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Article: Exosome Biomarkers Revolutionize Preclinical Diagnosis of Neurodegenerative Diseases and Assessment of Treatment Responses in Clinical Trials.

Kapogiannis, Dimitrios

Advances in experimental medicine and biology

2020 Volume 1195, Page(s) 149

Abstract: Alzheimer's disease and other neurodegenerative diseases have long preclinical phases with active and progressively irreversible pathology. Therefore, biomarkers are essential for identifying patients early in the course of these diseases, when they may ... ...

Abstract	Alzheimer's disease and other neurodegenerative diseases have long preclinical phases with active and progressively irreversible pathology. Therefore, biomarkers are essential for identifying patients early in the course of these diseases, when they may benefit the most from disease-modifying interventions. A limitation of biomarkers measured in the soluble phase of blood is their tenuous link to brain pathology. A new approach to biomarker discovery that addresses this limitation is deriving extracellular vesicles (EVs) enriched for neuronal and astrocytic origin from peripheral blood. EVs are membranous particles (subdivided into smaller exosomes and larger microvesicles) that are shed by all cells and found in all biofluids. Neuronal and astrocytic EVs have been implicated in the pathogenesis of several neurodegenerative diseases. Given their origin, neuronal and astrocytic enriched EVs harvested from blood can be used to interrogate brain pathologic processes previously inaccessible in vivo. In a long series of case control studies based on these EV subpopulations, we have identified candidate protein biomarkers for Alzheimer's disease and other neurodegenerative diseases. In GeNeDis 2018, an update of these studies and results from a validation study of these biomarkers in preclinical Alzheimer's disease will be presented. In addition, we will present results from studies demonstrating EV biomarker responses to experimental interventions. EV-based biomarkers are a valuable new tool that will enable researchers to test hypotheses in proof of concept studies with carefully selected participants at the preclinical phase, spearheading therapeutic discovery in neurodegenerative disease.
MeSH term(s)	Alzheimer Disease/diagnosis ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Alzheimer Disease/therapy ; Biomarkers/analysis ; Clinical Trials as Topic/methods ; Exosomes/chemistry ; Humans ; Neurodegenerative Diseases/diagnosis ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology ; Neurodegenerative Diseases/therapy ; Treatment Outcome
Chemical Substances	Biomarkers
Language	English
Publishing date	2020-05-28
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-030-32633-3_19
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Article ; Online: Long-COVID: Phase 2 of the COVID-19 Pandemic.

Goetzl, Edward J / Kapogiannis, Dimitrios

The American journal of medicine

2022 Volume 135, Issue 11, Page(s) 1277–1279

MeSH term(s)	Humans ; COVID-19/complications ; COVID-19/epidemiology ; Pandemics ; Post-Acute COVID-19 Syndrome/epidemiology ; SARS-CoV-2
Language	English
Publishing date	2022-08-15
Publishing country	United States
Document type	Editorial ; Research Support, N.I.H., Intramural
ZDB-ID	80015-6
ISSN	1555-7162 ; 1873-2178 ; 0002-9343 ; 1548-2766
ISSN (online)	1555-7162 ; 1873-2178
ISSN	0002-9343 ; 1548-2766
DOI	10.1016/j.amjmed.2022.07.017
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Article ; Online: Seeing Is Perceiving (Believing).

Yao, Pamela J / Kapogiannis, Dimitrios

Neuromolecular medicine

2022 Volume 24, Issue 3, Page(s) 257–260

Abstract: Our perception of distinct structures in brain cells and understanding of their function has been revised and updated overtime. Past approaches combined with current powerful technologies provide a more complete picture of the brain's organization, from ... ...

Abstract	Our perception of distinct structures in brain cells and understanding of their function has been revised and updated overtime. Past approaches combined with current powerful technologies provide a more complete picture of the brain's organization, from how the neurons connect with each other to finer details of every corner inside the neurons.
MeSH term(s)	Brain/physiology ; Neurons/physiology
Language	English
Publishing date	2022-01-27
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Intramural
ZDB-ID	2077809-0
ISSN	1559-1174 ; 1535-1084
ISSN (online)	1559-1174
ISSN	1535-1084
DOI	10.1007/s12017-021-08701-y
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Article: Alzheimer's Disease-Related Genes Identified by Linking Spatial Patterns of Pathology and Gene Expression.

Mullins, Roger / Kapogiannis, Dimitrios

Frontiers in neuroscience

2022 Volume 16, Page(s) 908650

Abstract: Background: Alzheimer's Disease (AD) is an age-related neurodegenerative disease with a poorly understood etiology, shown to be partly genetic. Glucose hypometabolism, extracellular Amyloid-beta (Aβ) deposition, and intracellular Tau deposition are ... ...

Abstract	Background: Alzheimer's Disease (AD) is an age-related neurodegenerative disease with a poorly understood etiology, shown to be partly genetic. Glucose hypometabolism, extracellular Amyloid-beta (Aβ) deposition, and intracellular Tau deposition are cardinal features of AD and display characteristic spatial patterns in the brain. We hypothesize that regional differences in underlying gene expression confer either resistance or susceptibility to AD pathogenic processes and are associated with these spatial patterns. Data-driven methods for the identification of genes involved in AD pathogenesis complement hypothesis-driven approaches that reflect current theories about the disease. Here we present a data driven method for the identification of genes involved in AD pathogenesis based on comparing spatial patterns of normal gene expression to Positron Emission Tomography (PET) images of glucose hypometabolism, Aβ deposition, and Tau deposition. Methods: We performed correlations between the cerebral cortex microarray samples from the six cognitively normal (CN) post-mortem Allen Human Brain Atlas (AHBA) specimens and PET FDG-18, AV-45, and AV-1451 tracer images from AD and CN participants in the Alzheimer's Disease and Neuroimaging Initiative (ADNI) database. Correlation coefficients for each gene by each ADNI subject were then entered into a partial least squares discriminant analysis (PLS-DA) to determine sets that best classified the AD and CN groups. Pathway analysis Results: We identified distinct sets of genes strongly associated with each PET modality. Pathway analyses implicated novel genes involved in mitochondrial function, and Notch signaling, as well as genes previously associated with AD. Conclusion: Using an unbiased approach, we derived sets of genes with expression patterns spatially associated with FDG hypometabolism, Aβ deposition, and Tau deposition in AD. This methodology may complement population-based approaches for identifying the genetic underpinnings of AD.
Language	English
Publishing date	2022-06-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2022.908650
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Article ; Online: The guaranteed euros: Probabilistic discounting in behavioural-variant frontotemporal dementia.

Boutoleau-Bretonnière, Claire / Kapogiannis, Dimitrios / El Haj, Mohamad

Journal of neuropsychology

2023

Abstract: Financial decision-making requires trading off between guaranteed and probabilistic outcomes and between immediate and delayed ones. While research has demonstrated that patients with behavioural-variant frontotemporal dementia (bvFTD) prefer immediate ... ...

Abstract	Financial decision-making requires trading off between guaranteed and probabilistic outcomes and between immediate and delayed ones. While research has demonstrated that patients with behavioural-variant frontotemporal dementia (bvFTD) prefer immediate rewards at the expense of future ones (i.e. temporal discounting), little is known about how patients choose between smaller, guaranteed and larger, but probabilistic, outcomes (i.e. probabilistic discounting). We thus investigated probabilistic discounting by inviting 18 patients with bvFTD and 20 control participants to choose between fixed smaller monetary amounts and a fixed larger monetary amount with a variated probability of occurrence (e.g. 'Would you rather have 40€ for sure or a 20% chance of winning 100€?'). Results demonstrated lower scores, indicating higher risk tolerance, on the probabilistic discounting task in patients with bvFTD (while impulsively choosing more immediate rewards on the temporal discounting task) compared to control participants. Probabilistic discounting was significantly correlated with a decline in general cognitive performance in patients with bvFTD. When dealing between smaller, guaranteed, and larger, but probabilistic, rewards, patients with bvFTD tend to prefer guaranteed rewards and discount the uncertain ones.
Language	English
Publishing date	2023-12-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2380753-2
ISSN	1748-6653 ; 1748-6645
ISSN (online)	1748-6653
ISSN	1748-6645
DOI	10.1111/jnp.12357
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Article ; Online: "Who am I?": Weakened sense of the self in patients with behavioral variant frontotemporal dementia.

El Haj, Mohamad / Kapogiannis, Dimitrios / Boutoleau-Bretonnière, Claire

Medicine

2023 Volume 102, Issue 14, Page(s) e33461

Abstract: While research has shown a distrusted sense of the self in patients with behavioral variant frontotemporal dementia (bvFTD), little is known about how patients describe their self-image. We used the "Who am I?" task to invite patients with bvFTD and ... ...

Abstract	While research has shown a distrusted sense of the self in patients with behavioral variant frontotemporal dementia (bvFTD), little is known about how patients describe their self-image. We used the "Who am I?" task to invite patients with bvFTD and control participants to produce statements beginning with "I am…." We distinguished between statements related to physical, social, and psychological self. Analyses showed fewer statements related to physical, social, and psychological self in the patients with bvFTD than in control participants. Another result was the proportionally similar production of statements describing physical, social, and psychological self in both patients with bvFTD and control participants. Finally, the total production of "Who am I?" statements was positively correlated with verbal fluency in both patients with bvTFD and control participants. Our findings demonstrate a diminished ability of patients with bvFTD to process self-images. Our study also paves the way toward the use of the "Who am I" task as a simple and ecologically valid tool allowing for the quantitative and qualitative assessment of the sense of self in patients with bvFTD.
MeSH term(s)	Humans ; Frontotemporal Dementia/psychology ; Neuropsychological Tests ; Alzheimer Disease/psychology
Language	English
Publishing date	2023-04-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	80184-7
ISSN	1536-5964 ; 0025-7974
ISSN (online)	1536-5964
ISSN	0025-7974
DOI	10.1097/MD.0000000000033461
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Article ; Online: The neutral past: emotional (dys)regulation of autobiographical memory in behavioural variant frontotemporal dementia.

El Haj, Mohamad / Kapogiannis, Dimitrios / Boutoleau-Bretonnière, Claire

Cognitive neuropsychiatry

2023 Volume 28, Issue 6, Page(s) 437–449

Abstract: Background: While affective disturbances are a key symptomatic indicator of behavioural variant frontotemporal dementia (bvFTD), little is known about how patients process the emotional load of their autobiographical (i.e. personal) memories.: Methods! ...

Abstract	Background: While affective disturbances are a key symptomatic indicator of behavioural variant frontotemporal dementia (bvFTD), little is known about how patients process the emotional load of their autobiographical (i.e. personal) memories. Methods: We assessed the interplay of emotional regulation and autobiographical memory by inviting 18 bvFTD and 20 control participants to remember past personal events. For each memory, participants rated its emotional valence "then" (i.e. when the event has occurred) vs "now" (i.e. when retrieving the event). Results: Patients with bvFTD described their memories as neutral at both times ( Conclusions: The lack of significant differences between the emotional characteristics during "then" than "now" in patients with bvFTD (and the flattening of both) may mirror their hampered ability for emotional generation, which may be associated with difficulties in reframing their past experiences to modify and adapt their meaning. The hampered emotional regulation in bvFTD may also be associated with an avoidance strategy and a passive attitude toward the past.
MeSH term(s)	Humans ; Frontotemporal Dementia/psychology ; Memory, Episodic ; Emotions ; Mental Recall/physiology
Language	English
Publishing date	2023-11-30
Publishing country	England
Document type	Journal Article
ZDB-ID	1324282-9
ISSN	1464-0619 ; 1354-6805
ISSN (online)	1464-0619
ISSN	1354-6805
DOI	10.1080/13546805.2023.2275337
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Article ; Online: Prediction of Post-Acute-Sequelae of COVID-19 by Cargo Protein Biomarkers of Blood Total Extracellular Vesicles in Acute COVID-19.

Goetzl, Edward J / Yao, Pamela J / Kapogiannis, Dimitrios

The American journal of medicine

2023 Volume 136, Issue 8, Page(s) 824–829

Abstract: Background: SARS-CoV-2 invades mitochondria of infected cells resulting in disordered metabolism, mitophagy, and abnormal levels of mitochondrial proteins in extracellular vesicles. Blood extracellular vesicle SARS-CoV-2 proteins and mitochondrial ... ...

Abstract	Background: SARS-CoV-2 invades mitochondria of infected cells resulting in disordered metabolism, mitophagy, and abnormal levels of mitochondrial proteins in extracellular vesicles. Blood extracellular vesicle SARS-CoV-2 proteins and mitochondrial proteins were quantified in COVID-19 to assess possible roles as biomarkers. Methods: Total extracellular vesicles were precipitated from blood of age- and gender-matched participants with no infection (n=10), acute COVID-19 (n=16), post-acute sequelae of COVID-19 (PASC or long COVID) (n=30), or post-acute COVID without PASC (n=8) and their extracted proteins quantified by enzyme-linked immunosorbent assays (ELISAs). Results: Total extracellular vesicle levels of S1 (receptor-binding domain [RBD]) protein were significantly higher in acute infections than in uninfected controls, post-acute infection without PASC, and PASC. Total extracellular vesicle levels of nucleocapsid (N) protein were significantly higher in PASC than in uninfected controls, acute infections, and post-acute infection without PASC. Neither acute levels of S1(RBD) or N proteins predicted progression to PASC. Levels of neither SARS-CoV-2 protein in established PASC correlated with neuropsychiatric manifestations. Significant decreases in total extracellular vesicle levels of the mitochondrial proteins MOTS-c, VDAC-1, and humanin, and elevations of levels of SARM-1 were observed in acutely infected patients who would develop PASC. Significant decreases in total extracellular vesicle levels of MOTS-c and humanin, but not VDAC-1, and elevations of total extracellular vesicle levels of SARM-1 were characteristic of PASC patients with neuropsychiatric manifestations. Conclusions: Total extracellular vesicle levels of SARS-CoV-2 proteins in COVID-19 indicate intracellular presence of SARS-CoV-2. Abnormal total extracellular vesicles levels of mitochondrial proteins in acute infections predict a high risk of PASC and later in established PASC are indicative of neuropsychiatric manifestations.
MeSH term(s)	Humans ; COVID-19/complications ; SARS-CoV-2 ; Post-Acute COVID-19 Syndrome ; Mitochondrial Proteins ; Extracellular Vesicles ; Biomarkers ; Disease Progression
Chemical Substances	Mitochondrial Proteins ; Biomarkers
Language	English
Publishing date	2023-04-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	80015-6
ISSN	1555-7162 ; 1873-2178 ; 0002-9343 ; 1548-2766
ISSN (online)	1555-7162 ; 1873-2178
ISSN	0002-9343 ; 1548-2766
DOI	10.1016/j.amjmed.2023.03.026
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Article ; Online: Brain Iron Dysregulation in Iron Deficiency Anemia-Related Restless Leg Syndrome Revealed by Neuron-Derived Extracellular Vesicles: A Case-Control Study.

Manolopoulos, Apostolos / York, William / Pucha, Krishna Ananthu / Earley, Christopher J / Kapogiannis, Dimitrios

Annals of neurology

2024

Abstract: Brain iron deficiency (ID) and, to a degree, systemic ID have been implicated in restless leg syndrome (RLS) pathogenesis. Previously, we found increased ferritin in neuron-derived extracellular vesicles (NDEVs) in RLS, suggesting a mechanism for ... ...

Abstract	Brain iron deficiency (ID) and, to a degree, systemic ID have been implicated in restless leg syndrome (RLS) pathogenesis. Previously, we found increased ferritin in neuron-derived extracellular vesicles (NDEVs) in RLS, suggesting a mechanism for depleting intracellular iron by secreting ferritin-loaded NDEVs. In this study, we hypothesized that increased NDEV ferritin occurs even in RLS accompanied by systemic ID and that neuronal intracellular iron depletion in RLS also manifests as NDEV abnormalities in other iron regulatory proteins, specifically, decreased transferrin receptor (TfR) and increased ferroportin. To address these hypotheses, we studied 71 women with ID anemia, 36 with RLS, and 35 without RLS. Subjects with RLS again showed higher NDEV ferritin and also decreased TfR, suggesting diminished neuronal capacity for iron uptake. Findings inform a more complete understanding of the pathogenic role of neuronal iron homeostasis and dissociate it from peripheral ID. ANN NEUROL 2024.
Language	English
Publishing date	2024-04-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	80362-5
ISSN	1531-8249 ; 0364-5134
ISSN (online)	1531-8249
ISSN	0364-5134
DOI	10.1002/ana.26941
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Article ; Online: Lipidomic Analysis of Plasma Extracellular Vesicles Derived from Alzheimer's Disease Patients.

Krokidis, Marios G / Pucha, Krishna A / Mustapic, Maja / Exarchos, Themis P / Vlamos, Panagiotis / Kapogiannis, Dimitrios

Cells

2024 Volume 13, Issue 8

Abstract: Analysis of blood-based indicators of brain health could provide an understanding of early disease mechanisms and pinpoint possible intervention strategies. By examining lipid profiles in extracellular vesicles (EVs), secreted particles from all cells, ... ...

Abstract	Analysis of blood-based indicators of brain health could provide an understanding of early disease mechanisms and pinpoint possible intervention strategies. By examining lipid profiles in extracellular vesicles (EVs), secreted particles from all cells, including astrocytes and neurons, and circulating in clinical samples, important insights regarding the brain's composition can be gained. Herein, a targeted lipidomic analysis was carried out in EVs derived from plasma samples after removal of lipoproteins from individuals with Alzheimer's disease (AD) and healthy controls. Differences were observed for selected lipid species of glycerolipids (GLs), glycerophospholipids (GPLs), lysophospholipids (LPLs) and sphingolipids (SLs) across three distinct EV subpopulations (all-cell origin, derived by immunocapture of CD9, CD81 and CD63; neuronal origin, derived by immunocapture of L1CAM; and astrocytic origin, derived by immunocapture of GLAST). The findings provide new insights into the lipid composition of EVs isolated from plasma samples regarding specific lipid families (MG, DG, Cer, PA, PC, PE, PI, LPI, LPE, LPC), as well as differences between AD and control individuals. This study emphasizes the crucial role of plasma EV lipidomics analysis as a comprehensive approach for identifying biomarkers and biological targets in AD and related disorders, facilitating early diagnosis and potentially informing novel interventions.
MeSH term(s)	Humans ; Alzheimer Disease/blood ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Extracellular Vesicles/metabolism ; Lipidomics/methods ; Female ; Male ; Aged ; Lipids/blood ; Case-Control Studies ; Aged, 80 and over ; Biomarkers/blood ; Biomarkers/metabolism ; Astrocytes/metabolism ; Middle Aged
Chemical Substances	Lipids ; Biomarkers
Language	English
Publishing date	2024-04-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells13080702
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