Functional markers for cerebral norepinephrine deficiency in Alzheimer's disease

Abstract

Pathological alterations of the locus coeruleus (LC)-norepinephrine (NE) system occur early in the course of Alzheimer’s disease (AD), and manifest in poor attention and distractibility. Cortical NE is released from the LC nucleus, located within the upper dorsolateral pontine tegmentum of the brainstem, and is substantially involved in the regulation of attentional processes. Effects of the impaired allocation of NE on cognitive deficits in AD are subject of extensive research. However, before the effectiveness of noradrenergic interventions can be proven, it is first necessary to identify behavioural and physiological correlates of NE-deficiency. The electrophysiological P3 component and the non-luminance mediated pupil dilation response (PDR) are extensively discussed physiological parameters of the LC-NE system. Accuracies and reaction times obtained in classical Attentional blink (AB2), simplified Attentional blink (AB1) and Oddball (OB) paradigms represent possible behavioural correlates. <br /> Aim of this thesis was to evaluate to what extent these non-invasive parameters can be established as markers for early NE deficiency in AD. To investigate potential disease-dependent alterations, the study included 24 patients with early AD and 26 healthy controls (HC). Additionally obtained structural measures of LC volumes were used to analyse correlations with physiological and behavioural parameters of LC-NE system functionality. <br /> This thesis shows that accuracies obtained in OB and AB1 paradigms were reliably decreased in early AD patients. Furthermore, HC demonstrated improved AB1 performances in association with higher LC intensities and larger LC volumes. This outcome suggests that the LC nucleus plays an important role for task performance. It was previously shown that tasks requiring stimulus detection, novelty and motivational relevance evoke phasic LC responses. These attributes can be ascribed to the here presented behavioural paradigms. Therefore, it is assumed that the significantly lower target accuracies in AD patients reflected degenerative alterations of the LC-NE system. This conclusion justifies the usage of the parameters OB-accuracy and AB1-accuracy as behavioural correlates for early NE deficiency in AD. The PDR evoked by the OB paradigm was significantly reduced in AD patients. The main parameter of interest was the entire pupillary deflection from baseline evaluated by using statistics correcting for the multiple comparison problem. Additionally, there was a significant relationship between PDR and structural LC dimensions. The PDR is therefore suggested to be an appropriate physiological correlate that is sensitive for NE deficiency in AD patients. <br /> The remaining investigated parameters were either not sensitive for degeneration of the LC-NE system or they indicated ambiguous outcomes. The AB2 paradigm induced floor effects that give rise to justified doubts about the validity of the test results. Based on the present data, it is not possible to evaluate the effects of the AD-related NE deficiency on the behavioural parameter AB2-accuracy. Performance of the AB1 paradigm failed to generate robust P3 components in both groups. The assumption is that the test conditions did not reliably activate the neural network that is involved in P3 generation. Some of the discrepancy concerning the electrophysiological P3 findings may be due to small statistical power. <br /> In conclusion, the present thesis identified three different correlates of NE deficiency: OB-accuracy, AB1-accuracy and the PDR evoked by an OB paradigm. These markers can support diagnosis and proof the effectiveness of new drugs targeting the LC-NE-system. In particular, they provide an important requirement for further pharmacological interventions that are based on beta-receptor agonists.