Faculty Bibliography

Introduction: White Matter Hyperintensities (WMHs) have been associated with depressive symptoms, reduced cognitive function, and the development of stroke in late-life. Sleep Disordered Breathing (S

Introduction: The ApoE4 allele is a major risk factor for development of Alzheimer Disease (AD). Symptoms of AD include early deficits in spatial orientation and alterations in sleep. The effects of ApoE4 on sleep architecture and sleep-dependent memory consolidation are less known, particularly at earlier time points before clinical manifestations are apparent. We investigated the effects of ApoE4 allele on sleep architecture and overnight spatial navigational memory consolidation in cognitively normal elderly individuals. Methods: We recruited 29 cognitively normal elderly subjects (age = 67 +/- 9 years) who underwent one night of standard polysomnography. Subjects performed training and 3 timed trials before and after sleep on the same computer-generated 3D spatial maze. Improvement in average completion time after sleep was calculated. A 20-minute psychomotor vigilance test (PVT) was performed in the morning prior to the maze trials. ApoE genotype was determined from serum. Individuals with at least 1 ApoE4 were considered at risk carriers. Results: Of 29 subjects, 17 were control and 12 had at least one ApoE4 allele. Both groups were similar in age, total sleep time, sleep efficiency, sleep architecture, severity of sleep disordered breathing, PVT performance, and pre-sleep baseline maze performance. The control group had significant improvements in maze performance after sleep (390 + 135 sec vs 302 + 121 sec, p < 0.002) while ApoE4 carriers had no significant change in performance (349 + 159 sec vs 358 + 178 sec, p = 0.82). We observed a trend toward a difference in the median of individual changes in overnight performance between groups (28.8% vs-11.8% respectively, p = 0.066). Conclusion: Cognitively normal subjects with at least one ApoE4 allele showed a decreased ability to consolidate spatial navigational memory during sleep. Sleep-dependent spatial memory deficits observed may represent an endophenotype of ApoE4 genotype or may help establish risk for development of subsequent AD

Introduction: Both hippocampal electrophysiology and behavioral performance evidence support a role for sleep in spatial navigational memory, but the role of particular sleep stages is less clear. While rodent models suggest REM sleep's importance in spatial navigational memory, a similar role for REM sleep has never been examined in humans. Materials and methods: Given the increased severity of obstructive sleep apnea (OSA) in REM associated with REM skeletal muscle atonia, we hypothesized disrupting human REM sleep via sleepstage specific OSA would impair proper consolidation of spatial memories. We recruited subjects with severe OSA who are well treated and adherent with continuous positive airway pressure (CPAP). Restricting CPAP withdrawal to REM through real-timemonitoring of the polysomnogram (PSG) provides a novel way of addressing the role of REM sleep in spatial navigational memory with a physiologically relevant stimulus. Individual subjects spent two different nights in the lab, during which subjects performed timed trials before and after sleep on one of two unique but equally difficult computer-generated 3D spatial mazes. One night's sleepwas normally consolidated with use of therapeutic CPAP throughout, while on the other night, CPAP was reduced only in REM sleep allowing REM OSA to recur. Results: REM disruption via this method caused reduction of REM sleep and significantly fragmented any remaining REM sleep without affecting total sleep time, sleep efficiency, or slow wave sleep. We observed improvements in maze completion time, distance traveled, and distance spent backtracking after a night of normal sleep that were significantly attenuated after a night of REM disruption without changes in psychomotor vigilance. Furthermore, the degree of improvement in maze completion time significantly positively correlated with the mean REM run duration across both sleep conditions. Conclusion: In conclusion, we demonstrate a novel role for REM sleep in human memory formation and highlight a significant cognitive consequence of OSA

In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-beta1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex(R) measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-beta1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-beta amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal fluid amyloid-beta1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE epsilon4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-beta1-42 values and APOE epsilon2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-beta1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-beta1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology.

Accumulation of toxic protein aggregates-amyloid-beta (Abeta) plaques and hyperphosphorylated tau tangles-is the pathological hallmark of Alzheimer disease (AD). Abeta accumulation has been hypothesized to result from an imbalance between Abeta production and clearance; indeed, Abeta clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Abeta is cleared from the brain. Extracellular Abeta deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood-brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Abeta (eAbeta) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAbeta from the brain, any alteration to their function could contribute to AD. An understanding of Abeta clearance might provide strategies to reduce excess Abeta deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Abeta.

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: Recently, several studies have provided evidence that Abeta dynamics are influenced by the sleep-wake cycle. In transgenic mice, soluble Abeta levels are higher in the interstitial space during wakefulness and lower during sleep, while sleep deprivation increases Abeta concentrations and accelerates Abeta plaque deposition. In humans, in a study where serial cerebrospinal fluid (CSF) samples were collected for 36 hours, Abeta42 concentrations fluctuated with a diurnal pattern, with the lowest Abeta42 levels in the morning sampling. This CSF Abeta diurnal pattern has been related to higher synaptic activity during wakefulness and decreased synaptic activity during slow wave sleep (SWS). In the elderly, brain soluble Abeta42 levels may be relatively increased as a result of: a) agedependent loss of SWS; and, b) sleep disturbances common in late-life that disrupt SWS. The present study examined whether SWS was associated with CSF Abeta42 levels in a morning lumbar puncture (LP) performed between 11:00 AM-01:00 PM. Methods: In a sample of 22 cognitively normal elderly (age 66.5+/-6.7; range 56-83) with available CSF results, we performed a nocturnal polysomnography (NPSG) (average time interval between the NPSG and the LP 12.9+/-10.1 months, range 0-31). 3 subjects had a CSF P-tau/ Abeta42 ratio suggestive of preclinical AD (based on our own dataset of cognitively normal and AD patients modeled to determine the optimal cut-off for diagnostic prediction of AD) and were excluded. Subjects were further divided by median Abeta42 levels (671.95 pg/mL) into High/Low Abeta42. Results: The percent time spent in SWS (%SWS) and absolute SWA were inversely associated with CSF Abeta42 levels (r=-0.70, p<0.01; r=-0.74, p<0.01). There were no associations with the percent time spent in N1, N2 or REM. Results were also significant after controlling for BMI, age, ApoE4 or after including the preclinical AD subjects in the analysis. In group comparisons, normalized SWA in the first cycle was lower in the 'High' Abeta42 group (C3 p<0.05; F4 p <0.1) (Figure 1). Conclusions: In the absence of AD pathology, reduced %SWS or SWA are associated with increases in CSF Abeta42. (Figure Presented)

OBJECTIVE: To examine whether the presence of sleep-disordered breathing (SDB) is associated with an earlier age at mild cognitive impairment (MCI) or Alzheimer disease (AD)-dementia onset in participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We also examined whether continuous positive airway pressure (CPAP) use is associated with delayed onset of cognitive decline. METHODS: From the ADNI cohort, 3 subsets with progressively stringent criteria were created in a step-wise manner. Age at MCI or AD-dementia onset was the main outcome variable. Analyses were performed separately for each subset in untreated SDB+ vs SDB- and untreated SDB+ vs CPAP+ groups. Chi-square and t tests were performed to examine between-group differences. Survival analyses were performed using the Kaplan-Meier method, compared by the log-rank test, and assessed by multivariate Cox regression adjusting for potential confounders. RESULTS: SDB+ patients had a younger age at MCI onset in all subsets (MC1: 72.63 vs 83.67; MC2: 72.15 vs 83.45; MC3: 77.40 vs 89.89; p < 0.01). SDB+ patients had a younger age at AD-dementia onset only in our most conservative subset (AC3: 83.46 vs 88.13; p < 0.05). In a combined outcome analysis, SDB+ patients had a younger age at onset to MCI or AD-dementia in all subsets. In subsets 1 and 2, CPAP use delayed the age at MCI onset (CMC1: 72.63 vs 82.10; CMC2: 72.11 vs 82.10; p < 0.01). CONCLUSIONS: Consistent with our hypothesis, the presence of SDB was associated with an earlier age at cognitive decline. Our findings in CPAP+ participants suggest that CPAP treatment of SDB may delay progression of cognitive impairment.

Objective Reduced CSF Abeta1-42 concentrations are found in the preclinical phase of Alzheimer's disease (AD), but infrequently elevations are reported. Our objective was to test the hypothesis that in the dementia trajectory of late onset AD (LOAD), Abeta1-42 elevations precede reductions. Methods Community residing normal subjects were recruited by random population sampling. We conducted a cross sectional study of subjects aged 21-88y (n=270) and a longitudinal study with 2y and 6y follow-ups (n=92 and 39 respectively). All subjects received standardized clinical, LP and imaging exams. Outcome measures included cognition, ventricular enlargement, PIB-PET, and CSF P-tau levels. Results Across the adult lifespan, increasing numbers of subjects show both elevations and reductions in CSF Abeta1-42 (p<.05). Quadratic relationships between the Abeta1-42 and both P-tau and cognition were observed indicating pathology with both high and low Abeta1-42 levels. Elevated PIB uptake and increased ventricle size also showed a quadratic association with Abeta1-42 levels, providing P-tau levels were elevated. Elevated Abeta1-42 predicted longitudinal reductions in Abeta1-42 levels suggesting direction. Longitudinally, cognitive decline was best predicted by P-tau/Abeta1-42 ratio, which in turn was predominantly driven by reductions in Abeta1-42. Conclusions Both elevated and reduced Abeta1-42 levels are found after age 60, and both are related to cognitive decline and elevated P-tau levels. In the presence of elevated P-tau, both elevated and reduced Abeta1-42 levels are further associated with brain atrophy and amyloid load. While still not possible to conclude that in LOAD CSF Abeta1-42 elevations precede the reductions, this trajectory remains a possibility

OBJECTIVE:Apathy is one of the most frequent symptoms of dementia, still needing better measurement methods. The objective of this study was to validate a new scale for apathy in institutionalized persons with dementia (APADEM-NH). METHODS:The scale includes 26 items distributed in three dimensions: Deficit of Thinking and Self-Generated behaviors (DT): 13 items, Emotional Blunting (EB): 7 items, and Cognitive Inertia (CI): 6 items. The sample included 100 institutionalized patients (90% female) with probable Alzheimer disease (AD) (57%), possible AD (13%), AD + cerebral vascular disease (17%), Lewy body dementia (11%), and Parkinson associated to dementia (2%), covering all stages of dementia severity according to the Global Deterioration Scale and Clinical Dementia Rating. Additional assessments were the Apathy Inventory, Neuropsychiatric Inventory, Cornell Scale for Depression, and the tested scale. Re-test and inter-rater reliability were carried out in 50 patients. RESULTS:All subscales lacked relevant floor and ceiling effects (<15%). Internal consistency for each dimension was (Cronbach's α): DT = 0.88, EB = 0.83, CI = 0.88; item-total correlations were >0.40; and item homogeneity 0.36-0.51. Test-retest reliability for the items was kW = 0.48-0.92; for the subscales, intraclass correlation coefficient (ICC) = 0.80-0.88; and for the total score, ICC = 0.90. Inter-rater reliability reached kW values of 0.84-1.00; subscales ICC, 0.97-0.99, and total score ICC, 0.99. Standard error of measurement for total score was 6.41 and internal validity ranged from rS = 0.69-0.80. CONCLUSIONS:APADEM-NH proved to be feasible, reliable, and valid for apathy assessment in institutionalized patients suffering mild to severe dementia, discerning well between apathy and depression.