Developing the ATX(N) classification for use across the Alzheimer disease continuum

Abstract Background: cerebrospinal fluid (CSF) amyloid-beta (Aβ) 42/40 ratio, threonine-181-phosphorylated-tau (p-tau) and total-tau (t-tau) represent core biomarkers of Alzheimer Disease (AD). The recent availability of automated platforms has represented a significant achievement for reducing the pre-analytical variability of these determinations in clinical setting. With respect to classical manual ELISAs, these platforms give us also the possibility to measure any single sample and to get the result within approximately 30 min. So far, reference values have been calculated from measurements obtained in frozen samples. In this work, we wanted to check if the values obtained in fresh CSF samples differ from those obtained in frozen samples, since this issue is mandatory in routine diagnostic work.Methods: fifty-eight consecutive CSF samples have been analyzed immediately after lumbar puncture and after one-month deep freezing (-80°C). As automated platform we used Lumipulse G600-II (Fujirebio Inc.). Both the fresh and the frozen aliquots were analyzed in their storage tubes. Results: in fresh samples, a mean increase of Aβ40 (6%), Aβ42 (2%), p-tau (2%) and t-tau (4%) was observed as compared to frozen samples, whereas a slight decrease was observed for Aβ42/Aβ40 ratio (4%), due to the higher deviation of Aβ40 in fresh samples compared to Aβ42.These differences are significant for Aβ40, Aβ42/Aβ40 ratio, p-tau and t-tau. Nevertheless, Aβ42/Aβ40 ratio showed a lower variability (smaller standard deviation of relative differences) with respect to Aβ42. With respect to the AD profile according to the A/T/(N) criteria for AD diagnosis, no significant changes in classification were observed when comparing results obtained in fresh vs frozen samples. Conclusions: small but significant differences have been found for Aβ40, Aβ42/Aβ40 ratio, p-tau and t-tau in fresh vs frozen samples. Importantly, these differences did not imply a modification in the A/T/(N) classification system. In order to know if different cut-offs for fresh and frozen samples are required, larger, multi-center investigations are needed.

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Measurement of CSF core Alzheimer Disease biomarkers for routine clinical diagnosis: do fresh vs frozen samples differ?

10.21203/rs.3.rs-22551/v1 ◽

2020 ◽

Author(s):

Giovanni Bellomo ◽

Samuela Cataldi ◽

Silvia Paciotti ◽

Federico Paolini Paoletti ◽

Davide Chiasserini ◽

...

Keyword(s):

Alzheimer Disease ◽

Disease Biomarkers ◽

Total Tau ◽

N Classification ◽

Significant Achievement ◽

Lower Variability ◽

Automated Platform ◽

Diagnostic Work ◽

Relative Differences ◽

T Tau

Abstract Background: cerebrospinal fluid (CSF) amyloid-beta (Aβ) 42/40 ratio, threonine-181-phosphorylated-tau (p-tau) and total-tau (t-tau) represent core biomarkers of Alzheimer Disease (AD). The recent availability of automated platforms has represented a significant achievement for reducing the pre-analytical variability of these determinations in clinical setting. With respect to classical manual ELISAs, these platforms give us also the possibility to measure any single sample and to get the result within approximately 30 min. So far, reference values have been calculated from measurements obtained in frozen samples. In this work, we wanted to check if the values obtained in fresh CSF samples differ from those obtained in frozen samples, since this issue is mandatory in routine diagnostic work.Methods: fifty-eight consecutive CSF samples have been analyzed immediately after lumbar puncture and after one-month deep freezing (-80°C). As automated platform we used Lumipulse G600-II (Fujirebio Inc.). Both the fresh and the frozen aliquots were analyzed in their storage tubes.Results: in fresh samples, a mean increase of Aβ40 (6%), Aβ42 (2%), p-tau (2%) and t-tau (4%) was observed as compared to frozen samples, whereas a slight decrease was observed for Aβ42/Aβ40 ratio (4%), due to the higher deviation of Aβ40 in fresh samples compared to Aβ42.These differences are significant for Aβ40, Aβ42/Aβ40 ratio, p-tau and t-tau. Nevertheless, Aβ42/Aβ40 ratio showed a lower variability (smaller standard deviation of relative differences) with respect to Aβ42. With respect to the AD profile according to the A/T/(N) criteria for AD diagnosis, no significant changes in classification were observed when comparing results obtained in fresh vs frozen samples.Conclusions: small but significant differences have been found for Aβ40, Aβ42/Aβ40 ratio, p-tau and t-tau in fresh vs frozen samples. Importantly, these differences did not imply a modification in the A/T/(N) classification system. In order to know if different cut-offs for fresh and frozen samples are required, larger, multi-center investigations are needed.

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Measurement of CSF core Alzheimer disease biomarkers for routine clinical diagnosis: do fresh vs frozen samples differ?

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00689-0 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Giovanni Bellomo ◽

Samuela Cataldi ◽

Silvia Paciotti ◽

Federico Paolini Paoletti ◽

Davide Chiasserini ◽

...

Keyword(s):

Alzheimer Disease ◽

Disease Biomarkers ◽

Total Tau ◽

N Classification ◽

Significant Achievement ◽

Lower Variability ◽

Automated Platform ◽

Diagnostic Work ◽

Relative Differences ◽

T Tau

Abstract Background Cerebrospinal fluid (CSF) amyloid-beta (Aβ) 42/40 ratio, threonine-181-phosphorylated-tau (p-tau), and total-tau (t-tau) represent core biomarkers of Alzheimer disease (AD). The recent availability of automated platforms has represented a significant achievement for reducing the pre-analytical variability of these determinations in clinical setting. With respect to classical manual ELISAs, these platforms give us also the possibility to measure any single sample and to get the result within approximately 30 min. So far, reference values have been calculated from measurements obtained in frozen samples. In this work, we wanted to check if the values obtained in fresh CSF samples differ from those obtained in frozen samples, since this issue is mandatory in routine diagnostic work. Methods Fifty-eight consecutive CSF samples have been analyzed immediately after lumbar puncture and after 1-month deep freezing (− 80 °C). As an automated platform, we used Lumipulse G600-II (Fujirebio Inc.). Both the fresh and the frozen aliquots were analyzed in their storage tubes. Results In fresh samples, a mean increase of Aβ40 (6%), Aβ42 (2%), p-tau (2%), and t-tau (4%) was observed as compared to frozen samples, whereas a slight decrease was observed for Aβ42/Aβ40 ratio (4%), due to the higher deviation of Aβ40 in fresh samples compared to Aβ42. These differences are significant for Aβ40, Aβ42/Aβ40 ratio, p-tau, and t-tau. Nevertheless, the Aβ42/Aβ40 ratio showed a lower variability (smaller standard deviation of relative differences) with respect to Aβ42. With respect to the AD profile according to the A/T/(N) criteria for AD diagnosis, no significant changes in classification were observed when comparing results obtained in fresh vs frozen samples. Conclusions Small but significant differences have been found for Aβ40, Aβ42/Aβ40 ratio, p-tau, and t-tau in fresh vs frozen samples. Importantly, these differences did not imply a modification in the A/T/(N) classification system. In order to know if different cutoffs for fresh and frozen samples are required, larger, multi-center investigations are needed.

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Biological subtypes of Alzheimer disease

Neurology ◽

10.1212/wnl.0000000000009058 ◽

2020 ◽

Vol 94 (10) ◽

pp. 436-448 ◽

Cited By ~ 15

Author(s):

Daniel Ferreira ◽

Agneta Nordberg ◽

Eric Westman

Keyword(s):

Alzheimer Disease ◽

Meta Analysis ◽

Age At Onset ◽

Cognitive Status ◽

Association Cortex ◽

Disease Modifying Drugs ◽

Neuroimaging Data ◽

N Classification ◽

Hippocampal Sparing ◽

Subtype Differences

ObjectiveTo test the hypothesis that distinct subtypes of Alzheimer disease (AD) exist and underlie the heterogeneity within AD, we conducted a systematic review and meta-analysis on AD subtype studies based on postmortem and neuroimaging data.MethodsEMBASE, PubMed, and Web of Science databases were consulted until July 2019.ResultsNeuropathology and neuroimaging studies have consistently identified 3 subtypes of AD based on the distribution of tau-related pathology and regional brain atrophy: typical, limbic-predominant, and hippocampal-sparing AD. A fourth subtype, minimal atrophy AD, has been identified in several neuroimaging studies. Typical AD displays tau-related pathology and atrophy both in hippocampus and association cortex and has a pooled frequency of 55%. Limbic-predominant, hippocampal-sparing, and minimal atrophy AD had a pooled frequency of 21%, 17%, and 15%, respectively. Between-subtype differences were found in age at onset, age at assessment, sex distribution, years of education, global cognitive status, disease duration, APOE ε4 genotype, and CSF biomarker levels.ConclusionWe identified 2 core dimensions of heterogeneity: typicality and severity. We propose that these 2 dimensions determine individuals' belonging to one of the AD subtypes based on the combination of protective factors, risk factors, and concomitant non-AD brain pathologies. This model is envisioned to aid with framing hypotheses, study design, interpretation of results, and understanding mechanisms in future subtype studies. Our model can be used along the A/T/N classification scheme for AD biomarkers. Unraveling the heterogeneity within AD is critical for implementing precision medicine approaches and for ultimately developing successful disease-modifying drugs for AD.

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Structural and Chemical Studies of Pathological Fibers in Human Neurofibrillary Degeneration

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010012031x ◽

1985 ◽

Vol 43 ◽

pp. 726-729

Author(s):

K.S. Kosik ◽

L.K. Duffy ◽

S. Bakalis ◽

C. Abraham ◽

D.J. Selkoe

Keyword(s):

Monoclonal Antibodies ◽

Alzheimer Disease ◽

Human Brain ◽

Neurofibrillary Tangles ◽

Morphological Analysis ◽

High Specificity ◽

Cytoskeletal Proteins ◽

Neuritic Plaque ◽

Protein Chemistry ◽

Chemical Studies

The major structural lesions of the human brain during aging and in Alzheimer disease (AD) are the neurofibrillary tangles (NFT) and the senile (neuritic) plaque. Although these fibrous alterations have been recognized by light microscopists for almost a century, detailed biochemical and morphological analysis of the lesions has been undertaken only recently. Because the intraneuronal deposits in the NFT and the plaque neurites and the extraneuronal amyloid cores of the plaques have a filamentous ultrastructure, the neuronal cytoskeleton has played a prominent role in most pathogenetic hypotheses.The approach of our laboratory toward elucidating the origin of plaques and tangles in AD has been two-fold: the use of analytical protein chemistry to purify and then characterize the pathological fibers comprising the tangles and plaques, and the use of certain monoclonal antibodies to neuronal cytoskeletal proteins that, despite high specificity, cross-react with NFT and thus implicate epitopes of these proteins as constituents of the tangles.

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