Catecholamine-Based Treatment in AD Patients: Expectations and Delusions

Abstract

In Alzheimer disease, the gap between excellence of diagnostics and efficacy of therapy is wide. Despite sophisticated imaging and biochemical markers, the efficacy of available therapeutic options is limited. Here we examine the possibility that assessment of endogenous catecholamine levels in cerebrospinal fluid (CSF) may fuel new therapeutic strategies. In reviewing the available literature, we consider the effects of levodopa, monoamine oxidase inhibitors, and noradrenaline (NE) modulators, showing disparate results. We present a preliminary assessment of CSF concentrations of dopamine (DA) and NE, determined by HPLC, in a small dementia cohort of either Alzheimer’s disease (AD) or frontotemporal dementia patients, compared to control subjects. Our data reveal detectable levels of DA, NE in CSF, though we found no significant alterations in the dementia population as a whole. AD patients exhibit a small impairment of the DA axis and a larger increase of NE concentration, likely to represent a compensatory mechanism. While waiting for preventive strategies, a pragmatic approach to AD may re-evaluate catecholamine modulation, possibly stratified to dementia subtypes, as part of the therapeutic armamentarium.

Monoaminergic neuropathology in Alzheimer’s disease

“…Additionally, polymorphisms in dopaminergic system genes are associated to BPSD in AD (Holmes et al, 2001; Borroni et al, 2004). Enhancement of dopaminergic transmission alleviates cognitive impairment in AD (Martorana et al, 2013; Stefani et al, 2015). …”

“…The early occurrence of these symptoms, especially mood change (most often depressive mood), anxiety, apathy, social withdrawal/socially intrusive behavior, confusion, irritability, agitation, restlessness, hyperactivity, aggression (first verbal then also physical), psychosis, disinhibition, and disturbances in wake-sleep cycle (“sundowning”), emotion and appetite, and others (hallucinations, delusions, etc. ), suggests primarily early involvement of the serotonergic raphe nuclei, particularly the DRN, but also of dopaminergic pathways (Borroni et al, 2010; Martorana et al, 2013; Stefani et al, 2015). An example of early neurofibrillary changes in the DRN of a subject with MCI and BPSD is given in Figure 6.…”

“…Dopamine is also variably decreased in the CSF of AD subjects (Tohgi et al, 1992; Stefani et al, 2015). D1 and D3 receptor polymorphisms have been linked with psychosis and aggression in AD (Holmes et al, 2001), while certain COMT polymorphisms lead to psychosis in AD (Borroni et al, 2004).…”

Causes, consequences, and cures for neuroinflammation mediated via the locus coeruleus: noradrenergic signaling system

“…The effects of MAO inhibitors in neurological diseases, particularly AD (Cai ; Stefani et al . ) and PD (Finberg ; Follmer ) have been reviewed several times and several inhibitors are used in MS as a second line treatment for depression (Perez et al . ).…”

Detecting a dexmedetomidine-evoked reduction of noradrenaline release in the human brain with the alpha2C-adrenoceptor PET ligand [11C]ORM-13070

“…Disrupted PPI as a sign of inadequate sensorimotor gating is present in many psychiatric disorders including attention disorders, anxiety disorders, and psychotic disorders, and a 2C -AR antagonism has been proposed as a novel strategy in the management of these disorders (Scheinin et al, 2001;Brosda et al, 2014). In addition, important neurodegenerative disorders such as PD and Alzheimer's disease have been linked to attenuated noradrenergic signaling originating from a disturbance in the LC (Marien et al, 2004;Robertson, 2013), and noradrenergic modulation is being explored as a possible treatment strategy in dementia (Stefani et al, 2015). The apparent involvement of noradrenergic circuits in neurological and psychiatric disorders has prompted the development of the novel PET method used in this study to enable future studies in affected human subjects, and to investigate the in vivo effects of various CNS drugs that modulate noradrenergic neurotransmission.…”