Corpora amylacea in human hippocampal brain tissue are intracellular bodies that exhibit a homogeneous distribution of neo-epitopes
Authors: Martin Krueger
N√∫ria Llor
Jordi Vilaplana
Ingo Bechmann
Elisabet Aug√©
Carme Pelegr√≠
Journal: Scientific Reports (2019)
Discipline: Multidisciplinary
Keywords: corpora amylacea; neo-epitopes; natural IgMs; ultrastructural study; confocal microscopy
Affiliations: Secci√≥ de Fisiologia, Departament de Bioqu√≠mica i Fisiologia, Universitat de Barcelona, Barcelona, Spain., Institut de Neuroci√®ncies, Universitat de Barcelona, Barcelona, Spain., Institute for Anatomy, University of Leipzig, Leipzig, Germany., Secci√≥ de Qu√≠mica Terap√®utica, Departament de Farmacologia, Toxicologia i Qu√≠mica Terap√®utica, Universitat de Barcelona, Barcelona, Spain., Centros de Biomedicina en Red de Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain., Institute for Anatomy, University of Leipzig, Leipzig, Germany. ., Secci√≥ de Fisiologia, Departament de Bioqu√≠mica i Fisiologia, Universitat de Barcelona, Barcelona, Spain. ., Institut de Neuroci√®ncies, Universitat de Barcelona, Barcelona, Spain. ., Centros de Biomedicina en Red de Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. .

Abstract:  Corpora amylacea are spherical bodies of unknown origin and function, which accumulate in the human brain during the aging process and neurodegenerative disorders. In recent work, we reported that they contain some neo-epitopes that are recognized by natural IgMs, revealing a possible link between them and the natural immune system. Here, we performed an ultrastructural study complemented with confocal microscopy in order to shed light on the formation of corpora amylacea and to precisely localize the neo-epitopes. We show that immature corpora amylacea are intracellular astrocytic structures formed by profuse cellular debris and membranous blebs entrapped in a scattered mass of randomly oriented short linear fibers. In mature corpora amylacea, the structure becomes compacted and fibrillary material constitutes the principal component. We also determined that the neo-epitopes were uniformly localized throughout the whole structure. All these observations reinforce the idea that corpora amylacea of human brain are equivalent to another type of polyglucosan bodies named PAS granules, present in mouse brain and originated from degenerative processes. All those findings support the hypothesis that corpora amylacea are involved in the entrapment of damaged materials and non-degradable products and have a role in protective or cleaning mechanisms. 

Retracted: No

PubPeer comments:
 Gherardi and Authier published their series of patients with macrophagic myofasciitis in Lupus (2012; 21: 184-189). This series corresponds to 457 adults presenting such a condition. It is surprising to note that median age was 45 years with ranges from 12 to 83. Patients that were 12-year-old are included even if they are not adults. The authors studied 12 items (sex ratio, middle age at time of muscle biopsy, number of alum-containing vaccine before biopsy, percentage of patient vaccinated against HBV, percentage of patients with chronic diffuse myalgia, percentage of patients with disabling chronic fatigue, percentage of patients with cognitive alterations, percentage of patients with dyspnea, median time elapsed from last vaccine administration and initial systemic symptoms, median time elapsed from last vaccine administration and first myalgia, time elapsed from last vaccine administration to biopsy and percentage of auto-immune diseases). This series helps the authors to delineate the clinical syndrome associated with macrophagic myofasciitis. Two years later, Gheradi, Authier and Cadusseau actualized their series in Bull Acad Natl Med (2014; 198: 37-48). This new series involves 583 cases (adding 126 new cases). I am very surprised to read that the results were strictly identical (except for the percentage of patients receiving vaccine agains HBV which rises from 85% to 89.7%). All the other 11 items were strictly identical. It is unlikely that all these items are exactly the same analyzing 457 cases first and then 583 cases. Anyway, I would be very interested if the authors could comment on these results and confirm that they observed exactly the same results for these 11 items in their two series. , 
 I have not been able to find a link for the French paper,  Biopersistence and systemic distribution of intramuscularly injected particles: What impact on long-term tolerability of alum adjuvants? (Bull Acad Natl Med 2014; 198: 37-48). If it does exist in an electronic, accessible form, a link would be gratefully received. Alternatively, surely it would come under the rubric of Allowable Use, if you could copy the relevant paragraph. There is a 2015 Frontiers paper by Gherardi et al. --  Biopersistence and brain translocation of aluminum adjuvants of vaccines . https: www.frontiersin.org articles 10.3389 fneur.2015.00004 full It mentions the 583 cases, but only specifies a couple of relevant details. *In a recent evaluation of 583 patients collected from 1994 to 2012 (45), the median time elapsed between the last alum administration and the biopsy was 65 months. Compared to our previous reports, this time had gradually increased from 36 months in 2001, i.e., shortly after the peak of French adult immunization, to 53 months in 2003 (46). An average number of 5.3 alum-containing shots had been administered during the 10 years prior to biopsy detecting MMF, mainly corresponding to vaccinations against hepatitis B (89.7%), tetanus (42.2%), and hepatitis A (8.8%).* , 
 The article from the Bulletin de l academia de medecine is available at: www.academie-medecine.fr wp-content uploads 2015 06 pages-37-54.pdf The article is published in French , 
 I think this is the article: https: www.researchgate.net publication 280908353_Biopersistence_and_systemic_distribution_of_intramuscularly_injected_particles_What_impact_on_long-term_tolerability_of_alum_adjuvants?ev=auth_pub It s in French, so you may not have had much luck because you were searching for the English translation of the title. I can t find any free access to the article, but you can always request it from the authors. , 
 #3 Thanks!  La plupart des patients sont des femmes (70 %) du2019u00e2ge moyen au moment de la biopsie (mu00e9diane 45 ans, extru00eames 12-83). Ils avaient reu00e7u 1 u00e0 17 administrations i.m. de vaccin contenant de lu2019aluminium (moyenne 5,3) dans les dix ans avant la du00e9tection de la MFM, et ceux-ci incluaient des vaccinations **anti-VHB dans 89,7 %** des cas, **anti-tu00e9tanique dans 67,9 %** des cas, et **anti-VHA dans 14,1 %** des cas. Please contrast with the values reported for the same 583 sample in the Frontiers paper: hepatitis B (89.7%), tetanus (42.2%), and hepatitis A (8.8%). , 
 Thanks Chromis Vanderbilt #1 #3 Indeed the two populations reported are very similar I construct a table just to highlight this  The total number of patients is different (green arrow) whereas all the data are strictly the same (except for the percentage of HBV vaccination : red arrow). Since there is no response of the authors, one may imagine that the results have been manipulated. The two papers should be retracted , 
 #6 *Since there is no response of the authors,* A response from authors is pleasant but we should not demand it as an entitlement. The notification from PubPeer may have been blocked, or filtered out as spam. If the authors received notification, they are under no obligation to respond. Your table might benefit further from the addition of values from the Frontiers paper, as another column. https: www.frontiersin.org articles 10.3389 fneur.2015.00004 full , 
 Thanks Hoya Camphorifolia #7 In fact the Frontiers paper you referred is confusing. The authors presented the results for a series of 583 cases. In fact, they referred to their own work published by Cadusseau et al. (Curr Med Chem 2014; 21: 511-517). In this paper, the reference population is indeed 583 cases but they extract 105  consecutive unselected cases. The analysis they reported corresponds to these sole 105 cases. Here are the results: - ages: 12-64 years - median time elapsed between the last alum-containing vaccine and biopsy: 6.5 years - immunization against HBV 89.7%, tetanus toxoid 67.9%, HAV 14.1% - arthromyalgias: 96 105 (91.4%) - fatigue: 88 105 (83.8%) - cognitive alterations: 102 105 (97.1%) I don t know if both the Lupus paper and the paper published by the French Academie of Medicine also involve restricted populations within their whole populations. Anyway, the mode of presentation is highly confusing. , 
 #8 Thanks! *Cadusseau et al. (Curr Med Chem 2014; 21: 511-517)* -- a paywalled Bentham journal, alas; not one that many institutions would subscribe to. If I am following your explanation correctly, Cadusseau et al. select and report results for 105 cases, those results then being repeated in the *Frontiers* paper as descriptive of the entire group of 583 cases? Those summary statistics agreeing in some details with those cited in the present Lupus paper, and in the *Bulletin* report, while disagreeing in others? As you say, this is highly confusing. , 
 The authors wrote:  In practice we consider MMF to be so when the time elapsed from last vaccine shot to MMF detection is 18 months. Unfortunately, they described a series of 457 patents in which  Time elapsed from last vaccine administration to biopsy was 65 months (range 3-219). The question is: how many patients should the authors excluded for fitting with their inclusion criteria? After excluding these patients, they should propose new percentages for the descriptive series. Furthermore, their percentages seem to be problematic: diffuse myalgia are reported in 89% of 457 patients (corresponding to 406.73 patients), chronique fatigue is present in 77% of 457 patients (corresponding to 351.89 patients), cognitive deficits in 51% (233.07 patients) and dyspnea in 50% (228.5 patients). These percentages and their correspondance suggest that the percentages were not calculated for the whole population. The authors should precise this specific point. At last, the authors wrote (about risk of chance association):  the risk also exists in adults but accounts for no more than 5-10% of MMF+ biopsies, including fully asymptomatic patients and patients investigated for hereditary disorders. How was calculated such a risk? , 
 #8  The analysis they reported corresponds to these sole 105 cases. Here are the results: ages: 12-64 years median time elapsed between the last alum-containing vaccine and biopsy: 6.5 years immunization against HBV **89.7%**, tetanus toxoid **67.9%**, HAV **14.1%** arthromyalgias: 96 105 (91.4%) fatigue: 88 105 (83.8%) cognitive alterations: 102 105 (97.1%) Some of these numbers do not work as fractions of 105 (or of 457). 94 105 = **89.5%**. 61 105 = **67.6%**. 15 105 = **14.3%**. There seem to have been many errors of transcription, or else other calculations are involved. , 
 #8  In this paper, the reference population is indeed 583 cases but they extract 105  consecutive unselected cases. The analysis they reported corresponds to these sole 105 cases. Here are the results: The most parsimonious explanation, then, is that the papers here; in [Bull Acad Natl Med 2014](http: www.academie-medecine.fr wp-content uploads 2015 06 pages-37-54.pdf); in [Frontiers 2015] ; in [Gherardi, Cadusseau Authier 2015] (duplicate publication of Frontiers 2015 as a book chapter); and in [Curr Med Chem 2014] , for either 457 or 583 cases, are all in fact repeating the **same results** for 105 consecutive cases. Hence all the values they share in common, but also with occasional errors of transcription (85% vs. 89.7%) and possibly missing data in some cases (when percentages are not compatible with 105).  , 
 I made a new table. Clearly I have too much spare time.  Here a yellow background indicates an explicit citation to Gherardi Authier (2003),  Aluminum inclusion macrophagic myofasciitis: a recently identified condition , as the source of a value, while a blue background indicates an explicit citation to the 105 cases in Cadusseau c (2014), Curr.Med.Chem. The different sources explain some but not all of the discrepancies. Yes, the 2015 book chapter cites Cadusseau et al. (2013) (rather than the present paper) as the source for some values that are not provided anywhere in Cadusseau et al.; this makes no sense but it is not my fault.  , 
 Hoya Camphorifolia (#13) thank you for this interesting table that suggests some  irregularities in authors results. It s also interesting to note that the author wrote in their Lupus paper (2012):  As previously reported, onset of these clinical symptoms was always posterior to, and delayed from, immunization. However, in their Brain paper (2001):  Thus in 4% of their cases, myalgia begin before immunization. This is also the case for their paper (Immunol Allergy Clin N Am 2003;23:699-712): - Myalgia: 88% - New onset (subsequent to vaccination) : 94% (I guess it is 94% of the myalgic patients). - Median delay from vaccination to myalgias: 11 months (range 0-72) For me, 0 month after vaccination is not delayed from immunization. What are the true results? ,