Brain bioenergetics and redox state measured by 31 P magnetic resonance spectroscopy in unaffected siblings of patients with psychotic disorders

Abstract

Background Brain bioenergetic anomalies and redox dysregulation have been implicated in the pathophysiology of psychotic disorders. The present study examined brain energy-related metabolites and the balance between nicotinamide adenine dinucleotide metabolites (oxidized NAD+ and reduced NADH) using 31P-magnetic resonance spectroscopy (31P-MRS) in unaffected siblings, compared to first episode psychosis (FEP) patients and healthy controls. Methods 21 unaffected siblings, 32 FEP patients (including schizophrenia spectrum and affective psychoses), and 21 controls underwent 31P-MRS in the frontal lobe (6×6×4 cm3) on a 4T MR scanner, using custom-designed dual-tuned surface coil with outer volume suppression. Brain parenchymal pH and steady-state metabolite ratios of high energy phosphate compounds were measured. NAD+ and NADH levels were determined using a 31P-MRS fitting algorithm. 13 unaffected sibling-patient pairs were related; other patients and siblings were unrelated. ANCOVA analyses were used to examine 31P-MRS measures, with age and gender as covariates. Results The phosphocreatine/adenosine triphosphate ratio was significantly reduced in both unaffected siblings and FEP patients, compared to controls. NAD+/NADH ratio was significantly reduced in patients compared to siblings and controls, with siblings showing a reduction in NAD+/NADH compared to controls that was not statistically significant. Compared to patients and controls, siblings showed significantly reduced levels of NAD+. Siblings did not differ from patients or controls on brain pH. Discussion Our results indicate that unaffected siblings show some, but not all the same abnormalities in brain energy metabolites and redox state as FEP patients. Thus, 31P-MRS studies may identify factors related both to risk and expression of psychosis.

Nutritional Ketosis Increases NAD+/NADH Ratio in Healthy Human Brain: An in Vivo Study by 31P-MRS

“…31 P MRS at high magnetic field is a powerful non-invasive method to measure metabolic and physiological parameters in the brain ( 30 ) including important 31 P-metabolites involved in brain energy metabolism (PCr, Pi, ATP) and membrane synthesis/degradation (PC, PE, GPC, GPE), metabolic fluxes (k f, CK and k f, ATPase ), intra-/extra-cellular pH, free Mg 2+ concentration, as well as most recently the redox state (NAD + /NADH) ( 11 – 13 ). To measure the aforementioned metabolic and physiological parameters with a focus on redox state and forward rate constants of CK(k f, CK ) and ATPase(k f, ATPase ), a scanning protocol of the occipital region was established in a pilot test-retest study in 6 healthy volunteers (method section and Supplementary Material).…”

“…[γ-ATP] was assumed to be 3 mM in the human occipital lobe and used as an internal concentration reference. To be comparable with literatures, NAD + , NADH, and UDPG concentrations were calculated assuming [α-ATP] of 2.8 mM ( 12 , 13 ).…”

“…Therefore, to test if ketones can increase the brain NAD + /NADH ratio in human or affect other energy metabolism pathways, we conducted a phosphorous magnetic resonance spectroscopy ( 31 P-MRS) study at 7 tesla, where brain energy related metabolites, redox state, and enzymatic activities were assessed before and after a nutritional ketogenic intervention. Recent advances in quantification of human brain NAD by 31 P MRS methods allow for direct quantification of NAD + and NADH concentrations despite their relatively low level, making it a unique and non-invasive methodology ( 11 – 13 ). To raise blood ketones, oral intake of Peptamen®, a complete liquid nutrition product containing high amount of medium chain triglycerides (MCT), was used.…”

Impaired insulin signaling in unaffected siblings and patients with first-episode psychosis

“…Dysfunctional energy metabolism and oxidative stress are key pathophysiologic mechanisms in T2DM 51 , and we now also have converging evidence in psychotic disorders for energy metabolism impairment in the brain 57 – 59 . 31 P magnetic resonance spectroscopy studies have revealed specific bioenergetic abnormalities and redox imbalance in FEP patients and unaffected siblings 60 , 61 . In psychotic and bipolar disorders, recent evidence suggests that obesity and abnormal glucose metabolism are associated with severity of illness, greater number of hospitalizations, suicide attempts, and neurochemical-structural abnormalities 62 – 65 .…”

Mitochondria and Mood: Mitochondrial Dysfunction as a Key Player in the Manifestation of Depression

“… Martins-de-Souza et al (2012) speculated that a reduction in ATP could be due to oxidative stress and that the increased levels of subunits of OXPHOS complexes were compensatory. In fact, ATP reduction and its relation to oxidative stress have been linked not only to depression (detailed below), but also to psychotic disorders (see Chouinard et al, 2017 ), autism ( Rose et al, 2014 ), anxiety ( Kumar and Chanana, 2017 ), Alzheimer’s disease (recently reviewed in Tramutola et al, 2017 ), and Huntington disease ( Quintanilla et al, 2017 ).…”