Reproducible network and regional topographies of abnormal glucose metabolism associated with progressive supranuclear palsy: Multivariate and univariate analyses in American and Chinese patient cohorts

Abstract

Progressive supranuclear palsy (PSP) is a rare movement disorder and often difficult to distinguish clinically from Parkinson's disease (PD) and multiple system atrophy (MSA) in early phases. In this study, we report reproducible disease-related topographies of brain network and regional glucose metabolism associated with PSP in clinically-confirmed independent cohorts of PSP, MSA, and PD patients and healthy controls in the USA and China. Using F-FDG PET images from PSP and healthy subjects, we applied spatial covariance analysis with bootstrapping to identify a PSP-related pattern (PSPRP) and estimate its reliability, and evaluated the ability of network scores for differential diagnosis. We also detected regional metabolic differences using statistical parametric mapping analysis. We produced a highly reliable PSPRP characterized by relative metabolic decreases in the middle prefrontal cortex/cingulate, ventrolateral prefrontal cortex, striatum, thalamus and midbrain, covarying with relative metabolic increases in the hippocampus, insula and parieto-temporal regions. PSPRP network scores correlated positively with PSP duration and accurately discriminated between healthy, PSP, MSA and PD groups in two separate cohorts of parkinsonian patients at both early and advanced stages. Moreover, PSP patients shared many overlapping areas with abnormal metabolism in the same cortical and subcortical regions as in the PSPRP. With rigorous cross-validation, this study demonstrated highly comparable and reproducible PSP-related metabolic topographies at network and regional levels across different patient populations and PET scanners. Metabolic brain network activity may serve as a reliable and objective marker of PSP, although cross-validation applying recent diagnostic criteria and classification is warranted.

Multicenter Validation of Metabolic Abnormalities Related to PSP According to the MDS‐PSP Criteria

“…In terms of the FDG-PET imaging data, both methods used in the group-level analysis identified a consistent topographical distribution of brain metabolic abnormalities in multicenter populations of PSP patients. The results of the univariate analysis (SPM) are consistent with previous studies, 16,17,[19][20][21][22]24 which described relative hypometabolism in some subcortical nuclei and frontal cortices and relative hypermetabolism in the cerebellum and sensorimotor cortices. Unfortunately, most of these publications were small single-center studies and partially addressed the problem of massive multiple comparisons.…”

“…As such, relative hypometabolism has been seen in the midbrain, basal ganglia, thalamus, and frontal lobes of patients with Richardson syndrome variant of PSP (PSP-RS). 16,[20][21][22][23][24] However, available studies using this approach show critical limitations, as they are typically small monocentric studies. Multivariate approaches have been applied to not only assess regional abnormalities in metabolism but also changes in brain connectivity.…”

“…[17][18][19][26][27][28] However, reproducibility with independent cross-validation populations is limited. 22 Moreover, most studies that have evaluated the utility of neuroimaging as a biomarker have only included PSP-RS. Nevertheless, the diagnostic value of these biomarkers for the full clinical spectrum of PSP remains unclear.…”

Metabolic network as an objective biomarker in monitoring deep brain stimulation for Parkinson’s disease: a longitudinal study

“…Next, the Z-score of each voxel was calculated, and the threshold of 3.35 was used to measure the reliability of voxel weight. The expression of the PDRP pattern of each subject was calculated using the topographic profile rating (TPR) algorithm and represented by a Z-transformed score using scores of the HC1 subjects [ 6 ]. The DBS treatment effects of PD patients were represented predominantly by PDRP expression changes.…”

“…In particular, abnormal PD-related metabolic covariance patterns (PDRP) have typically been identified by spatial covariance analysis, whose expression yields the better discrimination of PD patients at an individual level. It has been reported that PDRP activities could accurately discriminate PD patients not only from controls but also from individuals with atypical Parkinsonism (i.e., multiple system atrophy or progressive supranuclear palsy) [ 6 ]. Moreover, the increased expression of PDRP revealed consistent correlation with motor manifestations [ 7 ] and was useful for detecting the prodromal stage of parkinsonism (i.e., rapid eye movement sleep behavior disorder) by predicting phenoconversion toward subsequent development [ 8 , 9 ].…”