Human Prion Diseases in The Netherlands (1998–2009): Clinical, Genetic and Molecular Aspects

Prion diseases are rare and fatal neurodegenerative disorders that can be sporadic, inherited or acquired by infection. Based on a national surveillance program in the Netherlands we describe here the clinical, neuropathological, genetic and molecular characteristics of 162 patients with neuropathologically confirmed prion disease over a 12-year period (1998–2009). Since 1998, there has been a relatively stable mortality of Creutzfeldt-Jakob disease (CJD) in the Netherlands, ranging from 0.63 to 1.53 per million inhabitants per annum. Genetic analysis of the codon 129 methionine/valine (M/V) polymorphism in all patients with sporadic CJD (sCJD) showed a trend for under-representation of VV cases (7.0%), compared with sCJD cohorts in other Western countries, whereas the MV genotype was relatively over-represented (22,4%). Combined PrPSc and histopathological typing identified all sCJD subtypes known to date, except for the VV1 subtype. In particular, a “pure" phenotype was demonstrated in 60.1% of patients, whereas a mixed phenotype was detected in 39.9% of all sCJD cases. The relative excess of MV cases was largely accounted for by a relatively high incidence of the MV 2K subtype. Genetic analysis of the prion protein gene (PRNP) was performed in 161 patients and showed a mutation in 9 of them (5.6%), including one FFI and four GSS cases. Iatrogenic CJD was a rare phenomenon (3.1%), mainly associated with dura mater grafts. Three patients were diagnosed with new variant CJD (1.9%) and one with variably protease-sensitive prionopathy (VPSPr). Post-mortem examination revealed an alternative diagnosis in 156 patients, most commonly Alzheimer's disease (21.2%) or vascular causes of dementia (19.9%). The mortality rates of sCJD in the Netherlands are similar to those in other European countries, whereas iatrogenic and genetic cases are relatively rare. The unusual incidence of the VV2 sCJD subtype compared to that reported to date in other Western countries deserves further investigation

Immune Characterization of the Programmed Death Receptor Pathway in High Risk Prostate Cancer.

BACKGROUND: Programmed cell death-1 (PD-1), a T-cell inhibitory receptor, and its ligand, PD-L1, have been reported to be expressed in many tumor types, and this expression has led to the development of many drugs targeting the PD-1 pathway. The objective of this study was to determine the expression of PD-1 and PD-L1 in high-grade prostate cancer tissues, and correlate the expression with disease and patient characteristics. MATERIALS AND METHODS: Immunohistochemistry for PD-1 (CD279), PD-L1 (B7-H1), and CD3 was performed and scored from 0 to 5 on prostatectomy/biopsy tissue samples taken from 25 men with high-grade prostate cancer. Charts were then retrospectively reviewed for numerous patient and disease characteristics. Statistical analyses were done to investigate the association of these patient and disease characteristics with PD-1, PD-L1, and CD3 expression. RESULTS: A score of 3 to 5 on the semiquantitative 0 to 5 score was deemed high expression whereas a score of 0 to 2 was deemed low expression. Of the 25 samples, 2 (8%) scored high for PD-1 expression, 2 (8%) scored high for PD-L1 expression, and 18 (72%) scored high for CD3 expression. There was no statistically significant difference between high and low expression groups of PD-1, PD-L1, or CD3 for any of the variables we collected. CONCLUSION: An overall low expression of PD-1 and PD-L1, and a concurrent high expression of CD3+ T cells was found in high-risk prostate cancer tissue. No significant association was found between expression of PD-1, PD-L1, or CD3, and patient or disease characteristics. Because of this, one might be able to question the role of PD-L1 in local immune suppression in prostate cancer

Classification of sporadic CJD subtypes in the Dutch population based on combined molecular and histopathological assessment.

<p>Nomenclature is largely based on the codon 129 genotype, which can be either methionine (M) or valine (V) and the PrP^Sc type (type 1 or 2, according to Parchi <i>et al.</i>) Since both MM2 and MV2 groups are associated to 2 distinct phenotypes, these are further defined with a third parameter (<i>capital letter</i>) referring to distinctive histopathological features: <i>K</i> kuru type amyloid plaques, <i>C</i> predominant cortical pathology with confluent vacuoles and perivacuolar PrP staining, <i>T</i> prominent thalamic pathology with atrophy.</p>*<p>In 13 patients, neuropathological examination identified the distinctive feature of the MM/MV 2C subtype (i.e. grape-like clusters of spongiform change with a coarse PrP immunohistochemical staining pattern), but the type 2 band on immunoblotting was not detected.</p

Demographic characteristics of all patients with new variant CJD.

<p>M = methionine; V = valine.</p

Demographic characteristics of all patients with iatrogenic CJD (1998–2009).

<p>hGH = human Growth hormone; M = methionine; V = valine.</p

Patients sorted by clinical classification with autopsy results.

<p>CJD = Creutzfeldt-Jakob disease; sCJD = sporadic Creutzfeldt-Jakob disease; gCJD = genetic Creutzfeldt-Jakob disease; iCJD = iatrogenic Creutzfeldt-Jakob disease; vCJD = variant Creutzfeldt-Jakob disease; VPSPr = variably protease-sensitive prionopathy; CAA = cerebral amyloid angiopathy.</p

Demographic characteristics of patients with genetic CJD (1998–2009), caused by various mutations in <i>PRNP</i>.

<p>All Ins = insertion; bp = base pairs; M = methionine; V = valine; n.d. = not determined;</p><p>CJD patients with the same mutation belong to the same family.</p><p> = Creutzfeldt-Jakob disease; GSS = Gerstmann-Sträussler-Scheinker disease; FFI = Fatal Familial Insomnia; PrP-CAA = prion protein cerebral amyloid angiopathy.</p

Codon 129 distribution in the normal Caucasian and Dutch population and in sCJD patients [32], [35], [46].

<p>M = methionine; V = valine.</p