by Sharon Reynolds for NIH Research Matters

A protein called alpha-synuclein plays a major role in Parkinson’s disease as well as other brain disorders. In these conditions, the protein misfolds and aggregates (collects and sticks together) to create clumps called Lewy bodies within cells. Lewy bodies are thought to be toxic to certain neurons in the brain.

Parkinson’s disease and another disease involving alpha-synuclein, called multiple system atrophy (MSA), are particularly difficult to tell apart based on early symptoms. While there is no cure for either, the two diseases require different treatments to keep people with the conditions healthy as long as possible.

Researchers led by Dr. Claudio Soto from UTHealth in Houston used a test called protein misfolding cyclic amplification (PMCA) to detect small amounts of alpha-synuclein aggregates in cerebrospinal fluid (CSF). PMCA works by exposing regular alpha-synuclein protein to samples from patients that might contain misfolded alpha-synuclein. If present, the misfolded protein amplifies itself by misfolding regular alpha-synuclein. This copying process allows detection and analysis of the misfolded proteins, which aggregate and assemble into thin, twisted fibrils. Such fibrils form a large component of Lewy bodies.

Previous studies suggested that the fibrils produced in people with Parkinson’s disease and MSA may adopt slightly different shapes. To see if PMCA could be used to distinguish the different fibrils, the scientists tested CSF samples from people known to have Parkinson’s disease, MSA, and other neurological diseases not related to alpha-synuclein.

The research was funded in part by NIH’s National Institute on Aging (NIA) and National Institute of Neurological Disorders and Stroke (NINDS). Results were published on Feb. 13, 2020, in Nature.

The scientists confirmed that the PMCA products from people with Parkinson’s disease and MSA reacted differently with a fluorescent dye. They showed other differences as well, such as their ability to resist degradation by molecules that cut proteins. In studies looking at the structure of the alpha-synuclein fibrils, the team found that the fibrils twisted differently between Parkinson’s disease and MSA.

When tested in samples from 94 people with Parkinson’s disease and 75 with MSA, PMCA was able to tell the difference between the two diseases with about 95% accuracy. No signal was seen when samples were tested from 56 people with other neurological diseases not related to alpha-synuclein.

“By amplifying the abnormal [alpha synuclein] aggregates, we can detect with high efficiency which disease the patient has,” Soto says. “This has huge implications both for accurate diagnosis and clinical care of the patient, and the development of new specific treatments for both diseases.”

If you have been diagnosed with or care for someone with Parkinson’s Disease, please know that you are not alone at the Ventura Parkinson’s Disease Support Group.

For more information and meeting dates please call Patty Jenkins at 805-766-6070 or email her at [email protected].

by Dr. Melinda Kelley Office of the Director (OD).

A few years ago, NIA collaborated with the Agency for Healthcare Research and Quality (AHRQ) and the National Academies of Sciences, Engineering, and Medicine (NASEM) to assess the evidence for interventions to prevent cognitive decline and dementia. In 2018, in response to the emerging science presented at the 2017 National Research Summit on Care, Services, and Supports for Persons with Dementia and Their Caregivers, NIA embarked on a similar collaboration with AHRQ and NASEM — this time to assess care and caregiving interventions for people with dementia (PWD) and their caregivers. I wanted to take this opportunity to share an update about this project with you, as well as an important new opportunity for public input.

As we did for the previous review, NIA asked AHRQ to conduct — through its Evidence-based Practice Centers (EPC) program — a rigorous systematic review to understand the evidence base for effective care and caregiving interventions. For this study, we asked AHRQ to consider the complexities and multifaceted nature of dementia care and caregiving, including the diversity across populations of PWD and their caregivers, settings and intervention design and outcomes. A final review protocol, developed by the Minnesota EPC, describes the full scope of this review and the criteria for studies to be included.

From now through 04/21/2020, the draft review is posted online and is available for public comment. We invite all individuals with an interest in this topic to provide input directly to AHRQ via its evidence review page.

A second phase of this project will involve an assessment of the AHRQ-EPC evidence findings by an expert committee, established by NASEM on this topic, at the request of NIA. This committee is charged with assessing the quality of the existing evidence, based predominantly on the evidence presented by the AHRQ and the EPC in this newly released systematic review. They will also develop a detailed report to convey the current state of knowledge, identify which, if any, interventions might be ready for dissemination and implementation on a broad scale, and describe any relevant research gaps in the field.

On April 15, 2020, this NASEM committee will convene, along with other stakeholders and experts, a public workshop — to be held via videocast — to discuss the data contained in the draft AHRQ systematic review and to consider input from a range of stakeholders. We are excited to welcome the broader public, including “Inside NIA” blog readers, to join this virtual event. Following the workshop, the committee will draft a full report, expected to be released in early 2021.

We encourage you to take part in this important project by sharing your comments on the AHRQ evidence review and/or participating in the NASEM workshop. Your input is an invaluable contribution toward developing a comprehensive understanding of the best ways to help provide essential care and services for the millions of people living with dementia and their caregivers.

Stress-induced changes in protein connections in the brain contribute to the cognitive decline seen in Alzheimer’s disease. In mice, this malfunctioning protein network and its associated cognitive decline were reversed by an experimental drug, according to a recent study supported in part by NIA. The findings suggest a new way to look at how Alzheimer’s develops in the brain by focusing on protein networks.

Brain illustration scientists at New York’s Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College used laboratory, mouse and brain-tissue studies to examine the epichaperome — a dysregulated network of proteins that affects how cells communicate and accelerates the course of disease. A previous study revealed the workings of the epichaperome in cancer; this new study looked at Alzheimer’s disease.

Various stressors — such as genetic risk factors, vascular injury and diabetes — can damage brain circuitry in Alzheimer’s. According to the study, these stressors seem to interact with proteins and contribute to toxic changes that begin in the hippocampus, a brain region involved in learning and memory. The researchers explored how these protein networks stop working properly and can be restored.

Like faulty wires in a circuit board that lead to network failure, epichaperomes seem to remodel cellular processes that, in turn, “rewire” protein connections supporting normal brain function. The resulting imbalance in brain circuitry — which the authors call “protein connectivity-based dysfunction” — underlies synaptic failure and other neurodegenerative processes. The researchers studied a cellular model of Alzheimer’s and a mouse model of the protein tau, as well as human brain tissue, which showed significantly more epichaperomes in individuals who had Alzheimer’s than in cognitively healthy people.

The research team treated young and old mice bred to have Alzheimer’s with an epichaperome inhibitor they developed, called PU-AD, three times per week for three to four months. The treated mice performed better on memory and learning tests than untreated mice, had less tau (a protein seen in Alzheimer’s) and survived longer. What’s more, their brains looked like those of normal mice. PU-AD inhibited the faulty protein networks created by epichaperomes by correcting how the proteins connected and promoting nerve-cell survival, the authors explained.

“Our results point to a common [Alzheimer’s disease] mechanism, which we have demonstrated to be targetable and potentially druggable,” the authors wrote. They added that further studies of protein network connectivity may lead to new insights about the biology of Alzheimer’s and a possible new biomarker for disease onset.

PU-AD, developed with support through NIA’s Alzheimer’s Translational Research Program, has received an investigational drug status from the Food and Drug Administration and has begun safety testing in humans by the biotech company Samus Therapeutics.