Impaired Clearance From the Brain Increases the Brain Exposure to Metoclopramide in Elderly Subjects

We recently proposed a novel method that aggregates the multidimensional aging pattern across the brain to a single value. This method proved to provide stable and reliable estimates of brain aging – even across different scanners. While investigating longitudinal changes in BrainAGE in about 400 elderly subjects, we discovered that patients with Alzheimer’s disease and subjects who had converted to AD within 3 years showed accelerated brain atrophy by +6 years at baseline. An additional increase in BrainAGE accumulated to a score of about +9 years during follow-up. Accelerated brain aging was related to prospective cognitive decline and disease severity. In conclusion, the BrainAGE framework indicates discrepancies in brain aging and could thus serve as an indicator for cognitive functioning in the future.

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Sleep apnoea in the asymptomatic elderly: a real issue for the brain?

European Respiratory Journal ◽

10.1183/13993003.02450-2017 ◽

2018 ◽

Vol 51 (6) ◽

pp. 1702450 ◽

Cited By ~ 2

Author(s):

Sébastien Celle ◽

Claire Boutet ◽

Cédric Annweiler ◽

Jean-Claude Barthélémy ◽

Frédéric Roche

Keyword(s):

Cortical Thickness ◽

Brain Volume ◽

Sleep Apnoea ◽

Middle Temporal Gyrus ◽

Elderly Subjects ◽

Brain Volumes ◽

Control Subjects ◽

Surface Control ◽

The Brain ◽

Local Brain

The link between sleep apnoea and brain structure is unclear; although dysfunction of the hippocampus, middle temporal gyrus and brainstem/cerebellum have been observed previously. However, this link has been little explored in elderly subjects. The aim of this study was to explore the link between sleep apnoea and the brain in an elderly population.226 asymptomatic elderly subjects (age mean±sd 75.3±0.9 years, range 72.3–77.8 years) from the PROOF (Evaluation of Ageing, Autonomic Nervous System Activity and Cardiovascular Events) cohort study were explored using linear voxel-based or cortical thickness with apnoea/hypopnoea index (AHI; mean±sd 15.9±11.5 events·h−1, range 6–63.6 events·h−1) as a covariate of main interest. The brain volumes of 20 control subjects, 18 apnoeic (AHI >29 events·h−1) treated patients and 20 apnoeic untreated patients from this population were compared using voxel-based morphometry, cortical thickness or surface-based analyses.AHI was not associated with any change in local brain volume, cortical thickness or cortex surface. Control subjects, apnoeic treated and untreated patients were not different in terms of local brain volume, cortical thickness or surface.In a specific population of asymptomatic elderly healthy subjects, sleep apnoea does not seem to be associated with a change in local brain volume or in cortical thickness.

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A PET study in healthy subjects of brain exposure of 11C-labelled osimertinib – A drug intended for treatment of brain metastases in non-small cell lung cancer

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x19843776 ◽

2019 ◽

Vol 40 (4) ◽

pp. 799-807 ◽

Cited By ~ 4

Author(s):

Andrea Varrone ◽

Katarina Varnäs ◽

Aurelija Jucaite ◽

Zsolt Cselényi ◽

Peter Johnström ◽

...

Keyword(s):

White Matter ◽

Brain Metastases ◽

Blood Brain Barrier ◽

Healthy Subjects ◽

Standardized Uptake Value ◽

Brain Barrier ◽

Pharmacokinetic Parameters ◽

Blood Brain ◽

Brain Exposure ◽

The Brain

Osimertinib is a tyrosine kinase inhibitor (TKI) of the mutated epidermal growth factor receptor (EGFRm) with observed efficacy in patients with brain metastases. Brain exposure and drug distribution in tumor regions are important criteria for evaluation and confirmation of CNS efficacy. The aim of this PET study was therefore to determine brain distribution and exposure of 11C-labelled osimertinib administered intravenously in subjects with an intact blood–brain barrier. Eight male healthy subjects (age 52 ± 8 years) underwent one PET measurement with 11C-osimertinib. The pharmacokinetic parameters Cmax (brain) (standardized uptake value), Tmax (brain) and AUC0–90 min brain/blood ratio were calculated. The outcome measure for 11C-osimertinib brain exposure was the total distribution volume ( VT). 11C-osimertinib distributed rapidly to the brain, with higher uptake in grey than in white matter. Mean Cmax, Tmax and AUC0–90 min brain/blood ratio were 1.5 (range 1–1.8), 13 min (range 5–30 min), and 3.8 (range 3.3–4.1). Whole brain and white matter VT were 14 mL×cm−3 (range 11–18) and 7 mL×cm−3 (range 5–12). This study in healthy volunteers shows that 11C-osimertinib penetrates the intact blood–brain barrier. The approach used further illustrates the role of molecular imaging in facilitating the development of novel drugs for the treatment of malignancies affecting the brain.

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The Role of MRI Biomarkers and Their Interactions with Cognitive Status and APOE ε4 in Nondemented Elderly Subjects

Neurodegenerative Diseases ◽

10.1159/000495754 ◽

2018 ◽

Vol 18 (5-6) ◽

pp. 270-280 ◽

Cited By ~ 2

Author(s):

Xue Liang ◽

Zhenyu Yin ◽

Renyuan Liu ◽

Hui Zhao ◽

Sichu Wu ◽

...

Keyword(s):

Cortical Thickness ◽

Brain Structure ◽

Cognitive Status ◽

Elderly Subjects ◽

Linear Regression Models ◽

Hippocampal Subfields ◽

Apoe Ε4 ◽

Group 3 ◽

The Brain

Purpose: (1) To investigate atrophy patterns of hippocampal subfield volume and Alzheimer’s disease (AD)-signature cortical thickness in mild cognitive impairment (MCI) patients; (2) to explore the association between the neuropsychological (NP) and the brain structure in the MCI and older normal cognition group; (3) to determine whether these associations were modified by the apolipoprotein E (APOE) ε4 gene and cognitive status. Methods: The FreeSurfer software was used for automated segmentation of hippocampal subfields and AD-signature cortical thickness for 22 MCI patients and 23 cognitive normal controls (NC). The volume, cortical thickness, and the neuropsychological scale were compared with two-sample t tests. Linear regression models were used to determine the association between the NP and the brain structure. Results: Compared with the NC group, MCI patients showed a decreased volume of the left presubiculum, subiculum and right CA2_3 and CA4_DG (p < 0.05, FDR corrected). The volume of these regions was positively correlated with NP scores. Of note, these associations depended on the cognitive status but not on the APOE ε4 status. The left subiculum and presubiculum volume were positively correlated with the Montreal Cognitive Assessment (MoCA) scores only in the MCI patients. Conclusion: Atrophy of the hippocampal subfields may be a powerful biomarker for MCI in the Chinese population.

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The Brain Exposure Efficiency (BEE) Score

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.9b00650 ◽

2019 ◽

Vol 11 (2) ◽

pp. 205-224 ◽

Cited By ~ 1

Author(s):

Mayuri Gupta ◽

Thomas Bogdanowicz ◽

Mark A. Reed ◽

Christopher J. Barden ◽

Donald F. Weaver

Keyword(s):

Brain Exposure ◽

The Brain ◽

Exposure Efficiency

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Long-Term Safety of PEGylated Coagulation Factor VIII in the Immune-Deficient Rowett Nude Rat

Journal of Toxicology ◽

10.1155/2017/8496246 ◽

2017 ◽

Vol 2017 ◽

pp. 1-13 ◽

Cited By ~ 8

Author(s):

Caroline E. Rasmussen ◽

Jette Nowak ◽

Julie M. Larsen ◽

Emma Moore ◽

David Bell ◽

...

Keyword(s):

Factor Viii ◽

Hemophilia A ◽

Coagulation Factor ◽

Limit Of Quantification ◽

Toxicity Studies ◽

Clinical Observations ◽

Brain Exposure ◽

Human Proteins ◽

The Brain

Turoctocog alfa pegol (N8-GP) is a glycoPEGylated human recombinant factor VIII for the treatment of hemophilia A. The safety profile of rFVIII, and polyethylene glycols (PEG) technology, is well-established. Conducting long-term toxicity studies in animals using human proteins can be complicated by anti-drug antibody (ADA) development. To evaluate long-term safety of N8-GP, 26- and 52-week toxicity studies were conducted in immune-deficient rats dosed intravenously every fourth day with 0, 50, 150, 500, or 1200 IU/kg N8-GP. Observations included clinical observations, body weight, ophthalmoscopy, hematology, chemistry, coagulation, urinalysis, toxicokinetics, antibody analysis, and macroscopic/microscopic organ examination. Immunohistochemical staining examined the distribution of PEG in the brain. No adverse test item-related findings were seen and PEG was not detected in the brain. Exposure was confirmed for ~75% of the animals dosed with 500 and 1200 IU/kg N8-GP; the high lower limit of quantification of the bioanalysis assay prevented confirmation of exposure in the lower doses. A small number of animals developed ADAs, and the proportion of animals surviving until scheduled termination was >80%. N8-GP was well tolerated, and the immune-deficient rat proved suitable for testing long-term toxicity of human proteins that are immunogenic in animals.

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Differences in EEG Harmonic Driving Responses to Photic Stimulation between Normal Aging and Alzheimer's Disease

Clinical Electroencephalography ◽

10.1177/155005940203300208 ◽

2002 ◽

Vol 33 (2) ◽

pp. 86-92 ◽

Cited By ~ 11

Author(s):

Mitsuru Kikuchi ◽

Yuji Wada ◽

Yoshifumi Koshino

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Functional Organization ◽

Brain Activation ◽

The Elderly ◽

Normal Aging ◽

Photic Stimulation ◽

Elderly Subjects ◽

Absolute Power ◽

The Brain

In order to investigate whether Alzheimer's disease (AD) is the end result of aging of the brain or the result of some other mechanism, we analyzed EEGs showing the absolute power of harmonic responses to photic stimulation (PS) in younger subjects, non-demented elderly subjects and AD patients. At rest, the AD patients generally showed less absolute power than the younger and elderly subjects, with significant differences found at 10Hz and 20Hz. Analysis of EEGs recorded during PS indicated that the elderly subjects generally demonstrated more absolute power than the younger subjects and AD patients. These findings suggest a failure of stimulation-related brain activation in AD patients, and provide further evidence that normal aging and AD employ different mechanisms for functional organization during PS.

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A Brain Network Constructed on an L1-Norm Regression Model Is More Sensitive in Detecting Small World Network Changes in Early AD

Neural Plasticity ◽

10.1155/2020/9436406 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Hao Liu ◽

Haimeng Hu ◽

Huiying Wang ◽

Jiahui Han ◽

Yunfei Li ◽

...

Keyword(s):

Regression Model ◽

Pearson Correlation ◽

Brain Networks ◽

Small World ◽

Brain Network ◽

Clustering Coefficient ◽

Elderly Subjects ◽

Small World Network ◽

L1 Norm ◽

The Brain

Most previous imaging studies have used traditional Pearson correlation analysis to construct brain networks. This approach fails to adequately and completely account for the interaction between adjacent brain regions. In this study, we used the L1-norm linear regression model to test the small-world attributes of the brain networks of three groups of patients, namely, those with mild cognitive impairment (MCI), Alzheimer’s disease (AD), and healthy controls (HCs); we attempted to identify the method that may detect minor differences in MCI and AD patients. Twenty-four AD patients, 33 MCI patients, and 27 HC elderly subjects were subjected to functional MRI (fMRI). We applied traditional Pearson correlation and the L1-norm to construct the brain networks and then tested the small-world attributes by calculating the following parameters: clustering coefficient (Cp), path length (Lp), global efficiency (Eg), and local efficiency (Eloc). As expected, L1 could detect slight changes, mainly in MCI patients expressing higher Cp and Eloc; however, no statistical differences were found between MCI patients and HCs in terms of Cp, Lp, Eg, and Eloc, using Pearson correlation. Compared with HCs, AD patients expressed a lower Cp, Eloc, and Lp and an increased Eg using both connectivity metrics. The statistical differences between the groups indicated the brain networks constructed by the L1-norm were more sensitive to detect slight small-world network changes in early stages of AD.

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Age-Related EEG Power Reductions Cannot Be Explained by Changes of the Conductivity Distribution in the Head Due to Brain Atrophy

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.632310 ◽

2021 ◽

Vol 13 ◽

Author(s):

Mingjian He ◽

Feng Liu ◽

Aapo Nummenmaa ◽

Matti Hämäläinen ◽

Bradford C. Dickerson ◽

...

Keyword(s):

Neural Activity ◽

Underlying Mechanism ◽

Elderly Subjects ◽

Aging Brain ◽

Signal Attenuation ◽

Electrical Currents ◽

Age Related ◽

Eeg Power ◽

Electroencephalogram Eeg ◽

The Brain

Electroencephalogram (EEG) power reductions in the aging brain have been described by numerous previous studies. However, the underlying mechanism for the observed brain signal power reduction remains unclear. One possible cause for reduced EEG signals in elderly subjects might be the increased distance from the primary neural electrical currents on the cortex to the scalp electrodes as the result of cortical atrophies. While brain shrinkage itself reflects age-related neurological changes, the effects of changes in the distribution of electrical conductivity are often not distinguished from altered neural activity when interpreting EEG power reductions. To address this ambiguity, we employed EEG forward models to investigate whether brain shrinkage is a major factor for the signal attenuation in the aging brain. We simulated brain shrinkage in spherical and realistic brain models and found that changes in the conductor geometry cannot fully account for the EEG power reductions even when the brain was shrunk to unrealistic sizes. Our results quantify the extent of power reductions from brain shrinkage and pave the way for more accurate inferences about deficient neural activity and circuit integrity based on EEG power reductions in the aging population.

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Disconnectome Associated with Progressive Ischemic Periventricular White Matter Lesions

10.1101/2019.12.24.888081 ◽

2019 ◽

Author(s):

Zhengjun Li ◽

Sudipto Dolui ◽

Mohamad Habes ◽

Danielle S. Bassett ◽

David Wolk ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

White Matter ◽

Diffusion Tensor ◽

Normal Aging ◽

Elderly Subjects ◽

Periventricular White Matter ◽

Structural Connectome ◽

Virtual Lesion ◽

The Brain

AbstractPeriventricular white matter (PVWM) hyperintensities on T2-weighted MRI are ubiquitous in older adults and associated with dementia. Efforts to determine how PVWM lesions impact structural connectivity to impinge on brain function remain challenging in part because white matter tractography algorithms for diffusion tensor imaging (DTI) may lose fidelity in the presence of lesions. We used a “virtual lesion” approach to characterize the “disconnectome” associated with periventricular white matter (PVWM) lesions. We simulated progressive ischemic PVWM lesions using sub-threshold cerebral blood flow (CBF) masks derived from a previously published group-averaged map acquired from N=436 middle aged subjects in which the lowest CBF values were seen in PVWM and morphologically recapitulated the spatial pattern of PVWM hyperintensities seen in typical aging. We mimicked the age-dependent evolution of PVWM lesion burden by varying the threshold applied to the CBF map. We found that the optic radiations, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, corpus callosum, temporopontine tract and fornix were affected in early simulated PVWM lesion burdens, and that the connectivity of subcortical, cerebellar, and visual regions were significantly disrupted with increasing simulated PVWM lesion burdens. We also validated the use of virtual lesions to simulate the disconnectome due to WM hyperintensities in a cognitively normal elderly cohort (N=46) by evaluating correlations between structural and functional connectomes. The virtual lesion approach provides new insights into the spatial-temporal changes of the brain structural connectome under progressive PVWM burdens during normal aging.Significance StatementWe determined the disconnectomes caused by periventricular white matter (PVWM) lesions using the “virtual lesion” approach. We validated the approach using lesions, DTI and resting-state fMRI data from elderly subjects. We simulated disconnectome of progressive PVWM lesions using cerebral blood flow (CBF) masks in PVWM region with normative DTI data, which provides specificity for an ischemic mechanism and begins to address the possibility that connectivity may be affected by reduced CBF prior to the development of overt lesions on T2-weighted FLAIR MRI. The current study presented new insights into the spatial-temporal evolutions of the brain structural connectome under progressive PVWM burdens under normal aging.

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