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Prion diseases are transmissible neurodegenerative disorders characterised by the accumulation of a disease-associated misfolded form of the normal cellular prion protein PrP C in the central nervous system CNS , commonly referred to as PrP Sc [ 24 ].
PrP Sc is considered to be the major, if not the sole, component of the transmissible agents known as prions [ 55 ]. Unlike other neurodegenerative diseases, human prion diseases occur in sporadic, genetic and acquired forms [ 24 ]. One of the commonest causes of iCJD was treatment with human pituitary-derived growth hormone hGH by intramuscular or subcutaneous injection in children and young adults with primary or secondary growth hormone deficiency [ 8 , 64 ].
Treatment with hGH was first associated with iCJD in , since when the use of hGH was banned in many countries and replacement therapy with biosynthetic growth hormone was instigated [ 19 , 34 , 54 ]. Since , over cases of iCJD in hGH recipients have been reported in several countries [ 8 , 50 ], with the largest numbers of cases occurring in France cases and the United Kingdom UK 78 cases.
Unlike human prion diseases, there is no current evidence to suggest that individual cases of these neurodegenerative diseases are acquired [ 11 , 41 ], but there is an increasing body of experimental evidence to indicate that the abnormal protein aggregates in these diseases exhibit prion-like properties and can spread through the CNS in a highly predictable fashion along well-defined neuroanatomical pathways [ 12 , 21 , 30 , 56 , 61 , 62 ].
In order to address these questions, we have undertaken a detailed neuropathological, biochemical and genetic study of the largest cohort of UK hGH-iCJD cases yet reported, comprising 35 cases. The full biochemical and prion protein genetic data on a subset of 21 cases have been reported separately, along with some preliminary neuropathological findings [ 57 ]. Most importantly, we have a control cohort of 12 UK hGH recipients who did not develop iCJD, but died from complications of the underlying medical conditions that caused their hGH deficiency; no similar cohorts have yet been studied in this way.
The extensive laboratory-based data on these groups of patients is matched by detailed clinical data, including the dates and duration of hGH treatment in the 35 hGH-iCJD cases and the 12 hGH control cases, and the type of hGH preparations that were used during the period of treatment.
ABC score Hyman et al. Hybrid protocol from Love et al. Vertical bars represent the mean with standard deviation values. Sections from all CNS tissues were labelled with two monoclonal anti-PrP antibodies recognising different epitopes of the prion protein: All cases were also assessed for cerebral amyloid angiopathy CAA in vessels in the leptomeninges, the brain parenchyma and brain capillaries.
CAA was scored according to the criteria of Love et al. Subsequent genotype data was converted into APOE allele status [ 70 ]. Variant calling was performed using FreeBayes [ 18 ]. Subsequent analysis was restricted to on-target homozygous, heterozygous, and compound heterozygous variants with a minimum read depth of 10, and base quality score of All graphs were generated using GraphPad Prism 7.
The distribution, severity and nature of the spongiform change, gliosis, amyloid plaque formation and the accumulation of disease-associated prion protein on immunohistochemistry were recorded in all cases fixed tissue from case hGH-iCJD1 was not available for PrP immunohistochemical analysis. A widespread spongiform encephalopathy was present in all cases, accompanied by variable neuronal loss and gliosis, with amyloid plaques in the cerebellum identified in 16 cases.
Microvacuolation was observed in the lower layers of the cerebral cortex d with a combination of granular, perineuronal and plaque-like accumulations of PrP in the cerebral and cerebellar cortex h , l. No kuru-type amyloid plaques were present in any brain region.
Fourteen of the 15 codon MV patients showed a pathology closely associated with the sCJD MV2K histotype with predominantly microvacuolation in the cerebral cortex, hippocampus, basal ganglia and thalamus and cerebellar cortex.
Kuru-type amyloid plaques were present in the cerebellum in all 14 cases, and occasionally in the cerebral cortex. Perineuronal, kuru-type plaques and plaque-like PrP deposits were observed in the cerebellum, basal ganglia, thalamus, hippocampus and occasionally in the cerebral cortex Fig. The remaining codon MV case had a pathology more in keeping with the sCJD MV2C histotype, with a predominantly confluent spongiform change in the cerebral cortex and a perivacuolar pattern of PrP deposition.
Kuru-type amyloid plaques were not observed in this case. Patchy spongiform change was observed in the cerebellar cortex, with no amyloid plaques. PrP deposition showed a widespread granular pattern Fig. No evidence of a spongiform encephalopathy or prion protein immunoreactivity was found in any of the hGH-control cases. Case hGH-iCJD31 shared some of the atypical features seen in hGH-iCJD20, with predominantly microvacuolar spongiform change in the cerebral cortex, particularly in layers 5—6, hippocampus and basal ganglia Fig.
The thalamus and cerebellum showed less spongiform change, but no kuru-type plaques were identified in the cerebellum. PrP immunohistochemistry showed a combination of granular, perineuronal and plaque-like PrP deposits in a widespread distribution in the CNS. An occasional PrP plaque-like deposit was present in the parietal cortex, with intense labelling on PrP immunohistochemistry Fig. Cored plaques were less frequently observed in hGH-iCJD cases b with neuritic plaques demonstrated with the Bielschowsky silver stain c.
CAA with patchy meningeal deposits and circumferential deposition were observed in the superficial cortical vessels in hGH control cases j. This case also showed severe capillary CAA with marked thickening of vessel walls, the presence of dyshoric cortical vessel and vasculopathy shown with the splitting of an intracortical arteriole wall m — o.
CAA was present most often in the occipital meningeal vessels and occipital cortex, but occasional cases had isolated CAA in the parietal or frontal cortex.
A single case also had CAA in the cerebellar meningeal vessels, with no cerebellar parenchymal involvement Fig. No PrP labelling in these vessels was identified. Phospho-tau immunolabelling was present in all CJD cases analysed, irrespective of aetiology in the form of small neuritic dots in the neuropil as previously described [ 36 ].
Small numbers of AT8-positive pretangles and occasional neurofibrillary tangles labelled in the gliotic region in the inferior right temporal cortex in a single hGH control patient who had undergone resection of an ependymoma Online Resource Fig. Statistical analysis was performed using an unpaired t test.
Neither can be considered as highly penetrant monogenic alleles causing disease. No other variants were detected in the vCJD cases. The brain in the latter case was found to have a type 2 PrP res isoform in diagnostic Western blotting.
Densitometric analysis indicated that the levels of PrP res in the pituitary gland and dorsal root ganglion were around 0. Indeterminate results on NaPTA WB when two of the usual three PrP res bands were visible , was observed with adrenal gland, bone marrow, kidney, heart, lymph node, skeletal muscle and peripheral nerve.
Repeat NaPTA WB analysis of the indeterminate cases was attempted, but was restricted in some cases by tissue sample availability. This study provides a detailed description of the pathological phenotype of the largest series of iCJD cases 35 cases occurring in recipients of hGH in the UK or indeed any country. The most likely source of prions in hGH preparations is sCJD, which is the commonest form of human prion disease, occurring most frequently in elderly patients, who accounted for the majority of the UK hospital autopsies that were the main source of pituitary glands collected for hGH extraction.
With such close similarities in the neuropathological phenotypes between sCJD and hGH-iCJD cases, a detailed clinical history of any potential iatrogenic exposure to CJD prions is essential for diagnosis. The peripheral pathogenesis of hGH-iCJD following inoculation of infected hGH preparations by intramuscular and subcutaneous injection is not known.
These complex mechanisms partly explain the lengthy incubation period in prion diseases [ 32 ]. The results of this study on a limited range of non-CNS tissues available give some support for involvement of the peripheral nervous system nerves, dorsal root ganglia and trigeminal ganglia and, for the first time, involvement of lymphoid tissues in a single hGH-iCJD case.
It may be that hGH-iCJD has some similarities to vCJD in terms of its peripheral pathogenesis, but the levels of PrP res detected in lymphoid and peripheral nervous system structures appear lower and more restricted in distribution than in vCJD. Overall, no major differences are observed in the nature or range of severity of the pathology between the hGH-iCJD and hGH control groups.
The same could be said for the lack of a relationship between the duration of hGH treatment and the development of iCJD; prion contamination of the hGH inocula also having been variable and unpredictable. Subsequent studies of the hGH produced by the modified Wilhelmi protocol were reported in [ 63 ].
Questions have been raised on the clinical background of the patients included in the study by Jaunmuktane et al. The pretangles in hGH-iCJD 31 are more difficult to explain, but might represent a local reaction to a previous focal insult no longer apparent in the post-mortem brain. Pretangles in the brains of very young individuals were identified in a large study by Braak et al. However, subcortical pretangles or tangles were not found in this or any other case examined.
The severe CAA found in the older hGH control patients in this study suggests that surviving hGH recipients may be at future risk of the complications of CAA, including spontaneous lobar cerebral haemorrhage, perivascular inflammation and cognitive impairment [ 17 ] in addition to having lived with the knowledge of an increased risk of CJD.
Dr Peter Adlard is also funded by the Department of Health. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health or the Scottish Government. We would also like to express our gratitude to UK Neuropathologists and their laboratory staff and to the relatives of patients for their consent to conduct research on autopsy tissue specimens.
The authors declare that they have no conflicts of interest. Informed consent for the research use of autopsy tissue was obtained from the relatives of the deceased whenever necessary. This article does not contain any studies with animals performed by any of the authors. Introduction Prion diseases are transmissible neurodegenerative disorders characterised by the accumulation of a disease-associated misfolded form of the normal cellular prion protein PrP C in the central nervous system CNS , commonly referred to as PrP Sc [ 24 ].
Diagnoses were made according to internationally accepted criteria for human prion diseases [ 66 ]. Inclusion criteria for the cases investigated in this study were: Open image in new window. All hGH patients examined had received treatment with hGH during the period — with the duration of hGH treatment varying from 2— One form of UK pituitary-derived hGH, the modified Wilhelmi preparation, had been administered to all hGH recipients who had developed iCJD, albeit in varying quantities and over different time periods [ 59 , 64 ].
In agreement with our earlier data, statistically significant associations were found between the PRNP codon genotype and disease incubation periods and duration of illness in the hGH-iCJD patients [ 57 ]. Three major histotypes were identified in relation to the established classification of subtypes of sCJD [ 47 ]. All 11 codon VV cases showed a pattern closely resembling that of the sCJD VV2 histotype characterised by microvacuolation, often in a linear distribution in layer 5 of the cerebral cortex with severe spongiform change in the basal ganglia, the CA1 region of the hippocampus and the subiculum.
Severe neuronal loss and gliosis was apparent in the cerebellar cortex, often resulting in cerebellar cortical atrophy Fig.
PrP immunohistochemistry shows granular and perineuronal deposits in the cerebral cortex in layer 5, with decoration of apical ascending dendrites.
Plaque-like deposits occurred throughout the brain, but no true amyloid plaques were detected Fig. Of the 35 hGH-iCJD cases, 33 had sufficient paraffin-embedded tissue for further pathological analysis by immunohistochemistry. The plaque frequency varied from occasional diffuse grey mater plaques to more numerous diffuse and neuritic plaques up to CERAD score 2. Immunohistochemistry for phospho-tau showed only small numbers of fine neuritic processes around the Bielschowsky-positive neuritic plaques.
Phospho-tau-positive neurites were also sparse in hGH-iCJD cases, but more neurites were identified following labelling with the ubiquitin antibody Fig. There was considerable variability in the availability of fixed and frozen tissue for each individual case. PrP immunopositivity was found in the adrenal gland in three hGH-iCJD cases, generally in the chromaffin cells of the adrenal medulla Fig. PrP immunoreactivity was also observed in a single skeletal muscle sample hGH-iCJD15 , in a linear pattern with a distribution and morphology consistent with that of a small nerve, as previously reported Fig.
Over half of the pituitary glands examined showed PrP immunoreactivity predominantly in the neurohypophysis, as previously described Fig.
However, the level of detail in these reports, varies in both the descriptive pathology of the CNS and the results of associated genetic investigations. This study adds considerably to these reports in terms of the number of cases studied, the inclusion of hGH control cases without iCJD, and in the young age of the patients included. The detailed neuropathological description provided is comparable with that in Kovacs et al.
Study references Jaunmuktane et al.