Oral Tyrosine Supplementation Facilitates Conditions for the Preferential Transport of Tyrosine Across the Blood-Brain Barrier in Anorexia Nervosa: a Case Study Series

Abstract Background: Anorexia nervosa is a severe and complex illness associated with a lack of efficacious treatment. Ongoing tyrosine administration has been proposed as a possible treatment through increasing blood tyrosine sufficiently to facilitate brain catecholamine synthesis. Saturation with the noradrenergic precursor tyrosine could alleviate noradrenergic dysregulation with subsequent reduction in dietary restraint and eating, weight and shape concern. The effects of tyrosine supplementation in adolescents with anorexia nervosa remain to be tested. This feasibility study aimed to explore whether an oral tyrosine dosage raises plasma tyrosine sufficiently in adolescents with anorexia nervosa and healthy peers and is sustained over time to allow conditions for the preferential transport across the blood-brain barrier. Case Presentation: The first stage of this study explored the pharmacological response to a single, oral tyrosine load in adolescents (aged 12-15 years) with anorexia nervosa (n=2) and healthy peers (n=2). The second stage explored the pharmacological and psychological response to ongoing tyrosine administration in adolescents with anorexia nervosa. Peak tyrosine levels occurred at approximately two-three hours and approached baseline levels by eight hours. Blood tyrosine elevation was maintained over time in participants with anorexia nervosa. Some improvements in participant psychological tests were evident. There were no measured side effects. Conclusions: The considerable blood tyrosine increase appeared sufficient to facilitate conditions for the preferential transport of tyrosine across the blood-brain barrier which has the potential to improve noradrenergic brain function in people with anorexia nervosa. Further exploration of tyrosine as an adjunct treatment in anorexia nervosa is warranted.

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Safety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates

Scientific Reports ◽

10.1038/s41598-021-94188-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Antonios N. Pouliopoulos ◽

Nancy Kwon ◽

Greg Jensen ◽

Anna Meaney ◽

Yusuke Niimi ◽

...

Keyword(s):

Blood Brain Barrier ◽

Safety Profile ◽

Focused Ultrasound ◽

Multiple Case Study ◽

Brain Barrier ◽

Non Invasive ◽

Blood Brain ◽

Multiple Case ◽

Bbb Opening

AbstractAn emerging approach with potential in improving the treatment of neurodegenerative diseases and brain tumors is the use of focused ultrasound (FUS) to bypass the blood–brain barrier (BBB) in a non-invasive and localized manner. A large body of pre-clinical work has paved the way for the gradual clinical implementation of FUS-induced BBB opening. Even though the safety profile of FUS treatments in rodents has been extensively studied, the histological and behavioral effects of clinically relevant BBB opening in large animals are relatively understudied. Here, we examine the histological and behavioral safety profile following localized BBB opening in non-human primates (NHPs), using a neuronavigation-guided clinical system prototype. We show that FUS treatment triggers a short-lived immune response within the targeted region without exacerbating the touch accuracy or reaction time in visual-motor cognitive tasks. Our experiments were designed using a multiple-case-study approach, in order to maximize the acquired data and support translation of the FUS system into human studies. Four NHPs underwent a single session of FUS-mediated BBB opening in the prefrontal cortex. Two NHPs were treated bilaterally at different pressures, sacrificed on day 2 and 18 post-FUS, respectively, and their brains were histologically processed. In separate experiments, two NHPs that were earlier trained in a behavioral task were exposed to FUS unilaterally, and their performance was tracked for at least 3 weeks after BBB opening. An increased microglia density around blood vessels was detected on day 2, but was resolved by day 18. We also detected signs of enhanced immature neuron presence within areas that underwent BBB opening, compared to regions with an intact BBB, confirming previous rodent studies. Logistic regression analysis showed that the NHP cognitive performance did not deteriorate following BBB opening. These preliminary results demonstrate that neuronavigation-guided FUS with a single-element transducer is a non-invasive method capable of reversibly opening the BBB, without substantial histological or behavioral impact in an animal model closely resembling humans. Future work should confirm the observations of this multiple-case-study work across animals, species and tasks.

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Assessing the roles of inflammation and blood brain barrier permeability in cognitive impairment: A nationwide longitudinal study of patients receiving chemotherapy and non-cancer controls.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.12070 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 12070-12070

Author(s):

Elizabeth Belcher ◽

Nikesha Gilmore ◽

Amber Kleckner ◽

Ian Kleckner ◽

Eva Culakova ◽

...

Keyword(s):

Cognitive Impairment ◽

Blood Brain Barrier ◽

Inflammatory Cytokine ◽

Brain Barrier ◽

Barrier Permeability ◽

Blood Brain Barrier Permeability ◽

Blood Brain ◽

Brain Barrier Permeability ◽

Bbb Permeability ◽

Over Time

12070 Background: Cognitive impairment is a prevalent side effect of chemotherapy. We have previously shown that chemotherapy treatment is associated with worse performance on the Rapid Visual Processing test (RVP), an objective measure of sustained attention, over time compared to non-cancer controls. Better understanding of the biologic mechanisms underlying cognitive impairment in cancer patients is needed. The pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) has been implicated in increasing blood brain barrier (BBB) permeability, which in turn is associated with cognitive impairment. This study assessed the relationships of TNFα and S100β, a biomarker of BBB permeability, to each other and to RVP performance over time. Methods: We analyzed a subset of participants (n = 89 patients, n = 52 controls, mean age = 60) from a prospective longitudinal study of women with breast cancer receiving chemotherapy and non-cancer controls. TNFα and S100β were measured in serum pre-chemotherapy (T1, ≤7 days before first treatment) and post-chemotherapy (T2, ≤1 month after last treatment) and at corresponding times for controls. Sustained attention was assessed by total correct rejections on the RVP test at T1 and T2. Separate linear regression models including all participants were used to relate 1) baseline TNFα and S100β levels to change in RVP performance over time, 2) change in TNFα and S100β to change in RVP performance over time, and 3) change in TNFα to change in S100β. Models were adjusted for age. 4) T-tests were used to compare the TNFα and S100β change scores (T1 to T2) of patients vs controls. Results: Greater increase (T1 to T2) in the pro-inflammatory cytokine TNFα was associated with worse cognition, measured by performance on RVP over time (p = 0.02). Higher baseline S100β, a biomarker of BBB permeability, was associated with worse performance on RVP over time (p = 0.09). Increase in TNFα was associated with increase in S100β (p = 0.11). S100β increased from T1 to T2 in patients relative to controls (p = 0.09). Conclusions: These results suggest that higher TNFα may be related to increases in blood brain barrier permeability and worse cognition. Future studies will further define the link between inflammation, blood brain barrier permeability and chemotherapy-related cognitive decline, with the goal of informing the development of new interventions. Funding: R01CA231014, T32CA102618, DP2CA195765, UG1CA189961.

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Insight into the Cooperation of P-glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) at the Blood–Brain Barrier: A Case Study Examining Sorafenib Efflux Clearance

Molecular Pharmaceutics ◽

10.1021/mp200465c ◽

2012 ◽

Vol 9 (3) ◽

pp. 678-684 ◽

Cited By ~ 43

Author(s):

Sagar Agarwal ◽

William F. Elmquist

Keyword(s):

Breast Cancer ◽

Blood Brain Barrier ◽

Breast Cancer Resistance Protein ◽

Brain Barrier ◽

Cancer Resistance ◽

P Glycoprotein ◽

Blood Brain ◽

Resistance Protein ◽

Insight Into

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Evaluating Changes to Blood-Brain Barrier Integrity in Brain Metastasis over Time and after Radiation Treatment

Translational Oncology ◽

10.1016/j.tranon.2016.04.006 ◽

2016 ◽

Vol 9 (3) ◽

pp. 219-227 ◽

Cited By ~ 11

Author(s):

Donna H. Murrell ◽

Niloufar Zarghami ◽

Michael D. Jensen ◽

Ann F. Chambers ◽

Eugene Wong ◽

...

Keyword(s):

Brain Metastasis ◽

Blood Brain Barrier ◽

Radiation Treatment ◽

Brain Barrier ◽

Barrier Integrity ◽

Blood Brain ◽

Blood Brain Barrier Integrity ◽

Over Time

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The use of angiotensin-converting enzyme inhibitors vs. angiotensin receptor blockers and cognitive decline in Alzheimer’s disease: the importance of blood-brain barrier penetration and APOE ε4 carrier status

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00778-8 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Michael Ouk ◽

Che-Yuan Wu ◽

Jennifer S. Rabin ◽

Aaron Jackson ◽

Jodi D. Edwards ◽

...

Keyword(s):

Blood Brain Barrier ◽

Enzyme Inhibitors ◽

Recall Performance ◽

Angiotensin Receptor Blockers ◽

Angiotensin Converting Enzyme Inhibitors ◽

Brain Barrier ◽

Converting Enzyme Inhibitors ◽

Delayed Recall ◽

Blood Brain ◽

Over Time

Abstract Background The antihypertensive angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACE-Is) have similar indications and mechanisms of action, but prior work suggests divergence in their effects on cognition. Methods Participants in the National Alzheimer’s Coordinating Center database with a clinical diagnosis of dementia due to Alzheimer’s disease (AD) using an ACE-I or an ARB at any visit were selected. The primary outcome was delayed recall memory on the Wechsler Memory Scale Revised – Logical Memory IIA. Other cognitive domains were explored, including attention and psychomotor processing speed (Trail Making Test [TMT]-A and Digit Symbol Substitution Test [DSST]), executive function (TMT-B), and language and semantic verbal fluency (Animal Naming, Vegetable Naming, and Boston Naming Tests). Random slopes mixed-effects models with inverse probability of treatment weighting were used, yielding rate ratios (RR) or regression coefficients (B), as appropriate to the distribution of the data. Apolipoprotein (APOE) ε4 status and blood-brain barrier (BBB) penetrance were investigated as effect modifiers. Results Among 1689 participants with AD, ARB use (n = 578) was associated with 9.4% slower decline in delayed recall performance over a mean follow-up of 2.28 years compared with ACE-I use (n = 1111) [RR = 1.094, p = 0.0327]; specifically, users of BBB-crossing ARBs (RR = 1.25, p = 0.002), BBB-crossing ACE-Is (RR = 1.16, p = 0.010), and non-BBB-crossing ARBs (RR = 1.20, p = 0.005) had better delayed recall performance over time compared with non-BBB-crossing ACE-I users. An interaction with APOE ε4 status (drug × APOE × time RR = 1.196, p = 0.033) emerged; ARBs were associated with better delayed recall scores over time than ACE-Is in non-carriers (RR = 1.200, p = 0.003), but not in carriers (RR = 1.003, p = 0.957). ARB use was also associated with better performance over time on the TMT-A (B = 2.023 s, p = 0.0004) and the DSST (B = 0.573 symbols, p = 0.0485), and these differences were significant among APOE ε4 non-carriers (B = 4.066 s, p = 0.0004; and B = 0.982 symbols, p = 0.0230; respectively). Some differences were seen also in language and verbal fluency among APOE ε4 non-carriers. Conclusions Among APOE ε4 non-carriers with AD, ARB use was associated with greater preservation of memory and attention/psychomotor processing speed, particularly compared to ACE-Is that do not cross the blood-brain-barrier.

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Progressing our understanding of the impacts of nutrition on the brain and behaviour in anorexia nervosa: a tyrosine case study example

Journal of Eating Disorders ◽

10.1186/s40337-021-00439-z ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Melissa Hart ◽

David Sibbritt ◽

Lauren T. Williams ◽

Kenneth P. Nunn ◽

Bridget Wilcken

Keyword(s):

Anorexia Nervosa ◽

New England ◽

Ethics Committee ◽

Adjunct Treatment ◽

Human Research Ethics ◽

Pharmacological Response ◽

Efficacious Treatment ◽

The Brain ◽

Noradrenaline And Adrenaline

AbstractAnorexia nervosa is a severe and complex illness associated with a lack of efficacious treatment. The effects of nutrition on the brain and behaviour is of particular interest, though an area of limited research. Tyrosine, a non-essential amino acid, is a precursor to the catecholamines dopamine, noradrenaline and adrenaline. Ongoing tyrosine administration has been proposed as an adjunct treatment through increasing blood tyrosine sufficiently to facilitate brain catecholamine synthesis. The effects of tyrosine supplementation in adolescents with anorexia nervosa remain to be tested. This study had approval from the Hunter New England Human Research Ethics Committee (06/05/24/3.06). We aimed to explore the pharmacokinetics of tyrosine loading in adolescents with anorexia nervosa (n = 2) and healthy peers (n = 2). The first stage of the study explored the pharmacological response to a single, oral tyrosine load in adolescents (aged 12–15 years) with anorexia nervosa and healthy peers. Participants with anorexia nervosa then continued tyrosine twice daily for 12 weeks. There were no measured side effects. Peak tyrosine levels occurred at approximately two to three hours and approached baseline levels by eight hours. Variation in blood tyrosine response was observed and warrants further exploration, along with potential effects of continued tyrosine administration in anorexia nervosa.

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