Comorbidities in Neurology: Is adenosine the common link?

Abstract

Comorbidities in Neurology represent a major conceptual and therapeutic challenge. For example, temporal lobe epilepsy (TLE) is a syndrome comprised of epileptic seizures and comorbid symptoms including memory and psychiatric impairment, depression, and sleep dysfunction. Similarly, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are accompanied by various degrees of memory dysfunction. Patients with AD have an increased likelihood for seizures, whereas all four conditions share certain aspects of psychosis, depression, and sleep dysfunction. This remarkable overlap suggests common pathophysiological mechanisms, which include synaptic dysfunction and synaptotoxicity, as well as glial activation and astrogliosis. Astrogliosis is linked to synapse function via the tripartite synapse, but astrocytes also control the availability of gliotransmitters and adenosine. Here we will specifically focus on the ‘adenosine hypothesis of comorbidities’ implying that astrocyte activation, via overexpression of adenosine kinase (ADK), induces a deficiency in the homeostatic tone of adenosine. We present evidence from patient-derived samples showing astrogliosis and overexpression of ADK as common pathological hallmark of epilepsy, AD, PD, and ALS. We discuss a transgenic ‘comorbidity model’, in which brain-wide overexpression of ADK and resulting adenosine deficiency produces a comorbid spectrum of seizures, altered dopaminergic function, attentional impairment, and deficits in cognitive domains and sleep regulation. We conclude that dysfunction of adenosine signaling is common in neurological conditions, that adenosine dysfunction can explain comorbid phenotypes, and that therapeutic adenosine augmentation might be effective for the treatment of comorbid symptoms in multiple neurological conditions.

Upregulation of adenosine A2A receptor and downregulation of GLT1 is associated with neuronal cell death in Rasmussen's encephalitis

“…Those pathological findings are in line with a prominent role of inflammatory processes in various epileptic disorders (50). In line with inflammatory processes, disruption of adenosine metabolism and signaling has been associated with epilepsy and its cognitive comorbidities (7,43,46). Adenosine, acts as an endogenous neuromodulator with potent anti-ictogenic (8,21), anti-epileptogenic (32,34,36), anti-inflammatory (45,64) and pro-cognitive (56) functions.…”

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

“…ATP synthase α is found on the cell surface of neurons, where it binds oligomeric Aβ to initiate neurotoxicity (Xing et al ., 2013). Adenylate kinase overexpression is a common feature of AD, PD, ALS, and epilepsy (Boison & Aronica, 2015). Phosphatidylethanolamine‐binding protein is ~20% more abundant in hippocampus of AD than NC, where it is thought to inhibit proteasomes (Chen et al ., 2006).…”

Adenosine Kinase, a Common Pathologic Biomarker for Human Pharmacoresistant Epilepsy

“…Dysfunction of adenosine system has been demonstrated as one of the mechanisms underlying for comorbidities associated with epilepsy. In addition, focal augmentation of adenosine in the brain not only inhibits recurrent seizures but also improve comorbid symptoms associated with epilepsy [13]. Overexpression of ADK has recently proved to lead to cognitive and psychiatric symptoms associated with epilepsy [13,14].…”

“…In addition, focal augmentation of adenosine in the brain not only inhibits recurrent seizures but also improve comorbid symptoms associated with epilepsy [13]. Overexpression of ADK has recently proved to lead to cognitive and psychiatric symptoms associated with epilepsy [13,14]. Adenosine kinase has been extensively studied in experimental epilepsy models [9-11, 15, 16] and in patients with pharmacoresisitant epilepsy such as mesial temporal lobe epilepsy (MTLE) [11,17], tumor related epilepsy [18], Rasmussen encephalitis (RE) [19,20], focal cortical dysplasia (FCD) [21] and Sturge-Weber syndrome (SWS) [22].…”