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The kinetics of amyloid plaque formation and growth as one of the characteristic hallmarks of Alzheimer’s disease (AD) are fundamental issues in AD research. Especially the question how fast amyloid plaques grow to their final size after they are born remains controversial. By long-term two-photon in vivo imaging we monitored individual methoxy-X04-stained amyloid plaques over 6 weeks in 12 and 18 months old Tg2576 mice. We found that in 12 months old mice, newly appearing amyloid plaques were initially small in volume and subsequently grew over time. The growth rate of plaques was inversely proportional to their volume; thus amyloid plaques that were already present at the first imaging time point grew over time but slower compared to new plaques. Additionally, we analyzed 18 months old Tg2576 mice in which we neither found newly appearing plaques nor a significant growth of pre-existing plaques over 6 weeks of imaging. In conclusion, newly appearing amyloid plaques are initially small in size but grow over time until plaque growth can not be detected anymore in aged mice. These results suggest that drugs that target plaque formation should be most effective early in the disease, when plaques are growing. Electronic supplementary material The online version of this article (doi:10.1007/s00401-010-0787-6) contains supplementary material, which is available to authorized users.

Autism is characterized by a broad spectrum of clinical manifestations including qualitative impairments in social interactions and communication, and repetitive and stereotyped patterns of behavior. Abnormal acceleration of brain growth in early childhood, signs of slower growth of neurons, and minicolumn developmental abnormalities suggest multiregional alterations. The aim of this study was to detect the patterns of focal qualitative developmental defects and to identify brain regions that are prone to developmental alterations in autism. Formalin-fixed brain hemispheres of 13 autistic (4-60 years of age) and 14 age-matched control subjects were embedded in celloidin and cut into 200-mum-thick coronal sections, which were stained with cresyl violet and used for neuropathological evaluation. Thickening of the subependymal cell layer in two brains and subependymal nodular dysplasia in one brain is indicative of active neurogenesis in two autistic children. Subcortical, periventricular, hippocampal and cerebellar heterotopias detected in the brains of four autistic subjects (31%) reflect abnormal neuronal migration. Multifocal cerebral dysplasia resulted in local distortion of the cytoarchitecture of the neocortex in four brains (31%), of the entorhinal cortex in two brains (15%), of the cornu Ammonis in four brains and of the dentate gyrus in two brains. Cerebellar flocculonodular dysplasia detected in six subjects (46%), focal dysplasia in the vermis in one case, and hypoplasia in one subject indicate local failure of cerebellar development in 62% of autistic subjects. Detection of flocculonodular dysplasia in only one control subject and of a broad spectrum of focal qualitative neuropathological developmental changes in 12 of 13 examined brains of autistic subjects (92%) reflects multiregional dysregulation of neurogenesis, neuronal migration and maturation in autism, which may contribute to the heterogeneity of the clinical phenotype.

Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration : an update

Neuroimaging studies indicate reduced volumes of certain gray matter regions in survivors of prematurity with periventricular leukomalacia (PVL). We hypothesized that subacute and/or chronic gray matter lesions are increased in incidence and severity in PVL cases compared to non-PVL cases at autopsy. Forty-one cases of premature infants were divided based on cerebral white matter histol- ogy: PVL (n = 17) with cerebral white matter gliosis and focal periventricular necrosis; diVuse white matter gliosis (DWMG) (n = 17) without necrosis; and " Negative" group (n = 7) with no abnormalities. Neuronal loss was found almost exclusively in PVL, with signiW- cantly increased incidence and severity in the thalamus (38%), globus pallidus (33%), and cerebellar dentate nucleus (29%) compared to DWMG cases. The incidence of gliosis was signiWcantly increased in PVL compared to DWMG cases in the deep gray nuclei (thalamus/basal ganglia; 50-60% of PVL cases), and basis pontis (100% of PVL cases). Thalamic and basal ganglionic lesions occur almost exclusively in infants with PVL. Gray matter lesions occur in a third or more of PVL cases suggesting that white matter injury generally does not occur in isolation, and that the term "perinatal panencephalopathy" may better describe the scope of the neuropathology.

Intracellular calcium (Ca2+) has been shown to function as second messenger and to be associated with activation of different cell types including microglia. Previously, in human focal cerebral infarctions an early expression of macrophage-related protein-8 (MRP8/ S100A8), a member of the Ca2+-binding S100-protein family, in microglia has been reported. On the other hand, a delayed activation of microglia was observed following traumatic brain injury (TBI). We therefore examined immunohistochemically microglial expression of MRP8 and allograft inflammatory factor-1 (AIF-1), identical to microglial response factor-1 (mrf-1) and ionized calcium binding adaptor molecule-1 (ibal) in human brains after TBI and in control brains. Both, MRP8 and AIF-1 are Ca2+-binding peptides which have been associated with microglial activation in experimental models and in human cerebral infarctions. Detection of AIF-1 in controls confirmed constitutive expression of this peptide in a subset of microglial cells. After TBI, the density of AIF-1+ microglia did not increase significantly. Lesional expression of AIF-1 did not significantly differ from other brain regions. Furthermore, following TBI, we found no significant differences in the density of AIF-1+ microglia as compared to controls. Microglial MRP8 expression was not detectable in controls and within the first 3 days post TBI, but increased rapidly after 3 days post TBI, suggesting a subpopulation of microglial cells to be AIF-1-/MRP8+. We conclude that the delayed expression of MRP8 and the lack of AIF-1 up-regulation in microglia after TBI is in contrast to ischemic brain lesions and might reflect different activation cascades of microglia.

About 20 years ago I considered where to submit my first neuropathology paper, a case report, and concluded that Acta Neuropathologica "is" 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.

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.