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Cited by 53Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsTranscranial Magnetic Stimulation Studies

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Classification accuracy of blood-based and neurophysiological markers in the differential diagnosis of Alzheimer’s disease and frontotemporal lobar degeneration

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Benussi, Alberto, Cantoni, Valentina, Rivolta, Jasmine, Archetti, Silvana, Micheli, Anna, Ashton, Nicholas, Zetterberg, Henrik, Blennow, Kaj, Borroni, Barbara·2022·Alzheimer's Research & Therapy
DOI 10.1186/s13195-022-01094-5PMC PMC9558959
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Abstract

Background: In the last decade, non-invasive blood-based and neurophysiological biomarkers have shown great potential for the discrimination of several neurodegenerative disorders. However, in the clinical workup of patients with cognitive impairment, it will be highly unlikely that any biomarker will achieve the highest potential predictive accuracy on its own, owing to the multifactorial nature of Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD). Methods: In this retrospective study, performed on 202 participants, we analysed plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and tau phosphorylated at amino acid 181 (p-Tau 181) concentrations, as well as amyloid β42 to 40 ratio (Aβ 1–42/1–40) ratio, using the ultrasensitive single-molecule array (Simoa) technique, and neurophysiological measures obtained by transcranial magnetic stimulation (TMS), including short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), long-interval intracortical inhibition (LICI), and short-latency afferent inhibition (SAI). We assessed the diagnostic accuracy of combinations of both plasma and neurophysiological biomarkers in the differential diagnosis between healthy ageing, AD, and FTLD. Results: We observed significant differences in plasma NfL, GFAP, and p-Tau 181 levels between the groups, but not for the Aβ 1–42/Aβ 1–40 ratio. For the evaluation of diagnostic accuracy, we adopted a two-step process which reflects the clinical judgement on clinical grounds. In the first step, the best single biomarker to classify “cases” vs “controls” was NfL (AUC 0.94, p < 0.001), whilst in the second step, the best single biomarker to classify AD vs FTLD was SAI (AUC 0.96, p < 0.001). The combination of multiple biomarkers significantly increased diagnostic accuracy. The best model for classifying “cases” vs “controls” included the predictors p-Tau 181, GFAP, NfL, SICI, ICF, and SAI, resulting in an AUC of 0.99 (p < 0.001). For the second step, classifying AD from FTD, the best model included the combination of Aβ 1–42/Aβ 1–40 ratio, p-Tau 181, SICI, ICF, and SAI, resulting in an AUC of 0.98 (p < 0.001). Conclusions: The combined assessment of plasma and neurophysiological measures may greatly improve the differential diagnosis of AD and FTLD.

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  • Some studies reported elevated blood GFAP in participants with FTD compared to controls.

    “Indeed, some studies reported elevated blood GFAP in participants with FTD compared to controls [8–18] but others observed no such GFAP increase in FTD [19–22].”

    From Comprehensive cross-sectional and longitudinal comparisons of plasma glial fibrillary acidic protein and neurofilament light across FTD spectrum disorders (2025) · cites this paper as [14]

    The Results (Participant characteristics) report significantly increased GFAP in the pooled FTLD group compared with healthy controls. The Participants section shows that this group included people with bvFTD alongside other FTLD-spectrum syndromes; the passage does not establish a GFAP increase for participants with FTD separately. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Some investigators found that blood GFAP concentrations correlate with clinical markers of disease severity in participants with FTD.

    “Similarly, some investigators [8, 11, 14] but not others [9, 21–23] found that blood GFAP concentrations correlate with clinical markers of disease severity in participants with FTD.”

    From Comprehensive cross-sectional and longitudinal comparisons of plasma glial fibrillary acidic protein and neurofilament light across FTD spectrum disorders (2025) · cites this paper as [14]

    The Results section on correlations reports that blood GFAP was significantly correlated with MMSE score, a clinical measure. The study included participants with FTLD, but the reported correlation is not identified as specific to that group; it therefore does not establish the claim for participants with FTD alone. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Authors
Benussi, A., Cantoni, V., Rivolta, J., Archetti, S., Micheli, A., Ashton, N., Zetterberg, H., Blennow, K., & Borroni, B.
Affiliations
  • Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT)
  • University of Brescia (IT)
  • Casa di Cura Città di Roma (IT)
  • King's College London (GB)
  • Sahlgrenska University Hospital (SE)
Corresponding author
Borroni, Barbara
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2022-10-13
Volume
14
Issue
1
Pages
155-155
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-022-01094-5
PMC
PMC9558959
OpenAlex
W4304893067
Cited by
53
References
5
Citations by year
2026: 6 · 2025: 11 · 2024: 20 · 2023: 16
FWCI
7.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
  • Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
Funders
  • Fondazione Cariplo (2021-1516)
  • Associazione Italiana Ricerca Alzheimer
  • Swedish Research Council (2018-02532, 2017-00915)
  • European Research Council (681712)
  • Swedish State Support for Clinical Research (ALFGBG-71320)
  • Alzheimer's Drug Discovery Foundation (201809-2016862, RDAPB-201809-2016615)
  • AD Strategic Fund and the Alzheimer's Association (ADSF-21-831376-C)
  • Olav Thon Foundation
  • Erling-Persson Family Foundation
  • Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (FO2019-0228)
  • European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement (No 860197 (MIRIADE))
  • European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694)
  • UK Dementia Research Institute at UCL (UKDRI-1003)
  • Swedish Alzheimer Foundation (AF-742881)
  • Hjärnfonden, Sweden (FO2017-0243)
  • Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (ALFGBG-715986)
  • European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236)
  • National Institute of Health (NIH), USA (1R01AG068398-01)
  • Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495)
  • Italian Ministry of Health (RF-2018-12366665)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
Keywords
Alzheimer's disease, frontotemporal lobar degeneration, differential diagnosis, plasma biomarkers, neurofilament light chain, glial fibrillary acidic protein, p-tau181, amyloid-beta 42/40 ratio, transcranial magnetic stimulation, short-interval intracortical inhibition, short-latency afferent inhibition, intracortical facilitation, long-interval intracortical inhibition, Simoa, cognitive impairment, healthy aging, neurodegenerative diseases, diagnostic accuracy
MeSH terms
Alzheimer Disease, Amino Acids, Diagnosis, Differential, Glial Fibrillary Acidic Protein, Humans, Retrospective Studies, Biomarkers, Amyloid beta-Peptides, tau Proteins, Frontotemporal Lobar Degeneration, Frontotemporal Dementia

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