PMC7364264_01
Cortical dyslamination with presence of atypical neurons in case 1. Cortical dyslamination with presence of dystrophic pyramidal neurons (arrows) haphazardly spanning cortical layers II-III of the AG (A), and large dystrophic pyramidal neurons in cortical layer II of the IFG (B), and of case 1. H&E. Bars: A = 250 microns; B = 25 microns.
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Neuroimaging revealed left greater than right biparietal atrophy (Supplementary Fig. 1). PiB-PET was positive for cortical binding (Supplementary Fig. 1). Cortical dyslamination with the presence of conspicuous large pyramidal neurons in clusters was observed spanning cortical layers II-III in AG (Fig. 1A), IFG (Fig. 1B), STG/MTG and PCC.
PMC7364264_02
Cortical dyslamination with presence of atypical neurons in case 1. Cortical dyslamination with presence of dystrophic pyramidal neurons (arrows) haphazardly spanning cortical layers II-III of the AG (A), and large dystrophic pyramidal neurons in cortical layer II of the IFG (B), and of case 1. H&E. Bars: A = 250 microns; B = 25 microns.
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Neuroimaging revealed left greater than right biparietal atrophy (Supplementary Fig. 1). PiB-PET was positive for cortical binding (Supplementary Fig. 1). Cortical dyslamination with the presence of conspicuous large pyramidal neurons in clusters was observed spanning cortical layers II-III in AG (Fig. 1A), IFG (Fig. 1B), STG/MTG and PCC.
PMC7364264_03
Cortical dyslamination with presence of atypical neurons in case 1. Cortical dyslamination with presence of dystrophic pyramidal neurons (arrows) haphazardly spanning cortical layers II-III of the AG (A), and large dystrophic pyramidal neurons in cortical layer II of the IFG (B), and of case 1. H&E. Bars: A = 250 microns; B = 25 microns.
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PMC7364264_03_fcz027f1.jpg
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Neuroimaging revealed left greater than right biparietal atrophy (Supplementary Fig. 1). PiB-PET was positive for cortical binding (Supplementary Fig. 1). Cortical dyslamination with the presence of conspicuous large pyramidal neurons in clusters was observed spanning cortical layers II-III in AG (Fig. 1A), IFG (Fig. 1B), STG/MTG and PCC.
Tau immunohistochemistry of atypical neurons. Abnormal cortical organization with presence of frequent pyramidal tau immunoreactive neurons cortical layer II of the IFG of case 1 (A) and STG of case 2 (B). Atypically large neuron in the cortical layer II of the STG of case 3 with consistently tau negative cell body (arrows) (C). CP13 immunohistochemistry. Bars: A, B = 250 micron; C = 25 microns.
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IFG showed abnormal apical dendrite orientation. Virtually all of these neurons displayed diffuse or granular cytoplasmic tau immunoreactivity and, in a few instances, harboured NFT (Fig. 2A). In addition, they were strongly immunoreactive to antibodies against non-phosphorylated neurofilaments (SMI-32; Fig. 3A and B), NeuN-positive and GFAP-negative. The majority of these neurons displayed diffuse or granular cytoplasmic tau immunoreactivity and, in a few instances, harboured NFT (Fig. 2B). The cell body of atypically large neurons was remarkably spared of any tau immunoreactivity (Fig. 2C), and in contrast, displayed abundant SMI-32 cytoplasmic staining (Fig. 3E and F).
Abnormal neurofilament immunostaining in atypical cortical neurons. Abundant non-phosphorylated neurofilaments (SMI32) immunostaining of atypical large pyramidal neurons in cortical layer II of the IFG of case 1 (A, B), and case 2 (C, D). Abundant SMI32 immunostaining was also observed in large, ballooned atypical neurons of cortical layer II of the inferior frontal gyrus of case 3 (E, F). Bars: A, C, E = 250 microns; B, D, F = 25 microns.
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IFG showed abnormal apical dendrite orientation. Virtually all of these neurons displayed diffuse or granular cytoplasmic tau immunoreactivity and, in a few instances, harboured NFT (Fig. 2A). In addition, they were strongly immunoreactive to antibodies against non-phosphorylated neurofilaments (SMI-32; Fig. 3A and B), NeuN-positive and GFAP-negative. Large pyramidal neurons in cortical layers II-III were strongly immunoreactive with antibodies against non-phosphorylated neurofilaments (Fig. 3C and D).
Tau immunohistochemistry of ectopic neurons in dyslexia. Tau immunohistochemistry of cortical layer I-II (A), and juxtacortical white matter (B) of the AG of case 1. (A) A tau immunoreactive ectopic neuron in layer I, with abundant tau immunoreactive neuropil threads and frequent pyramidal neurons also containing tau cytoplasmic inclusions in cortical layer II. (B) Numerous tau immunoreactive interstitial white matter neurons (asterisks) and a few oligodendroglial coiled bodies are seen. Bars: A = 25 microns; B = 250 microns.
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A few heterotopic large neurons, with abundant diffuse cytoplasmic tau immunoreactivity, were observed in cortical layer I of the insula, IFG and AG (Fig. 4A). Finally, tau immunoreactive interstitial white matter neurons were observed in juxtacortical STG and AG white matter (Fig. 4B;Supplementary Table 2). 
Cortical dyslamination with presence of atypical neurons in case 2. Cortical dyslamination with presence of dystrophic pyramidal neurons in clusters (arrows) haphazardly spanning cortical layers II-III of the AG (A), and large dystrophic pyramidal neurons in cortical layers II-III of the IFG (B), and of case 2. H&E. Bars: 250 microns.
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The major features were clusters of large pyramidal neurons spanning cortical layers II-III or IV-V (Fig. 5A and B).
Cortical dysplasia with presence of atypical ballooned neurons in case 3. Cortical dyslamination with presence of clusters of large atypical neurons (arrowheads) in cortical layers II-III of the IFG of case 3 (A, B). Several neurons display large round cytoplasm, atypical orientation of the apical dendrite and haphazard cortical localization, which resemble the histological features of FCD. H&E. Bars: 250 microns.
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Numerous atypically large neurons, resembling pyramidal cells of cortical layer 5, were seen at the junction between cortical layers II and III of IFG (Fig. 6A and B), and to a lesser extent in STG/MTG and AG. ACC, PCC and insula. A considerable proportion of these cells displayed large, rounded cytoplasm, lacking features suggestive of neuronal degeneration such as shrunken, eccentric nuclei (Fig. 6B). These cells had often no obvious polarity, absent or atypically oriented apical dendrites and occurred in clusters that appeared to deepen tangentially to join other clusters of similar cells in cortical layer 5 (Fig. 6A).