ABSTRACT
BACKGROUND: Genomic technologies are increasingly used to guide clinical decision-making in cancer control. Economic evidence about the cost-effectiveness of genomic technologies is limited, in part because of a lack of published comprehensive cost estimates. In the present micro-costing study, we used a time-and-motion approach to derive cost estimates for 3 genomic assays and processes-digital gene expression profiling (gep), fluorescence in situ hybridization (fish), and targeted capture sequencing, including bioinformatics analysis-in the context of lymphoma patient management. METHODS: The setting for the study was the Department of Lymphoid Cancer Research laboratory at the BC Cancer Agency in Vancouver, British Columbia. Mean per-case hands-on time and resource measurements were determined from a series of direct observations of each assay. Per-case cost estimates were calculated using a bottom-up costing approach, with labour, capital and equipment, supplies and reagents, and overhead costs included. RESULTS: The most labour-intensive assay was found to be fish at 258.2 minutes per case, followed by targeted capture sequencing (124.1 minutes per case) and digital gep (14.9 minutes per case). Based on a historical case throughput of 180 cases annually, the mean per-case cost (2014 Canadian dollars) was estimated to be $1,029.16 for targeted capture sequencing and bioinformatics analysis, $596.60 for fish, and $898.35 for digital gep with an 807-gene code set. CONCLUSIONS: With the growing emphasis on personalized approaches to cancer management, the need for economic evaluations of high-throughput genomic assays is increasing. Through economic modelling and budget-impact analyses, the cost estimates presented here can be used to inform priority-setting decisions about the implementation of such assays in clinical practice.
ABSTRACT
Acute lymphoblastic leukemia (ALL) is a malignant disease of the white blood cells. The etiology of ALL is believed to be multifactorial and likely to involve an interplay of environmental and genetic variables. We performed a genome-wide association study of 355 750 single-nucleotide polymorphisms (SNPs) in 474 controls and 419 childhood ALL cases characterized by a t(12;21)(p13;q22) - the most common chromosomal translocation observed in childhood ALL - which leads to an ETV6-RUNX1 gene fusion. The eight most strongly associated SNPs were followed-up in 951 ETV6-RUNX1-positive cases and 3061 controls from Germany/Austria and Italy, respectively. We identified a novel, genome-wide significant risk locus at 3q28 (TP63, rs17505102, P(CMH)=8.94 × 10(-9), OR=0.65). The separate analysis of the combined German/Austrian sample only, revealed additional genome-wide significant associations at 11q11 (OR8U8, rs1945213, P=9.14 × 10(-11), OR=0.69) and 8p21.3 (near INTS10, rs920590, P=6.12 × 10(-9), OR=1.36). These associations and another association at 11p11.2 (PTPRJ, rs3942852, P=4.95 × 10(-7), OR=0.72) remained significant in the German/Austrian replication panel after correction for multiple testing. Our findings demonstrate that germline genetic variation can specifically contribute to the risk of ETV6-RUNX1-positive childhood ALL. The identification of TP63 and PTPRJ as susceptibility genes emphasize the role of the TP53 gene family and the importance of proteins regulating cellular processes in connection with tumorigenesis.
Subject(s)
Core Binding Factor Alpha 2 Subunit/genetics , Genetic Predisposition to Disease , Germ-Line Mutation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Proto-Oncogene Proteins c-ets/genetics , Repressor Proteins/genetics , Case-Control Studies , Child , Chromosomes, Human, Pair 3 , Genome-Wide Association Study , Humans , Polymorphism, Single Nucleotide , Quantitative Trait Loci , ETS Translocation Variant 6 ProteinABSTRACT
Several molecular subtypes of sporadic Creutzfeldt-Jakob disease have been identified and electroencephalogram and cerebrospinal fluid biomarkers have been reported to support clinical diagnosis but with variable utility according to subtype. In recent years, a series of publications have demonstrated a potentially important role for magnetic resonance imaging in the pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease. Magnetic resonance imaging signal alterations correlate with distinct sporadic Creutzfeldt-Jakob disease molecular subtypes and thus might contribute to the earlier identification of the whole spectrum of sporadic Creutzfeldt-Jakob disease cases. This multi-centre international study aimed to provide a rationale for the amendment of the clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Patients with sporadic Creutzfeldt-Jakob disease and fluid attenuated inversion recovery or diffusion-weight imaging were recruited from 12 countries. Patients referred as 'suspected sporadic Creutzfeldt-Jakob disease' but with an alternative diagnosis after thorough follow up, were analysed as controls. All magnetic resonance imaging scans were assessed for signal changes according to a standard protocol encompassing seven cortical regions, basal ganglia, thalamus and cerebellum. Magnetic resonance imaging scans were evaluated in 436 sporadic Creutzfeldt-Jakob disease patients and 141 controls. The pattern of high signal intensity with the best sensitivity and specificity in the differential diagnosis of sporadic Creutzfeldt-Jakob disease was identified. The optimum diagnostic accuracy in the differential diagnosis of rapid progressive dementia was obtained when either at least two cortical regions (temporal, parietal or occipital) or both caudate nucleus and putamen displayed a high signal in fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging. Based on our analyses, magnetic resonance imaging was positive in 83% of cases. In all definite cases, the amended criteria would cover the vast majority of suspected cases, being positive in 98%. Cerebral cortical signal increase and high signal in caudate nucleus and putamen on fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging are useful in the diagnosis of sporadic Creutzfeldt-Jakob disease. We propose an amendment to the clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease to include findings from magnetic resonance imaging scans.
Subject(s)
Creutzfeldt-Jakob Syndrome/diagnosis , 14-3-3 Proteins/analysis , Adult , Aged , Aged, 80 and over , Anti-Inflammatory Agents/therapeutic use , Biomarkers/analysis , Cerebral Cortex/pathology , Codon/genetics , Creutzfeldt-Jakob Syndrome/cerebrospinal fluid , Creutzfeldt-Jakob Syndrome/genetics , Electroencephalography , False Positive Reactions , Female , Genotype , Humans , International Cooperation , Magnetic Resonance Imaging , Male , Middle Aged , Reference StandardsABSTRACT
BACKGROUND: With respect to sporadic Creutzfeldt-Jakob disease (sCJD), six molecular subtypes (MM1, MM2, MV1, MV2, VV1, and VV2) have been described, which vary with respect to age at disease onset, disease duration, early symptoms, and neuropathology. MRI signal alterations were reported to correlate with distinct Creutzfeldt-Jakob disease (CJD) subtypes. This multicenter, international study aimed to describe the brain MRI findings associated with each of the sCJD molecular subtypes. METHODS: Pathologically confirmed sCJD cases with codon 129 genotype (MM, MV, and VV), PrP(Sc) type, and fluid-attenuated inversion recovery (FLAIR) or diffusion-weighted imaging (DWI) were collected in seven countries. All MRI scans were assessed for signal changes according to a standard protocol encompassing seven cortical regions, basal ganglia, thalamus, and cerebellum. RESULTS: MRI scans were evaluated in 211 CJD patients (98 MM1, 23 MM2, 19 MV1, 30 MV2, 9 VV1, and 32 VV2). Basal ganglia hyperintensities occurred most frequently in MV2, VV2, and MM1 subtypes (79, 77, and 70%). Wide cerebral cortical signal increase was most common in VV1, MM2, and MV1 subtypes (86, 77, and 77%). Thalamic hyperintensities occurred most often in VV2 (45%) and MV2 (43%). The most consistent finding across most subtypes was high signal in basal ganglia, with these abnormalities found in 63% (FLAIR) and 71% (DWI). CONCLUSION: Cortical signal increase and hyperintensities in the basal ganglia and thalamus are detected by MRI across all molecular sporadic Creutzfeldt-Jakob disease subtypes. Our findings argue that characteristic MRI lesion patterns may occur for each molecular subtype.
Subject(s)
Brain/pathology , Creutzfeldt-Jakob Syndrome/pathology , Magnetic Resonance Imaging/methods , Basal Ganglia/anatomy & histology , Basal Ganglia/pathology , Basal Ganglia/physiopathology , Brain/anatomy & histology , Brain/physiopathology , Cerebral Cortex/anatomy & histology , Cerebral Cortex/pathology , Cerebral Cortex/physiopathology , Codon , Creutzfeldt-Jakob Syndrome/classification , Creutzfeldt-Jakob Syndrome/genetics , DNA Mutational Analysis , Diffusion Magnetic Resonance Imaging/methods , Disease Progression , Genetic Testing , Genotype , Humans , Nerve Fibers, Myelinated/pathology , Observer Variation , Odds Ratio , PrPSc Proteins/genetics , Predictive Value of Tests , Sensitivity and Specificity , Thalamus/anatomy & histology , Thalamus/pathology , Thalamus/physiopathologyABSTRACT
OBJECTIVE: Iatrogenic Creutzfeldt-Jakob disease (iCJD) is mainly associated with dura mater (DM) grafts and administration of human growth hormones (hGH). Data on disease course in DM-CJD are limited. We describe the clinical and diagnostic findings in this patient group with special emphasis on MRI signal alterations. METHODS: Ten DM-CJD patients were studied for their clinical symptoms and diagnostic findings. The MRIs were evaluated for signal increase of the cortical and subcortical structures. RESULTS: DM-CJD patients had a median incubation time of 18 years and median disease duration of 7 months. The majority of patients were MM homozygous at codon 129 of the prion protein gene (PRNP) and presented with gait ataxia and psychiatric symptoms. No correlation between the graft site and the initial disease course was found. The MRI showed cortical and basal ganglia signal increase each in eight out of ten patients and thalamic hyperintensity in five out of ten cases. Of interest, patients with thalamic signal increase were homozygous for methionine. CONCLUSION: The MRI findings in DM-CJD largely resemble those seen in sporadic CJD, as the cortex and basal ganglia are mainly affected.
Subject(s)
Brain Tissue Transplantation/adverse effects , Brain/pathology , Creutzfeldt-Jakob Syndrome/complications , Creutzfeldt-Jakob Syndrome/pathology , Dura Mater/transplantation , Iatrogenic Disease , Adult , Aged , Ataxia/complications , Creutzfeldt-Jakob Syndrome/diagnosis , DNA Mutational Analysis , Female , Humans , Infectious Disease Incubation Period , Magnetic Resonance Imaging , Male , Mental Disorders/complications , Middle Aged , Prion Proteins , Prions/genetics , Time FactorsABSTRACT
Hurler's syndrome is an inborn error of mucopolysaccharide metabolism leading to premature death in childhood. Allogeneic hematopoietic SCT can achieve long-term survival by correcting the enzymatic deficiency. In an attempt to improve long-term engraftment and to reduce regimen-related toxicity (RRT), a prospective multicenter approach was initiated in Germany using a fludarabine-based radiation-free preparative regimen. Between 2001 and 2008, 12 children were enrolled. Median age at SCT was 14 months (range, 4-31 months). The conditioning regimen contained fludarabine, BU, melphalan and antithymocyte globulin. CD34 positively selected PBSC were used in 10 children with a matched unrelated donor. Median cell dose was 24.6 x 10(6) CD34+ cells per kg (range 10.0-54.8). Two children with a matched sibling donor received non-manipulated BM. Donor lymphocyte infusions were given in 6/12 children for mixed hematopoietic chimerism. At a median follow-up of 29 months (range 2-85 months), all children engrafted and have either stabilized or improved neurological function. In total, 12/12 patients showed donor-derived engraftment with 9/12 having full and 3/12 having mixed hematopoiesis. One developed acute GVHD >or=grade II. RRT >or=grade II was observed in two patients.
Subject(s)
Hematopoietic Stem Cell Transplantation , Mucopolysaccharidosis I/therapy , Adoptive Transfer , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child, Preschool , Cyclophosphamide/therapeutic use , Female , Graft vs Host Disease/etiology , Humans , Infant , Male , Prospective Studies , Transplantation Conditioning , Transplantation, HomologousABSTRACT
BACKGROUND: The 14-3-3 protein is a physiological cellular protein expressed in various tissues, and its release to CSF reflects extensive neuronal damage as in Creutzfeldt-Jakob disease (CJD), but also in other neurological diseases. 14-3-3 protein in CSF in the proper clinical context is a reliable diagnostic tool for sporadic CJD. However, the sensitivity varies across molecular CJD subtypes. OBJECTIVE: We determined the level of the 14-3-3 protein in CSF from 70 sporadic CJD patients with distinct molecular subtypes using an improved enzyme-linked immunosorbent assay (ELISA) protocol technique. RESULTS: The 14-3-3 levels varied markedly across various molecular subtypes. The most elevated levels of 14-3-3 protein were observed in the frequently occurring and classical subtypes, whereas the levels were significantly lower in the subtypes with long disease duration and atypical clinical presentation. PRNP codon 129 genotype, PrP(sc) isotype, disease stage and clinical subtype influenced the 14-3-3 level and the test sensitivity. CONCLUSIONS: The 14-3-3 protein levels differ across molecular subtypes and might be used for their early pre-mortem identification when the codon 129 genotype is known, especially for the less common molecular subtypes such as MV2 and MM2.
Subject(s)
14-3-3 Proteins/cerebrospinal fluid , 14-3-3 Proteins/classification , Creutzfeldt-Jakob Syndrome/cerebrospinal fluid , Aged , Creutzfeldt-Jakob Syndrome/genetics , Disease Progression , Enzyme-Linked Immunosorbent Assay , Female , Genotype , Humans , Male , Middle Aged , PrPSc Proteins/genetics , PrPSc Proteins/metabolism , Prion Proteins , Prions/genetics , Retrospective Studies , Statistics, NonparametricABSTRACT
BACKGROUND AND PURPOSE: To establish radiological features in the atypical MV2 subtype of sCJD compared with the classical MM1 subtype, as well as region- and sequence-dependent inter-observer correlation. METHODS: MRI hyperintensity of basal ganglia (BG), cortex and thalamus was evaluated in 31 MM1 and 32 MV2 patients. Each MR scan was analyzed independently by two neuroradiologists blinded to PRNP genotype/prion protein type. RESULTS: Cumulative T2-sensitivity for BG hyperintensity was higher in the MV2 subtype (84% for both observers versus 61% in observer 1/42% in observer 2 in MM1 patients). Significant inter-observer agreement was found for BG and thalamus on T2, FLAIR, PD and DWI, but for cortex only on DWI. Thalamic changes were significantly more frequent in MV2 than in MM1 patients (cumulative sensitivity 86% vs. 12.5% on DWI). DISCUSSION: The high frequency of thalamic hyperintensity in the MV2 subtype allowed differentiation from MM1 patients. Good inter-observer agreement was found for BG and thalamus in all sequences. DWI showed the highest inter-observer correlation independent of the investigated brain region and was therefore not only highly sensitive but also relatively independent of investigator bias. Since inter-observer correlation for cortical hyperintensity in T2, FLAIR and PD is relatively low, the cortical changes should not be over-interpreted with these sequences.
Subject(s)
Brain/pathology , Creutzfeldt-Jakob Syndrome/pathology , Magnetic Resonance Imaging , Aged , Female , Humans , Male , Middle Aged , Reproducibility of ResultsABSTRACT
BACKGROUND AND PURPOSE: Hyperintense basal ganglia on MR imaging support the diagnosis of sporadic Creutzfeldt-Jakob disease (CJD). Our aim was to study the frequency of patients with sporadic CJD presenting with and without characteristic basal ganglia lesions on MR imaging and to examine the corresponding patient characteristics. MATERIALS AND METHODS: Fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted images (DWI) of 55 patients with CJD were assessed for signal-intensity increase (FLAIR) or restricted diffusion (DWI) in 7 cortex regions and the basal ganglia, thalamus, and cerebellum. Patient characteristics as well as electroencephalography, CSF, and codon 129 genotype of the prion protein gene (PRNP) were correlated with the most frequent MR imaging lesion patterns. RESULTS: Two major lesion patterns were identified by DWI: cortex and basal ganglia involvement (two thirds) and isolated cortex involvement (one third). In the latter patient group, the cortex involvement was widespread (at least 3 regions affected in 89% on DWI) and usually included the frontal and parietal lobes (78%). The length of the disease course was significantly prolonged (median, 12 versus 5 months). No significant differences were observed concerning electroencephalography and CSF findings and codon 129 genotype distributions. Of 4 patients with normal MR imaging findings, the CSF was positive for the 14-3-3 protein in 3. CONCLUSION: A high number of patients with CJD present without basal ganglia lesions on MR imaging. Isolated cortex involvement on DWI and FLAIR should lead to suggestion of CJD, even if the disease course is only slowly progressive. Additional 14-3-3 protein analysis in the CSF may support the CJD diagnosis.
Subject(s)
Basal Ganglia Diseases/diagnosis , Basal Ganglia/pathology , Creutzfeldt-Jakob Syndrome/diagnosis , Image Interpretation, Computer-Assisted/methods , Magnetic Resonance Imaging/methods , Adult , Aged , Female , Humans , Male , Middle Aged , Reproducibility of Results , Sensitivity and SpecificitySubject(s)
Anemia, Sickle Cell/therapy , Anticonvulsants/adverse effects , Bone Marrow Transplantation , Drug Hypersensitivity , Graft Rejection/chemically induced , Phenytoin/adverse effects , Anticonvulsants/administration & dosage , Child , Female , Humans , Male , Phenytoin/administration & dosage , Syndrome , Transplantation, HomologousABSTRACT
We report a retrospective analysis of 11 children with Down syndrome (DS) treated by SCT in eight German/Austrian SCT centres. Indications for transplantation were acute lymphoblastic leukaemia (N=8) and acute myeloid leukaemia (N=3). A reduced intensity conditioning (RIC) containing 2 Gy TBI was given to two patients, another five received a myeloablative regimen with 12 Gy TBI. Treosulphan or busulphan was used in the remaining four children. Four of eleven (36%) patients are alive. All of them were treated with a myeloablative regimen. One of the four surviving children relapsed 9 months after SCT and is currently receiving palliative outpatient treatment. The main cause of death was relapse (5/11). Two children died of regimen-related toxicity (RRT), one from severe exfoliative dermatitis and multiorgan failure after a treosulphan-containing regimen, the other from GvHD-related infections after RIC. Acute GvHD of the skin was observed in 10 of 10 evaluable patients, and chronic GvHD in 4 of 8. Our data show that DS patients can tolerate commonly used, fully myeloablative preparative regimens. The major cause of death is relapse rather than RRT resulting in an event-free survival of 18% and over all survival of 36%.
Subject(s)
Down Syndrome/complications , Hematopoietic Stem Cell Transplantation/adverse effects , Leukemia, Myeloid, Acute/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Adolescent , Child , Child, Preschool , Female , Graft vs Host Disease/prevention & control , Humans , Male , Recurrence , Retrospective Studies , Transplantation Conditioning/adverse effects , Treatment FailureABSTRACT
BACKGROUND AND PURPOSE: High cortical signal intensity on diffusion-weighted (DW) or fluid-attenuated inversion recovery (FLAIR) images is increasingly described in sporadic Creutzfeldt-Jakob disease (sCJD). The aim of this study was to assess the extent and location of high cortical signal intensity, to investigate whether DW or FLAIR is superior in showing changes in cortical signal intensity, and to find out whether the distribution of the signal intensity changes is random or follows a common pattern. MATERIALS AND METHODS: We analyzed FLAIR and DW MR imaging scans of 39 patients with sCJD for hyperintense cortical signal intensity. We compared the sensitivity of the DW and FLAIR scans. We correlated the extent and location of the cortical signal intensity changes with concomitant changes in deep gray matter and the genotype of codon 129 of the prion protein gene. RESULTS: There was high signal intensity in the insula, the cingulate gyrus, and the superior frontal gyrus in 95%. The cortical areas near the midline also frequently showed the abnormal signal intensity (precuneus 87%, paracentral lobe 77%). The precentral and postcentral gyri were affected less frequently (41% and 28%, respectively). The DW MR imaging showed the cortical changes more effectively than FLAIR. There was no correlation between the distribution of changes and additional signal alterations in deep gray matter or the genotype of codon 129. CONCLUSION: The distribution of cortical signal intensity abnormalities in patients with sCJD follows a common pattern, affecting mainly the cortical areas near the midline, the insula, cingulum, and the superior frontal cortex. DW imaging is superior to FLAIR in the detection of cortical high signal intensity.
Subject(s)
Cerebral Cortex/pathology , Creutzfeldt-Jakob Syndrome/pathology , Diffusion Magnetic Resonance Imaging/methods , Image Interpretation, Computer-Assisted/methods , Female , Humans , Male , Middle AgedABSTRACT
Creutzfeldt-Jakob disease (CJD) is a rare and fatal neurodegenerative disorder with a worldwide incidence of 1-1.5 per million. As in other countries, a CJD surveillance unit with a clinical and neuropathological approach was established in Goettingen (Germany) in 1993. Here we report the epidemiological data from a prospective 12-year surveillance. Since 1993, there has been an increasing incidence of CJD, from 0.7 in 1993 to 1.6 in 2005 with a quite stable level since 1998. During this period, the proportion of patients with MV and VV codon 129 genotype rose, possibly because of better identification of atypical subtypes. Six percent of all patients had a PRNP mutation, mainly D178N-129M (FFI), E200K and V210I. Iatrogenic CJD was a rare phenomenon. No patient infected by cadaveric growth hormone extracts was reported. Furthermore, no variant CJD patient has yet been identified in Germany. Differential diagnoses revealed a variety of neurodegenerative diseases, with Alzheimer's disease in the lead. One-third of the non-CJD patients included in this study suffered from a potentially treatable disorder such as metabolic or inflammatory diseases. The incidence and mortality rates in Germany are similar to those in other European countries. In contrast, however, acquired forms, such as iatrogenic and variant CJD are still rare in Germany or have not yet been identified.
Subject(s)
Creutzfeldt-Jakob Syndrome/epidemiology , Adult , Age Distribution , Aged , Aged, 80 and over , Creutzfeldt-Jakob Syndrome/diagnosis , Diagnosis, Differential , Genotype , Germany/epidemiology , Humans , Incidence , Middle Aged , Polymorphism, Genetic , Population Surveillance/methods , PrPSc Proteins/genetics , Prospective StudiesABSTRACT
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only definitive treatment for severe bone marrow dysfunction and clonal disorders in patients diagnosed with Shwachman-Diamond syndrome (SDS). In an attempt to minimize regimen-related toxicity (RRT), we have initiated a fludarabine/treosulfan/melphalan-based pilot protocol avoiding the combination of busulfan and cyclophosphamide. Median age at transplantation was 9.6 years (range 1.5-17 years). All three patients received conditioning with fludarabine (30 mg/m2/day x 6), treosulfan (12 g/m2/day x 3) and melphalan (140 mg/m2/day x 1). CAMPATH-1H (0.1 mg/kg x 2) was added in two cases, while rabbit ATG (Genzyme; 3 x 2.5 mg/kg) was given to the cord blood recipient. One patient was transplanted with a non-manipulated marrow graft from an HLA-identical sibling, one with a marrow graft from a 10/10 matched unrelated donor, and one with a 9/10 matched unrelated umbilical cord blood (UCB) unit. Mean cell doses given were 3.6 x 10(8) nucleated cells/kg BW for the bone marrow recipients and 4.2 x 10(7) nucleated cells/kg BW for UCB recipient. Overall, two of three patients are alive and display 100% donor chimerism. Acute graft-versus-host disease grade II was seen in one patient, while no GVHD exceeding grade I occurred in the remaining two.
Subject(s)
Bone Marrow Diseases/drug therapy , Busulfan/analogs & derivatives , Hematopoietic Stem Cell Transplantation/methods , Melphalan/administration & dosage , Transplantation Conditioning/methods , Vidarabine/analogs & derivatives , Abnormalities, Multiple/drug therapy , Adolescent , Busulfan/administration & dosage , Child , Child, Preschool , Cyclophosphamide , Drug Therapy, Combination , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/mortality , Humans , Infant , Male , Pilot Projects , Syndrome , Transplantation, Homologous , Treatment Outcome , Vidarabine/administration & dosageABSTRACT
BACKGROUND AND PURPOSE: MR imaging has played an increasingly important role in the diagnosis of Creutzfeldt-Jakob disease (CJD) since basal ganglia abnormalities on T2-weighted images have been described; thus, the aim of our study was to compare the value of different MR images in the diagnosis of CJD. METHODS: One hundred fifty-seven patients with CJD underwent MR imaging examinations. Ninety-two patients were neuropathologically confirmed, and 65 were clinically classified as having CJD through the CJD Surveillance Unit (probability of 95%). There was no standardized MR imaging protocol; thus, the examinations included 143 T2-weighted, 43 proton attenuation (PD)-weighted, 84 fluid-attenuated inversion recovery (FLAIR), and 44 diffusion-weighted images (DWI). The MR images were reviewed for pathologic changes of the basal ganglia, thalamus, and cerebral cortex. RESULTS: Cortical abnormalities were present in 70 patients (45%) and were visible in 80% (35/44) of all available DWI examinations. The basal ganglia were affected in 94 patients (60%), in particular in the caudate nucleus; the most sensitive sequences were DWI (64%) and PD-weighted (63%). A thalamic involvement was more frequently diagnosed on PD-weighted images (19%) and DWI (14%) than on FLAIR or T2-weighted images. CONCLUSION: PD-weighted images and DWI showed better results in the diagnosis of signal intensity changes in the basal ganglia compared with T2-weighted or FLAIR images; however, in the diagnosis of cortical changes, DWI was clearly superior. Our data suggest that DWI is the most sensitive MR imaging technique in the diagnosis of CJD.
Subject(s)
Creutzfeldt-Jakob Syndrome/diagnosis , Magnetic Resonance Imaging/methods , Basal Ganglia/pathology , Caudate Nucleus/pathology , Cerebral Cortex/pathology , Creutzfeldt-Jakob Syndrome/pathology , Diffusion Magnetic Resonance Imaging/methods , Humans , Image Enhancement/methods , Putamen/pathology , Retrospective Studies , Sensitivity and Specificity , Thalamus/pathologyABSTRACT
BACKGROUND: Recently, six molecular subtypes of sporadic CJD (sCJD) have been identified showing differences regarding the disease course, neuropathologic lesion patterns, and sensitivity to diagnostic tools. Only isolated cases of the rare VV1 type have been reported so far. OBJECTIVE: To describe the clinical characteristics and neuropathologic lesion profiles in nine cases. METHODS: In the years 1993 until late 2003, 571 definite neuropathologically confirmed cases of sporadic CJD were identified in Germany. Of these, nine were homozygous for valine and displayed type 1 of the pathologic PrPSc in the brain (VV1 type). RESULTS: The authors describe eight men and one woman belonging to the VV1 type. All patients were relatively young at disease onset (median 44 years vs 65 years in all sCJD) with prolonged disease duration (median 21 months vs 6 months in all sCJD). During the initial stages, their main clinical signs were personality changes and slowly progressive dementia as well as focal neurologic deficits. None of the nine VV1 patients had periodic sharp-wave complexes (PSWCs) in the EEG. Only two out of seven displayed the typical signal increase of the basal ganglia on MRI, whereas signal increase of the cortex was seen in all patients. The 14-3-3 protein levels were elevated in CSF in all cases tested. CONCLUSIONS: The clinical diagnosis of the VV1 type of sCJD can be best supported by the 14-3-3 test and cortical signal increase on MRI. Because of the young age at onset vCJD is sometimes suspected as a differential diagnosis. MRI plays an important role in differentiating these two disease types and should be performed early during the disease course.