Association between globular glial tauopathies and frontotemporal dementia-expanding the spectrum of gliocentric disorders: a review

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Abstract

Importance: Globular glial tauopathies (GGTs), as defined by a consensus study in 2013, belong to the group of frontotemporal lobar degenerations and expand the spectrum of glial-predominant neurodegenerative diseases. Three neuropathological subtypes of GGT (types I-III) are characterized by phosphorylated tau-immunopositive inclusions that are predominantly in oligodendroglia and/or astroglia in the frontal, temporal, and/or precentral cortices. Type II is largely restricted to the corticospinal system. The low incidence of GGT (<10% of cases of frontotemporal lobar degeneration with tau pathology), together with its unusual combination of neuronal and nonneuronal pathology, has hindered identification and accurate diagnosis. This review collated clinical, demographic, neuropathological, and genetic data from 88 published GGT cases identified on PubMed to examine the association between GGT and frontotemporal dementia and associated disorders. Observations: Among 88 patients with GGT (46 female [52.3%]; mean [SD] age at disease onset, 65 [11] years), 44 patients (50.0%) had idiopathic disease, and 21 patients (23.9%) had a variation in the microtubule-associated protein tau (MAPT) gene. Those with idiopathic GGT compared with those with a variation in MAPT had a mean (SD) age at symptom onset of 70 (8) years vs 54 (9) years and a mean (SD) disease duration of 7 (3) years vs 6 (3) years, respectively. A similar sex distribution was observed among patients with GGT; however, female patients were typically 6 years older at symptom onset than male patients (mean [SD] age, 68 [11] years vs 62 [11] years, respectively). Disease duration was similar in both sexes (mean [SD], 6 [3] years for women and 6 [4] years for men). The most common predominant clinical features were primary progressive aphasia (22 patients [25.0%]), behavioral-variant frontotemporal dementia (20 patients [22.7%]), upper motor neuron signs (11 patients [12.5%]), memory impairment (7 patients [8.0%]), and Richardson syndrome (7 patients [8.0%]). Although some demographic differences between GGT subtypes were identified, the predictive value of the clinical presentation was low, calling into question the need for neuropathological subtyping. Further neuropathological studies are needed to clarify whether GGT type II should be interpreted as atypical progressive supranuclear palsy or a separate entity. Few cases (7 patients [8.0%]) had coexisting proteinopathies. Conclusions and Relevance: This review of the published data suggests an association between regional distribution of glial tau pathology and neuronal degeneration. Targeting glial tau accumulation or sustaining their neuron-supportive function might require different therapeutic or neuroprotective strategies and more accurate preclinical models to explore disease mechanisms and track progression. Emerging data support the important role of glia in the pathogenesis of neurodegenerative disorders, highlighting the need to raise awareness of GGT in clinical and research settings.
Original languageEnglish
Pages (from-to)1004-1014
Number of pages11
JournalJAMA Neurology
Volume78
Issue number8
Early online date21 Jun 2021
DOIs
Publication statusPublished - 1 Aug 2021

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