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 co-morbid phenotypes, and that therapeutic
adenosine augmentation might be effective for the treatment of comorbid symptoms in multiple neurological conditions.