Correction to "Functional near-infrared spectroscopy as a biomarker of TMS efficacy in treatment-resistant depression".

Parkinson's disease (PD) is the second most common neurodegenerative disease. Current treatments can reduce some PD symptoms but no therapies prevent progressive neurodegeneration. However, recent research has demonstrated that impaired brain bioenergetics are a key factor in PD. Specifically, the mitochondrial toxin MPTP causes parkinsonism in humans and animal models of PD, and PD-causing mutations can disrupt cellular respiration. Furthermore, advancing age is the major risk factor for developing PD and is associated with disrupted energy metabolism, as is seen in the brains of PD patients. Therefore, interventions targeting energy metabolism have potential to slow or halt the progressive neuron loss seen in PD. Recent studies discovered that terazosin (TZ), an α-1 adrenergic receptor antagonist used to treat benign prostatic hypertrophy and hypertension, has an additional independent target in phosphoglycerate kinase 1 (PGK1). PGK1 is the first ATP-producing enzyme in glycolysis, and interestingly, human mutations in PGK1 are associated with parkinsonism. TZ's ability to enhance energy metabolism via activation of PGK1 suggested that it might improve impaired PD bioenergetics. In testing that hypothesis, we found that TZ enhanced glycolysis and mitochondrial activity, increased ATP levels in the brain, and importantly, slowed or prevented neurodegeneration in diverse cellular and animal models of PD. Those discoveries were complemented by several large epidemiological studies that associated TZ use with a decreased risk of developing PD and slower disease progression in people with PD. However, there are epidemiological reports suggesting that medications like TZ may not be protective for PD but rather that comparator medications, such as tamsulosin, may increase the likelihood of receiving a diagnosis of PD. These contradicting results demonstrate the need for further studies of TZ in humans. Additionally, a small pilot study suggested TZ engaged its target and increased ATP levels in people with PD. Although these findings are encouraging, key questions remain. First, animal studies suggest TZ penetrates the blood-brain barrier (BBB); does TZ cross the BBB in humans, enabling it to reach its intended target? Second, because TZ is predominantly prescribed to treat benign prostatic hyperplasia, epidemiological studies only included men; does TZ similarly influence energy metabolism in men and women? Third, orthostatic hypotension is more common in women than men, and PD can cause orthostatic hypotension; compared to men, does TZ place women at a greater risk for orthostatic hypotension? Fourth, TZ has a biphasic effect on energy metabolism in vitro and in vivo; what is the relationship between TZ dose and changes in measures of energy metabolism? To answer these questions, we studied the pharmacokinetic and pharmacodynamic properties of TZ in older healthy adults. To test target engagement, we measured whole blood ATP levels corrected for hemoglobin (ATP/Hgb), phosphorous-magnetic resonance spectroscopy (P-MRS) to assay the ratio of βATP to inorganic phosphate (Pi) in the brain, F-fludeoxyglucose positron emission tomography (FDG-PET) to examine metabolic activity patterns, and plasma metabolites to assess systemic metabolic changes.