Altered d-glucose in brain parenchyma and cerebrospinal fluid of early Alzheimer’s disease detected by dynamic glucose-enhanced MRI

Altered cerebral glucose uptake is one of the hallmarks of Alzheimer’s disease (AD). A dynamic glucose-enhanced (DGE) magnetic resonance imaging (MRI) approach was developed to simultaneously monitor d-glucose uptake and clearance in both brain parenchyma and cerebrospinal fluid (CSF). We observed substantially higher uptake in parenchyma of young (6 months) transgenic AD mice compared to age-matched wild-type (WT) mice. Notably lower uptakes were observed in parenchyma and CSF of old (16 months) AD mice. Both young and old AD mice had an obviously slower CSF clearance than age-matched WT mice. This resembles recent reports of the hampered CSF clearance that leads to protein accumulation in the brain. These findings suggest that DGE MRI can identify altered glucose uptake and clearance in young AD mice upon the emergence of amyloid plaques. DGE MRI of brain parenchyma and CSF has potential for early AD stratification, especially at 3T clinical field strength MRI.

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Microglial Function and Regulation during Development, Homeostasis and Alzheimer’s Disease

Cells ◽

10.3390/cells10040957 ◽

2021 ◽

Vol 10 (4) ◽

pp. 957

Author(s):

Brad T. Casali ◽

Erin G. Reed-Geaghan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune Cells ◽

Expression Patterns ◽

Brain Parenchyma ◽

Primary Role ◽

And Function ◽

Inflammatory Milieu ◽

The Brain ◽

Homeostatic State

Microglia are the resident immune cells of the brain, deriving from yolk sac progenitors that populate the brain parenchyma during development. During development and homeostasis, microglia play critical roles in synaptogenesis and synaptic plasticity, in addition to their primary role as immune sentinels. In aging and neurodegenerative diseases generally, and Alzheimer’s disease (AD) specifically, microglial function is altered in ways that significantly diverge from their homeostatic state, inducing a more detrimental inflammatory environment. In this review, we discuss the receptors, signaling, regulation and gene expression patterns of microglia that mediate their phenotype and function contributing to the inflammatory milieu of the AD brain, as well as strategies that target microglia to ameliorate the onset, progression and symptoms of AD.

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The association between biomarkers in cerebrospinal fluid and structural changes in the brain in patients with Alzheimer's disease

Journal of Internal Medicine ◽

10.1111/joim.12164 ◽

2013 ◽

Vol 275 (4) ◽

pp. 418-427 ◽

Cited By ~ 31

Author(s):

X. Li ◽

T.-Q. Li ◽

N. Andreasen ◽

M. K. Wiberg ◽

E. Westman ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Structural Changes ◽

The Brain

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Signaling Mechanisms of Selective PPARγ Modulators in Alzheimer’s Disease

PPAR Research ◽

10.1155/2018/2010675 ◽

2018 ◽

Vol 2018 ◽

pp. 1-20 ◽

Cited By ~ 18

Author(s):

Manoj Govindarajulu ◽

Priyanka D. Pinky ◽

Jenna Bloemer ◽

Nila Ghanei ◽

Vishnu Suppiramaniam ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Adverse Effects ◽

Therapeutic Potential ◽

Protein Accumulation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Continuous Increase ◽

Therapeutic Benefits ◽

The Brain

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidence of AD with the aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists such as rosiglitazone and pioglitazone reduce amyloid and tau pathologies, inhibit neuroinflammation, and improve memory impairments in several rodent models and in humans with mild-to-moderate AD. However, these agonists display poor blood brain barrier permeability resulting in inadequate bioavailability in the brain and thus requiring high dosing with chronic time frames. Furthermore, these dosing levels are associated with several adverse effects including increased incidence of weight gain, liver abnormalities, and heart failure. Therefore, there is a need for identifying novel compounds which target PPARγ more selectively in the brain and could provide therapeutic benefits without a high incidence of adverse effects. This review focuses on how PPARγ agonists influence various pathologies in AD with emphasis on development of novel selective PPARγ modulators.

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A Large-scale Comparison of Cortical and Subcortical Structural Segmentation Methods in Alzheimer’s Disease: a Statistical Approach

10.1101/2020.08.18.256321 ◽

2020 ◽

Author(s):

Jafar Zamani ◽

Ali Sadr ◽

Amir-Homayoun Javadi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Large Scale ◽

Automated Segmentation ◽

Resonance Imaging ◽

Brain Areas ◽

Segmentation Methods ◽

Magnetic Resonance Imaging Mri ◽

Underlying Mechanisms ◽

The Brain

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease that leads to anatomical atrophy, as evidenced by magnetic resonance imaging (MRI). Automated segmentation methods are developed to help with the segmentation of different brain areas. However, their reliability has yet to be fully investigated. To have a more comprehensive understanding of the distribution of changes in AD, as well as investigating the reliability of different segmentation methods, in this study we compared volumes of cortical and subcortical brain segments, using automated segmentation methods in more than 60 areas between AD and healthy controls (HC).MethodsA total of 44 MRI images (22 AD and 22 HC, 50% females) were taken from the minimal interval resonance imaging in Alzheimer’s disease (MIRIAD) dataset. HIPS, volBrain, CAT and BrainSuite segmentation methods were used for the subfields of hippocampus, and the rest of the brain.ResultsWhile HIPS, volBrain and CAT showed strong conformity with the past literature, BrainSuite misclassified several brain areas. Additionally, the volume of the brain areas that successfully discriminated between AD and HC showed a correlation with mini mental state examination (MMSE) scores. The two methods of volBrain and CAT showed a very strong correlation. These two methods, however, did not correlate with BrainSuite.ConclusionOur results showed that automated segmentation methods HIPS, volBrain and CAT can be used in the classification of AD and HC. This is an indication that such methods can be used to inform researchers and clinicians of underlying mechanisms and progression of AD.

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The Diagnosis of Alzheimer’s Disease: An Ensemble Approach

Fuzzy Systems and Data Mining VI - Frontiers in Artificial Intelligence and Applications ◽

10.3233/faia200689 ◽

2020 ◽

Author(s):

Jingyan Qiu ◽

Linjian Li ◽

Yida Liu ◽

Yingjun Ou ◽

Yubei Lin

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Deep Learning ◽

Large Scale ◽

Early Stage ◽

Training Transfer ◽

Detection And Diagnosis ◽

Magnetic Resonance Imaging Mri ◽

Deep Learning Model ◽

The Brain

Alzheimer’s disease (AD) is one of the most common forms of dementia. The early stage of the disease is defined as Mild Cognitive Impairment (MCI). Recent research results have shown the prospect of combining Magnetic Resonance Imaging (MRI) scanning of the brain and deep learning to diagnose AD. However, the CNN deep learning model requires a large scale of samples for training. Transfer learning is the key to enable a model with high accuracy by using limited data for training. In this paper, DenseNet and Inception V4, which were pre-trained on the ImageNet dataset to obtain initialization values of weights, are, respectively, used for the graphic classification task. The ensemble method is employed to enhance the effectiveness and efficiency of the classification models and the result of different models are eventually processed through probability-based fusion. Our experiments were completely conducted on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) public dataset. Only the ternary classification is made due to a higher demand for medical detection and diagnosis. The accuracies of AD/MCI/Normal Control (NC) of different models are estimated in this paper. The results of the experiments showed that the accuracies of the method achieved a maximum of 92.65%, which is a remarkable outcome compared with the accuracies of the state-of-the-art methods.

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O4-11-02: The path to regulatory qualification of cerebrospinal fluid biomarkers as enrichment tools in clinical trials of patients with early Alzheimer's disease: For the coalition against major diseases

Alzheimer s & Dementia ◽

10.1016/j.jalz.2015.07.406 ◽

2015 ◽

Vol 11 (7S_Part_6) ◽

pp. P296-P296

Author(s):

Hugo Marcel Vanderstichele ◽

Diane Stephenson ◽

Leslie M. Shaw ◽

Maria Carrillo ◽

Robert Umek ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Cerebrospinal Fluid ◽

Cerebrospinal Fluid Biomarkers ◽

Early Alzheimer’S Disease

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Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease

Nature Communications ◽

10.1038/s41467-020-15436-0 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 30

Author(s):

Shorena Janelidze ◽

Erik Stomrud ◽

Ruben Smith ◽

Sebastian Palmqvist ◽

Niklas Mattsson ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Amyloid Β ◽

Pet Tracer ◽

Positron Emission ◽

Diagnostic Work ◽

Work Up ◽

The Brain ◽

Better Than

AbstractCerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD), reflecting abnormal tau metabolism in the brain. Here we investigate the performance of CSF p-tau217 as a biomarker of AD in comparison to p-tau181. In the Swedish BioFINDER cohort (n = 194), p-tau217 shows stronger correlations with the tau positron emission tomography (PET) tracer [18F]flortaucipir, and more accurately identifies individuals with abnormally increased [18F]flortaucipir retention. Furthermore, longitudinal increases in p-tau217 are higher compared to p-tau181 and better correlate with [18F]flortaucipir uptake. P-tau217 correlates better than p-tau181 with CSF and PET measures of neocortical amyloid-β burden and more accurately distinguishes AD dementia from non-AD neurodegenerative disorders. Higher correlations between p-tau217 and [18F]flortaucipir are corroborated in an independent EXPEDITION3 trial cohort (n = 32). The main results are validated using a different p-tau217 immunoassay. These findings suggest that p-tau217 might be more useful than p-tau181 in the diagnostic work up of AD.

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Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease

Science Advances ◽

10.1126/sciadv.aaz9360 ◽

2020 ◽

Vol 6 (43) ◽

pp. eaaz9360 ◽

Cited By ~ 1

Author(s):

Lenora Higginbotham ◽

Lingyan Ping ◽

Eric B. Dammer ◽

Duc M. Duong ◽

Maotian Zhou ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Wide Spectrum ◽

Csf Biomarkers ◽

Protein Biomarkers ◽

Cerebrospinal Fluid Biomarkers ◽

Brain Proteome ◽

The Brain ◽

Underlying Pathophysiology

Alzheimer’s disease (AD) lacks protein biomarkers reflective of its diverse underlying pathophysiology, hindering diagnostic and therapeutic advancements. Here, we used integrative proteomics to identify cerebrospinal fluid (CSF) biomarkers representing a wide spectrum of AD pathophysiology. Multiplex mass spectrometry identified ~3500 and ~12,000 proteins in AD CSF and brain, respectively. Network analysis of the brain proteome resolved 44 biologically diverse modules, 15 of which overlapped with the CSF proteome. CSF AD markers in these overlapping modules were collapsed into five protein panels representing distinct pathophysiological processes. Synaptic and metabolic panels were decreased in AD brain but increased in CSF, while glial-enriched myelination and immunity panels were increased in brain and CSF. The consistency and disease specificity of panel changes were confirmed in >500 additional CSF samples. These panels also identified biological subpopulations within asymptomatic AD. Overall, these results are a promising step toward a network-based biomarker tool for AD clinical applications.

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Magnetic Nanoparticles as In Vivo Tracers for Alzheimer’s Disease

Magnetochemistry ◽

10.3390/magnetochemistry6010013 ◽

2020 ◽

Vol 6 (1) ◽

pp. 13

Author(s):

Bhargy Sharma ◽

Konstantin Pervushin

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Diagnosis ◽

Contrast Agents ◽

Neurological Diseases ◽

Pulse Sequences ◽

Experimental Conditions ◽

Magnetic Resonance Imaging Mri ◽

The Brain

Drug formulations and suitable methods for their detection play a very crucial role in the development of therapeutics towards degenerative neurological diseases. For diseases such as Alzheimer’s disease, magnetic resonance imaging (MRI) is a non-invasive clinical technique suitable for early diagnosis. In this review, we will discuss the different experimental conditions which can push MRI as the technique of choice and the gold standard for early diagnosis of Alzheimer’s disease. Here, we describe and compare various techniques for administration of nanoparticles targeted to the brain and suitable formulations of nanoparticles for use as magnetically active therapeutic probes in drug delivery targeting the brain. We explore different physiological pathways involved in the transport of such nanoparticles for successful entry in the brain. In our lab, we have used different formulations of iron oxide nanoparticles (IONPs) and protein nanocages as contrast agents in anatomical MRI of an Alzheimer’s disease (AD) brain. We compare these coatings and their benefits to provide the best contrast in addition to biocompatibility properties to be used as sustainable drug-release systems. In the later sections, the contrast enhancement techniques in MRI studies are discussed. Examples of contrast-enhanced imaging using advanced pulse sequences are discussed with the main focus on important studies in the field of neurological diseases. In addition, T1 contrast agents such as gadolinium chelates are compared with the T2 contrast agents mainly made of superparamagnetic inorganic metal nanoparticles.

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