Blennow, Kaj

Abstract Background The quantification of Neurofilament Light chain (NfL) in blood and cerebrospinal fluid (CSF) has proven valuable for diagnosing and prognosing various neurological disorders, including Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, parkinsonism, multiple sclerosis, and ischemic damage. However, there is considerable variability in clinical and laboratory practices between centers, primarily due to different contexts of use (COU), analytical methods, and the application of cutoffs or scales. Additionally, for the same biochemical profile, the interpretation and reporting of results may vary from one center to another, raising concerns about the commutability of the tests. To date, no consensus has been reached among laboratories to define the most appropriate use of cutoffs or conclusions/comments based on NfL profiles. Method This international project involves 38 laboratories across 18 countries, all specialized in the biochemical diagnosis of neurological disorders. Using a questionnaire, we obtained descriptions from each center regarding their COU, pre‐analytical and analytical protocols (including the biological fluid and methods used to quantify NfL). Through a consensus approach, we developed a harmonized strategy for the use and reporting of NfL results across different centres according to their respective COU. Results Among the centers, 63% quantified NfL in the CSF, 87% in blood and 53% in both fluids. COU were as follow: frontotemporal dementia (71%), Alzheimer disease (71%), multiple sclerosis (61%), amyotrophic lateral sclerosis (61%), psychiatric syndrome (45%), Creutzfeldt‐Jakob disease (32%), Parkinson disease (39%), peripheral neuropathy (29%), traumatic brain injury (21%), Huntington's disease (13%), amyloid transthyretin related (11%) and cardiac arrest (8%). Most of the centers define pathological cutoffs based on publications (50%) and take age into account for this purpose (42%). Reporting is mostly transmitted through numeric results (95%). Conclusion Harmonizing cutoffs, reporting, and interpretation across various clinical contexts will facilitate the incorporation of this biomarker into routine clinical practice.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI). In CTE, hyperphosphorylated tau (p-tau) aggregates are found in neurons at the depth of cortical sulci close to the gray matter/white matter (GM/WM) boundary. To date, CTE can only be diagnosed postmortem by neuropathological examination. Traumatic encephalopathy syndrome (TES) is the clinical syndrome purported to be associated with CTE pathology. The aim of this study is to investigate microstructural properties at the GM/WM boundary in individuals with a history of exposure to RHI and clinical features of CTE (i.e., TES). Diffusion magnetic resonance imaging (dMRI), TES diagnoses, and cerebrospinal fluid (CSF) biomarkers were acquired from 165 male former American football players (age: 57.29 ± 8.23 years) from the DIAGNOSE CTE Research Project, a multicenter, observational cohort study. Fractional anisotropy (FA) was measured at the GM/WM boundary of the whole brain. In addition, a widely used method (tract-based spatial statistics [TBSS]) was applied to measure FA of central WM. We used analyses of covariance to test associations between FA and TES. Furthermore, we used linear regressions to test associations between FA and nine CSF biomarkers (i.e., p-tau-181, -217, -231, total tau, amyloid β [Aβ] 1–40 , Aβ 1–42 , glial fibrillary acidic protein [GFAP], neurofilament light [NfL], and soluble triggering receptor expressed on myeloid cells-2 [sTREM2]). We report an association between higher FA at the GM/WM boundary and higher levels of certainty for CTE pathology ( F (1, 147) = 5.781, 95% confidence interval (CI) = 0.0003–0.003, p = 0.035) as well as neurobehavioral dysregulation ( F (1, 148) = 7.559, 95% CI = 0.001–0.009, p = 0.020), and functional dependence/dementia ( F (1, 148) = 5.046, 95% CI = 0.0004–0.006, p = 0.039). In addition, we report an association between higher FA at the GM/WM boundary and higher CSF p-tau-181 (β = 0.272, 95% CI = 0.078–0.466, p = 0.029) and p-tau-217 (β = 0.295, 95% CI = 0.102–0.488, p = 0.027). FA of the central WM was not associated with TES diagnoses. Taken together, these findings suggest that dMRI at the GM/WM boundary could be used to investigate microstructural alterations suggestive of tau pathology-associated neurodegeneration in individuals with TES, the clinical presentation of CTE. Future studies are needed to validate this approach and to identify clinically useful cutoff values for dMRI metrics.

Importance Advances in Alzheimer disease (AD) have shifted research focus to earlier disease stages, necessitating more scalable approaches to identify cognitively unimpaired individuals with amyloid β (Aβ) pathology. Objective To assess the utility of plasma phosphorylated tau 217 (p-tau217) for classifying Aβ status in cognitively unimpaired individuals, both as a stand-alone test and in a 2-step approach where positive plasma results were confirmed using a second modality (Aβ positron emission tomography [PET] or cerebrospinal fluid [CSF]). Design, Setting, and Participants This cross-sectional cohort study used data collected between June 2009 and March 2024. We included 2916 cognitively unimpaired participants from 12 international independent observational cohorts in the US, Europe, Australia, and Canada with available plasma p-tau217 levels and CSF or PET Aβ biomarkers. Performance comparisons between mass spectrometry and immunoassay-based p-tau217 measurements were also performed (n = 964). Exposures Plasma p-tau217 levels measured by immunoassay. Main Outcome and Measures Aβ status, determined by CSF or Aβ PET biomarkers. Results Participants had a mean (SD) age of 66.9 (9.9) years; 971 (33.3%) were Aβ positive by either CSF or PET, 1667 (57.2%) were women, and 1108 (38.1%) carried at least 1 APOE ε4 allele. As a stand-alone test, plasma p-tau217 achieved a positive predictive value (PPV) of 79% (95% CI, 74-84) and an overall accuracy of 81% (95% CI, 80-82). In a 2-step workflow, the PPV and accuracy significantly increased to 91% (95% CI, 86-95). While this approach required screening of 677 individuals with plasma p-tau217 to identify 100 Aβ-positive individuals, compared to 536 participants when using PET alone, it reduced the need for PET testing to 124. Immunoassays demonstrated comparable PPVs to mass spectrometry (80% [95% CI, 74-86] vs 85% [95% CI, 81-90]; P = .12) but significantly lower overall accuracy (82% [95% CI, 79-84]% vs 88 [95% CI, 86-90]; P < .001) and true Aβ-positive detection rate (49% [95% CI, 43-55] vs 69% [95% CI, 64-75]; P < .001). Conclusions and Relevance The findings highlight the potential of plasma p-tau217 as a stand-alone test—or when used in a sequential 2-step approach alongside PET or CSF testing—as a cost-effective, scalable, and minimally burdensome strategy for identifying preclinical AD. Tailored screening workflows that incorporate p-tau217 can improve efficiency in participant selection for preclinical AD trials and, in the future, help guide access to disease-modifying treatments.

AbstractBackgroundGlial fibrillary acidic protein (GFAP) is a marker of cerebral astrogliosis and occasionally elevated in patients with dementia. GFAP in cerebrospinal fluid (CSF), is routinely requested in referrals to neurochemistry laboratories; however, its ability to differentiate dementias and diagnostic capability is unclear. Our aim was to elucidate this, using two large datasets.MethodFirst, GFAP data measured since 2015 was retrieved from the database of the Clinical Neurochemistry Laboratory at the Sahlgrenska University hospital. We then cross‐referenced with the Swedish dementia registry (SveDem). Here, information on ten different diagnoses such as early onset AD (EAD [<65 years]), late onset AD (LAD [≥65 years]), Parkinson disease with dementia (PDD), vascular dementia (VaD) and frontotemporal dementia (FTD), each with specific diagnostic criteria, were retrieved.The GFAP data was log10‐transformed, followed by an analysis of covariance (ANCOVA) and a subsequent post‐hoc Tukey’s test, with GFAP as dependent variable, diagnosis as independent variable and sex and age as covariates.ResultIn total, 1912 individuals (mean [SD] age, 71.9 [8.2] years; 52% male), were included. Lower log10‐transformed GFAP concentrations were seen in PDD (mean [SD], 2.68, [0.28] pg/mL), than in EAD, LAD, VaD and FTD; here, mean concentrations of 2.76 (0.24), 2.89 (0.23), 2.89 (0.32) and 2.76 (0.25) pg/mL were observed, respectively.In the post hoc analysis, GFAP differentiated VaD from EAD (p<0.001). PDD concentrations were significantly different from VaD (p<0.001) and LAD (p<0.001). Further, it also differentiated FTD from VaD (p=0.006) and LAD (p=0.001).ConclusionCSF GFAP could on a group level help differentiate VaD from EAD, FTD and PDD. Also, it could differentiate PDD from LAD. These results bear potential clinical relevance, where clinicians in some uncertain cases could use this marker as a differential tool.

AbstractINTRODUCTIONBlood‐based biomarkers offer a promising approach for the detection of neuropathologies from repetitive head impacts (RHI). We evaluated plasma biomarkers of amyloid, tau, neurodegeneration, and inflammation in former football players.METHODSThe sample included 180 former football players and 60 asymptomatic, unexposed male participants (aged 45–74). Plasma assays were conducted for beta‐amyloid (Aβ) 40, Aβ42, hyper‐phosphorylated tau (p‐tau) 181+231, total tau (t‐tau), neurofilament light (NfL), glial fibrillary acidic protein (GFAP), interleukin‐6 (IL‐6), Aβ42/p‐tau181 and Aβ42/Aβ40 ratios. We evaluated their ability to differentiate the groups and associations with RHI proxies and traumatic encephalopathy syndrome (TES).RESULTSP‐tau181 and p‐tau231(padj = 0.016) were higher and Aβ42/p‐tau181 was lower(padj = 0.004) in football players compared to controls. Discrimination accuracy for p‐tau was modest (area under the curve [AUC] = 0.742). Effects were not attributable to AD‐related pathology. Younger age of first exposure (AFE) correlated with higher NfL (padj = 0.03) and GFAP (padj = 0.033). Plasma GFAP was higher in TES‐chronic traumatic encephalopathy (TES‐CTE) Possible/Probable (padj = 0.008).DISCUSSIONPlasma p‐tau181 and p‐tau231, GFAP, and NfL may offer some usefulness for the characterization of RHI‐related neuropathologies.Highlights Former football players had higher plasma p‐tau181 and p‐tau231 and lower Aβ42/ptau‐181 compared to asymptomatic, unexposed men. Younger age of first exposure was associated with increased plasma NfL and GFAP in older but not younger participants. Plasma GFAP was higher in participants with TES‐CTE possible/probable compared to TES‐CTE no/suggestive.