Alzheimer’s Disease and Neurosyphilis: Meaningful Commonalities and Differences of Clinical Phenotype and Pathophysiological Biomarkers

Article type: Research Article

Authors: Milano, Chiara^{a; *} | Hoxhaj, Domeniko^a | Del Chicca, Marta^a | Pascazio, Alessia^a | Paoli, Davide^a | Tommasini, Luca^a | Vergallo, Andrea^b | Pizzanelli, Chiara^a | Tognoni, Gloria^a | Nuti, Angelo^{c; †} | Ceravolo, Roberto^a | Siciliano, Gabriele^a | Hampel, Harald^b | Baldacci, Filippo^{a; b} | Neurodegeneration Precision Medicine Initiative (NPMI)

Affiliations: [a] Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy | [b] Sorbonne University, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Paris, France | [c] Division of Neurology, Versilia Hospital, Lido di Camaiore, Italy

Correspondence: [*] Correspondence to: Dr. Chiara Milano, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. E-mail: [email protected] and Prof. Filippo Baldacci, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. E-mail: [email protected].

Note: [†] Deceased.

Abstract: Background:Neurosyphilis-associated cognitive and behavioral impairment— historically coined as “general paralysis of the insane”— share clinical and neuroradiological features with the neurodegenerative disease spectrum, in particular Alzheimer’s disease (AD). Anatomopathological similarities have been extensively documented, i.e., neuronal loss, fibrillary alterations, and local amyloid-β deposition. Consequently, accurate classification and timely differential diagnosis may be challenging. Objective:To describe clinical, bio-humoral, brain MRI, FDG-PET, and amyloid-PET features in cases of neurosyphilis with an AD-like phenotypical presentation, as well as clinical outcome in terms of response to antibiotic therapy. Methods:We selected the studies comparing patients with AD and with neurosyphilis associated cognitive impairment, to investigate candidate biomarkers classifying the two neurological diseases. Results:The neuropsychological phenotype of general paralysis, characterized by episodic memory impairment and executive disfunction, substantially mimics clinical AD features. Neuroimaging often shows diffuse or medial temporal cortical atrophy, thus contributing to a high rate of misdiagnosis. Cerebrospinal fluid (CSF)-based analysis may provide supportive diagnostic value, since increased proteins or cells are often found in neurosyphilis, while published data on pathophysiological AD candidate biomarkers are controversial. Finally, psychometric testing using cross-domain cognitive tests, may highlight a wider range of compromised functions in neurosyphilis, involving language, attention, executive function, and spatial ability, which are atypical for AD. Conclusion:Neurosyphilis should be considered a potential etiological differential diagnosis of cognitive impairment whenever imaging, neuropsychological or CSF features are atypical for AD, in order to promptly start antibiotic therapy and delay or halt cognitive decline and disease progression.

Keywords: Alzheimer’s disease, biomarkers, general paralysis, neurosyphilis, treatable dementia

DOI: 10.3233/JAD-230170

Journal: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 611-625, 2023