Molecular imaging of serotonin degeneration in mild cognitive impairment

Abstract

Neuropathological and neuroimaging studies have consistently demonstrated degeneration of monoamine systems, especially the serotonin system, in normal aging and Alzheimer’s disease. The evidence for degeneration of the serotonin system in mild cognitive impairment is limited. Thus, the goal of the present study was to measure the serotonin transporter in vivo in mild cognitive impairment and healthy controls. The serotonin transporter is a selective marker of serotonin terminals and of the integrity of serotonin projections to cortical, subcortical and limbic regions, as well as the cell bodies of origin (raphe nuclei). Twenty-eight participants with mild cognitive impairment (age 66.6 ± 6.9, 16 males) and 28 healthy, cognitively normal, demographically matched controls (age 66.2 ± 7.1, 15 males) underwent magnetic resonance imaging for measurement of grey matter volumes and high-resolution positron emission tomography with well-established radiotracers for the serotonin transporter and regional cerebral blood flow. Beta-amyloid imaging was performed to describe, in combination with the neuropsychological testing, the likelihood of subsequent cognitive decline in the participants with mild cognitive impairment. The following hypotheses were tested: 1) the serotonin transporter would be lower in mild cognitive impairment compared to controls in cortical and limbic regions, 2) in mild cognitive impairment relative to controls, serotonin transporter would be lower to a greater extent and more widespread than lower grey matter volumes or regional cerebral blood flow and 3) lower cortical and limbic serotonin transporters would be correlated with greater deficits in auditory-verbal and visual-spatial memory in mild cognitive impairment, not in controls. Reduced serotonin transporter availability was observed in mild cognitive impairment compared to controls in cortical and limbic areas typically affected by Alzheimer’s disease pathology, as well as in sensory and motor areas, striatum and thalamus that are relatively spared in Alzheimer’s disease. The reduction of the serotonin transporter in mild cognitive impairment was greater than grey matter atrophy or reductions in regional cerebral blood flow compared to controls. Lower cortical serotonin transporters were associated with worse performance on tests of auditory-verbal and visual-spatial memory in mild cognitive impairment, not in controls. The serotonin system may represent an important target for prevention and treatment of MCI, particularly the post-synaptic receptors (5-HT4 and 5-HT6), which may not be as severely affected as presynaptic aspects of the serotonin system.

Fluoxetine-induced recovery of serotonin and norepinephrine projections in a mouse model of post-stroke depression

“…Whether similar mechanisms are induced by chronic FLX in other non-injury forms of depression associated with stress or genetic risk factors remains to be examined 80 , 81 . In major depression and mild cognitive impairment, deficits in gray matter volume and 5-HT innervation are seen in the PFC 82 , 83 , and reduced cortical thickness has been associated with 5-HT genetic markers 84 , 85 . The finding that effective treatment of major depression is associated with a reversal of reduced cortical thickness 86 and increased connectivity to the 5-HT system 87 , 88 suggests that SSRI-induced axonal neuroplasticity may be an important mechanism in its antidepressant actions in humans 8 , 71 .…”

Depression in Alzheimer’s Disease: The Roles of Cholinergic and Serotonergic Systems

“…Similar to that for depression, 5-HT 4 agonism alleviates Alzheimer' s amyloidogenic pathology whereas 5-HT 6 antagonism augments memory and learning in the Alzheimer' s patients (72). Moreover, a decrease in SERT accompanies the decrease in the receptors of interest which results in an extensive disruption in the serotonergic signaling in Alzheimer' s disease (73). Overall, the serotonergic system, as summarized in Figure 3, plays a crucial role in both Alzheimer' s disease and depression and constitutes a highly promising treatment target which may ease depressive mood while soothing cognitive deficits in the Alzheimer' s patients with depression.…”

Benzo(a)pyrene exposure induced neuronal loss, plaque deposition, and cognitive decline in APP/PS1 mice

“…Slc6a4, a gene encoding SERT (serotonin transporter), was significantly downregulated in APP/PS1 mice with or without BaP exposure ( Table 1). The brain of AD patients show reduced SERT in both protein and mRNA, and reduced SERT is associated with depression and anxiety in AD [24,25]. Acetylcholinesterase (AChE) was remarkably upregulated in WT and APP/PS1 mice after BaP exposure (Table 1).…”