Failure to Recover from Proactive Semantic Interference and Abnormal Limbic Connectivity in Asymptomatic, Middle-Aged Offspring of Patients with Late-Onset Alzheimer’s Disease

Article type: Research Article

Authors: Sánchez, Stella M.^{a; b; h; 1} | Abulafia, Carolina^{a; b; c; 1} | Duarte-Abritta, Barbara^a | de Guevara, M. Soledad Ladrón^{a; b} | Castro, Mariana N.^{a; b; f} | Drucaroff, Lucas^{a; b; f} | Sevlever, Gustavo^d | Nemeroff, Charles B.^e | Vigo, Daniel E.^{b; c} | Loewenstein, David A.^e | Villarreal, Mirta F.^{a; b; h} | Guinjoan, Salvador M.^{a; b; f; g; *}

Affiliations: [a] Service of Psychiatry, FLENI Foundation, Buenos Aires, Argentina | [b] National Council for Scientific and Technological Research (CONICET), Argentina | [c] Institute for Biomedical Research (BIOMED), Pontifical Catholic University of Argentina, and The National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina | [d] Department of Neuropathology and Molecular Biology, FLENI Foundation, Buenos Aires, Argentina | [e] Department of Psychiatry and Behavioral Sciences and Center on Aging, Miller School of Medicine, University of Miami, Miami, FL, USA | [f] Department of Psychiatry and Mental Health, University of Buenos Aires School of Medicine, Argentina | [g] Neurophysiology I, University of Buenos Aires School of Psychology, Argentina | [h] Department of Physics (FCEyN), University of Buenos Aires, Argentina

Correspondence: [*] Correspondence to: Salvador M. Guinjoan, MD, PhD, Chief of Psychiatry, FLENI Foundation, Associate Professor of Psychiatry and Neurophysiology, University of Buenos Aires Schools of Medicine and Psychology, Principal Investigator, CONICET, Montañeses 2325 5th floor, C1428AQK Buenos Aires, Argentina. Tel.: +54 11 57773200/Ext.2514; E-mail: sguinjoan@fleni.org.ar.

Note: [1] These authors contributed equally to this work.

Abstract: Background:We have obtained previous evidence of limbic dysfunction in middle-aged, asymptomatic offspring of late-onset Alzheimer’s disease (LOAD) patients, and failure to recover from proactive semantic interference has been shown to be a sensitive cognitive test in other groups at risk for LOAD. Objective:To assess the effects of specific proactive semantic interference deficits as they relate to functional magnetic resonance imaging (fMRI) neocortical and limbic functional connectivity in middle aged offspring of individuals with LOAD (O-LOAD) and age-equivalent controls. Methods:We examined 21 O-LOAD and 20 controls without family history of neurodegenerative disorders (CS) on traditional measures of cognitive functioning and the LASSI-L, a novel semantic interference test uniquely sensitive to the failure to recover from proactive interference (frPSI). Cognitive tests then were correlated to fMRI connectivity of seeds located in entorhinal cortex and anterodorsal thalamic nuclei among O-LOAD and CS participants. Results:Relative to CS, O-LOAD participants evidenced lower connectivity between entorhinal cortex and orbitofrontal, anterior cingulate, and anterior temporal cortex. In the offspring of LOAD patients, LASSI-L measures of frPSI were inversely associated with connectivity between anterodorsal thalamus and contralateral posterior cingulate. Intrusions on the task related to frPSI were inversely correlated with a widespread connectivity network involving hippocampal, insular, posterior cingulate, and dorsolateral prefrontal cortices, along with precunei and anterior thalamus in this group. Different patterns of connectivity associated with frPSI were observed among controls. Conclusion:The present results suggest that both semantic interference deficits and connectivity abnormalities might reflect limbic circuit dysfunction as a very early clinical signature of LOAD pathology, as previously demonstrated for other limbic phenotypes, such as sleep and circadian alterations.

Keywords: Entorhinal cortex, functional connectivity, late-onset Alzheimer’s disease, limbic, proactive semantic interference, thalamus

DOI: 10.3233/JAD-170491

Journal: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1183-1193, 2017