NOTE: This lecture with slides presented can be found on the Brain Ponderings YouTube Channel.

This episode begins by highlighting recent evidence showing adverse effects on the brain of excessive activation of the mTOR pathway as a consequence of dietary branched chain amino acid consumption. Then I describe evidence that Beyond the age of 40 years brain aging results in progressive decrements in function which are associated with reductions in gray matter and synapse numbers particularly in brain regions that play critical roles in memory, executive functions, and task switching. Recent progress has been made in identifying molecular markers of brain aging in samples of blood or cerebrospinal fluid heralding a better understanding of factors that accelerate or retard brain aging. This episode reviews some of the salient research in these areas.

NOTE: This lecture with slides presented can be found on the Brain Ponderings YouTube Channel.

This video describes 12 major changes that occur in brain cells during aging and their involvement in decline in brain function and the development of neurodegenerative disorders including dementia and Parkinson's disease.

The lipid membrane bilayer of cells is composed of fats including phospholipids, cholesterol, and sphingomyelin. Enzymes called sphingomyelinases can cleave sphingomyelin resulting in the liberation of ceramides which can diffuse within the cell and act as signaling molecules. In this episode I talk with Tulane University Professor Norm Haughey about research in his laboratory and others which have shown that levels of certain ceramides are increased in the brain, cerebrospinal fluid, and blood of patients with Alzheimer's disease, HIV-associated cognitive disorder, and other neurological disorders. Elevated ceramides may provide a biomarker for individuals at risk for these disorders. Dr. Haughey and his collaborators have shown that drugs that inhibit a particular sphingomyelinase can prevent degeneration of neurons and associated cognitive impairment in animal models of Alzheimer's disease and HIV.

Norm Haughey's laboratory webpage: https://haugheylab.org/

Relevant articles

https://pmc.ncbi.nlm.nih.gov/articles/PMC2907186/pdf/nihms-209661.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC2933928/pdf/nihms200180.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC3144420/pdf/nihms309072.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC3414665/pdf/znl633.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC7852391/pdf/aba5210.pdf

https://www.sciencedirect.com/science/article/pii/S0969996123000013?via%3Dihub

https://pmc.ncbi.nlm.nih.gov/articles/PMC10334757/pdf/pnas.202219543.pdf

Brain tumor cells interact with neurons, glial cells, and immune cells in complex ways that often benefit the cancer cells while compromising the function of normal neural cells. In this episode I talk with Washington University Neurology Professor David Gutmann about brain cancer cells and their communication with surrounding normal cells. A major component of Dr. Gutmann's research program focuses on Neurofibromatosis a rare genetic disorder that causes non-malignant brain tumors as well as abnormal growth of cells in other organ systems. The disease results from loss-of-function mutations in the NF1 protein which normally functions to constrain cell growth. Discoveries concerning the 'sociobiology' of brain tumors is providing a foundation for the development of new approaches for treating a range of cancers.

LINKS

Dr. Gutmann's Wikipedia page: https://en.wikipedia.org/wiki/David_H._Gutmann

Related articles:

https://pmc.ncbi.nlm.nih.gov/articles/PMC10107403/pdf/nihms-1872327.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC9883043/pdf/nihms-1861630.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC11972679/pdf/djae249.pdf

There is considerable evidence that exposure to certain chemicals in the environment cause Parkinson's disease in many people. In this episode neurologist Ray Dorsey talks about some of the chemicals that may cause Parkinson's disease including the pesticides paraquat and rotenone, and trichloroethylene and perchloroethylene which are chemicals used for degreasing and dry-cleaning.

LINKS

Relevant journal articles:

https://www.thelancet.com/action/showPdf?pii=S1474-4422%2825%2900287-X

file:///Users/markmattson/Downloads/Annals%20of%20Neurology%20-%202008%20-%20Gash%20-%20Trichloroethylene%20%20Parkinsonism%20and%20complex%201%20mitochondrial%20neurotoxicity%20(1).pdf

Book on how to reduce one's risk for Parkinson's disease:

https://www.amazon.com/Parkinsons-Plan-Path-Prevention-Treatment/dp/1541705386/ref=sr_1_1?adgrpid=186412556077&dib=eyJ2IjoiMSJ9.8jetPIdc_D3gQSod-GXEVDXUJcI1IMKFz7jXpUf0jZt-LxGsRBm9oV9TQGQJK_FDpWNY4KOJrayE8WoGPJsMXbouqzGwj3UhO0CZZGHmz8g.M4hWGhlS7Crp9zwfODlDDDNnseiHLTdHHBLooZ1LR-M&dib_tag=se&hvadid=779621628364&hvdev=c&hvexpln=0&hvlocphy=9007816&hvnetw=g&hvocijid=14825241056223650898--&hvqmt=b&hvrand=14825241056223650898&hvtargid=aud-2443140936121%3Akwd-936298351901&hydadcr=15520_13558534_8423&keywords=ray+dorsey+parkinson&mcid=c3eec2c85d703461a8216f138ac2c1e7&qid=1762952366&sr=8-1#averageCustomerReviewsAnchor

A shared feature of neurodegenerative disorders is accumulation of aggregated proteins within neurons: Tau in Alzheimer's disease; alpha-synuclein in Parkinson's disease; huntingtin in Huntington's disease; and TDP43 in amyotrophic lateral sclerosis. In this episode Ai Yamamoto – an Associate Professor Neurology at Columbia University – talks about the trail of discoveries that led to the identification of a protein called ALFY that can prevent and reverse the accumulation of such pathogenic proteins. Remarkably, her team and collaborators found that some people have a variant of the gene encoding ALFY that confers resistance of those individuals to Huntington's disease. This discovery opens many new and exciting directions for future research aimed at better understanding what goes wrong in neurodegenerative disorders and for developing interventions counteract the disease process.

LINKS

Yamamoto Laboratory web page: https://www.aiyamamoto-lab.org/

Dr. Yamamoto's publications: https://scholar.google.com/citations?hl=en&user=HuJslgMAAAAJ&pagesize=80&view_op=list_works

Key research articles:

https://www.cell.com/action/showPdf?pii=S0896-6273%2825%2900624-5

file:///Users/markmattson/Downloads/s41583-022-00588-3.pdf

https://www.cell.com/action/showPdf?pii=S0896-6273%2819%2931045-1

Remarkable advances are being made in the development and clinical applications of stimulation devices that enable recovery of motor function in patients who have suffered a spinal cord injury, a stroke, and even those with rare disabling genetic disorders. At the forefront of this research is Marco Capogrosso at the University of Pittsburgh. He has shown that certain patterns of stimulation of sensory pathways in the spinal cord can activate motor neurons that were otherwise silenced by the injury or stroke. Initial clinical trials have shown that this approach results in recovery of function which are in some cases very dramatic in patients that have had a stroke, a spinal cord injury, and in people with the genetic disorder spinal muscular atrophy. In this episode Dr. Capogrosso talks about the development of this stimulation-based therapeutic approach, the clinical trials, and the potential applications of this technology to other neurodegenerative disorders.

LINKS

Dr. Capogrosso's profile at the University of Pittsburgh:

https://www.neurosurgery.pitt.edu/people/marco-capogrosso

Key studies discussed in this podcast:

Stroke

https://pmc.ncbi.nlm.nih.gov/articles/PMC10291889/pdf/nihms-1904547.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC12393459/pdf/nihpp-rs7271578v1.pdf

Spinal cord injury

https://pmc.ncbi.nlm.nih.gov/articles/PMC5108412/pdf/emss-70056.pdf

https://www.cell.com/neuron/fulltext/S0896-6273(25)00658-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627325006580%3Fshowall%3Dtrue#

Spinal muscular atrophy

https://www.nature.com/articles/s41591-024-03484-8