Alzheimer’s Disease Research Center Research Spotlight
Learn more about investigators at NYU Langone’s Alzheimer’s Disease Research Center, the problems they focus on in their research, and the techniques they use to study these problems.
PET Imaging for Alzheimer’s Disease: From Research to Everyday Practice
Medical imaging, including MRI and PET, has become a key technique to study Alzheimer’s disease and related dementias. MRI and PET have complementary strengths. MRI provides an exquisitely detailed view of brain anatomy as well as information about brain physiology. Different types of PET can create a picture of brain metabolism and the buildup of harmful proteins associated with Alzheimer’s disease.
At NYU Langone’s Alzheimer’s Disease Research Center, combined PET/MRI is used to obtain a complete imaging workup of the brain simultaneously with both techniques. Researchers work to maximize the benefits of PET/MRI and make this imaging modality part of everyday practice in research and clinical management of aging brain diseases.
PET is performed after an injection of radioactively labeled tracer that contains carrier molecules labeled with a radioactive isotope. In the body, the carrier binds to a specific target and the radioactive isotope decays and emits a positron, which then interacts with a nearby electron, releasing a pair of photons traveling in opposite directions. These photons are detected by the PET system and used to construct three-dimensional images reflecting the distribution of the tracer in human tissues.
The most widely used PET tracer is FDG (F-18-labeled fluorodeoxyglucose), a form of glucose. Glucose is the primary source of energy for brain neurons. As FDG is taken up by the brain, the resulting PET images reflect the metabolic activity in brain tissue. In normal aging, brain metabolism gradually declines in a predictable fashion. In subjects with memory loss and cognitive decline, decreased metabolism in specific brain areas may signal the presence of Alzheimer’s disease or other dementias. Researchers at NYU Langone were first to show that FDG PET can predict cognitive decline in normal older subjects and their progression to mild cognitive impairment and developed standardized methods to differentiate Alzheimer’s disease from other dementias with 96 percent accuracy. Tracking patients over time, researchers demonstrated the progression of cognitive decline and dementia, and showed that metabolic changes appeared on PET images many years before subjects developed clinical symptoms.
Since the early 2000s, special PET tracers have been developed to detect pathological hallmarks of Alzheimer’s disease—amyloid beta and tau proteins. Amyloid PET is highly sensitive to the presence of amyloid plaques, and all Alzheimer’s disease patients have amyloid deposits. Amyloid is also present in 25 percent of cognitively healthy individuals over the age of 75. Therefore, amyloid PET alone is not sufficient for a definitive diagnosis. However, a negative amyloid PET scan can help to rule out Alzheimer’s disease. Amyloid PET is extensively used in brain aging research, for example, to assess factors that increase the risk of developing Alzheimer’s disease. An amyloid PET study led by the scientists at NYU Langone’s Alzheimer’s Disease Research Center showed that dementia-free subjects with maternal family history of Alzheimer’s disease have increased amyloid buildup in brain areas vulnerable to Alzheimer’s disease. Amyloid PET may also be used to select patients for clinical trials of anti-amyloid treatments and study the effectiveness of such therapies.
Another family of PET tracers targets the accumulation of tau protein found in Alzheimer’s disease and other neurodegenerative conditions. Progressive accumulation of tau over time is associated with cognitive decline and can be used to predict disease progression. Tau PET is still new and under development, but researchers believe that it will have an important role in early detection of underlying Alzheimer’s disease tissue pathology.
PET/MR offers important advantages over using these techniques separately, but also presents unique image-processing problems. For example, when PET images are reconstructed from raw data, they must be corrected for the attenuation of the photons that travel through the body on the way to the detectors. In conventional PET/CT imaging, the attenuation images are obtained from CT data. For PET/MRI, researchers at NYU Langone, together with their international collaborators and Siemens Healthineers, developed a hybrid method of PET reconstruction that creates the attenuation map from a combination of a specially acquired MRI-based segmentation image with a model-based map of the skull bones.
A 2019 study led by Timothy M. Shepherd, MD, PhD, showed that MR-based reconstruction improved the quality of PET images and increased confidence in the diagnosis of seizure-causing lesions in subjects with epilepsy. The hybrid reconstruction method compared favorably to other novel approaches, received U.S. Food and Drug Administration (FDA) approval, and has now become the standard method for all PET/MRI systems provided by Siemens Healthineers in the United States and Europe. PET/MRI assessments are now routinely used at the NYU Langone’s Pearl I. Barlow Center for Memory Evaluation and Treatment, to assess patients with cognitive symptoms, in addition to being used in numerous research studies of brain aging at the Alzheimer’s Disease Research Center.
Sleep and Brain Health
Recent research suggests that sleep is critical for brain health and healthy aging. Almost 40 percent of adults over the age of 65 complain of chronic sleep problems. Poor sleep in older adults is associated with worse memory and higher risk of falling, depression, and cognitive decline. Sleep disturbances are also a common early symptom of Alzheimer’s disease. Does poor sleep lead to dementia or do dementia-related brain changes cause sleep problems? “The relationship between sleep and brain health appears to be two-way,” says Ricardo M. Osorio Suarez, MD, associate professor in the Department of Psychiatry and director of the Brain Aging and Sleep Center at NYU Grossman School of Medicine. “How exactly sleep contributes to brain health is yet unknown. But understanding the mechanism of sleep may help to develop approaches to lower the risk of developing Alzheimer’s disease or slowing its progression. Sleep may end up being an important factor in secondary prevention of dementia, along with physical activity, social engagement, and education.”
There is ample evidence that poor sleep is linked to cognitive decline and increased risk of Alzheimer’s disease. Meta-analysis has found that people with sleep problems have a 1.7 times higher risk of developing cognitive impairment than those with normal sleep. Poor sleep at midlife is associated with worse cognitive function later in life, as shown by a 20-year follow-up study of over 2,300 twins. A study of sleep quality in older men, assessed through self-reports and a wrist-worn device tracking movements during sleep, demonstrated that participants who slept poorly were more likely to experience cognitive decline than those who slept well.
Sleep apnea and other sleep-disordered breathing problems disrupt sleep and cause intermittent hypoxia (lack of oxygen). Among older adults, these disorders, which affect almost 50 percent of men and 25 percent of women, are linked with worse cognition. A study at NYU Langone’s Alzheimer’s Disease Center examined multiple imaging, physiological, and cognitive characteristics in more than 2,000 older adults and demonstrated that sleep apnea was associated with an earlier age of onset of mild cognitive impairment and dementia. “We also showed that treating sleep apnea slows down cognitive decline. This is good news for many patients who can use continuous positive airway pressure (CPAP) devices to restore correct breathing and improve their sleep,” says Dr. Osorio Suarez, the lead author on this study. Treatment of sleep apnea is one of the few therapies that has shown to slow down cognitive decline among Alzheimer’s disease patients.
The disruption of sleep commonly seen in Alzheimer’s disease was often assumed to be the result of accumulation of amyloid beta protein. However, research shows that disturbed sleep may increase the buildup of amyloid beta and lead to neurodegeneration and cognitive decline. A brain imaging study of older adults using amyloid PET showed that participants who slept less or less well had more amyloid deposits than subjects with longer and better sleep. Another amyloid PET study showed that normal older subjects who had sleep apnea accumulated more amyloid over a two-year period than subjects with normal sleep. Biomarker studies of cognitively healthy older adults at risk of Alzheimer’s disease demonstrated that those subjects who slept poorly had lower levels of circulating amyloid beta in their cerebrospinal fluid (CSF), an early sign of Alzheimer’s disease.
Studies of sleep and its impact on health are becoming increasingly complex and often employ multiple different techniques. These techniques include medical imaging, actigraphy (measurements of movements during sleep), and polysomnography (or sleep study), which records electrical activity in the brain, as well as blood oxygen level, blood pressure, heart rate, and breathing. Sleep studies are currently analyzed by trained readers. This approach is often subjective and reader dependent. Machine learning approaches are currently employed to develop more objective, effective, automatic methods for interpreting sleep studies. Researchers at NYU Langone have developed an algorithm to detect spindles—short bursts of brain activity during non–rapid eye movement (REM) sleep—and showed that it provides fast and accurate analysis of publicly available expert-validated EEG datasets. “Machine learning algorithms take advantage of the large databases of sleep studies and really boost our ability to analyze sleep data in both humans and animals,” says Dr. Osorio Suarez. Another fascinating research question is REM sleep, or “paradoxical sleep,” which plays an important but still mysterious role in the formation of certain types of memory, especially navigation memory. “We know that this type of memory is often affected in patients with Alzheimer’s disease, who might wander away and get lost on the way home, so studying this mechanism may be important for our understanding of dementia.”
Although sleep is fundamental for human health, our understanding of it is still limited. Much remains to be learned, but the recognition of the importance of sleep for brain health and the advances in experimental techniques that enable to probe the brain activity during sleep promise new insights into the role of sleep in the development of Alzheimer’s disease and other neurodegenerative disorders as well as methods of their prevention.
Harnessing the Immune System to Fight Alzheimer’s Disease
In a healthy brain, the immune system protects the brain tissue from injury or infection. With aging, the immune cells become less effective at fighting disease and may even damage the brain tissue. Researchers at the Alzheimer’s Disease Research Center study how restoring the function of these immune cells helps to improve their ability to remove amyloid beta and tau from the brain. These studies have shown that stimulating the immune system with a well-characterized compound reduces amyloid beta deposits and improves cognition.
Immunotherapy, which uses the immune system to fight diseases, is actively studied as a potential treatment for Alzheimer’s disease. At NYU Langone’s Alzheimer’s Disease Research Center, a multipronged effort led by Thomas M. Wisniewski, MD, explores immunotherapeutic approaches targeting proteins associated with Alzheimer’s disease, amyloid beta and tau. These approaches include, among others, the development of monoclonal antibodies (Fernando R. Goñi, PhD), passive immunization against amyloid beta (Martin Sadowski, MD, PhD), and tau-targeting therapies (Einar M. Sigurdsson, PhD). In partnership with the Alzheimer’s Disease Research Center, Henrieta Scholtzova, MD, PhD, associate professor in the Department of Neurology, and her team investigate how the innate immune system—the first line of the body’s defense against microbes—can be harnessed to counteract the Alzheimer’s disease–related brain pathology.
The innate immune system is intimately involved in the development of Alzheimer’s disease. Microglia, the brain’s resident macrophages, help to maintain healthy brain tissue by scavenging damaged cells and plaques. In the presence of an infection or injury, microglia transform into a pro-inflammatory state, migrate to the affected site, and destroy pathogens and debris through phagocytosis. Microglia also release signaling molecules, such as cytokines and chemokines, which help to recruit and direct the response of the peripheral immune system. When the inflammation subsides, microglia return to an anti-inflammatory state that supports tissue remodeling and repair.
Early in Alzheimer’s disease, microglia and the peripheral macrophages that migrate to the brain accumulate in areas of pathology and help to break down and remove amyloid beta by phagocytosis. With aging and progressive disease, these immune cells may become dysfunctional and lose their ability to clear amyloid beta and protect the brain, which may lead to further neurodegeneration.
Microglia are extremely sensitive to changes in the brain microenvironment in response to both local and peripheral stimuli. Dr. Scholtzova’s immunotherapeutic approach is based on the idea that by stimulating the innate immune system, it may be possible to “rejuvenate” microglia, restore their phagocytic function, and thus reduce the buildup of harmful proteins in the brain. “Immune cell recruitment is a complex process that depends on multiple factors, including microenvironment, cell population, and disease stage,” says Dr. Scholtzova. “Through our experiments in animal models, we are uncovering the details of this process that are essential for translating this treatment to humans.”
To stimulate the immune system, Dr. Scholtzova uses molecules that contain a short, single-stranded DNA motif called unmethylated cytosine-phosphate-guanine (CpG). This motif is often present in the DNA of bacteria and viruses, but is rarely found in vertebrate DNA. The receptors on certain immune cells can also be activated by synthetic compounds containing CpG motifs, known as CpG oligodeoxynucleotides (ODNs), which have shown excellent safety profiles in clinical trials of therapies for infectious disease, cancer, asthma, and allergies.
Dr. Scholtzova has pioneered translational studies of immunomodulation induced by CpG ODN and its effect on Alzheimer’s disease pathology. In 2019, this approach was recognized by a U.S. patent. Successful innate immunity modulation has been first shown Dr. Scholtzova and her team in transgenic mice. Mice treated with CpG showed large reductions in brain amyloid, including vascular amyloid—deposits accumulated in the blood vessel walls. The reductions in brain pathology were accompanied by cognitive improvements, as demonstrated by the animals’ enhanced ability to navigate a maze. Importantly, treated animals did not show an increase in microbleeds or neuroinflammation, common limiting factors of immunotherapy.
In a long-term treatment study, aged squirrel monkeys (Saimiri boliviensis boliviensis) that received monthly injections of CpG ODN over 24 months showed reduced total amyloid burden the brain regions involved in cognition and memory. Treatment also had cognitive benefits: On cognitive tests, old monkeys that received CpG treatment performed comparably to much younger animals. Squirrel monkeys have cerebrovascular and immune systems that are similar to human systems and with age, they spontaneously develop amyloid beta deposits, mainly in the form of vascular amyloid. This makes squirrel monkeys an excellent and by now well-characterized model of Alzheimer’s disease. “We showed for the first time in squirrel monkeys that treatment with CpG ODN can effectively and safely reduce amyloid deposits, including vascular amyloid,” says Dr. Scholtzova. “The immune activation profiles vary with the animal model. For a successful translation of this type of therapeutic intervention to humans, we need to understand the mechanism of the treatment-induced immune response.”
In the next phase of this research, Dr. Scholtzova and her collaborators have undertaken pioneering in vivo MRI studies to evaluate the safety and efficacy of the CpG ODN treatment in squirrel monkeys. For in vivo MRI, Dr. Scholtzova has formed a collaboration with NYU Langone’s Preclinical Imaging Laboratory directed by Youssef Z. Wadghiri, PhD, associate professor in the Department of Radiology, and with the researchers at the Small Animal Imaging Facility (SAIF), at the Department of Imaging Physics, University of Texas MD Anderson Cancer Center. In addition, ex vivo imaging is performed in partnership with Dr. Wadghiri and his team.
Dr. Scholtzova concludes, “The CpG ODN treatment is a promising approach. Our animal studies showed that it appears to be safe in the long term, probably because of the mild and transient nature of the immunomodulation induced by the peripheral administration of CpG ODN.” The insight gained from these studies is a step toward bench-to-bedside translation of this innovative therapy.