New Imaging Molecule Captures Brain Changes Tied to Progressive Multiple Sclerosis

Novel PET tracer detected abnormal inflammation in the cerebral grey matter of patients with MS, reflecting patients’ clinical severity

Secondary progressive multiple sclerosis (MS) is a relentless disease. Over time, patients experience worsening physical, mental and mood-related symptoms. And yet, even as their symptoms progress, the brain white matter lesions found on a patient’s MRI scans often remain unchanged. Suspecting that changes in the grey matter regions of the brain may be playing a critical role in the disease’s progression, investigators from Brigham and Women’s Hospital conducted an initial study assessing the differences in the activity of microglial cells in the grey matter regions of healthy volunteers versus those with MS. Using a novel tracer molecule known as [F-18]PBR06 and Positron Emission Tomography (PET) imaging, the team detected widespread and abnormal activation of microglia in MS patients and a link to brain atrophy, physical disability, and progressive MS. The team’s findings are published in the July 2019 issue of Neurology: Neuroimmunology & Neuroinflammation, an official journal of the American Academy of Neurology.

“There’s more to multiple sclerosis than white matter lesions,” said corresponding author Tarun Singhal, MD, a neurologist at the Ann Romney Center for Neurologic Diseases at the Brigham. “There’s evidence of inflammation in the brain’s grey matter, not just the white matter. Here we have a technique to detect it and a path to develop this technique for use in the clinic in looking for early signs of progression and the effects of treatments.”

Currently, there are several disease-modifying drugs on the market to help patients with relapsing remitting MS experience fewer and less severe relapses, but few drugs exist for patients with secondary progressive MS. Investigations to develop new drugs are underway, but many questions remain about the underlying biology of the disease and how it progresses.

The new study leverages the novel radioisotope, [F-18]PBR06, a tracer that targets a specific protein (TSPO) found in activated microglia, key immune cells found in the brain. Many other research projects use C-11, an isotope with a much shorter half-life. But, unlike C-11, the F-18 tracer has a significantly longer half-life and a higher potential to be used in the clinic.

For the pilot study, investigators evaluated results for 12 patients with MS — seven with relapsing remitting MS and five with secondary progressive MS — and compared it with healthy controls using the F-18 tracer. They found more grey matter microglial activation in the MS patients as compared to healthy controls, particularly in hippocampus, parahippocampus, cingulate gyrus and amygdala regions of the brain. These regions of the brain are known to influence critical processes, including emotion, memory and cognition, all of which may be affected in MS patients. Brain structures in the deep grey matter, particularly the thalamus, showed higher microglial activation in secondary progressive MS than in the relapsing remitting MS patients and healthy controls. This correlated significantly with physical disability and brain atrophy.

The authors note that the pilot study is small and its findings will require additional confirmation in larger studies with a longitudinal design, but it offers the first assessment of [F-18]PBR06 PET for grey matter changes in MS, demonstrating the potential value of this technique.

“Unless we can measure the progress of a disease accurately, our ability to treat that disease remains limited,” said Singhal. “When a patient tells us that their symptoms are worsening, we want to have a technology that can reflect that, or better yet, predict the progression before it is clinically obvious. This technique may have the potential to do that and give us critical insights into neurodegeneration and its relationship with neuroinflammation.”

Other authors of this paper include Kelsey O’Connor, Shipra Dubey, Hong Pan, Renxin Chu, Shelley Hurwitz, Steven Cicero, Shahamat Tauhid, David Silbersweig, Emily Stern, Marie Kijewski, Marcelo DiCarli, Howard L Weiner, and Rohit Bakshi.

Funding for this work was provided by Nancy Davis Foundation’s “Race to Erase MS” program, Ann Romney Center for Neurologic Diseases, Harvard NeuroDiscovery Center, and Water Cove Charitable Foundation. Co-authors have received grant support from Spectrum Dynamics, Merck-Serono and Sanofi-Genzyme, Verily Life, EMD Serono, and Sanofi-Genzyme, and consulting fees from GE, Sanofi, Biogen, Tiziana, Novartis, Merck-Serono, Teva, Bayer, Celgene, EMD Serono, Genentech, Guerbet, Sanofi-Genzyme, and Shire.

Paper cited: Singhal, T et al. “Grey Matter Microglial Activation in Relapsing versus Progressive Multiple Sclerosis: An Initial Experience using [F-18]PBR06-PET” Neurology: Neuroimmunology & Neuroinflammation. DOI: 10.1212/NXI.0000000000000587

Foundational Study Explores Role of Diet in Diabetes Complications

A new study set out to determine which components of the Western diet may worsen diabetes complications. The team examined the effects of different dietary fats on the earliest molecular signs of retinal inflammation.

Type 1 and type 2 diabetes affect the health of the inner lining of blood vessels. People with diabetes often experience complications in the eyes, heart, and other organs because of worsening blood vessel damage over the long term. One of the earliest signs of systemic inflammation in the blood vessels is the increased sticking of immune cells to the inner lining. As inflammation and microvascular damage continues in the light-sensitive tissue in the back of the eye — the retina — diabetic retinopathy can ensue. Diabetic retinopathy is a leading cause of severe vision loss and blindness. A pressing question in diabetes research is how elevated blood levels of sugar, cholesterol, and fat may contribute to blood vessel damage in relation to the diet. A new study by investigators from Brigham and Women’s Hospital set out to determine which components of the Western diet — one rich in sugar, cholesterol and fat — may worsen diabetes complications. The team examined the effects of different dietary fats on the earliest molecular signs of retinal inflammation and damage in an experimental rodent model of type 1 diabetes.  The results are published in The FASEB Journal.

“Solid information about the effects of nutrition on disease development or progression is a rarity, but foundational work in preclinical models can help set the stage for clinical implications,” said corresponding author Ali Hafezi-Moghadam, MD, PhD, Director of the Molecular Biomarkers Nano-Imaging Laboratory at the Brigham and Associate Professor of Radiology at Harvard Medical School. “We want to understand who is at risk for diabetic retinopathy and what dietary steps can be taken to slow down disease progression, but to take those steps, we must first understand the effects and interplay of the various components of diet.”

To do so, the team used an established rat model of type 1 diabetes, known as streptozotocin (STZ)-diabetic rats. This model is characterized by the inability to produce insulin and by elevated levels of sugar and fat in the blood. The research team generated high-fat diets with varying fatty acid compositions, moderate amounts of carbohydrates and no sugars to tease out the effects of specific dietary components on the diabetic vascular damage. The team fed these diets to the STZ-diabetic rats and then examined the accumulation of immune cells and other related readouts in the retinal blood vessels.

To examine the rat retina, the team previously developed a unique nanoprobe-based molecular imaging technique. The nanoprobes injected into the blood stream of the rats targeted specific molecules to which immune cells bind in the retina. Using laser-scanning confocal microscopy in live animals, the team produced images from the rats’ retinas that visualized the accumulation of the nanoprobes. Hafezi-Moghadam likens the image of the brightly fluorescing nanoprobes in the retina to a “starry sky” at night, where “the number of stars tells us a whole lot about the condition of the retina.”

The investigators found that neither high levels of saturated nor unsaturated fats increased retinal damage in this animal model, but that the combination of high levels of dietary cholesterol with specific saturated fatty acids that are abundant in the Western diet exacerbated the damage.

Elevated blood sugar (hyperglycemia) is a common symptom of type 1 and type 2 diabetes, however the diseases have different mechanisms. Because diabetes complications in patients are often clinically observed after long exposure to hyperglycemia, the study of the mechanisms of complications in animal models has traditionally put less emphasis on the manner in which the animals develop hyperglycemia. The lab introduced and is currently developing a realistic model of type 2 diabetes known as the Nile Grass Rat. In the future, the team will leverage this model and explore the contributions of other dietary components to vascular damage in type 2 diabetes.

“This work lays the foundation for further examination of the relationship between levels of fat in the blood, dietary fats, and the development of diabetes complications,” said lead author Aliaa Barakat, PhD, a senior research scientist in the Molecular Biomarkers Nano-Imaging Laboratory at the Brigham. “Dietary carbohydrates and dietary fats have related and overlapping metabolic effects. Future experiments are warranted across a spectrum of hormonal changes characteristic of treated type 1 diabetes and treated and untreated type 2 diabetes. Subsequent work will also address mechanisms behind our findings involving the interaction between dietary sugar, cholesterol and saturated fatty acids.”

New ACC/AHA High Blood Pressure Guidelines Could Increase Detection of Gestational Hypertension
In a study of more than 16,000 women, improvements in diagnoses might lead to reduction in maternal and neonatal risk

Gestational hypertension — high blood pressure during pregnancy — can have persisting adverse effects on the health of mothers and their infants. In 2017, the American College of Cardiology (ACC) and the American Heart Association (AHA) released clinical guidelines for hypertension in non-pregnant adults, which lowered the blood pressure threshold to diagnose hypertension, compared to previously established ones. However, the new ACC/AHA guidelines have not been adapted or applied to pregnant women. Researchers at Brigham and Women’s Hospital and colleagues conducted the first-ever study to evaluate the impact these guidelines could have on detecting gestational hypertension. The results of the retrospective cohort study were published today in the journal Circulation Research.

“Timely, accurate diagnosis of gestational hypertension is crucial for preventing associated conditions for pregnant women like preeclampsia and postpartum chronic hypertension,” said Jie Hu, MD, PhD, a postdoctoral researcher in the Division of Women’s Health in the Department of Medicine at Brigham and Women’s Hospital and the study’s first author. “Infants born to women with gestational hypertension are more susceptible to preterm birth and adverse long-term health outcomes like young adulthood cardiovascular diseases.”

Hu and the international collaborative team used systolic and diastolic blood pressure measurements obtained from the medical records of 16,345 women from a maternal and child health care hospital in Wuhan, China. Blood pressure measurements were recorded by obstetricians during prenatal care visits across various stages of pregnancy.

Using the 2017 ACC/AHA guidelines, the investigators identified 4,100 women (25.1 percent) with hypertension. In contrast, only 678 (4.2 percent) of the women were found to have hypertension using the previous guidelines, indicating a substantial increase in the prevalence of gestational hypertension compared to the previous definition.

The investigators acknowledge that the findings will need to be replicated in more ethnically, racially and socioeconomically diverse populations, as well as in other nations aside from China. Future studies are necessary to determine whether more frequent diagnoses of hypertension lead to improved neonatal outcomes for mothers and infants.

According to the researchers, current management strategies for gestational hypertension include continued observation and careful follow-up of blood pressure. Medication is only used in severe cases.

“Incorporating the 2017 ACC/AHA guidelines into prenatal care practice could improve detection of high blood pressure during pregnancy and the efforts to reduce adverse maternal and neonatal outcomes in the perinatal period that are related to gestational hypertension,” said Hu.

Dr. Shunqing Xu of Huazhong University of Science and Technology is the senior author of this study. Funding for this study was provided by the National Key Research and Development Plan of China, the National Natural Science Foundation of China, and the Fundamental Research Funds for the Central Universities, Huazhong University of Science and Technology.

Paper Cited: Hu, J., et al. “Impact of the 2017 ACC/AHA Guideline for High Blood Pressure on Evaluating Gestational Hypertension Associated Risks for Newborns and Mothers: A Retrospective Birth Cohort Study.” Circulation Research. DOI: 10.1161/CIRCRESAHA.119.314682
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Study Connects Low Social Engagement to Amyloid Levels and Cognitive Decline

Low social engagement may be a marker of cognitive vulnerability in older adults with evidence of changes in the brain tied to Alzheimer’s disease

Social relationships are essential to aging well; research has shown an association between lack of social engagement and increased risk of dementia. A new study by investigators from Brigham and Women’s Hospital found that higher brain amyloid-β in combination with lower social engagement in elderly men and women was associated with greater cognitive decline over three years. The results of the study were published last month in The American Journal of Geriatric Psychiatry.

“Social engagement and cognitive function are related to one another and appear to decline together,” said senior author Nancy Donovan, MD, chief of the Division of Geriatric Psychiatry at the Brigham. “This means that social engagement may be an important marker of resilience or vulnerability in older adults at risk of cognitive impairment.”

The investigators sampled 217 men and women enrolled in the Harvard Aging Brain Study, a longitudinal observational study looking for early neurobiological and clinical signs of Alzheimer’s disease. The participants, aged 63-89, were cognitively normal, but some individuals showed high levels of amyloid-β protein, a pathologic hallmark of Alzheimer’s disease detected with neuroimaging techniques.

The investigators used standard questionnaires and examinations to assess participants’ social engagement (including activities such as spending time with friends and family and doing volunteer work) and cognitive performance at baseline and three years later.

Social engagement was particularly relevant to cognition in participants with evidence of Alzheimer’s disease brain changes. The researchers report that, among cognitively normal older adults with high levels of amyloid-β, those who had lower social engagement at baseline showed steeper cognitive decline than those who were more socially engaged. This association was not observed in those with low amyloid-β.

Donovan and her team used a standard measure of social engagement that did not capture all the intricacies of digital communication or the qualitative aspects of relationships. They reported that a more contemporary and comprehensive assessment of social engagement could be a valuable outcome measure in future clinical trials of Alzheimer’s disease.

The team cited that future studies with follow-up periods longer than three years may further gauge cognitive decline over time and help untangle the complex mechanisms of Alzheimer’s disease progression.

“We want to understand the breadth of this issue in older people and how to intervene to protect high-risk individuals and preserve their health and well-being,” said Donovan.

Funding for this work was provided by National Institute on Aging (R21 AG054953), and the Harvard Aging Brain Study (NIA P01 AG036694, AG046396). Donovan has received salary support from Eisai and Eli Lilly. She has served as a paid consultant to Avanir. Co-authors also report receiving fees from pharmaceutical companies that manufacture drugs for the treatment of Alzheimer’s disease. For a full list of disclosures please see the paper.

Paper cited: Biddle, K et al, “Social Engagement and Amyloid-b-Related Cognitive Decline in Cognitively Normal Older Adults.” The American Journal of Geriatric Psychiatry. DOI: https://doi.org/10.1016/j.jagp.2019.05.005

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Long-term Statin Use Associated with Lower Glaucoma Risk

Study finds that people who used statins for five years or more had a 21 percent lower chance of primary open-angle glaucoma

A new study brings the connection between statin use and risk of glaucoma into sharper focus. Investigators from Brigham and Women’s Hospital have found that using statins for five or more years is associated with lower risk of primary open-angle glaucoma. Results of the study were published recently in JAMA Ophthalmology.

Glaucoma, a leading cause of blindness, is a condition where pressure commonly builds up in the eye and affects the optic nerve. Recent research suggests that statins — cholesterol-lowering drugs prescribed to treat and prevent cardiovascular disease — also lower intraocular pressure and promote blood flow to the optic nerve, which may help lower glaucoma risk.

“Our study suggests possible protective associations beyond cardiovascular conditions for long-term statin use. Statins may also strengthen neuroprotective mechanisms that prevent degeneration of cells in the optic nerve,” said Jae Hee Kang, ScD, an assistant professor of medicine in the Channing Division of Network Medicine at Brigham and Women’s Hospital.

Kang and her team tracked 136,782 healthy individuals aged 40 and older and identified a total of 886 primary open-angle glaucoma cases between 2000 and 2015. The researchers used questionnaires to gather self-reported data on participants’ serum cholesterol levels and statin use.

While previous observational studies have been inconsistent about the association of primary open-angle glaucoma risk with long-term cholesterol and statin use, the results showed that use of statins for five years or longer, versus never using statins, is associated with a 21 percent lower chance of primary open-angle glaucoma. In addition, every 20 mg/dL increase in total serum cholesterol level is associated with a 7 percent increase in risk of primary open-angle glaucoma. These results suggest that elevated cholesterol levels may heighten glaucoma risk.

Investigators point out that a limitation of the study is that it relied exclusively on self-reported statin use and cholesterol levels. In addition, future studies could benefit from sampling more ethnically diverse populations.

Kang notes that these findings do not mean that individuals with family histories of glaucoma should use statins or other cholesterol medications for glaucoma prevention. Randomized clinical trials will be needed to determine if a causal link exists between statin use and glaucoma prevention before physicians can recommend statins for lowering risk of primary open-angle glaucoma. Particularly in elderly populations, statins have potential side effects, including risk of muscle damage and liver or kidney dysfunction.

The team’s research provides a jumping-off point for further understanding the complex biological mechanisms of glaucoma.

“As high cholesterol and statin use have been associated with other neurodegenerative diseases, the interrelationships between cholesterol, glaucoma and these outcomes is also fertile ground for further scientific inquiry,” said Kang.

Funding for this work was provided by the National Institutes of Health (grants UM1 CA186107, UM1 CA176726, UM1 CA167552, EY09611, EY015473). Co-authors reported receiving personal fees from Allergan, Novartis, Thea, Grafton Optical, Santen, Bausch & Lomb, and Eyenovia.

Paper cited: Kang, J., et al. “Association of Statin Use and High Serum Cholesterol Levels With Risk of Primary Open-Angle Glaucoma.” JAMA Ophthalmology.doi:10.1001/jamaophthalmol.2019.0900

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