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New MRI Technique Can Visualize Brain Molecular Composition, Study Shows

MRI molecular composition

A new magnetic resonance imaging (MRI) technique allows for the visualization of molecular changes in the brain, a study reports.

This technique will allow researchers to further understand how the brain works and how it changes with ageing or during the onset of neurodegenerative diseases like Parkinson’s.

Moreover, in the future, clinicians may use the brain’s “molecular signature” for early diagnoses — allowing patients to get access to treatment at early stages of disease and increasing their likelihood for better outcomes.

The study, “Disentangling molecular alterations from water-content changes in the aging human brain using quantitative MRI,” was published in the journal Nature Communications.

An MRI scan is obtained using magnetic fields and powerful detectors that track water compositions in tissues. However, brain function depends vastly on molecular interactions within the brain that current MRI scans fail to detect.

“When we take a blood test, it shows us the exact number of white blood cells [key cells of the immune system] in our body and whether that number is higher than normal due to illness,” Shir Filo, a PhD student and the study’s first author, said in a press release.

“MRI scans provide images of the brain but don’t show changes in the composition of the human brain, changes that could potentially differentiate normal aging from the beginnings of Alzheimer’s or Parkinson’s,” Filo added.

Now, researchers found a way to “see” the brain composition at the molecular level. The technique, called quantitative MRI, is able to detect changes in the molecular composition of lipid (fat) molecules within the brain.

The research was led by Aviv Mezer and his team at the Hebrew University of Jerusalem (HUJI)’s Edmond and Lily Safra Center for Brain Sciences.

“Instead of images, our quantitative MRI model provides molecular information about the brain tissue we’re studying. This could allow doctors to compare brain scans taken over time from the same patient, and to differentiate between healthy and diseased brain tissue, without resorting to invasive or dangerous procedures, such as brain tissue biopsies,” Mezer said.

Researchers started by testing their new MRI technique in synthetic, or lab-made complex fat mixtures to validate whether the MRI scans were sensitive enough to detect changes at the molecular level.

The results revealed their technique was able to distinguish between different lipids with high sensitivity. Because the brain is rich in lipids — such as phosphatidylcholine, sphingomyelin or phosphatidylcholine-cholesterol — the team used a measurement called macromolecular tissue volume (MTV) that provides quantitative information about these molecules in a sample.

Quantitative MRI scans of human brains revealed that MTV measures changed depending on the brain region analyzed, demonstrating that this technique works like a detailed map of the living brain.

Importantly, using post-mortem (after death) brain samples, the team found that the variability of certain MTV parameters between human brain regions also correlated with specific gene-expression profiles. Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.

Next, the researchers investigated whether the molecular composition of the brain varied according to age, specifically young versus old. They scanned 23 young adults (mean age 27 years) and 18 older adults (mean age 67 years).

Researchers focused their analysis on the brain’s white and gray matter. White matter is made up of nerve cell projections, known as axons or fibers, that connect distinct parts of gray matter. The length and condition of the fibers influence the way the brain processes information. Gray matter includes neuronal cell bodies as well as synapses, or the junctions between nerve cells that allow them to communicate with each other.

The results showed not only evident changes in the brain’s size, but also tiny and region-specific molecular changes in various brain regions related to aging. Even in the absence of age-related reductions in brain size, molecular changes were detected using the new MRI technique.

Overall, this supports the potential of this new type of MRI method to better understand how our brains age.

“[W]hen we scanned young and old patients’ brains, we saw that different brain areas ages differently. For example, in some white-matter areas, there is a decrease in brain tissue volume, whereas in the gray-matter, tissue volume remains constant. However, we saw major changes in the molecular makeup of the gray matter in younger versus older subjects,” Mezer said.

Researchers hope that, in the future, they can apply this new MRI technique to provide an early diagnosis of diseases like Parkinson’s. That could allow access to treatment that may delay or even halt disease progression.

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Lewy Bodies Are Made of Much More than Alpha-Synuclein, Study Finds

Lewy bodies

Insoluble alpha-synuclein protein has long been thought to be the main component of Parkinson’s hallmark Lewy bodies, but researchers have now reported these abnormal aggregates are also made of cell membrane fragments, fat-like substances, and other cellular components.

This finding was reported in a study, “Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes,” that was published in the journal Nature Neuroscience.

Parkinson’s disease is a neurodegenerative disorder characterized by selective death of midbrain dopamine-producing neurons due to clustering of a protein called alpha-synuclein in structures commonly known as Lewy bodies.

For decades, scientists have believed that alpha-synuclein fibrils (meaning “small fibers”) were the main component of and at Lewy bodies’ core. However, investigators have now contested such belief after studying postmortem human brain tissue from patients with Parkinson’s disease.

Combining imaging techniques, the researchers were able to re-create the 3D structures of these disease-associated clusters. They found that besides alpha-synuclein, Lewy bodies also have membrane fragments, vesicular structures, and abnormal organelles (organ-like structures found inside cells) such as mitochondria — cells’ powerhouses.

Many, but not all, Lewy bodies with alpha-synuclein within them had protein fibers scattered between membrane fragments and organelles. Importantly, a non-fibrillar form of alpha-synuclein was also found to be intermingled with the other contents of the Lewy bodies.

“We used correlative light and electron microscopy and other advanced light microscopy methods to take a closer look at the brain of deceased Parkinson’s patients and discovered that the Lewy bodies consist mainly of membrane fragments from mitochondria and other organelles, but have in most cases no or only negligible quantities of protein fibrils,” Henning Stahlberg, PhD, professor and researcher at the University of Basel in Switzerland, and one of the study’s senior authors, said in a press release.

“The discovery that alpha-synuclein did not present in the form of fibrils was unexpected for us and the entire research field,” Stahlberg said.

The researchers also found that the bodies carried fat-like substances similar to those found in healthy brain cells, like myelin (nerve cells’ protective fatty layer) or fatty components of cell membranes.

“We present here a new theoretical model in which lipid membrane fragments and distorted organelles together with a non-fibrillar form of [alpha-synuclein] are the main structural building blocks for the formation of Lewy pathology,” the researchers stated.

Several studies have linked disturbances in intracellular movement of molecules and organelles with Parkinson’s disease. In addition, alpha-synuclein has been shown to be capable of disrupting the integrity of mitochondrial membranes, manipulating and reorganizing membrane components, and leading membranes to form vesicles under specific biochemical conditions.

Collectively, the study’s findings support the hypothesis of abnormal movement of organelles as a potential driver of Parkinson’s disease mechanism. Also, they “emphasize the need to consider population heterogeneity of Lewy pathology” and show that lipids (cells’ fatty molecules) could play an important role, the researchers said.

“The questions why it has taken so long to better characterize Lewy bodies can perhaps be answered with the previous sample preparation and electron microscopy methods. Today’s technologies enable us to have a much more detailed look into the morphology of [the] human brain,” Stahlberg said. “The big question for us now is: How does alpha-synuclein contribute to the formation of Lewy bodies, if not present in [the] form of fibrils?”

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Enzyme Linking Fatty Acids to Alpha-synuclein Could Be Parkinson’s Therapeutic Target, Study Suggests

alpha-synuclein, fatty acids

Inhibiting an enzyme that regulates the production of fatty acids may protect against brain toxicity induced by alpha-synuclein in Parkinson’s disease and may become a therapeutic target for these patients, a study reports.

The study, “Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment,” was published in the journal Molecular Cell.

The brain is rich in lipids, or fats, which are key for neural development and nerve cell communication. Brain cells tightly regulate lipid production and uptake, as well as the distribution of its precursors, such as fatty acids. Imbalance of the brain’s lipids has been implicated in several neurodegenerative diseases, including Parkinson’s.

Alpha-synuclein, the main component of protein clumps known as Lewy bodies, interacts with fatty acids and favors their storage as triglycerides — the most common type of fat in the body — in lipid droplets in cells.

These droplets prevent the toxic effects of lipid accumulation, but may also contribute to the deposition of alpha-synuclein. Proteins related to lipid metabolism have been identified as risk factors for Parkinson’s. However, little is known about the impact of lipid metabolism on alpha-synuclein assembly and cellular alterations.

Researchers first measured lipids and fatty acid alterations in yeast that had been engineered to produce alpha-synuclein. This showed an increase in components of the neutral lipids pathway — storage lipids lacking positively and/or negatively charged groups — including a monounsaturated fatty acid called oleic acid. The team thereby hypothesized that high oleic acid levels promote the binding of alpha-synuclein to the cell membrane, increasing toxicity.

These findings were then replicated in patient cell lines, in a mouse model of familial Parkinson’s, and in a model of dopamine-producing neuron degeneration (a hallmark of Parkinson’s) in the nematode worm Caenorhabditis elegans.

“It was fascinating to see how excess [alpha-synuclein] had such consistent effects on the neutral lipid pathway across model organisms,” Ulf Dettmer, PhD, co-senior author of the study from the Brigham and Women’s Hospital and Harvard Medical School, said in a press release. “All our models clearly pointed at oleic acid as a mediator of [alpha]-synuclein toxicity.”

Researchers investigated possible ways to target fatty acids or the processes leading to their production that could protect against Parkinson’s. They found that triglycerides protect from alpha-synuclein-induced toxicity by preventing the accumulation of oleic acid and diglyceride, a type of fat composed of two fatty acid chains.

Importantly, they found that inhibiting an enzyme known as stearoyl-CoA-desaturase (SCD), which is key in the production of oleic acid, protected against cell toxicity, formation of alpha-synuclein aggregates, and a decrease in the amount of protective alpha-synuclein tetramers (natural structure formed by four subunits) relative to its aggregation-prone monomers, or single-protein chains.

“Our findings thus indicate that partial inhibition of SCD would be a rational therapeutic approach to [alpha-synuclein] neurotoxicity,” the researchers wrote.

“We’ve identified a pathway and a therapeutic target that no one has pursued before,” said Saranna Fanning, PhD, the study’s lead author.

Co-senior author Dennis Selkoe, MD, said the findings present “a unique opportunity for small-molecule therapies to inhibit the enzyme in models of [Parkinson’s] and, ultimately, in human diseases.”

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