Regional cerebral blood flow during wakeful rest in older subjects with mild to severe obstructive sleep apnea

Objectives: To evaluate changes in regional cerebral blood flow (rCBF) during wakeful rest in older subjects with mild to severe obstructive sleep apnea (OSA) and healthy controls, and to identify markers of OSA severity that predict altered rCBF. Design: High-resolution 99mTc-HMPAO SPECT images during wakeful rest. Setting: Research sleep laboratory affiliated with a University hospital. Participants: Fifty untreated OSA patients aged between 55 and 85 years divided into mild, moderate and severe OSA and 20 age-matched healthy controls. Interventions: N/A Measurements: Using statistical parametrical mapping, rCBF was compared between groups and correlated with clinical, respiratory and sleep variables. Results: Whereas no rCBF change was observed in mild and moderate groups, participants with severe OSA had reduced rCBF compared to controls in the left parietal lobules, precentral gyrus, bilateral postcentral gyri, and right precuneus. Reduced rCBF in these regions and in areas of the bilateral frontal and left temporal cortex was associated with more hypopneas, snoring, hypoxemia, and sleepiness. Higher apnea, micro-arousal, and body mass indexes were correlated to increased rCBF in the basal ganglia, insula, and limbic system. Conclusions: While older individuals with severe OSA had hypoperfusions in the sensorimotor and parietal areas, respiratory variables and subjective sleepiness were correlated with extended regions of hypoperfusion in the lateral cortex. Interestingly, OSA severity, sleep fragmentation and obesity correlated with increased perfusion in subcortical and medial cortical regions. Anomalies with such a distribution could result in cognitive deficits and reflect impaired vascular regulation, altered neuronal integrity, and/or undergoing neurodegenerative processes

Sleep deprivation reveals altered brain perfusion patterns in somnambulism

BACKGROUND: Despite its high prevalence, relatively little is known about the pathophysiology of somnambulism. Increasing evidence indicates that somnambulism is associated with functional abnormalities during wakefulness and that sleep deprivation constitutes an important drive that facilitates sleepwalking in predisposed patients. Here, we studied the neural mechanisms associated with somnambulism using Single Photon Emission Computed Tomography (SPECT) with 99mTc-Ethylene Cysteinate Dimer (ECD), during wakefulness and after sleep deprivation. METHODS: Ten adult sleepwalkers and twelve controls with normal sleep were scanned using 99mTc-ECD SPECT in morning wakefulness after a full night of sleep. Eight of the sleepwalkers and nine of the controls were also scanned during wakefulness after a night of total sleep deprivation. Between-group comparisons of regional cerebral blood flow (rCBF) were performed to characterize brain activity patterns during wakefulness in sleepwalkers. RESULTS: During wakefulness following a night of total sleep deprivation, rCBF was decreased bilaterally in the inferior temporal gyrus in sleepwalkers compared to controls. CONCLUSIONS: Functional neural abnormalities can be observed during wakefulness in somnambulism, particularly after sleep deprivation and in the inferior temporal cortex. Sleep deprivation thus not only facilitates the occurrence of sleepwalking episodes, but also uncovers patterns of neural dysfunction that characterize sleepwalkers during wakefulness

Obstructive sleep apnea during REM sleep and daytime cerebral functioning : a regional cerebral blood flow study using high-resolution SPECT

Obstructive sleep apnea (OSA) predominantly during rapid eye movement (REM) sleep may have impacts on brain health, even in milder OSA cases. Here, we evaluated whether REM sleep OSA is associated with abnormal daytime cerebral functioning using high-resolution single-photon emission computed tomography (SPECT). We tested 96 subjects (25 F, age: 65.2 ± 6.4) with a wide range of OSA severity from no OSA to severe OSA (apnea–hypopnea index: 0–97 events/h). More respiratory events during REM sleep were associated with reduced daytime regional cerebral blood flow (rCBF) in the bilateral ventromedial prefrontal cortex and in the right insula extending to the frontal cortex. More respiratory events during non-REM (NREM) sleep were associated with reduced daytime rCBF in the left sensorimotor and temporal cortex. In subjects with a lower overall OSA severity (apnea–hypopnea index<15), more respiratory events during REM sleep were also associated with reduced daytime rCBF in the insula and extending to the frontal cortex. Respiratory events that characterized OSA during NREM versus REM sleep are associated with distinct patterns of daytime cerebral perfusion. REM sleep OSA could be more detrimental to brain health, as evidenced by reduced daytime rCBF in milder forms of OSA

Altered regional cerebral blood flow in idiopathic hypersomnia

Objectives Idiopathic hypersomnia is characterized by excessive daytime sleepiness despite normal or long sleep time. Its pathophysiological mechanisms remain unclear. This pilot study aims at characterizing the neural correlates of idiopathic hypersomnia using single photon emission computed tomography. Methods Thirteen participants with idiopathic hypersomnia and sixteen healthy controls were scanned during resting wakefulness using a high-resolution single photon emission computed tomography scanner with 99mTc-ethyl cysteinate dimer to assess cerebral blood flow. The main analysis compared regional cerebral blood flow distribution between the two groups. Exploratory correlations between regional cerebral blood flow and clinical characteristics evaluated the functional correlates of those brain perfusion patterns. Significance was set at p <0.05 after correction for multiple comparisons. Results Idiopathic hypersomnia participants showed regional cerebral blood flow decreases in medial prefrontal cortex, posterior cingulate cortex and putamen, as well as increases in amygdala and temporo-occipital cortices. Lower regional cerebral blood flow in the medial prefrontal cortex was associated with higher daytime sleepiness. Conclusions These preliminary findings suggest that idiopathic hypersomnia is characterized by functional alterations in brain areas involved in the modulation of vigilance states, which may contribute to the daytime symptoms of this condition. The distribution of regional cerebral blood flow changes was reminiscent of the patterns associated with normal non-rapid-eye-movement sleep, suggesting the possible presence of incomplete sleep-wake transitions. These abnormalities were strikingly distinct from those induced by acute sleep deprivation, suggesting that the patterns seen here might reflect a trait associated with idiopathic hypersomnia rather than a non-specific state of sleepiness

18 F-MK-6240 tau-PET in genetic frontotemporal dementia

Tau is one of several proteins associated with frontotemporal dementia. While knowing which protein is causing a patient\u27s disease is crucial, no biomarker currently exists for identifying tau in vivo in frontotemporal dementia. The objective of this study was to investigate the potential for the promising 18F-MK-6240 PET tracer to bind to tau in vivo in genetic frontotemporal dementia. We enrolled subjects with genetic frontotemporal dementia, who constitute an ideal population for testing because their pathology is already known based on their mutation. Ten participants (three with symptomatic P301L and R406W MAPT mutations expected to show tau binding, three with presymptomatic MAPT mutations and four with non-tau mutations who acted as disease controls) underwent clinical characterization, tau-PET scanning with 18F-MK-6240, amyloid-PET imaging with 18F-NAV-4694 to rule out confounding Alzheimer\u27s pathology, and high-resolution structural MRI. Tau-PET scans of all three symptomatic MAPT carriers demonstrated at least mild 18F-MK-6240 binding in expected regions, with particularly strong binding in a subject with an R406W MAPT mutation (known to be associated with Alzheimer\u27s like neurofibrillary tangles). Two asymptomatic MAPT carriers estimated to be 5 years from disease onset both showed modest 18F-MK-6240 binding, while one ∼30 years from disease onset did not exhibit any binding. Additionally, four individuals with symptomatic frontotemporal dementia caused by a non-tau mutation were scanned (two C9orf72; one GRN; one VCP): 18F-MK-6240 scans were negative for three subjects, while one advanced C9orf72 case showed minimal regionally non-specific binding. All 10 amyloid-PET scans were negative. Furthermore, a general linear model contrasting genetic frontotemporal dementia subjects to a set of 83 age-matched controls showed significant binding only in the MAPT carriers in selected frontal, temporal and subcortical regions. In summary, our findings demonstrate mild but significant binding of MK-6240 in amyloid-negative P301L and R406W MAPT mutation subjects, with higher standardized uptake value ratio in the R406W mutation associated with the presence of NFTs, and little non-specific binding. These results highlight that a positive 18F-MK-6240 tau-PET does not necessarily imply a diagnosis of Alzheimer\u27s disease and point towards a potential use for 18F-MK-6240 as a biomarker in certain tauopathies beyond Alzheimer\u27s, although further patient recruitment and autopsy studies will be necessary to determine clinical applicability

Changes in regional cerebral perfusion over time in idiopathic REM sleep behavior disorder

Background Idiopathic rapid eye movement sleep behavior disorder is associated with increased risk of neurodegeneration, but the temporal evolution of regional perfusion, a marker of cerebral activity, has not been characterized. The objective of the current study was to study longitudinal regional perfusion in patients with idiopathic rapid eye movement sleep behavior disorder. Methods Thirty‐seven patients and 23 controls underwent high‐resolution single‐photon emission computed tomography. After 17 months on average, scans were repeated for idiopathic rapid eye movement sleep behavior disorder patients. We compared regional cerebral blood flow between groups and over time. Results At baseline, patients showed lower relative regional perfusion in the anterior frontal and lateral parietotemporal cortex compared with controls. However, over time, patients showed an increase in relative regional perfusion in the anterior frontal, lateral parietal, and occipitotemporal cortex, reverting toward normal control levels. Conclusions Patients with idiopathic rapid eye movement sleep behavior disorder showed significant areas of relative regional hypoperfusion, which disappeared over time to finally return to average levels, suggesting possible developing compensation in areas affected by neurodegeneration

Longitudinal blood biomarker trajectories in preclinical Alzheimer's disease

INTRODUCTION: Plasma biomarkers are altered years prior to Alzheimer's disease (AD) clinical onset. METHODS: We measured longitudinal changes in plasma amyloid-beta (Aβ)42/40 ratio, pTau181, pTau231, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in a cohort of older adults at risk of AD (n = 373 total, n = 229 with Aβ and tau positron emission tomography [PET] scans) considering genetic and demographic factors as possible modifiers of these markers' progression. RESULTS: Aβ42/40 ratio concentrations decreased, while NfL and GFAP values increased over the 4-year follow-up. Apolipoprotein E (APOE) ε4 carriers showed faster increase in plasma pTau181 than non-carriers. Older individuals showed a faster increase in plasma NfL, and females showed a faster increase in plasma GFAP values. In the PET subsample, individuals both Aβ-PET and tau-PET positive showed faster plasma pTau181 and GFAP increase compared to PET-negative individuals. DISCUSSION: Plasma markers can track biological change over time, with plasma pTau181 and GFAP markers showing longitudinal change in individuals with preclinical AD. HIGHLIGHTS: Longitudinal increase of plasma pTau181 and glial fibrillary acidic protein (GFAP) can be measured in the preclinical phase of AD. Apolipoprotein E ε4 carriers experience faster increase in plasma pTau181 over time than non-carriers. Female sex showed accelerated increase in plasma GFAP over time compared to males. Aβ42/40 and pTau231 values are already abnormal at baseline in individuals with both amyloid and tau PET burden

Potential Utility of Plasma P-Tau and Neurofilament Light Chain as Surrogate Biomarkers for Preventive Clinical Trials

OBJECTIVE: To test the utility of longitudinal changes in plasma phosphorylated tau 181 (p-tau181) and neurofilament light chain (NfL) as surrogate markers for clinical trials targeting cognitively unimpaired (CU) populations. METHODS: We estimated the sample size needed to test a 25% drug effect with 80% of power at a 0.05 level on reducing changes in plasma markers in CU participants from Alzheimer's Disease Neuroimaging Initiative database. RESULTS: We included 257 CU individuals (45.5% males; mean age = 73 [6] years; 32% β-amyloid [Aβ] positive). Changes in plasma NfL were associated with age, whereas changes in plasma p-tau181 with progression to amnestic mild cognitive impairment. Clinical trials using p-tau181 and NfL would require 85% and 63% smaller sample sizes, respectively, for a 24-month than a 12-month follow-up. A population enrichment strategy using intermediate levels of Aβ PET (Centiloid 20-40) further reduced the sample size of the 24-month clinical trial using p-tau181 (73%) and NfL (59%) as a surrogate. DISCUSSION: Plasma p-tau181/NfL can potentially be used to monitor large-scale population interventions in CU individuals. The enrollment of CU with intermediate Aβ levels constitutes the alternative with the largest effect size and most cost-effective for trials testing drug effect on changes in plasma p-tau181 and NfL

The use of random forests to classify amyloid brain PET

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.Purpose: To evaluate random forests (RFs) as a supervised machine learning algorithm to classify amyloid brain PET as positive or negative for amyloid deposition and identify key regions of interest for stratification. Methods: The data set included 57 baseline 18F-florbetapir (Amyvid; Lilly, Indianapolis, IN) brain PET scans in participants with severe white matter disease, presenting with either transient ischemic attack/lacunar stroke or mild cognitive impairment from early Alzheimer disease, enrolled in a multicenter prospective observational trial. Scans were processed using the MINC toolkit to generate SUV ratios, normalized to cerebellar gray matter, and clinically read by 2 nuclear medicine physicians with interpretation based on consensus (35 negative, 22 positive). SUV ratio data and clinical reads were used for super- vised training of an RF classifier programmed in MATLAB. Results: A 10,000-tree RF, each tree using 15 randomly selected cases and 20 randomly selected features (SUV ratio per region of interest), with 37 cases for training and 20 cases for testing, had sensitivity = 86% (95% confidence in- terval [CI], 42%–100%), specificity = 92% (CI, 64%–100%), and classification accuracy = 90% (CI, 68%–99%). The most common features at the root node (key regions for stratification) were (1) left posterior cingulate (1039 trees), (2) left middle frontal gyrus (1038 trees), (3) left precuneus (857 trees), (4) right an- terior cingulate gyrus (655 trees), and (5) right posterior cingulate (588 trees). Conclusions: Random forests can classify brain PET as positive or negative for amyloid deposition and suggest key clinically relevant, regional features for classification.CIHR MITNEC C6 || Linda C Campbell Foundation || Lilly-Avid Radiopharmaceuticals

The Use of Random Forests to Identify Brain Regions on Amyloid and FDG PET Associated With MoCA Score

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.Purpose: The aim of this study was to evaluate random forests (RFs) to identify ROIs on 18F-florbetapir and 18F-FDG PET associated with Montreal Cognitive Assessment (MoCA) score. Materials and Methods: Fifty-seven subjects with significant white matter disease presenting with either transient ischemic attack/lacunar stroke or mild cognitive impairment from early Alzheimer disease, enrolled in a mul- ticenter prospective observational trial, had MoCA and 18F-florbetapir PET; 55 had 18F-FDG PET. Scans were processed using the MINC toolkit to gen- erate SUV ratios, normalized to cerebellar gray matter (18F-florbetapir PET), or pons (18F-FDG PET). SUV ratio data and MoCA score were used for su- pervised training of RFs programmed in MATLAB. Results: 18F-Florbetapir PETs were randomly divided into 40 training and 17 testing scans; 100 RFs of 1000 trees, constructed from a random subset of 16 training scans and 20 ROIs, identified ROIs associated with MoCA score: right posterior cingulate gyrus, right anterior cingulate gyrus, left precuneus, left posterior cingulate gyrus, and right precuneus. Amyloid in- creased with decreasing MoCA score. 18F-FDG PETs were randomly di- vided into 40 training and 15 testing scans; 100 RFs of 1000 trees, each tree constructed from a random subset of 16 training scans and 20 ROIs, identified ROIs associated with MoCA score: left fusiform gyrus, left precuneus, left posterior cingulate gyrus, right precuneus, and left middle orbitofrontal gyrus. 18F-FDG decreased with decreasing MoCA score. Conclusions: Random forests help pinpoint clinically relevant ROIs associ- ated with MoCA score; amyloid increased and 18F-FDG decreased with de- creasing MoCA score, most significantly in the posterior cingulate gyrus.CIHR MITNEC C6 || Linda C Campbell Foundation || Lilly-Avid Radiopharmaceuticals