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Curr Alzheimer Res. 2018;15(7):691-700. doi: 10.2174/1567205015666180110113238.

Relevance of Follow-Up in Patients with Core Clinical Criteria for Alzheimer Disease and Normal CSF Biomarkers.

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University Lille, Inserm U1171, Centre Memoire de Ressources et de Recherche & CNR-MAJ, CHU Lille, F-59000 Lille, France.
Centre Memoire de Ressources et de Recherche Paris Nord, Unite d`Histologie et de Biologie du Vieillissement, Groupe Hospitalier Lariboisiere FW Saint-Louis, APHP, Universite Paris Diderot, et INSERM U942, Paris, France.
Centre Memoire de Ressources et de Recherche, Departement de Neurologie, Hopital Universitaire Gui de Chauliac, Universite de Montpellier, INSERM U1183, Hopital Saint Eloi, Montpellier, France.
Unite de Neuropsychologie et Centre Memoire Ressources Recherche, service de Neurologie, Hopitaux Universitaires de Strasbourg, et Laboratoire ICube, Universite de Strasbourg et CNRS, Strasbourg, France.
Centre Memoire de Ressources et de Recherche & CNR-MAJ, INSERM U1079, 76000, Rouen University Hospital, France.
Centre Memoire de Ressources et de Recherche, service de Neurologie, CHU de Besancon, France.
Laboratoire de Biochimie et de Biologie Moleculaire, Hopitaux Universitaires de Strasbourg, et Laboratoire de Neurosciences Cognitives et Adaptatives, Universite de Strasbourg et CNRS, Strasbourg, France.
CHU de Montpellier, Hopital St Eloi Universite de Montpellier and INSERM U1183, IRMB, CRB, Laboratoire de Biochimie Proteomique Clinique, Montpellier, France.
Laboratoire de Biochimie & Centre de Recherche Biologique, Hopital Universitaire, Rouen, France.
Service de Biochimie et Biologie moleculaire, Hopital Lariboisiere-Fernand Widal, APHP, Universite Paris Diderot, Universite Paris Descartes, Paris, France.
University Lille, INSERM, CHU-Lille, Alzheimer & Tauopathies, F-59000 Lille, France.
University Lille, CHU-Lille, Centre de Biologie Pathologie UF de Neurobiologie, F-59000 Lille, France.



Few patients with a normal cerebrospinal fluid (CSF) biomarker profile fulfill the clinical criteria for Alzheimer disease (AD).


The aim of this study was to test the hypothesis of misdiagnoses for these patients.


Patients from the e-PLM centers fulfilling the core clinical criteria for probable AD dementia or mild cognitive impairment due to AD (AD-MCI), with normal CSF Aβ1-42, T-tau and P-tau biomarkers and clinical follow-up, were included. Clinical and imaging data were reviewed by an independent board, from baseline (visit with clinical evaluation and CSF analysis) to the end of the follow-up, for a final diagnosis.


In the e-PLM cohort of 1098 AD patients with CSF analysis, 37 (3.3%) patients (20 with AD dementia core clinical criteria and 17 with AD-MCI core clinical criteria) had normal CSF biomarker profile and a clinical follow-up. All patients presented with episodic memory impairment and 27 (73%) had medial temporal lobe atrophy on MRI-scan. After a median follow-up of 36 months (range 7-74), the final diagnosis was AD MCI or dementia for 9 (24%) patients, and unlikely due to AD for 28 (76%) patients. A misdiagnosis was corrected in 18 (49%) patients (mood disorders, non-AD degenerative dementia, vascular cognitive impairment, alcohol cognitive disorders, temporal epilepsy and hippocampal sclerosis), and 10 (27%) patients had cognitive disorders of undetermined etiology.


AD diagnosis (MCI or dementia) with normal CSF biomarkers is a rare condition. A clinical follow- up is particularly recommended to consider an alternative diagnosis.


Alzheimer disease; biomarker; cerebrospinal fluid; dementia; depression; frontotemporal dementia; mild cognitive impairment; vascular dementia.

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