Heslegrave, Amanda

Abstract Background Plasma phosphorylated‐tau217 (pTau217) is a blood‐based biomarker of Alzheimer's Disease (AD) pathology. Cognitive resilience describes the presence of neurodegenerative pathology and preserved cognition. Cognitive resistance describes avoidance of neurodegeneration. This post hoc analysis of the Post‐Operative Delirium Belfast (PODB) cohort aimed to define cognitive resilience using plasma pTau217 and Mini Mental State Examination (MMSE) measures. Methods PODB was an observational cohort study, investigating people aged 65 and over, without a diagnosis of dementia, undergoing elective hip and knee replacement between 2012‐2014 with subsequent long‐term follow‐up. In this analysis, pre‐operative plasma pTau217 was used as a marker of neuropathology. A cutoff of 0.42 pg/mL was used (Ashton NJ et al. 2024). Pre‐operative and 8‐year follow‐up MMSE scores were used as a marker of cognition. A score of ≥24 was considered preserved. Definitions used were: Cognitive resilience = pTau217 ≥0.42 pg/mL plus MMSE ≥24. Cognitive resistance = pTau217 <0.42pg/mL plus MMSE ≥24. Affected = pTau217 ≥0.42 pg/mL plus MMSE <24. Those with normal markers plus poor cognition were defined as pTau217 <0.42pg/mL plus MMSE <24. These four groups were identified at baseline and follow‐up, respectively. In this analysis, 231 participants were included at baseline, 104 at follow‐up. Results Of the n = 231 participants included at baseline, n = 147/231 (64%) were cognitively resilient, n = 65/231 (28%) resistant, n = 17/231 (7%) affected, and n = 2/231 (<1%) had normal markers and MMSE <24. Of the n = 104 participants with follow‐up information included in this analysis, n = 61/104 (59%) were cognitively resilient, n = 33/104 (32%) were resistant, n = 8/104 (8%) affected, and n = 2/104 (<1%) had normal markers and MMSE <24. Cognitively resilient participants at baseline were younger ( p = 0.011) and tended to be female ( p = 0.977) compared to affected participants. At follow‐up, those who were cognitively resilient tended to be younger ( p = 0.196) and female ( p = 0.212) compared to affected participants (Table 1). Of those cognitively resilient at follow up, n = 59/61 (97%) of these participants were also cognitively resilient at baseline. Conclusions Using pTAu217, at the cut‐off quoted, we found a high incidence of cognitive resilience in an older elective surgical cohort.

Abstract In animal models, brain neurodegeneration biomarkers drain into cervical lymph nodes (CLNs), and this drainage function is reduced with ageing. If this occurred in humans, CLNs may provide a readily accessible measure of this aspect of protein clearance. We tested this hypothesis in people using ultrasound-guided fine needle aspiration. We measured amyloid-beta 40 and 42, phosphorylated tau 181 (pTau181), glial fibrillary acidic protein and neurofilament light using single molecule array in CLN aspirates and plasma from: (i) a discovery cohort of 25 autoimmune patients; and (ii) plasma, CLNs and capillary blood in four healthy volunteers, an optimization cohort. Ultrasound-guided fine needle aspiration was well-tolerated by all participants. In both cohorts, all biomarkers were detected in all plasma and CLN samples, other than neurofilament light (8/17 of discovery cohort). CLN biomarker concentrations were significantly greater than plasma concentrations for all except neurofilament light, most markedly for pTau181 (266-fold; P &lt; 0.02), whose CLN concentrations decreased with age (Spearman r = −0.66, P = 0.001). This study presents the first evidence that neurodegenerative biomarkers are detectable in human CLNs. Raised CLN:plasma biomarker ratios suggest their concentration in CLNs may offer a distinct compartment for minimally-invasive measurement of brain clearance and lymphatic drainage, with potential applicability to study of ageing and future clinical trials.

AbstractBackground and purposeClinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures.MethodsTo evaluate total tau (t‐tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy‐terminal hydrolase L1 (UCHL1) and neurofilament light‐chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n = 143) and controls (n = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD‐1 platform. Eleven ATXN3 mutation carrier cerebrospinal fluid samples were analysed for t‐tau and phosphorylated tau (p‐tau181). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t‐tau levels.ResultsPlasma t‐tau levels were higher in mutation carriers below the age of 50 compared to controls, and the Inventory of Non‐Ataxia Signs was associated with t‐tau in ataxic patients (p = 0.004). Pre‐ataxic carriers showed higher cerebrospinal fluid t‐tau and p‐tau181 concentrations compared to ataxic patients (p = 0.025 and p = 0.014, respectively). Cerebellar t‐tau was elevated in MJDTg mice compared to wild‐type (p = 0.033) only in the early stages of the disease. GFAP and UCHL1 did not show higher levels in mutation carriers compared to controls. Plasma NfL concentrations were higher in mutation carriers compared to controls, and differences were greater for younger carriers. The Scale for the Assessment and Rating of Ataxia was the strongest predictor of NfL in ataxic patients (p < 0.001).ConclusionOur results suggest that tau might be a marker of early disease stages in SCA3. NfL can discriminate mutation carriers from controls and is associated with different clinical variables. Longitudinal studies are required to confirm their potential role as biomarkers in clinical trials.