A risk stratification model for post-operative paediatric CMS could flag patients at increased or reduced risk pre-operatively which may influence strategies for surgical treatment of cerebellar tumours. Following future testing and prospective validation, this risk scoring scheme will be proposed for use during the surgical consenting process.

Interest in the cerebellum is expanding given evidence of its contributions to cognition and emotion, and dysfunction in various psychopathologies. However, research into its genetic architecture and shared influences with liability for mental disorders is lacking. We conducted a genome-wide association study (GWAS) of total cerebellar volume and underlying cerebellar lobe volumes in 33,265 UK-Biobank participants. Total cerebellar volume was heritable (h2SNP = 50.6%), showing moderate genetic homogeneity across lobes (h2SNP from 35.4% to 57.1%; mean genetic correlation between lobes rg ≈ 0.44). We identified 33 GWAS signals associated with total cerebellar volume, of which 6 are known to alter protein-coding gene structure, while a further five mapped to genomic regions known to alter cerebellar tissue gene expression. Use of summary data-based Mendelian randomisation further prioritised genes whose change in expression appears to mediate the SNP-trait association. In total, we highlight 21 unique genes of greatest interest for follow-up analyses. Using LD-regression, we report significant genetic correlations between total cerebellar volume and brainstem, pallidum and thalamus volumes. While the same approach did not result in significant correlations with psychiatric phenotypes, we report enrichment of schizophrenia, bipolar disorder and autism spectrum disorder associated signals within total cerebellar GWAS results via conditional and conjunctional-FDR analysis. Via these methods and GWAS catalogue, we identify which of our cerebellar genomic regions also associate with psychiatric traits. Our results provide important insights into the common allele architecture of cerebellar volume and its overlap with other brain volumes and psychiatric phenotypes.

The role of glycogen in the central nervous system is intimately linked with the glycolytic pathway. Glycogen is synthesized from glucose, the primary substrate for glycolysis, and degraded to glucose-6-phosphate. The metabolic cost of shunting glucose via glycogen exceeds that of simple phosphorylation of glucose to glucose-6-phosphate by hexokinase; thus, there must be a metabolic advantage in utilizing this shunt pathway. The dogmatic view of glycogen as a storage depot persists, based on initial descriptions of glycogen supporting neural function in the face of aglycemia. The variable latency to conduction failure, dependent upon tissue glycogen levels, provided convincing evidence of the role played by glycogen in supporting neural function. Glycogen is located predominantly in astrocytes in the central nervous system, thus for glycogen to benefit neural elements, intercellular metabolic communication must exist in the form of astrocyte to neuron substrate transfer. Experimental evidence supports a model where glycogen is metabolized to lactate in astrocytes, with cellular expression of monocarboxylate transporters and enzymes appropriately located for lactate shuttling between astrocytes and neural elements, where lactate acts as a substrate for oxidative metabolism. Biosensor recordings have demonstrated a significant steady concentration of lactate present on the periphery of both central white matter and peripheral nerve under unstimulated baseline conditions, indicating continuous cellular efflux of lactate to the interstitium. The existence of this lactate pool argues we must reexamine the “on demand” shuttling of lactate between cellular elements, and suggests continuous lactate efflux surplus to immediate neural requirements.

Background Thyroid hormone is essential for optimal human neurodevelopment and may modify the risk of attention-deficit hyperactivity disorder (ADHD). However, the brain structures involved are unknown and it is unclear if the adult brain is also susceptible to changes in thyroid status. Methods We used international classification of disease-10 codes, polygenic thyroid scores at different thresholds of association with thyroid traits (pT-values) and image-derived phenotypes in UK Biobank (n=18,825) to investigate the effects of a recorded diagnosis of thyroid disease and genetic risk for thyroid status on cerebellar and subcortical grey matter volume. Regional genetic pleiotropy between thyroid status and ADHD was explored using the GWAS-pairwise method. Results A recorded diagnosis of hypothyroidism (n=419) was associated with significant reductions in total cerebellar and pallidum grey matter volumes (β[95%CI] = -0.14[-0.23, -0.06], p = 0.0005 and β[95%CI] = -0.12[-0.20, -0.04], p = 0.0042, respectively), mediated in part by increases in Body Mass Index. Whilst we found no evidence for total cerebellar volume alterations with increased polygenic scores for any thyroid trait, opposing influences of increased polygenic scores for hypo- and hyperthyroidism were found in the pallidum (pT<1e-3: β[95%CI] = -0.02[-0.03,-0.01], p = 0.0003 and pT<1e-7: β[95%CI] = 0.02[0.01,0.03], p = 0.0003, respectively). Neither hypo- nor hyperthyroidism showed evidence of regional genetic pleiotropy with ADHD. Conclusions Thyroid status affects grey matter volume in adults, particularly at the level of the cerebellum and pallidum, with potential implications for the regulation of motor, cognitive and affective function.