Cerri, S. | bioRxiv Science

bioRxiv2025

Association between white-matter lesion volume and heart-rate variability: A comparison of T1, T1-T2 and T1-FLAIR-based segmentations using FreeSurfer SAMSEG

BackgroundHeart disease is a crucial risk factor for brain degeneration, but the exact mechanisms are still under investigation. Notably, a growth in white-matter lesion (WML) volume, a hallmark of cerebral small-vessel disease (cSVD) with connections to progressive neurodegeneration and cognitive decline, has been linked to cardiovascular disease. As such, measures of cardiovascular function such as heart rate variability may represent early and accessible predictors of WML development. MethodsThis study used data from healthy adults drawn from the Leipzig Study for Mind-Body-Emotion Interactions (LEMON) dataset to examine heart function through measures of heart rate variability (HRV), as well as their relationship to cSVD as quantified through WML volumes, using FreeSurfer SAMSEG. WML volumes were segmented using 3T T1+FLAIR, T1+T2 or T1 images alone. ResultsResults indicate that both young and old adults exhibited WMLs, and that lower HRV was associated with higher WML volume. This was particularly strong for high-frequency HRV across both young and older adults, but it was low-frequency HRV that was related to WML volume in an age-specific manner. Moreover, we showed that the WML-HRV relationship that is apparent using T1+FLAIR or T1+T2 based WML volumes could be observed even with T1w-based WML estimation alone. ConclusionsThese results suggest HRV not only as an avenue through which cardiovascular risk translates into brain degeneration, but also as a potential early and readily measurable non-invasive predictor of later WML development and cognitive impairment. Research Perspective- Differences in heart rate variability show consistent associations with the volume of white-matter lesions in the brain, with low-frequency heart rate variability uniquely sensitive to age effects on lesion volume. - Associations between heart rate variability and white matter lesion volume are detectable using T1-weighted volume estimation in absence of more intensive T1-weighted + T2-weighted or T1-weighted + FLAIR lesion estimations. - The neuroanatomical basis for this relationship, particularly the difference in high- and low-frequency heart rate variability associations, will require incorporating lifestyle, hormonal, and genetic factors, as well as targeted examination of high-versus low-frequency heart rate variability bands.

neuroscience↗

bioRxiv2020

Sphingolipid changes in Parkinson L444P GBA mutation fibroblasts promote α-synuclein aggregation

Intraneuronal accumulation of aggregated -synuclein is a pathological hallmark of Parkinsons disease. Therefore, mechanisms capable of promoting -synuclein deposition bear important pathogenetic implications. Mutations of the glucocerebrosidase 1 (GBA) gene represent a prevalent Parkinsons disease risk factor. They are associated with loss of activity of a key enzyme involved in lipid metabolism, glucocerebrosidase, supporting a mechanistic relationship between abnormal -synuclein-lipid interactions and the development of Parkinson pathology. In this study, the lipid membrane composition of fibroblasts isolated from control subjects, patients with idiopathic Parkinsons disease (iPD) and Parkinson patients carrying the L444P GBA mutation (PD-GBA) was assayed using shotgun lipidomics. The lipid profile of PD-GBA fibroblasts differed significantly from that of control and iPD cells. It was characterized by an overall increase in sphingolipid levels. It also featured a significant change in the proportion of ceramide, sphingomyelin and hexosylceramide molecules with shorter and longer hydrocarbon chain length; levels of shorter-chain molecules were increased while the percent of longer-chain sphingolipids was decreased in PD-GBA lipid extracts. The extent of this shift was correlated to the degree of reduction of fibroblast glucocerebrosidase activity. In a second set of experiments, lipid extracts from control and PD-GBA fibroblasts were added to incubations of recombinant -synuclein. The kinetics of -synuclein aggregation, as assessed by the binding of thioflavin T to amyloid structures, was significantly accelerated after addition of PD-GBA extracts as compared to control samples. Amyloid fibrils collected at the end of these incubations contained lipids, indicating -synuclein-lipid co-assembly. Lipids extracted from -synuclein fibrils were also analysed by shotgun lipidomics. Data revealed that the lipid content of these fibrils was significantly enriched of shorter-chain sphingolipids. Taken together, findings of this study indicate that the L444P GBA mutation and consequent enzymatic loss are associated with a distinctly altered membrane lipid profile that provides a biological fingerprint of this mutation in Parkinson fibroblasts. This altered lipid profile, which includes an increased content of shorter-chain sphingolipids, could also be an indicator of increased risk for -synuclein aggregate pathology. Shorter-chain molecules may act as preferred reactants during lipid-induced -synuclein fibrillation.

biochemistry↗