Effects of Baseline CSF α-Synuclein on Regional Brain Atrophy Rates in Healthy Elders, Mild Cognitive Impairment and Alzheimer's Disease

Background: Cerebrospinal fluid (CSF) alpha-synuclein is reduced in synucleinopathies, including dementia with Lewy bodies, and some studies have found increased CSF alpha-synuclein in Alzheimer's disease (AD). No study has explored effects of CSF alpha-synuclein on brain atrophy. Here we tested if baseline CSF alpha-synuclein affects brain atrophy rates and if these effects vary across brain regions, and across the cognitive spectrum from healthy elders (NL), to patients with mild cognitive impairment (MCI) and AD. Methods: Baseline CSF alpha-synuclein measurements and longitudinal structural brain magnetic resonance imaging was performed in 74 NL, 118 MCI patients and 55 AD patients. Effects of baseline CSF alpha-synuclein on regional atrophy rates were tested in 1) four pre-hoc defined regions possibly associated with Lewy body and/or AD pathology (amygdala, caudate, hippocampus, brainstem), and 2) all available regions of interest. Differences across diagnoses were tested by assessing the interaction of CSF alpha-synuclein and diagnosis (testing NL versus MCI, and NL versus AD). Results: The effects of CSF alpha-synuclein on longitudinal atrophy rates were not significant after correction for multiple comparisons. There were tendencies for effects in AD in caudate (higher atrophy rates in subjects with higher CSF alpha-synuclein, P=0.046) and brainstem (higher atrophy rates in subjects with lower CSF alpha-synuclein, P=0.063). CSF alpha-synuclein had significantly different effects on atrophy rates in NL and AD in brainstem (P=0.037) and caudate (P=0.006). Discussion: With the possible exception of caudate and brainstem, the overall weak effects of CSF alpha-synuclein on atrophy rates in NL, MCI and AD argues against CSF alpha-synuclein as a biomarker related to longitudinal brain atrophy in these diagnostic groups. Any effects of CSF alpha-synuclein may be attenuated by possible simultaneous occurrence of AD-related neuronal injury and concomitant Lewy body pathology, which may elevate and reduce CSF alpha-synuclein levels, respectively.