The study covered in this summary was published on medRxiv.org as a preprint and has not yet been peer reviewed.
High tCr and low glutamate+glutamine (Glx) metabolite levels in the left inferior frontal gyrus (IFG) correlate with greater PPA disease severity.
Brain tCr levels varied among PPA subtypes; tCr levels were lowest among patients with logopenic variant PPA (lvPPA) and highest among patients with semantic variant PPA (svPPA) patients in both the left IFG and the right sensorimotor cortex (SMC).
Why This Matters
This study is the first analysis to report differences in brain chemistry between the PPA subtypes and associations of brain chemistry with symptom severity.
The findings of this study suggest that tCr could serve as a biomarker to differentiate between PPA subtypes, and both tCr and Glx may have utility for better understanding PPA disease mechanisms and tracking disease progression.
All patients enrolled in the study were diagnosed with PPA by expert clinicians and were right-handed, educated until at least 12th grade, and had English as a first language.
Patients were excluded if they were older than age 90 years, were not premorbidly proficient spellers, had progressed to advanced stages of PPA or other dementia, naproxen injection had any diagnosed comorbid neurologic conditions, or if they had any contraindications for MRI scanning.
Three PPA subtypes were analyzed, and a total cohort consisted of 27 patients with lvPPA (characterized by deficits in word retrieval and difficulty repeating words and sentences), 12 patients with svPPA (characterized by severe deficits in single-word comprehension and naming, but preserved grammar and fluency), and 22 patients with nonfluent variant PPA (nfvPPA), which is characterized by deficits in grammar and speech production and slow, effortful, apraxic speech, but preserved word comprehension and naming
PPA symptom severity was assessed by the FrontoTemporal Dementia Clinical Dementia Rating Scale (FTD-CDR), a measure of overall disease severity, including language function, memory, attention, and independence, with scores ranging from 0 (no impairment) to 24 (severe impairment).
Magnetic resonance spectroscopy (MRS) was used to assess brain chemicals in vivo including tCr, Glx, total N-acetyl aspartate (tNAA), and total choline (tCho) measured by standard short-TE PRESS acquisition, and gamma-aminobutyric acid (GABA) measured by MEGA-PRESS acquisition. MRS data were analyzed using the open-source analysis toolbox Osprey (v2.0.0) within MATLAB R2021b and statistical analysis used R 4.0.0 within RStudio.
Brain tCr levels differed by subtype; patients with svPPA had higher mean tCr compared with patients with lvPPA (P = .019) with no other difference in brain metabolite levels based on PPA subtype (P > .05).
Brain metabolite levels differed by brain region; tNAA was lower in the IFG compared to the SMC (P < .001) and tCho, tCr, and Glx were higher in the IFG compared with the SMC (P < .001). GABA levels did not differ by brain region (P = .626).
Worse PPA symptoms and longer disease duration were associated with higher IFG tCr levels (P = .007) and lower IFG Glx levels (P = .012).
The cross-sectional approach of this study precluded assessment of metabolite levels prior to PPA onset and disease progression.
Because of the lack of a normal aging control group, changes in brain metabolite levels due to normal aging for PPA subtypes could not be assessed.
MRS methods have inherent limitations that do not allow distinction between glutamate vs glutamine signals or phosphocreatine vs creatine signals.
Changes in water and metabolite relaxation rates with aging and disease were not quantified and could impact metabolite quantification.
Patients with PPA who had difficulty remaining still in the scanner could have affected spectral quality and the ability to complete an MRI scan precluded enrollment of extremely advanced PPA cases in this cohort.
This work was supported by grants from the National Institute on Aging (K00 AG068440- 03, R00 AG062230, R01 DC014475-05, and R01 AG068881-02) and grants from the National Institute of Biomedical Imaging and Bioengineering (R01 EB016089 and P41 EB031771).
None of the authors disclosed any competing interests.
This is a summary of a preprint research study, “Brain total creatine differs between primary progressive aphasia (PPA) subtypes and correlates with disease severity,” written by Kathleen E. Hupfeld, Johns Hopkins University School of Medicine and Kennedy Krieger Institute, Baltimore, Maryland and colleagues on medRxiv.org, provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on medRxiv.org.
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