Here we provide a SOP to outline the correct procedures for performing Immunohistochemistry (IHC) to detect pathological TDP-43 in FFPE-preserved human tissue using the TDP-43 RNA Aptamer, as described in Spence and Waldron et al., 2024 published in Acta Neuropathologica (DOI: 10.1007/s00401-024-02705-1). Users with access to Sequenza immunostaining racks and histological facilities (with fume hood) should be able to carry out all steps over two days. This protocol uses the TDP-43APT sequence published in Zacco et al., 2022. The sequence is: CGGUGUUGCU with a 3' Biotin-TEG modification, purified using HPLC, scale: 1.0 µM synthesis. References for citation of this method Please cite both of these below if using this method: The citation, Spence and Waldron et al., 2024, for the first publication for the development, modification and employment of theTDP-43 RNA aptamer to stain human tissue published in Acta Neuropathologica. RNA aptamer reveals nuclear TDP-43 pathology is an early aggregation event that coincides with STMN-2 cryptic splicing and precedes clinical manifestation in ALS. Holly Spence*, Fergal M. Waldron*, Rebecca S. Saleeb, Anna-Leigh Brown, Olivia M. Rifai, Martina Gilodi, Fiona Read, Kristine, Roberts, Gillian Milne, Debbie Wilkinson, Judi O’Shaughnessy, Annalisa Pastore, Pietro Fratta, Neil Shneider, Gian Gaetano Tartaglia, Elsa Zacco, Mathew H. Horrocks, Jenna M. Gregory‡. Acta Neuropathologica 2024 Mar 5;147(1):50. DOI: 10.1007/s00401-024-02705-1. *equal contributions, ‡corresponding author. The citation, Waldron and Spence et al., 2024, for this SOP published on protocols.io is: TDP-43 RNA aptamer staining to detect pathological TDP-43 in FFPE human tissue, as described in Spence and Waldron et al., 2024 (Acta Neuropathologica): A SOP and tick-sheet. v2. Fergal M. Waldron*, Holly Spence*, Jenna M. Gregory‡. protocols.io 2024; DOI: dx.doi.org/10.17504/protocols.io.eq2lyjo4mlx9/v2. *equal contributions, ‡corresponding author.
As an author, there is almost nothing in the publication business that bothers me more than that of the delayed editorial decisions. I often felt annoyed or I despaired when a journal did not respond for 4 or 6 months after I had submitted a paper. I felt that editors and referees should recall that a scientific paper is not only the final result of hard work, but is kind of a baby with some of the corresponding emotional implications, and that careless treatment by a journal represents an offence towards authors. In fact, one major reason why I became an editor was my own negative experience with tardy journals. I am therefore happy in this regard that the Acta Neuropathologica perform better than most other journals. During the past 3 years, the time from submission to first decision has been around 17 days for original submissions, and between 2 and 8 days for revised versions (Table 1). It has been encouraging to learn from authors that our fast turnaround time has been noticed increasingly and has been much appreciated. Because data on decision times are usually not published and thus not generally available, there is not much pressure on editors to become faster. If rankings of editorial speed were published (like impact factors), effort and efficiency of many journals would certainly increase and the service to authors would improve. Since most journals use similar or identical online submission systems where metadata can easily be retrieved, a transparent comparison of decision times is feasible. Table 1 Mean time from submission to decision (days) The major reason for our fast decision time is the dedication and hard work of our referees. In 2007, they submitted reviews within a mean time of 11 days after agreeing to review. This accomplishment is related to careful selection of referees. The first experts who come to mind after reading a submission are often not the most efficient referees. For each manuscript, I perform a PubMed search and then I screen websites of institutions to identify colleagues who might have the greatest interest in this paper. Indicators that correlate with excellent review performance include previous review activities for Acta (frequencies of accept vs. decline to review, speed and quality of reviews) and academic position (Chairmen tend to be overcommitted), among others. Some simple measures can considerably reduce review times, such as verification of e-mail addresses via websites, and a tight first response time (for accept or decline to review) of 3 days. A remarkable 64% of invited referees have accepted to deliver within 14 days, while the remaining 36% declined or did not respond. In addition to external referees, the Editorial Board of the Acta consists of particularly dedicated experts who are willing to review up to 12 papers per year, each of them within 14 days. Editorial Board members are also expected to review occasional papers lying somewhat outside of their own area of research, but for which no other suitable external referees could be identified within a week or so. Furthermore, we are pertinacious in reminding late referees. If several reminders for 10 days have not been successful, we usually contact the referee by telephone. If we do not expect the review soon, we terminate this review, which has been necessary in only four cases in 2007. The longest time in 2007 for receiving a review was 39 days. I am always much impressed about the high motivation and enthusiasm of our referees. Additional reasons of fast decision include short times from submission to editor assignment (0.2 days), and from editor assignment to reviewer invitation (0.5 days); a simple structure of the Editorial Board without multiple levels of decision; and instantaneous beginning of checking for formal accuracy (format of references, resolution of figures, etc.) in parallel to the initiation of the review process so that no delay is introduced. Interestingly, the time to decision may even be too fast for some authors. In 2007, 15% of manuscripts submitted to Acta Neuropathologica were rejected without consulting referees, for example, because they lacked novelty or because the subject was unrelated to neuropathology. This negative decision can often be made on the day of submission. Usually, the act of submitting a manuscript is the final outcome of laborious scientific work, writing and formatting, and provides authors with a good deal of relief and satisfaction. A negative decision within 2 h impairs this good feeling (especially if the author is still online). Furthermore, I have received letters from authors stating that ultrafast decisions are unfair, because a manuscript cannot be evaluated carefully enough. On the other hand, it seems fair to both authors and referees to reject an unacceptable paper straightaway. Authors would like to receive not only speedy reviews but also fair and careful reviews. The question is, therefore, whether speed and quality of reviews are related. Because in this journal all reviews are rated from 0 (worst) to 100 (best), we plotted speed versus quality. As reflected in Fig. 1, there is no indication that review time is related to the quality of a review. Fig. 1 Review quality score, shown as mean ± SD, is not related to time of review (based on a total of 680 reviews performed in 2007) I should also mention that the Acta are fast in other respects as well. Springer Publishers have organized production such that the time between acceptance and sending out proofs is only a few days, and the time between acceptance and online publication is about 2 weeks. Accordingly, online publication is possible within 30 days following the submission. An example is the study by Neumann et al. on TDP-43 (Acta Neuropathol 113: 543–548, 2007) for which the interval between submission and first decision was 12 days, for revision by the authors was 1 day, for resubmission to final decision was 0 days, and from final acceptance to publication in PubMed was 17 days. To summarize, making speedy and careful decisions is quite easy for an editor, but only with the support of dedicated referees, with an enthusiastic Editorial Board and with an efficient editorial office. We are aware that speed of editorial decision is just one, but an important indicator of journal quality. We are working hard to maintain and improve all aspects of quality to make Acta Neuropathologica an even better journal. Please let me know if you have any ideas and suggestions or if you would like to contribute.
About 20 years ago I considered where to submit my first neuropathology paper, a case report, and concluded that Acta Neuropathologica the appropriate journal. I therefore should be red-faced when admitting that it was only a few years ago (I was already an Editor of this journal) when I realized that “Acta” is not singular, but it represents the plural form of the Latin word actum, meaning file. Acta Neuropathologica stands for something like “Roman Files of Neuropathology”. In my defence, I could only say that the Latin word acta does indeed exist and means beach, so that at a time when searching PubMed and submitting papers can be done online and through wireless on the beach, the singular form would be up-to-date. On the other hand, I suggest that the founding editors of this journal could have intended the plural meaning and this is reflected in the title of my editorial.
An error occurred during the publication of a number of articles in Acta Neuropathologica Communications. Several articles were published in volume 7 with a duplicate citation number.
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including electron microscopy, histochemistry, biochemistry, cell culture, and neurophysiology.Seitelberger's idea was to create an international, interdisciplinary journal covering all available techniques and approaches in the wide field of neuroscience, resembling Heinrich Obersteiner's idea of the ''International Brain Commission'' as precursor of the International Brain Research
Hoffmann L, Coras R, Kobow K, et al. Correction to: Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes. <em>Acta Neuropathologica</em>. 2023.
Fragile X [fraX] syndrome is a common hereditary disorder associated with a fragile site marker at Xq27.3 which clinically presents as a form of mental retardation (MR). Postmortem investigation of 3 fraX positive males with mild to moderate MR did not document any gross neuropathological changes. Golgi analysis of neocortical dendritic spine morphology extended our previous observations of immature, long, tortuous spines in one adult case of fraX (Rudelli, et al., Acta Neuropathologica 67:289-295, 1985) to 2 new cases. Evidence for similar dendritic spine abnormalities was found, although Golgi analysis was less than optimal because of incomplete dendritic stain impregnation. Neocortical intra-layer cell density was also investigated in all 3 cases. Cresyl violet stained neurons were counted in 10 randomly selected fields in neocortical layers II-VI of cingulate and temporal association areas (Brodmann's areas 23 and 38). Neuron counts in fraX and control neocortex showed no significant differences. Thus, abnormal dendritic spine morphology with preservation of neuronal density appears to characterize the neocortex in individuals with this common form of mental retardation.
The Wnt/β-catenin pathway comprises a family of proteins that play critical roles in embryonic development and adult tissue homeostasis. The deregulation of Wnt/β-catenin signalling often leads to various serious diseases, including cancer and non-cancer diseases. Although many articles have reviewed Wnt/β-catenin from various aspects, a systematic review encompassing the origin, composition, function, and clinical trials of the Wnt/β-catenin signalling pathway in tumour and diseases is lacking. In this article, we comprehensively review the Wnt/β-catenin pathway from the above five aspects in combination with the latest research. Finally, we propose challenges and opportunities for the development of small-molecular compounds targeting the Wnt signalling pathway in disease treatment.
The blood-brain barrier (BBB) is vital for maintaining brain homeostasis by enabling an exquisite control of exchange of compounds between the blood and the brain parenchyma. Moreover, the BBB prevents unwanted toxins and pathogens from entering the brain. This barrier, however, breaks down with age and further disruption is a hallmark of many age-related disorders. Several drugs have been explored, thus far, to protect or restore BBB function. With the recent connection between the BBB and gut microbiota, microbial-derived metabolites have been explored for their capabilities to protect and restore BBB physiology. This review, will focus on the vital components that make up the BBB, dissect levels of disruption of the barrier, and discuss current drugs and therapeutics that maintain barrier integrity and the recent discoveries of effects microbial-derived metabolites have on BBB physiology.
BACKGROUND: Recent autopsy data suggests a high incidence of leptomeningeal metastases (LM), Acta Neuropathologica 2014; 128: 573 and subventricular spread (SVS), Acta Neuropathologica 2014; 127: 605 in pediatric diffuse intrinsic pontine gliomas, but both LM and SVS also occur in adult glioblastoma (GBM). Autopsy is required to fully appreciate this tumor behavior. METHODS: From January 1, 2014 to January 3, 2015 we conducted 239 adult autopsies, 8 of which were identified on search to be GBMs. RESULTS: Of these 8 GBMs, one-half showed bulky spread (SVS (n = 2), LM (n = 2), bone marrow (n = 1)), and 2 of these 4 additionally had microscopic LM. In patient 1 GBM with a very minor epithelioid component on the surgical specimen spread evolved to a predominantly epithelioid GBM (E-GBM) phenotype in the clinically-unsuspected LM at autopsy. Patient 2, with malignant glioma with primitive neuroectodermal tumor (MGPNET), had a secondary GBM with a noncanonical isocitrate dehydrogenase 1 (IDH1) mutation and 11-year-survival; autopsy showed encasement of the entire bilateral ventricular system by SVS. Patient 3, also with an IDH1- positive secondary GBM, had survived 10 years, only to develop thrombocytopenia and succumb to extensive bone marrow replacement by his tumor. Patient 4 had a radiation-induced posterior fossa GBM that demonstrated LM/SVS spread pattern identical to that described in pediatric diffuse pontine gliomas. CONCLUSIONS: Several subtypes of adult GBM (MG-PNET, posterior fossa GBMs, E-GBMs) have recently been recognized to have a propensity for LM; autopsy permission should especially be sought for these tumor types. Correlation between genetics and LM/SVS is now possible and may shed further light on this behavior.
iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.
Parkinson's disease prevalence is rapidly increasing in an aging global population. With this increase comes exponentially rising social and economic costs, emphasizing the immediate need for effective disease-modifying treatments. Motor dysfunction results from the loss of dopaminergic neurons in the substantia nigra pars compacta and depletion of dopamine in the nigrostriatal pathway. While a specific biochemical mechanism remains elusive, oxidative stress plays an undeniable role in a complex and progressive neurodegenerative cascade. This review will explore the molecular factors that contribute to the high steady-state of oxidative stress in the healthy substantia nigra during aging, and how this chemical environment renders neurons susceptible to oxidative damage in Parkinson's disease. Contributing factors to oxidative stress during aging and as a pathogenic mechanism for Parkinson's disease will be discussed within the context of how and why therapeutic approaches targeting cellular redox activity in this disorder have, to date, yielded little therapeutic benefit. We present a contemporary perspective on the central biochemical contribution of redox imbalance to Parkinson's disease etiology and argue that improving our ability to accurately measure oxidative stress, dopaminergic neurotransmission and cell death pathways in vivo is crucial for both the development of new therapies and the identification of novel disease biomarkers.
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Parkinson's disease is a progressive neuropathological disorder that belongs to the class of synucleinopathies, in which the protein alpha-synuclein is found at abnormally high concentrations in affected neurons. Its hallmark are intracellular inclusions called Lewy bodies and Lewy neurites. We here report the structure of cytotoxic alpha-synuclein fibrils (residues 1-121), determined by cryo-electron microscopy at a resolution of 3.4 Å. Two protofilaments form a polar fibril composed of staggered β-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50-57, containing three of the mutation sites associated with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft at one end of the fibril may have implications for fibril elongation, and invites for the design of molecules for diagnosis and treatment of synucleinopathies.