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Huntington's disease (HD) is an inherited neurodegenerative disorder characterised by progressive cognitive and motor decline driven by basal ganglia (BG) atrophy. Clinical trials of novel disease-modifying therapies are ongoing, creating a need for sensitive non-invasive imaging biomarkers. Soma and Neurite Density Imaging (SANDI) is a multi-shell diffusion MRI model that estimates intracellular signal fractions from sphere-shaped soma and shows promise as a marker of neurodegeneration. The...

BackgroundAmenable mortality, deaths preventable through timely and effective healthcare, is a widely used indicator of health system performance, yet evidence is lacking on its individual-level determinants in Brazil.MethodsWe used data from the Brazilian Longitudinal Study of Aging (ELSI-Brazil), a representative cohort of adults aged 50 and older. Deaths were classified as amenable using both the Brazilian and the Pan American Health Organization's definitions. Semi-parametric competing risks...

An experimental GLP-1 pill helped people with obesity or overweight lose as much as 12.1% of their body weight in just 36 weeks. Unlike injectable drugs such as Wegovy and Ozempic, aleniglipron is a small molecule that can be taken once daily with or without food and could potentially be produced more easily at scale.

Very high levels of the inherited cholesterol-related particle Lp(a) were linked to a greater risk of major cardiovascular events, particularly stroke and cardiovascular death, in a study of more than 20,000 people. Since elevated Lp(a) often flies completely under the radar, a simple blood test could uncover hidden heart risk that standard cholesterol testing may miss.

As climate change heats up the continent, experts say countries must shift focus toward preventing fires, rather than just suppressing them

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the second most common cause of autosomal-dominant Parkinson's disease (PD), and increased LRRK2 kinase activity is also observed in idiopathic PD, making LRRK2 a major actionable therapeutic target. LRRK2 is a 286-kDa multidomain enzyme containing a Ras-like GTPase (ROC) and a kinase domain. Using cryo-electron microscopy (cryo-EM), biochemical reconstitution, and cell-based assays, we show that the ROC GTPase governs switching between...

Deficiencies in glucocerebrosidase (GCase) are associated with Parkinson's disease (PD). The mechanistic basis of this association is being intensively investigated, and new treatments are being developed aiming to boost brain GCase activity in patients. Despite the importance of GCase in PD, studies are hampered by the continued reliance on weak and non-selective inhibitors like conduritol B epoxide. Here, we report easily prepared and selective irreversible inhibitors and complementary...

Neurons accumulate somatic mutations with age, but how mutation processes vary among neuronal types remains unclear. Characterizing this variability may elucidate the role of genome integrity in brain function and disease and reveal determinants of mutation rates and patterns. Using high-fidelity duplex DNA sequencing, we profiled somatic mutations across the lifespan in human cerebellar Purkinje and granule neurons, which differ markedly in size and physiology. Surprisingly, they exhibited...

Dioscin, a naturally occurring steroidal saponin isolated from various kinds of herbs with pleiotropic pharmacological properties, remains mechanistically undefined regarding its mammalian aging modulation. This study discovered that dioscin extended the lifespan of Caenorhabditis elegans. Concurrently, dioscin improved the motor function of C. elegans and reduced age pigment accumulation, while having no effect on the reproductive performance of the C. elegans. By pathway screening, we...