Cerebrospinal Fluid α-Synuclein and Lewy Body-Like Symptoms in Normal Controls, Mild Cognitive Impairment, and Alzheimer's Disease

Article type: Research Article

Authors: Mackin, R. Scott^{a; b} | Insel, Philip^a | Zhang, Jing^c | Mohlenhoff, Brian^{a; b; d} | Galasko, Douglas^e | Weiner, Michael^{a; f} | Mattsson, Niklas^{a; f; g; *} | for the Alzheimer's Disease Neuroimaging Initiative¹

Affiliations: [a] Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA | [b] Department of Psychiatry, University of California, San Francisco, CA, USA | [c] Department of Pathology, University of Washington, Seattle, WA, USA | [d] Mental Health Service, Veterans Affairs Medical Center, San Francisco, CA, USA | [e] Department of Neurosciences, University of California, San Diego, CA, USA | [f] Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA | [g] Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden

Correspondence: [*] Correspondence to: Niklas Mattsson, MD, PhD, Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA 94121, USA. Tel.: +1 415 494 1139; E-mail: [email protected].

Note: [1] Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.ucla.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: Background:Reduced cerebrospinal fluid (CSF) α-synuclein has been described in synucleinopathies, including dementia with Lewy bodies (DLB). Common symptoms of DLB include visual hallucinations and visuospatial and executive deficits. Co-occurrence of Lewy body pathology is common in Alzheimer's disease (AD) patients, but it is unknown if reduced CSF α-synuclein is associated with Lewy body-like symptomatology in AD. Objective:Determine associations between CSF α-synuclein and Lewy body-like symptomatology. Methods:We included 73 controls (NC), 121 mild cognitive impairment (MCI) patients, and 61 AD patients (median follow-up 3.5 years, range 0.6–7.8). We tested associations between baseline CSF α-synuclein and visual hallucinations and (longitudinal) cognition. Models were tested with and without co-varying for CSF total tau (T-tau), which is elevated in AD patients, and believed to reflect neurodegeneration. Results:Hallucinations were reported in 20% of AD patients, 13% of MCI patients, and 8% of NC. In AD, low CSF α-synuclein was associated with hallucinations. When adjusting for CSF T-tau, low CSF α-synuclein was associated with accelerated decline of executive function (NC, MCI, and AD), memory (MCI and AD), and language (MCI). Conclusion:The associations of low CSF α-synuclein with hallucinations and poor executive function, which are hallmarks of DLB, indirectly suggest that this biomarker may reflect underlying synuclein pathology. The associations with memory and language in MCI and AD suggests either that reduced CSF α-synuclein also partly reflects global impaired neuronal/synaptic function, or that non-specific overall cognitive deterioration is accelerated in the presence of synuclein related pathology. The findings will require autopsy verification.

Keywords: Alpha-synuclein, Alzheimer's disease, cerebrospinal fluid, cognition, hallucinations, tau

DOI: 10.3233/JAD-141287

Journal: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 1007-1016, 2015