In the News

Link between mitochondrial dysfunction and age-dependent cognitive disorders

Patients with rare skin cancer face 40% recurrence rate

New artificial intelligence tool detects often overlooked heart diseases

Telehealth makes a big difference

Study questions the role of vitamin D2 in human health but its sibling, vitamin D3, could be important for fighting infections

Link between mitochondrial dysfunction and age-dependent cognitive disorders

Increased oxidative damage is linked to neurodegenerative disorders such as Alzheimer's disease (AD). Even though the pathophysiology of AD has been widely investigated, the likely relationship between mitochondrial dysfunction and the disease remains largely unknown. A research team led by Prof. Koji Fukui from Japan's Shibaura Institute of Technology has confirmed that AD progression is linked to oxidative brain damage, which impairs cognitive function in AD transgenic mice in an age-dependent manner.

The mitochondrial electron transport chain, which is required for generating energy during cellular processes, also produces reactive oxygen species (ROS) that attack tissue and cause oxidative damage. This damage can cause mitochondrial dysfunction and even lead to cell death. Since our brain uses more oxygen than other organs, it is more vulnerable to this ROS damage.

According to literature, ROS also causes the buildup of amyloid-β (Aβ), which marks the onset of Alzheimer's disease (AD), a serious irreversible neurodegenerative disorder. Treatments for AD do not stop its progression, necessitating the development of new therapeutics.

In a prior study, a team of scientists found that oxidation levels were substantially higher in older rats with vitamin E deficiency than in younger rats. Furthermore, ROS production via mitochondrial oxidation could damage brain cells, implying a strong link between AD and mitochondrial dysfunction. To improve this understanding, the same group of scientists has now demonstrated that the progression of AD is closely associated with oxidative brain damage. The study, led by Prof. Koji Fukui, along with his colleagues Mr Naoki Yoshida, Mr. Yugo Kato, and Prof. Hirokatsu Takatsu, was recently published in Biomedicines. "We showed that oxidation negatively impacted the mitochondria which led to cognitive dysfunction," explains Prof. Fukui, who is the corresponding author of the study.

The scientists used three groups of AD mice aged 3, 6, and 20 months, along with healthy controls. For testing their cognitive and coordination abilities, the mice were examined in two well-known experiments: the Morris water maze and the Rota-rod test. They discovered that the AD mice took longer to complete their maze goals but did not slow down. In the Rota-rod test, the 6- and 20-month-old AD mice stayed on the rod for a longer time, while the age-matched control mice fell quicker. Prof. Fukui explains, "The difference in fall time could be attributed to the weight difference between the two groups, as the control mice were heavier than the AD mice." These results suggested that AD mice were cognitively impaired but did not have any coordination issues.

To identify which AD-related proteins were responsible for such cognitive impairment, the authors collected tissue samples from various parts of the brain from both groups of mice and assessed the levels of oxidative markers in the samples. First, they found that AD mice had higher levels of Aβ, with a gradual increase observed with age. To their surprise, the AD-related protein Aβ1-42 was significantly higher in the hippocampus than in other parts of the brain. However, they did not find any alterations in the levels of the tau protein, which is another marker that accumulates in AD pathology. Overall, it was confirmed that Aβ1-42 aggregation in the hippocampus caused cognitive impairment in AD mice.

The team also had speculations about ROS-induced mitochondrial damage being closely related to neuron survival. To validate their hypothesis, they determined the levels of some key mitochondrial oxidative enzymes, including nicotinamide-nucleotide adenylyltransferase (NMNAT)-3, which exhibits anti-ageing effects. While NMNAT-3 was found to be lowered, levels of 3-NT (3-nitrotyrosine), an indicator of higher oxidation, increased with age in AD mice. "With reduced levels of NMNAT-3 and higher levels of 3-NT, it is evident that oxidation causes mitochondrial dysfunction, and eventually leads to cognitive dysfunction," comments Prof. Fukui.

The team is optimistic about the potential implications of their results, particularly in increasing the intake of antioxidant compounds that can help our bodies mitigate ROS. In fact, many natural antioxidants, such as vitamins E and C, can be obtained from dietary sources. Prof. Fukui concludes by surmising, "If mitochondria can be protected from ROS, mitochondrial function and cognitive function may be maintained. Future research should concentrate on developing diagnostic markers to detect early alterations in the brain, as well as exploring compounds with high antioxidant activity in mitochondria."

Source: Shibaura Institute of Technology

Patients with rare skin cancer face 40% recurrence rate

Patients treated for Merkel cell carcinoma (MCC) face a five-year recurrence rate of 40% -- markedly higher than the recurrence rates for melanoma and other skin cancers, according to research published today in JAMA Dermatology.

Additionally, in the study cohort of more than 600 patients, 95% of MCC recurrences happened in the first three years, suggesting that surveillance efforts should be focused on that span the authors wrote.

"Merkel cell cancer is a life-changing diagnosis. It can be time-consuming, costly and exhausting to undergo clinic visits, imaging studies and blood draws. Now we have data on the time intervals and cancer stages that merit higher or lower surveillance intensity," said Dr. Aubriana McEvoy, who led the research while she was at the University of Washington School of Medicine. She is currently a dermatology resident at Washington University in St. Louis.

Merkel cell cancer is a rare, aggressive skin cancer, more often fatal than invasive melanoma and basal-cell and squamous-cell carcinomas. Merkel cell carcinoma is composed of cells that look very similar to 'Merkel' cells that are a key part of the epidermis, the skin's outer layer. Normal Merkel cells communicate touch-related information such as pressure and texture to the brain.

This study comprised 618 patients (37% female) whose ages ranged from 11 to 98 and whose median age was 69. In this cohort, initial treatment (surgery, radiation and systemic therapy) had a median duration of 90 days.

The authors sought to characterize post-treatment recurrence risk of MCC diagnosed at pathologic (listed below) and clinical stages.

Risk of recurrence at one year was found to be:

11% among patients diagnosed with stage I disease

33% among patients diagnosed with stages IIA/IIB disease

30% among patients diagnosed with stages IIIA disease

45% among patients diagnosed with stage IIIB disease

58% among patients diagnosed with stage IV disease

The investigators found four factors associated with higher recurrence risk: advanced age, male sex, immunosuppression, and a known primary lesion amid clinically detectable nodal disease.

As expected, survival among cohort patients was strongly dependent on cancer stage at time of diagnosis: The MCC-specific survival rate at five years post-treatment was 95% for patients diagnosed at stage I vs. 41% for patients diagnosed at stage IV.

MCC survival "is a more accurate measure of disease risk than overall survival," the authors wrote, because patients, with a median age of 70 at diagnosis, are at "considerable" risk of death from conditions unrelated to cancer. Again, stage at diagnosis was associated with a meaningful difference: 90% of deaths among patients with stage IV disease were attributed to MCC, whereas just 57% of deaths among patients diagnosed at stage I were attributed to the disease.

"This is a tricky cancer to beat because it comes back -- after optimal therapy in almost half of patients. We want to help patients figure out how much remaining risk of recurrence they have at various times after diagnosis," said Dr. Paul Nghiem, chair of dermatology at the UW School of Medicine. He is the study's senior author and an expert on Merkel cell cancer.

He added that the UW's database is likely the most comprehensive anywhere for MCC case therapies and outcomes.

"These are all patients who were followed meticulously to know why they're doing well or not doing well. The size of the data set has allowed us to see patterns more clearly, and we need data to drive optimal decision-making," Nghiem said.

U.S. incidence of MCC is low relative to other skin cancers, but also is on a steep upward trajectory because the disease is closely associated with age. About 3,200 cases will be diagnosed this year, according to a 2018 study by Nghiem and colleagues.

By contrast, about 100,000 new melanomas will be diagnosed this year. Basal cell carcinoma is far more common, with 3.6 million cases diagnosed annually, and squamous cell carcinoma numbers 1.8 million new cases a year, according to the Skin Cancer Foundation.

Each of these cancers has a significantly lower post-treatment recurrence rate than MCC, the authors noted: melanoma 19%, squamous cell 5-9%, basal cell 1-2%.

This research was supported by funding from the National Institutes of Health/National Cancer Institute (P01 CA225517 and Cancer Center Support Grant P30 CA015704), the MCC Patient Gift Fund, and the Kelsey Dickson Team Science Courage Research Team Award from the Prostate Cancer Foundation.

Source:  University of Washington School of Medicine/UW Medicine

New artificial intelligence tool detects often overlooked heart diseases

Physician-scientists in the Smidt Heart Institute at Cedars-Sinai have created an artificial intelligence (AI) tool that can effectively identify and distinguish between two life-threatening heart conditions that are often easy to miss: hypertrophic cardiomyopathy and cardiac amyloidosis. The new findings were published in JAMA Cardiology.

"These two heart conditions are challenging for even expert cardiologists to accurately identify, and so patients often go on for years to decades before receiving a correct diagnosis," said David Ouyang, MD, a cardiologist in the Smidt Heart Institute and senior author of the study. "Our AI algorithm can pinpoint disease patterns that can't be seen by the naked eye, and then use these patterns to predict the right diagnosis."

The two-step, novel algorithm was used on over 34,000 cardiac ultrasound videos from Cedars-Sinai and Stanford Healthcare's echocardiography laboratories. When applied to these clinical images, the algorithm identified specific features -- related to the thickness of heart walls and the size of heart chambers -- to efficiently flag certain patients as suspicious for having the potentially unrecognized cardiac diseases.

"The algorithm identified high-risk patients with more accuracy than the well-trained eye of a clinical expert," said Ouyang. "This is because the algorithm picks up subtle cues on ultrasound videos that distinguish between heart conditions that can often look very similar to more benign conditions, as well as to each other, on initial review."

Without comprehensive testing, cardiologists find it challenging to distinguish between similar appearing diseases and changes in heart shape and size that can sometimes be thought of as a part of normal aging. This algorithm accurately distinguishes not only abnormal from normal, but also between which underlying potentially life-threatening cardiac conditions may be present -- with warning signals that are now detectable well before the disease clinically progresses to the point where it can impact health outcomes. Getting an earlier diagnosis enables patients to begin effective treatments sooner, prevent adverse clinical events, and improve their quality of life.

Cardiac amyloidosis, often called "stiff heart syndrome," is a disorder caused by deposits of an abnormal protein (amyloid) in the heart tissue. As amyloid builds up, it takes the place of healthy heart muscle, making it difficult for the heart to work properly. Cardiac amyloidosis often goes undetected because patients might not have any symptoms, or they might experience symptoms only sporadically.

The disease tends to affect older, Black men or patients with cancer or diseases that cause inflammation. Many patients belong to underserved communities, making the study results an important tool in improving healthcare equity, Ouyang said.

Hypertrophic cardiomyopathy is a disease that causes the heart muscle to thicken and stiffen. As a result, it's less able to relax and fill with blood, resulting in damage to heart valves, fluid buildup in the lungs, and abnormal heart rhythms.

Although separate and distinct conditions, cardiac amyloidosis and hypertrophic cardiomyopathy often look very similar to each other on an echocardiogram, the most commonly used cardiac imaging diagnostic.

Importantly, in the very early stages of disease, each of these cardiac conditions can also mimic the appearance of a non-diseased heart that has progressively changed in size and shape with aging.

"One of the most important aspects of this AI technology is not only the ability to distinguish abnormal from normal, but also to distinguish between these abnormal conditions, because the treatment and management of each cardiac disease is very different," said Ouyang.

The hope, Ouyang said, is that this technology can be used to identify patients from very early on in their disease course. That's because clinicians know that earlier is always better for getting the most benefit from therapies that are available today and that can be very effective for preventing the worst possible outcomes, such as heart failure, hospitalizations, and sudden death.

Researchers plan to soon launch clinical trials for patients flagged by the AI algorithm for suspected cardiac amyloidosis. Patients enrolled in the trial will be seen by experts in the cardiac amyloidosis program at the Smidt Heart Institute, one of only a handful of programs on the West Coast dedicated to the disease.

A clinical trial for patients flagged by the algorithm for suspected hypertrophic cardiomyopathy just started at Cedars-Sinai.

"The use of artificial intelligence in cardiology has evolved rapidly and dramatically in a relatively short period of time," said Susan Cheng, MD, MPH, director of the Institute for Research on Healthy Aging in the Department of Cardiology at the Smidt Heart Institute and co-senior author of the study. "These remarkable strides -- which span research and clinical care -- can make a tremendous impact in the lives of our patients.

Source:  Cedars-Sinai Medical Center

Telehealth makes a big difference

When the nearest psychiatrist's office is dozens or even hundreds of miles away, a virtual connection may be enough to help people living with serious mental health conditions get effective care through their local primary care clinic, a new study shows.

The randomized study of just over 1,000 people with post-traumatic stress disorder, bipolar disorder or both conditions shows that most patients engaged with either of two types of telehealth. The study also gives insights into which patients might need additional support when getting such care.

Half of the patients connected directly with a far-away psychiatrist and psychologist, while the other half mostly engaged with team members at the local primary care clinic who received guidance from distant psychiatrist.

Either way, most patients responded well to medication and/or psychotherapy (sometimes called 'talk therapy') for their condition.

One major difference emerged: Those patients who were assigned to get a form of psychotherapy from a specially trained nurse or social worker on staff at their local clinic ended up completing 60% more such sessions than those who were assigned to connect with a psychologist via video. The ongoing in-person contact with their nurses or social workers checking on their other health needs may have been a contributing factor.

The findings, published in the Journal of General Internal Medicine, come from the Study to Promote Innovation in Rural Integrated Telepsychiatry, or SPIRIT trial, which involved patients from 24 safety-net clinics in Michigan, Washington and Arkansas.

Jennifer Severe, M.D., of the Department of Psychiatry at Michigan Medicine, the University of Michigan's academic medical center, led this secondary analysis of the SPIRIT data along with fellow U-M psychiatrist Paul Pfeiffer, M.D., M.S., and John Fortney, Ph.D. of the Department of Psychiatry and Behavioral Sciences at the University of Washington. The study was conducted before the COVID-19 pandemic.

"The study started at a time where clinicians had reservations about treating psychiatrically complex patients with telehealth or integrated care models. Understandably, engagement in care was one of the many concerns," said Severe. "This study showed that patients with multiple psychiatric conditions and who also struggle with several chronic physical health problems can engage well in mental health treatment with their primary care doctors or remote mental health specialists."

The two approaches used in the study were:

Telepsychiatry Collaborative Care, in which a psychiatrist makes the initial diagnosis via video and the local clinic team provides brief psychotherapy while the local primary care physician handles medication prescriptions with consultation from the telepsychiatrist

Telepsychiatry/Telepsychology Enhanced Referral, in which a psychiatrist makes the initial diagnosis and handles medication prescriptions, and a psychologist provides psychotherapy by telehealth

Last summer, another study using data from the SPIRIT trial showed that patients in both groups reported substantially and statistically significant improvements in perceived access to care, decreases in their mental health symptoms and medication side effects, and improvements in their quality of life. There was no difference between the groups, and there were no differences in outcomes regarding age, gender, race or ethnicity.

The new study dives deeper into how patients' own clinical characteristics affected their experience with telehealth, and how well they stuck with the treatment course. Two-thirds of the patients in the study had incomes or disabilities that made them eligible for Medicaid, and 50% were unemployed.

The analysis shows that patients who have issues with drugs, and those experiencing manic symptoms from their bipolar disorder, may need additional support to get started on psychotherapy or to stay with it.

It also shows that those who have multiple physical health conditions may be most likely to keep pace with their mental health medications and talk therapy programs, likely because they are already coming to the primary care clinic for other types of care.

Severe, Pfeiffer and co-author Rebecca Sripada, Ph.D., also of the U-M Department of Psychiatry, are members of the U-M Institute for Healthcare Policy and Innovation.

The study was funded by the Patient-Centered Outcomes Research Institute (PCORI -- PCS-1406-19295)

Source:  Michigan Medicine - University of Michigan

Study questions the role of vitamin D2 in human health but its sibling, vitamin D3, could be important for fighting infections

New research has found significant differences between the two types of vitamin D, with vitamin D2 having a questionable impact on human health. However, the study found that vitamin D3 could balance people's immune systems and help strengthen defences against viral infections such as Covid-19.

In a collaborative study by the Universities of Surrey and Brighton, researchers investigated the impact of vitamin D supplements -- D2 and D3 -- taken daily over a 12-week period on the activity of genes in people's blood.

Contrary to widely held views, the research team discovered that both types of vitamin D did not have the same effect. They found evidence that vitamin D3 had a modifying effect on the immune system that could fortify the body against viral and bacterial diseases.

Professor Colin Smith, lead-author of the study from the University of Surrey, who began this work while at the University of Brighton, said: "We have shown that vitamin D3 appears to stimulate the type I interferon signalling system in the body -- a key part of the immune system that provides a first line of defence against bacteria and viruses. Thus, a healthy vitamin D3 status may help prevent viruses and bacteria from gaining a foothold in the body.

"Our study suggests that it is important that people take a vitamin D3 supplement, or suitably fortified foods, especially in the winter months."

Although some foods are fortified with vitamin D, like some breakfast cereals, yoghurts, and bread, few naturally contain the vitamin. Vitamin D3 is produced naturally in the skin from exposure to sunlight or artificial ultraviolet UVB light, while some plants and fungi produce vitamin D2.

Many people have insufficient levels of vitamin D3 because they live in locations where sunlight is limited in the winter, like the UK. The Covid-19 pandemic has also limited people's natural exposure to the sun due to people spending more time in their homes.

Professor Susan Lanham-New, co-author of the study and Head of the Department of Nutritional Sciences at the University of Surrey, said:

"While we found that vitamin D2 and vitamin D3 do not have the same effect on gene activity within humans, the lack of impact we found when looking at vitamin D2 means that a larger study is urgently required to clarify the differences in the effects. However, these results show that vitamin D3 should be the favored form for fortified foods and supplements."

Source: University of Surrey