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A multiple hits hypothesis for memory dysfunction in Parkinson disease

Nature Reviews Neurology volume 20, pages 50–61 (2024)Cite this article

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Abstract

Cognitive disorders are increasingly recognized in Parkinson disease (PD), even in early disease stages, and memory is one of the most affected cognitive domains. Classically, hippocampal cholinergic system dysfunction was associated with memory disorders, whereas nigrostriatal dopaminergic system impairment was considered responsible for executive deficits. Evidence from PD studies now supports involvement of the amygdala, which modulates emotional attribution to experiences. Here, we propose a tripartite model including the hippocampus, striatum and amygdala as key structures for cognitive disorders in PD. First, the anatomo-functional relationships of these structures are explored and experimental evidence supporting their role in cognitive dysfunction in PD is summarized. We then discuss the potential role of α-synuclein, a pathological hallmark of PD, in the tripartite memory system as a key mechanism in the pathogenesis of memory disorders in the disease.

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Fig. 1: Long-term memory organization.
Fig. 2: The tripartite model of memory.
Fig. 3: Cholinergic and dopaminergic systems in a physiological condition versus PD.
Fig. 4: The progressive involvement of α-synuclein and Lewy bodies in the memory system in PD.
Fig. 5: α-Synuclein toxicity mechanisms.

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Authors and Affiliations

  1. Neurology Section, Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy

    Salvatore Citro, Angelo Tiziano Cimmino, Guido Maria Giuffrè, Camillo Marra & Paolo Calabresi

  2. Neurology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy

    Giulia Di Lazzaro, Guido Maria Giuffrè, Camillo Marra & Paolo Calabresi

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P.C.: manuscript conception. S.C.: literature search and first draft. A.T.C. and G.D.L.: figure preparation. P.C., G.D.L., G.M.G. and C.M.: revision of the manuscript, critical discussion, and proofreading of the final version.

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P.C. received/receives research support, speaker honoraria, and support to attend national and international conferences (not related to the present study) from Abbvie, Bayer Schering, Bial, Biogen-Dompè, Biogen-Idec, Eisai, Lilly, Lundbeck, Lusofarmaco, Merck-Serono, Novartis, Sanofi-Genzyme, Teva, UCB Pharma and Zambon. The other authors reported no funding from any institution, including personal relationships, interests, grants, employment, affiliations, patents, inventions, honoraria, consultancies, royalties, stock options/ownership, or expert testimony for the last 12 months, biomedical financial interests or potential conflicts of interest.

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Citro, S., Lazzaro, G.D., Cimmino, A.T. et al. A multiple hits hypothesis for memory dysfunction in Parkinson disease. Nat Rev Neurol 20, 50–61 (2024). https://doi.org/10.1038/s41582-023-00905-z

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