Faculty Bibliography

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.

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.

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.

During wakefulness, extracellular levels of metabolites in the brain increase. These include amyloid beta (Abeta), which contributes to the pathogenesis of Alzheimer's disease (AD). Counterbalancing their accumulation in the brain, sleep facilitates the removal of these metabolites from the extracellular space by convective flow of the interstitial fluid from the para-arterial to the para-venous space. However, when the sleep-wake cycle is disrupted (characterized by increased brain levels of the wake-promoting neuropeptide orexin and increased neural activity), the central nervous system (CNS) clearance of extracellular metabolites is diminished. Disruptions to the sleep-wake cycle have furthermore been linked to increased neuronal oxidative stress and impaired blood-brain barrier function - conditions that have also been proposed to play a role in the development and progression of AD. Notably, recent human and transgenic animal studies have demonstrated that AD-related pathophysiological processes that occur long before the clinical onset of AD, such as Abeta deposition in the brain, disrupt sleep and circadian rhythms. Collectively, as proposed in this review, these findings suggest the existence of a mechanistic interplay between AD pathogenesis and disrupted sleep-wake cycles, which is able to accelerate the development and progression of this disease.

Introduction: Slow wave sleep (SWS) is thought to benefit spatial memory consolidation. This study investigates whether disrupting SWS via sleep-stage specific OSA affects spatial memory consolidation and how sleep fragmentation and intermittent hypoxia differentially impact this effect. Methods: We recruited 5 subjects with severe OSA who are well treated and compliant with CPAP. Individual subjects spent 3 different nights in the lab and performed timed trials before and after sleep on unique but equally difficult 3D spatial mazes. The 3 conditions included: 1) consolidated sleep with treated OSA 2) CPAP withdrawn exclusively in SWS (SWS-OSA) and 3) CPAP withdrawn exclusively in SWS with simultaneous addition of supplemental oxygen (SWS-OSA+O2). Results: CPAP withdrawal in SWS both decreased %SWS (21% +/- 11% during consolidated sleep vs. 13% +/- 7% with SWS-OSA), and fragmented remaining SWS (SWS apnea hypopnea index with 3% oxygen desaturation or arousal (AHI3A) = 0.5/hour +/- 1 during consolidated sleep vs. 36/hour +/- 12 with SWS-OSA). During SWSOSA+ O2, SWS was also reduced (11% +/ 8%) and respiratory events continued (AHI3A 31/hour +/- 20), however indices of oxygen desaturation were minimized (%time below 90% in SWS = 4.3% +/- 1.7% during SWS-OSA vs 0.5% +/- 0.9% during SWS-OSA+O2; average oxygen saturation during respiratory event = 88.7% +/- 3.3% during SWS-OSA vs. 94% +/- 1.4% during SWS-OSA+O2). During consolidated sleep, median completion time improved from 180 sec pre-sleep (range 86 to 248 sec) to 111 sec post-sleep (range 87 to 412 sec) (38%). During SWS-OSA median completion time improved from 138 sec pre-sleep (range 116 to 272 sec) to 133 sec post-sleep (range 73 to 453 sec) (4%) and during SWS-OSA+O2 median completion time improved from 172 sec pre-sleep (range 61 to 339 sec) to 161 sec postsleep (range 51 to 306 sec) (6%). Conclusion: CPAP withdrawal during SWS in subjects with severe OSA reduces and fragments SWS. The addition of supplemental oxygen during CPAP withdrawal minimizes the associated intermittent hypoxia. Early evidence suggests a greater benefit of consolidated sleep on overnight change in spatial navigation performance than sleep with SWS disruption either with or without intermittent hypoxia

Introduction: Sleep may play a role in AD pathogenesis, but the timing, role, and extent to which sleep disturbances in late-life are associated with increasing burden of AD neuropathology remains unclear. Sleep spindles have been implicated in sleep quality. Wakefulness is mediated by an arousal system beginning in the brainstem and continuing on to the diencephalon and innervating the thalamus, the region where sleep spindle oscillations are generated. In AD pathology, hyperphosphorylated tau (P-Tau) protein accumulates in the brainstem, from where it spreads to the entorhinal cortices, hippocampi and other brain regions. These tau aggregates may interfere with the sleep-wake cycle resulting in down-regulation of sleep spindles and associated sleep disruption. Increased CSF P-tau and T-tau levels are likely related to the formation of neurofibrillary tangles in the brainstem and limbic system (Braak stages I-IV). Methods: 49 cognitively normal (CDR=0) elderly (66.95 +/- 7.76 years) subjects completed a structural MRI, lumbar puncture (LP) and nocturnal polysomnography (NPSG) within 4.65 +/- 6.81 months of the LP. From the NPSG, spindle frequency and density were analyzed for stages NREM1, NREM2 and NREM3, using an automated optimization algorithm which decomposes the EEG as a sum of transient and oscillatory components. This was used to detect the spindles and a Fourier analysis was performed to evaluate the spindle frequency in Hz. Results: Spindle frequency and density in NREM2 sleep were inversely associated with CSF P-tau (r= -0.355, p<0.05; r=-0.476, p<0.05) and CSF T-tau (r=-0.405, p<.05; r=-0.542, p<.05) using partial correlation controlling for age and ApoE4 allele. There were no associations between spindle frequency or density and CSF P-tau or CSF T-tau in stages NREM1, NREM3. Conclusion: The association of spindle frequency and density in NREM2 to CSF P-tau and CSF T-tau in cognitively normal elderly suggest either that tau pathology may produce an early downstream effect on sleep spindles, or that changes in sleep spindles can identify a process relating to tau pathology. Whether the association of tau to spindles is a non-specific effect of tau on increasing sleep fragmentation in general remains an area of active investigation