From Cerebrospinal Fluid Neurochemistry to Clinical Diagnosis of Alzheimer’s Disease in the Era of Anti-Amyloid Treatments. Report of Four Patients

Abstract

Analysis of classical cerebrospinal fluid biomarkers, especially when incorporated in a classification/diagnostic system such as the AT(N), may offer a significant diagnostic tool allowing correct identification of Alzheimer’s disease during life. We describe four patients with more or less atypical or mixed clinical presentation, in which the classical cerebrospinal fluid biomarkers amyloid peptide with 42 and 40 amino acids (Aβ42 and Aβ40, respectively), phospho-tau (τP-181) and total tau (τΤ) were measured. Despite the unusual clinical presentation, the biomarker profile was compatible with Alzheimer’s disease in all four patients. The measurement of classical biomarkers in the cerebrospinal fluid may be a useful tool in identifying the biochemical fingerprints of Alzheimer’s disease, especially currently, due to the recent approval of the first disease-modifying treatment, allowing not only typical but also atypical cases to be enrolled in trials of such treatments.

Plasma P-Tau181 for the Discrimination of Alzheimer’s Disease from Other Primary Dementing and/or Movement Disorders

“…Lumbar puncture was performed using a standard, 21–22 G, Quincke type needle, at the L4–L5 interspace, between 9 and 12 a.m. according to widely accepted recommendations on standardized operative procedures for CSF biomarkers [ 17 ], as described elsewhere [ 18 ]. In brief, CSF was collected in 6 polypropylene tubes.…”

“…Classical CSF biomarkers (Aβ 42 , Aβ 40 , τ P-181 and τ T ) were measured in two laboratories: In the Neurocheimistry and Biological Markers Unit of the 1st Dept. of Neurology, the CSF biomarkers of 16 patients were determined in a Euroimmun Analyzer I (Euroimmun, Lübeck, Germany), in duplicate, with double sandwich enzyme-linked immunosorbent assay (ELISA) using commercially available kits (EUROIMMUN Beta-Amyloid (1–42) ELISA, EUROIMMUN Beta-Amyloid (1–40) ELISA, EUROIMMUN pTau(181) ELISA and EUROIMMUN Total-Tau ELISA, respectively, Euroimmun, Lübeck, Germany), according to manufacturer’s instructions and by the use of 4-parameter logistic curves, as previously described [ 18 ]. Biomarkers were considered normal according to cut-off values of the Unit of Neurochemistry and Biological Markers (Aβ 42 > 480 pg/mL, Aβ 42 /Aβ 40 > 0.092, τ P-181 < 60 pg/mL, τ T < 400 pg/mL) [ 18 , 19 ].…”

“…of Neurology, the CSF biomarkers of 16 patients were determined in a Euroimmun Analyzer I (Euroimmun, Lübeck, Germany), in duplicate, with double sandwich enzyme-linked immunosorbent assay (ELISA) using commercially available kits (EUROIMMUN Beta-Amyloid (1–42) ELISA, EUROIMMUN Beta-Amyloid (1–40) ELISA, EUROIMMUN pTau(181) ELISA and EUROIMMUN Total-Tau ELISA, respectively, Euroimmun, Lübeck, Germany), according to manufacturer’s instructions and by the use of 4-parameter logistic curves, as previously described [ 18 ]. Biomarkers were considered normal according to cut-off values of the Unit of Neurochemistry and Biological Markers (Aβ 42 > 480 pg/mL, Aβ 42 /Aβ 40 > 0.092, τ P-181 < 60 pg/mL, τ T < 400 pg/mL) [ 18 , 19 ]. At Tzartos NeuroDiagnostics, CSF biomarkers of 20 patients were measured by chemilumisence on a Lumipulse 600 G automatic analyzer (Fujirebio, Gent, Belgium), with strict adherence to manufacturer’s instructions.…”

Plasma Phospho-Tau-181 as a Diagnostic Aid in Alzheimer’s Disease

“…More recently, they have been considered as core features for the definition of AD as an in vivo biological process [ 4 ], regardless of the presence or absence of symptoms and their type or severity (mild cognitive impairment or dementia). They have proven to be useful as diagnostic tools for the diagnostic work-up of dementia [ 5 , 6 , 7 , 8 ] and some movement disorders [ 9 , 10 ] during life. Additional candidate CSF biomarkers, including α-synuclein [ 11 , 12 ] and the transactive response DNA binding protein-43 (TDP-43) [ 13 ], are being thoroughly investigated, but work still has to be done before they become established biomarkers.…”

Molecular Research on Alzheimer’s Disease

“…The first topic discussed in this Special Issue is related to current and future molecular methods suggested to improve AD diagnosis. Often, patients cannot be selected for specific treatments, studies, or enrolled in clinical trials due to mixed or atypical presentations: in these settings, AD diagnosis should be enriched with cerebrospinal fluid (CSF) biomarker interpretation, which still represent the cornerstone for differential diagnosis in the setting of neurodegenerative diseases, allowing one to differentiate AD from other forms of dementia, such as vascular forms [1]. Moreover, integrating clinical, neuropsychological, and radiological data with the AT(N) biochemical profiling system (amyloid, tau pathology, and neural loss) allows the researcher and the physician to refine AD diagnosis for both research and clinical purposes, allowing one correctly frame the patient, even in atypical clinical presentations.…”