Focused ultrasound and microbubbles targeting alpha-synuclein pathology-related dementia (FUMA)

Descripción del proyecto

Un enfoque eficaz para frenar la demencia asociada al Parkinson

Más de la mitad de las personas diagnosticadas con la enfermedad de Parkinson desarrollan demencia. Este deterioro cognitivo está relacionado con agregados de proteínas tóxicas en el cerebro y con una actividad microglial deficiente (las células encargadas de eliminar estos residuos). En el proyecto FUMA, financiado con fondos europeos, se investigará si el empleo de ultrasonidos focalizados con microburbujas puede prevenir la aparición de demencia. Esta técnica atraumática abre temporalmente la barrera hematoencefálica, lo que ayuda al cerebro a eliminar las proteínas perjudiciales y restablecer la salud sináptica. El equipo de FUMA empleará modelos murinos de demencia asociada al Parkinson para evaluar si este método mejora la cognición y ralentiza la neurodegeneración. También identificará biomarcadores para imagenología y vías moleculares. Si los resultados son positivos, el nuevo método podría sentar las bases de una nueva terapia más segura para la demencia asociada al Parkinson.

Objetivo

Over half of Parkinson Disease patients develop cortical dysfunctions leading to Parkinson Disease Dementia (PDD). The cognitive changes are primarily driven by pathological alpha-synuclein (a-syn) protein aggregates with secondary synaptic dysfunctions in the cortex. Microglia plays a key role in synapse maintenance and clearance of aggregated a-syn proteins, however, this is impaired in PD.
Low intensity focused ultrasound (FUS) combined with intravenous microbubbles (MB) can non-invasively increase the permeability of the blood-brain barrier, resulting in a transient and controlled entry of blood-born substances. In animal models of Alzheimer disease, FUS-MB treatments increase microglial-mediated clearance of extra- and intracellular protein aggregates and improve synapse health. In small patient cohorts in the clinic, FUS-MB treatments are safe and results suggest decreased levels of pathological proteins in Alzheimer disease patients.
HYPOTHESIS: FUS-MB applications targeted to the cortex promote cortical a-syn clearance and synapse maintenance which can prevent or slow the development of dementia in PD.
In a mouse model of PDD we will determine the ability of FUS-MB treatment to increase microglial-mediated clearance of a-syn, maintain synapse health, and inhibit the development of cognitive dysfunctions. In addition, we aim to evaluate non-invasive positron emission tomography and magnetic resonance imaging as biomarkers of the effects of FUS-MB treatment. Finally, we will investigate the underlying pathway of potentially beneficial effects of FUS-MB treatments by measuring changes in specific pathways of interest as well as perform an unbiased screen for novel targets.
Both the researcher and supervisor have a background in Parkinson disease research. The researcher brings expertise in FUS-MB treatments of mouse models and the supervisor is an expert in preclinical and clinical neuromodulation, the latter with FUS.