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Complexin-1 and foxp1 expression changes are novel brain effects of
alpha-synuclein pathology
(2014)
As the second most frequent neurodegenerative disorder of the aging population, Parkinson’s disease (PD) is characterized by progressive deficits in spontaneous movement, atrophy of dopaminergic midbrain neurons and aggregation of the protein alpha-synuclein (SNCA). To elucidate molecular events before irreversible cell death, we studied synucleinopathy-induced expression changes in mouse brain and identified 49 midbrain/brainstem-specific transcriptional dysregulations. In particular complexin-1 (Cplx1), Rabl2a and 14-3-3epsilon (Ywhae) downregulation, as well as upregulation of the midbrain-specific factor forkhead box P1 (Foxp1) and of Rabgef1, were interesting as early mRNA level effects of alpha-synuclein triggered pathology. The protein levels of complexin-1 were elevated in midbrain/brainstem tissue of mice with A53T-SNCA overexpression and of mice with SNCA-knockout. The response of CPLX1 and Foxp1 levels to SNCA deficiency supports the notion that these factors are regulated by altered physiological function of alpha-synuclein. Thus, their analysis might be useful in PD stages before the advent of Lewy pathology. Because both alpha-synuclein and complexin-1 modulate vesicle release, our findings support presynaptic dysfunction as an early event in PD pathology.
Memory Concerns, Memory Performance and Risk of Dementia in Patients with Mild Cognitive Impairment
(2014)
Background: Concerns about worsening memory (“memory concerns”; MC) and impairment in memory performance are both predictors of Alzheimer's dementia (AD). The relationship of both in dementia prediction at the pre-dementia disease stage, however, is not well explored. Refined understanding of the contribution of both MC and memory performance in dementia prediction is crucial for defining at-risk populations. We examined the risk of incident AD by MC and memory performance in patients with mild cognitive impairment (MCI).
Methods: We analyzed data of 417 MCI patients from a longitudinal multicenter observational study. Patients were classified based on presence (n = 305) vs. absence (n = 112) of MC. Risk of incident AD was estimated with Cox Proportional-Hazards regression models.
Results: Risk of incident AD was increased by MC (HR = 2.55, 95%CI: 1.33–4.89), lower memory performance (HR = 0.63, 95%CI: 0.56–0.71) and ApoE4-genotype (HR = 1.89, 95%CI: 1.18–3.02). An interaction effect between MC and memory performance was observed. The predictive power of MC was greatest for patients with very mild memory impairment and decreased with increasing memory impairment.
Conclusions: Our data suggest that the power of MC as a predictor of future dementia at the MCI stage varies with the patients' level of cognitive impairment. While MC are predictive at early stage MCI, their predictive value at more advanced stages of MCI is reduced. This suggests that loss of insight related to AD may occur at the late stage of MCI.