completed using a home sleep recording device. Measurements and Main Results: We found that severity of OSA indices (AHIall [F1,88 = 4.26; P < 0.05] and AHI4% [F1,87 = 4.36; P < 0.05]) were associated with annual rate of change of cerebrospinal fluid amyloid &bgr;42 using linear regression after adjusting for age, sex, body mass index, and apolipoprotein E4 status. AHIall and AHI4% were not associated with increases in ADPiB‐mask (Alzheimers disease vulnerable regions of interest Pittsburg compound B positron emission tomography mask) most likely because of the small sample size, although there was a trend for AHIall (F1,28 = 2.96, P = 0.09; and F1,28 = 2.32, not significant, respectively). Conclusions: In a sample of cognitively normal elderly, OSA was associated with markers of increased amyloid burden over the 2‐year follow‐up. Sleep fragmentation and/or intermittent hypoxia from OSA are likely candidate mechanisms. If confirmed, clinical interventions for OSA may be useful in preventing amyloid build‐up in cognitively normal elderly.

Survival predictors of Burkitt's lymphoma in children, adults and elderly in the United States during 2000–2013

Burkitts Lymphoma (BL) has three peaks of occurrence, in children, adults and elderly, at 10, 40 and 70 years respectively. To the best of our knowledge, no study has been conducted to assess predictors of survival in the three age groups. We hypothesized that survival predictors may differ by age group. We, therefore, sought to determine survival predictors for BL in these three groups: children (<15 years of age), adults (40–70 years of age) and elderly (>70 years of age). Using the Surveillance, Epidemiology, and End Results (SEER) database covering the years 2000‐2013, we identified 797 children, 1,994 adults and 757 elderly patients newly diagnosed with BL. We used adjusted Cox proportional hazards regression models to determine prognostic factors for survival for each age group. Five‐year relative survival in BL for children, adults and elderly were 90.4, 47.8 and 28.9%, respectively. Having at least Stage II disease and multiple primaries were associated with higher mortality in the elderly group. In adults, multiple primaries, Stage III or IV disease, African American race and bone marrow primary were associated with increased mortality whereas Stage IV disease and multiple primaries were associated with worse outcome in children. These findings demonstrate commonalities and differences in predictors of survival that may have implications for management of BL patients.

EFFECT OF OBSTRUCTIVE SLEEP APNEA (OSA) ON RATE OF CHANGE OF AD BIOMARKERS IN COGNITIVELY NORMAL, MCI AND AD ELDERLY: FINDINGS FROM THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE (ADNI) COHORT

Background: Evidence from numerous research implicates disturbed sleep or lack of sleep as one of the risk factors for Alzheimer’s disease (AD) and in a recent meta-analysis, we confirmed the association providing an “average” magnitude of effect. However, the extent of the risk of the association of disturbed sleep with AD biomarkers remains uncertain. We conducted further subgroup meta-analyses to quantify the effect of disturbed sleep on cognitive impairment; preclinical AD and symptomatic AD respectively. Methods:PubMed, Embase, Web of Science, and the Cochrane library were used to identify original published literature for this review. Sleep problems and/or disorders were the risk factor of interest in this meta-analysis, and grouped as sleep quality, sleep duration, circadian rhythm abnormalities, insomnia, and obstructive sleep apnea (OSA) for sub-group analyses. Our target variables included the use of cognitive tests assessing cognitive impairment; the use of AD biomarkers or abnormal proteins assessing preclinical AD; and the use of ICD9/DSMIV diagnoses of symptomatic AD. Effect estimates of individual studies were pooled and relative risks (RR) and 95% confidence intervals (CI) were calculated using random effects models. Meta-regression analyses examining the effect of potential influencing factors was also conducted. Results:Twentyseven observational studies (n 1⁄4 69,216 participants) that provided 52 RR estimates were included in the meta-analysis. Subgroup meta-analytic findings showed a RR increase inverse to diagnostic confidence (e.g., 1.60, 1.70 and 3.80 for AD, Cognitive Impairment and preclinical AD, P-value <.001 for all). Relative risk for AD and/or cognitive decline was (RR: 2.37, 1.86, 1.62, 1.38 and 1.38, p<.001 for all) for OSA, sleep quantity, sleep quality, insomnia, and circadian rhythm abnormalities respectively. Meta-regression results suggested that sample size might have significantly influenced the effect size such that larger sample size studies tended to result in smaller risk and vice versa. Conclusions:Our findings suggest that disturbed sleep had a four-fold association with AD biomarkers. OSA also appeared to be a strong risk factor for AD. Since changes in AD biomarkers are predictive of persons that ultimately develop AD, these results highlight potential mechanistic relationships that are vital for potential prevention of AD.

Clinical characteristics and survival of patients with multiple metachronous esophageal tumor

BACKGROUND The aim of this study is to determine the clinical characteristics and predictors of survival for patients with multiple metachronous esophageal tumors (MMET) and to compare the survival with patients that have single esophageal tumor (SET). METHOD We identified all cases of primary esophageal cancer from the Surveillance, Epidemiology and End Results program database from 2000 to 2013. The primary outcome was the development of a second esophageal cancer six months after the diagnosis of the first tumor. A secondary outcome was disease-specific death from esophageal cancer. Chi-square test was used to compare the tumor and demographic characteristics of patients with SET versus the first and second tumor characteristics of patients with MMET. Logistic regression was used to obtain the odds ratios between patients with secondary tumors and those with primary tumors. Accelerated life model was performed for patients with MMET to determine the predictors of survival. RESULTS Patients with MMET were more likely to have localized stage disease compared to those with SET (P < 0.0001). Distant stage disease for both first tumor (β = -0.402, P = 0.003) and second tumor (β = -0.301, P = 0.033) were predictors of increased mortality. The interval between the first and second tumor affected survival. Intervals of 2-5 years and > 5 years were associated with a reduced hazard with a β = 0.53 and 1.13, P < 0.0001, respectively. CONCLUSION Early development of a second tumor in MMET is associated with poorer survival. Patients with MMET may benefit from regular follow-up and intervention to prevent the development of a second tumor.

SLEEP DISORDERED BREATHING AND BRAIN BETA-AMYLOID BOTH PREDICT TIME-TO-PROGRESSION FROM COGNITIVE NORMAL TO MILD COGNITIVE IMPAIRMENT WITH BRAIN BETA-AMYLOID MODIFYING THE PROGRESSION RISK

and maximally for protocol-3 at 17446687 mm. The linearregression between protocol-2-3 showed the strongest relationship (p< 0.001; r 1⁄4 0.92), while the relationship between “penumbra” volumes for Protocol-1-2 (p1⁄4 0.003; r1⁄4 0.68) and Protocol-1-3 (p 1⁄4 0.013; r 1⁄4 0.56) were less robust. In addition, protocol-3 appeared optimal for co-registration of diffusion tensor and arterial spin labeling imaging for the detection of pre-WMH pathologic changes within the “penumbra“. Conclusions: Reliable volumetric quantification methodologies are essential for the determination of longitudinal WMH change over a one-year period, amenable to use in future clinical trials of small vessel ischemic disease. Future work, validating our optimal WMH “penumbra” quantification protocol amenable to multi-site studies is underway currently.

OBSTRUCTIVE SLEEP APNEA, BRAIN BETA-AMYLOID MEASURES AND TIME-TO-PROGRESSION FROM MILD COGNITIVE IMPAIRMENT TO ALZHEIMER’S DISEASE

Age, years, mean (SD) 76.7 (8.16) Female, n (%) 82 (51.9%) White, n (%) 124 (78.5%) Education, years, mean (SD) 17.2 (2.29) APOE e4+, n (%) 35 (27.1%) PiB+, n (%) 48 (30.4%) Clinical diagnosis, n (%) Cognitively normal 153 (96.8%) Mild cognitive impairment 3 (1.90%) Dementia 2 (1.27%) Follow-up duration, years, mean (SD) 2.50 (3.15) Individuals with: 1 visit, n (%) 71 (44.9%) 2 visits 35 (22.2%) 3 visits 20 (12.7%) 4 visits 11 (6.96%) 5 visits 10 (6.33%) 6-8 visits 11 (6.96%)

OBSTRUCTIVE SLEEP APNEA IS ASSOCIATED WITH LONGITUDINAL INCREASES IN AMYLOID BURDEN IN ELDERLY MILD COGNITIVE IMPAIRMENT INDIVIDUALS

Cross sectional analysis has shown an association between Obstructive Sleep Apnea (OSA) severity and A burden using amyloidPET among Mild Cognitive Impairment (MCI) patients. However, whether OSA accelerates longitudinal increases in amyloid beta (A ) burden in MCI patients is presently unclear. Study participants included a total of 798 subjects with a diagnosis of MCI and were a subset of the ADNI cohort (adni.loni.usc.edu). OSA was self-reported and participants were labeled either as OSA+ or OSA . A burden was determined by florbetapir SUVRs. To test whether OSA is associated with the rate of change in A data longitudinally, multilevel mixed effects linear regression was used to fit the models with randomly varying intercepts and slopes allowing dependence on OSA status. The final model was adjusted for age, sex, body mass index, education, CPAP use status, history of respiratory disease, hypertension, diabetes, and history of cardiovascular disease. A significant variation in the change (slope) in A volumes over time was seen (p<.0001). The covariance between the baseline A level and A volume change over time indicated that OSA subjects experienced greater mean change differences in brain A volumes over time (p < .0001). The rate of change in A deposition also varied significantly across OSA groups over the follow-up period. Obstructive Sleep Apnea possibly facilitates longitudinal increases in amyloid burden in elderly Mild Cognitive Impairment individuals. Further research examining mechanisms underlying effects of OSA on the longitudinal increases in A burden is needed.

SLEEP DISORDERED BREATHING, CSF P-TAU, HIPPOCAMPAL ATROPHY AND B-AMYLOID DEPOSITION IN MILD COGNITIVE IMPAIRMENT PATIENTS

cerebellum reference) to generate Centiloids. The relationship between Centiloids versus CERAD and Thal stages was investigated. Finally, we assessed the performance of two a priori thresholds previously introduced by our group (liberal –SUVR 1.21 1⁄4 7.47 Centiloids; conservative –SUVR 1.40 1⁄4 27.48 Centiloids), and further derived an empirical threshold by performing ROC analysis of the current dataset, using CERAD moderate-frequent plaques as the standard of truth. Results: CERAD none-sparse patients had a mean of -4.8566.88 Centiloids; the moderate-frequent group had 66.02650.45 Centiloids (t-test, p<0.001). The ROC analysis identified 9.50 Centiloids as the optimal threshold with 0.89 sensitivity (95% CI:0.71-0.97), 1.00 specificity (0.86 – 1.00); AUC 0.91 (0.808-1.000) (Figure 1). The a priori liberal threshold had identical sensitivity and specificity as the ROC-derived threshold. These thresholds also distinguished between Thal phases 0-2 and 3-5 (Figure 2). The a priori conservative threshold had sensitivity of 0.68 (0.48-0.83) and specificity of 1.00 (0.86-1.0). Conclusions: The a priori liberal threshold (7.47 Centiloids) and the ROCderived threshold (9.50 Centiloids) showed excellent sensitivity/ specificity, and could be considered for detection of early amyloid signal. By the time of AAIC we anticipate processing at least 100 additional cases currently being provided by multiple sites in order to validate these preliminary results.

ACTIGRAPHIC AND SELF-REPORTED SLEEP QUALITY AND THE RISK OF COGNITIVE DECLINE AND ALZHEIMER’S DEMENTIA: A SYSTEMATIC REVIEW AND META-ANALYSIS

affecting some 20-40% of the elderly population. Headaches have been linked to an increased risk of stroke and white matter hyperintensities which, in turn, have been associated with a higher risk of dementia. A few studies have investigated the relationship between migraine and cognitive decline or dementia in the young-old with mostly negative findings. Recently, any headache was more likely to be reported by young-old individuals who were later included in a Norwegian dementia registry. Aim of the present study was to prospectively investigate the association between history of headache and the occurrence of dementia among the oldest-old in a population-based study of 80-years and older residents in Varese province, Italy (Monzino 80-plus Study). Methods:At initial visit, history of headache was ascertained administering a standardized questionnaire to the subject and primary informant, usually a family member. Diagnosis of dementia was made according to DSM-IV criteria. Results: At first visit, information on history of headache was available from 2,184 participants (mean age: 90 years; mean education: 5 years). Women (72.7%) were more likely to report a history of headache than men (23.0% versus 13.8%, p<0.0001). At baseline, prevalence of headache was significantly higher among oldest-old without dementia (22.7% versus 16.8%; OR: 1.46, 95%CI: 1.17-1.83; p1⁄40.0008). After adjustment for age, sex and education, this difference was no longer significant (OR: 1.19, 95%CI: 0.94-1.52; p1⁄40.1498). Among the 1,120 participants free of dementia at baseline and with at least one follow-up available, the frequency of incident cases of dementia during the following 13 years (3.9 years on average) was significantly higher among the oldest-old who had not reported a history of headache at first visit (HR: 1.30, 95%CI: 1.06-1.60; p1⁄40.0119). This association was no longer significant when age, sex and education were entered into a multivariable Cox model relating headache to dementia (HR: 1.20, 95%CI: 0.981.49; p1⁄40.0824). Limiting the analyses to the oldest-old with a past and current history of headache (7.7%) gave similar results. Conclusions: In the present prospective population-based study, history of headache was not independently associated with dementia among the oldest-old.