ARTAG in the basal forebrain: widening the constellation of astrocytic tau pathology
© The Author(s). 2016
Received: 27 April 2016
Accepted: 1 June 2016
Published: 13 June 2016
Tauopathies are disorders characterised by the abnormal accumulation of hyperphosphorylated tau protein within neurons and glial cells. Alzheimer’s disease (AD), the most common form of tauopathy, features a stereotypical, staged progression of neurofibrillary tangle (NFT) and neuritic tau pathology through the brain . However, age-related NFT and neuritic tau pathologies have also commonly been identified in cognitively normal and ‘tangle-only dementia’ cases in the absence of amyloid-β peptide (Aβ) pathology. This has now been given the term ‘primary age-related tauopathy’ (PART) to distinguish it from AD . Furthermore, astroglial tau aggregations have been increasingly recognised to be present within the aging brain independently of any co-existing neuropathological disorders or cognitive impairment. This unique astroglial tau pathology has been termed aging-related tau astrogliopathy (ARTAG) . ARTAG exists in two distinct morphological forms as thorn-shaped astrocytes (TSA) and granular/fuzzy astrocytes (GFA). In addition, these tau immunoreactive astrocytes show a unique distribution within the brain, with TSA and/or GFA commonly found in subpial, subependymal and perivascular locations, as well as in clusters within the white and grey matter.
In a large population-based cohort study, Wharton and colleagues attempted to elucidate the relationship between astroglial tau pathology and neuronal tau and to correlate it with dementia status in aged brains . Although no significant correlation was identified, astroglial tau pathology was found to be prevalent, with TSA present in 40 % of the cases. In particular, the authors mentioned that TSA are commonly found in a subpial location inferior to the substantia innominata but no detailed quantitative or morphological assessment was described.
Demographics and presence of ARTAG pathology of screened cases
Primary neuropathological diagnosis
Dementia with Lewy bodies
M:F (% male)
8:18 (30.8 %)
98:57 (63.2 %)
13:7 (65.0 %)
11:13 (45.8 %)
Mean age at death (SD)
Cases with presence of ARTAG in basal forebrain (%)
13 (50.0 %)
48 (31.0 %)
5 (25.0 %)
10 (41.7 %)
Presence of ARTAG pathology among different age groups
Cases with presence of ARTAG (%)
Cases with absence of ARTAG (%)
0 (0.0 %)
4 (100.0 %)
7 (25.9 %)
20 (74.1 %)
21 (28.0 %)
54 (72.0 %)
40 (38.5 %)
64 (61.5 %)
8 (53.3 %)
7 (46.7 %)
ARTAG pathology in the aging brain shares a similar distribution and morphology to that seen in chronic traumatic encephalopathy (CTE), a neurodegenerative sequala of repeated traumatic brain injury . Co-morbid neurodegenerative disorders have also been identified within CTE cases . Within a large cohort of neurodegenerative diseases and controls, Ling et al reported evidence of CTE pathology in 32 out of 268 (11.9 %) screened cases and in 12.8 % of age-matched controls, and 30 (93.8 %) of CTE-positive cases had history of traumatic brain injury . However, in another study where CTE pathology was screened in cortical brain sections of 198 controls and 66 individuals with a history of involvement in contact sports , CTE pathology was only identified in 21 of the 66 individuals at risk but not in the control group. This conflicting finding could be due to the different age ranges of the cases screened in these two studies. The 32 CTE-positive cases identified in the Ling et al study were all over the age of 60 (mean age = 80.97), and the 6 CTE-positive control subjects had a mean age of 92.17 which is considerably higher than the all cases screened in the Bieniek et al study (mean age ~75). This suggests that CTE and ARTAG possibly share a common aetiological pathway. The predominance of ARTAG pathology in males in our cohort is similar to that seen in CTE. Detailed retrospective clinical note analysis was not performed but a number of cases had a recorded history of head injury, participation in contact sport or military service. Furthermore, CTE pathology may reflect advanced aging or injury induced ARTAG or both. Wharton and colleagues noted the presence of corpora amylacea in close proximity to astroglial tau accumulations , and we report a similar observation in the basal forebrain (Fig. 1d). The accumulation of corpora amylacea is hypothesised to be involved in a disposal pathway of tau aggregates, which might further explain the close proximity of these bodies to tau pathology. Further work in a large cohort is needed to examine the relationship between CTE and ARTAG pathology throughout the brain and further clinicopathological research will add to our understanding of the pathogenesis of CTE and ARTAG in relation to the process of normal aging and neurodegenerative disorders.
The work conducted on human tissue was under ethical approval held by the Parkinson’s UK Brain Bank at Imperial College London (Registered charity in England and Wales (258197) and in Scotland (SC037554); Multicentre Research Ethics Committee approval reference number: 07/MRE09/72). Parkinson’s UK Brain Bank is an approved Research Tissue Bank by the Wales Research Ethics Committee (Ref. No. 08/MRE09/31 + 5). Further tissues were provided by the Newcastle Brain Tissue Resource, which is funded in part by a grant from the UK Medical Research Council (G0400074) and by Brains for Dementia research, a joint venture between Alzheimer’s Society and Alzheimer’s Research UK.
Aging-related tau astrogliopathy
Brains for Dementia Research
Chronic traumatic encephalopathy
Dementia with Lewy bodies
Lewy body disorders
Primary age-related tauopathy
The authors would like to thank Parkinson’s UK, registered charity 258197, for their continued support as well as the donors and family for their invaluable donation of brain tissue to the Parkinson’s UK Tissue Bank and the Brains for Dementia Research (BDR) Tissue Bank.
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