An Inflammatory View of Early Alzheimer’s Disease
Posted on by Lawrence Tabak, D.D.S., Ph.D.
Detecting the earliest signs of Alzheimer’s disease (AD) in middle-aged people and tracking its progression over time in research studies continue to be challenging. But it is easier to do in shorter-lived mammalian models of AD, especially when paired with cutting-edge imaging tools that look across different regions of the brain. These tools can help basic researchers detect telltale early changes that might point the way to better prevention or treatment strategies in humans.
That’s the case in this technicolor snapshot showing early patterns of inflammation in the brain of a relatively young mouse bred to develop a condition similar to AD. You can see abnormally high levels of inflammation throughout the front part of the brain (orange, green) as well as in its middle part—the septum that divides the brain’s two sides. This level of inflammation suggests that the brain has been injured.
What’s striking is that no inflammation is detectable in parts of the brain rich in cholinergic neurons (pink), a distinct type of nerve cell that helps to control memory, movement, and attention. Though these neurons still remain healthy, researchers would like to know if the inflammation also will destroy them as AD progresses.
This colorful image comes from medical student Sakar Budhathoki, who earlier worked in the NIH labs of Lorna Role and David Talmage, National Institute of Neurological Disorders and Stroke (NINDS). Budhathoki, teaming with postdoctoral scientist Mala Ananth, used a specially designed wide-field scanner that sweeps across brain tissue to light up fluorescent markers and capture the image. It’s one of the scanning approaches pioneered in the Role and Talmage labs [1,2].
The two NIH labs are exploring possible links between abnormal inflammation and damage to the brain’s cholinergic signaling system. In fact, medications that target cholinergic function remain the first line of treatment for people with AD and other dementias. And yet, researchers still haven’t adequately determined when, why, and how the loss of these cholinergic neurons relates to AD.
It’s a rich area of basic research that offers hope for greater understanding of AD in the future. It’s also the source of some fascinating images like this one, which was part of the 2022 Show Us Your BRAIN! Photo and Video Contest, supported by NIH’s Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative.
 NeuRegenerate: A framework for visualizing neurodegeneration. Boorboor S, Mathew S, Ananth M, Talmage D, Role LW, Kaufman AE. IEEE Trans Vis Comput Graph. 2021;Nov 10;PP.
 NeuroConstruct: 3D reconstruction and visualization of neurites in optical microscopy brain images. Ghahremani P, Boorboor S, Mirhosseini P, Gudisagar C, Ananth M, Talmage D, Role LW, Kaufman AE. IEEE Trans Vis Comput Graph. 2022 Dec;28(12):4951-4965.
Alzheimer’s Disease & Related Dementias (National Institute on Aging/NIH)
Role Lab (National Institute of Neurological Disorders and Stroke/NIH)
Talmage Lab (NINDS)
The Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)
Show Us Your BRAINs! Photo and Video Contest (BRAIN Initiative)
NIH Support: National Institute of Neurological Disorders and Stroke
Getting Closer to a Blood Test for Alzheimer’s Disease?
Posted on by Dr. Francis Collins
As research on Alzheimer’s disease (AD) advances, a desperate need remains for an easy blood test to help diagnose the condition as early as possible. Ideally, such a test could also distinguish AD from other forms of dementia that produce similar symptoms. As published recently in Nature Medicine, an NIH-funded research team has designed a simple blood test that is on course to meet these criteria .
The latest work builds on a large body of work showing that one secret to predicting a person’s cognitive decline and treatment response in AD lies in a protein called tau. Using the powerful, but expensive, approach of PET scan imaging, we know that tau builds up in the brain as Alzheimer’s disease progresses. We also know that some tau spills from the brain into the bloodstream.
The trouble is that the circulating tau protein breaks down far too quickly for a blood test to offer a reliable measure of what’s happening in a person’s brain. A few years ago, researchers discovered a possible solution: test for blood levels of a slightly different and more stable version of the protein called pTau181 . (The “p” in its name comes from the addition of phosphorus in a particular part of the protein’s structure.)
In the latest study, researchers in the lab of Adam Boxer, University of California, San Francisco, followed up further on this compelling lead. Boxer’s team measured pTau181 levels in blood samples from 362 people between the ages of 58 and 70. Those samples included 56 people with an Alzheimer’s diagnosis, along with 47 people with mild cognitive impairment and 69 healthy controls.
The researchers also included another 190 people diagnosed with frontotemporal lobar degeneration (FTLD). It is a relatively rare form of dementia that leads to a gradual decline in behavior, language, and movement, often in connection with a buildup of tau in the brain.
The study found that levels of pTau181 were roughly 3.5-times higher in the blood of people with AD compared to people without AD. Those with mild cognitive impairment due to underlying AD also showed an intermediate increase in blood levels of pTau181.
Importantly, people with FLTD had normal blood levels of pTau181. As a result, the blood test could reliably distinguish between a person with AD and a person with FLTD. That’s important because, while FLTD is a relatively rare condition, its prevalence is similar to AD in people under the age of 65. But both conditions have similar symptoms, making it often challenging to distinguish them.
The findings add to evidence that the new blood test can help in diagnosing AD and in distinguishing it from other neurodegenerative conditions. In fact, it does so with an accuracy that often rivals more expensive PET scans and more invasive cerebrospinal fluid tests, which are now the only reliable ways to measure tau.
There’s still plenty of work to do before this blood test is ready for a doctor’s office. But these initial findings are very promising in helping to simplify the diagnosis of this devastating condition that now affects an estimated 5.5 million Americans .
 Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Thijssen EH, La Joie R, Wolf A, Strom A, Wang P, Iaccarino L, Bourakova V, Cobigo Y, Heuer H, Spina S, VandeVrede L, Chai X, Proctor NK, Airey DC, Shcherbinin S, Duggan Evans C, Sims JR, Zetterberg H, Blennow K, Karydas AM, Teunissen CE, Kramer JH, Grinberg LT, Seeley WW, Rosen H, Boeve BF, Miller BL, Rabinovici GD, Dage JL, Rojas JC, Boxer AL; Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) investigators. Nat Med. 2020 Mar 2.
 Plasma phospho-tau181 increases with Alzheimer’s disease clinical severity and is associated with tau- and amyloid-positron emission tomography. Mielke MM, Hagen CE, Xu J, Chai X, Vemuri P, Lowe VJ, Airey DC, Knopman DS, Roberts RO, Machulda MM, Jack CR Jr, Petersen RC, Dage JL. Alzheimers Dement. 2018 Aug;14(8):989-997.
 Alzheimer’s Disease Fact Sheet. National Institute on Aging, May 22, 2019.
Alzheimer’s Disease & Related Dementias (National Institute on Aging/NIH)
What Are Frontotemporal Disorders? (NIA)
Accelerating Medicines Partnership: Alzheimer’s Disease (NIH)
Adam Boxer (University of California, San Francisco)
NIH Support: National Institute on Aging; National Institute of Neurological Disorders and Stroke; National Center for Advancing Translational Sciences
Discovering the Brain’s Nightly “Rinse Cycle”
Posted on by Dr. Francis Collins
Getting plenty of deep, restful sleep is essential for our physical and mental health. Now comes word of yet another way that sleep is good for us: it triggers rhythmic waves of blood and cerebrospinal fluid (CSF) that appear to function much like a washing machine’s rinse cycle, which may help to clear the brain of toxic waste on a regular basis.
The video above uses functional magnetic resonance imaging (fMRI) to take you inside a person’s brain to see this newly discovered rinse cycle in action. First, you see a wave of blood flow (red, yellow) that’s closely tied to an underlying slow-wave of electrical activity (not visible). As the blood recedes, CSF (blue) increases and then drops back again. Then, the cycle—lasting about 20 seconds—starts over again.
The findings, published recently in the journal Science, are the first to suggest that the brain’s well-known ebb and flow of blood and electrical activity during sleep may also trigger cleansing waves of blood and CSF. While the experiments were conducted in healthy adults, further study of this phenomenon may help explain why poor sleep or loss of sleep has previously been associated with the spread of toxic proteins and worsening memory loss in people with Alzheimer’s disease.
In the new study, Laura Lewis, Boston University, MA, and her colleagues at the Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston. recorded the electrical activity and took fMRI images of the brains of 13 young, healthy adults as they slept. The NIH-funded team also built a computer model to learn more about the fluid dynamics of what goes on in the brain during sleep. And, as it turns out, their sophisticated model predicted exactly what they observed in the brains of living humans: slow waves of electrical activity followed by alternating waves of blood and CSF.
Lewis says her team is now working to come up with even better ways to capture CSF flow in the brain during sleep. Currently, people who volunteer for such experiments have to be able to fall asleep while wearing an electroencephalogram (EEG) cap inside of a noisy MRI machine—no easy feat. The researchers are also recruiting older adults to begin exploring how age-related changes in brain activity during sleep may affect the associated fluid dynamics.
 Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Fultz NE, Bonmassar G, Setsompop K, Stickgold RA, Rosen BR, Polimeni JR, Lewis LD. Science. 2019 Nov 1;366(6465):628-631.
Sleep and Memory (National Institute of Mental Health/NIH)
Sleep Deprivation and Deficiency (National Heart, Lung, and Blood Institute/NIH)
Alzheimer’s Disease and Related Dementias (National Institute on Aging/NIH)
NIH Support: National Institute of Mental Health; National Institute of Biomedical Imaging and Bioengineering; National Institute of Neurological Disorders and Stroke