R Scott Mackin1, Philip Insel2, Jing Zhang3, Brian Mohlenhoff4, Douglas Galasko5, Michael Weiner6, Niklas Mattsson7. 1. Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA Department of Psychiatry, University of California, San Francisco, CA, USA. 2. Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA. 3. Department of Pathology, University of Washington, Seattle, WA, USA. 4. Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA Department of Psychiatry, University of California, San Francisco, CA, USA Mental Health Service, Veterans Affairs Medical Center, San Francisco, CA, USA. 5. Department of Neurosciences, University of California, San Diego, CA, USA. 6. Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA. 7. Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
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.
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 ADpatients (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 ADpatients, and believed to reflect neurodegeneration. RESULTS:Hallucinations were reported in 20% of ADpatients, 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.
Entities:
Keywords:
Alpha-synuclein; Alzheimer's disease; cerebrospinal fluid; cognition; hallucinations; tau
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