Medical Bulletin 08/ March/ 2024

Scientists from the Broad Institute of MIT, Harvard Medical School, and McLean Hospital have found similar gene activity changes in brain tissue from individuals with schizophrenia and older adults. These findings imply a shared biological foundation for cognitive decline seen in both groups.

The study published in the Journal Nature, revealed that in individuals with schizophrenia and in older adults without schizophrenia, two brain cell types called astrocytes and neurons reduced their expression of genes that support the junctions between neurons called synapses, compared to healthy or younger people.

Schizophrenia is a challenging mental disorder marked by symptoms like hallucinations, delusions, and cognitive decline. Treatment involves medication, therapy, and support services, but managing the disorder can still be complex due to its multifaceted nature and limited treatment options for cognitive decline.

The team analysed gene expression in more than a million individual cells from postmortem brain tissue from 191 people and discovered tightly synchronised gene expression changes in the two cell types: when neurons decreased the expression of certain genes related to synapses, astrocytes similarly changed the expression of a distinct set of genes that support synapses. The team called this coordinated set of changes the Synaptic Neuron and Astrocyte Program (SNAP). Even in healthy, young people, the expression of the SNAP genes always increased or decreased in a coordinated way in their neurons and astrocytes.

"Science often focuses on what genes each cell type expresses on its own," said Steve McCarroll, a co-senior author on the study and an institute member at the Broad Institute. "But brain tissue from many people, and machine-learning analyses of those data, helped us recognize a larger system. These cell types are not acting as independent entities, but have really close coordination. The strength of those relationships took our breath away."

The findings revealed that SNAP varied greatly even among people without schizophrenia, suggesting that SNAP could be involved in cognitive differences in healthy humans. Much of this variation was explained by age; SNAP declined substantially in many -- but not all -- older individuals, including both people with and without schizophrenia.

“With better understanding of SNAP, it might be possible to identify life factors that positively influence SNAP, and develop medicines that help stimulate SNAP, as a way to treat the cognitive impairments of schizophrenia or help people maintain their cognitive flexibility as they age.” concluded McCarroll.

Reference: Emi Ling, James Nemesh, Melissa Goldman, Nolan Kamitaki, Nora Reed, Robert E. Handsaker, Giulio Genovese, Jonathan S. Vogelgsang, Sherif Gerges, Seva Kashin, Sulagna Ghosh, John M. Esposito, Kiely Morris, Daniel Meyer, Alyssa Lutservitz, Christopher D. Mullally, Alec Wysoker, Liv Spina, Anna Neumann, Marina Hogan, Kiku Ichihara, Sabina Berretta, Steven A. McCarroll. A concerted neuron–astrocyte program declines in ageing and schizophrenia. Journal: Nature, 2024; DOI: 10.1038/s41586-024-07109-5

Elevated BMI is notably linked to poorer mental health, particularly among women

According to a study published in PLoS ONE, increased adiposity is linked with depression and well-being. Higher BMI is significantly associated with worse mental health, especially in women.

High BMI levels have been linked with increased risk of depression, anxiety, and other mental health disorders among women. Factors such as societal pressure, body image concerns, and hormonal changes such as alterations in estrogen and leptin levels, can affect neurotransmitter function and mood regulation may contribute to this association. Overall, these factors contribute to the complex relationship between higher BMI and poor mental health in women.

A cross-sectional study was conducted that employed 1,821 men and women aged 46–73 years, randomly selected from a large primary care centre. Depression and well-being were assessed using the 20-item Centre for Epidemiologic Studies Depression Scale (CES-D) and the World Health Organization-Five (WHO-5) Well-Being Index.

Linear regression analyses were performed to examine relationships between mental health scores (dependent variable) and adiposity (independent variable) defined using body mass index (BMI) and waist-height ratio while adjusting for demographic characteristics, lifestyle factors and disease conditions.

The findings revealed that BMI and waist-height ratio had a significant positive association with depression scores and a significant inverse association with well-being scores in males and females.

When disease conditions were adjusted for, BMI (β = 0.743, p < .001) and waist-height ratio (β = 0.719, p < .001) associations with the CES-D score remained significant. In stratified analyses, relationships between measures of adiposity and depression were found to be stronger in females (BMI: β = 0.806, p = .007; waist-height ratio: β = 0.768, p = .01) than males (BMI: β = 0.573, p = .049; waist-height ratio: β = 0.593, p = .044) but no effect modification was identified.

The results suggested that increased adiposity is significantly associated with poorer mental health, independent of lifestyle factors and disease conditions. Targeted interventions for reducing depression should include better population-level weight management measures.

Reference: Lonergan C, Millar SR, Kabir Z (2024) Associations between adiposity measures and depression and well-being scores: A cross-sectional analysis of middle- to older-aged adults. Journal: PLoS ONE 19(3): e0299029. https://doi.org/10.1371/journal.pone.0299029

A novel role of neutrophils in combating cancer, finds research

A study published in the journal Cell on March 5 2024, revealed an unexpected level of complexity within neutrophils. These cells, once considered a relatively uniform population of short-lived immune cells, now appear to possess intricate characteristics.

Using cutting-edge single-cell RNA sequencing technology, the researchers analysed individual neutrophils across a remarkable 17 different cancer types from 143 patients and revealed that neutrophils can adopt at least 10 highly specialized and distinct functional states related to inflammation, blood vessel formation, and—most excitingly—presenting antigens to activate potent cancer-killing T cells.

"We were surprised to find such intricate complexity and divergent roles embedded within neutrophils, which have been overlooked for so long as a simple population," said Prof. ZHANG Xiaoming from the Shanghai Institute of Immunity and Infection (SIII) of the Chinese Academy of Sciences. "What is especially remarkable is their newly discovered capacity to act as antigen-presenting cells, maturing and rallying T cells against cancer. In addition, the abundance of antigen-presenting neutrophils is associated with improved patient prognosis across many tumour types revealed in this study."

After extensive analysis, researchers discovered that metabolic signalling of the amino acid leucine can activate the antigen-presenting state in neutrophils, leading to epigenetic changes. Validating these findings in vivo, they observed that delivering antigen-presenting neutrophils or adjusting the leucine diet significantly enhanced the anti-tumour immune response in mice. Moreover, these treatments notably improved outcomes of PD-1 checkpoint immunotherapy for various cancer types.

“We've uncovered a way to wake up an untapped army already living within our immune system. Strategically activating these neutrophil states or modulating their behaviour through metabolic or dietary means represents an entirely new paradigm to empower cancer immunotherapy,” said Prof. ZHANG.

"This completely changes how we perceive neutrophils in the context of cancer," said Profs. GAO Qiang from Fudan University. "Now we know we could harness the diverse hidden identities of neutrophils to strengthen the effectiveness of immunotherapies. We're thrilled to further explore the potential benefits of these newly uncovered mechanisms in clinics."

Reference: Yingcheng Wu, Jiaqiang Ma, Xupeng Yang , Jia Fan, Xiaoming Zhang, Qiang Gao; Journal: Cell; DOI: 10.1016/j.cell.2024.02.005