Sodium selenate: A potential future treatment for early-onset dementia

13/05/2022

Researchers assessed the safety and tolerability of sodium selenate when treating dementia.
They found that sodium selenate is safe and well-tolerated by patients.
They now plan to conduct a larger, placebo-controlled trial.

Behavioral variant frontotemporal dementia (bvFTD) is the second most common form of dementia in younger patients and can occur as early as age 45.

Around 45% of bvFTD cases are caused by excessive tau protein in the brain, which interferes with neuronal structure and leads to neurodegeneration.

The levels and activity of an enzyme called phosphatase 2 (PP2A) are linked to reduced levels of neurodegeneration. Stabilizing and upregulating this enzyme may thus help reduce tau build-ups.

Sodium selenate has been shown to upregulate PP2A activity and reduce tau levels in animal models of dementia and mild-moderate Alzheimer’s disease.

Knowing whether these findings may be replicated in humans could pave the way for new treatment options.

Recently, researchers conducted a Phase 1b trial to understand the safety and tolerability profile of sodium selenate in patients with bvFTD.

The researchers found that sodium selenate is safe and well-tolerated in patients with bvFTD, and that further study is now warranted to investigate the drug.

The study was published in the Alzheimer’s Association’s journal Translational Research and Clinical Interventions.

Phase 1b trial

For the study, the researchers enrolled 12 participants with bvFTD with a median age of 61 years old. Each received 10 mg of sodium selenate three times a day, at week 4 they started receiving 15 mg of sodium selenate which was maintained for 52 weeks.

Patients underwent clinical visits at baseline, during treatment, and four weeks after completion.

Clinical measures included MRI scans at baseline and at week 52 to calculate brain volume change, alongside blood and cerebrospinal fluid samples to verify changes in neurodegenerative markers.

The patients also filled in various questionnaires to track cognitive, emotional, and behavioral measures.

In the end, the researchers found that sodium selenate was safe and well-tolerated by patients with bvFTD.

While patients experienced no serious adverse events, all experienced at least one adverse effect, the most common of these being alopecia and nail disorders.

Beyond safety and tolerability, the researchers noted that patients underwent a small decline in cognition and behavior over the study period. They also experienced no change in tau levels following treatment.

While a small number of participants showed a substantial loss in brain volume, most experienced relatively slow brain atrophy rates.

Underlying mechanisms

When asked how sodium selenate may theoretically treat bvFTD, Dr. Lucy Vivash, research fellow at Monash University and lead scientist of the study, explained to Medical News Today:

“In its ‘normal’ form, tau forms part of the transport mechanisms within the neuron. However, tau can become phosphorylated. In its phosphorylated form, the tau protein is more sticky, and it disassociates from the neuronal transport mechanisms. This ‘sticky’ tau then accumulates both inside and outside of neurons which leads to neuronal death and atrophy of the brain.”

Dr. Vivash said sodium selenate activated protein phosphatase 2 A (PP2A), an enzyme that controls the cell cycle as well as cell death (apoptosis), within the brain.

She elaborated:

“This enzyme is responsible for more than 70% of dephosphorylation that occurs in the brain, and is therefore the primary mechanism by which tau is dephosphorylated. Increasing the activity of PP2A reduces the levels of tau in the brain, which prevents further neuronal death and the progression of disease symptoms.”

Dr. Barbara Cardoso, lecturer in nutrition dietetics and food at Monash University, who was not involved in the study, added that sodium selenate is also associated with antioxidant response, which may further protect against neurodegeneration.

The researchers concluded that their findings warrant a double-blind, placebo-controlled study to further evaluate sodium selenate as a potential treatment to slow or stop disease progression in patients with bvFTD.

When asked about the study’s limitations, Dr. Vivash said that the drug has so far only been studied on a small number of patients and that larger groups of patients, alongside a placebo, are needed to confirm the findings.

Dr. Cardoso said that as the study is preliminary in nature, its clinical findings should be interpreted with caution.

“The study has assessed classic adverse effects associated with selenium intake, but it doesn’t seem to have assessed clinical markers such as blood glucose levels, which have been demonstrated to be associated with increased intake of selenium. This is of utmost importance given that this study uses a high dose of selenium which surpasses the Tolerable Upper Intake Level (UL) established by dietary guidelines,” she noted.

“Also, knowing the baseline selenium status of the participants as well as how much the treatment was effectively uptaken by the body may provide precious information regarding the participants’ response to the treatment,” she added.

General use

Sodium selenate is currently only being researched for bvFTD and progressive supranuclear palsy (PSP)—a neurodegenerative disorder that causes problems with walking, balance, eye movements, and eventually swallowing.

Dr. Vivash said, however, that the treatment has potential for use in other conditions caused by tau build-ups.

She noted that these include:

Primary age-related tauopathy (PART)
Chronic traumatic encephalopathy (CTE)
Primary progressive aphasias (PPAs) and the movement disorders
Progressive supranuclear palsy (PSP)
Corticobasal syndrome (CBS)

“We previously investigated sodium selenate as a treatment for Alzheimer’s disease,” she said.

“The results showed the patients with the greatest increase in selenium levels showed no change in memory tests (i.e. no decline), whereas those who showed no/minimal change in their selenium levels (indicating low compliance with the medication) continued to show a worsening of their memory,” she concluded.

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