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Walz, R.

Publications and source records attributed to Walz, R..

3 recordsLinked to original sources

Sample size buys detection, not localisation: an identifiability limit for hippocampal subfield morphometry

Automated segmentation has made hippocampal subfield volumes a routine measurement, and studies now report which subfield relates to an outcome rather than whether the hippocampus does. Those reports do not agree with one another, and the standard explanation is insufficient statistical power. We argue that a second limit operates independently of sample size. Using 638 participants from a population-derived adult lifespan cohort, we first show that no individual subfield contributes to a general cognitive factor beyond a single global size component: no coefficient interval excludes zero, the local block carries half a percent of outcome variance, and no model improves out-of-sample prediction over the global factor alone. Because an observed null cannot distinguish an absent effect from an effect the design cannot locate, we then planted effects of known location and size in the measured design and in a whitened copy of it that preserves sample size, dimensionality and effect size while removing only the correlation between subfields. The arms were paired down to the noise vector. Collinearity did not place recovery out of reach; it multiplied the required sample size by a factor of roughly two to three, and the penalty widened as cohorts grew. At the effect sizes this literature reports, neither design reached an adequate recovery rate at any sample size, and coarsening the parcellation rescued neither. The choice of estimator moved recovery further than collinearity did. We provide a calibration surface on which a planned design can be located before data collection.

neuroscience↗

Ageing conserves and redistributes local geometry in the human structural connectome: an Ollivier-Ricci curvature analysis across the adult lifespan

Network measures of the ageing connectome are dominated by magnitude: connection strength and density decline, and the topological summaries built on them decline with them. Whether the geometry of the network follows the same course is not known, because the quantities in common use do not separate how strong a connection is from how it sits among the connections around it. We computed the Ollivier-Ricci curvature of every edge in structural connectomes from 307 participants spanning the adult lifespan, a quantity defined by optimal transport between the neighbourhoods of connected regions, and asked how it changes with age. The total geometric separation between within-network and between-network connections did not change across seven decades. Underneath that constancy, individual network pairs moved substantially and in opposite directions, gaining curvature around the salience and ventral attention system and losing it between the control and default mode networks. Curvature and connection strength reached half of their age-related variation almost four decades apart, and a small set of prefrontal nodes moved against the global trend. Ageing appears to conserve the local redundancy of the structural connectome in total while relocating it, on a timescale distinct from that of connection strength.

neuroscience↗

Crucial neuroprotective roles of the metabolite BH4 in dopaminergic neurons

Dopa-responsive dystonia (DRD) and Parkinsons disease (PD) are movement disorders caused by the dysfunction of nigrostriatal dopaminergic neurons. Identifying druggable pathways and biomarkers for guiding therapies is crucial due to the debilitating nature of these disorders. Recent genetic studies have identified variants of GTP cyclohydrolase-1 (GCH1), the rate-limiting enzyme in tetrahydrobiopterin (BH4) synthesis, as causative for these movement disorders. Here, we show that genetic and pharmacological inhibition of BH4 synthesis in mice and human midbrain-like organoids accurately recapitulates motor, behavioral and biochemical characteristics of these human diseases, with severity of the phenotype correlating with extent of BH4 deficiency. We also show that BH4 deficiency increases sensitivities to several PD-related stressors in mice and PD human cells, resulting in worse behavioral and physiological outcomes. Conversely, genetic and pharmacological augmentation of BH4 protects mice from genetically- and chemically induced PD-related stressors. Importantly, increasing BH4 levels also protects primary cells from PD-affected individuals and human midbrain-like organoids (hMLOs) from these stressors. Mechanistically, BH4 not only serves as an essential cofactor for dopamine synthesis, but also independently regulates tyrosine hydroxylase levels, protects against ferroptosis, scavenges mitochondrial ROS, maintains neuronal excitability and promotes mitochondrial ATP production, thereby enhancing mitochondrial fitness and cellular respiration in multiple preclinical PD animal models, human dopaminergic midbrain-like organoids and primary cells from PD-affected individuals. Our findings pinpoint the BH4 pathway as a key metabolic program at the intersection of multiple protective mechanisms for the health and function of midbrain dopaminergic neurons, identifying it as a potential therapeutic target for PD.

neuroscience↗