Globular glial tauopathies (GGT): consensus recommendations

Abstract

Rrecent studies have highlighted a group of 4-repeat (4R) tauopathies that are characterised neuropathologically by widespread, globular glial inclusions (GGIs). Tau immunohistochemistry reveals 4R immunore-active globular oligodendroglial and astrocytic inclusions and the latter are predominantly negative for Gallyas silver staining. These cases are associated with a range of clinical presentations, which correlate with the severity and distribution of underlying tau pathology and neurodegeneration. Their heterogeneous clinicopathological features combined with their rarity and under-recognition have led to cases characterised by GGIs being described in the literature using various and redundant terminologies. In this report, a group of neuropathologists form a consensus on the terminology and classification of cases with GGIs. After studying microscopic images from previously reported cases with suspected GGIs (n = 22), this panel of neuropathologists with extensive experience in the diagnosis of neurodegenerative diseases and a documented record of previous experience with at least one case with GGIs, agreed that (1) GGIs were present in all the cases reviewed; (2) the morphology of globular astrocytic inclusions was different to tufted astrocytes and finally that (3) the cases represented a number of different neuropathological subtypes. They also agreed that the different morphological subtypes are likely to be part of a spectrum of a distinct disease entity, for which they recommend that the overarching term globular glial tauopathy (GGT) should be used. Type I cases typically present with frontotemporal dementia, which correlates with the fronto-temporal distribution of pathology. Type II cases are characterised by pyramidal features reflecting motor cortex involvement and corticospinal tract degeneration. Type III cases can present with a combination of frontotemporal dementia and motor neuron disease with fronto-temporal cortex, motor cortex and corticospinal tract being severely affected. extrapyramidal features can be present in Type II and III cases and significant degeneration of the white matter is a feature of all GGT subtypes. Improved detection and classification will be necessary for the establishment of neuropathological and clinical diagnostic research criteria in the future.

Patterns of Hippocampal Tau Pathology Differentiate Neurodegenerative Dementias

“…of type 1) are distinct tauopathy entities showing a unique distribution of tau pathology also in the hippocampus. Recently, GGTs have been grouped into three forms [4]; from these we included those where the uniform feature of widespread oligodendroglial tau pathology predominates [23]. Our observations show that the unique involvement of hippocampal white matter may isolate the hippocampus from the functionally relevant connections leading to severe cognitive decline.…”

“…These were recruited either from the tissue bank obtained from routine diagnostic practice of the Institute of Neurology (PSP, CBD, and PiD cases), or included cases (GGT, tau-astrogliopathy of the elderly, and AD-related pathology with or without AGD) from previously published studies [5,6,23]. The following tauopathies have been studied: (1) pure AD-related pathology (40 cases), divided into Braak and Braak (BB) stages I-VI of the neurofibrillary pathology [24,25]; (2) AGD [26] associated with AD-related pathology, BBI-IV (18 cases: 2 with BBI, 9 with BBII, 3 with BBIII and 4 with BBIV); (3) PiD (8 cases); (4) CBD (6 cases); (5) PSP (7 cases); (6) uniform cases of GGT (5 cases of type 1 according to recent consensus nomenclature [4]) previously published as white matter tauopathy with globular glial inclusions [23], and (7) tau-astrogliopathy of the elderly [5] [10 cases; further stratified as 5 cases of the medial temporal lobe-predominant (MTL-predominant) group and 5 cases of the limbic-subcortical type; see below]. All cases have been evaluated in diagnostic sessions involving 2 or more certified neuropathologists following diagnostic criteria [27].…”

“…Deposition of the abnormally phosphorylated tau is a hallmark of a group of neurodegenerative diseases designated as tauopathies. These include Alzheimer's disease (AD), argyrophilic grain disease (AGD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Pick's disease (PiD) [2], and neurofibrillary tangle-only dementia [3], as well as disorders with globular glial inclusions, also called globular glial tauopathies (GGTs) [4]. In addition, there are constellations of tauopathies seen in elderly patients, which cannot be diagnosed by established neuropathologic diagnostic criteria, characterized by tau-astrogliopathy as a common feature [5,6].…”

Emerging Diagnostic and Therapeutic Strategies for Tauopathies

“…Less common tauopathies include other 4R tau predominant findings of argyrophilic grain-like inclusions largely constrained to limbic regions (i.e., argyrophilic grain disease, AGD) [53], globular glial tau inclusions (GGT) [54], and aging-related tau astrogliopathy (ARTAG) [55]. GGT has been described in rare cases of clinical FTD, sometimes with concurrent motor neuron disease, while AGD and ARTAG may be found in cognitively normal aged individuals and the clinical significance is currently unclear.…”

Protein aggregate formation in oligodendrocytes: tau and the cytoskeleton at the intersection of neuroprotection and neurodegeneration

“…Besides tau the inclusion bodies often contain other cytoskeletal proteins and positively stain with antibodies against a variety of heat shock proteins and ubiquitin (Chin and Goldman, 1996;Richter-Landsberg and Bauer 2004;Richter-Landsberg and Goldbaum, 2007). Furthermore, tau-positive globular oligodendroglial inclusions have been identified in motor neuron diseases and frontotemporal dementias, termed globular glial tauopathies (Ahmed et al, 2013).…”