Dementia is a clinical syndrome characterised by a progressive decline in memory, language and brain function, and which can lead to changes in personality and behaviour. Alzheimer’s disease (AD) is by far the most common cause of dementia, accounting for up to 80 % of all dementia diagnoses. “Care and support for patients with dementia has wide-ranging consequences for families, healthcare systems, and society as a whole,” notes PANA project coordinator Tomás Sobrino from the Galician Healthcare Service (website in Galician) in Spain. “With an ageing global population, issues of age-related memory impairment will only become more important and relevant to quality of life.” While early diagnoses of AD are critical to enabling individuals to receive the care and treatments they need, this has proven to be extremely challenging. For one, there is considerable overlap between many neurodegenerative disorders, making diagnoses difficult. Secondly, changes in brain function can occur years before the onset of the first symptoms. “First interventions after a diagnosis of AD are usually too late,” says Sobrino. “Without an accurate and early diagnosis, it is very difficult to modify the neurodegenerative course of the disease. This is the main challenge.”
Early diagnostic tools
This is why the PANA project set out to develop innovative new early diagnostic tools. To do this, the team focused on finding novel ways of detecting specific proteins associated with disease progression. The expression of a neuronal protein called tau for example is known to increase as AD progresses. “Tau also undergoes modifications that make this protein more toxic,” adds Sobrino. “We developed an in vitro system that allows scientists to quickly identify tau modifications in cerebrospinal fluid samples from individuals.” For non-invasive in vivo detection, the project team developed nanoparticle contrast agents, which not only recognise tau protein modifications in the body, but can also be tracked using non-invasive imaging technologies such as MRI. “This innovation could enable medical staff to quickly identify patients at risk of developing AD, when they might only have mild neurological impairments,” says Sobrino. Finally, the team performed preclinical studies to test the therapeutic properties of novel antibodies – molecules that selectively recognise a protein – against tau protein modification. The team wanted to see if the antibodies could block tau modifications and be used to monitor disease progress at the same time. “Our initial findings are that AD mice tested with this antibody showed less neurodegeneration,” remarks Sobrino. “We were therefore able to develop not only new diagnostic strategies, but also therapeutic ones.”
The project’s advances in the development of both diagnostic and therapeutic tools could be hugely significant for the treatment of AD. More specifically, PANA has pushed forward three promising innovations: an in vitro system for early AD detection; using nanoparticles to non-invasively detect protein changes in the body; and using antibodies to both treat and monitor disease progression. “Early diagnosis creates the potential to modify the course of the disease,” he adds. “Nonetheless, there is still a lot of work to do. The in vitro immunodiagnostic kits are the closest to market, but we need to be sure they are compliant with regulations.” More preclinical research is needed for the nanotech contrast agents. Crossing the blood-brain barrier, for example, remains a challenge. The antibodies, meanwhile, are well-positioned to be tested in the near future. “We tested the efficacy and toxicity of these antibodies, which laid the groundwork for future clinical trials,” notes Sobrino.
PANA, Alzheimer’s, brain, disease, dementia, protein, tau, MRI, therapeutic