Henrik Zetterberg’s research while affiliated with University of Wisconsin–Madison and other places

Background Patients with chronic kidney disease (CKD) have a high prevalence of cerebrovascular disease and cognitive impairment. The objective was to analyse whether plasma concentrations of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP) and phosphorylated Tau231 (p-Tau231) are elevated in patients with CKD and to identify independent predictors of these biomarkers, with an emphasis on the role of measured glomerular filtration rate (mGFR). Methods In this cross-sectional cohort study, we included 110 patients with CKD stages 3 and 4 (estimated GFR 15–59 ml/min/1.73 m²) without manifest cerebrovascular disease or dementia, and 55 healthy controls. Biomarkers of neurological disorders were measured with ultrasensitive single molecule array methods. Results Plasma concentrations (median [IQR]) of NfL (37.5 [22.1–47.5] vs. 13.4 [10.5–16.7] ng/L, p < 0.001), p-Tau231 (25.7 [19.1–38.7] vs. 13.9 [10.5–16.3] ng/L, p < 0.001) and GFAP (190 [140–281] vs. 153 [116–211] ng/L, p < 0.001) were elevated in patients with CKD vs. controls. Measured GFR was negatively correlated with NfL (r = − 0.706, p < 0.001), p-Tau231 (r = − 0.561, p < 0.001), and GFAP (r = − 0.385, p < 0.001). In multivariable linear regression models, mGFR was an independent predictor of log-transformed plasma concentrations of NfL (standardized beta coefficient [β] = − 0.439, p < 0.001) and GFAP (β = − 0.321, p < 0.001). Conclusion Patients with CKD had elevated plasma concentrations of NfL, p-Tau231 and GFAP compared with controls, and these biomarkers were inversely correlated with mGFR. Measured GFR was a significant, independent predictor of plasma concentrations of NfL and GFAP in patients with CKD. The mechanisms underlying this association need further investigation. Plasma levels of NfL and GFAP should be interpreted cautiously in patients with marked reductions in GFR.

Importance As amyloid-targeted therapies have become commercially available, the monitoring of cerebral amyloid angiopathy (CAA), which is an important risk factor for amyloid-related imaging abnormalities, has received increasing attention. However, comprehensive evidence on the association between Alzheimer disease (AD) plasma biomarkers and various CAA imaging markers is still lacking. Objective To examine the association of CAA imaging markers with downstream AD plasma biomarkers in relation to amyloid-β (Aβ) uptake on positron emission tomography (PET) and whether their interplay is associated with cognitive changes. Design, Setting, and Participants This registry-based cohort study in 25 hospitals across South Korea recruited participants aged 45 years or older who were registered between January 1, 2016, and December 31, 2023. Participants were categorized as having no cognitive impairment, mild cognitive impairment, or dementia of the Alzheimer type. Exposures Cerebral amyloid angiopathy imaging markers assessed by magnetic resonance imaging, including cerebral microbleeds (CMBs), cortical superficial siderosis, white matter hyperintensities, lacunes, and enlarged perivascular spaces. Main Outcomes and Measures Plasma phosphorylated tau-217 (p-tau217) was measured using a commercial assay. Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were measured using a single-molecule assay on a single platform. All participants underwent amyloid PET imaging. Associations of CAA and vascular imaging markers with downstream AD plasma biomarkers were investigated using linear regression. Results A total of 1708 participants were included (mean [SD] age, 71.2 [8.4] years; 1044 female [61.1%]). The mean (SD) follow-up period was 4.3 (3.1) years. Lobar CMB counts and the presence of CAA were associated with downstream AD plasma biomarkers, including p-tau217 (β = 0.12 [95% CI, 0.05-0.18] and 0.29 [95% CI, 0.12-0.47], respectively), GFAP (β = 0.07 [95% CI, 0.03-0.12] and 0.20 [95% CI, 0.09-0.31], respectively), and NfL (β = 0.07 [95% CI, 0.03-0.11] and 0.16 [95% CI, 0.06-0.25], respectively) with and without the mediation of Aβ uptake on PET (indirect effect: lobar CMBs–p-tau217, 59.8% [β = 0.07 (95% CI, 0.03-0.11)]; lobar CMBs-GFAP, 49.3% [β = 0.04 (95% CI, 0.01-0.06)]; lobar CMBs-NfL, 20.9% [β = 0.01 (95% CI, 0.01-0.03)]; CAA–p-tau217, 50.9% [β = 0.15 (95% CI, 0.06-0.24)]; CAA-GFAP, 39.2% [β = 0.08 (95% CI, 0.03-0.13)]; CAA-NfL, 19.2% [β = 0.03 (95% CI, 0.01-0.05)]). Amyloid-β uptake fully mediated the associations between cortical superficial siderosis and downstream AD plasma markers. In contrast, hypertensive arteriosclerotic vascular imaging markers, including lacunes, deep CMBs, and enlarged perivascular spaces in basal ganglia, were associated with only NfL levels (β = 0.07 [95% CI, 0.01-0.13], 0.20 [95% CI, 0.08-0.32], and 0.14 [95% CI, 0.06-0.23], respectively), regardless of Aβ uptake on PET. Finally, there were interactive associations of lobar CMBs in conjunction with p-tau217 levels (β = −0.56 [95% CI, −0.79 to −0.34]) and GFAP levels (β = −0.44 [95% CI, −0.70 to −0.17]) with annual Mini-Mental State Examination changes. Conclusions and Relevance In this cohort study of participants with no cognitive impairment, mild cognitive impairment, or dementia of the Alzheimer type, a novel association was found among CAA imaging markers, downstream AD plasma biomarkers, and cognitive declines in relation to brain Aβ burdens. The findings emphasize the importance of understanding the clinical effects of amyloid-related imaging abnormality–like CAA imaging markers in light of upcoming amyloid-targeted therapies.

INTRODUCTION To understand the role of neuroinflammation in Alzheimer's disease (AD), we characterized immune‐related proteins in central and peripheral biofluids. METHODS Selection of participants from the Translational Biomarker of Aging and Dementia (TRIAD) cohort with available translocator protein (TSPO) positron emission tomography (PET), cerebrospinal fluid (CSF) (n = 97), and plasma (n = 165). Biofluid samples analyzed with Olink technology (368 inflammation proteins). RESULTS Elevated proteins levels in CSF of TSPO‐positive individuals were identified. Functional enrichment analysis of CSF proteins revealed processes implicated in AD (MAPK, ERK cascades, cytokine, and leukocyte signaling). Selected candidates (CXCL1 and TNFRSF11B) showed high correlation with each other in CSF and with TSPO PET signal, but weaker associations with amyloid and tau PET. No significantly changed proteins in plasma between TSPO groups were found. DISCUSSION This explorative study identified two potential targets in CSF showing correlations with TSPO, amyloid and tau PET, suggesting a direct link between neuroinflammation, expression of these proteins and their potential implication in AD. Highlights Several proteins are elevated in CSF of TSPO PET‐positive individuals, linking them to neuroinflammation. Elevated CSF proteins were enriched in pathways such as MAPK, ERK, and cytokine signaling, linking them to the AD pathophysiology. Candidate proteins (CXCL1 and TNFRSF11B) correlated strongly with TSPO PET, particularly in brain regions known to be affected in AD. Although none of the plasma proteins remained significant after multiple comparisons correction when comparing their expression between TSPO groups, as done for CSF, candidate CSF proteins were found to correlate with plasmatic proteins, highlighting the complexity of the immune system.

Background and Objectives Biomarkers for predicting disease severity and outcome in Guillain‐Barré syndrome (GBS) are scarce. We aimed to determine if brain‐derived tau in serum (sBD‐tau) and cerebrospinal fluid (CSF BD‐tau) are associated with long‐term outcome and disease severity in GBS. Methods In this retrospective study of 100 GBS patients, we measured sBD‐tau and CSF BD‐tau at diagnosis. Outcome was defined as GBS disability scale (GBSDS) > 2 and overall neuropathy limitation scale (ONLS) at 12 months, disease severity as respiratory support and ONLS at nadir. BD‐tau levels were compared between groups and correlated with ONLS scores. Regression analyses and receiver operator characteristic curve analyses were performed for GBSDS > 2 at 12 months. Results BD‐tau levels were higher for GBSDS > 2 at 12 months in serum and CSF. Odds ratio for sBD‐tau was 1.9 (95% CI 1.08–3.2, p = 0.03) and for CSF BD‐tau was 5.9 (95% CI 1.4–25, p = 0.02). Area under curve for sBD‐tau was 0.75 (95% CI 0.57–0.9, p < 0.001) and for CSF BD‐tau was 0.78 (95% CI 0.65–0.9, p = 0.001). ONLS at 12 months correlated with sBD‐tau (ρ = 0.34 [95% CI 0.12–0.53], p = 0.002) and CSF BD‐tau (ρ = 0.33 [95% CI 0.08–0.54], p = 0.01). Statistically significant difference in BD‐tau levels was not seen for respiratory support or ONLS at nadir. Conclusion BD‐tau at GBS onset is associated with long‐term outcome but not disease severity. Because BD‐tau is essentially a CNS biomarker, our results suggest that CNS involvement influences recovery.

INTRODUCTION Biomarkers play a crucial role in understanding Alzheimer's disease (AD) pathogenesis and treatment effects. However, comparing biomarker measures without standardization and appreciating their magnitude relative to the disease can be challenging. METHODS To address this issue, we propose the CentiMarker approach, similar to Centiloid, which provides a standardized scale between normal (0) and nearly maximum abnormal AD (100) ranges. We applied this scale to cerebrospinal fluid (CSF) biomarkers in dominantly inherited AD and sporadic AD cohorts. RESULTS CentiMarkers facilitated the interpretation of disease abnormality, demonstrating comparable changes and distributions of AD biomarkers across disease stages. CentiMarkers make the treatment effect more comparable than their original scales across various biomarkers. DISCUSSION The versatility of CentiMarkers makes it a valuable tool for standardized biomarker comparison in AD research, enabling informed cross‐study comparisons and contributing to accelerated therapeutic development. Adoption of the CentiMarker scale could enhance biomarker reporting and advance our understanding of AD. Highlights Comparing fluid biomarkers without appreciating their magnitude relative to the disease can be challenging. We propose a CentiMarker metric to standardize biomarker measures from normal (0) and nearly maximum abnormal AD (100) ranges. CentiMarkers make the treatment effect more comparable across various biomarkers than when using the original scales.

OBJECTIVE The aim of this study was to investigate whether the biomarkers neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and tau (total [t] and brain-derived [BD]) are elevated in plasma preoperatively; if there is a dynamic biomarker response to surgery; and if the biomarker levels are related to long-term outcome in chronic subdural hematomas (CSDHs). METHODS Eighty-five CSDH patients surgically treated between 2022 and 2023 at Uppsala University Hospital, Uppsala, Sweden, were included in this prospective, observational study. NSE, GFAP, NfL, t-tau, and BD-tau were evaluated in plasma pre- and postoperatively (6–24 hours after surgery) and in the CSDH fluid. Health-related quality of life was evaluated using the 5-level EQ-5D (EQ-5D-5L) at 6 months postoperatively. RESULTS GFAP, NfL, and tau levels decreased after CSDH surgery (p < 0.02). NSE and BD-tau levels also decreased, but not significantly. Older age and larger CSDH volume were associated with higher preoperative GFAP, NfL, and BD-tau levels (p < 0.05). Higher preoperative values and greater dynamics (Δ [postoperative value − preoperative value]) of GFAP, NfL, and BD-tau correlated significantly with worse levels of several EQ-5D-5L domains (p < 0.05). A higher preoperative NfL level in plasma was independently associated with a lower EQ-5D-5L visual analog scale score (p < 0.001). CONCLUSIONS Surgical CSDH patients exhibit ongoing central nervous system cellular injury, demonstrated via increased fluid biomarkers for brain injury preoperatively, which immediately improved after surgery and was strongly related to long-term outcome. The extent of preoperative biomarker elevation could aid in the decision-making for surgical indication and urgency.

Rates of cognitive decline in Alzheimer’s disease (AD) are extremely heterogeneous. Although biomarkers for amyloid-beta (Aβ) and tau proteins, the hallmark AD pathologies, have improved pathology-based diagnosis, they explain only 20–40% of the variance in AD-related cognitive impairment (CI). To discover novel biomarkers of CI in AD, we performed cerebrospinal fluid (CSF) proteomics on 3,397 individuals from six major prospective AD case–control cohorts. Synapse proteins emerged as the strongest correlates of CI, independent of Aβ and tau. Using machine learning, we derived the CSF YWHAG:NPTX2 synapse protein ratio, which explained 27% of the variance in CI beyond CSF pTau181:Aβ42, 11% beyond tau positron emission tomography, and 28% beyond CSF neurofilament, growth-associated protein 43 and neurogranin in Aβ⁺ and phosphorylated tau⁺ (A+T1+) individuals. CSF YWHAG:NPTX2 also increased with normal aging and 20 years before estimated symptom onset in carriers of autosomal dominant AD mutations. Regarding cognitive prognosis, CSF YWHAG:NPTX2 predicted conversion from A+T1+ cognitively normal to mild cognitive impairment (standard deviation increase hazard ratio = 3.0, P = 7.0 × 10–4) and A+T1+ mild cognitive impairment to dementia (standard deviation increase hazard ratio = 2.2, P = 8.2 × 10–16) over a 15-year follow-up, adjusting for CSF pTau181:Aβ42, CSF neurofilament, CSF neurogranin, CSF growth-associated protein 43, age, APOE4 and sex. We also developed a plasma proteomic signature of CI, which we evaluated in 13,401 samples, which partly recapitulated CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 as a robust prognostic biomarker for cognitive resilience versus AD onset and progression, highlight the potential of plasma proteomics in replacing CSF measurement and further implicate synapse dysfunction as a core driver of AD dementia.