Chapter 59 : Prion Diseases

(A) The structure of mouse PrPC solved by NMR spectroscopy ( 53 ) shows an unstructured amino terminal domain (blue) and a well-ordered C-terminal domain with three α-helices (green) and an anti-parallel β-sheet (red). A disulfide bond links α2 to α3 (yellow). (B) A long straight fibril from PrPSc derived from a prion-infected brain shows a single twist (arrowhead) ( 292 ). A model of the fibril composed of multimeric PrPSc is shown that accounts for available biophysical measurements ( 75 ). Note that all α-helices have been converted to β-sheets, and PrP molecules are stacked. Each PrP molecule is represented by a different color and molecules are aligned parallel and in-register. The locations of the glycans are shown in orange. (C) Model for the conformational conversion of PrPC into PrPSc. The “seeding” or nucleated polymerization model proposes that PrPC forms a highly ordered nucleus, which requires overcoming a high-energy barrier. Further monomeric PrPC is recruited into the growing PrPSc aggregate. Fragmentation of PrPSc aggregates increases the number of nuclei, which each recruit PrPC monomers, resulting in amplification of the prion aggregates. (Modified from references [ 293 ] and [ 75 ]).

Schematic representation of human PrP showing the known mutations and polymorphisms. The cleaved signal sequences are shown in dark gray and the octapeptide repeat region in purple. Shown are the pathogenic mutations (red) and the nonpathogenic variants (green). OPRD: octapeptide repeat deletion; OPRI: octapeptide repeat insertion. (Modified from reference [ 294 ]).

A typical electroencephalogram in a sporadic Creutzfeldt–Jakob disease patient, with diffuse slowing and 1-Hz periodic sharp wave complexes (PSWCs). (Modified from Geschwind. Editors: Daroff, Jankovic, Mazziotta and Pomeroy ( 295 )).

Diffusion-weighted (dw) and fluid-attenuated inversion recovery (flair) magnetic resonance imaging (MRI) in sporadic Creutzfeldt–Jakob disease (sCJD) and variant (v)CJD. Three common MRI patterns in sCJD are predominantly subcortical (A, B), both cortical and subcortical (C, D), and predominantly cortical (E, F). A patient with probable vCJD is shown in G and H. Note that in sCJD, the abnormalities are more evident on DWI (A, C, E) than on FLAIR (B, D, F) images. The three sCJD cases (A-F) are verified by pathology. A, B: A 52-year-old woman with MRI showing strong hyperintensity in bilateral caudate (solid arrow) and putamen (dashed arrow) and slight hyperintensity in bilateral mesial and posterior thalamus (dotted arrow). C, D: A 68-year-old man with MRI showing hyperintensity in bilateral caudate and putamen (note anteroposterior gradient in the putamen, which is commonly seen in CJD), thalamus, right insula (dotted arrow), anterior and posterior cingulate gyrus (solid arrow, L > R), and left temporal-parietal-occipital junction (dashed arrow). E, F: A 76-year-old woman with MRI showing diffuse hyperintense signal, mainly in bilateral temporoparietal (solid arrows) and occipital cortex (dotted arrow), right posterior insula (dashed arrow), and left inferior frontal cortex (arrowhead) but no significant subcortical abnormalities. G, H: A 21-year-old woman with probable vCJD, with MRI showing bilateral thalamic hyperintensity in the mesial pars (mainly dorsomedian nucleus) and posterior pars (pulvinar) of the thalamus, called the double hockey stick sign. Also note the pulvinar sign, with the posterior thalamus (pulvinar; arrow) being more hyperintense than the anterior putamen. (Modified from references [ 231 ] and [ 295 ]).

Histological features of prion diseases. CNS parenchyma of sCJD (A and B) and vCJD (C and D) showing astrogliosis and widespread spongiform changes. PrP depositions are synaptic (A and B) and in the form of florid plaques (asterisk, C and D). A and C are hematoxylin and eosin stains, B and D are immunohistochemically labeled for PrP (scale bar = 50 micrometers). (Note: from previous version of this chapter.)

Western blot analysis of PrPSc. The classification schemes for CJD discriminate PrPSc types based on the mobility of the unglycosylated band of PrPSc and the signal intensity of di-, mono-, and unglycosylated PrPSc forms. Types 1 and 2 PrPSc have distinct electrophoretic mobilities due to different sizes of their respective protease-resistant fragments (type 2 is smaller than type 1). The PrPSc types are distinguished by their different migration on electrophoresis, particularly after cleavage of the sugars by the enzyme peptide N glycosidase F (PNGase). (Modified from Puotri GP et al. ( 204 )).

Olfactory mucosa brushing and RT-QuIC assay for PrPSc. (A) To collect olfactory neurons, the operator inserts a rigid fiberoptic rhinoscope and a sterile brush into the nasal cavity and gently rolls the brush on the mucosal surface. (B) Nasal brush cells were immunostained with antiolfactory marker protein (OMP) antibody to show clusters of OMP positive olfactory neurons (40X). (C) A cytocentrifuged sample of the OM pellet was stained immunocytochemically for an olfactory marker protein to detect olfactory neurons. (D) The average percent thioflavin T (ThT) fluorescence readings from four replicate reactions in samples of OM and CSF from patients with possible, probable, or definite Creutzfeldt–Jakob disease and from controls without Creutzfeldt–Jakob disease. The means (thick lines) with standard deviations (thin lines) of those averages are shown as a function of RT-QuIC reaction time. (E) The final average relative ThT fluorescence readings for each person with Creutzfeldt–Jakob disease (CJD) and for each control with either a neurologic disease other than Creutzfeldt–Jakob disease (other neurologic disease (OND) or no neurologic disease (NND)) are shown. Inherited CJD refers to patients with the E200K PRNP genetic mutation causing CJD. (Modified from reference [ 247 ]).