Serotonin 1A receptors in the living brain of Alzheimer's disease patients

Abstract

[F-18]MPPF ͉ brain 5-HT1A receptors ͉ neuronal loss ͉ positron emission tomography E xtensive brain cell loss in vulnerable cortical neuronal populations is one of the most striking hallmarks of Alzheimer's disease (AD). Neuronal loss appears to be correlated with the presence of abundant intraneuronal neurofibrillary tangles (NFTs) and is also an excellent parameter to correlate with the degree of dementia (1). Among the vulnerable neurons affected in the earliest stages of the disease are large pyramidal neurons in the CA1 and subicular regions of hippocampus, a part of the medial temporal lobe (MTL) system supporting declarative memory (2). The pattern of neuronal loss in AD is distinctively different from the cell loss observed in normal aging and is highest in entorhinal cortex and hippocampus CA1 region (1, 3). Although these large pyramidal neurons are glutamatergic in nature, they receive inhibitory serotonergic input from the dorsal raphe nucleus via the serotonin 1A (5-HT 1A ) receptors located on their axonal hillock (4). The correlation between the loss of glutamatergic pyramidal neurons in CA1 field of hippocampus and the decrease in 5-HT 1A receptor densities in the same areas was demonstrated earlier by using in vitro 4- [F-18] and can be partially attributed to the neuronal loss in epileptic foci (6). Availability of methods for 5-HT 1A receptor density quantification with PET therefore offers an excellent opportunity for in vivo assessment of neuronal damage in 5-HT 1A receptor-rich areas in AD, particularly in hippocampus. In this work, changes in 5-HT 1A receptor densities in the living brain of AD patients (ADs) and mild cognitive impairment patients (MCIs) were also correlated with global and regional measures of glucose metabolic activity, with the extent and spatial distribution of the NFT͞␤-amyloid senile plaque deposition and with behavioral measures [e.g., Mini Mental State Exam (MMSE) and Buschke scores]. In vitro autoradiography in ADs and normal subject brain specimens was used in support of the observations in living subjects.

Soluble βamyloid1‐42: a critical player in producing behavioural and biochemical changes evoking depressive‐related state?

“…As expected, we found that 5-HT content was selectively reduced in the PFC of Ab-treated animals, but not in the STR or NAc. These results are supported by demonstrations that impairments of the 5-hydroxytryptaminergic system are present in the very early stages of AD (Versijpt et al, 2003;Egashira et al, 2005;Kepe et al, 2006). In this regard, it is well known that impaired 5-hydroxytryptaminergic neurotransmission in the prefrontal area is central to depressive disorders (Krishnan and Nestler, 2008), but could also have an important role in the pathogenesis of several neurodegenerative diseases Egashira et al, 2005).…”

Correlation of brain amyloid with “aerobic glycolysis”: A question of assumptions?

“…Vaishnavi et al (1) and Vlassenko et al (2) show that higher levels of aerobic glycolysis are concentrated in the default mode network (DMN), an anatomically defined brain network-involving the medial temporal lobe and the medial prefrontal subsystems that converge for integration in the posterior cingulate gyruspreferentially active when individuals Brain regional correlations between markers for amyloid tau deposition, glucose hypometabolism, and neuronal losses and corresponding alterations in neuropsychiatric measures were demonstrated in humans with AD and mild cognitive impairment (MCI) (10). These results strengthened earlier suggestions that clinical symptoms characteristic for AD stem from the disruption of major neuronal circuits caused by the extensive loss of neurons forming these circuits associated with early pathological Aβ and τ deposition initially affecting the entorhinal cortex.…”

Current and future uses of neuroimaging for cognitively impaired patients

“…25 Regional cortical hypometabolism correlates with greater cognitive losses, and [ 18 F]FDG-PET can also differentiate patients with MCI from those with AD and controls (figure 3). 71,72 Diagnostic accuracy for AD seems better when [ 18 F]FDG-PET is added to the standard clinical assessment of dementia, providing increased sensitivity and specificity of diagnosis that is similar to that observed on clinical assessment 4 years after baseline. 73 In September 2004, the US Centers for Medicare and Medicaid Services approved Medicare reimbursement for [ 18 F]FDG-PET scans to assist with the differential diagnosis of AD and frontotemporal dementia, which is useful clinical information since the latter dementia does not seem to respond well to currently available symptomatic treatments.…”

“…91 Our group has developed a fluorine-18 tau and amyloid PET probe, [ 18 figure 3). 72 The differential binding potential of MPPF in the hippocampus is indicative of neuronal losses and might eventually provide an early diagnostic measure even before symptoms are present.…”