The monoaminergic footprint of depression and psychosis in dementia with Lewy bodies compared to Alzheimer’s disease

Abstract

IntroductionDepression and psychosis are two of the most severe neuropsychiatric symptoms (NPS) in dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). Both NPS have negative effects on cognitive performance and life expectancy. The current study aimed to investigate and compare monoaminergic etiologies between both neurodegenerative conditions, given the lack of an efficient pharmacological treatment until present.MethodsEleven behaviorally relevant brain regions of the left frozen hemisphere of 10 neuropathologically confirmed AD patients with/without depression (AD + D/-D; 5 were psychotic within AD + D), 10 confirmed DLB patients, all of whom were depressed (DLB + D; 5 psychotic patients), and, finally, 10 confirmed control subjects were regionally dissected. All patients were retrospectively assessed before death using the Behavioral Pathology in Alzheimer’s Disease Rating Scale (Behave-AD) and Cornell Scale for Depression in Dementia amongst others. The concentrations of dopamine (DA), serotonin (5-HT), (nor)adrenaline and respective metabolites, i.e. 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), 5-hydroxy-3-indoleacetic acid (5-HIAA), and, 3-methoxy-4-hydroxyphenylglycol (MHPG), were determined using reversed-phase high-performance liquid chromatography with electrochemical detection.ResultsDLB subjects had the overall lowest monoamine and metabolite concentrations regarding 33 out of 41 significant monoaminergic group alterations. Moreover, MHPG levels were significantly decreased in almost 8 out of 11 brain regions of DLB- compared to AD patients. We also observed the lowest 5-HT and 5-HIAA levels, and 5-HIAA/5-HT turnover ratios in DLB + D compared to AD + D subjects. Additionally, a 4- and 7-fold increase of DOPAC/DA and HVA/DA turnover ratios, and, a 10-fold decrease of thalamic DA levels in DLB + D compared to AD + D patients and control subjects was noticed. Regarding psychosis, hippocampal DA levels in the overall DLB group significantly correlated with Behave-AD AB scores. In the total AD group, DA levels and HVA/DA ratios in the amygdala significantly correlated with Behave-AD AB scores instead.ConclusionsMonoaminergic neurotransmitter alterations contribute differently to the pathophysiology of depression and psychosis in DLB as opposed to AD, with a severely decreased serotonergic neurotransmission as the main monoaminergic etiology of depression in DLB. Similarly, psychosis in DLB might, in part, be etiologically explained by dopaminergic alterations in the hippocampus, whereas in AD, the amygdala might be involved.

Neuronal Pentraxin 2 predicts medial temporal atrophy and memory decline across the Alzheimer’s disease spectrum

“…Sutphen and colleagues (Sutphen et al, 2015) similarly found in middle-aged, cognitively normal participants that YKL-40 (i.e., C3LP1) levels increased with age and APOE4 status, where longitudinal but not baseline associations were seen with amyloid positivity. Kester and colleagues (Kester et al, 2015) found that YKL-40 levels at baseline and longitudinally were higher in patients with MCI and AD.…”

“…As microglial activation is important for potentiating specific aspects of AD pathogenesis (Bales et al, 2000), related biomarkers have been investigated such as Chitinase 3-like Protein 1 (C3LP1). C3LP1, a derivative of chitin protein, is a marker of macrophage/microglial activation (Canto et al, 2015; Kester et al, 2015; Kzhyshkowska et al, 2007; Lautner et al, 2011; Lee et al, 2011; Sutphen et al, 2015). Serum and CSF C3LP1 levels are increased in preclinical and early AD (Canto et al, 2015; Craig-Schapiro et al, 2010), further suggesting its potential utility.…”

EEG Resting-State Networks in Dementia with Lewy Bodies Associated with Clinical Symptoms

“…Interestingly, there is substantial evidence that the mPFC is one of the key regions involved in the pathogenesis of major depressive disorder [75-77]. More specifically, MRI and neurochemical studies revealed that DLB patients with depression had significant reductions in the cortical volume and serotonin level, suggesting reduced activities in areas of self-referential and visual perception networks [78, 79]. It is noteworthy that unlike the NPI-depression, a different depression scale, the GDS-15, used in our study, showed no correlation with eLORETA-ICA results.…”

In-vitro and in-vivo evaluation of the modulatory effects of the multitarget compound ASS234 on the monoaminergic system

“…It has been reported that in patients with AD the levels of DA and NA are decreased in cortex and hippocampus, while those of 5‐HT are decreased in hippocampus . Furthermore, characteristic clinical symptoms of AD including depressive disorders, psychosis and memory impairment are related to alterations in serotonergic, catecholaminergic and cholinergic neurotransmissions . Although we are not able to explain all the in‐vivo effects, it is clear that the present increased monoaminergic levels in hippocampus and prefrontal cortex of the rat are the net observed effects of ASS234.…”