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

Acute effects of Delta 9-tetrahydrocannabinol (THC) on resting state brain function and their modulation by COMT genotype

Cannabis produces a broad range of acute, dose-dependent psychotropic effects. Only a limited number of neuroimaging studies have mapped these effects by examining the impact of cannabis on resting state brain neurophysiology. Moreover, how genetic variation influences the acute effects of cannabis on resting state brain function is unknown. Here we investigated the acute effects of ∆9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, on resting state brain neurophysiology, and their modulation by catechol-methyl-transferase (COMT) Val158Met genotype. Thirty-nine healthy volunteers participated in a pharmacological MRI study, where we applied Arterial Spin Labelling (ASL) to measure perfusion and functional MRI to assess resting state connectivity. THC increased perfusion in bilateral insula, medial superior frontal cortex, and left middle orbital frontal gyrus. This latter brain area showed significantly decreased connectivity with the precuneus after THC administration. THC effects on perfusion in the left insula were significantly related to subjective changes in perception and relaxation. These findings indicate that THC enhances metabolism and thus neural activity in the salience network. Furthermore, results suggest that recruitment of brain areas within this network is involved in the acute effects of THC. Resting state perfusion was modulated by COMT genotype, indicated by a significant interaction effect between drug and genotype on perfusion in the executive network, with increased perfusion after THC in Val/Met heterozygotes only. This finding suggests that prefrontal dopamine levels are involved in the susceptibility to acute effects of cannabis

Acute effects of ∆9-tetrahydrocannabinol (THC) on resting state brain function and their modulation by COMT genotype

Cannabis produces a broad range of acute, dose-dependent psychotropic effects. Only a limited number of neuroimaging studies have mapped these effects by examining the impact of cannabis on resting state brain neurophysiology. Moreover, how genetic variation influences the acute effects of cannabis on resting state brain function is unknown. Here we investigated the acute effects of ∆9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, on resting state brain neurophysiology, and their modulation by catechol-methyl-transferase (COMT) Val158Met genotype. Thirty-nine healthy volunteers participated in a pharmacological MRI study, where we applied Arterial Spin Labelling (ASL) to measure perfusion and functional MRI to assess resting state connectivity. THC increased perfusion in bilateral insula, medial superior frontal cortex, and left middle orbital frontal gyrus. This latter brain area showed significantly decreased connectivity with the precuneus after THC administration. THC effects on perfusion in the left insula were significantly related to subjective changes in perception and relaxation. These findings indicate that THC enhances metabolism and thus neural activity in the salience network. Furthermore, results suggest that recruitment of brain areas within this network is involved in the acute effects of THC. Resting state perfusion was modulated by COMT genotype, indicated by a significant interaction effect between drug and genotype on perfusion in the executive network, with increased perfusion after THC in Val/Met heterozygotes only. This finding suggests that prefrontal dopamine levels are involved in the susceptibility to acute effects of cannabis.</p

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

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

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

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

<p>M = methionine; V = valine.</p