👤 Daniel C Cullinane

Progressive supranuclear palsy (PSP) is a heterogeneous neurodegenerative disease characterised by the accumulation of misfolded 4-repeat tau within neurones and glial cells. There are limited longitudinal data on pathologically confirmed PSP patients with phenotypes other than classic Richardson's syndrome (RS) and the pathomechanisms responsible for the broad variability in clinical phenotype and progression are not well understood. An unresolved question in this context is whether distinct spatiotemporal patterns of tau pathology propagation exist within the clinicopathological spectrum of PSP. We included 241 consecutive, pathologically confirmed patients with PSP from the Queen Square Brain Bank for Neurological Disorders (2010-2022). Phenotyping was performed based on clinical features present within the first 3 years from symptom onset according to the Movement Disorder Society (MDS) criteria, and specific clinical features and disease milestones were recorded. Genotyping was performed using Illumina NeuroBooster and NeuroChip arrays and MAPT haplotype, APOE genotype, TRIM11 rs564309 and SLC2A13 rs2242367 single nucleotide polymorphism data were collated. Tissue sections from eight brain regions, mounted on glass slides, were immunostained for hyperphosphorylated tau and digitised using whole-slide scanning. Forty-one anatomical regions of interest were manually segmented, and total tau pathology burden was quantified using an automated, machine learning-based algorithm. The associations between survival and both clinicogenetic features and regional tau pathology burden were modelled using Cox regression and generalised linear models, respectively and the Subtype and Stage Inference (SuStaIn) algorithm was used to identify subgroups with distinct progression patterns. We have identified: (i) several clinical predictors of survival in PSP and the relationship between regional tau pathology burden and survival; (ii) novel anatomical reference standards for the expected distribution of tau pathology across MDS-defined PSP phenotypes, including region-specific white matter involvement in patients with corticobasal syndrome and speech/language variants; (iii) associations potentially linking biological sex, MAPT haplotype and TDP-43 co-pathology to clinical phenotype and regional tau pathology burden; (iv) patterns of covariance in regional tau pathology implicating inter-regional connectivity in tau spreading; and (v) three distinct spatiotemporal patterns of tau pathology progression: one characterised by initial involvement of subcortical grey matter followed by rostral spread to cortical regions and two characterised by early, simultaneous involvement of subcortical grey matter and cortical regions. Taken together, these results indicate that PSP clinicopathological heterogeneity is mediated by propagation of tau pathology along anatomically connected networks and via intrinsic regional susceptibility mechanisms, possibly influenced by sex, genetic factors and co-pathology. Show less

Dementia in Lewy body diseases (LBD) is common and arises through heterogeneous and incompletely understood pathways. Evidence suggests contributions from genetic factors, including APOE ε4 genotype, co-pathology including concomitant Alzheimer's disease pathology and hypoperfusion related to orthostatic hypotension. However, the relative impact of these factors remains unclear. To address this, we analysed 399 post-mortem brains from LBD cases comprising Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies, and controls, integrating APOE genotype, clinical data and assessment of ischaemic pathology alongside large-scale digital pathology quantification. We established an image analysis pipeline utilising machine learning to enable automated, standardised measurement of α-synuclein, amyloid-β, and phosphorylated tau burden across multiple brain regions. Quantitative pathology strongly correlated with semi-quantitative ratings and outperformed conventional staging in predicting dementia. Across multiple analytical approaches, APOE ε3 and ε4 carriers showed distinct dementia risk profiles. APOE ε3 carriers developed dementia at lower quantitative α-synuclein and amyloid-β thresholds than ε4 carriers, although overall dementia risk was dominated by ε4 genotype, consistent with ε4 both promoting greater pathology accumulation and modifying the threshold for dementia onset. Orthostatic hypotension and ischaemic pathology increased dementia risk only in ε3 carriers with low Lewy and Alzheimer's proteinopathy burden, while male sex further modulated dementia risk for this subgroup. The Subtype and Stage Inference (SuStaIn) algorithm identified four trajectories of Lewy pathology progression. Two corresponded to recognised patterns, one brainstem-first and the other with early amygdala and concomitant brainstem involvement. Two further patterns showed early cortical involvement, one with early cingulate cortex involvement together with brainstem pathology and the other starting in neocortex before limbic and brainstem involvement. Co-pathology progression modelling identified subtypes with early predominance of amyloid-β, phosphorylated tau, or α-synuclein, and showed that Lewy subtypes follow two propagation trajectories in opposite directions. Together, these findings demonstrate that integrating quantitative pathology with genotype and clinical data reveals distinct yet overlapping pathways to dementia in LBD, refining disease progression models and providing a basis for genotype- and pathology-informed patient stratification in therapeutic trials. Show less

Surgical resection is the primary treatment approach for patients with breast cancer. Despite optimal multimodal treatment, metastatic recurrence remains a risk. Surgery-mediated systemic inflammation and local tissue inflammation generate an immunosuppressive and wound-healing environment that may accelerate cancer recurrence and metastasis post-operatively. Investigating the impact of surgery on local and systemic inflammation may provide knowledge for improvement of patient prognosis and treatment opportunities. Systemic cytokines were quantified in the blood plasma of patients with breast cancer pre-operatively, early post-operatively, and late post-operatively. Early post-operative levels of IL-6 were significantly elevated in patients who underwent mastectomy compared with wide local excision. Post-operative IL-6 levels correlate with clinicopathological features (age and BMI). The transcriptomes of local matched tumour and normal tumour adjacent (normal) breast tissue, from patients with breast cancer, were analysed by RNA-Seq. Elevated gene expressions of IL6, ADIPOQ, FABP4, LPL, PPARG, and CD36 in normal tissue were associated with worse overall survival of patients with ER-positive breast cancer. In tissue with higher expression of IL6 and ADIPOQ, a higher abundance of M2-like macrophage gene expression was identified. This study revealed perioperative systemic dynamics of inflammatory mediators and identified local immune-adipose-metabolism gene expression in tumour-adjacent tissue associated with pro-tumour function. Show less

We sought to determine the outcome of suicidal hanging and the impact of targeted temperature management (TTM) on hanging-induced cardiac arrest (CA) through an Eastern Association for the Surgery of Trauma (EAST) multicenter retrospective study. We analyzed hanging patient data and TTM variables from January 1992 to December 2015. Cerebral performance category score of 1 or 2 was considered good neurologic outcome, while cerebral performance category score of 3 or 4 was considered poor outcome. Classification and Regression Trees recursive partitioning was used to develop multivariate predictive models for survival and neurologic outcome. A total of 692 hanging patients from 17 centers were analyzed for this study. Their overall survival rate was 77%, and the CA survival rate was 28.6%. The CA patients had significantly higher severity of illness and worse outcome than the non-CA patients. Of the 175 CA patients who survived to hospital admission, 81 patients (46.3%) received post-CA TTM. The unadjusted survival of TTM CA patients (24.7% vs 39.4%, p < 0.05) and good neurologic outcome (19.8% vs 37.2%, p < 0.05) were worse than non-TTM CA patients. However, when subgroup analyses were performed between those with an admission Glasgow Coma Scale score of 3 to 8, the differences between TTM and non-TTM CA survival (23.8% vs 30.0%, p = 0.37) and good neurologic outcome (18.8% vs 28.7%, p = 0.14) were not significant. Targeted temperature management implementation and post-CA management varied between the participating centers. Classification and Regression Trees models identified variables predictive of favorable and poor outcome for hanging and TTM patients with excellent accuracy. Cardiac arrest hanging patients had worse outcome than non-CA patients. Targeted temperature management CA patients had worse unadjusted survival and neurologic outcome than non-TTM patients. These findings may be explained by their higher severity of illness, variable TTM implementation, and differences in post-CA management. Future prospective studies are necessary to ascertain the effect of TTM on hanging outcome and to validate our Classification and Regression Trees models. Therapeutic study, level IV; prognostic study, level III. Show less