Faculty Bibliography

Introduction: Increasing evidence suggests sleep can influence the risk for development of Alzheimer disease (AD), but the precise features of sleep architecture influencing this risk and the role of obstructive sleep apnea (OSA) in contributing to this risk remain only partially characterized. Current models of AD suggest that pathological changes, including the accumulation of proteins beta-amyloid (Ab) and tau, can occur years to even decades before clinical symptoms of memory impairment become evident. In this study, we examined the impact of OSA severity on longitudinal changes in Ab measured both in cerebrospinal fluid (CSF) and with brain PET imaging with Pittsburgh compound B (PiB). In subsets of individuals without significant OSA, we examined the impact of features of sleep architecture such as slow wave activity (SWA) and spindles on concentrations CSF Ab and tau at cross-section. Materials and Methods: 208 cognitively normal elderly subjects (68 +/- 7 years, CDR score = 0) received medical, neurological, and psychiatric evaluations, home polysomnography (PSG) for OSA severity, structural magnetic resonance imaging (MRI) scans, a lumbar puncture (LP) and/or PiB PET scans. A subset of 109 subjects completed a second LP 2.4 +/- 0.9 years after the first LP, and a subset of 34 subjects completed a second brain PiB PET scan 2.5 +/- 0.4 years after the first. A subset of 50 subjects without significant OSA (AHI4% < 15/hour) completed in-laboratory nocturnal PSG for measurements of sleep architecture. SWA was calculated using the average power density in the 0.5-4.0 Hz range at the F4- lead during full night EEG recordings. Spindles were isolated and quantified using DETOKS in which the EEG from the C3-lead was decomposed into oscillatory and non-oscillatory components. Oscillatory components were further scored for sleep spindles using threshold values in the frequency band of 11-16 Hz and time duration of 0.5 to 3 seconds. Results: OSA increased amyloid burden over the years, as a significant association was found between longitudinal decreases in CSF Ab42 and increasing OSA severity indices AHI-all (F1,88 = 4.26, p< .05) and AHI4% (F1,87 = 4.36, p< .05). This was corroborated by a trend toward longitudinal increases in brain PiB PET uptake positively associating with increasing OSA severity by AHI-all (F1,28 = 2.96, p=.09). At cross-section, in those subjects without significant OSA, low frontal SWA was significantly associated with high concentrations of CSF Ab42 and low sleep spindle counts and density were significantly associated with high levels of total and phosphorylated tau in the CSF

OBJECTIVE: This observational multimodality brain imaging study investigates emergence of endophenotypes of late-onset Alzheimer disease (AD) risk during endocrine transition states in a cohort of clinically and cognitively normal women and age-matched men. METHODS: Forty-two 40- to 60-year-old cognitively normal women (15 asymptomatic perimenopausal by age [CNT], 13 perimenopausal [PERI], and 14 postmenopausal [MENO]) and 18 age- and education-matched men were examined. All patients had volumetric MRI, 18F-fluoro-2-deoxyglucose (FDG)-PET (glucose metabolism), and Pittsburgh compound B-PET scans (beta-amyloid [Abeta] deposition, a hallmark of AD pathology). RESULTS: As expected, the MENO group was older than the PERI and CNT groups. Otherwise, groups were comparable on clinical and neuropsychological measures and APOE4 distribution. Compared to CNT women and to men, and controlling for age, PERI and MENO groups exhibited increased indicators of AD endophenotype, including hypometabolism, increased Abeta deposition, and reduced gray and white matter volumes in AD-vulnerable regions (p < 0.001). AD biomarker abnormalities were greatest in MENO, intermediate in PERI, and lowest in CNT women (p < 0.001). Abeta deposition was exacerbated in APOE4-positive MENO women relative to the other groups (p < 0.001). CONCLUSIONS: Multimodality brain imaging indicates sex differences in development of the AD endophenotype, suggesting that the preclinical AD phase is early in the female aging process and coincides with the endocrine transition of perimenopause. These data indicate that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process.

There is a paucity of data related to sports injuries, concussions, and computerized neurocognitive testing (CNT) among very young athletes playing sports in recreational settings. The purpose of this study was to report baseline CNT results among male and female children, ages 5-11, playing sports in Hillsborough County, Florida using ImPACT Pediatric, which is specifically designed for this population. Data were collected from 2016 to 2017. The results show that 657 baseline tests were conducted and t-tests and linear regression were used to assess mean significant differences in composite scores with sex and age. Results showed that females scored better on visual memory and in general as age increased, baseline scores improved. The results can be used to build further studies on the use of CNT in recreational settings and their role in concussion treatment, management, and interventions.

Neuropsychiatric symptoms (NPSs) are hallmarks of Alzheimer's disease (AD), causing substantial distress for both people with dementia and their caregivers, and contributing to early institutionalization. They are among the earliest signs and symptoms of neurocognitive disorders and incipient cognitive decline, yet are under-recognized and often challenging to treat. With this in mind, the Alzheimer's Association convened a Research Roundtable in May 2016, bringing together experts from academia, industry, and regulatory agencies to discuss the latest understanding of NPSs and review the development of therapeutics and biomarkers of NPSs in AD. This review will explore the neurobiology of NPSs in AD and specific symptoms common in AD such as psychosis, agitation, apathy, depression, and sleep disturbances. In addition, clinical trial designs for NPSs in AD and regulatory considerations will be discussed.

Evidence supporting the hypothesis that reduced cerebrospinal fluid (CSF) clearance is involved in the pathophysiology of Alzheimer's disease (AD) comes from primarily from rodent models. However, unlike rodents where predominant extra-cranial CSF egress is via olfactory nerves traversing the cribriform plate, human CSF clearance pathways are not well characterized. Using dynamic Positron Emission Tomography (PET) with 18F-THK5117 a tracer for tau pathology, the ventricular CSF time activity was used as a biomarker for CSF clearance. We tested three hypotheses: 1. Extra-cranial CSF is detected at the superior turbinates; 2. CSF clearance is reduced in AD; and 3. CSF clearance is inversely associated with amyloid deposition. Methods: 15 subjects, 8 with AD and 7 normal control volunteers were examined with 18F-THK5117. 10 subjects additionally received 11C-PiB PET scans and 8 were PiB positive. Ventricular time activity curves (TAC) of 18F-THK5117 were used to identify highly correlated TAC from extra-cranial voxels. Results: For all subjects, the greatest density of CSF positive extra-cranial voxels was in the nasal turbinates. Tracer concentration analyses validated the superior nasal turbinate CSF signal intensity. AD patients showed ventricular tracer clearance reduced by 23% and 66% fewer superior turbinate CSF egress sites. Ventricular CSF clearance was inversely associated with amyloid deposition. Conclusion: The human nasal turbinate is part of the CSF clearance system. Lateral ventricle and superior nasal turbinates CSF clearance abnormalities are found in AD. Ventricular CSF clearance reductions are associated with increased brain amyloid depositions. These data suggest that PET measured CSF clearance is a biomarker of potential interest in AD and other neurodegenerative diseases.

BACKGROUND: Automated single-channel spindle detectors, for human sleep EEG, are blind to the presence of spindles in other recorded channels unlike visual annotation by a human expert. NEW METHOD: We propose a multichannel spindle detection method that aims to detect global and local spindle activity in human sleep EEG. Using a non-linear signal model, which assumes the input EEG to be the sum of a transient and an oscillatory component, we propose a multichannel transient separation algorithm. Consecutive overlapping blocks of the multichannel oscillatory component are assumed to be low-rank whereas the transient component is assumed to be piecewise constant with a zero baseline. The estimated oscillatory component is used in conjunction with a bandpass filter and the Teager operator for detecting sleep spindles. RESULTS AND COMPARISON WITH OTHER METHODS: The proposed method is applied to two publicly available databases and compared with 7 existing single-channel automated detectors. F1 scores for the proposed spindle detection method averaged 0.66 (0.02) and 0.62 (0.06) for the two databases, respectively. For an overnight 6 channel EEG signal, the proposed algorithm takes about 4min to detect sleep spindles simultaneously across all channels with a single setting of corresponding algorithmic parameters. CONCLUSIONS: The proposed method attempts to mimic and utilize, for better spindle detection, a particular human expert behavior where the decision to mark a spindle event may be subconsciously influenced by the presence of a spindle in EEG channels other than the central channel visible on a digital screen.

OBJECTIVE:Apathy is one of the most frequent symptoms of dementia, whose underlying neurobiology is not well understood. The objective was to analyze the correlations of apathy and its dimensions with gray and white matter damage in the brain of patients with advanced Alzheimer's disease (AD). METHODS:The setting of the study was at the Alzheimer Center Reina Sofía Foundation Research Unit. Participants include 37 nursing home patients with moderate to severe AD, 78.4% were women, and mean Standard Deviation (SD) age is 82.7 (5.8). Several measurements were taken: severe mini-mental state examination and Global Deterioration Scale for cognitive and functional status, Neuropsychiatric Inventory for behavioral problems, and Apathy In Dementia-Nursing Home Version Scale for apathy, including total score and subscores of emotional blunting, deficit of thinking, and cognitive inertia. 3T magnetic resonance imaging measures (voxel-based morphometry, fluid-attenuated inversion recovery, and diffusion tensor imaging) were also conducted. RESULTS:Moderate levels of apathy (mean Apathy In Dementia-Nursing Home Version Scale: 31.1 ± 18.5) were found. Bilateral damage to the corpus callosum and internal capsule was associated with apathy severity (cluster size 2435, p < 0.0005, family-wise error [FWE]-corrected). A smaller and more anteriorly located region of the right internal capsule and corpus callosum was associated with higher emotional blunting (cluster size 334, p < 0.0005, FWE-corrected). Ischemic damage in the right periventricular frontal region was associated with higher deficit of thinking (cluster size 3805, p < 0.005, FWE-corrected). CONCLUSIONS:Brain damage related to apathy may have different features in the advanced stages of AD and differs between the three apathy dimensions. Besides atrophy, brain connectivity and vascular lesions are relevant in the study of apathy, especially in the more severe stages of dementia. Further magnetic resonance imaging studies should include multimodal techniques. Copyright © 2016 John Wiley & Sons, Ltd.

OBJECTIVE: To evaluate differences in cerebrovascular reactivity (CVR) to mild hypercapnia in obese/overweight individuals with and without insulin resistance (IR) compared to comparable lean controls. METHODS: A total of 60 cognitively normal participants (20 lean controls and 24 obese/overweight individuals with and 16 without IR) were evaluated using a high spatial resolution arterial spin labeling MRI technique at rest and during mild hypercapnia. We analyzed group differences in CVR in cerebral cortex and ascertained the relationships between CVR, IR, and body mass index (BMI). RESULTS: Obese/overweight participants with and without IR had significantly lower CVR to hypercapnia than lean controls after controlling for age, sex, and the presence of hypertension (F2,53 = 5.578, p = 0.006 eta2p = 0.174). In the obese/overweight participants with IR, there was a significant correlation between higher CVR and a measure of insulin sensitivity, even after accounting for BMI (rp = 0.575, p = 0.004). In contrast, there was no relationship between CVR and BMI when controlling for IR. No such relationships existed for the other 2 groups. CONCLUSIONS: IR is associated with impaired CVR; the relationship appears to be driven by the degree of IR and not by obesity. These rarely reported results suggest that early forms of cerebrovascular dysfunction exist among obese middle-aged individuals with significant IR but without type 2 diabetes mellitus. These functional vascular abnormalities may help explain the associations among IR, diabetes, and dementia, and suggest that interventions aiming to improve IR or CVR may help prevent cognitive decline later in life.

This study compared differences in both maladaptive beliefs and attitudes about sleep between African American (heareafter referred to as black) men at risk for obstructive sleep apnea (OSA) and those without OSA risk. METHODS: A convenience sample of 120 community-dwelling men provided sociodemographic, health and sleep data. A validated questionnaire was used to identify men at high risk for OSA and the Dysfunctional Beliefs and Attitudes about Sleep (DBAS-16) scale was used to measure endorsed attitudes and beliefs about sleep. RESULTS: The mean age of the sample was 42 +/- 15 years. Men reported difficulty falling asleep (23%), difficulty maintaining sleep (23%), early morning awakening (35%), and use of sleep medicine (6%). 27% were at high risk for OSA. Men at high OSA risk had greater DBAS scores [F1, 92=13.68, p<0.001]; OSA risk was related to greater rate of sleep dissatisfaction overall [46% vs. 13%, Chi2=24.52, p<0.001]. CONCLUSION: The findings suggest that maladaptive beliefs and attitudes about sleep are important characteristics of black men at risk for OSA, and potential screenings around sleep difficulties should also consider these factors.

Functional neuroimaging techniques have accelerated progress in the study of sleep disorders. Considering the striking prevalence of these disorders in the general population, however, as well as their strong bidirectional relationship with major neuropsychiatric disorders, including major depressive disorder, their numbers are still surprisingly low. This review examines the contribution of resting state functional MRI to current understanding of two major sleep disorders, insomnia disorder and obstructive sleep apnoea. An attempt is made to learn from parallels of previous resting state functional neuroimaging findings in major depressive disorder. Moreover, shared connectivity biomarkers are suggested for each of the sleep disorders. Taken together, despite some inconsistencies, the synthesis of findings to date highlights the importance of the salience network in hyperarousal and affective symptoms in insomnia. Conversely, dysfunctional connectivity of the posterior default mode network appears to underlie cognitive and depressive symptoms of obstructive sleep apnoea.