In 2021, the World Health Organization reclassified glioblastoma, the most common form of adult brain cancer, into isocitrate dehydrogenase (IDH)-wild-type glioblastomas and grade IV IDH mutant (G4 IDHm) astrocytomas. For both tumor types, intratumoral heterogeneity is a key contributor to therapeutic failure. To better define this heterogeneity, genome-wide chromatin accessibility and transcription profiles of clinical samples of glioblastomas and G4 IDHm astrocytomas were analyzed at single-cell resolution. These profiles afforded resolution of intratumoral genetic heterogeneity, including delineation of cell-to-cell variations in distinct cell states, focal gene amplifications, as well as extrachromosomal circular DNAs. Despite differences in IDH mutation status and significant intratumoral heterogeneity, the profiled tumor cells shared a common chromatin structure defined by open regions enriched for nuclear factor 1 transcription factors (NFIA and NFIB). Silencing of NFIA or NFIB suppressed in vitro and in vivo growths of patient-derived glioblastomas and G4 IDHm astrocytoma models. These findings suggest that despite distinct genotypes and cell states, glioblastoma/G4 astrocytoma cells share dependency on core transcriptional programs, yielding an attractive platform for addressing therapeutic challenges associated with intratumoral heterogeneity.

Background

Large-scale brain networks such as the default mode network (DMN) are often disrupted in Alzheimer's disease (AD). Numerous studies have examined DMN functional connectivity in those with mild cognitive impairment (MCI), a presumed AD precursor, to discover a biomarker of AD risk. Prior reviews were qualitative or limited in scope or approach.

Objective

We aimed to systematically and quantitatively review DMN resting state fMRI studies comparing MCI and healthy comparison (HC) groups.

Methods

PubMed was searched for relevant articles. Study characteristics were abstracted and the number of studies showing no group difference or hyper- versus hypo-connnectivity in MCI was tallied. A voxel-wise (ES-SDM) meta-analysis was conducted to identify regional group differences.

Results

Qualitatively, our review of 57 MCI versus HC comparisons suggests substantial inconsistency; 9 showed no group difference, 8 showed MCI > HC and 22 showed HC > MCI across the brain, and 18 showed regionally-mixed directions of effect. The meta-analysis of 31 studies revealed areas of significant hypo- and hyper-connectivity in MCI, including hypoconnectivity in the posterior cingulate cortex/precuneus (z = -3.1, p < 0.0001). Very few individual studies, however, showed patterns resembling the meta-analytic results. Methodological differences did not appear to explain inconsistencies.

Conclusions

The pattern of altered resting DMN function or connectivity in MCI is complex and variable across studies. To date, no index of DMN connectivity qualifies as a useful biomarker of MCI or risk for AD. Refinements to MCI diagnosis, including other biological markers, or longitudinal studies of progression to AD, might identify DMN alterations predictive of AD risk.