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Researchers from Indiana University School of Medicine are studying why neuropsychiatric symptoms, such as apathy and irritability, appear in most Alzheimer’s disease patients before the onset of memory loss.
The study, led by Yao-Ying Ma, MD, PhD, assistant professor of pharmacology and toxicology, was recently featured in the publication Molecular Psychiatry. The team of researchers identified a receptor in the brain that leads to a loss of neurons and synaptic structure when used in an Alzheimer’s disease model.
The investigation focused on the nucleus accumbens, a critical brain region processing motivation. Located in the ventral striatum, this region is not studied much among Alzheimer’s disease researchers, Ma said; it’s mainly researched to understand motivational and emotional processes. Previous studies, Ma said, have shown that the volume of nucleus accumbens, like the cortical and hippocampal regions in the brain, is reduced in adults with Alzheimer’s disease.
Ma, who is relatively new to the field of Alzheimer’s disease research, has a background in drug addiction studies and synaptic communication — the process by which neurons talk to each other in the brain. Some of the neuropsychiatric symptoms among people who suffer from substance abuse — apathy, mood swings, anxiety — are also found in Alzheimer’s disease patients.
“Even before the onset of cognitive deficits, a significant number of Alzheimer’s patients start showing mood swings, and they have a greater chance to have symptoms of depression,” Ma said.
These neuropsychiatric symptoms, however, tend to occur earlier than memory loss, but no effective treatments are available, Ma said. She emphasized that there is an urgent need to understand why those symptoms exist and how they correlate with cognitive deficits. Ma said this study identified synaptic calcium permeable receptors (CP-AMPARs) in the nucleus accumbens in an Alzheimer’s disease model. The receptor, which is normally absent in that part of the brain, gives permission for calcium to enter the neurons. This leads to an overload of calcium, which leads to a breakdown of its synaptic structure. In turn, calcium accumulation triggers a cascade of intracellular changes that can be lethal to the neuron by amplifying calcium overload via a positive feedback mechanism.
This synaptic loss in the brain causes motivation deficits. Knowing this, Ma said that targeting these receptors in the brain and blocking them could prevent or delay the onset of Alzheimer’s disease associated neuropsychiatric symptoms, and ultimately cognitive deficits.
“If we can postpone the pathological progression in one of the affected areas, like the nucleus accumbens,” Ma said, “that may delay pathological changes in other regions.”
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Materials provided by Indiana University School of Medicine. Note: Content may be edited for style and length.

A multi-year study of the role of E. coligut bacteria in Crohn’s disease finds that intestinal inflammation liberates chemicals that nourish the bacteria’s growth and promotes their ability to cause inflammation.
The results identify new avenues for treatments that selectively disrupt the compounds that feed E. coli.
The study, “Mucosal Metabolites Fuel the Growth and Virulence of E. coli Linked to Crohn’s Disease,” published April 12 in the journal JCI Insight, focuses on ileal Crohn’s disease, an inflammatory bowel disease that affects the last part of the small intestine.
A particular type of E. coli, called adherent and invasive E.coli (AIEC), which stick to and invade cultured epithelial cells from the intestine (the gut lining) and replicate in defensive white blood cells (macrophages), has been isolated in 21 to 63% of patients with ileal Crohn’s disease, leading researchers to suspect AIEC plays a key role in the disease process.
The researchers adopted a patient-based multidisciplinary approach to identify factors found in patients associated with ileal AIEC, and the impact of these factors on growth and virulence of AIEC. Dr. Shiying Zhang, a senior research associate in the College of Veterinary Medicine, spearheaded the experiments related to AIEC, guided by the multi-pronged analyses of Dr. Xochitl Morgan at the University of Otago.
“This study gives us a whole new patient-based roadmap of things we might want to target to stop Crohn’s associated E.coli from growing and inciting inflammation,” said senior author Kenneth Simpson, professor in the Department of Clinical Sciences in the College of Veterinary Medicine and at Weill Cornell Medicine in New York City.

Engineered tissues have become a critical component for modeling diseases and testing the efficacy and safety of drugs in a human context. A major challenge for researchers has been how to model body functions and systemic diseases with multiple engineered tissues that can physiologically communicate — just like they do in the body. However, it is essential to provide each engineered tissue with its own environment so that the specific tissue phenotypes can be maintained for weeks to months, as required for biological and biomedical studies. Making the challenge even more complex is the necessity of linking the tissue modules together to facilitate their physiological communication, which is required for modeling conditions that involve more than one organ system, without sacrificing the individual engineered tissue environments.
Novel plug-and-play multi-organ chip, customized to the patient
Up to now, no one has been able to meet both conditions. Today, a team of researchers from Columbia Engineering and Columbia University Irving Medical Center reports that they have developed a model of human physiology in the form of a multi-organ chip consisting of engineered human heart, bone, liver, and skin that are linked by vascular flow with circulating immune cells, to allow recapitulation of interdependent organ functions. The researchers have essentially created a plug-and-play multi-organ chip, which is the size of a microscope slide, that can be customized to the patient. Because disease progression and responses to treatment vary greatly from one person to another, such a chip will eventually enable personalized optimization of therapy for each patient. The study is the cover story of the April 2022 issue of Nature Biomedical Engineering.
“This is a huge achievement for us — we’ve spent ten years running hundreds of experiments, exploring innumerable great ideas, and building many prototypes, and now at last we’ve developed this platform that successfully captures the biology of organ interactions in the body,” said the project leader Gordana Vunjak-Novakovic, University Professor and the Mikati Foundation Professor of Biomedical Engineering, Medical Sciences, and Dental Medicine.
Inspired by the human body
Taking inspiration from how the human body works, the team has built a human tissue-chip system in which they linked matured heart, liver, bone, and skin tissue modules by recirculating vascular flow, allowing for interdependent organs to communicate just as they do in the human body. The researchers chose these tissues because they have distinctly different embryonic origins, structural and functional properties, and are adversely affected by cancer treatment drugs, presenting a rigorous test of the proposed approach.

An international team of researchers has identified DNA mutations in a gene that senses viral RNA, as a cause of the autoimmune disease lupus, with the finding paving the way for the development of new treatments.
Lupus is a chronic autoimmune disease which causes inflammation in organs and joints, affects movement and the skin, and causes fatigue. In severe cases, symptoms can be debilitating and complications can be fatal.
There is no cure for the disease, which affects around 50,000 people in the UK, and current treatments are predominantly immune-suppressors which work by dialling down the immune system to alleviate symptoms.
In their study, published in Nature today (27 April), the scientists carried out whole genome sequencing on the DNA of a Spanish child named Gabriela, who was diagnosed with severe lupus when she was 7 years old. Such a severe case with early onset of symptoms is rare and indicates a single genetic cause.
In their genetic analysis, carried out at the Centre for Personalised Immunology at the Australian National University, the researchers found a single point mutation in the TLR7 gene. Via referrals from the US and the China Australia Centre of Personalised Immunology (CACPI) at Shanghai Renji Hospital, they identified other cases of severe lupus where this gene was also mutated.
To confirm that the mutation causes lupus, the team used CRISPR gene-editing to introduce it into mice. These mice went on to develop the disease and showed similar symptoms, providing evidence that the TLR7 mutation was the cause. The mouse model and the mutation were both named ‘kika’ by Gabriela, the young girl central to this discovery.

A molecule produced in the liver in response to low-carb “ketogenic” diets has a powerful effect in suppressing colorectal tumor growth and may be useful as a preventive and treatment of such cancers, according to a new study from researchers at the Perelman School of Medicine at the University of Pennsylvania.
In the study, published in Nature, researchers initially found that mice on low-carb, high-fat ketogenic diets have a striking resistance to colorectal tumor development and growth. The scientists then traced this effect to beta-hydroxybutyrate (BHB), a small organic molecule produced in the liver in response to keto diets or starvation.
“Our findings suggest that this natural molecule, BHB, could someday become a standard part of colorectal cancer care and prevention,” said study co-senior author Maayan Levy, PhD, an assistant professor of Microbiology at Penn Medicine, whose laboratory collaborated with the lab of Christoph Thaiss, PhD, also an assistant professor of Microbiology. The study’s first author was Oxana Dmitrieva-Posocco, PhD, a postdoctoral researcher in Levy’s lab.
Colorectal cancer is one of the most common cancer types and kills more than 50,000 Americans annually, making it the country’s third leading cause of cancer mortality. Alcohol use, obesity, red meat, and low-fiber and high-sugar diets have all been linked to greater colorectal cancer risk.
In the study, Levy, Thaiss and their teams set out to determine, with experiments in mice, whether different types of diet could inhibit colorectal cancer development and growth. They put six groups of mice on diets that had varying fat-to-carb ratios, and then used a standard chemical technique that normally induces colorectal tumors.
They found that the two most ketogenic diets, with 90 percent fat-to-carb ratios — one used lard (pig fat), the other Crisco (mostly soybean oil) — prevented colorectal tumor development in most of the animals on those diets. By contrast, all the animals on the other diets, including low-fat, high-carb diets, developed tumors. Even when the researchers started the mice on these diets after colorectal tumors had started growing, the diets showed a “treatment effect” by markedly slowing further tumor growth and proliferation.

Cognitive function at middle age is a strong predictor of whether a person may develop dementia later in life. Now, a new study led by a Boston University School of Public Health (BUSPH) researcher has found that increasing greenspace in residential areas could help improve cognition function in middle-aged women and that this association might be explained by a reduction in depression, which is also a risk factor for dementia.
Published in the journal JAMA Network Open, the study found that exposure to greenspace around one’s home and surrounding neighborhood could improve processing speed and attention, as well as boost overall cognitive function. The results also showed that lowered depression may help explain the association between greenspace and cognition, bolstering previous research that has linked exposure to parks, community gardens, and other greenery with improved mental health.
“Some of the primary ways that nature may improve health is by helping people recover from psychological stress and by encouraging people to be outside socializing with friends, both of which boost mental health,” says Dr. Marcia Pescador Jimenez, study lead and corresponding author, and assistant professor of epidemiology at BUSPH. “This study is among the few to provide evidence that greenspace may benefit cognitive function in older ages. Our findings suggest that greenspace should be investigated as a potential population-level approach to improve cognitive function.”
For the study, Pescador Jimenez and colleagues from BUSPH, Harvard T.H. Chan School of Public Health, Brigham and Women Hospital, Harvard Medical School, and Rush Medical College estimated residential greenspace with a satellite image-based metric called the Normalized Difference Vegetation Index (NDVI). They measured psychomotor speed, attention, learning, and working memory among 13,594 women aged 61 on average and primarily White, from 2014 to 2016. The women were participants in the Nurses’ Health Study II, the second of three studies that are among the largest investigations into the risk factors for chronic diseases among US women.
Adjusting for age, race, and individual and neighborhood socioeconomic status, the researchers found that greenspace exposure was associated with psychomotor speed and attention, but not learning or working memory.
In addition to depression, the researchers also examined the potential roles of air pollution and physical activity in explaining the association between greenspace and cognitive function, and they were surprised to only find evidence of depression as a mediating factor.
“We theorize that depression might be an important mechanism through which green space may slow down cognitive decline, particularly among women, but our research is ongoing to better understand these mechanisms,” Pescador Jimenez says. “Based on these results, clinicians and public health authorities should consider green space exposure as a potential factor to reduce depression, and thus, boost cognition. Policymakers and urban planners should focus on adding more green space in everyday life to improve cognitive function.”
While the study shows evidence of this association, the greenspace metric that the researchers used to measure greenspace exposure does not differentiate between specific types of vegetation. In a new project, Pescador Jimenez will apply deep learning algorithms to Google Street View images to better understand which specific elements of greenery, such as trees or grass, could be the driving factors for health.
The researchers also hope that their study is replicated among other racial/ethnic populations and assesses associations with cognitive decline over longer periods of time.
“The distribution of green spaces in cities is not uniform,” says Pescador Jimenez. “Increasing everyday access to vegetation across vulnerable groups in urban cities is a crucial next step to achieve health equity.”
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Materials provided by Boston University School of Public Health. Original written by Jillian McKoy. Note: Content may be edited for style and length.

Under propofol general anesthesia very slow frequency traveling waves transform and dominate, redirecting and disrupting the higher frequency traveling waves associated with conscious function.
Imagine the conscious brain as a sea roiling with the collisions and dispersals of waves of different sizes and shapes, swirling around and flowing across in many different directions. Now imagine that an ocean liner lumbers through, flattening everything that trails behind with its powerful, parting wake. A new study finds that unconsciousness induced by the commonly used drug propofol has something like that metaphorical effect on higher frequency brain waves, appearing to sweep them aside and, as an apparent consequence, sweeping consciousness away as well.
Put more prosaically, the study in the Journal of Cognitive Neuroscience by MIT scientists at The Picower Institute for Learning and Memory shows that propofol substantially alters how different frequencies of brain waves travel across the brain’s surface, or cortex. Whereas conscious brains exhibit a mixture of waves of various frequencies rotating or traveling straight in various directions, brains under propofol anesthesia became dominated by powerful, very low frequency “delta” waves that roll straight outward in opposite directions instead of slowly rotating around central points as they do during consciousness. Higher frequency “beta” waves, meanwhile, became fewer and more erratically structured, traveling only in directions not dominated by the surging delta waves.
Traveling waves are hypothesized to perform many important functions as they coordinate the activity of brain cells over the areas of the brain they cover. These include reading information out from memory and holding it there while it waits to be used in cognition. They may also aid in perception and act as a means of time keeping in the brain. The findings therefore illustrate how profoundly anesthesia alters the state of the state of the brain as it induces and maintains unconsciousness, said senior author Earl K. Miller, Picower Professor of Neuroscience in MIT’s Department of Brain and Cognitive Sciences.
“The rhythms that we associate with higher cognition are drastically altered by propofol,” Miller said. “The beta traveling waves seen during wakefulness are pushed aside, redirected by delta traveling waves that have been altered and made more powerful by the anesthetic. The deltas come through like a bull in a china shop.”
Co-senior author Emery N. Brown said the findings illustrate that there are many ways anesthetic drugs can act on the brain.

New data shows that the symptoms suffered by people with advanced Alzheimer’s disease and related dementias who live in the community occur at a strikingly similar rate to those of dementia patients in a nursing home. The study from Regenstrief Institute and Indiana University School of Medicine is one of the first to look at dementia symptom prevalence in the community population.
Dementia currently affects about 5 million older adults in the U.S., and its incidence is expected to more than double over the next 40 years. More than 21 million people in the U.S. are providing unpaid care for someone living with dementia. Because there is no cure for the disease, the goal is to manage dementia symptoms to alleviate patient discomfort and reduce caregiver burden.
Researchers took baseline survey data from a five-year randomized clinical trial funded by the National Institute on Aging named IN-PEACE (Indiana Palliative Excellence in Alzheimer’s Care Efforts) and analyzed responses from caregivers regarding symptoms.
The most common symptoms include: Pain Agitation Anxiety Resistance to care”We found that both the rate and types of symptoms suffered by community-dwelling people with dementia were very similar to those in a nursing home setting,” said first author Kurt Kroenke, M.D., Regenstrief research scientist and professor of medicine at IU School of Medicine.
“More than 40 percent of these people were experiencing these symptoms at least weekly. The symptoms are not subtle, they are not infrequent, and they do have a significant impact on the quality of life for patients and caregivers,” Dr. Kroenke continued. “However, they often go unreported in primary care settings. It’s an area that requires more attention during routine care.”
Regenstrief and IU School of Medicine researchers and clinicians are attempting to address this issue with palliative care interventions through the IN-PEACE trial. They are testing a collaborative care model using nurses and community health workers to help manage symptoms and provide caregivers with support.
“These baseline numbers will help us to see if palliative care eases the symptom burden,” said senior author Greg Sachs, M.D., a Regenstrief research scientist and a professor of medicine at IU School of Medicine. “While we gather data from the clinical trial, this initial information shows the need for providers to make room for symptom discussion in primary care.”
A unique aspect of IN-PEACE: more than 40 percent of enrolled subjects are Black. Dementia clinical trials often have 10 percent or a smaller proportion of subjects who are Black.
“Prevalence and Predictors of Symptoms in Persons with Advanced Dementia Living in the Community” is published online ahead of print in the Journal of Palliative Medicine. This research was supported by the National Institutes of Health’s National Institute on Aging, R01 award (R01 AG057733).
In addition to Drs. Kroenke and Sachs, authors are Sujuan Gao, PhD of IU School of Medicine; Kelly M. Mosesso, M.A. of IU School of Medicine; Susan Hickman, PhD of Regenstrief Institute and Indiana University School of Nursing; Laura R. Holtz, M.S. of Regenstrief, Alexia M. Torke. M.D., M.S. of Regenstrief and IU School of Medicine and Nina M. Johnson, B.S. of Regenstrief Institute.
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Materials provided by Regenstrief Institute. Note: Content may be edited for style and length.

It has long been understood that environmental and socio-economic factors — including income disparity, family poverty, and air pollution — increase a person’s risk of developing psychotic-like experiences, such as subtle hallucinations and delusions that can become precursors to a schizophrenia diagnosis later in life. Research has long focused on young adults but now, thanks to the data from the Adolescent Brain Cognitive Development (ABCD) Study, researchers at the University of Rochester have found these risk factors can be observed in pre-adolescent children.
“These findings could have a major impact on public health initiatives to reduce the risk of psychotic like experiences,” said Abhishek Saxena, a graduate student in the department of Psychology at the University of Rochester and first author of the study recently published in Frontiers in Psychiatry. “Past research has largely focused on the biological factors that lead to development of schizophrenia spectrum disorders, but we now know that social and environmental factors can also play a large role in the risk and development of schizophrenia. And this research shows these factors impact people starting at a very young age.”
Researchers looked at data collected from 8,000 kids enrolled in the ABCD study. They found that the more urban of an environment a child lived in — proximity to roads, houses with lead paint risks, families in poverty, and income disparity — the greater number of psychotic like experiences they had over a year’s time. These findings are in line with past research conducted in young adults, but have not been found like this in pre-adolescences.
“It is disconcerting that the association between these exposures and psychotic-like experiences are already present in late childhood,” said David Dodell-Feder, Ph.D., assistant professor of Psychology and Neuroscience and lead author of this study. “The fact that the impact of these exposures may occur as early as pre-adolescence highlights the importance of early prevention.”
This research was supported by the National Institute of Mental Health.
The University of Rochester Medical Center is one of 21 research sites across the country collecting data for the National Institutes of Health ABCD Study. Since 2017, 340 children from the greater Rochester area have been participating in the 10-year study. In all, the study is following 11,750 children through early adulthood looking at how biological development, behaviors, and experiences impact brain maturation and other aspects of their lives, including academic achievement, social development, and overall health.
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Materials provided by University of Rochester Medical Center. Original written by Kelsie Smith Hayduk. Note: Content may be edited for style and length.

Our body is like a sophisticated network with a myriad of peripheral blood vessels connected from the heart to the extremities. If blood fails to pass through these peripheral blood vessels, a wound may not heal or even lead to necrosis. Peripheral vascular diseases require particular attention as it mostly appears in the foot, crucial to a person’s well-being and livelihood. Recently, a Korean research team has developed a 3D foot imaging technique that vividly captures peripheral blood vessels, even thinner than 1 mm.
A POSTECH research team led by Professor Chulhong Kim (Belonging to the Departments of Convergence IT Engineering, Electrical Engineering, and Mechanical Engineering) has developed an imaging technique that combines the photoacoustic and ultrasound images. The findings from the study were recently published in the international journal Radiology.
Conventionally, the ankle-brachial index test was used to measure the blood pressure of the wrist, ankle, or toe to calculate the ratio to diagnose peripheral vascular diseases. As for imaging modalities, the Doppler ultrasonography, which measures the blood flow, angiography using computed tomography (CT), or magnetic resonance imaging (MRI) were widely used.
Although these methods can detect abnormalities in major arteries, they have limitations in clearly capturing the thin and numerous peripheral blood vessels. They can also cause pain or side effects because a contrast agent must be injected into the patient.
To overcome these issues, the researchers combined photoacoustic and ultrasound images to and visualize 3D images of blood vessels thinner than 1 mm without a contrast agent by. Using the photoacoustic effect — in which sound waves are formed following light absorption in a material — blood vessels in the body can be imaged using the light absorption of the blood without a contrast agent. Adding the ultrasound image to this can visualize the structural image of blood vessels with the image of the skin and bone structures simultaneously.
The new modality can provide the information to aid in diagnosing and treating peripheral vascular diseases since it provides functional diagnostic values for the blood supply to tissues, such as total hemoglobin concentration or blood oxygen saturation, using a wavelength-convertible laser. In order to improve the reliability and reproducibility of the image results, the researchers also developed a contour scan technology where the imaging probe detects various curves of the foot and moves it along the contour.
To present its applicability as a diagnostic technology, the researchers conducted an experiment on the feet of healthy participants. By acquiring photoacoustic and ultrasound images of the entire foot in vivo, it was verified that the blood vessels, skin, and bone structures of the foot could be clearly displayed simultaneously. In addition, the researchers used a pressure cuff on the healthy participants to artificially occlude the peripheral blood flow and observed significant changes in the hemoglobin concentration and vessel density before and after occlusion. Based on the results of this study, the researchers have confirmed the new imaging technology’s applicability for diagnosing peripheral vascular diseases in the future.
This study was conducted with the support from the Ministry of Science and ICT, Ministry of Education, and the National Research Foundation of Korea.
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Materials provided by Pohang University of Science & Technology (POSTECH). Note: Content may be edited for style and length.