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.
Highlights
Depression and psychosis are two of the most severe neuropsychiatric symptoms (NPS) in dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD)
As part of their differential diagnostic work-up of dementia, besides the general physical and neurological examinations, blood screening tests, structural neuroimaging by computed tomography (CT), magnetic resonance imaging (MRI) or single photon emission computed tomography (SPECT), neuropsychological evaluations (for example, Mini-Mental State Examination (MMSE) scores) and optional cerebrospinal fluid (CSF)/blood sampling for biomarker and/or DNA analyses, a baseline behavioral assessment was routinely performed
Psychosis and its dopaminergic pathogenesis in DLB versus AD Based upon our findings, we suggest that psychosis in AD might be pathophysiologically associated with a decreased dopaminergic neurotransmission solely restricted to the amygdala, whereas an impaired and rather increased dopaminergic activity across the mesolimbic system and locus coeruleus (LC) might clinically account for psychosis in DLB
Summary
Depression 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. Dementia with Lewy bodies (DLB) is the second most common neurodegenerative disorder following Alzheimer’s disease (AD) and accounts for up to 20% of all autopsy-confirmed dementias in the elderly [1,2]. Depressive symptoms in AD and DLB are associated with a greater cognitive decline [8] and, in AD, significantly relate to lower survival rates over a three-year period [9]. Delusions and hallucinations may trigger other NPS, such as agitation or aggression, which regularly leads to early nursing home admission [12]
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