Introduction
Alzheimer’s disease neuropathologic change (ADNC) in the form of b-amyloid (Ab) deposits occurs in a variety of neuropathological settings [43,56]. Hence, Ab is a ‘signature’ pathological lesion of Alzheimer’s disease (AD) [45,55] and also plays a significant role in the pathology of Down’s syndrome (DS) [12,31,48,57]. In addition, Ab deposits have been reported as a ‘co-pathology’ in many neurodegenerative disorders including in some cases of dementia with Lewy bodies (DLB) [14], Parkinson’s disease (PD) [59], Pick’s disease (PiD) [59], corticobasal degeneration (CBD) [6,59], amyotrophic lateral sclerosis (ALS) [36], progressive supranuclear palsy (PSP) [59], and chronic traumatic encephalopathy (CTE) [66].
Ab peptides are generated in brain by b- and g-secretase cleaving of amyloid precursor protein (APP), resulting in the formation of aggregated protein deposits [35,40]. A number of morphological types of Ab deposit have been described in histological sections in AD and DS, but the majority can be classified into three subtypes [3,26]. First, diffuse (‘pre-amyloid’) deposits are closely associated with neuronal cell bodies, and may be the earliest type to develop [1,3,4]. Second, primitive (‘neuritic’) deposits are more mature deposits which incorporate dystrophic neurites (DN) [3]. Third, classic (‘dense-cored’) Ab deposits consist of a distinct central ‘core’ surrounded by a ‘corona’ of DN and are frequently located adjacent to prominent blood vessels [5]. In AD, all three types of Ab deposit are distributed unevenly across the cortex with peaks of density in different cortical layers, the primitive and classic Ab deposits often reaching maximum density in the upper and lower layers respectively while the diffuse deposits have a more variable distribution [2,8].
A previous study [10] investigated the spatial patterns of Ab deposits in the upper cortex parallel to the pia mater and found considerable similarities in their pattern of clustering in different disorders. The laminar distribution of Ab deposits may indicate the pattern of degeneration across the cortical layers and has been studied quantitatively in AD [2,8]. The specific objective of this study was to directly compare laminar distributions of Ab deposits in five neurodegenerative disorders including not only AD but also CBD, DLB, DS, and CTE which have been less studied quantitatively to determine whether there were differences associated with variations in the clinical and pathological setting. Hence, AD, CBD, and CTE are ‘tauopathies’ [32] in which the deposition of abnormal forms of the microtubule-associated protein (MAP) tau in the form of neurofibrillary tangles (NFT), glial inclusions (GI), and dot-like grains (DLG) is a ‘signature’ pathological feature [47]. By contrast, DLB is a ‘synucleinopathy’ in which the misfolded forms of the synaptic protein a-synuclein are deposited as Lewy bodies (LB), Lewy neurites (LN), and Lewy grains (LG) [32,65]. In DS, increased Ab deposition may result from triplication of the APP gene [60], while in CTE, Ab deposition may be a consequence of traumatic brain injury (TBI) [30,44,50,66].
Material and methods
Cases
Demographic data and diagnostic criteria for the five disorders are listed in Table I [54,55,68]. Informed consent was given for the removal of all brain tissue according to the 1996 Declaration of Helsinki (as modified Edinburgh 2000). Case material for AD, CBD, DLB, and DS, in the form of original microscope slides, was obtained from the Brain Bank, Department of Neuropathology, Institute of Psychiatry, King’s College, London, UK. By contrast, because of its scarcity, case material for CTE was obtained from Boston University’s CTE Center (VA-BU-CLF Brain Bank) as a series of scanned microscope images (Aperio Image-Scope Software, Leica Biosystems Inc. Buffalo Grove, IL, USA) [17,18]. To check whether determination of laminar distribution was affected by observation of scanned images rather than the original slides, a random sample of regions from the AD cases was also studied both from microscope slides and from scanned images, no differences in distribution being detected.
Histological methods
Blocks of frontal cortex, at the level of the genu the of corpus callosum and temporal cortex, at the level of the lateral geniculate nucleus, were taken from each case to study the superior frontal gyrus (SFG) (B8), lateral-occipito temporal gyrus (LOT) (B36), and parahippocampal gyrus (PHG) (B28), gyri which frequently have high densities of Ab deposits in AD and related disorders [2,6,12,14]. Tissue was fixed in 10% phosphate buffered formal-saline and embedded in paraffin wax. 7 µm coronal sections were stained with rabbit polyclonal antibodies raised against Ab42 [64,66]. Sections were also stained with hematoxylin. The antibodies clearly revealed the diffuse, primitive, and classic subtypes of Ab deposit and were identified in the sections using previously defined criteria [3,26] (Fig. 1). Hence, diffuse Ab deposits were 10-200 µm in diameter, irregular in shape with diffuse boundaries, and were lightly immunolabelled. Primitive Ab deposits were 20-60 mm in diameter, well demarcated, more symmetrical in shape, and strongly immunolabelled, while the classic Ab deposits were 20-100 mm, comprising a distinct and strongly immunolabelled central ‘core’ surrounded by a ‘corona’ of DN.
Morphometric methods
The laminar distribution of the Ab deposits in each gyrus was studied using methods described previously [8,28]. Hence, five traverses extending from the pia mater to the edge of the white matter were located at random locations along each gyrus where significant densities of Ab deposits were present. All diffuse, primitive, and classic Ab deposits were counted in 200 × 1000 µm sample fields arranged contiguously along the traverse, the larger dimension of the field orientated parallel with the surface of the pia mater. In AD, CBD, DLB, and DS, an eye-piece micrometer was used as the sample field and was moved down each traverse one step at a time from the pia mater to the edge of the white matter. In CTE, the sample fields were superimposed over the scanned images using either the draw or rectangle options [17,18]. Histological features of the section were used to correctly position the field. The mean of the counts from the five traverses was calculated to study variations in density of histological features across each cortical gyrus.
Data analysis
The degree of cortical degeneration present in many gyri, especially in AD and CTE, made laminar identification difficult especially in the SFG in all disorders because it exhibits a heterotypical structure, i.e., six layers cannot always be clearly identified and vary in prominence from case to case [8]. In addition, Ab deposits appeared to exhibit complex patterns of distribution across the cortex rather than being confined to individual layers. Instead, variations in density of Ab deposits with distance across the cortex were analyzed using a polynomial curve-fitting procedure (STATISTICA software, StatSoft Inc., 2300 East 14th St, Tulsa, OK, 74104, USA) [2,63]. For each gyrus, polynomials of order 1, 2, 3 up to the 4th order were fitted successively to the data. With each fitted polynomial, the correlation coefficients (Pearson’s r), regression coefficients (b), standard errors (SE), values of t, and the residual mean square (MS) were obtained. A polynomial was accepted as the ‘best’ fit when either a non-significant value of F was obtained for the next higher order polynomial or there was little gain in explained variance [58]. As a large number of statistical tests were performed without pre-planned hypotheses, the Bonferroni correction was applied to each set of comparisons, i.e., among deposit types within a disorder, among disorders, and among individual disorders for each type of deposit [7]. Where significant changes in density occurred across the cortex, the analyses were used to establish the approximate location of any significant peaks. In the majority of gyri, there was either a single density peak in the upper or lower cortex (unimodal distribution), corresponding to layers IIII or V/VI respectively, or two peaks in the upper and lower cortex (bimodal distribution).
Results
Examples of the laminar distributions of Ab deposits observed are shown in Figures 2 and 3. Figure 2 shows the distribution of Ab deposits in the LOT of a case of CTE located primarily in the upper cortex and associated with many Ab-immunolabelled cell bodies. By contrast, Figure 3 shows the distribution of Ab deposits in the SFG of a case of DLB affecting the lower layers with only a few scattered diffuse deposits in the upper layers.
Examples of the polynomial curve fitting procedure in the SFG of a case of AD are shown in Figure 4. The distribution of the diffuse Ab deposits was fitted by a third-order polynomial (r = 0.70, p < 0.05), suggesting a bimodal distribution, high densities being present in the superficial layers and a density peak in the lower cortex. By contrast, the primitive Ab deposits were fitted by a first-order linear regression (r = 0.82, p < 0.01), with the highest density of deposits in the upper cortex, and with a linear decline in density across the cortex. The classic Ab deposits were fitted best by a third-order polynomial (r = 0.64, p < 0.05), and although there was less change in density compared with the diffuse and primitive deposits, the greatest densities were present in the upper cortex.
A summary of the frequencies of the different types of laminar distribution of the diffuse, primitive, and classic Ab deposits in the five disorders is shown in Table II. Overall, the most frequent distribution present was a density peak of Ab deposits in the upper layers, a distribution observed in 120/266 (45%) of all gyri measured. A distribution in which Ab deposits were scattered across all layers of the cortex was the second most common, and present in 61/266 (23%) gyri. Differences in distribution were observed among Ab deposit subtypes within a disorder in AD (c2 = 27.35, p < 0.001) and DLB (c2 = 13.37, p < 0.05), but only those in AD remained significant after Bonferroni correction. Hence, in AD the diffuse and primitive Ab deposits were more likely to be distributed in the upper cortex while the distribution of the classic deposits was more variable.
Differences in laminar distribution of the diffuse (c2 = 32.40, p < 0.001) and classic Ab deposits (c2 = 21.96, p < 0.05) were also evident among all disorders, but only those for the diffuse deposits were significant after Bonferroni correction. Diffuse deposits were distributed most frequently in the upper cortex in AD, CTE and DLB, while responses were more variable in DS and CBD. Some differences in distribution were also observed among individual disorders. First, the primitive deposits were distributed differently in AD and CTE (c2 = 17.68, p < 0.001), most frequently in the upper cortex in AD and distributed across all cortical layers in CTE. Second, in DLB, the primitive deposits were more likely to exhibit a bimodal distribution compared with CTE (c2 = 15.96, p < 0.001).
Discussion
Laminar distributions are similar to those reported previously with regard to Ab deposits in sporadic [2] and familial AD [8] and in other studies of AD reporting high densities of silver-stained senile plaques (SP) in the upper cortical layers [22,23,28,38]. Few studies have been carried out on the laminar distribution of Ab deposits in disorders other than AD, but the tau-immunoreactive pathology in CBD [15] and in CTE [19] is frequently distributed primarily in the upper cortex. By contrast, DLB is an exception in that LB pathology often exhibits a bimodal distribution but with higher densities in the lower cortex [13].
The density peak of the diffuse Ab deposits in the upper cortical layers could result from the spatial association of these deposits with large neuronal perikarya [1,4]. These deposits may represent an early stage in degeneration of the large pyramidal cells in the upper cortex, many of which are the cells of origin of the feed-forward cortico-cortical pathways (FF-CC) [3]. Similarly, the primitive Ab deposits commonly exhibit a density peak in the upper cortex and may result from the maturation of diffuse deposits [3] and also suggest degeneration of the FF-CC [2,24,38] in all five disorders. Third, the classic ‘cored’ deposits occur most frequently in the lower layers in AD [2,21], but the present study reveals a more variable distribution which could result from the relationship between the classic Ab deposits and cerebral blood vessels [5].
Ab deposits were more likely to be distributed across all cortical layers in AD and especially in CTE. AD and CTE are both tauopathies, but CTE is associated specifically with TBI [30,34,44,51-53,62] while the cause of sporadic AD is likely to be more complex [11], identifying this disorder as having the most widespread laminar degeneration among those studied. The distribution of the classic Ab deposits may be of particular significance in CTE as it could reflect blood vessel damage [5]. Hence, the tau-immunoreactive pathology in CTE occurs at higher density in sulci compared with gyri, where blood vessels are densest [17,46,52], accompanied by a marked perivascular distribution of NFT and AT [51,53]. The remaining tauopathy CBD exhibits a laminar distribution which closely resembles that of AD, which could explain why the diagnosis of CBD is difficult, diverse presentations being present and frequently resembling other disorders such as AD [27]. DS and AD share many pathological similarities [48,57,69], particular accumulations of Ab deposits being observed between the ages of 30 and 50 years [42] and this study confirms the considerable similarity in their laminar distributions. The synucleinopathy DLB exhibits some differences compared with the other disorders, and especially CTE, in the frequency of bimodal distribution of the primitive deposits, and which could be the result of two pathological processes, viz. neuronal degeneration affecting the lower layers associated with a-synuclein-mediated LB formation [13] and degeneration affecting the upper layers.
Variation in laminar distribution could represent different stages in a dynamic process reflecting the hypothesized ‘prion-like’ spread of Ab among regions via neuro-anatomical pathways [9,33,67]. The observation that Ab deposits in AD exhibit very similar spatial patterns in the tissue to PrPsc deposits in Creutzfeldt-Jakob disease (CJD) supports this hypothesis [16]. The following hypothesis is suggested to account for the observed laminar distributions. First, messenger RNA (mRNA) of amyloid precursor protein (APP) is preferentially expressed by the large pyramidal neurons [20]. Degeneration of these neurons, initially in layer III, results in increased secretion of APP and formation of diffuse Ab deposits in association with one or more neurons [4]. Second, interleukin-immunoreactive microglia (IL-Mg) have a similar laminar distribution to APP-immunoreactive neuritic plaques (NP) and contribute to the maturation of Ab to form the primitive Ab deposits [61]. Degeneration of blood vessels may be an additional factor involved in the formation of the cored classic deposits [5]. Third, Ab spreads via local interneurons from upper to lower layers to gradually affect all cortical layers, a process evident in AD and most especially in CTE. Release of APP and maturation into amyloid associated with neurons in layer V may also contribute to this spread in AD and CTE. Fourth, further spread of Ab occurs among cortical gyri via pathways including the short and long cortico-cortical pathways [24].
NFT also occur in greater abundance in the upper cortical layers in AD [38]. Whether there is a direct link between the laminar distribution of Ab deposits and that of NFT, as suggested in AD by the amyloid cascade hypothesis (ACH), is unclear [37]. SP and NFT can develop alone in different disorders, e.g., NFT in tangle-only dementia [70] and Ab in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHA-D) [41]. SP and NFT may exhibit distinct but independently distributed topographic patterns in the cerebral cortex in AD [41]. In addition, Braak and Braak [23] showed that tau pathology occurred first in the entorhinal cortex, often in the absence of SP, whereas the subsequent spread and distribution of Ab was more variable. Moreover, SP and NFT may be temporally separated in the brain [49], NFT preceding the appearance of SP in some regions. Nevertheless, it is also possible that Ab and tau formation are different consequences of degeneration of the same neurons, SP forming on the axonal terminals of NFT-containing neurons, and the respective laminar distributions of the SP and NFT may reflect this anatomical association [24].
In conclusion, cortical laminar distributions of Ab deposits in AD, CBD, CTE, DLB, and DS show considerable similarities and some differences. Differences among individual cases and disorders could reflect variations in the pathological spread of Ab among brain regions via anatomical pathways and may play a significant role in the timing and sequence of clinical symptoms exhibited by the patient.
Acknowledgements
The assistance of the Brain Bank, Institute of Psychiatry, King’s College London, UK and Boston University Alzheimer’s Disease Center CTE Program Brain Bank, Boston University School of Medicine, Boston, MA, USA in supplying case material for this study are gratefully acknowledged.
Disclosure
The author reports no conflict of interest.
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