Degeneration in two brain regions causes severe narcolepsy symptoms

For nearly 25 years, scientists believed they knew what caused the most severe form of narcolepsy. A new UCLA Health study now suggests they were only half correct.

In a study published in Nature Communications, UCLA Health researchers discovered that narcolepsy with sudden loss of muscle strength, known as cataplexy, involves degeneration of neurons in not one, but two regions of the brain.

Using a combination of postmortem brains and animal models, UCLA researchers found degeneration of neurons in a second critical region located on the brainstem known as the locus coeruleus. This small but important cluster of cells produces norepinephrine, a neurotransmitter involved in arousal and the regulation of muscle tone.

"The locus coeruleus has both upward connections that contribute to wakefulness and downward connections that help maintain muscle tone," said the study's first author Thomas Thannickal, associate researcher at the David Geffen School of Medicine at UCLA. "That makes it a compelling candidate for explaining both of the defining symptoms of narcolepsy of sleepiness and cataplexy in a way that the neuronal degeneration in the hypothalamus alone does not fully account for."

Narcolepsy affects roughly one in 2,000 people and is characterized by excessive daytime sleepiness. In its most severe form (known as narcolepsy type 1), it can cause sudden episodes of muscle weakness triggered by emotion, a symptom known as cataplexy.

In the study, researchers used postmortem brain tissue from 11 individuals diagnosed with narcolepsy with cataplexy and five neurologically healthy controls. Every single narcolepsy patient showed a substantial loss of neurons in the locus coeruleus. On average, narcolepsy patients had 46% fewer of these norepinephrine-producing neurons compared to controls, with losses in individual patients ranging from 28% to 66%.

Notably, the neurons that survived were about 18% larger than normal, which suggests the remaining cells must work harder to compensate for their lost neighbors.

The research team also found signs of neuroinflammation in the locus coeruleus. The brain's immune cells, known as microglial cells, were more than twice as numerous in narcolepsy patients as in controls and were significantly larger. A similar pattern of microglial clustering was observed around hypocretin neurons in the hypothalamus.

Together, these findings point toward an immune-mediated process, consistent with the well-established link between narcolepsy and certain immune system genes.

The surviving locus coeruleus neurons also showed few of the protein deposits typically seen in Parkinson's or Alzheimer's disease, suggesting the cell loss in narcolepsy follows a distinct and likely immune-driven pathway rather than a typical neurodegenerative one.

To test whether the locus coeruleus loss was simply a consequence of losing hypocretin neurons, the researchers examined two mouse models of narcolepsy and narcoleptic dogs. None of these models showed any reduction in their locus coeruleus neurons. This finding indicates that the brainstem damage observed in the human patients is not merely a downstream effect of hypocretin loss, but rather a separate feature of the human disease.

The study also found deposits of tau and alpha-synuclein (proteins associated with Alzheimer's and Parkinson's diseases respectively) in the locus coeruleus of narcolepsy patients, a finding the authors say warrants further investigation.

The research adds context to a long-standing puzzle in narcolepsy diagnosis: between 15-30% of patients who meet clinical criteria for narcolepsy with cataplexy have normal hypocretin levels in their cerebrospinal fluid. The involvement of a second neuronal system may help account for cases that don't fit neatly into the hypocretin-deficiency model.

The findings may also help explain why certain treatments work. Drugs that boost norepinephrine activity, such as reboxetine and solriamfetol, produce meaningful symptom relief, which is consistent with a significant role for the locus coeruleus in the disease.

Co-authors of the study included neuropathologist Dr. Marcia Cornford at Harbor-UCLA Medical Center and Dr. Ming-Fung WU from UCLA health.

Source:

University of California - Los Angeles Health Sciences

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