Measuring brain lactate and other metabolites in schizophrenia at 3T using an enhanced MR spectroscopy approach

Project Summary
Schizophrenia (SZ) is a severe mental disorder characterized by hallucinations, delusions, disorganized
thought, impaired emotional and motivational processes, and cognitive dysfunction. Antipsychotic medications
help diminish positive symptoms but do not alleviate negative symptoms or cognitive impairments.
Our understanding of the potential role of lactate in energy metabolism during brain activation has changed
radically over the past three decades, shifting from waste product to supplemental fuel and signaling molecule.
The lactate produced within astrocytes can also be shuttled through extracellular space into neurons as a
substrate for mitochondrial oxidative metabolism. Emerging evidence suggests lactate generated by glycolysis
in glial cells constitutively supports synaptic transmission and plays a key role in memory consolidation and
high attentional load in cognitive tasks. It has been hypothesized that defects in bioenergetic interplay of
astrocytes and neurons likely contribute to negative symptoms and impaired cognition in SZ.
Unlike bipolar disorder (BD), few brain lactate studies are reported in SZ. This is beginning to change with a
recent series of studies performed on 7 T. With the strong overlapping macromolecule signal and its low
concentration, lactate measurement is subject to low reliability with existing techniques either on 3 T or 7 T.
Lactate quantification is challenging and many scans in studies need to be excluded even with relatively loose
quantification criteria (e.g. Cramer Rao Lower Bound or CRLB < 30%). We recently developed an MRS
sequence which we term HOPE (Half-intensity with macrOmolecule-suPprEssion). HOPE achieves substantial
improvement of lactate measurements with CRLB ~ 13% with a 10 min scan time, using a modified SPECIAL
sequence with macromolecule suppression. Other metabolites such as glutamate (Glu) and glutathione (GSH)
can also be measured with minimal macromolecule contamination using this approach.
We propose to measure lactate in dorsolateral prefrontal cortex (DLPFC), centrum semiovale (CSO) and
ventricles. With their different compositions of GM (enriched for neuronal cell bodies), WM (with more glial cells
and myelin) and CSF (extracellular space), we aim to provide novel insights concerning bioenergetics in the
schizophrenia (SZ) brain. These comprehensive lactate measurements will be performed in both first episode
(FE) and chronic SZ for the first time, together with a series of functional and behavioral assessments. We will
correlate lactate levels from DLPFC, white matter tracts and CSF with clinical assessments, especially
negative subscale of PANSS (negative symptoms), Multnomah Community Ability Scale (community function)
and Brief Assessment of Cognition in Schizophrenia (cognition). This design will also provide preliminary
evidence on the dynamic progression of lactate abnormalities in SZ which can be interpreted in the context of
other biological processes which unfold from early to later phases of illness.

Grant Number: 5R21MH133114-02
NIH Institute/Center: NIH
Principal Investigator: Xi Chen