TSOI News - 01/23/2023

jluedke60
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TSOI News - 01/23/2023

Post by jluedke60 »

Therapeutic Solutions International Spin-Off Campbell Neurosciences Provides Progress Update in Quest for Addressing Suicide as a Medical Condition

https://www.businesswire.com/news/home/ ... 005417/en/

ELK CITY, Idaho--(BUSINESS WIRE)--Therapeutic Solutions International (TSOI) announced today an update on progress made by its subsidiary Campbell Neurosciences, Inc.

Campbell was founded on the principle that suicide in numerous situations is a result of biological factors that can be diagnosed and addressed using medical approaches. In contrast to other fields of medicine, to date, suicidal tendencies are only identified by subjective approaches without any biological basis. Campbell aims to reverse this.

Campbell Score: Identification and Validation of Objective Biomarker for Suicidal Ideation

The Company’s initial goal, to identify molecules associated with propensity towards suicide, was accomplished through the successful completion of phase 1/2 clinical trials demonstrating correlation between its patent-pending biomarker and suicide attempts1.

The diagnostic test, termed the “Campbell Score” utilizes proprietary technology to accurately quantify an immunological cytokine which historically has been shown to be associated with brain inflammation. However, it has not been practically utilized as a marker of suicidality until now. Having proven the viability of this marker, the Company is currently focusing on accelerating development of a saliva-based method of assessment, which will provide in-office, real-time results. Rationale for testing of inflammatory markers as a means of quantifying suicidal tendencies was described in a paper published by the Company2.

Publication and Issuance of Patents on Intervening in Suicide-Prone/Addiction/Depression

In order to provide therapeutic approaches for preventing suicide, based on reducing brain inflammation and stimulating neural regeneration, the Company has licensed and developed numerous therapeutic products. Intellectual property to both the diagnostic test and interventions has been exclusively licensed from Therapeutic Solutions International. Some of the exciting patents that have been published/issued are listed below:

1. Immunotherapy for Opioid Addiction3. This 700-claim published patent application provides means of using oxytocin and various biologics as novel treatments for opioid addiction through stimulation of neural regeneration combined with anti-inflammatory effects. Campbell is planning to partner/license with various organizations to accelerate development and/or augment existing therapeutic approaches.

2. Treatment of Major Depressive Disorder and Suicidal Ideations Through Stimulation of Hippocampal Neurogenesis Utilizing Plant-Based Approaches4. Various compositions of matter are disclosed which reduce depressive symptoms using non-SSRI approaches. Some of the disclosed treatment compositions include combinations of minocycline with human chorionic gonadotrophin, as well as mixtures of various inhibitors of the inflammatory pathway NF-kappa B. The compositions disclosed can be utilized as monotherapies or can be incorporated into existing conventional psychotherapy protocols. The patent application also provides means of quantifying efficacy of the intervention before clinical effects are observed.

3. Personalized Immunotherapies for Reduction of Brain Inflammation and Suicide Prevention5. Protocols are disclosed for generation of unique patient-specific therapeutics to reduce some of the pathological pathways associated with propensity towards self-harm. This patent is based in part on some of the findings discovered in the Campbell Score trial.

4. Upregulation of Therapeutic T Regulatory Cells and Suppression of Suicidal Ideations in Response to Inflammation by Administration of Nutraceutical Compositions Alone or Combined with Minocycline6. Means of increasing levels of immune cells which possess ability to reduce brain inflammation and indirectly stimulate regeneration of damaged brain tissue are disclosed.

5. Neuroprotection and Neurodegeneration by Pterostilbene and Compositions Thereof7. The ability to utilize various natural compounds alone or in combination for stimulation of brain inflammation suppressing mechanisms are disclosed in this issued patent.

6. Treatment of Major Depressive Disorder by Low Dose Interleukin-28. Interleukin-2 is an FDA approved immune modulating drug that has conventionally been used in treatment of cancer. Disclosed are means of using lower concentrations of this drug to induce specific immune alterations that possess therapeutic activities in major depressive disorder and other mental conditions.

7. Therapeutic Monocytes for Prevention of Suicidal Ideation9. Monocytes are manipulated in vitro and/or in vivo to endow specific phenotypes that induce immunological processes typically associated with remission from mental disease and/or suicidal ideations.

Expansion of Internationally Renowned Advisory Board

The Company has assembled an advisory board comprising of Dr. Peter Farrell10, Benjamin Floyd, Howard Leonhard, Dr. Pablo Guzman, J Christopher Mizer, Darren Maggot and Justin Parsons. The latest addition was Dr. Bradley Messmer (CEO of NASDAQ public company Aegirbio (AEGIR) who has successfully developed several diagnostic devices.

Closing First PPM and Increased Valuation

The Company closed its private placement memorandum at 25 cents a share in August 2022 which funded the mentioned progress. The Company has launched a new PPM at $1.00 a share in January of this year.

The protein marker that we identified has subsequently been accepted by the scientific community as playing a role in the neuroinflammatory processes associated with tendency for self-harm and other mental health issues. Based on advice from our advisory board, the Company made the decision to focus on leveraging existing data into development of a saliva-based test identifying the same protein marker. This decision was made in part because the majority of end users (psychiatrists) do not have readily available access to blood draw. Additionally, making it simpler and less traumatic is believed to increase greater compliance.

About Therapeutic Solutions International, Inc.

Therapeutic Solutions International is focused on immune modulation for the treatment of several specific diseases. The Company's corporate website is www.therapeuticsolutionsint.com.

1 Therapeutic Solutions International Spin-Off Campbell Neurosciences Announces Positive Clinical Trial Results for Campbell Score Blood Based Suicide Prediction | BioSpace
2 Suicide: An Immunological Disorder? by Kalina O'Connor :: SSRN
3 US Patent Application for IMMUNOTHERAPY FOR OPIOID ADDICTION Patent Application (Application #20220193127 issued June 23, 2022) - Justia Patents Search
4 US20220175701 TREATMENT OF MAJOR DEPRESSIVE DISORDER AND SUICIDAL IDEATIONS THROUGH STIMULATION OF HIPPOCAMPAL NEUROGENESIS UTILIZING PLANT-BASED APPROACHES (wipo.int)
5 US Patent Application for Personalized Immunotherapies for Reduction of Brain Inflammation and Suicide Prevention Patent Application (Application #20220088086 issued March 24, 2022) - Justia Patents Search
6 US Patent Application for Upregulation of Therapeutic T Regulatory Cells and Suppression of Suicidal Ideations in Response to Inflammation by Administration of Nutraceutical Compositions Alone or Combined with Minocycline Patent Application (Application #20220062367)
7 11504410 (uspto.gov)
8 US Patent Application for TREATMENT OF MAJOR DEPRESSIVE DISORDER BY LOW DOSE INTERLEUKIN-2 Patent Application (Application #20220362341 issued November 17, 2022) - Justia Patents Search
9 20220280574 (uspto.gov)
10 Therapeutic Solutions International Announces Titan of Industry Dr. Peter Farrell Joins Advisory Board of its Suicide Prevention Spin-Off Campbell Neurosciences (prnewswire.com)
RR19
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Re: TSOI News - 01/23/2023

Post by RR19 »

Great progress with CNSI.

What does 25c ppm and now a 1$ ppm mean interms of valuation for CNSI?


Thanks for all the life saving work.
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trader32176
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Re: TSOI News - 01/23/2023

Post by trader32176 »

some great excerpts from the latest PR:
-imo
the Company is currently focusing on accelerating development of a saliva-based method of assessment, which will provide in-office, real-time results.
In order to provide therapeutic approaches for preventing suicide, based on reducing brain inflammation and stimulating neural regeneration, the Company has licensed and developed numerous therapeutic products.
The Company closed its private placement memorandum at 25 cents a share in August 2022 which funded the mentioned progress. The Company has launched a new PPM at $1.00 a share in January of this year.
The protein marker that we identified has subsequently been accepted by the scientific community as playing a role in the neuroinflammatory processes associated with tendency for self-harm and other mental health issues. Based on advice from our advisory board, the Company made the decision to focus on leveraging existing data into development of a saliva-based test identifying the same protein marker. This decision was made in part because the majority of end users (psychiatrists) do not have readily available access to blood draw. Additionally, making it simpler and less traumatic is believed to increase greater compliance.

https://www.businesswire.com/news/home/ ... 005417/en/
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trader32176
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Re: TSOI News - 01/23/2023

Post by trader32176 »

many methods must have been looked @
before the decision to go for the saliva test.

thx CNSI for keeping us current on the method for determining the Campbell Score.
:D
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trader32176
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Re: TSOI News - 01/23/2023

Post by trader32176 »

CNSI Board Members

yes, they added Board members .that's what happens w/ a sub that's private :lol:

Try to keep up, it's very hard for me to do that in all of my year.

The Company has assembled an advisory board comprising of Dr. Peter Farrell, Benjamin Floyd, Howard Leonhard, Dr. Pablo Guzman, J Christopher Mizer, Darren Maggot and Justin Parsons. The latest addition was Dr. Bradley Messmer (CEO of NASDAQ public company Aegirbio (AEGIR) who has successfully developed several diagnostic devices.
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trader32176
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Re: TSOI News - 01/23/2023

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Bradley Messmer

CEO, CSO and Member of the Board

Dr. Bradley Messmer is the founder and CEO of Abreos Bioscience, a wholly owned subsidiary of AegirBio and a biotechnology expert.

Dr. Messmer invented the Veritope platform while a faculty researcher at UC San Diego and has developed the technology since 2013. Prior, his academic worked focused on technology development for diagnostic and therapeutic approaches to cancer and autoimmunity.
In addition to the above roles, Bradley Messmer has no other ongoing assignments. Bradley Messmer has previously held the position of Chairman of the Board of Abreos Sweden AB.

He holds a PhD in molecular biology from Rockefeller University.

https://www.aegirbio.com/team/bradley-messmer/
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trader32176
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Re: TSOI News - 01/23/2023

Post by trader32176 »

Saliva based tests examples below ;

Validation of a Saliva-Based Test for the Molecular Diagnosis of SARS-CoV-2 Infection

https://pubmed.ncbi.nlm.nih.gov/35035611/
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trader32176
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Re: TSOI News - 01/23/2023

Post by trader32176 »

Are saliva tests Molecular?
Molecular tests

A positive PCR, NAAT, or other molecular amplification test result means a person currently has COVID-19. They are given with a nasal swab or by taking a saliva sample.

https://www.health.state.mn.us/diseases ... types.html
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trader32176
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Re: TSOI News - 01/23/2023

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Detecting viruses by using salivary diagnostics

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262792/
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Re: TSOI News - 01/23/2023

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Salivary Biomarkers as Indicators of TBI Diagnosis and Prognosis: A Systematic Review

https://pubmed.ncbi.nlm.nih.gov/35048328/


Abstract

Background and objective: Traumatic brain injuries are physical injuries to the head that result in disruptions to normal brain function. Diagnostic tools such as computed tomography scans have commonly been used to detect traumatic brain injuries but are costly and not ubiquitously available. Recent research on diagnostic alternatives has focused on using salivary biomarkers, but there is no consensus on the utility of these methods. The objective of this manuscript is to address the gap in the literature pertaining to the effectiveness of salivary biomarkers for TBI diagnosis and prognosis.

Methods: A systematic review was conducted between November 2020 and October 2021 using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Six databases were searched using the terms "traumatic brain injury," "TBI," "saliva," and "biomarkers." Literature published prior to 2010 was excluded, and two authors reviewed each full-text article to ensure its relevance.

Results: A total of 18 articles were included in this review, with nine articles on salivary microRNA, three on salivary hormones, three on salivary extracellular vesicles, and three on salivary proteins.

Conclusions: Studies reported changes in salivary biomarkers after traumatic brain injuries and indicated a possible link between salivary biomarker expression and traumatic brain injury severity. However, it is unclear the degree to which salivary biomarkers accurately predict traumatic brain injury diagnosis and prognosis; some studies reported significant associations while others reported weaker associations. More research into the robustness of salivary biomarkers is needed to fully elucidate their utility for the traumatic brain injury population.

Peripheral Biomarkers: Basic Concepts and Focus on Traumatic Brain Injury

Elevated BBB permeability, or dysfunction, occurs in response to an acute injury (e.g., head trauma, stroke, and status epilepticus) and may be present throughout CNS disease progression (e.g., neurodegeneration, epileptogenesis, and multiple sclerosis), often due to inflammation (5–7, 13). Peripheral biological fluids represent suitable matrices to detect and quantify brain-derived proteins reporting BBB permeability and susceptibility to glio-neuronal damage (27–29, 53). Table 1 provides a list of protein biomarkers and their characteristics, properties, and proposed use in diagnostics. In general, peripheral biomarker proteins must (i) be present in brain interstitial fluids or be released by neurovascular cells into the interstitial or perivascular spaces, reaching the peripheral blood across a leaky BBB or by cerebrospinal fluid (CSF)–blood exchange (Figures 2A, 3A,B); (ii) have a concentration gradient driving passive diffusion [Figure 2C; see (29)]; (iii) have a known and appropriate half-life to allow diagnostic interpretation (29) (biomarker half-life in peripheral fluids may impact usefulness in acute vs. long-term settings; see Table 1); and (iv) have a low molecular weight to allow a rapid egress across the damaged barriers or interfaces (19, 25, 27).

The bulk of neurological clinical biomarker literature has often focused on traumatic brain injury (TBI), with a recent emphasis on mild TBI (mTBI) (18, 54). Within this framework, the astrocytic protein S100B (55) has been examined as a peripheral biomarker of BBB permeability and gliosis (Table 1 and Figures 3A,B). Early proof-of-principle studies showed serum S100B levels to rapidly increase in response to a sudden BBB permeability, supporting the hypothesis that perivascular S100B can readily exit the brain (27, 28, 56). S100B was reported to rule out mTBI sequelae in emergency room settings (57), and measurement of blood S100B levels displayed a 99.7% negative predictive value (NPV) (57–60). Further evidence indicated that monitoring S100B after a mTBI could override the need for a CT scan for the identification of intracranial injury, with an excellent NPV (61). However, another study reported no relationship between serum S100B concentration and mTBI severity (62). In sports, S100B blood levels increased immediately after football games as compared to pregame baselines in players experiencing repeated head hits (25, 63). The evidence of a rapid S100B surge in blood after sub concussive hits was confirmed in follow-up studies (63–65). Importantly, extra-CNS sources of S100B were reported, representing a potential confounding factor if timing of blood draws in relation to injury is not adequately controlled and standardized (18, 66). These concerns have been discussed in (23, 67, 68).

The astrocytic glial fibrillary actin protein (GFAP) and the neuronal ubiquitin carboxyl-terminal hydrolase isoenzyme L1 (UCH-L1) are important biomarker candidates for glioneuronal damage (Table 1 and Figures 3A,B). UCH-L1 is also expressed at the neuromuscular junction (69, 70) while the contribution of extracranial sources of GFAP is debated (20, 71, 72). Monitoring of blood GFAP and UCH-L1 levels was used to grade brain injury after TBI. GFAP and UCH-L1 levels were increased in non-concussive and concussive head trauma as compared to body trauma (73, 74). The analysis of blood GFAP (or S100B) levels within 24 h from the head injury was proposed as a means to improve the detection of TBI and to identify patients in need of a subsequent MRI, in addition to routine CT surveillance (75, 76). GFAP and UCH-L1 blood levels were used to rule out intracranial injuries and the need for CT scans, showing high test sensitivity and NPV (21). One study reported no significant difference in blood UCH-L1 between control and players who sustained repetitive head hits (77). Collectively, this evidence points to GFAP as a diagnostic candidate to be used in TBI (33, 54, 71, 72). In two studies (78, 79), however, GFAP and UCH-L1 levels were below the lower limits of quantification or detection (LLOQ or LLOD, respectively) in a percentage of both TBI and trauma control groups, representing a possible concern for estimating NPV (20, 80).

Important biomarkers detecting neuronal damage are myelin basic protein (MBP), neuron-specific enolase (NSE), tau, and neurofilament light chain [NfL; Table 1 and Figures 3A,B; see (43)]. Blood MBP levels were unchanged in a pediatric mTBI population as compared to controls. Interestingly, MBP levels remained elevated for up to 2 weeks in case of intracranial hemorrhage (81). NfLs are found in axons and have been proposed as biomarkers of axonal damage triggered by mTBI, for example, after an amateur boxing bout (82–84). S100B levels were also increased following amateur boxing (85). Further evidence indicated neurofilament heavy chain increase after mTBI (82). Finally, NSE levels in CSF were shown to be proportional to TBI severity, in the setting of moderate or severe TBI (86–88). NSE in the blood is less investigated due to its presence in erythrocytes (89, 90). Collectively, these data support the further development of blood biomarker toolkits of TBI, with a special relevance to mild head injury and sport-related (sub)concussions, when emergency and sideline diagnostic solutions need to be readily accessible.

Phosphorylated TAU as an Emerging Blood Biomarker of Alzheimer's and Neurodegenerative Diseases

Accumulating evidence points to blood phosphorylated tau as a promising biomarker to improve the diagnosis and staging of and to enable trials in Alzheimer's disease (AD) subjects. In a cross-sectional study performed in AD patients, phosphorylated tau isoforms were used as diagnostic biomarkers to track disease progression (91). A method measuring attomolar concentrations of tau isoforms in plasma was implemented using stable isotope labeling kinetics and mass spectroscopy. Changes in plasma p-tau, particularly p-tau217, mirrored specific changes in CSF to detect phosphorylation of soluble tau and amyloidosis. No correlation was found between CSF and plasma p-tau202 levels. Plasma p-tau217 level distinguished amyloid-negative from amyloid-positive groups regardless of the cognitive status, indicating that p-tau217 in plasma may be an accurate biomarker of abnormal brain tau metabolism. Furthermore, a longitudinal study of familial AD (presenting pathogenic mutations in PSEN1 or APP genes) included 19 symptomatic and 51 asymptomatic participants where plasma p-tau181 levels were quantified by using a single-molecule array (Simoa) method (92). Elevated plasma p-tau181 concentrations segregated symptomatic mutation carriers from non-carriers. In another cross-sectional study including the Arizona-based neuropathology cohort (37 AD and 47 without AD), the Swedish BioFINDER 2 cohort [121 AD, 178 mild cognitive impairment [MCI], 301 without AD, and 99 other neurological disorders], and a Columbian autosomal-dominant AD kindred (365 PSEN1 E280A mutation carriers and 257 mutation non-carriers), plasma tau phosphorylated at the threonine 217 (p-tau217) was quantified by the Meso Scale Discovery (MSD) assay as a diagnostic AD biomarker (93). Among 1,402 participants from the three cohorts, plasma p-tau217 discriminated AD from other neurological disorders with higher accuracy compared with plasma p-tau181, plasma Nfl, CSF p-tau181, and CSF Aβ42:Aβ40 ratio. A positive correlation between CSF and plasma p-tau217 was found in the Swedish BioFINDER 2 cohort. Finally, a high-sensitivity immunoassay measuring p-tau181 in plasma and serum was developed (94). A positive correlation was reported between plasma and CSF p-tau181 levels, distinguishing Aβ-negative cognitively unimpaired older adults from Aβ-positive older adults and Aβ-positive individuals with MCI.

Furthermore, at the BBB, the low-density receptor-related protein 1 (LRP1) plays an important role in regulating cerebrovascular permeability (95). sLRP1, a truncated soluble form of LRP1, freely circulates in plasma, and it sequesters unbound Aβ in the peripheral circulation (96). Plasma sLRP1 levels are significantly reduced in AD patients, and sLRP1 binding to Aβ is disrupted by oxidation (96, 97). Impaired sLRP1-mediated binding of plasma Aβ was suggested as an early biomarker for MCI preceding AD-type dementia (97). In summary, this evidence supports the further development of tau-based blood biomarkers as an accessible test for the screening and diagnosis of AD within the spectrum of cognitive impairments and dementia.

Peripheral Biomarkers of BBB Permeability and Seizure Conditions

The use of blood biomarkers extends to epilepsies, a cluster of diseases where BBB damage represents an etiological or a contributing pathophysiological player (98–100). A first study (67) demonstrated that blood S100B is elevated at seizure onset and after seizures, in support of the hypothesis that BBB damage may trigger a seizure (7, 101–103). A systematic review analyzed 18 studies and a total of 1,057 subjects, indicating that epileptic patients displayed elevated S100B blood levels as compared to controls (104). Meta-regression analyses showed that gender and mean age can impact serum S100B levels (104). Another study correlated MRI T1 peri-ictal imaging to blood S100B in drug-resistant epileptic patients, confirming the increase in BBB permeability during a seizure (105). Increased S100B blood levels were reported in pediatric temporal lobe epilepsy, with blood samples obtained 30 min after a complex partial seizure (106).

Children suffering from intractable focal epilepsy displayed elevated blood S100B levels as compared to controls (107). One study included 39 patients suffering from simple febrile seizures and age- and sex-matched controls, showing no S100B differences between groups when assessed immediately after seizures (108). These findings were corroborated in a follow-up study, (109) with the conclusion that febrile seizures are relatively harmless to the developing brain. Currently, a clinical trial is investigating whether S100B, as well as other protein biomarkers, increase in blood after a first generalized seizure could be used to predict first-to-chronic seizure conversion in adult subjects (https://clinicaltrials.gov/ct2/show/NCT02424123). Moreover, NSE elevations were reported in blood over time in patients affected by temporal lobe and extratemporal lobe epilepsies (110). Finally, recent evidence indicates miRNA in blood, or body fluids, as potential biomarkers indicating neurovascular and neuroinflammatory modifications occurring in specific forms of epilepsies [see (111–113) for comprehensive topic reviews]. In summary, blood biomarkers could represent a surrogate method of clinical electroencephalographic explorations to examine damage and brain neurophysiology in epileptic patients.

Imaging BBB Permeability and Brain Damage: Is the Integration With Blood Biomarkers Possible?

Available evidence supports the prospective use of blood biomarkers to detect NVU damage in acute and chronic neurological conditions. In this context, can peripheral biomarkers replace brain imaging? This is an important question especially if one considers the logistics (scarce imaging availability in rural areas and emergency, sport, and combat settings) and economic advantages that come with peripheral biomarkers, notwithstanding the complications associated with radiation exposure (e.g., CT scan). As a result, the diagnostic equivalence of blood biomarkers and enhanced MRI or CT scans (114–119) is being investigated. Accumulating evidence has shown that mTBI represents an optimal clinical arena to study the usefulness of imaging and peripheral biomarkers, also fulfilling an urgent clinical need (120–122). Neuroimaging techniques [CT scan (61)] show limitations for the diagnosis of mTBI patients (122, 123). Importantly, blood levels of GFAP, tau, and NfL were higher in patients with TBI-related findings on CT as compared to subjects presenting with normal CT, where the only significant predictor of damage was GFAP (124). Combining the biomarkers tau, NfL, and GFAP showed a good discriminatory power for detecting MRI abnormalities, even in mTBI patients with a normal CT (124). Furthermore, peak serum S100B levels negatively correlated with resting-state brain connectivity and behavioral outcomes in mTBI to severe TBI cases (125). S100B has proven its high NPV to rule out intracranial bleeding in patients after mTBI. However, its specificity for brain parenchyma structural lesions remains debated, and MRI is required for a specific explanation of clinical symptoms (76, 126, 127). Positron emission tomography (PET) and radiolabeled biomarkers were tested along with blood biomarkers. The [18F]AV1451 (flortaucipir) tau ligand was detected at the white/gray matter junction in frontal, parietal, and temporal brain regions, a typical localization of chronic traumatic encephalopathy (CTE) and tauopathy in veterans. Elevated levels of Nfl were also reported in plasma (43). Finally, TBI is associated with inflammation as blood levels of IL6, TNFα, and VEGF were increased in CT- and MRI-positive patients as compared to controls (126).

Importantly, newer brain imaging approaches are being tested. Proton magnetic resonance spectroscopy (1H-MRS) represents an emerging neuroimaging modality to track the metabolic changes occurring after TBI (128, 129). Spectroscopy can predict changes of key metabolites such N-acetylaspartate (NAA), a marker of neuronal loss (130), and its early decrease associates with long-term poor outcomes in clinical pediatric mTBI and moderate TBI (130). Experimentally, spectroscopy modifications post injury were linked to altered astrocyte metabolism (131). Brain structural changes observed using diffusion tensor imaging were correlated to astrocyte dysfunction and astrogliosis at early (1–7 days) and late (60 days) time points after injury (132, 133). Tractography provides an opportunity for measuring structural alterations in the white matter that are not detected by conventional structural MRI (134). Magnetic encephalography has also been proposed to study mTBI damage, in addition to being used for post-traumatic stress disorders (135, 136). Collectively, these data underscore the need for integrating the temporal and quantitative profiles of emerging imaging read-outs with the dynamics of peripheral biomarker of NVU damage. These studies will allow us to fully understand whether blood biomarkers can reliably act as surrogates for brain imaging.

Saliva as a Biomarker Matrix: General Concepts

Another key cellular “barrier” can be exploited for diagnostic purposes, namely, the salivary glands and gingival vessels, both interfacing with the peripheral blood (Figures 4A,B) (53, 137–144). While plasma and serum are considered as classic biofluids for assessment of systemic biomarkers, saliva is being increasingly viewed as a matrix with a high diagnostic value (141, 145). Saliva collection is economical, safe and can be performed without the assistance of specialized health care personnel, allowing for point-of-injury (POI) sampling. Saliva lacks cellular and soluble components (e.g., coagulation cascade). As the leakage of brain-derived biomarkers in saliva undergoes a process of biological filtration (53, 137, 146), the use of saliva does not require separation steps that are an obstacle to the development of POI blood tests (138, 139). Human saliva is a clear, slightly acidic (pH 6.0–7.0) heterogeneous biofluid composed of water (99%), proteins (0.3%), and inorganic substances (0.2%) (147). Saliva contains enzymes, hormones, antibodies, nucleic acids, antimicrobial constituents, and cytokines (148), which accumulate in salivary glands and are secreted into the oral cavity through acinar cell ducts (149). Available protocols indicate that saliva samples can be stored short term at room temperature and long term at −20°C or −80°C without significant protein degradation, similar to serum or plasma samples (150, 151). Relevant information inherent to the preparation and the technical handling of saliva samples can be found in (150, 152–154).

Salivary Biomarkers of NVU Damage: a New Diagnostic Opportunity?

The salivary proteome has been characterized in CNS disease conditions, such as schizophrenia, bipolar disorders, and genetic disorders including Down's syndrome and Wilson disease (164). An overview of biomarkers identified in saliva for the diagnosis of neurodegenerative diseases such as AD, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis is provided in (165). Inflammatory biomarkers (e.g., IL-1β, TNF-α, and IL-6) have been quantified in saliva (166).

The deployment of POI salivary tests represents an opportunity for the detection of time-sensitive brain injuries (139–141, 167, 168). NSE was shown as a possible diagnostic salivary biomarker for neuronal damage in patients post stroke (169). Saliva samples have been analyzed for S100B levels, pro-inflammatory factors, and microRNAs in the settings of TBI (168, 170, 171). In particular, S100B levels in saliva were elevated in children post TBI (171). In another pilot study, 15 adult patients with suspected TBI and 15 control subjects were studied. Average salivary S100B level was 3.9-fold higher than blood S100B level, regardless of the presence of pathology [S100B]saliva correlated positively with [S100B]serum, and salivary S100B levels were as effective in differentiating TBI patients from control subjects as serum levels (172).

In an attempt to further accentuate the diagnostic significance of salivary testing, we reviewed the literature to obtain potential blood-to-saliva ratios for a number of proteins (Figure 4C). This search was directed to proteins that are not secreted by salivary glands. These proteins can access the salivary fluid by pericellular capillary leak, primarily the crevicular fluid. Importantly, it is currently unknown whether the steady-state permeability of the blood-to-saliva protein diffusion is preserved even at times when the BBB is breached due to brain insults. Literature references were used to examine insulin (173, 174), EGF (175), HGH (19, 176), S100B (18, 54–56, 177–180), adiponectin (181), prostate-specific antigen (PSA) (182), and cytokines (183). To our knowledge, there are no reports of salivary BDNF or NFL levels. All retrieved values were plotted to outline the theoretical cutoff properties of salivary filtration (Figure 4C). Large molecules (e.g., IgG) can be present in saliva owing to active secretion or local production.

Finally, we examined whether blood-to-saliva biomarkers' passage could be empirically predicted or modeled (153). Available data indicate that saliva is not a diluted substitute for the determination of plasma protein levels, as indicated by the incoherent plasma and saliva proteomes (152). Therefore, understanding the kinetic protein passage from blood to saliva is difficult. In the past, a model describing the passage of biomarkers from the brain into the peripheral blood was proposed (27–29). A physiologically based pharmacokinetic model can be used to describe the distribution of drugs and small molecules in body fluids (184). This computational approach can estimate the extent and time course of salivary biomarkers originating from the brain, offering the likelihood of a protein in saliva to be blood-borne (185). The physiologically based pharmacokinetic model used to describe the distribution of brain-derived biomarkers in blood was expanded to include an idealized salivary gland receiving its vascular supply from the external carotid. The venous output was mimicked according to the properties of jugular vein branches. To approximate the combined contribution of transcellular and paracellular pathways of protein extravasation across capillary endothelial cells and salivary gland epithelia, the following equation was used to calculate Js, the transfer of protein from blood to saliva:

Js=Jv∗(1−R)*Cp+(Cp−Ci)*PS (1)

where Js (mol/min) is the mass transfer from blood to saliva, Jv (ml/min) is the blood flow to the salivary gland, R is the reflectance of the vascular wall, Cp (mol/L) is the concentration of biomarker in the serum, Ci (mol/L) is the concentration of biomarker in the saliva, and P and S refer to permeability (cm/s) and surface of exchange (cm2), respectively. The value of reflectance has no dimension and has a range from one (no passage of protein) to 0 (protein passage dictated by diffusion alone). The value of reflectance is derived from pore radius and molecular radius. To estimate PS, we used PS = Jv * Ci/(Cp – Ci) with salivary flow at 1 ml/min and Ci and Cp at 2.5 and 61.5 mg/ml, respectively. These values were derived by measurements and transfer of albumin levels from blood and saliva. The equation can be greatly simplified by fitting experimental data to confirm their accuracy. Once this is done, the predictors of passage of a given protein are primarily related to its molecular size (vascular wall reflectance) and the presence of a gradient for passage from blood to crevicular fluid. For (1), note that if the reflectance tends toward 1 (large molecular weight), the first term equals zero, thus leaving only the permeability of the capillary wall and the osmotic gradient as variables. Considering that permeability also depends on molecular size, a cutoff for extravasation seems to be mostly related to the size of the permeating protein. By using other computational models, it was shown that the physicochemical properties of proteins were the main predictors of presence in saliva. Among several properties, molecular size was the most relevant (185, 186).

It is important to underscore that the use of saliva samples comes with confounding factors. For instance, gingivitis or periodontal disease can affect the identification and quantification of proteins. It has been shown that submandibular saliva flow rates are lower in AD patients as compared to controls (187), possibly impacting the proportion of proteins detectable (188). In summary, fully defining the qualitative and quantitative characteristics of salivary biomarkers in physiological and neuropathological conditions is important to develop non-invasive point of care applicable to NVU screening.

Pushing the BBB Limits: Relevance of Peripheral Blood Biomarkers in Human Models of Extreme Brain Physiology

Here, we focus on extreme sport settings that can be exploited as ‘human' models to study BBB permeability, neuronal damage, and hemodynamic modifications in a controlled spatiotemporal manner. We review the evidence supporting the use of blood biomarkers to detect neurovascular modifications associated with extremes of cerebral blood flow (Figure 5A). These models share similar pathophysiological features unified by the cerebral formation of free radicals, associated reactive oxygen/nitrogen species (ROS/RNS), and impaired cerebral autoregulation (CA).

Exercise, Cerebrovascular Regulation, and Blood Biomarkers

Evidence indicates that moderate-intensity continuous training (MICT) and corresponding improvements in cardiorespiratory fitness (CRF) can increase cerebral perfusion and vasoreactivity across the human life span (192, 193), translating into a lower risk of stroke mortality and dementia (194, 195). The primary mechanisms include accelerated neurogenesis, in particular of the hippocampal dentate gyrus (196); reduction in β-amyloid (197); neuro-oxidative inflammatory nitrosative stress (198); proprioceptive adaptations incurred by movements that require sustained mental effort (199); increased brain-derived neurotrophic factor that modulates brain plasticity by promoting neuritic outgrowth and synaptic function (200); and improved BBB integrity and bolstering of tight junctions (201). More recently, high-intensity interval training (HIIT) has emerged as a more time-efficient model of exercise that can potentially promote superior improvements in CRF and cerebrovascular adaptation (191). However, this type of exercise characterized by high-flow/high-arterial-pressure transmission poses unique challenges for the brain with emerging evidence suggesting that an acute bout of HIIT could increase BBB permeability in the absence of neuronal injury (e.g., increased blood S100B and no NSE changes), subsequent to a free radical-mediated impairment in dynamic CA that persists into the recovery period (202) (Figure 5B).
High-Altitude Mountaineering, Freediving, NVU Dynamics, and Blood Biomarkers

High-altitude (HA) mountaineering (Figure 6A) and freediving (Figure 6B) represent unique physiological models to study severe arterial hypoxemia (O2 lack) and hypocapnia/hypercapnia (CO2 lack/excess) in ‘extreme' athletes who consistently operate at, or very close to, the limits of human consciousness (189, 212). Diffusion-weighted magnetic resonance imaging has identified increases in brain volume, T2 relaxation time (T2-rt), and apparent diffusion coefficients (ADCs) in healthy participants acutely exposed to hypoxia, taken to reflect extracellular vasogenic edematous brain swelling (205, 206). These changes were pronounced in the splenium and genu of the corpus callosum, the likely consequence of a unique vascular constitution. Densely packed horizontal fibers characterized by short arterioles that lack adrenergic tone likely render it more susceptible to hyperperfusion edema in the setting of hypoxic cerebral vasodilatation and/or autoregulatory impairment (205, 206). Local sampling of CSF and arterial–jugular venous blood concentration gradients of biomarkers including S100B indicated that BBB disruption is likely minor and linked to increased free radical formation (207, 216).

Some mountaineers, notably those who ascend (too) rapidly to altitudes above 2,500 m and thus not adequately acclimatized, can develop acute mountain sickness (AMS), a primary disorder of the CNS characterized by headache that is associated with, if not the primary trigger for, other vegetative symptoms (217). Traditionally, AMS has been considered a mild form of HA cerebral edema (HACE, the most malignant of all HA illnesses, oftentimes proving fatal) with a common pathophysiology of intracranial hypertension subsequent to vasogenic edematous brain swelling at opposing ends of a clinical continuum. An increase in intracranial pressure (ICP) could potentially result in the mechanical stimulation of pain-sensitive unmyelinated fibers that reside within the trigeminal–vascular system, triggering the symptoms of a headache (218). This makes intuitive sense in light of an early study that identified an increased T2 signal in the white matter of mountaineers with moderate to severe AMS in whom clinical HACE had not yet developed (no ataxia or altered consciousness) (219). However, follow-up MRI studies consistently failed to support this concept, with no clear relationships observed between hypoxia-induced increases in brain volume or T2-rt and cerebral AMS scores (206, 220). Indeed, the only defining morphological feature that distinguishes the AMS brain from its healthy counterpart is a selective attenuation in the ADC signal taken to reflect intracellular (cytotoxic) edema that likely coexists with extracellular vasogenic edema (206, 220). Attenuation of the ADC signal likely reflects fluid redistribution from within the extracellular space, as intracellular (astrocytic) swelling proceeds without any additional increment in brain volume, edema, or ICP (221). The underlying causes and temporal sequence are unknown, perhaps a reflection of ion pump suppression subsequent to (free radical-mediated) downregulation of Na+/K+-ATPase activity (211). More recent evidence suggests that a functional impairment in cerebral ‘venous outflow' at the level of the transverse venous sinus may prove the unifying risk factor for AMS (222).

Freediving (Figure 6B) offers yet another remarkable model of severe arterial hypoxemia (189, 212). The static apnea world record currently stands at an impressive 11 min 35 s held by Stéphane Mifsud. However, unlike mountaineers, apnea results in severe hypercapnia, further compounding the cerebral hyperemic stimulus (Figure 6B), with freedivers also having to contend with the additional challenge of elevated hydrostatic pressure when competing ‘at depth' in select disciplines and complications associated with pulmonary barotrauma, nitrogen narcosis, decompression sickness, and high-pressure neurologic syndrome (212). Competitive freedivers oftentimes experience shallow-water blackout due to severe cerebral hypoxia and loss of motor control, clinical signs that are the frustrating cause for disqualification from competition, notwithstanding immunochemical evidence for structural NVU damage, e.g., increased peripheral blood S100B and NSE after a maximal apnea, with potential long-term neuropsychological consequences (223, 224).

More recent, direct approaches have taken advantage of sampling arterial–jugular venous blood and combining regional measurements of CBF during the course of an apnea in champion freedivers (213, 214). Despite no detectable O2 gradient across the brain, a truly remarkable observation, CDO2 subsequent to increased perfusion was well maintained even at PaO2s as low as 23 mmHg (Figure 6B). Similar to the aforementioned acute hypoxia study (207), apnea was associated with a net trans-cerebral outflow of free radicals and S100B (in the absence of any local gradients in NSE or MBP) that may reflect minor BBB permeability due to the combination of hemodynamic (increased intracranial pressure) and molecular (increased free radical formation) stress in the absence of neuronal damage (214). Rather than consider this simply as a damaging maladaptive response, vasogenic edematous brain swelling may prove the adaptive phenotypical response in the hypoxia-tolerant human brain (211, 225).

Gravitational Stress, Cerebrovascular Regulation, and Blood Biomarkers

Alterations in gravitational fluid pressure gradients caused by the microgravity of orbital spaceflight and hypergravity associated with takeoff and landing pose unique physiological challenges for the astronaut brain. Recent interest has focused on the complex pathophysiology underlying a constellation of debilitating neurological, ophthalmological, and neurovestibular symptoms, known collectively as spaceflight-associated neuro-ocular syndrome (SANS) (226). At the cellular level, microgravity has been associated with a loss of cytoskeletal integrity through dissociation of actin and tubulin bundles (227), and evidence obtained using animal models suggests that BBB disruption may occur during the early phases of unloading induced by suspension or microgravity (228) and during hypergravity induced by prolonged centrifugation (229, 230). In a recent study (215), parabolic flight (PF), a ground-based spaceflight analog, was used as a human model to induce rapidly alternating shifts in central blood volume during repeated exposures to microgravity (0 Gz) interspersed with hypergravity (1.8 Gz) (231) to explore how altered CBF impacts the NVU (232) (Figure 6C). Blood flow to the posterior cerebral circulation (vertebral arteries) was selectively elevated during the most marked gravitational differential from microgravity to hypergravity. Posterior hyperperfusion was associated with a free radical-mediated reduction in nitric oxide bioavailability (oxidative–nitrosative stress) and selective increases in blood S100B and GFAP that persisted following return to microgravity, whereas blood biomarkers of neuronal–axonal damage (NSE, NFL, UCH-L1, and tau) remained stable (215). These findings suggest that the cumulative effects of repeated gravitational transitions may promote minor BBB damage due to the combined effects of hemodynamic-molecular stress. While we appreciate that PF is an entirely different stimulus dominated by hypergravity, these findings provide important mechanistic insight to help understand the neurological risks associated with prolonged microgravity during spaceflight, given that increased BBB permeability directly impacts neuronal function, predisposing to neurological sequelae and brain disease (6).

Blood Biomarkers of NVU Damage: Available Analytical Tools, Limitations, and Controversies

No single ideal peripheral biomarker exists; rather, a suite of biomarkers could have a significant diagnostic impact. In recent years, innovative methods for biomarker detection have been implemented (Table 2). Reaching high sensitivity has several advantages, particularly in the context of neurological settings. Foremost is the ability to detect biomarkers such as NfL, Tau, or GFAP that are readily present in the CSF and in low concentrations in the blood. New technology has enabled the quantification of brain-derived protein biomarkers in blood, getting one step closer to a minimally invasive diagnosis of brain damage and neurodegenerative processes. Furthermore, high-sensitivity methods use microliter quantities of biofluid, allowing the quantification of several analytes and multiplex measurement. As an example, we here provide NfL, GFAP, and tau serum baseline levels as measured in our laboratory using Simoa (Table 2). We include specific LLOD and LLOQ values relative to our particular experience. Obviously, this new technology presents limitations. A shortcoming of high-sensitivity assay resides in the fact that Research Use Only (RUO) kits are not able to provide, yet, a level of robustness and precision that one would expect for a clinical in vitro diagnostics (IVD) use. To date, the impact of analytic interference is not sufficiently investigated. Therefore, the expectations formulated following cohort-based studies need confirmations in large preclinical studies and multicentric clinical trials.

Although the use of blood biomarkers of BBB or neuronal damage is appealing, a number of clinical stumbling blocks currently limit full applicability. The usefulness of blood biomarkers in a given human depends on the availability of reference values, correcting for age, ethnicity, kidney function, and body mass index (29). Adequateness of the blood sampling schedule and availability of baseline controls are crucial for a reliable biomarker outcome. Sample readiness before and after pathological events (e.g., inpatient seizure monitoring and head trauma as in contact sports) provides the optimal framework to calculate biomarker differential in the same individual and within a controlled time frame (24, 25). Availability of ad hoc baseline samples (e.g., specific enrollments for sport events and military personnel) represents a robust method enabling personalized medicine.

As examined so far, the appearance of NVU proteins in blood is reported for neurodegenerative diseases (91, 94), brain tumors (115, 117), TBI (25, 233), neurologic manifestations of systemic disease (234), psychiatric diseases, and seizures (21, 53, 235). Peripheral biomarkers have an excellent NPV to rule out disease(s) but have a poor positive predictive value (PPV) to identify a specific pathological condition (27, 28, 46, 53, 236–238). Another concern is the potential contamination related to extra-CNS sources of protein biomarkers. For example, S100B could be derived from adipose tissue with levels directly depending on body mass index (239). A study excluded the impact of adipose tissue on S100B serum levels (23). Elevated serum S100B was reported in patients presenting with extracranial pathology (240), such as polytrauma and burns (66).

Another important question is whether peripheral biomarkers have a prognostic value for the development of long-term brain pathology. Currently, there is no collective agreement on whether an unhealthy BBB may already exist, and could be diagnosed, in an otherwise apparently healthy brain (241, 242). However, recent evidence indicates that subjects presenting early cognitive impairment had preexisting BBB damage. The platelet-derived growth factor receptor beta (PDGFRβ; Table 1) (243, 244) shedding from perivascular pericytes was proposed as a biomarker of BBB integrity anticipating and predicting neurodegeneration (39, 243). A high-sensitivity method for detecting pericyte injury quantifying PDGFRβ in CSF was recently proposed (245). This method could be extended to study brain pericyte–endothelial damage in neurodegenerative disorders. Moreover, repetitive head hits during contact sports [American football (25)] were shown to associate with recurrent BBB permeability and S100B increases in blood. Players experiencing recurrent BBB permeability presented higher serum reactive autoantibodies, with a possible correlation with cognitive defects (25). The clinical significance of repeated BBB damage in sports is currently debated, with evidence pointing to a role in accelerated neurodegeneration (73). Moreover, total tau in blood was reported as a biomarker of axonal damage in hockey (24). Tau and amyloid monitoring in CSF is undergoing validation processes for dementia and AD (246, 247).

Outlook and Final Remarks

Using peripheral biomarkers to monitor BBB permeability could extend to clinical cases where opening of the BBB is necessary to enhance drug penetration into the brain (13) or when re-establishment of physiological BBB tightness is justified to treat brain diseases (248, 249). Emerging evidence supports a holistic approach to tackle CNS diseases, where neuronal and cerebrovascular contributors of diseases are synchronously targeted. An increasing number of BBB-repairing molecules are currently being tested [for review, see (5, 6)], targeting NVU cells and neuroinflammation. Importantly, BBB biomarker and repairing strategies could become important in the settings of acute or chronic peripheral diseases (infections, metabolic or inflammatory) where immunity and inflammation negatively impact BBB permeability and, consequentially, synaptic transmission (5, 7, 250).

In conclusion, the NVU represents a modern and integrated entry point for the investigations of brain functions, and a continuous technological advancement will be instrumental to improve our ability to link NVU damage with diagnostics. The field of biomarkers of NVU damage, or dysfunction, is expanding together with the use of omic techniques and machine-learning routines for the discovery of signatures of acute or chronic disease conditions.
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Peripheral Blood and Salivary Biomarkers of Blood–Brain Barrier Permeability and Neuronal Damage: Clinical and Applied Concepts

https://www.frontiersin.org/articles/10 ... 77312/full

Damir Janigro1,2, Damian M. Bailey3, Sylvain Lehmann4, Jerome Badaut5, Robin O'Flynn4, Christophe Hirtz4 and Nicola Marchi6*

1Department of Physiology Case Western Reserve University, Cleveland, OH, United States
2FloTBI Inc., Cleveland, OH, United States
3Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Wales, United Kingdom
4IRMB, INM, UFR Odontology, University Montpellier, INSERM, CHU Montpellier, CNRS, Montpellier, France
5Brain Molecular Imaging Lab, CNRS UMR 5287, INCIA, University of Bordeaux, Bordeaux, France
6Cerebrovascular and Glia Research, Department of Neuroscience, Institute of Functional Genomics (UMR 5203 CNRS—U 1191 INSERM, University of Montpellier), Montpellier, France

Within the neurovascular unit (NVU), the blood–brain barrier (BBB) operates as a key cerebrovascular interface, dynamically insulating the brain parenchyma from peripheral blood and compartments. Increased BBB permeability is clinically relevant for at least two reasons: it actively participates to the etiology of central nervous system (CNS) diseases, and it enables the diagnosis of neurological disorders based on the detection of CNS molecules in peripheral body fluids. In pathological conditions, a suite of glial, neuronal, and pericyte biomarkers can exit the brain reaching the peripheral blood and, after a process of filtration, may also appear in saliva or urine according to varying temporal trajectories. Here, we specifically examine the evidence in favor of or against the use of protein biomarkers of NVU damage and BBB permeability in traumatic head injury, including sport (sub)concussive impacts, seizure disorders, and neurodegenerative processes such as Alzheimer's disease. We further extend this analysis by focusing on the correlates of human extreme physiology applied to the NVU and its biomarkers. To this end, we report NVU changes after prolonged exercise, freediving, and gravitational stress, focusing on the presence of peripheral biomarkers in these conditions. The development of a biomarker toolkit will enable minimally invasive routines for the assessment of brain health in a broad spectrum of clinical, emergency, and sport settings.
Introduction: From Blood–Brain Barrier to Blood–Brain Dynamic Interface

The blood–brain barrier (BBB) is the complex and finely tuned network of brain capillaries governing the homeostatic exchange of ions, molecules, and cells between the brain and the peripheral blood (1–3). The importance of the BBB in the understanding and diagnosis of neurological disorders and brain health is recognized (4). The notion of BBB has evolved from that of a static brain shield to that of a dynamic blood–brain interface where endothelial cells continuously communicate with mural cells (pericytes and smooth muscle) and glia (astrocytes and microglia), located near neurons and spatially assembled to constitute the neurovascular unit (NVU) (Figure 1) (2). A precise layering of cells and extracellular matrixes forms an impermeable wall (Figure 1B). BBB dysfunction has etiologic and diagnostic significance (4), and BBB permeability is a key element of perivascular and neuroinflammation (Figure 1B1) (5, 6). Increased BBB permeability provokes an immediate loss of homeostatic control of ions, ATP, and neurotransmitters levels in the brain, promoting abnormal synaptic transmission or neuronal firing, possibly leading to neurological sequelae (6–13). On the other hand, neuronal activity significantly influences cerebrovascular functions in health and disease conditions (14, 15). Diagnostically and because of increased BBB permeability, peripherally injected imaging contrast agents can access the brain parenchyma while a suite of central nervous system (CNS) proteins (see Table 1) or nucleic acids [circulating free DNA and microRNA; for a review see (44, 45)] can exit into the peripheral blood (Figures 2A–C, 3A–C). Contrast MRI and CT scans are common clinical tools, while monitoring the levels of CNS proteins in peripheral body fluids represents a novel strategy for identifying BBB and neuronal damage (46). Importantly, the NVU connects with specialized brain acellular spaces through which the cerebrospinal and interstitial fluids carry ions, molecules, and proteins across the parenchyma or toward waste clearance pathways (Figure 2B) (47–50). This spatial perivascular and interstitial connectivity is important in the context of contrast-based brain imaging, possibly influencing the availability of biomarkers and their exit trajectories from the CNS [Figure 2; see (46, 51, 52) for a review]. Starting from these fundamental concepts, we here examine the evidence supporting the development and the use of specific peripheral biomarker proteins to detect glioneuronal damage and BBB permeability in a plethora of clinical, emergency and sport-related settings.
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The diagnostic potential of fluid and imaging biomarkers in chronic traumatic encephalopathy (CTE)

https://www.sciencedirect.com/science/a ... 2221013895

Abstract

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by cognitive, affective, and motor dysfunction. The main pathophysiological mechanisms are chronic neuroinflammation, hyper-phosphorylated tau (p-tau) accumulation and neurodegeneration. CTE is mostly caused by exposure to multiple mild traumatic brain injuries, placing people participating in, for example, high contact sports at increased risk. Currently, CTE can solely be diagnosed post mortem based on the spatial pattern of tau-accumulation. Herein, we review candidate imaging and molecular biomarkers for their sensitivity and specificity and we look whether these are sufficient for reliable ante mortem diagnosis. Of the imaging biomarkers, PET appears to have the best potential. Candidate fluid biomarkers consist of genes and proteins found in brain derived extracellular vesicles, as well as cerebrospinal fluid (CSF) p-tau levels. However, neither these biomarkers nor the imaging biomarkers have the discriminatory power to differentiate between CTE and other tauopathies, highlighting the need for further validation. Future research could incorporate machine learning methodologies to differentiate between the tau accumulation patterns detected by PET/fMRI in Alzheimer’s and CTE patients. Additionally, proteomic and metabolomic profiling of CSF and plasma associated with chronic mild traumatic brain injuries could highlight potential biomarkers for identifying at risk patients.
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The Role of Salivary Biomarkers in the Early Diagnosis of Alzheimer’s Disease and Parkinson’s Disease

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926361/

Abstract

Many neurodegenerative diseases present with progressive neuronal degeneration, which can lead to cognitive and motor impairment. Early screening and diagnosis of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are necessary to begin treatment before the onset of clinical symptoms and slow down the progression of the disease. Biomarkers have shown great potential as a diagnostic tool in the early diagnosis of many diseases, including AD and PD. However, screening for these biomarkers usually includes invasive, complex and expensive methods such as cerebrospinal fluid (CSF) sampling through a lumbar puncture. Researchers are continuously seeking to find a simpler and more reliable diagnostic tool that would be less invasive than CSF sampling. Saliva has been studied as a potential biological fluid that could be used in the diagnosis and early screening of neurodegenerative diseases. This review aims to provide an insight into the current literature concerning salivary biomarkers used in the diagnosis of AD and PD. The most commonly studied salivary biomarkers in AD are β-amyloid1-42/1-40 and TAU protein, as well as α-synuclein and protein deglycase (DJ-1) in PD. Studies continue to be conducted on this subject and researchers are attempting to find correlations between specific biomarkers and early clinical symptoms, which could be key in creating new treatments for patients before the onset of symptoms.

1. Introduction

Neurodegenerative diseases are characterized by the progressive degeneration of cells of the central and peripheral nervous system, which ultimately lead to cognitive and motor function deficits. Various processes such as oxidative stress, proteotoxic stress and neuroinflammation can induce neuronal degeneration [1,2]. The most common neurodegenerative disorders among the ageing population are Alzheimer’s disease (AD) and Parkinson’s disease (PD), where AD accounts for approximately 80% of all dementia cases [3]. Although PD mainly causes motor deficits, about 30% of all PD cases manifest as full-blown dementia or cognitive impairment [4,5]. The development of dementia in neurodegenerative diseases such as AD and PD begins with mild cognitive impairment (MCI) and increases with age. Deficits of cognitive functions in AD progress from short-term memory impairment, speech deficits and “loss of words” to disturbances in orientation, concentration and attention. In the advanced stages of the disease, symptoms of depression, apathy, sleep disturbance, delusions and hallucinations are observed. Cognitive deficits in PD may precede motor symptoms and include an impairment in planning, abstract thinking, mental flexibility, visuospatial functions, attention as well as memory, and are considered as the main non-motor manifestations of PD [4]. The most characteristic feature of AD and PD is the occurrence of discrete, most often unrecognized neuropathological changes that precede full-blown clinical symptoms. Together with the clinical symptoms they form the basis for the diagnosis and differentiation, as well as the identification of different subtypes of the disease. The well-known neuropathological changes observed in AD are the accumulation of β-amyloid (Aβ) peptides and neurofibrillary tangles (NFTs) in the brain [6]. PD is characterized by the progressive reduction of dopamine levels in the substantia nigra, degeneration of dopaminergic neurons and the formation of intracytoplasmic α-synuclein protein aggregates, known as Lewy bodies, which lead to clinical motor symptoms such as tremors, muscle stiffness, akinesia and bradykinesia, as well as cognitive impairment [7]. These neuropathological changes can commence several years prior to any obvious clinical symptoms, cognitive deficits and memory loss. These clinical observations of AD progression have led to the identification of different AD stages. In the past, the first criteria that addressed the disease described only the later stages, when symptoms of dementia were already evident. According to the updated guidelines, the full spectrum of AD gradually changes over a period of many years. These changes include the preclinical stages of AD, MCI and dementia due to AD. In the preclinical stage, significant clinical symptoms are not yet evident. The MCI stage is characterized by symptoms of memory loss, which are enough to be noticed and measured, but do not compromise the person’s independence. Patients with MCI may or may not progress to AD dementia [8,9,10]. It is estimated that 40 to 60% of MCI patients develop full-blown AD dementia usually many years after the onset of the preclinical stage [11]. Of particular importance is the detection and differentiation between the preclinical and MCI stages so that the diagnosis of AD will not be limited to the diagnosis of dementia due to AD. A similar progression in the disease is seen in PD. Unfortunately, there are no certain diagnostic criteria for the diagnosis of early stages of PD, and most PD patients are correctly diagnosed on the basis of motor symptoms, which are visible when 70% of dopaminergic neurons are lost [12]. The diagnostic frequency of neurodegenerative diseases and accompanying disorders increases with the patients age. Therefore, both AD and PD are mostly diagnosed in elderly people of 65 years and older and are manifested as the last-onset, advanced and fatal neurodegenerative diseases [11]. Delayed diagnosis of AD and PD hinders the implementation of effective therapy and worsens the prognosis. Due to the high prevalence of neurodegenerative diseases among the ageing population, it is important to be able to diagnose and monitor the clinical progression of these diseases at the earliest possible stage. The updated National Institute on Aging and Alzheimer’s Association (NIA-AA) diagnostic criteria for AD distinguish the preclinical and MCI stages of the disease, as well as allow its certain confirmation not only on the basis of an autopsy but also in living patients in the early stages of the disease by means of neuroimaging and biomarker determination [13]. The early diagnosis of AD is based on the identification and analysis of specific biomarkers in the cerebrospinal fluid (CSF) and radiological evaluation using structural or functional magnetic resonance imaging (MRI), as well as Positron Emission Tomography (PET) [11,13,14,15]. These diagnostic methods are not only invasive but time consuming and expensive. PET uses specific tracers to visualize and evaluate Aβ and TAU accumulations in the brain, whereas MRI scans assess function and show brain atrophy, especially in the hippocampus [10]. However, MRI is considered to be reliable only in the later stages of the disease. Another type of imaging modality used in AD diagnosis is 18F-2-fluoro-2-deoxy-D-glucose (FDG) PET scans which monitor glucose metabolism mechanism and identify areas of decreased brain activity [13]. According to the assumptions of the introduced diagnostic guidelines, biomarkers obtained from CSF are to help in the identification of the early stages of the disease and in the assessment of the disease progression. However, their use as a diagnostic method is clinically limited due to insufficient standardization of the analytical results, limited availability and a lack of evidence correlating biomarker concentration with AD pathology. In AD, all biomarkers are classified into an A/T/N system, in which A represents Aβ concentration, T refers to TAU levels, and N includes neurodegeneration and neuronal injury biomarkers [13]. To sum up, according to the NIA-AA, diagnosis of AD on the basis of biomarkers is based on the determination of a reduced level of Aβ1-42 and Aβ1-42/ Aβ1-40 ratio in CSF or the detection of Aβ aggregates on PET scans, as well as increased TAU levels in CSF and its aggregates detection on PET scans. Currently, only the detection of TAU and Aβ in CSF or alternatively their aggregates on PET scans are considered reliable in the diagnosis of AD. Attempts are being made to determine these biomarkers in other body fluids as an alternative to CSF or to search for other biomarkers specific to AD, as well as to differentiate its different stages. Similar attempts to identify and introduce biomarkers into diagnostics were carried out in PD. Due to its presence in the subarachnoid space and ventricular system of the brain and spinal cord, as well as reflecting pathological changes in the brain, CSF is a natural source of diagnostic biomarkers in neurodegenerative diseases. However, the CSF sampling is an invasive procedure which involves pain, risk of complications, and is unsuitable for frequent repetition in routine practice. Hence, the continuous search for the use of biomarkers derived from other peripheral body fluids. Blood has also been suggested as a diagnostic tool, considering that it is safer than a lumbar puncture and less invasive. However, studies have shown that AD-specific biomarkers in blood are difficult to isolate due to their low concentration, which would require a highly sensitive technical modality [14]. Moreover, AD is comorbid with vascular risk factors, thus, the presence of these variables may affect the results obtained [13]. Researchers have been focused on finding an alternative, less invasive and more affordable diagnostic tool that would allow to identify specific biomarkers in neurodegenerative diseases at an early stage. Moreover, these biomarkers could be helpful in the monitoring of disease progression and therapy effectiveness, as well as in the identification of different subgroups in AD and PD. Easy accessible biomarkers could be used as a screening tool in the most predilected patients [11,15,16].

Saliva is an alternative biological fluid that has been widely used as a diagnostic material in areas such as toxicology, infectious diseases, endocrinology and cardiology [17,18]. Some salivary proteins have also been used in the identification of neurologic and psychiatric disorders [2,19]. Saliva plays an important function in the protection and maintenance of healthy oral mucosa and teeth through its buffering capacity and its antibacterial and antiviral properties. It can be treated as an equivalent of serum. Saliva is a suitable biomaterial that can be used as a diagnostic method because it is relatively easy to obtain, the procedure is non-invasive, its processing is simple, it possesses lower protein content than blood and urine, and is less expensive [20,21,22]. A summary of the main advantages and disadvantages of saliva as a biological fluid in the diagnosis of neurodegenerative diseases when compared to other biological fluids such as CSF and blood .
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Salivary Redox Biomarkers in Different Stages of Dementia Severity

https://www.mdpi.com/2077-0383/8/6/840

Abstract
This study is the first to evaluate oxidative stress biomarkers in saliva/blood of patients with varying degrees of dementia progression. The study included 50 healthy controls and 50 dementia patients divided into two groups: those with mild and moderate dementia (MMSE 11–23) and patients suffering from severe dementia (MMSE 0–10). Cognitive functions of the subjects were assessed using the Mini Mental State Examination (MMSE). Enzymatic and non-enzymatic antioxidants, oxidative damage products and protein glycoxidative modifications were determined in non-stimulated (NWS) and stimulated (SWS) saliva as well as erythrocyte/plasma samples. Generally, in dementia patients, we observed the depletion of antioxidant defences leading to oxidative and glycoxidative damage in NWS, SWS and blood samples. Both salivary and blood oxidative stress increased with the severity of the disease, and correlated with a decrease of cognitive functions. Interestingly, in dementia patients, reduced glutathione (GSH) in NWS correlated not only with the severity of dementia, but also with GSH concentration in the plasma. In receiver operating characteristic (ROC) analysis, we have demonstrated that salivary GSH clearly distinguishes patients with severe dementia from those suffering from mild or moderate dementia (area under the curve (AUC) = 1). Therefore, salivary GSH can be used as a non-invasive biomarker of cognitive impairment.
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trader32176 wrote: Wed Jan 25, 2023 1:09 pm The diagnostic potential of fluid and imaging biomarkers in chronic traumatic encephalopathy (CTE)

https://www.sciencedirect.com/science/a ... 2221013895

Abstract

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by cognitive, affective, and motor dysfunction. The main pathophysiological mechanisms are chronic neuroinflammation, hyper-phosphorylated tau (p-tau) accumulation and neurodegeneration. CTE is mostly caused by exposure to multiple mild traumatic brain injuries, placing people participating in, for example, high contact sports at increased risk. Currently, CTE can solely be diagnosed post mortem based on the spatial pattern of tau-accumulation. Herein, we review candidate imaging and molecular biomarkers for their sensitivity and specificity and we look whether these are sufficient for reliable ante mortem diagnosis. Of the imaging biomarkers, PET appears to have the best potential. Candidate fluid biomarkers consist of genes and proteins found in brain derived extracellular vesicles, as well as cerebrospinal fluid (CSF) p-tau levels. However, neither these biomarkers nor the imaging biomarkers have the discriminatory power to differentiate between CTE and other tauopathies, highlighting the need for further validation. Future research could incorporate machine learning methodologies to differentiate between the tau accumulation patterns detected by PET/fMRI in Alzheimer’s and CTE patients. Additionally, proteomic and metabolomic profiling of CSF and plasma associated with chronic mild traumatic brain injuries could highlight potential biomarkers for identifying at risk patients.
This article stated "currently, CTE can solely be diagnosed postmortem". Isn't that incorrect as TSOI has diagnosed and treated several people with CTE under RTT with FDA approval?
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