A. de Mendonça

Adenosine receptors in the nervous system: pathophysiological implications

Adenosine is a ubiquitous homeostatic substance released from most cells, including neurones and glia. Once in the extracellular space, adenosine modifies cell functioning by operating G-protein-coupled receptors (GPCR; A(1), A(2A), A(2B), A(3)) that can inhibit (A(1)) or enhance (A(2)) neuronal communication. Interactions between adenosine receptors and other G-protein-coupled receptors, ionotropic receptors and receptors for neurotrophins also occur, and this might contribute to a fine-tuning of neuronal function. Manipulations of adenosine receptors influence sleep and arousal, cognition and memory, neuronal damage and degeneration, as well as neuronal maturation. These actions might have therapeutic implications for neurodegenerative diseases such as Parkinsons disease, Alzheimers disease, as well as for other neurological situations such as epilepsy, idiopathic pain or even drug addition. Peripheral side effects associated with adenosine receptor agonists limit their usefulness in therapeutics; in contrast, adenosine receptor antagonists appear to have less side effects as it is the case of the well-known non-selective antagonists theophylline (present in tea) or caffeine (abundant in coffee and tea), and their emerging beneficial actions in Parkinsons disease and Alzheimers disease are encouraging. A(1) receptor antagonism may also be useful to enhance cognition and facilitate arousal, as well as in the periphery when deficits of neurotransmitter release occur (e.g. myasthenic syndromes). Enhancement of extracellular adenosine levels through drugs that influence its metabolism might prove useful approaches in situations such as neuropathic pain, where enhanced activation of inhibitory adenosine A(1) receptors is beneficial. One might then consider adenosine as a fine-tuning modulator of neuronal activity, which via subtle effects causes harmonic actions on neuronal activity. Whenever this homeostasis is disrupted, pathology may be installed and selective receptor antagonism or agonism required.

Does caffeine intake protect from Alzheimer's disease?

Caffeine is the most widely consumed behaviourally active substance in the western world. Neuroprotective effects of caffeine in low doses, chronically administered, have been shown in different experimental models. If caffeine intake could protect against neurodegeneration in Alzheimers disease (AD), then higher levels of caffeine consumption in normal subjects as compared with AD patients should be detectable in the presumably long period before diagnosis when insidious pathogenic changes are taking place. A case–control study was used: cases were 54 patients with probable AD fulfilling the National Institute of Neurologic and Communicative Disorders and Stroke and the AD and Related Disorders Association criteria, in a Dementia Clinics setting. Controls were 54 accompanying persons, cognitively normal, matched for age (±3 years) and sex. Patients with AD had an average daily caffeine intake of 73.9 ± 97.9 mg during the 20 years that preceded diagnosis of AD, whereas the controls had an average daily caffeine intake of 198.7 ± 135.7 mg during the corresponding 20 years of their lifetimes (P < 0.001, Wilcoxon signed ranks test). Using a logistic regression model, caffeine exposure during this period was found to be significantly inversely associated with AD (odds ratio=0.40, 95% confidence interval=0.25–0.67), whereas hypertension, diabetes, stroke, head trauma, smoking habits, alcohol consumption, non‐steroid anti‐inflammatory drugs, vitamin E, gastric disorders, heart disease, education and family history of dementia were not statistically significantly associated with AD. Caffeine intake was associated with a significantly lower risk for AD, independently of other possible confounding variables. These results, if confirmed with future prospective studies, may have a major impact on the prevention of AD.

Endogenous adenosine modulates long-term potentiation in the hippocampus

The effect of endogenous adenosine on frequency-induced long-term potentiation of the responses evoked by stimulation of the Schaffer fibres and recorded in the CA1 area was studied in hippocampal slices of the rat. Long-term potentiation was facilitated in the presence of the selective A1 adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (10-20 nM), and was reduced in the presence of the adenosine uptake blocker, nitrobenzylthioinosine (5 microM), suggesting that endogenous adenosine exerted a tonic inhibitory role on long-term potentiation, which was mediated through adenosine A1 receptors. We also found that long-term potentiation was increased in the presence of the selective A2 receptor agonist, CGS 21680 (30 nM), suggesting that the activation of adenosine A2 receptors may have excitatory effects on long-term potentiation. We suggest that, endogenous adenosine is able to modulate mechanisms of synaptic plasticity, such as long-term potentiation, in the hippocampus.

Mild cognitive impairment: deficits in cognitive domains other than memory.

Patients with mild cognitive impairment (MCI) typically present with memory complaints, but may have mild deficits in other cognitive domains. We compared the neuropsychological profiles of a series of consecutive MCI patients (n = 116) with a control group of healthy elderly subjects (n = 63). The presence of a memory deficit on delayed recall was consistent in the MCI sample, as it was an inclusion criterion in the study. Impairment on immediate recall was present in 62.6% of the patients on paragraph recall of the logical memory test and in 63.1% of the patients on the word paired-associate learning test. Remarkably, patients with MCI frequently had deficits in cognitive domains beyond memory. As much as 68.7% of the patients had deficits in temporal orientation, 30.2% had deficits in semantic fluency, 33.7% in the Token test, 23.4% in calculation, and 23.9% in motor initiative. If detailed neuropsychological testing is performed, the majority of MCI patients will have deficits in cognitive domains other than memory.

Verbal learning and memory deficits in Mild Cognitive Impairment

Criteria for amnestic MCI rely on the use of delayed recall tasks to establish the presence of memory impairment. This study applied the California Verbal Learning Test to detail memory performance in MCI patients (n = 70), as compared to control subjects (n = 92) and AD patients (n = 21). Learning across the 5 trials was different among the 3 groups. Learning strategy was also different, the MCI group showing less semantic clustering than the control group. However, both MCI patients and controls could benefit from semantic cueing. This study showed that beyond consolidation deficits, MCI patients have marked difficulties in acquisition and recall strategies.

Modification of adenosine modulation of synaptic transmission in the hippocampus of aged rats

We compared the modulation of synaptic transmission by adenosine A1 receptors in the hippocampus of aged (24 months) and young adult rats (6 weeks). The adenosine A1 receptor agonist, N6‐cyclopentyladenosine, was less potent (P<0.05) to inhibit synaptic transmission in aged (EC50=53 nM) than young adult (EC50=14 nM) hippocampal slices, these effects being prevented by the A1 receptor antagonist, 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX). In contrast with the lower effect of the A1 receptor agonist, it was observed that blockade of A1 receptors with DPCPX (50 nM), or removal of endogenous extracellular adenosine with adenosine deaminase (2 u ml−1), caused a more pronounced disinhibition of synaptic transmission in aged rats. Also consistent with a more intense A1 receptor‐mediated inhibitory tonus by endogenous adenosine in aged rats was the finding that to fully prevent the depression of synaptic transmission induced by 3 min hypoxia, a higher concentration of DPCPX was required in slices from aged (100 nM) than from young (50 nM) rats. It is concluded that in hippocampal slices of aged rats the efficiency of A1 receptors to modulate synaptic transmission is reduced, but this may be compensated by an enhanced inhibitory tonus by endogenous adenosine.

Hypoxia-induced desensitization and internalization of adenosine A1 receptors in the rat hippocampus

Activation of A1 adenosine receptors is important for both the neuromodulatory and neuroprotective effects of adenosine. However, short periods of global ischemia decrease A1 adenosine receptor density in the brain and it is not known if a parallel loss of functional efficiency of A1 adenosine receptors occurs. We now tested if hypoxia leads to changes in the density and efficiency of A1 adenosine receptors to inhibit excitatory synaptic transmission in rat hippocampal slices. In control conditions, the adenosine analog 2-chloroadenosine, inhibited field excitatory post-synaptic potentials with an EC50 of 0.23 microM. After hypoxia (95% N2 and 5% CO2, for 60 min) and reoxygenation (30 min), the EC50 increased to 0.73 microM. This EC50 shift was prevented by the presence of the A1 adenosine receptor antagonist 8-phenyltheophyline, but not by the A(2A)R antagonist 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c] pyrimidine, during the hypoxic period. This decreased efficiency of A1 adenosine receptors was not paralleled by a global change of A1 adenosine receptor density or affinity (as evaluated by the binding parameters obtained in nerve terminal membranes). However, the density of biotinylated A1 adenosine receptors at the plasma membrane of nerve terminals was reduced by 30% upon hypoxia/reoxygenation, in a manner prevented by the A1 adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine and mimicked by prolonged (60 min) supra-maximal activation of A1 adenosine receptors with 2-chloroadenosine (10 microM). These results indicate that hypoxia leads to a rapid (<90 min) homologous desensitization of A1 adenosine receptor-mediated inhibition of synaptic transmission that is likely due to an internalization of A1 adenosine receptors in nerve terminals.

The use of neuropsychological tests across Europe: the need for a consensus in the use of assessment tools for dementia

Background and purpose:  The centres dedicated to dementia throughout Europe use different neuropsychological tests in clinical practice. The European Federation of Neurological Societies task force on neuropsychological tests produced this survey on neuropsychological tests currently being used in different European countries to gather knowledge on the practice of dementia centres and to promote the harmonization of such instruments and future multicentre collaborations.