News about the Role of Fluid and Imaging Biomarkers in Neurodegenerative Diseases

Biomarkers are molecules that are variable in their origin, nature, and mechanism of action; they are of great relevance in biology and also in medicine because of their specific connection with a single or several diseases. Biomarkers are of two types, which in some cases are operative with each other. Fluid biomarkers, started around 2000, are generated in fluid from specific proteins/peptides and miRNAs accumulated within two extracellular fluids, either the central spinal fluid or blood plasma. The switch of these proteins/peptides and miRNAs, from free to segregated within extracellular vesicles, has induced certain advantages including higher levels within fluids and lower operative expenses. Imaging biomarkers, started around 2004, are identified in vivo upon their binding by radiolabeled molecules subsequently revealed in the brain by positron emission tomography and/or other imaging techniques. A positive point for the latter approach is the quantitation of results, but expenses are much higher. At present, both types of biomarker are being extensively employed to study Alzheimer’s and other neurodegenerative diseases, investigated from the presymptomatic to mature stages. In conclusion, biomarkers have revolutionized scientific and medical research and practice. Diagnosis, which is often inadequate when based on medical criteria only, has been recently improved by the multiplicity and specificity of biomarkers. Analogous results have been obtained for prognosis. In contrast, improvement of therapy has been limited or fully absent, especially for Alzheimer’s in which progress has been inadequate. An urgent need at hand is therefore the progress of a new drug trial design together with patient management in clinical practice.

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Essential role of oligodendrocytes in the formation and maintenance of central nervous system nodal regions

Development ◽

10.1242/dev.128.23.4881 ◽

2001 ◽

Vol 128 (23) ◽

pp. 4881-4890 ◽

Cited By ~ 1

Author(s):

Carole Mathis ◽

Natalia Denisenko-Nehrbass ◽

Jean-Antoine Girault ◽

Emiliana Borrelli

Keyword(s):

Na Channels ◽

Myelinated Axons ◽

K Channels ◽

Protein Levels ◽

Ankyrin G ◽

Specific Proteins ◽

Jimpy Mice ◽

The Brain

The membrane of myelinated axons is divided into functionally distinct domains characterized by the enrichment of specific proteins. The mechanisms responsible for this organization have not been fully identified. To further address the role of oligodendrocytes in the functional segmentation of the axolemma in vivo, the distribution of nodal (Na+ channels, ankyrin G), paranodal (paranodin/contactin-associated-protein) and juxtaparanodal (Kv1.1 K+ channels) axonal markers, was studied in the brain of MBP-TK and jimpy mice. In MBP-TK transgenic mice, oligodendrocyte ablation was selectively induced by FIAU treatment before and during the onset of myelination. In jimpy mice, oligodendrocytes degenerate spontaneously within the first postnatal weeks after the onset of myelination. Interestingly, in MBP-TK mice treated for 1-20 days with FIAU, despite the ablation of more than 95% of oligodendrocytes, the protein levels of all tested nodal markers was unaltered. Nevertheless, these proteins failed to cluster in the nodal regions. By contrast, in jimpy mice, despite a diffused localization of paranodin, the formation of nodal clusters of Na+ channels and ankyrin G was observed. Furthermore, K+ channels clusters were transiently visible, but were in direct contact with nodal markers. These results demonstrate that the organization of functional domains in myelinated axons is oligodendrocyte dependent. They also show that the presence of these cells is a requirement for the maintenance of nodal and paranodal regions.

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Novel PET Biomarkers to Disentangle Molecular Pathways across Age-Related Neurodegenerative Diseases

Cells ◽

10.3390/cells9122581 ◽

2020 ◽

Vol 9 (12) ◽

pp. 2581

Author(s):

Heather Wilson ◽

Marios Politis ◽

Eugenii A. Rabiner ◽

Lefkos T. Middleton

Keyword(s):

Neurodegenerative Diseases ◽

Protein Misfolding ◽

Imaging Technique ◽

Emission Tomography ◽

Imaging Biomarkers ◽

Synaptic Dysfunction ◽

Molecular Pathways ◽

Age Related ◽

Positron Emission

There is a need to disentangle the etiological puzzle of age-related neurodegenerative diseases, whose clinical phenotypes arise from known, and as yet unknown, pathways that can act distinctly or in concert. Enhanced sub-phenotyping and the identification of in vivo biomarker-driven signature profiles could improve the stratification of patients into clinical trials and, potentially, help to drive the treatment landscape towards the precision medicine paradigm. The rapidly growing field of neuroimaging offers valuable tools to investigate disease pathophysiology and molecular pathways in humans, with the potential to capture the whole disease course starting from preclinical stages. Positron emission tomography (PET) combines the advantages of a versatile imaging technique with the ability to quantify, to nanomolar sensitivity, molecular targets in vivo. This review will discuss current research and available imaging biomarkers evaluating dysregulation of the main molecular pathways across age-related neurodegenerative diseases. The molecular pathways focused on in this review involve mitochondrial dysfunction and energy dysregulation; neuroinflammation; protein misfolding; aggregation and the concepts of pathobiology, synaptic dysfunction, neurotransmitter dysregulation and dysfunction of the glymphatic system. The use of PET imaging to dissect these molecular pathways and the potential to aid sub-phenotyping will be discussed, with a focus on novel PET biomarkers.

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PET and the multitracer concept in the study of neurodegenerative diseases

Dementia & Neuropsychologia ◽

10.1590/1980-57642015dn94000343 ◽

2015 ◽

Vol 9 (4) ◽

pp. 343-349 ◽

Cited By ~ 1

Author(s):

Henry Engler ◽

Andres Damian ◽

Cecilia Bentancourt

Keyword(s):

Positron Emission Tomography ◽

Molecular Imaging ◽

Neurodegenerative Diseases ◽

Brain Tissue ◽

Neurodegenerative Disorders ◽

Clinical Symptoms ◽

Emission Tomography ◽

Positron Emission ◽

The Brain

ABSTRACT The complexity of the pathological reactions of the brain to an aggression caused by an internal or external noxa represents a challenge for molecular imaging. Positron emission tomography (PET) can indicate in vivo,anatomopathological changes involved in the development of different clinical symptoms in patients with neurodegenerative disorders. PET and the multitracer concept can provide information from different systems in the brain tissue building an image of the whole disease. We present here the combination of 18F-flourodeoxyglucose (FDG) and N-[11C-methyl]-L-deuterodeprenyl (DED), FDG and N-[11C-methyl] 2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (PIB), PIB and L-[11C]-3'4-Dihydrophenylalanine (DOPA) and finally PIB and [15O]H2O.

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Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core

International Journal of Molecular Sciences ◽

10.3390/ijms21145030 ◽

2020 ◽

Vol 21 (14) ◽

pp. 5030

Author(s):

Elena Vacchi ◽

Alain Kaelin-Lang ◽

Giorgia Melli

Keyword(s):

Neurodegenerative Diseases ◽

Alpha Synuclein ◽

Anatomical Connectivity ◽

Peripheral Tissues ◽

Parkinson’S Diseases ◽

Relevant Role ◽

The Brain ◽

Dying Back

In neuronal cells, tau is a microtubule-associated protein placed in axons and alpha synuclein is enriched at presynaptic terminals. They display a propensity to form pathologic aggregates, which are considered the underlying cause of Alzheimer’s and Parkinson’s diseases. Their functional impairment induces loss of axonal transport, synaptic and mitochondrial disarray, leading to a “dying back” pattern of degeneration, which starts at the periphery of cells. In addition, pathologic spreading of alpha-synuclein from the peripheral nervous system to the brain through anatomical connectivity has been demonstrated for Parkinson’s disease. Thus, examination of the extent and types of tau and alpha-synuclein in peripheral tissues and their relation to brain neurodegenerative diseases is of relevance since it may provide insights into patterns of protein aggregation and neurodegeneration. Moreover, peripheral nervous tissues are easily accessible in-vivo and can play a relevant role in the early diagnosis of these conditions. Up-to-date investigations of tau species in peripheral tissues are scant and have mainly been restricted to rodents, whereas, more evidence is available on alpha synuclein in peripheral tissues. Here we aim to review the literature on the functional role of tau and alpha synuclein in physiological conditions and disease at the axonal level, their distribution in peripheral tissues, and discuss possible commonalities/diversities as well as their interaction in proteinopathies.

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Development of PET Radioligands Targeting COX-2 for Colorectal Cancer Staging, a Review of in vitro and Preclinical Imaging Studies

Frontiers in Medicine ◽

10.3389/fmed.2021.675209 ◽

2021 ◽

Vol 8 ◽

Author(s):

Caroline Dagallier ◽

François Avry ◽

Yann Touchefeu ◽

Frédéric Buron ◽

Sylvain Routier ◽

...

Keyword(s):

Colorectal Cancer ◽

Imaging Techniques ◽

Cancer Staging ◽

Markers Of Inflammation ◽

Positron Emission ◽

Public Health Challenge ◽

Cox 2

Colorectal cancer (CRC) is the second most common cause of cancer death, making early diagnosis a major public health challenge. The role of inflammation in tumorigenesis has been extensively explored, and among the identified markers of inflammation, cyclooxygenase-2 (COX-2) expression seems to be linked to lesions with a poor prognosis. Until now, COX-2 expression could only be accessed by invasive methods, mainly by biopsy. Imaging techniques such as functional Positron Emission Tomography (PET) could give access to in vivo COX-2 expression. This could make the staging of the disease more accurate and would be of particular interest in the exploration of the first metastatic stages. In this paper, we review recent progress in the development of COX-2 specific PET tracers by comparing the radioligands' characteristics and highlighting the obstacles that remain to be overcome in order to achieve the clinical development of such a radiotracer, and its evaluation in the management of CRC.

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Preclinical Imaging Biomarkers for Postischaemic Neurovascular Remodelling

Contrast Media & Molecular Imaging ◽

10.1155/2019/3128529 ◽

2019 ◽

Vol 2019 ◽

pp. 1-21

Author(s):

Richa Gandhi ◽

Charalampos Tsoumpas

Keyword(s):

In Vivo Imaging ◽

Imaging Techniques ◽

Small Animal ◽

Imaging Biomarkers ◽

Positron Emission ◽

Increasing Trend ◽

Restorative Therapy ◽

Small Animal Models ◽

Published Research

In the pursuit of understanding the pathological alterations that underlie ischaemic injuries, such as vascular remodelling and reorganisation, there is a need for recognising the capabilities and limitations of in vivo imaging techniques. Thus, this review presents contemporary published research of imaging modalities that have been implemented to study postischaemic neurovascular changes in small animals. A comparison of the technical aspects of the various imaging tools is included to set the framework for identifying the most appropriate methods to observe postischaemic neurovascular remodelling. A systematic search of the PubMed® and Elsevier’s Scopus databases identified studies that were conducted between 2008 and 2018 to explore postischaemic neurovascular remodelling in small animal models. Thirty-five relevant in vivo imaging studies are included, of which most made use of magnetic resonance imaging or positron emission tomography, whilst various optical modalities were also utilised. Notably, there is an increasing trend of using multimodal imaging to exploit the most beneficial properties of each imaging technique to elucidate different aspects of neurovascular remodelling. Nevertheless, there is still scope for further utilising noninvasive imaging tools such as contrast agents or radiotracers, which will have the ability to monitor neurovascular changes particularly during restorative therapy. This will facilitate more successful utility of the clinical imaging techniques in the interpretation of neurovascular reorganisation over time.

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On the Role of Vascularization in Pathoconnectomics

10.20944/preprints202104.0185.v1 ◽

2021 ◽

Author(s):

Jordi Manuello ◽

Alessandro Vercelli ◽

Tommaso Costa ◽

Franco Cauda

Keyword(s):

Metabolic Disorders ◽

Brain Research ◽

Vascular System ◽

Imaging Techniques ◽

Limited Attention ◽

Functional Profile ◽

In Vivo Detection ◽

The Brain

In recent years, pathoconnectomics emerged as an interesting framework for the investigation and better comprehension of disorders affecting the brain. Research in this field has used so far structural, functional, metabolic and genetic data, but limited attention was addressed to the possible role of vascularization. In the present work the following aspects making it a valuable candidate to pathoconnectomics investigation are discussed: i) The vascular system is by its nature a network, endowed with directionality information on the basis of circulation; ii) The current imaging techniques allow in vivo detection of the vascular system to a good level of detail; iii) The information extracted from this kind of data could interact in a meaningful way with the functional profile of the brain, being the BOLD effect in turn based on blood flow; iv) Further evidence could be found in support of the trophic failure hypothesis; v) Data about vascularization could allow to bring in the pathoconnectomics framework cardiovascular and metabolic disorders. We suggest, therefore, that the evaluation of vascular connectivity (which we propose to name “vesselomics”) could enhance the pathoconnectomics paradigm, and provide new elements towards the understanding of brain pathology.

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Imaging Biomarkers for Monitoring the Inflammatory Redox Landscape in the Brain

Antioxidants ◽

10.3390/antiox10040528 ◽

2021 ◽

Vol 10 (4) ◽

pp. 528

Author(s):

Eduardo Felipe Alves Fernandes ◽

Dennis Özcelik

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Inflammatory Diseases ◽

Redox Homeostasis ◽

Translocator Protein ◽

Imaging Biomarkers ◽

Positron Emission ◽

Diagnostic Applications ◽

The Brain

Inflammation is one key process in driving cellular redox homeostasis toward oxidative stress, which perpetuates inflammation. In the brain, this interplay results in a vicious cycle of cell death, the loss of neurons, and leakage of the blood–brain barrier. Hence, the neuroinflammatory response fuels the development of acute and chronic inflammatory diseases. Interrogation of the interplay between inflammation, oxidative stress, and cell death in neurological tissue in vivo is very challenging. The complexity of the underlying biological process and the fragility of the brain limit our understanding of the cause and the adequate diagnostics of neuroinflammatory diseases. In recent years, advancements in the development of molecular imaging agents addressed this limitation and enabled imaging of biomarkers of neuroinflammation in the brain. Notable redox biomarkers for imaging with positron emission tomography (PET) tracers are the 18 kDa translocator protein (TSPO) and monoamine oxygenase B (MAO–B). These findings and achievements offer the opportunity for novel diagnostic applications and therapeutic strategies. This review summarizes experimental as well as established pharmaceutical and biotechnological tools for imaging the inflammatory redox landscape in the brain, and provides a glimpse into future applications.

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In Vivo Imaging of Biodegradable Implants and Related Tissue Biomarkers

Polymers ◽

10.3390/polym13142348 ◽

2021 ◽

Vol 13 (14) ◽

pp. 2348

Author(s):

Leon Riehakainen ◽

Chiara Cavallini ◽

Paolo Armanetti ◽

Daniele Panetta ◽

Davide Caramella ◽

...

Keyword(s):

Imaging Modality ◽

Imaging Techniques ◽

Special Focus ◽

Tissue Remodelling ◽

Biodegradable Implant ◽

Advantages And Disadvantages ◽

Non Invasive ◽

Positron Emission ◽

Longitudinal Imaging

Non-invasive longitudinal imaging of osseointegration of bone implants is essential to ensure a comprehensive, physical and biochemical understanding of the processes related to a successful implant integration and its long-term clinical outcome. This study critically reviews the present imaging techniques that may play a role to assess the initial stability, bone quality and quantity, associated tissue remodelling dependent on implanted material, implantation site (surrounding tissues and placement depth), and biomarkers that may be targeted. An updated list of biodegradable implant materials that have been reported in the literature, from metal, polymer and ceramic categories, is provided with reference to the use of specific imaging modalities (computed tomography, positron emission tomography, ultrasound, photoacoustic and magnetic resonance imaging) suitable for longitudinal and non-invasive imaging in humans. The advantages and disadvantages of the single imaging modality are discussed with a special focus on preclinical imaging for biodegradable implant research. Indeed, the investigation of a new implant commonly requires histological examination, which is invasive and does not allow longitudinal studies, thus requiring a large number of animals for preclinical testing. For this reason, an update of the multimodal and multi-parametric imaging capabilities will be here presented with a specific focus on modern biomaterial research.

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The role of CYP2D in rat brain in methamphetamine-induced striatal dopamine and serotonin release and behavioral sensitization

Psychopharmacology ◽

10.1007/s00213-021-05808-9 ◽

2021 ◽

Author(s):

Marlaina R. Stocco ◽

Ahmed A. El-Sherbeni ◽

Bin Zhao ◽

Maria Novalen ◽

Rachel F. Tyndale

Keyword(s):

Neurotransmitter Release ◽

Behavioral Sensitization ◽

Serotonin Release ◽

Striatal Dopamine ◽

Irreversible Inhibitor ◽

Drug Concentrations ◽

Metabolite Concentrations ◽

The Brain

Abstract Rationale Cytochrome P450 2D (CYP2D) enzymes metabolize many addictive drugs, including methamphetamine. Variable CYP2D metabolism in the brain may alter CNS drug/metabolite concentrations, consequently affecting addiction liability and neuropsychiatric outcomes; components of these can be modeled by behavioral sensitization in rats. Methods To investigate the role of CYP2D in the brain in methamphetamine-induced behavioral sensitization, rats were pretreated centrally with a CYP2D irreversible inhibitor (or vehicle) 20 h prior to each of 7 daily methamphetamine (0.5 mg/kg subcutaneous) injections. In vivo brain microdialysis was used to assess brain drug and metabolite concentrations, and neurotransmitter release. Results CYP2D inhibitor (versus vehicle) pretreatment enhanced methamphetamine-induced stereotypy response sensitization. CYP2D inhibitor pretreatment increased brain methamphetamine concentrations and decreased the brain p-hydroxylation metabolic ratio. With microdialysis conducted on days 1 and 7, CYP2D inhibitor pretreatment exacerbated stereotypy sensitization and enhanced dopamine and serotonin release in the dorsal striatum. Day 1 brain methamphetamine and amphetamine concentrations correlated with dopamine and serotonin release, which in turn correlated with the stereotypy response slope across sessions (i.e., day 1 through day 7), used as a measure of sensitization. Conclusions CYP2D-mediated methamphetamine metabolism in the brain is sufficient to alter behavioral sensitization, brain drug concentrations, and striatal dopamine and serotonin release. Moreover, day 1 methamphetamine-induced neurotransmitter release may be an important predictor of subsequent behavioral sensitization. This suggests the novel contribution of CYP2D in the brain to methamphetamine-induced behavioral sensitization and suggests that the wide variation in human brain CYP2D6 may contribute to differential methamphetamine responses and chronic effects.

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