Faculty Bibliography

STUDY OBJECTIVES: Emerging evidence suggests a role for sleep in contributing to the progression of Alzheimer disease (AD). Slow wave sleep (SWS) is the stage during which synaptic activity is minimal and clearance of neuronal metabolites is high, making it an ideal state to regulate levels of amyloid beta (Abeta). We thus aimed to examine relationships between concentrations of Abeta42 in the cerebrospinal fluid (CSF) and measures of SWS in cognitively normal elderly subjects. METHODS: Thirty-six subjects underwent a clinical and cognitive assessment, a structural MRI, a morning to early afternoon lumbar puncture, and nocturnal polysomnography. Correlations and linear regression analyses were used to assess for associations between CSF Abeta42 levels and measures of SWS controlling for potential confounders. Resulting models were compared to each other using ordinary least squared linear regression analysis. Additionally, the participant sample was dichotomized into "high" and "low" Abeta42 groups to compare SWS bout length using survival analyses. RESULTS: A significant inverse correlation was found between CSF Abeta42 levels, SWS duration and other SWS characteristics. Collectively, total SWA in the frontal lead was the best predictor of reduced CSF Abeta42 levels when controlling for age and ApoE status. Total sleep time, time spent in NREM1, NREM2, or REM sleep were not correlated with CSF Abeta42. CONCLUSIONS: In cognitively normal elderly, reduced and fragmented SWS is associated with increases in CSF Abeta42, suggesting that disturbed sleep might drive an increase in soluble brain Abeta levels prior to amyloid deposition.

In animal models, inflammation is both a cause and consequence of seizures. Less is known about the role of inflammation in human epilepsy. We performed positron emission tomography (PET) using a radiotracer sensitive to brain inflammation in a patient with frontal epilepsy ~36 h after a seizure as well as during a seizure-free period. When statistically compared to a group of 12 matched controls, both of the patient's scans identified a frontal (supplementary motor area) region of increased inflammation corresponding to his clinically defined seizure focus, but the postseizure scan showed significantly greater inflammation intensity and spatial extent. These results provide new information about transient and chronic neuroinflammation in human epilepsy and may be relevant to understanding the process of epileptogenesis and guiding therapy.

STUDY OBJECTIVES: To evaluate the role of orexin-A with respect to cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers, and explore its relationship to cognition and sleep characteristics in a group of cognitively normal elderly individuals. METHODS: Subjects were recruited from multiple community sources for National Institutes of Health supported studies or normal aging, sleep and CSF biomarkers. Sixty-three participants underwent home monitoring for sleep-disordered breathing, clinical, sleep and cognitive evaluations, as well as a lumbar puncture to obtain CSF. Individuals with medical history or with magnetic resonance imaging evidence of disorders that may affect brain structure or function were excluded. Correlation and linear regression analyses were used to assess the relationship between orexin-A and CSF AD-biomarkers controlling for potential sociodemographic and sleep confounders. RESULTS: Levels of orexin-A, amyloid beta 42 (Abeta42), phosphorylated-tau (P-Tau), total-tau (T-Tau), Apolipoprotein E4 status, age, years of education, reported total sleep time, number of awakenings, apnea-hypopnea indices (AHI), excessive daytime sleepiness, and a cognitive battery were analyzed. Subjects were 69.59 +/- 8.55 years of age, 57.1% were female, and 30.2% were apolipoprotein E4+. Orexin-A was positively correlated with Abeta42, P-Tau, and T-Tau. The associations between orexin-A and the AD-biomarkers were driven mainly by the relationship between orexin-A and P-Tau and were not influenced by other clinical or sleep characteristics that were available. CONCLUSIONS: Orexin-A is associated with increased P-Tau in normal elderly individuals. Increases in orexin-A and P-Tau might be a consequence of the reduction in the proportion of the deeper, more restorative slow wave sleep and rapid eye movement sleep reported with aging. TRIAL REGISTRATION: Clinicaltrials.gov registration number NCT01962779.

INTRODUCTION: Down Syndrome (DS) adults experience accumulation of Alzheimer's disease (AD)-like amyloid plaques and tangles and a high incidence of dementia and could provide an enriched population to study AD-targeted treatments. However, to evaluate effects of therapeutic intervention, it is necessary to dissociate the contributions of DS and AD from overall phenotype. Imaging biomarkers offer the potential to characterize and stratify patients who will worsen clinically but have yielded mixed findings in DS subjects. METHODS: We evaluated 18F fluorodeoxyglucose positron emission tomography (PET), florbetapir PET, and structural magnetic resonance (sMR) image data from 12 nondemented DS adults using advanced multivariate machine learning methods. RESULTS: Our results showed distinctive patterns of glucose metabolism and brain volume enabling dissociation of DS and AD effects. AD-like pattern expression corresponded to amyloid burden and clinical measures. DISCUSSION: These findings lay groundwork to enable AD clinical trials with characterization and disease-specific tracking of DS adults.

INTRODUCTION: Hypertension, hypercholesterolemia, and obesity increase the risk of dementia. Although their detection is commonly followed by an introduction of treatment, little is known about how medications frequently used to treat vascular risk affect amyloid deposition. METHODS: A cross-sectional study of 156 subjects who underwent positron emission tomography with PiB. Using linear regression, we tested whether blood pressure, cholesterol, overweight/obese status, angiotensin receptor blockers (ARBs), beta-blockers, diuretics, angiotensin converting enzyme inhibitors, and statins predicted amyloid deposition. RESULTS: The use of ARBs (beta = -.15, P = .044) and diuretics (beta = -.20, P = .006) predicted less amyloid accumulation; older age (beta = .29, P < .001) and statins (beta = .23, P = .004) were related to greater amyloid deposition. Overweight and/or obese women had more cortical amyloid than their peers. DISCUSSION: Prospective studies should confirm effects of drugs and increased body weight on amyloid accumulation and establish whether they translate into measurable clinical outcomes. Women may be more susceptible to harmful effects of obesity.

Background: The association of blood pressure (BP) and dementia in the elderly is debated. Whereas hypertension in mid-life appears to increase the risk of Alzheimer's dementia (AD); lower BP in the elderly is associated with a greater risk of cognitive decline. White matter lesions (WML) are the result of impaired cerebral blood flow, possibly due to insufficient perfusion pressure. The hippocampus, an early site of AD pathology, is also among the brain structures most sensitive to hypoperfusion. We tested the hypothesis that elderly normotensive subjects with WML represent a group suffering from subclinical cerebral hypoperfusion, which increases their risk for AD. We examined 24-hour ambulatory blood pressure (ABP), hippocampal volume and memory in four groups of subjects: hypertensive (HTN+) and normotensive (HTN-) subjects with (WML+) and without (WML-) white matter changes. Methods: Sixty-six subjects (mean age 72.63 6 8.48, 62% female) underwent a thorough medical assessment, brain magnetic resonance imaging (MRI), 24 hour ABP monitoring, and memory testing. Fluid attenuated inversion recovery images were used to determine the WML using the Fazekas scale. Periventricular (PWML) and deep white matter lesions (DWML) were graded separately and summed to create the total load. High load (WML+) was defined as a total load >3. Brain volumes were obtained from T1- weighted MRI images using FreeSurfer. Memory tests were converted to age, education and gender adjusted standardized scores. HTN was determined based on antihypertensive medication use and the results of 24 h APBM. Results: Groups differed in age, but not in education or gender (Table 1). HTNWML+ group had the lowest mean systolic BP (F=43.0, p<.001), and the lowest mean awake systolic BP (F=45.0, p<.001) (Table 1). Post hoc contrast analyses showed that hippocampal volumes, but not whole brain volumes, decreased linearly from HTN-WML-, through HTN+WML- and HTN+WML+, to HTN-WML+ group (p=.006) (for the entire model F=2.7, p=.049) (Figure 1). Memory scores showed a similar trend (p=.10) (for the entire model F=1.9, p=.10) (Figure 2). Conclusions: Normotensive elderly with WML have lower BP, lower hippocampal volumes and poorer memory overall. This constellation of clinical and imaging characteristics may increase their risk of developing AD. (Figure Presented)

Background: Metabolic syndrome (MetS) is a multiplex risk factor for cardiovascular disease that deserves significant attention. While there is a growing recognition of the link between MetS and cognition, little is known about how MetS relates to cortical amyloid deposition. The detection of vascular risk is commonly followed by an introduction of appropriate treatment aimed at risk modification. The treatment itself may affect accumulation of brain amyloid, but this issue is largely unknown. Our aim was to assess the relationships between MetS, antihypertensive and antilipid medications, and cortical amyloid binging of Pittsburgh compound B (PiB) in cognitively healthy adults and elderly. Methods: A crosssectional study of subjects (n=155) participating in studies of brain aging who underwent Positron Emission Tomography (PET) imaging with PiB. Sixty-seven percent were women, mean age of the entire group was 60.4+/-10.5 years, mean education 16.6+/-2.0 years. General linear models were used to compare groups. Predictors of cortical amyloid accumulation were tested with linear regression models. Tested predictors included MetS, visceral obesity, blood pressure, glucose, HDL and triglycerides levels, treatment with angiotensin receptor blockers (ARBs), beta-blockers, diuretics, angiotensin converting enzymes inhibitor, statins, antidepressants, demographics, and ApoE 4 carrier status. Results: After accounting for age and the treatment with antidepressants, the use of ARBs (b=-.15, p=.048) and diuretics (b=-.28, p=.001) predicted less amyloid accumulation, while statins (b=.19, p=.015) were the related to more cortical amyloid deposition. Although MetS was not related to amyloid deposition, central obesity was associated with greater cortical amyloid in women irrespective of medication status. Conclusions: ARBs and diuretics were associated with less amyloid deposition. Prospective studies should confirm this benefit of antihypertensive drugs and establish whether such modifications translate into measurable clinical outcomes. Women may be particularly sensitive to detrimental effects of obesity on the aging brain. This must be taken into consideration while planning future interventions

Epidemiological evidence linking diet-one of the most important modifiable lifestyle factors-and risk of Alzheimer's disease (AD)-the most common cause of dementia-is rapidly increasing. However, the biological mechanisms underlying the relationship between dietary nutrients, brain aging, and risk of AD are largely unexplored. Recent studies using brain imaging and biological markers of AD have begun to clarify how diet and nutrition modulate risk of AD in cognitively normal individuals, especially those at increased genetic risk. Such knowledge is critical prior to implementing dietary recommendations for prevention and treatment of disease.