br Methods br Results br Discussion Agitation in

Methods
Results
Discussion Agitation in dementia has recently been defined as a syndrome characterized by inferred or observed evidence of emotional distress associated with at least one behavioral component, i.e. excessive motor activity, verbal or physical aggression (Cummings et al., 2015). Subjective distress is a core feature due to the consensus that agitated behavior is an expression of the person’s distressed emotional state, which can manifest as rapid changes in mood, irritability or emotional outbursts. This points to potential deficits in emotion regulation in agitated individuals with AD. A recent review (Rosenberg et al., 2015) found neuroimaging evidence of dysfunction in what could be termed ‘agitation circuits’ in AD subjects, comprising frontal cortex, ACC, orbitofrontal cortex, amygdala and insula, regions also implicated in anxiety (Grupe and Nitschke, 2013). Neuroimaging studies of emotion regulation have revealed that subcortical emotion structures (especially the amygdala) are under direct regulatory control of the PFC (Ochsner et al., 2004), and frontal lobe or fronto-subcortical dysfunction results in greater disinhibition and reduced regulation of emotion and aggressive behaviors (Seo et al., 2008). From a neuropsychological perspective, agitation in AD could arise from a tendency to misinterpret/overestimate potential threats and respond with heightened emotional reactivity. This provides a testable hypothesis that can potentially be translated to human studies, although the applicability of such neuropsychological paradigms (which have usually been developed in healthy young adults) to patients with AD, especially in those with severe cognitive impairment, needs further study. In terms of the underlying neurobiological mechanisms, the prevalence of agitation increases with disease severity (Lyketsos et al., 2000), which suggests an association between the neurochemical processes accompanying AD disease progression and agitation. Nonetheless, the precise nature and combined effect of multiple neurochemical imbalances have not yet been fully elucidated. Surprisingly few studies have focused on TUG-770 regions proposed to be part of the ‘agitation circuit’ in AD subjects comprising frontal cortex, ACC, orbitofrontal cortex, amygdala and insula. Additional gaps identified in the research literature include the potential roles of 5-HT3 receptor and GABAA receptor subtypes. There were numerous conflicting findings especially within genetic studies, and many studies would benefit from replication. The main methodological issues of studies are addressed below.
Conclusion
Acknowledgements
Introduction Alzheimer’s disease (AD) is the most common cause for dementia and it is generally accepted that patients suffering from AD are at a higher risk for epilepsy than individuals without AD [[1], [2]] and this association has been shown to be particularly strong in subjects with dementia onset at a young age [2]. One explanation is that the progression of a neurodegenerative disease, neurotrauma and events such as cerebrovascular stroke may trigger EP in the elderly population [3]. Therefore, the association between epilepsy and neurodegenerative diseases, especially AD, is being actively studied. Previous studies have shown that the incidence of EP is the highest in the persons aged more than 75 years [4]. It has been suggested that the appearance of epileptic seizures in patients with AD may be a marker for cortical neurodegeneration and for late stages of the disease process [5]. In the early stages of AD, seizures may reflect an aggressive progression of the disease or could be attributable to other factors such as susceptibility to hypersynchronous electrical activity [1]. Despite of the modern imaging modalities and proteomic analysis, a systematic neuropathological examination is still the golden diagnostic standard and especially valuable for assessing the concomitant pathology, which is often present in the brain of elderly subjects. The number of studies on the topic of epilepsy and AD including a full neuropathological investigation is unfortunately relatively small and this may lead to biased findings and conclusions. The purpose of this clinicopathological study was to characterize the neuropathological and clinical findings in a well-defined study group of aged AD subjects with and without epilepsy.