Am J Neurodegener Dis 2014;3(2):64-71 www.AJND.us /ISSN:2165-591X/AJND0001617

Original Article Greater loss of von Economo than loss of layer II and III neurons in behavioral variant

Alexander F Santillo1,2, Elisabet Englund3

1Clinical Memory Research Unit, Department of Clinical Medicine, 2Geriatric Psychiatry, Department of Clinical Medicine, 3Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden Received July 30, 2014; Accepted August 8, 2014; Epub September 6, 2014; Published September 15, 2014

Abstract: Previous studies have shown a selective reduction of von Economo neurons (VENs) in behavioral variant frontotemporal dementia (bvFTD). However, the alleged selectivity rests on the comparison between VENs and other neurons in cortical layer V, while it has been established that neurons in the superficial cortical layers (I-III) are particularly affected in bvFTD. The purpose of this study was to examine loss the loss of VENs in comparison with that of non-VEN-neurons of superficial cortical layers. VENs and non-VEN-neurons of cortical layer V and layers II+III were quantified in the anterior in 16 cases of bvFTD, 12 non-demented controls and 10 cases of Alzheimer’s disease (AD). In bvFTD VENs were more depleted than non-VEN-neurons of layers V and II+III. Also, non-VEN-neurons of layer II+III showed a greater density reduction than those of layer V in bvFTD. VEN density was also reduced in AD, albeit to a lesser extent than in bvFTD, and the differences between bvFTD and AD were only significant when relating VEN loss to that of layer V neurons. Our study strengthens the view of VENs as a particularly sensitive neuronal type of bvFTD, and appears to be on a continuum with the loss of other neurons both in bvFTD and between conditions.

Keywords: Frontotemporal dementia, frontotemporal lobar degeneration, von Economo neurons, anterior cingu- late cortex

Introduction not been unraveled, their distribution, receptor expression, ontogenetic and evolutionary devel- Behavioral variant frontotemporal dementia opment is indicative of higher emotional cogni- (bvFTD) is a neurodegenerative condition char- tive integration [3-5, 11]. Their location over- acterized clinically by progressive disturbance laps with that of the [12, 13], of behaviour, and language [1]. The a functional MRI resting state network that has cortical atrophy in early bvFTD involves the been shown to be disturbed in bvFTD [14, 15]. anterior cingulate (ACC) and frontoinsular (FI) cortex [2]. This pattern corresponds to the cor- In studies showing loss of VENs in bvFTD, VEN tical regions harboring von Economo neurons numbers have been compared to numbers of (VENs), the large bipolar projection neurons neighboring neurons in layer V [6-8] or across that are almost exclusively found in layer V of all cortical layers [9], indicating the VENs to be the ACC and FI [3] (for two recent reviews see selectively affected in the frontotemporal lobar [4, 5]). VENs have been shown to be selectively degeneration (FTLD) disease process (FTLD is affected in early bvFTD [6-9]. This finding may the term used for the neuropathological pro- explain the anatomical distribution of cortical cesses underlying the clinical syndrome- bv- atrophy in bvFTD, if VENs are the cellular start- FTD). However, from the early descriptions of ing point of the neurodegenerative process FTLD [16, 17] and more recent quantifications [10]. Alternatively, they could be a component [18, 19] it is clear that deeper cortical layers (V, of the cellular loss with important functional VI) are generally less affected by neuronal consequences. While the function of VENs has degeneration, gliosis and atrophy in FTLD, com- Cingulate VEN loss in FTD pared with the superficial, supragranular layers followed in a memory or neurological clinic, and (I-III). Thus the alleged selectivity of the loss of the clinical investigation included structural VENs has to be assessed with a parallel evalu- neuroimaging, cerebral blood flow examination ation of the loss of supragranular neurons. The and neuropsychological examination in most purpose of the current study was thus to exam- cases. It was not possible to retrospectively ine loss of VENs in relation to loss of neurons in determine the severity of dementia at death superficial cortical layers in bvFTD, compared from the clinical records, but symptom duration with Alzheimer’s disease (AD) and non-dement- in years was extracted. Non-demented controls ed controls (NDC). (NDC, n=12) and AD patients (n=10) were selected in order to match bvFTD cases with Material and methods respect to age and sex. NDC were required to neither to have a history of dementia nor to Selection of cases reveal any neuropathological signs of dement- ing disorder. Neuropathological diagnosis was Archival histopathological sections from cerebral ischemia (n=5), tumor (n=4), neurode- neuropathologically diagnosed FTLD in clinical- generative disease without cognitive deficits ly diagnosed bvFTD cases (n=16) were selected (n=2, Multiple System Atrophy, Cerebellar Ata- from the Department of Neuropathology in xia), or no pathological findings (n=1). AD cases Lund, with the primary morphologic evaluations had a neuropathological diagnosis of AD accor- being made during 1994-2012. The post-mor- ding to established criteria [20, 23]. Quantitative tem diagnosis of FTLD, including protein pathol- levels of VENs have been previously reported ogy FTLD subtype assessment (Tau, TAR DNA for 13 of the bvFTD cases, 10 of the controls binding protein 43-[TDP-43] or Fused in Sar- and all of the 10 AD patients [8]. The study was coma- [FUS]), was established at the routine approved by the Regional Ethical Review Board neuropathological examination, according to in Lund, Sweden (number 2010/229). standard procedures within the department [20] applying established international criteria Region sampling and area delineation for the micromorphology [21, 22]. For the pro- tein pathology subtype assessment, the follow- The methodology described was also previous- ing antibodies were used: AT-8 for tau (DAKO, ly used for quantifying VENs [8]. The area of Copenhagen), pTDP-43 (Cosmo Bio Ltd., Tokyo) interest (the right dorsal ACC) was identified on and FUS (Sigma-Aldrich LLS, St Louis, MO). whole brain coronal sections, sampled at a Neuropathological exclusion criteria were sig- level immediately posterior to the anterior tip of nificant concomitant AD pathology, defined as the genu of the corpus callosum (Figure 1A and Braak stage >III [23], or significant cerebrovas- 1B). The right hemisphere was chosen through- cular pathology (defined as any vascular-isch- out since VEN density shows some lateraliza- emic burden other than solitary microinfarcts). tion right over left [26]. The slices, 6 µm thick, Gross severity of atrophy was assessed using a one for each case, were stained with a double rating scale developed for FTD [24], grading staining for cell nuclei (Cresyl Violet/Nissl) and defined regional atrophy as stages 1 to 4 on (Luxol Fast Blue). The entire area of two coronal whole brain slices. For the present interest was scanned on a motorized light study, only cases with stages 1 or 2 were microscope at X200 enlargement (Olympus selected, as this was considered pertinent to BX53; Olympus Europe Group, Hamburg, Ger- assessing the issue of VEN selectivity in early many). On the digitalized images a subdivision cases. of the ACC into subarea BA24a, 24b and 24c was made, according to descriptions [27, 28] Clinical charts were reviewed, and only patients (Figure 1C). BA24b was chosen as the subarea with bvFTD as a first clinical syndrome accord- of interest, since this area has the highest VEN ing to Neary criteria [25] were accepted. Indi- density [3]. The cortical layers of interest (II+III viduals exhibiting concomitant ALS were includ- and V) were manually outlined on the digitalized ed, but not those progressing into syndromes images. For layer V (including Va and Vb) the such as progressive supranuclear paralysis, superficial definition was just over the inner corticobasal degeneration, or other parkinso- pyramidal layer and the basal delineation above nian disorder. The patients had previously been the emergence of layer VI. For layers II and III,

65 Am J Neurodegener Dis 2014;3(2):64-71 Cingulate VEN loss in FTD

Table 1. Demographic and clinical data of subjects. Values are the median with range n M/F age duration bvFTD 16 6/10 68.5 (34-82) 5 (1-11) AD 10 6/4 67.5 (57-76) 8 (3-14) NDC 12 5/7 63.5 (54-82) na

and II (Figure 1C). Cortical segments that showed irregularities in structure or were dam- aged, preventing layer delineation, were omit- ted. Mean thickness of layers was calculated by dividing their area by the mean of upper and lower horizontal delineation.

Cell quantification

The areas of interest (layer II+III and layer V of the dorsal ACC, subregion 24b) were systemati- cally scanned through on the digitalized imag- es, twice, and VENs and non-VEN neurons (NVNs) were counted. The criteria for VENs were based on standard criteria [3]: a size equal to or above pyramidal neurones, a long elongated with one basal and one apical process of similar thickness, emerging at approximately 180 degrees from each other, with the cell and it’s processes aligned in the main cellular direction (Figure 1D, 1E). VENs were counted if more than 50% of the cell was inside the delineated area. Criteria for NVNs were a non-VEN appearance, an intact nucleus with one single defined nucleolus, a clearly vis- ible soma, and not exhibiting typical glial appearance. Only cells entirely inside the delin- eated area were counted. All counting was done blinded for diagnosis. Reliability for this cell counting procedure has been established in our previous study [8]. The intraclass correla- tion coefficient (ICC) for VEN counting was 0.96 (0.86-0.99, p<0.001) for intrarater and 0.97 (0.66- Figure 1. Schematic illustration of sampling scheme 0.99, p<0.001) for interrater comparisons. For in sagittal (A) and coronal (B) view. The anterior cin- NVNs counting, the intrarater reliability was gulate cortex is in grey. (C) Outline of region of inter- est (BA24b) with delineation of cortical layers (II+III 0.98 (0.91-0.99, p<0.001), the interrater reli- and V) in the dorsal anterior cingulate cortex. (D, E) ability being 0.89 (0.72-0.98, p<0.001). The von Economo neurons, x 400 magnification, with a primary approach to quantify VEN loss, as used pyramidal (*). (C-E) are stained with Cresyl previously [6-8], was to normalize the number Violet and Luxol Fast Blue. (C) is adapted from [8], of VENs to the number of NVNs of the same with permission. Scale bar in (D, E) 10 µm. area of interest. In our case VENs were normal- ized to 10000 NVNs of layer V and layer II+III, the basal delineation was the same as the respectively, of the same cortical section. This superficial surface of layer V (the ACC being provides a relative measure of VEN loss com- agranular and thus lacking a layer IV), while the pared to loss of NVNs, allows for comparisons outer definition was the border between layer I across conditions (bvFTD, AD), and partially

66 Am J Neurodegener Dis 2014;3(2):64-71 Cingulate VEN loss in FTD

Figure 2. A. Comparison between von Economo neurons (VENs) per 10.000 non- VEN-neurons (NVN) in cortical layers II and III, in non-demented controls (NDC), cases with Alzheimer’s disease (AD), and behavioral variant fron- totemporal dementia (bvFTD). B. Densities NVN of layer V (NVNV), of layer II and III (NVNII+III), and of VENs, expressed as percentage of controls, in cases with FTD and AD. Bars represent mean and error bars one standard deviation. *=significant at p<0.05, ns=not significant. compensates for neurodegenerative non-neu- t-test (between diagnostic categories), signifi- ronal tissue loss and effects of shrinkage. In cance set to p<0.05. For all correlations a two- order to compare densities of NVNs of the corti- tailed Pearson’s test of correlation was cal layers and densities of VENs, we calculated employed. NVN and VEN density, which was corrected with the mean thickness of each cortical layer, an Results approach used for cases where shrinkage could be differentially affected across cytoar- Demographical data of patients and controls chitectural layers [29]. Cellular densities were are presented in Table 1. There were no statis- then expressed as percentage of control densi- tically significant differences in age or sex dis- ties, in order to compare NVNs and VEN densi- tribution between patients and controls. Me- ties between layers. dian duration of symptoms was longer in AD (median 8 years) than in FTD (median 5 years), Statistical analysis with a borderline statistical difference (p= 0.050). Regarding macroscopic brain atrophy Differences in age, symptom duration, and sex among the FTD cases, 6 patients were at stage distribution between groups were compared 1 and 10 at stage 2. Eleven cases were TDP-43 with the Kruskal-Wallis and Mann-Whitney test positive, three were tau positive, one was FUS for age and symptom duration and the Fisher’s positive, and one case was negative for all exact test for sex distribution, with significance three antibody stainings. In the AD cases, neu- set to p<0.05. Shapiro-Wilk tests were run on ropathological severity was reflected in Braak all data in order to assess normal distribution. stage III (2/10), IV (3/10), V (2/10) and VI (3/10). When occasionally this requirement was not met, the parametric test was only used if the In the NDC group, mean VEN/10000 NVNII+III non-parametric equivalent showed the same was 326 (± SD 180), while the bvFTD group result regarding statistical significance. Number showed a 46% reduction, with VEN/10000 of VEN/10000 NVN was compared between NVNII+III of 177 (± SD 124) and AD patients a groups using a one-way ANOVA, with Tukey’s 21% reduction with mean VEN/10000 NVNII+III HSD as post-hoc test, significance set to of 257 (± SD 139) (Figure 2A). Significant differ- p<0.05. Thickness-corrected cellular densities, ences between diagnosis groups in VEN/10000 expressed as percentage of control mean, were NVNII+III were identified (F=3.538, p=0.040), compared with either paired t-test (within the with the difference between bvFTD and NDC respective diagnostic category) or independent being statistically significant (p=0.032, 95% CI

67 Am J Neurodegener Dis 2014;3(2):64-71 Cingulate VEN loss in FTD of reduction 88-3,4%), but not that between V in our study is in accordance with previous bvFTD and AD (p=0.379) nor between AD and studies which all have resulted in a similar pat- NDC (p=0.527). The thickness-corrected densi- tern, although the numbers differ widely. This is ties showed an expected pattern in bvFTD with most probably this is because of variability in NVN densities of layer V being almost identical cases, difference in neuropathological severity, to controls (a slight increase with mean per- and the different methods of quantification. centage of controls 106.2%, ± SD 34), lower Seeley and coworkers found, as in the study by densities in layer II and III (mean percentage of Tan [9], a slight increase [6] in neuron density in controls 86.8%, ± SD 28.5), while VEN densi- layer V of the ACC when using stereological ties showed a more marked reduction with den- methods, similar to the findings of the present sities at 52% of controls (± SD 38.9) (Figure study. In contrast, other studies [30] reported 2B). VEN densities were statistically different density reductions of 35-45% in layer III and V, from both NVNV (p<0.001, 95% CI -71, -38%) or even more [18]. and NVNII+III densities (p=0.003, 95% CI -56, -14%,) in bvFTD. Differences between densities Region of interest delineation and choice of tar- of layer II+III and V were borderline statistically get is an issue to bear in mind in the interpreta- significant in bvFTD (p=0.061). A similar, but tion of the results. We chose not to separately smaller scale pattern emerged in AD, with NVNV delineate layers II and III, but instead merging densities being 77.4% (± SD 25) of controls, these cell populations, since the layer II is NVNII+III 75.4% (± SD 19.1), and VENs 63.9% (± underdeveloped in the ACC and the distinction SD 36) (Figure 2B). None of the neuronal densi- between layer II and III is difficult [28], particu- ties in AD were significantly different from each larly in diseased cases. Thus our layer II+III other. Comparing densities between bvFTD and mainly consists of layer III neurones: and it is AD these were significant for NVNV (p=0.030) possible that more detailed delineations of lay- but not for NVNII+III (p=0.279) or VENs (p=0.442). ers, or subareas of layers, would show greater non-VEN neuronal loss. We omitted layer I, The mean number of VENs/10000 NVNV was where neuronal density is very low. Layer I is 457 (± SD 166) in NDC, 198 (± SD 113) in heavily affected in FTD, possibly even more patients with bvFTD and 338 (± SD 129) in than layer II and III [17]. patients with AD. Differences across diagnosis group were significant (F=12.6, p<0.001). bv- In this study we identified a selective loss of FTD showed a significant reduction compared VENs also in AD, however less pronounced than with NDC (57%, p<0.001, 95% CI of reduction in FTD and statistically non-significant. Similar 85-29%), and compared with AD (42% reduc- loss of VENs in AD has been shown previously, tion, p=0.038, 95% CI of reduction 81% to in the study by Kim and co-workers [6] (statisti- 2.0%). The difference between AD and NDC cally nonsignificant), and in the study by was not significant (26% reduction, p=0.120). Nimchinsky and colleagues [3] (statistically sig- nificant). Comparing the analysis of densities Discussion and VENs normalized to NVNs, it is apparent that “absolute” densities of VENs do not differ Our data show that VENs are more selectively significantly between bvFTD and AD, while the degenerated than neurons not only of deep but values for VENs/10000 NVN do. In our cohort, also of superficial layers in bvFTD. This strength- we chose the AD patients to match bvFTD ens the hypothesis of VENs as a particularly cases with regard to age and gender, but we did affected neuronal type in frontotemporal not have the possibility to match for disease dementia. In previous studies, VEN loss has duration, severity of disease at time of death, been evaluated in relation to neuronal loss or neuropathological severity. Since our AD within layer V, where VENs are found [6-8], or group had a longer disease duration than FTD within all cortical layers [9]. As expected, loss of patients, and VEN density had a negative cor- VENs relative to supragranular layers was less relation with duration in AD (r=-0.30, ns), differ- than the loss of VENs relative to layer V neu- ent duration and/or severity could be a factor rons, since supragranular layers were more to consider in these comparisons. In summary, affected than deeper layers. This more pro- however, it appears than VEN loss is not an “all nounced loss of neurons in layer II+III vs. layer or nothing” phenomenon, but instead is part of

68 Am J Neurodegener Dis 2014;3(2):64-71 Cingulate VEN loss in FTD a continuum of degeneration in and in between loss, is more common in the superficial layers conditions. in FTLD [16, 18, 19], this would affect NVNII+III more than NVNV. As some of the neuropatho- What could be the reason for VEN selectivity? logical characteristics of FTLD can be appreci- The possibilities are both structural, biochemi- ated in Nissl staining, and as the whole gyrus cal, due to local connectivity within or regional was visible for the rater, loss of blinding could connectivity outside the cortex. From a struc- have been a source of bias in our study. tural point of view, the morphology of VENs Generally, stereological methods are regarded (large, implying large , possibly rapid fir- as more accurate in the quantification of cells ing) suggest increased metabolic requirements densities. Regarding VENs, our method could and elevated structural requirements that increase the likelihood of counting other cell could make these cells sensitive to a vast num- types (elongated or inverted pyramidal neu- ber of pathological processes [3, 11]. As a con- rons, basket cells) as VENs. However, since sequence, it is anticipated that AD cases show non-VEN neurons are less affected than VENs, intermediary VEN selectivity, as the tau-positive this should rather diminish differences between FTD cases in our previous study. Still the height- conditions. ened loss in FTLD, and the genetic, biochemi- cal and pathological relationship with ALS, In conclusion, our study strengthens the notion another TPD-43 disease which initially targets of VENs being a particularly sensitive cell popu- large rich neurons such as Betz lation in bvFTD. Further studies should aim to cells and α-motoneurons [31], suggest that this explore whether VENs are particularly sensitive could indeed be a phenomenon that is more for the biochemical processes in FTLD, and specifically linked to FTLD protein pathology, make a more detailed comparison between such as TDP-43. The recent finding of selective- loss of VENs and more defined cortical layers, ly reduced densities of VENs in semantic e.g. separating I, II and III. VEN loss in other dementia (another TDP-43 condition) [9], may neurodegenerative disorders other than bvFTD, support his notion. AD and SD remains to be explored. Clearly, an Another possible explanation of selective VEN important step in understanding VEN function loss, together with layer II and III selectivity is their connectivity. Since VENs have been could be the local intracortical connectivity. recently described in primate laboratory ani- VENs have a considerably smaller dendritic mals [34], tracing studies are now possible. tree than other layer V pyramidal neurons [32], Acknowledgements and their sparse apical sampling could make them particularly vulnerable for synaptoden- Histotechnical work: Anna Härfstrand, Camilla dritic pathology, which is more evident in the Lidman, Sanaz Mojighashghaei. Funding: Gover- upper layers in FTD [17]. Atrophy in the struc- nment funding of clinical research within NHS tures to which VENs connect could also be Sweden (ALF), The Swedish Dementia Foun- another explanation for VEN selectivity. Whe- dation, The Trolle-Wachtmeister Foundation. reas exact VEN connectivity is not known, they are most probably projection neurons [3], with Disclosure of conflict of interest long destination axons, projecting subcortically [33], with a minor callosal portion [34]. This None to declare. would suggest a subcortical target that is early Address correspondence to: Alexander Frizell San- involved in FTD, such as the [35], or tillo, Clinical Memory Research Unit, c/o Memory possibly the subcortical anchor points of the Clinic, Skåne University Hospital, SE 221 85 Lund, salience network, the periaqueductal grey and Sweden. Tel: +46-(0)-46-177479; Fax: +46-(0)-46- the parabrachial nucleus [14]. 177457; E-mail: [email protected] Several possible sources of bias in the current References study should be mentioned. One is the possible counting of as NVN neurons, thus [1] Piguet O, Hornberger M, Mioshi E and Hodges underestimating the neuronal loss. In Nissl JR. Behavioural-variant frontotemporal demen- staining, separating astrocytes from neurones tia: diagnosis, clinical staging, and manage- is generally regarded as straight-forward, but ment. Lancet Neurol 2011; 10: 162-172. classification could be more difficult with acti- [2] Seeley WW, Crawford R, Rascovsky K, Kramer vated astrocytes. Since astrocytosis, like cell JH, Weiner M, Miller BL and Gorno-Tempini ML.

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