Altered CSF orexin and α-synuclein levels in dementia patients

Molecular Memory Research Unit, The Wallenberg Laboratory, Skåne University Hospital (SUS) Malmö, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 12/2011; 29(1):125-32. DOI: 10.3233/JAD-2012-111655
Source: PubMed


Neurodegenerative dementia, most frequently represented by Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), is often accompanied by altered sleeping patterns and excessive daytime sleepiness. Studies showing an association between the neuropeptide orexin and AD/DLB-related processes such as amyloid-β (Aβ)1-42 plaque formation, α-synuclein accumulation and inflammation indicate that orexin might play a pathogenic role similar to the situation in narcolepsy. Our study of patients with AD (n = 26), DLB (n = 18), and non-demented controls (n = 24) shows a decrease in cerebrospinal fluid (CSF) orexin concentrations in DLB versus AD patients and controls. The observed differences in orexin levels were found to be specific to female DLB patients. We also show that the female DLB patients exclusively displayed lower levels of α-synuclein compared to AD patients and controls. Orexin was linked to α-synuclein and total-tau in female non-demented controls whereas associations between orexin and Aβ1-42 concentrations were absent in all groups regardless of gender. Thus, the proposed links between orexin, Aβ, and α-synuclein pathology could not be monitored in CSF protein concentrations. Interestingly, α-synuclein was strongly correlated to the CSF levels of total-Tau in all groups, suggesting α-synuclein to be an unspecific marker of neurodegeneration. We conclude that lower levels of CSF orexin are specific to DLB versus AD and appear unrelated to Aβ1-42 and α-synuclein levels in AD and DLB. Alterations in CSF orexin and α-synuclein levels may be related to gender which warrants further investigation.

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Available from: Henrietta M Nielsen
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    • ") (Brownell and Conti 2010) @BULLETCell loss (Fronczek et al. 2012) @BULLETCell loss (Thannickal et al. 2007) (Lessig et al. 2010) @BULLETDecreased plasma orexin concentration (Çoban et al. 2013) @BULLETLoss of fibers (Stanley and Fadel 2012)(Downs et al. 2007) (Zhang et al. 2005) @BULLETDecreased CSF orexin concentration (Fronczek et al. 2012) @BULLETLewy Bodies (Fronczek et al. 2007) @BULLETDecreased CSF orexin concentration in DLB (Wennström et al. 2012) @BULLETDecreased responsiveness to orexin in projection areas (Stanley and Fadel 2012) Noradrenergic Locus Coeruleus (LC) @BULLETDecreased noradrenaline reuptake at terminals (Shores et al. 1999)(Zhu et al. 2005)(Shirokawa et al. 2003) @BULLETCell loss (Brunnström et al. 2011) @BULLETCell loss (Brunnström et al. 2011) @BULLETLoss of neuron pigmentation (Hoogendijk et al. 1995) @BULLETCell loss (Brunnström et al. 2011) @BULLETDecreased DBH (Zhu et al. 2005) @BULLETNFTs (Grudzien et al. 2007) @BULLETLewy Bodies (Seidel et al. 2014) @BULLETIntracellular inclusion bodies (Iwanaga et al. 1997) @BULLETIncreased CHOP (Naidoo et al. 2011) "
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    • "Administration of an orexin-1 receptor antagonist, SB-334867, systemically or directly into the basal forebrain disrupts attentional performance (Boschen et al. 2009). These findings have supported the idea that orexins may be useful for treating cognitive deficits associated with the disruption of cortical cholinergic projections, such as in Alzheimer's disease (Fadel et al. 2013; Fronczek et al. 2012; Slats et al. 2012; Wennstrom et al. 2012). The orexin-1 receptor has a much higher affinity for binding orexin A compared with orexin B (Sakurai et al. 1998). "
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    ABSTRACT: Rationale Orexins are neuropeptides released in multiple brain regions from neurons that originate within the lateral hypothalamus and contiguous perfornical area. The basal forebrain, a structure implicated in attentional processing, receives orexinergic inputs. Our previous work demonstrated that administration of an orexin-1 receptor antagonist, SB-334867, systemically or via infusion directly into the basal forebrain, can disrupt performance in a task that places explicit demands on attentional processing. Objectives Given that the orexin-1 receptor binds orexin A with high affinity, we tested whether orexin A could enhance attention in rats. Methods Attentional performance was assessed using a task that required discrimination of variable duration visual signals from trials when no signal was presented. We also tested whether infusions of orexin A into the lateral ventricle could attenuate deficits following lesions of medial prefrontal cortical cholinergic projections that arise from the basal forebrain. Results Infusions of orexin A into the basal forebrain attenuated distracter-induced decreases in attentional performance. Orexin A attenuated deficits in lesioned animals when a visual distracter was presented. Conclusion The present results support the view that orexin A can enhance attentional performance via actions in the basal forebrain and may be beneficial for some conditions characterized by attentional dysfunction due to disruption of cortical cholinergic inputs.
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