Inside Neuroscience: Linking Dementia and the Vascular System

Dementia is a broad class of cognitive impairment that is increasingly common as the population ages — a reported 5.7 million people in the U.S. live with Alzheimer’s disease alone. Vascular dementia, a form of dementia caused by reduced blood flow to the brain, is one of the most prevalent forms of the disease and often appears alongside Alzheimer’s disease diagnoses.

Neuroscience research in this area has focused on the breakdown and impairment of neurons and neural connections as well as the significant cognitive decline that results. In particular, much attention has been paid to the buildup of Alzheimer’s trademark byproducts amyloid beta and tau. Now a relatively new focus has emerged on the connection between the vascular system and dementia.

In an effort to share the most advanced research in this area with those living with the consequences of dementia, SfN organized a press conference at Neuroscience 2018 entitled, “The Link Between Dementia and Cardiovascular Disease.” Through their research into the relationship between the vascular system and dementia, the speakers have found not only new methods for diagnosis but also opened new possibilities for management and even preventative treatment.

The APOE4 gene has been found to be the strongest genetic risk factor for Alzheimer’s disease. The gene can disrupt the blood-brain barrier, but whether it can be targeted to treat vascular and neuronal injury in Alzheimer’s disease is unknown. To find out, researchers at the Keck School of Medicine of the University of Southern California (USC) conducted a study using dye and MRIs to look at the brain vasculature in mice with Alzheimer’s disease.

Their analysis quantified bleeding and disruption in the brain’s vascular system — the blood-brain barrier was “leakier,” and the brains had decreased blood flow and more microbleeds than non-Alzheimer mice. Looking at neuronal effects, the brains also had more of the traditional buildup of amyloid-beta.

Debio-025, a drug used to treat hepatitis C, can protect the blood-brain barrier. The researchers used the treatment on the APOE4 Alzheimer’s mice. In doing so, “we can protect the barrier, and then we have improvement of cognitive function,” said Axel Montagne, assistant professor and lead author. “We also have a slowdown of amyloid-beta [accumulation].” In other words, Debio-025 blocked the negative vascular and cognitive impacts associated with APOE4 genetic risk in Alzheimer’s disease.

Early detection and intervention for Alzheimer’s disease would greatly help treatment but does not yet exist. Accumulation of amyloid-beta and tau proteins are pathologies of the disease, but it is hypothesized that vascular dysfunction actually precedes neuronal and cognitive decline. Researchers in the same lab at USC sought to understand if the effect APOE4 has on the blood-brain barrier could be used as a biomarker.

To do so, they studied the living human brain using a new MRI technique that measured blood-brain permeability in brains of individuals with early cognitive impairment compared to healthy controls. They found greater blood-brain barrier permeability in APOE4 carriers and during early cognitive impairment — irrespective of factors including age, sex, and education level. The researchers also studied biomarkers in cerebrospinal fluid that indicate dysfunction of pericytes, which maintain the integrity of the blood-brain barrier. APOE4 carriers also had more pericyte injury. The blood-brain barrier breakdown in APOE4 carriers was independent of amyloid-beta and tau.

“Blood-brain barrier breakdown in APOE4 carriers is an early biomarker of subtle cognitive impairment… and we showed this with two independent markers,” said Melanie Sweeney, postdoctoral research fellow and co-author. Now, the researchers are asking the question: do these biomarkers predict cognitive impairment better than amyloid-beta and tau?

At the moment, vascular dementia cannot be diagnosed until it is in later stages of development. Like Alzheimer’s disease, it could benefit from identification of a biomarker that would enable earlier treatment. Researchers at the National University of Singapore hoped to study whether the fatty molecule sphingosine-1-phosphate (S1P), which contributes to the development and survival of neurons, might be one such biomarker for vascular dementia.

Human subjects (both with dementia and without) provided plasma for study, and researchers noticed a lower amount of one variant of the molecule, C16-S1P, in the subjects with dementia. “We think...what’s happening biologically is that, at normal levels, this S1P reduces the amount of inflammation in the brain. When the levels of this S1P are decreased in our vascular dementia patients, it leads to chronic inflammation that exacerbates the disease,” said Deron R. Herr, assistant professor and lead author.

Lower C16-S1P might help identify patients with vascular dementia earlier and could affect treatment decisions — and activation of C16-S1P may be viable as a treatment option.

One of the defining features of vascular dementia is damage to the white matter (the brain’s wiring and insulation), which can be mitigated by exercise. McGill University researchers aimed to study in mice how exercise can prevent vascular dementia.

In the study, mice with vascular dementia showed memory loss except in the cases where they were allowed to exercise. Mice who exercised had increased blood flow in the brain and had fewer collapsed blood vessels present than in the other mice. “In human brain imaging studies, there is some evidence that there are white matter changes occurring early… but what these changes actually mean, are not fully understood. An advantage of working with mice is that we can look directly in their brains once we do see memory problems arise to better pinpoint the source of the problem,” said Lianne Trigiani, graduate student and lead author.

The study implies that a decrease in blood flow in the brain can lead to inflammation and damage in white matter, which impacts communication between brain regions. Exercise can prevent these events, at least in mouse models — and future research will focus on related human treatments.

When a healthy human brain disposes of waste, it uses cerebrospinal fluid to carry it through lymphatic vessels that exist around the borders of the brain. If this lymphatic drainage system somehow becomes impaired — either via dementia or normal aging — impaired brain function can result.

VEGF-c, a growth factor molecule that can impact lymphatic function, was used by University of Virginia researchers to increase and decrease the efficacy of the drainage system in mice. When added, VEGF-c boosted drainage and improve cognitive function and, when taken away, exacerbated amyloid plaque in diseased mice.

“These results suggest that if you have humans with impaired lymphatic drainage, this might be an aggravating factor that we have to take into account, and that we may be able to manipulate it in order to be able to improve disease pathology and brain function in Alzheimer’s disease,” said Sandro Da Mesquita, postdoctoral research fellow and lead author. Future therapies are designed to target particular genes to improve lymphatic function.

These new directions of research have begun to look beyond the more well-studied areas of Alzheimer’s disease and dementia — amyloid beta and tau among them — to examine the early signs, symptoms, and causes of the diseases from a different perspective. In doing so, researchers aim to unveil effective clinical treatments.

Richard Wainford, associate professor at Boston University School of Medicine and moderator of the press conference explained, “Knowledge of the neurobiology and mechanisms involved open the door to being able to identify dementia early, which offers hope of potential new treatments and interventions that could help patients and their families around the world.”