PMC8485779_01
In vivo and postmortem MRI showing white matter lesions, brain atrophy, and enlarged ventricles. (A-C) FLAIR scans acquired in 2016 (A) and 2017 (B) show periventricular WMHs (arrows in A) and a lacune (arrowhead) in right parietal white matter. The corpus callosum is thinned and has WMHs in both genu and splenium (arrows in B). WMHs become confluent in the frontal and parietal regions in the postmortem T2 scan of the right hemisphere (C). (D-F) Segmentation of the lateral ventricles and subcortical nuclei on T1 scans acquired in 2016 (D) and 2017 (E). White matter lesions in the right temporal lobe are observed on both in vivo MRI scans (arrow) as well as the postmortem T2* scan (F). (G,H) The MCP sign (arrows) on T2 scans acquired in 2016 (G) and 2017 (H). (I,J) Segmentation of the cerebellum on T1scans acquired in 2016 (I) and 2017 (J).
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F1
Brain MRI during the initial evaluation showed a large middle cerebellar peduncles (MCP) sign, thin corpus callosum and white matter disease (WMD) in the splenium and genu of his corpus callosum and WMD in the right temporal lobe and periventricular areas (Figures 1A,D,G,I). The ventricles were larger and the corpus callosum was thinner when compared to the MRI taken 16 months prior (Figures 1B,E). A quantitative analysis of brain atrophy was performed using volBrain software pipeline that implements a multi-atlas label fusion technique for segmenting the intracranial cavity, brain, lateral ventricle, cerebellar lobules, and subcortical nuclei (Manjon et al.,; Manjon and Coupe,; Romero et al.,) (Figures 1D,E,I,J). T2 scan (Figure 1C) indicating further WMH expansion during the last 2 years of life and tissue loss in anterior temporal white matter (Figure 1F). Transverse relaxation rate, R2*, sensitive to iron content in the tissue, was estimated by fitting an ordinary lease squares function to the signal intensities of the multi-echo T2* scan (Peran et al.,).
CGG repeat size and methylation status were determined by a combination of Southern blots (A) and capillary electrophoresis (B) on genomic DNA isolated from a female, negative control (lane 1), from a full mutation control (>200 CGG repeats) (lane 2). The SB analysis demonstrates the presence of an unmethylated premutation alleles in the proband (lane 3). M = DNA marker, 1 kb ladder. Normal unmethylated band (2.8 kb) and normal methylated band (5.2 kb) shown on the left. The electrophoregram (B) shows the presence of a single peak representing the premutation allele. The X-axis indicates the size of the allele in base pairs and the Y-axis indicates the fluorescence intensity of each allele.
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F2
FMR1 mRNA expression levels, measured by real time qRT-PCR (Tassone et al.,), were 2.5-fold higher than normal (2.58 StErr 0.04) (Figure 2).
Gross and microscopic brain evaluation. (A) Severe frontal and temporal lobes atrophy, thin corpus callosum, sclerotic changes in basilar artery. (B) Ubiquitin positive intranuclear inclusions in the post central gyrus confirming definite diagnosis of FXTAS. (C) Tau positive plaques and neuropils in the prefrontal gyrus. (D) Iron deposits in the globus pallidus. (E) Tau positive neuropils in the SN (F) Amyloid beta positive plaques in the middle temporal gyrus. (A-A') scale bar 2 cm; (B) scale bar 50 mum; (C,D) scale bar 200 mum; (C') scale bar 10 mum;; (D insert) scale bar 20 mum; (E) scale bar 50 mum; (F) scale bar 50 mum; (F') scale bar 20 mum, Graph shows a summary of brain regions sampled for histopathology evaluation. Abeta, amyloid beta; AT8, phosphorylated Tau.
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F3
Gross anatomy showed atrophy in the frontal and temporal lobes (Figure 3A), as well as mild ventricular enlargement, more predominant posteriorly. Evidence of mild atherosclerosis was found within the basilar artery (Figure 3A). We found ubiquitin-positive intranuclear inclusions in neurons and astrocytes of the prefrontal cortex (Figure 3B), confirming the definite diagnosis of FXTAS. We also noted either neurofibrillary tangles and/or neuropils and/or neuritic plaques in all the studied areas except for the globus pallidus and the cerebellum (Figure 3C). High amounts of iron deposits were visualized in the globus pallidus and the putamen consistent with MRI findings (Figure 3D). Tau aggregates were found in the neuromelanin containing neurons of the SN; however, no Lewy bodies were identified by alpha-synuclein immunostaining (Figure 3E), excluding a pathological diagnosis of concomitant Lewy body disease based on current criteria. Extracellular deposition of beta-amyloid (core/diffuse plaques) was found in cortical areas and the hippocampus (Figure 3F), but absent in the basal ganglia, brainstem, and cerebellum. beta-amyloid assessment met Thal phase (2) criteria (Thal et al.,); scattered beta-amyloid positivity in leptomeningeal and cortical vessels, and capillaries, was also seen, but insufficient to fully assess CAA.