Haraguchi, Takashi

Ikeda, Chikako

Ikeuchi, Takeshi

Ishizu, Hideki

Miki, Tomoko

Miyashita, Akinori

Takenoshita, Shintaro

Terada, Seishi

Yokota, Osamu

English

Osamu Yokota

Tomoko Miki

Chikako Ikeda

Hideki Ishizu

Takashi Haraguchi

Akinori Miyashita

Takeshi Ikeuchi

Shintaro Takenoshita

Seishi Terada

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Free Neuropathology 3:18 (2022) Yokota et al doi: https://doi.org/10.17879/freeneuropathology-2022-4285 page 1 of 5     Copyright: © 2022 The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited, a link to the Creative Commons license is provided, and any changes are indicated. The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.  Amygdala granular fuzzy astrocytes as lesions preceding development of argyrophilic grains: data from 239 autopsy cases Osamu Yokota1,2,3,4, Tomoko Miki1,2,3,4, Chikako Ikeda2,3, Hideki Ishizu3, Takashi Haraguchi4, Akinori Miyashita5, Takeshi Ikeuchi5, Shintaro Takenoshita6, Seishi Terada2 1 Department of Psychiatry, Kinoko Espoir Hospital, Kasaoka, Japan 2 Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceuti-cal Sciences, Okayama, Japan 3 Department of Laboratory Medicine and Pathology, Zikei Institute of Psychiatry, Okayama, Japan 4 Department of Neurology, National Hospital Organization Minami-Okayama Medical Center, Okayama, Japan 5 Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan 6 Department of Neuropsychiatry, Okayama University Hospital, Okayama, Japan Corresponding author: Osamu Yokota · Department of Neuropsychiatry · Okayama University Graduate School of Medicine · Dentistry and Pharmaceutical Sciences · 2-5-1 Shikata-cho · Okayama 700-8558 · Japan oyokota1@yahoo.co.jp Additional resources and electronic supplementary material: supplementary material Submitted: 15 June 2022 · Accepted: 21 July 2022 · Copyedited by: Irati Bastero · Published: 27. July 2022  Keywords: Amygdala, Argyrophilic grain disease, ARTAG, Blood vessel, Granular fuzzy astrocyte, Tau  Letter Cases of argyrophilic grain disease (AGD) fre-quently have astrocytes containing non-argyrophilic tau-positive fine granules in the foot processes sprouting from cell bodies in the amygdala. They were first called bush-like astrocytes by Botez et al. [1], and later they were classified as one of the age-related tau astrogliopathies and re-named granular fuzzy astrocytes (GFAs) [2]. In our previous studies, the formation of GFAs was not simply associated with age alone, and their distributions were influ-enced by underlying tauopathies [3,4]. Especially in AGD cases, GFAs preferentially develop in the amyg-dala rather than the frontal cortex and striatum [3]. Kovacs et al. previously noted the possibility that GFAs in the amygdala might be a forerunner of argy-rophilic grains [5]. However, there is no comprehen-sive pathological data regarding the relationship be-tween the frequencies and severities of AGD and GFAs in the amygdala, and whether argyrophilic grains develop in the absence of amygdala GFAs re-mains unclear. To address these issues, first, we an-alyzed the relationship between the presence or ab-sence of AGD and the severity of amygdala GFAs in a case series. Then, their spatial relationship was ex-amined using double staining with the Gallyas method and anti-phospho-tau (AT8) immunohisto-chemistry.Letter Free Neuropathology 3:18 (2022) Yokota et al doi: https://doi.org/10.17879/freeneuropathology-2022-4285 page 2 of 5     Figure 1. Relationship between the formation of AGD and amygdala GFAs (A) The relationship between the occurrence of AGD and the presence or absence of amygdala GFAs. AGD was noted only in cases having amygdala GFAs. (B) The severity of AGD by amygdala GFA stage. The frequency and severity of AGD increase with the amygdala GFA stage in presence of amygdala GFAs. (C-E) GFAs in the amygdala. AT8 immunohistochemistry. GFAs are often in contact with vessel walls (as-terisks). Further, argyrophilic grains are scattered around GFAs (arrows). (F-H) Gallyas method. The amygdala. Argyrophilic grains (arrows) are scattered at a distance around blood vessels (asterisks). (I-K) Gallyas (black)-AT8 (light blue) double staining. The amygdala. Argy-rophilic grains (black) are scattered around GFAs (light blue) contacting the vessel walls (asterisks). All scale bars: 30 μm.Free Neuropathology 3:18 (2022) Yokota et al doi: https://doi.org/10.17879/freeneuropathology-2022-4285 page 3 of 5    Among a total of 1,166 autopsy cases regis-tered in our database, 474 cases that were evalu-ated using modern standardized methods, including a panel of immunohistochemistry, modified Bielschowsky silver stain, and Gallyas-Braak silver stain from 2001 to 2022, were selected (Supplemen-tary file 1). All cases died in psychiatric hospitals or neurological departments of general hospitals. Of these cases, we extracted 263 cases for which semi-quantitative data of the AT8-positive GFAs, as well as the Saito AGD stage [6] (the distribution of argy-rophilic grains in the cerebrum) assessed using the Gallyas method, are available. Then, 24 cases having progressive supranuclear palsy, corticobasal degen-eration, Pick’s disease, globular glial tauopathies, post-encephalitic parkinsonism, and myotonic dys-trophy were excluded because distinct tau-positive astrocytic lesions were noted. Finally, 239 cases were included in the present study. In all of these cases, GFAs were semiquantitatively assessed in the frontal cortex, caudate nucleus, putamen, and amygdala on AT8-stained sections, using the follow-ing grading system (GFA stage): stage 0, no lesion in the anatomical region (i.e., the superior frontal gy-rus, caudate nucleus, putamen, and amygdala); stage 1, more than one lesion in the anatomical re-gion but less than one lesion per ×200 visual field; stage 2, one lesion per ×200 visual field; or stage 3, two or more lesions per ×200 visual field. Among the 239 cases, 112 had at least one GFA in the amygdala, while 127 lacked amygdala GFAs (amygdala GFA stage 0) (Table 1). The age at death was significantly higher in the amygdala GFA stage 1, 2, and 3 groups than in the amygdala GFA stage 0 group (p<0.001, 0.0025, and 0.0023, Kruskal-Wallis and Steel-Dwass tests). However, the sex ratio, brain weight, Braak stage, Thal phase, proportions of Lewy body disease (LBD) pathological subtypes, and pro-portions of TAR DNA-binding protein 43 (TDP-43) proteinopathy pathological subtypes did not signifi-cantly differ between the four amygdala GFA stage groups. AGD was noted only when a case had at least one GFA in the amygdala; that is, there was no case that lacked amygdala GFAs but had AGD (Figure 1A). On the other hand, cases having amygdala GFAs did not always have AGD: of all 112 cases having amyg-dala GFAs, 40 cases (35.7%) had argyrophilic grains in the amygdala (Figure 1A). The frequency of cases with AGD increased parallel to the amygdala GFA stage: 18.7% in GFA stage 1, 61.5% in GFA stage 2, and 75.0% in GFA stage 3 groups (Figure 1B). The Saito AGD stage was significantly correlated with the amygdala GFA stage (ρ=0.5878, p<0.001, Spearman rank-order correlation test). The binomial logistic re-gression analysis was used to evaluate whether the age at death, Braak stage, Thal phase, frontal lobe GFA stage, caudate nucleus GFA stage, putamen GFA stage, or amygdala GFA stage could be used as possible predictors of the development of AGD, and it demonstrated that the amygdala GFA stage (the standardized partial regression coefficient (β), 1.79; odds ratio, 6.63; 95% confidence interval (CI), 3.57–12.32; p<0.001), the age at death (β, 1.34; odds ra-tio, 1.09; 95% CI, 1.02–1.16; p<0.001), the frontal lobe GFA stage (β, 0.62; odds ratio, 3.47; 95% CI, 1.06–11.33; p=0.0391), and the putamen GFA stage (β, 0.64; odds ratio, 3.10; 95% CI, 1.005–9.56; p=0.0490) were significant independent predictors of the occurrence of argyrophilic grains. As previously reported [3,4], GFAs with tau-positive astrocytic endfeet were often in contact with blood vessel walls on AT8-immunostained sec-tions of the amygdala (Figures 1C-1E). In addition, a small number of AT8-positive argyrophilic grains were often scattered around the GFAs (Figures 1C-1E). Although GFAs are not stained by the Gallyas method, a potential association between argy-rophilic grains and vessels was also noted on Gal-lyas-stained sections: a few argyrophilic grains are scattered at a distance around vessels (Figures 1F-1H). Likewise, double staining with the Gallyas method and AT8 immunohistochemistry showed the proximity of argyrophilic grains, GFAs, and blood vessels (Figures 1I-1K). Noteworthy, these phenom-ena could be observed only in regions where argy-rophilic grains were relatively scarce rather than abundant. The findings presented here support the notion that amygdala GFAs may develop prior to the for-mation of argyrophilic grains in the amygdala [5] and suggest that amygdala GFAs may play some role in the occurrence of argyrophilic grains, which are preferably formed in the dendrospinal portion of neurons [7]. These findings also suggest that at least some cases having amygdala GFAs but lacking argy-rophilic grains may be in the earliest ‘pre-grain’  Free Neuropathology 3:18 (2022) Yokota et al doi: https://doi.org/10.17879/freeneuropathology-2022-4285 page 4 of 5     Table 1. Demographic data in all subjects stratified by severity of GFAs  GFA: granular fuzzy astrocyte, AGD: argyrophilic grain disease, N: number of cases, NFT: neurofibrillary tangles, LBD: Lewy body disease, LATE-NC: Limbic-predominant age-related TDP-43 encephalopathy neuropathological change, ALS-TDP: amyotrophic lateral sclerosis with TDP-43-positive inclusions, FTLD-TDP: frontotemporal lobar degeneration with TDP-43-positive inclusions.Free Neuropathology 3:18 (2022) Yokota et al doi: https://doi.org/10.17879/freeneuropathology-2022-4285 page 5 of 5    stage in the pathological process of AGD (Supple-mentary file 2). Whether amygdala GFAs affect cog-nitive function and psychiatric status, especially in elderly people, also needs to be explored. Finally, Table 1 shows that some cases had GFAs in the frontal cortex, caudate nucleus, and/or putamen even when the case lacked amygdala GFAs and argyrophilic grains (amygdala GFA stage 0). Based on our previously reported findings [3], this fronto-striatal-predominant distribution pattern of GFAs led us to consider the possibility that the case has an early pathological process of progressive su-pranuclear palsy (PSP). For a better understanding of the relationship between argyrophilic grains, GFAs, subcortical neuronal tau accumulation, and PSP as the pathological disease entity, the sequence of the appearance of these lesions and pathological conditions needs to be further examined. Declarations Ethics approval Autopsy was carried out after written informed consent was obtained from family members, and all experiments in this study were approved by the eth-ical committees of the Okayama University Gradu-ate School of Medicine, Dentistry and Pharmaceuti-cal Sciences, National Hospital Organization Minami-Okayama Medical Center, Niigata Univer-sity, and Zikei Hospital. Competing interests OY is an editorial board member but was not involved in the editorial handling of this manuscript. The other authors declare that they have no con-flicts of interest. Funding This work was supported by grants from the Strategic Research Program for Brain Sciences from the Japan Agency for Medical Research and Devel-opment (AMED, JP22wm0425019, JP22dk020704) and grants from the Zikei Institute of Psychiatry. Authors’ contributions OY, TM, ShT, and SeT macroscopically and his-topathologically assessed all subjects; CI, HI, and TH conducted the autopsies; NH, AM, and TI adminis-tered the brain bank; OY and TM drafted the manu-script. All authors reviewed the manuscript. Acknowledgements We thank Ms. Y. Matsuo for her technical assis-tance. References1. Botez G, Probst A, Ipsen S, et al.: Astrocytes expressing hyperphosphorylated tau protein without glial fibrillary tangles in argyrophilic grain disease. Acta Neuropathol 1999;98:251-6. https://doi.org/10.1007/s004010051077. 2. Kovacs GG, Ferrer I, Grinberg LT, et al.: Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy. Acta Neuropathol 2016;131:87–102. https://doi.org/10.1007/s00401-015-1509-x. 3. Miki T, Yokota O, Haraguchi T, et al.: Factors associated with development and distribution of granular/fuzzy astrocytes in neurodegenerative diseases. Brain Pathol 2020;30:811-830. https://doi.org/10.1111/bpa.12843. 4. Ikeda C, Yokota O, Nagao S, et al.: The relationship between development of neuronal and astrocytic tau pathologies in subcortical nuclei and progression of argyrophilic grain disease. Brain Pathol 2016;26:488-505. https://doi.org/10.1111/bpa.12319. 5. Kovacs GG, Xie SX, Robinson JL, et al.: Sequential stages and distribution patterns of aging-related tau astrogliopathy (ARTAG) in the human brain. Acta Neuropathol Commun 2018;6:50. https://doi.org/10.1186/s40478-018-0552-y. 6. Saito Y, Ruberu NN, Sawabe M, et al.: Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol 2004;63:911-918. https://doi.org/10.1093/jnen/63.9.911. 7. Ikeda K, Akiyama H, Kondo H, et al.: A study of dementia with argyrophilic grains. Possible cytoskeletal abnormality in dendrospinal portion of neurons and oligodendroglia. Acta Neuropathol 1995;89:409-414. https://doi.org/10.1007/BF00307644.    

Amygdala granular fuzzy astrocytes as lesions preceding development of argyrophilic grains: data from 239 autopsy cases

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Amygdala granular fuzzy astrocytes as lesions preceding development of argyrophilic grains: data from 239 autopsy cases

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