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Researchers Work to Reverse Cognitive Decline as People Age

Depression results in lower levels of synaptic density, which come with associated cognitive symptoms. | Peterschreiber Media/Adobe Stock

Depression accelerates aging in the brain, but scientists are expanding their understanding of its effects and making strides toward developing drugs to treat associated cognitive symptoms, according to research revealed at a Feb. 14 news briefing at the 2019 AAAS Annual Meeting in Washington, D.C.

The healthy aging brain sees a gradual decline in the density of synapses – the structures that transfer information between cells in the brain – said Irina Esterlis, associate professor of psychiatry at Yale University.

This process unfolds over many decades, so “you’re not going to notice cognitive, emotional or social changes until later in life,” Esterlis said.

The brain of a person with depression, by contrast, sees a more rapid decline in synaptic density, she said. This lower synaptic density causes accelerated aging in the brain, which is associated with cognitive decline.

The lower the synaptic density, the less effective are an individual’s skills related to working and visual memory, visual perception and attention, Esterlis explained. Lower synaptic density is also associated with higher levels of anhedonia – the inability to feel pleasure, she said.

Esterlis has used positron emission topography scans to identify the differences in the brains of healthy individuals from those with depression, which can be seen as early as age 40. Her PET imaging studies also reveal that more severe depression results in lower levels of synaptic density – and thus more severe cognitive symptoms – than those with less severe depression.

Irina Esterlis, Etienne Sibille and Daniela Kaufer spoke in a press briefing Thursday at the 2019 AAAS Annual Meeting. | Robb Cohen Photography & Video

Despite that symptoms like memory decline are associated with many neuropsychiatric disorders, no medication currently used to treat such disorders specifically addresses cognitive symptoms, said Etienne Sibille, professor of psychiatry, pharmacology and toxicology at the University of Toronto. “What we need is novel drugs with novel mechanisms,” said Sibille.

Researchers are making progress on a drug to address the underlying causes of the symptoms, identifying a particular deficit at the cellular level and developing molecules to address the deficit, he said.

Sibille shared the effects of this compound on animals: Older mice and mice that have been stressed see deficits in their working memory abilities. Within 30 minutes of injection of the drug, the older or stressed mice performed at the same levels as young mice. Newly released data also show that after two months of treatment with the drug, the synapse levels of old mice have been brought back to the levels seen in young mice, “rejuvenating the brain,” said Sibille.

The researchers submitted a patent for the compound shortly before their briefing and aim to begin testing the compound in a clinical setting in about two years, Sibille said.

Daniela Kaufer, professor of integrative biology at the University of California, Berkeley, shared progress toward addressing another cause of cognitive decline: dysfunction of the blood-brain barrier. The blood-brain barrier ordinarily protects the brain, but Kaufer’s work shows that when the barrier falters, itself a sign of aging, proteins can enter brain cells called astrocytes, which causes inflammation in the brain and leads to cognitive impairments.

Teaming up with molecular chemists to create a drug to address this dysfunction, Kaufer expected that its use in animals might only prevent future cognitive decline. In fact, it reversed the underlying cause of the dysfunction, which resulted in older animals performing at the levels of young animals, Kaufer said.

“This understanding from the mice is very exciting for us. The next step is to ask questions of what this means for humans,” said Kaufer, noting that other researchers are taking up this mantle.

“If we can identify those who have lower synaptic density, for example, in the hippocampus, and we can identify them early on,” Esterlis said, the ability to treat cognitive decline can improve the lives of individuals suffering from these symptoms.