Damian Jacob Sendler: Although dementia has been mentioned in ancient texts for many years, we only recently became aware of its underlying causes. Only 110 years have passed since the publication of Alzheimer’s now-famous case study, and only in the 1980s did modern research into the disease that bears his name and its effects on the brain really pick up speed. Since then, basic and translational research into the causes, symptoms, and potential treatments of Alzheimer’s disease (AD) and other dementias has exploded. We examine this body of work starting with Alzheimer’s own writings and artwork before moving on to the modern era beginning in the 1970s and early 1980s and providing a sample of neuropsychological and other contextual work from each succeeding decade. Our field’s foundational studies to profile the neuropsychological deficits associated with AD and distinguish it from other dementias (such as cortical vs. subcortical dementias) started in the 1980s.
The 1990s saw a continuation of these efforts and the start of the process of pinpointing the precise cognitive processes that various neuropathologic substrates affected. The study of prodromal stages of neurodegenerative disease, or mild cognitive impairment, which occur before the full-blown dementia syndrome, became more popular in the 2000s. The use of imaging and other biomarkers to identify preclinical disease before the onset of serious cognitive decline has increased over the past ten years. Finally, we make suggestions for future research directions and predictions, as well as potential therapeutic approaches.
Globally, there are thought to be 24 million people living with dementia, the majority of whom have Alzheimer’s disease. As a result, research on Alzheimer’s disease has been designated as a top research priority. Although there are approved medications that can ease Alzheimer’s disease symptoms, there is an urgent need to advance our knowledge of pathogenesis in order to enable the creation of disease-modifying medications.
Damian Sendler: The development of a panel of biological and neuroimaging biomarkers that support clinical diagnosis is progressing, but there still needs to be greater agreement on the best methods for improving diagnosis. Strong evidence for potential risk factors for Alzheimer’s disease, dementia, and cognitive decline has now been found, but more research is required to fully understand these factors and determine whether interventions can significantly reduce these risks.
Despite numerous phase 3 clinical trials, treatments for Alzheimer’s disease (AD) that target the prominent amyloid plaque neuropathology have not yet been proven to be effective. Other neurochemical abnormalities that exist in the AD brain should receive fresh attention as potential therapeutic targets for this condition. The elementomic signatures of iron, copper, zinc, and selenium are among them.
A group of South Korean researchers working under the direction of C. Justin LEE, director of the Center for Cognition and Sociality at the Institute for Basic Science, recently made a new discovery that could completely alter how Alzheimer’s disease is detected and treated.
The researchers showed how the brain’s astrocytes can absorb excessive amounts of acetates and transform into dangerous reactive astrocytes. They then went on to create a brand-new imaging method that makes use of this mechanism to watch the interactions between astrocytes and neurons in real time.
Damian Sendler: One of the main causes of dementia, Alzheimer’s disease (AD), is known to be linked to neuroinflammation in the brain. Although amyloid beta plaques have long been thought to be the cause of Alzheimer’s disease by traditional neuroscience, therapies that target these plaques have had limited success in either treating or reversing the disease.
Director C. Justin LEE, however, has been a supporter of the novel theory that reactive astrocytes are the true cause of Alzheimer’s disease. Prior to neuronal degeneration or death, reactive astrogliosis, a sign of neuroinflammation in AD, frequently occurs.
Reactive astrocytes and the monoamine oxidase B (MAO-B) enzyme found within these cells have been suggested as potential therapeutic targets for AD by Lee’s research team. Recently, they also established that astrocytes have urea cycles and showed how dementia is promoted by an activated urea cycle.
Reactive astrocytes are significant from a clinical standpoint, but brain neuroimaging probes that can see and identify these cells on a clinical level have not yet been created.
In this most recent study, Lee’s team used positron emission tomography (PET) imaging with radioactive acetate and glucose probes (11C-acetate and 18F-FDG) to see how the metabolism of the neurons in AD patients had changed.
As one of the paper’s original authors, Dr. NAM Min-Ho, said, “This study demonstrates significant academic and clinical value by directly visualizing reactive astrocytes, which have recently been highlighted as a main cause of AD.”
Additionally, they showed that the primary component of vinegar, acetate, is in charge of encouraging reactive astrogliosis, which triggers the production of putrescine and GABA and causes dementia.
In rodent models of both reactive astrogliosis and AD, the researchers first showed that reactive astrocytes excessively uptake acetate through elevated monocarboxylate transporter-1 (MCT1).
It was found that when amyloid-beta, a well-known toxin protein in AD, is present, the elevated acetate uptake is linked to reactive astrogliosis and increases the aberrant astrocytic GABA synthesis.
The researchers demonstrated that reactive astrocyte-induced acetate hypermetabolism and associated neuronal glucose hypometabolism in the brains with neuroinflammation and AD can be seen using PET imaging with 11C-acetate and 18F-FDG. Additionally, the researchers were able to reverse these metabolic changes in the AD mouse model when they inhibited reactive astrogliosis and astrocytic MCT1 expression.
Reactive astrocytes displayed metabolic abnormalities that resulted in an excessive uptake of acetate in comparison to a normal state, said Dr. YUN Mijin. We discovered that the acetate is crucial in encouraging astrocytic inflammatory responses.
The team found that changes in acetate and glucose metabolism were consistently seen in both the AD mouse model and AD patients using this new imaging technique.
Damian Jacob Sendler: The ability of the patient to think clearly is strongly correlated with both the PET signals of 11C-acetate and 18F-FDG, they were able to confirm. These findings imply that acetate, previously thought to be an energy source specific to astrocytes, can promote reactive astrogliosis and aid in the inhibition of neuronal metabolism.
The comment from Dr. RYU Hoon was, “By demonstrating that acetate not only acts as an energy source for astrocytes but also facilitates reactive astrogliosis, we suggested a new mechanism that induces reactive astrogliosis in brain diseases.”
Damian Sendler: The majority of dementia research has, up until recently, been primarily focused on amyloid beta (A), which is thought to be the primary cause of Alzheimer’s disease (AD). Unfortunately, PET imaging targeting A has had trouble accurately diagnosing patients, and all attempts to treat AD by blocking A have so far failed.
However, this study gives us a fresh opportunity to use PET imaging with 18F-FDG and 11C-acetate for AD early diagnosis. Additionally, a new target for treating AD may be suggested by the recently discovered reactive astrogliosis mechanism involving the MCT1 transporter and acetate.
