Brain Ponderings podcast with Mark Mattson

There are approximately 7000 rare diseases each affecting fewer than 200,000 Americans.  Most rare disorders are caused by gene mutations, manifest in childhood, include neurological problems, and progress rapidly resulting in death in the first several decades of life. Examples include fragile X and Rett syndromes, some childhood epilepsies, Batten diseases, and several types of ataxias,  In most instances there are no treatments that slow or reverse the disease process. In this episode I talk with Professor Erika Augustine who is the Associate Chief Science Officer and Director of the Clinical Trials Unit at the Kennedy – Krieger Institute which is devoted to research on and treatment of neurological conditions caused by genetic disorders, birth complications, or traumatic injuries with a focus on children and adolescents.  Dr. Augustine talks about the scope of the problems faced by patients with a rare disorder, their families, neurologists, government agencies, and the pharmaceutical industry. To exemplify both the challenges and progress towards effective treatments Dr. Augustine focuses on Batten diseases caused by mutations that impair lysosome functions and cause severe progressive neurological deficits that begin early in life. An effective treatment for one of the Batten diseases was recently approved by the FDA providing one of the first successes in moving from basic research to the clinic. LINKS: Dr. Augustine’s biography in Wikipedia: https://en.wikipedia.org/wiki/Erika_F._Augustine Kennedy – Krieger Institute: https://www.kennedykrieger.org/?gad_source=1&gclid=CjwKCAjwl6-3BhBWEiwApN6_ksQGX9fZCTAZpUSzJNw4sHdr2EyRmm_d3tYPHzQpAEOpBuC0uDGZVRoCSGQQAvD_BwE Batten Diseases Clinical Trials: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736171/pdf/nihms-1641434.pdf Enzyme replacement therapy for CLN2 Batten disease: https://www.pedneur.com/action/showPdf?pii=S0887-8994%2820%2930149-1 Gene therapy for rare neurological disorders: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527017/pdf/fnmol-14-695937.pdf

In this episode I provide an overview of what happens in brain cells during aging and how those changes result in impaired brain function and predispose to Alzheimer’s and Parkinson’s diseases. I then describe three lifestyle anti-aging interventions that are known to slow brain aging and counteract disease process: physical exercise; intermittent fasting; and intellectual challenges.  LINKS Hallmarks of brain aging: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039826/pdf/nihms979409.pdf Exercise and brain health: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880155/pdf/cshperspectmed-BEX-a029736.pdf Intermittent fasting and brain health: https://www.amazon.com/Intermittent-Fasting-Revolution-Optimizing-Performance/dp/0262046407 Environmental enrichment: https://pubmed.ncbi.nlm.nih.gov/30723309/ Hormesis and brain health: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096685/pdf/10.1177_1559325818784501.pdf

Chronic pain is a highly prevalent problem in need to improved treatments. In this episode I talk with Dr. Shiqian Shen of Harvard Medical School about his research on interactions between the immune and nervous systems in chronic pain. He has found an interesting connection between the gut microbiota, immune cells, and neurons in chronic pain. These findings suggest new approaches for treating chronic pain.   LINKS https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575957/pdf/nihms887104.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9974100/pdf/jci-133-166408.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11320346/pdf/ACEL-23-e14177.pdf

Anxiety disorders are all too common in children and adolescents and their incidence has increased considerably during the past decade. Social interactions (positive or negative) in the home, schools, and the digital world have a major influence on a child’s risk for anxiety and major depression. In this episode I talk with Dr. Danny Pine at the National Institute of Mental Health who has devoted his career to the problem of mental health problems in children. His research has advanced an understanding of the complex factors that determine whether or not a child develops an anxiety disorder, the brain circuits involved, and the behavioral and pharmacological interventions that can provide effective treatments.  LINKS  Dr. Pine’s NIH webpage: https://www.nimh.nih.gov/research/research-conducted-at-nimh/research-areas/clinics-and-labs/edb/sdan Articles https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9248771/pdf/nihms-1797515.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490291/pdf/nihms-1734583.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9931491/pdf/nihms-1858084.pdf    

Cells in all organ systems experience the same ‘hallmarks of aging’ which include the accumulation of oxidatively damaged proteins, DNA, membranes and mitochondria, impaired DNA repair and autophagy, senescence, and inflammation. In this episode Professor Ron DePinho of the MD Anderson Cancer Center in Houston talks about his remarkable career during which he and his trainees established fundamental mechanisms that control cell proliferation and differentiation in normal development and how alterations in these mechanisms result in aging and cancers. He then describes how the telomerase protein influences hallmarks of aging by controlling gene expression, and how age-related reductions in telomerase levels contribute to normal aging and the pathogenesis of Alzheimer’s disease. Ron and his colleagues have recently identified a chemical called TAC that can increase telomerase levels in cells. Treatment of old mice with TAC rejuvenates multiple organ systems, and can restore neuroplasticity and cognition in mouse models of Alzheimer’s disease.  LINKS: DePinho laboratory web page: https://www.mdanderson.org/research/departments-labs-institutes/labs/depinho-laboratory.html Related Articles: https://www.cell.com/action/showPdf?pii=S0092-8674%2820%2931750-5 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733214/pdf/nihms487161.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759755/pdf/nihms-1761822.pdf https://pubmed.ncbi.nlm.nih.gov/38908367/

All cells including neurons in the brain release tiny (~ 100 nanometers in diameter) bubble-like vesicles that contain various molecules produced by the cell. These extracellular vesicles (EVs) are thought to have a variety of functions including sending molecular messages between cells and removing molecular garbage from the cells. Some EVs released from cells throughout the body and brain make their way into the bloodstream. Dimitrios Kapogiannis at the National Institute on Aging Biomedical Research Center in Baltimore, developed a technology for isolating EVs produced by neurons from the blood. By measuring amounts of abnormal Tau protein in neuronal EVs from patients with Alzheimer’s disease (AD) and controls, and in longitudinal studies of people in the years preceding their cognitive impairment,  he showed that his test can identify people who will very likely become symptomatic.  It turns out that neuronal EVs have insulin receptors in their membrane and Dimitrios provided evidence that neuronal EVs from AD patients exhibit insulin resistance. Because intermittent fasting can increase the sensitivity of cells to insulin and is effective in countering the disease process in AD mouse models, Dimitrios performed a clinical trials of intermittent fasting in older individuals with insulin resistance and found that it improved their performance on several memory tests. More recently he headed a clinical trial of a ketone ester in patients in older people at risk for AD. This episode is all about EVs – where they come from, the kinds of molecules they contain, their normal functions, and changes in EVs in Alzheimer’s disease (AD) and other brain disorders that can be used for diagnosis and in clinical trials.   LINKS  Dr. Kapogiannis’ NIA webpage: https://www.nia.nih.gov/about/staff/kapogiannis-dimitrios Review articles on EVs: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439289/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9985115/pdf/nihms-1878107.pdf  Key publications: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314222/?report=printable https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632160/?report=printable https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146429/pdf/cells-10-00993.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10060702/pdf/awac258.pdf

While upon casual inspection the left and right sides of the human brain seem symmetrical. But it turns out there are left – right differences in both the structure and functionality of neuronal networks in many brain regions. One well-known example of a brain asymmetry is that regions involved in language comprehension and speech which are located in the left hemisphere. Another example concerns handedness for which neural circuits are more robust on the contralateral side of the brain. In this episode I talk with professor Sebastian Oklenburg about his research on lateralized brain functions including their evolutionary and developmental origins, their adaptive value, their roles in cognition and emotion, and how they are impacted in certain brain disorders.  LINKS Professor Ocklenburg’s blog on Psychology Today: https://www.psychologytoday.com/us/blog/the-asymmetric-brain Brain lateralization – evolutionary perspective: https://journals.physiology.org/doi/epdf/10.1152/physrev.00006.2019  Brain asymmetries and neurological disorders: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8712556/pdf/fnsys-15-733898.pdf Building an asymmetric brain: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524718/pdf/fpsyg-10-00982.pdf

The ‘exposome’ is a term used to describe all of the environmental exposures encountered by an individual throughout their life and how these exposures affect their health and contribute to (or protect against) aging and disease. The exposures may be physical (e.g., temperature), chemical (e.g., toxic chemicals), biological (e.g., viruses), or social (psychological trauma).  In this episode I talk with University of Michigan professor of neurology Eva Feldman, about research aimed at identifying environmental factors that promote, cause, or protect against  neurological disorders. Exposome research is of vital practical importance because environmental factors and aging are responsible for the most common neurological disorders.   LINKS Dr. Feldman’s webpage https://medicine.umich.edu/dept/mneuronet/about/eva-l-feldman-md-phd Exposome review articles https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.26897 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10643494/pdf/11357_2023_Article_913.pdf https://www.annualreviews.org/docserver/fulltext/pharmtox/63/1/annurev-pharmtox-051922-113350.pdf?expires=1722005819&id=id&accname=guest&checksum=97B61448008EE60ABAA4CA80EFF3D878

It turns out that regardless of which organ they affect tumors contain a web of axons coursing throughout them. Recent research has shown that interactions between the neurons and the cancer cells influence the proliferation of the cancer cells within the tumor as well as metastasis (the spread of cancer cells to other organs). In this episode I talk with University of Newcastle Professor Hubert Hondermarck about his research on interactions between neurons and cancer cells, and the roles of neurotrophic factors and neurotransmitters in facilitating tumor growth. Knowledge gained from this research is leading to new pharmacological approaches to treating cancers. LINKS Professor Hondermarck’s webpage: https://www.newcastle.edu.au/profile/hubert-hondermarck Review “The Neural Addiction of Cancers”: https://www.proquest.com/docview/2806715386/fulltextPDF/7785F348C7744E4PQ/9?accountid=11752&sourcetype=Scholarly%20Journals

Plants sense their environment and respond in ways consistent with advanced decision-making capabilities. The cellular mechanisms that control the behaviors of plants are similar to those of animals and include electrically excitable cells capable of transmitting information via calcium waves and volatile messengers such as nitric oxide throughout roots, shoots, and leaves. Molecular genetic studies have shown that plants have receptors for the neurotransmitters glutamate and GABA, and that these neurotransmitters control many plant behaviors. Individual plants communicate with other plants, insects, fungi, and bacteria via the stimulus-dependent production and release of a myriad of chemicals. In this episode I talk with Bonn University Professor Frantisek Baluska about the behavioral repertoire of plants, the underlying cellular mechanisms, and the rationale and value of considering plants as sentient and intelligent organisms.  LINKS  Individuality and Sociality of Plants: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934911/pdf/rstb.2019.0760.pdf  Anesthetics and Plant Consciousness: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907011/pdf/709_2020_Article_1594.pdf  Predictive Coding Model of Plant Behavior: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5047902/pdf/fpsyg-07-01505.pdf  Plants Behaviors and Climate Change: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054678/pdf/EMBR-21-e50109.pdf