Cholinergic–serotonergic imbalance contributes to cognitive and behavioral symptoms in Alzheimer’s disease

Abstract

Neuropsychiatric symptoms seen in Alzheimer's disease (AD) are not simply a consequence of neurodegeneration, but probably result from differential neurotransmitter alterations, which some patients are more at risk of than others. Therefore, the hypothesis of this study is that an imbalance between the cholinergic and serotonergic systems is related to cognitive symptoms and psychological syndromes of dementia (BPSD) in patients with AD. Cholinergic and serotonergic functions were assessed in post-mortem frontal and temporal cortex from 22 AD patients who had been prospectively assessed with the Mini-Mental State examination (MMSE) for cognitive impairment and with the Present Behavioral Examination (PBE) for BPSD including aggressive behavior, overactivity, depression and psychosis. Not only cholinergic deficits, but also the cholinacetyltransferase/serotonin ratio significantly correlated with final MMSE score both in frontal and temporal cortex. In addition, decreases in cholinergic function correlated with the aggressive behavior factor, supporting a dual role for the cholinergic system in cognitive and non-cognitive disturbances associated to AD. The serotonergic system showed a significant correlation with overactivity and psychosis. The ratio of serotonin to acetylcholinesterase levels was also correlated with the psychotic factor at least in women. It is concluded that an imbalance between cholinergic-serotonergic systems may be responsible for the cognitive impairment associated to AD. Moreover, the major findings of this study are the relationships between neurochemical markers of both cholinergic and serotonergic systems and non-cognitive behavioral disturbances in patients with dementia.

Platelet serotonin concentration and monoamine oxidase type B activity in female patients in early, middle and late phase of Alzheimer's disease

“…The reduced 5-HT concentration in the present and previous (Mimica et al 2008) study in platelets, CSF (Tohgi et al 1992) and brain (Garcia-Alloza et al 2005) of patients in the late phase of AD would suggest the decrease in 5-HT synthesis. The main factors that influence 5-HT synthesis are plasma availability of its precursor tryptophan, and the activity of the rate-limiting enzyme tryptophan hydroxylase (TPH).…”

“…Reduced TPH activity was found in some brain areas of patients with AD (Gottfries, 1990) that might be associated with a decrease in 5-HT synthesis (Garcia-Alloza et al 2005). It has been shown that tetrahydrobiopterin and folic acid are two cofactors necessary for TPH activity.…”

“…The neurobiological background of AD includes the accumulation of amyloid plaques and neurofibrillary tangles in the brain, and dysfunction in the cholinergic function (Pakaski and Kalman, 2008). The alterations in the other neurotransmitter systems, especially serotonergic and dopaminergic, are also thought to be responsible for the cognitive deficits and the behavioral disturbances observed in patients with AD (Garcia-Alloza et al 2005;Terry et al 2008). …”

Serotonin transporter polymorphism, memory and hippocampal volume in the elderly: association and interaction with cortisol

“…6 Serotonergic activity is implicated in cognitive function, and is proposed to interact with the cholinergic system to impact memory and attention. [7][8][9] Schultz et al 10 observed an association between increased phobic symptoms and lower global cognitive function in older adults, with a trend for this association to be exacerbated in those with the 5-HTT s allele. In healthy, nondepressed adults, Canli et al…”

Synthesis and biological evaluation of novel N1-phenylsulphonyl indole derivatives as potent and selective 5-HT6R ligands for the treatment of cognitive disorders

“…These behavioral and psychological symptoms of dementia (BPSD) include hallucinations, delusions, aggressive behavior, over activity, anxiety and affective disturbances 1,2 . Current options for treating the cognitive symptoms associated with Alzheimer's are inadequate, giving urgency to the search for novel therapeutic strategies [3][4][5] .…”