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Kaj Blennow
University of Gothenburg, Sweden
Abstract: Cerebrospinal fluid (CSF) biomarkers reflecting the core AD pathologies amyloid deposition (A), tau pathology (T), neurodegeneration (N) have been developed and show very high performance for diagnosis. These tests are also available on fully automated lab analyzers, with superior precision. Newly developed blood biomarkers for AD show promise for use as screening tools and therapy monitoring, which will be of great importance when the new amyloid immunotherapies will be available in the clinic.
The plasma Ab42/40 ratio, measured using either immunoassays or immunoprecipitation - mass spectrometry (IP-MS) methods show high concordance (AUCs of 80-90%) with brain amyloidosis evaluated by PET. However, the effect size (fold change) in PET positive cases for the Ab42/40 ratio is low, when measured in plasma, with only around 10% decrease and a major overlap.
Very promising data have been reported for several phosphorylated tau species (P-tau181, P-tau217, and P-tau231) in blood, showing a specific increase in AD and high concordance with tau PET. In addition, plasma P-tau is increased in cognitively unimpaired elderly who have positive amyloid, but negative tau, PET scans. Recent studies show high correlations between these P-tau species in both CSF and plasma, suggesting that differences are minor.
Neurofilament light (NFL) levels are increased in both CSF and blood in AD, but NFL is a general neurodegeneration biomarker showing high levels in many other neurodegenerative disorders. AD. High plasma GFAP is also found in cases with PET evidence of brain amyloidosis and shows promise as a biomarker for glial activation and neuroinflammation.
To implement the blood biomarkers in clinical routine diagnostics, data on the robustness of these biomarkers is needed. For a robust biomarker, the combined biological, pre-analytical, and analytical variability is markedly lower than the fold change (percent difference between patients and controls), also with repeated measurements. For this reason, blood biomarkers may better fit for risk prediction, in algorithms together with APOE and age, than as diagnostic tools. Even so, blood biomarkers will be very useful in the clinical setting.
Fernando Gonzalez-Ortiz1, Michael Turton2, Przemysław R. Kac1, Denis Smirnov3, Enrico Premi4, Roberta Ghidoni5, Luisa Benussi5, Valentina Cantoni4, Claudia Saraceno5, Jasmine Rivolta5, Nicholas J. Ashton1,6,7,8, Barbara Borroni4, Douglas Galasko4, Peter Harrison2, Henrik Zetterberg1,9,10,11,12, Kaj Blennow1,9, Thomas K. Karikari1,13
1Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology,
The Sahlgrenska Academy, University of Gothenburg, Sweden
2Bioventix Plc, 7 Romans Business Park, East Street, Farnham, Surrey GU9 7SX, UK
3University of California, San Diego and Shiely-Marcos Alzheimer’s Disease Research Center, La Jolla, CA, USA
4Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
5Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di DioFatebenefratelli, Brescia, Italy
6Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden
7King’s College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, UK
8NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London, UK
9Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
10Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
11UK Dementia Research Institute at UCL, London, UK
12Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China
13Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
Abstract: Blood-based biomarkers for amyloid-beta and phosphorylated-tau (p-tau) show good diagnostic accuracies and agreements with their corresponding cerebrospinal fluid (CSF) and neuroimaging biomarkers in the amyloid/tau/neurodegeneration (AT(N)) framework for Alzheimer’s disease (Alzheimer’s disease). However, the blood-based neurodegeneration marker neurofilament light (NfL) is not specific to Alzheimer’s disease while total-tau (t-tau) shows lack of correlation with CSF t-tau. Recent studies suggest that blood t-tau originates principally from peripheral, non-brain sources. We generated an anti-tau antibody that selectively binds brain-derived tau (BD-tau) and avoids the peripherally-expressed “big tau” isoform. We applied this antibody to develop an ultrasensitive bloodbased assay for BD-tau, and validated it in five independent cohorts (n=609) including a blood-to-autopsy cohort, CSF biomarker-classified cohorts, and memory clinic cohorts. In paired samples, serum and CSF BD-tau were significantly correlated (r=0.85,P<0.0001), while serum and CSF t-tau were not (r=0.23,P=0.3364). Blood-based BD-tau showed equivalent diagnostic performance as CSF t-tau and CSF BD-tau to separate biomarker-positive Alzheimer’s disease participants from biomarker-negative controls. Furthermore, plasma BD-tau accurately distinguished autopsy-confirmed Alzheimer’s disease from other neurodegenerative diseases (AUCs=86.4%) while NfL did not (AUC=54.3%). These performances were independent of the presence of concomitant pathologies. Plasma BD-tau (r=0.52-0.67 p=0.003), but not NfL (r=-0.14-0.17 p=0.501), was associated with global and regional amyloid-plaque and neurofibrillary-tangle counts. These results were further verified in two memory clinic cohorts where serum BD-tau was increased in Alzheimer’s disease but not in a range of other neurodegenerative disorders, including frontotemporal lobar degeneration and atypical Parkinsonian disorders. Notably, plasma/serum BD-tau correlated with NfL only in AD but not in other neurodegenerative groups. Across cohorts, plasma/serum BD-tau was associated with CSF and plasma AT(N) biomarkers and cognitive function.
BD-tau is a new blood-based biomarker that outperforms plasma t-tau and, unlike NfL, shows specificity to Alzheimer’s disease-type neurodegeneration. Thus, BD-tau demonstrates potential to complete the AT(N) scheme in blood, and will be useful to evaluate Alzheimer’s disease-dependent neurodegenerative processes for clinical and research purposes.
Przemysław R. Kac1,Fernando González Ortiz1, Nicholas J. Ashton1,6,7,8, Henrik Zetterberg1,2,3,4,5, Kaj Blennow1,2, Thomas K. Karikari1,9
1Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
2Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Molndal, Sweden
3Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
4UK Dementia Research Institute at UCL, London, UK
5Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China
6Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
7King’s College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, UK
8NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London, UK
9Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
Abstract: Biofluid based phosphorylated-tau (p-tau) variants measurements are providing great diagnostic value in Alzheimer’s disease (AD). Core cerebrospinal fluid (CSF) biomarkers are total-tau, p-tau181 and the amyloid ß42(Aß42) to amyloid ß40(Aß40) ratio (Aß42/40). However, tau phospohorylation at other epitopes may provide novel insights into AD pathogenesis. We aimed to investigate if p-tau212 has capacity to differentiate between biomarker-negative controls or biomarker-positive AD and to correlate with the core CSF biomarkers. We developed and validated a novel, ultrasensitive immunoassay for p-tau212. We then measured this biomarker in CSF of n=40 participants (n=20 biomarker-negative controls and n=20 biomarker-positive AD) and its diagnostic accuracy and correlations were evaluated.
CSF p-tau212 was increased in biomarker positive-AD versus biomarker-negative controls (median=213.1pg/ml versus 30.07pg/ml; P<0.0001), AUC=100% (95%-CI-100%). We observed positive correlation between CSF p-tau212 and each of CSF p-tau181 (r=0.91;P=<0.0001) and CSF total-tau (r=0.95;P=<0.0001). We observed negative correlation (r=-0.62;P=<0.0001) between CSF p-tau212 and CSF Aß42.
Our results show CSF p-tau212 can effectively discriminate biomarker-positive AD from biomarker-negative controls in this relatively small cohort. Further measurements will be done to compare utility of p-tau212 with other conventional p-tau epitopes such as p-tau217 and p-tau231. Efforts are underway to develop a blood-based version of the p-tau212 biomarker.
Patrycja Dzianok, Ewa Kublik
Laboratory of Emotions Neurobiology, Nencki Institute of Experimental Biology PAS, Warsaw, Poland
Abstract: Alzheimer's disease (AD) is a global problem, with a usually delayed diagnosis and no effective drugs. Earlier diagnosis and prevention of AD could be facilitated by biomarkers, which should be detectable with inexpensive and widely available techniques such as EEG (electroencephalography). A number of changes in spontaneous EEG have been shown in patients with AD and mild cognitive impairment.
We have tested 79 healthy middle-aged adults during a resting-state EEG session. AD risk genes, the APOE (rs429358/rs7412) and PICALM (rs3851179/rs541458) alleles were determined using the traditional Sanger sequencing protocol.
We have found several signal features in the AD risk-carriers group, including the so-called “slowing of the EEG” (which is the most noticeable and sensitive EEG marker among AD patients), i.e., higher delta relative power, lower alpha relative power, and slower alpha frequency (in males). A loss of signal complexity was also noticeable among the AD risk-carriers, in line with earlier reports that these two measures, complexity and EEG slowing, are strongly related.
These results are consistent with the current literature describing EEG features in AD patients and were obtained for the very first time in healthy risk-carriers. However, longitudinal studies are planned to confirm them as valid AD biomarkers.
Funding: This work was funded by the Polish National Science Centre (NCN) grant no. 2018/31/N/HS6/03551 and 2016/20/W/NZ4/00354.
