In total, CSF analysis of dementia markers (14-3-3, tau, phosphorylated tau, amyloid β1–42) were performed on 29 022 samples. The main analysis (patient’s with definite clinical diagnosis) comprised 3616 samples from patients with various forms of transmissible spongiform encephalopathies (3254 samples being from patients with sporadic Creutzfeldt–Jakob disease) and 7115 from control subjects ().
Diagnoses of rapid progressive dementias in 14-3-3 test referrals
demonstrates the rapid progressive dementia diagnoses in patients with suspected Creutzfeldt–Jakob disease referred for CSF protein 14-3-3 testing between the years 1998 and 2008. Differential diagnoses were divided into: prion disorders (n= 3616), primary and secondary forms of neurodegenerative dementia (n= 3034, including vascular dementia and normal pressure hydrocephalus) and acute neurological disorders such as stroke, CNS inflammation, CNS tumour or epileptic fit (n= 1941). Non-neurological causes were from psychiatric (e.g. pseudo-dementia in depression) or metabolic origin (e.g. hyponatraemia) or related to ‘other diagnosis’ (n= 2140). The most frequent differential diagnosis was sporadic Creutzfeldt–Jakob disease with 30.3%, followed by neurodegenerative dementia with 28.3% and patients with ‘other diagnosis’ (11.2%). Regarding acute neurological disorders, the group of CNS inflammation was most frequent with 7.4%, followed by stroke (5.4%) and paraneoplastic/CNS tumour (3.2%). Rapid cognitive disturbance from a non-neurological cause comprised 4.3% psychiatric and 4.5% metabolic origin. If we exclude all patients with transmissible spongiform encephalopathies from the analysis, the distribution was as follows: 42.6% neurodegenerative dementia, 27.3% acute neurological disease (most frequently: 11.2% CNS inflammation, 8.2% stroke) and 13.2% non-neurological, potentially treatable cognitive deterioration (6.8% metabolic and 6.4% psychiatric disease).
Cerebrospinal fluid dementia markers in rapid progressive dementias
In the individual reference laboratories we observed a trend towards increased 14-3-3 test referrals not only for Creutzfeldt–Jakob disease, but also in screening of CSF dementia markers in patients with rapid progressive dementia (A). Going along with this finding, we observed a decrease in our positive predictive values over time. The negative predictive value remains stable (C) Because of this trend, we were able to collect substantial data on dementia markers in these patients. Hereby, we analysed tau, phosphorylated tau and amyloid-β1–42 according to subgroups of neurodegenerative, acute neurological or non-neurological (potentially reversible) origin in a similar fashion to 14-3-3.
Figure 1 (A) Total CSF samples tested by years [blue = no transmissible spongiform encephalopathy (TSE) diagnosis; red = transmissible spongiform encephalopathy diagnosis] from all participating countries. (B) Protein14-3-3 specificity and sensitivity by years. (more ...)
summarizes collective data on 14-3-3, tau, phosphorylated tau and amyloid-β1–42
. As previously described, 14-3-3 was negative in 93% of all patients with neurodegenerative disorders. The test became more often false positive in acute neurological events (inflammation 19.2%, stroke 15.2%, epileptic fits 17% and CNS tumour 18.4%) causing a drop in specificity than neurodegenerative and non-neurological forms of dementia. With respect to tau we observed a similar trend. Levels at a cut-off >1300 pg/ml are considered highly suggestive for Creutzfeldt–Jakob disease (Otto et al., 2002
; Sanchez-Juan et al., 2006
) and were referred to as ‘tau positive’ in our analysis. ‘Tau negative’ results were obtained in 95% of all neurodegenerative diseases. ‘Tau positive’ results were similarly obtained as 14-3-3 in patients with epileptic fits (24%), CNS tumour/paraneoplastic (22%) and stroke (18.4%).
Overview on 14-3-3 and levels of tau, phosphorylated tau, amyloid β1–42 in differential diagnosis of rapid dementia (excluding Creutzfeldt–Jakob disease)
For phosphorylated tau and amyloid-β1–42
no particular cut-off points are established in Creutzfeldt–Jakob disease diagnosis. For this reason calculation of ‘false positive’ or ‘false negative’ results in the differentiation of Creutzfeldt–Jakob disease from other rapid dementia diagnoses was not possible. However patients with low amyloid-β1–42
and high phosphorylated tau levels are at a clear risk of Alzheimer’s disease (Hertze et al. 2010
). We observed a pathologically elevated phosphorylated tau median in the group with epileptic fits (64.5 pg/ml) only. For amyloid-β1–42
, we found pathologically decreased levels in the group of neurodegenerative CNS diseases (413 pg/ml). This was expected as it represents a typical result in patients with Alzheimer’s disease (see later). Of interest, in non-neurological patients with the diagnosis ‘metabolic disorders’ we also detected decreased median levels of amyloid-β1–42
Cerebrospinal fluid dementia markers in neurodegenerative diseases, vascular dementia and normal pressure hydrocephalus
As predetermined cut-off values are not available for the majority of differential diagnoses in this study, the next analysis describes results of CSF dementia marker profiles in various neurodegenerative dementias. Data on CSF dementia markers (14-3-3, tau, phosphorylated tau and amyloid-β1–42) were evaluated in a total of 3034 patients (28.3% of the total group) with a neurodegenerative disease diagnosis. Out of these patients, 941 (37.4%) displayed a diagnosis of Alzheimer’s disease, followed by 486 patients (19.3%) with unclassified dementia, 362 patients with Lewy body disease (14.4.%), 172 patients with vascular dementia (6.8%), 162 patients with frontotemporal dementia (6.4%), 142 patients with Parkinson’s disease (5.6%), 74 patients with multisystem atrophy (2.9%), 62 patients with progressive supranuclear palsy (2.5%), 57 patients with corticobasal degeneration (2.3%), 33 patients with Huntington’s disease (1.3%), 16 patients with normal pressure hydrocephalus (0.6%) and 10 patients with motor neuron disease (0.4%) ().
Figure 2 Distribution of neurodegenerative dementia diagnosis. AD = Alzheimer’s disease; CBD = corticobasal degeneration; FTD = frontotemporal dementia; HD = Huntington’s disease; LBD = Lewy body disease; MND = motor neuron disease; MSA = multisystem (more ...)
A positive 14-3-3 test was seen in patients with vascular dementia (10.7%) followed by Alzheimer’s disease (5.8%) and Lewy body disease (5.3%) (). A ‘positive tau’ (at Creutzfeldt–Jakob disease cut-off >1300 pg/ml) was obtained in vascular dementia (7.8%), Alzheimer’s disease (7.6%), Parkinson’s disease (2.0%) and Lewy body disease (1.8%) (). The median tau ranged highest in the group of Alzheimer’s disease (314 pg/ml) and Huntington’s disease (383 pg/ml) followed by vascular dementia (206 pg/ml) and Lewy body disease (216 pg/ml) (). Median phosphorylated tau levels of other neurodegenerative dementias ranged at normal levels; however, all neurodegenerative disease groups displayed pathologically elevated phosphorylated tau levels at maximum range. For amyloid-β1–42, pathologically decreased levels (<450 pg/ml) were observed in Alzheimer’s disease (median 404 pg/ml), Lewy bodydisease (336 pg/ml) and Huntington’s disease (321 pg/ml) ().
Results of positive 14-3-3 tests in neurodegenerative dementia (excluding Creutzfeldt–Jakob disease)
Results of positive tau tests (>1300 pg/ml) in neurodegenerative dementia (excluding Creutzfeldt–Jakob disease)
Overview on levels of tau, phosphorylated tau and amyloid β1–42 in neurodegenerative dementia (excluding Creutzfeldt–Jakob disease)
To illustrate our findings, we have grouped diseases according to similar pathology: (i) Alzheimer’s disease, (ii) vascular dementia, (iii) α-synucleinopathies including Parkinson’s disease, Lewy body disease and multisystem atrophy and (iv) tauopathies including frontotemporal dementia and progressive supranuclear palsy (A–C). Here we can show that median levels of tau and phosphorylated tau generally range higher in Alzheimer’s disease, vascular dementia and Lewy body disease whereby in contrast, median levels of amyloid-β1–42 are generally reduced in patients with Alzheimer’s disease and patients with Lewy body disease when compared with other disease groups here.
Figure 3 (A) Boxplot of tau levels. (B) Boxplot of phosphorylated tau (P-Tau) levels. (C) Boxplot of amyloid-β1–42 levels in neurodegenerative dementia diagnosis. AD = Alzheimer’s disease; FTD = frontotemporal dementia; LBD = Lewy body (more ...)
Cerebrospinal fluid test referrals per year
We observed a constant increase in CSF test referrals per year between 1998 and 2008 that was seen in all participating countries (A). In spite of the increase in CSF tests, there was no increase in the total number of cases with identified transmissible spongiform encephalopathies. In the years 1998–2005 we identified between 330 and 422 cases with transmissible spongiform encephalopathies per year. Between 2005 and 2008, the number of cases with transmissible spongiform encephalopathies appeared reduced (139–194 cases per year), because collective data was not available from all participating countries during this time period.
Cerebrospinal fluid 14-3-3 specificity in sporadic Creutzfeldt–Jakob disease
Despite of the increasing number of CSF referrals per year for detection of 14-3-3 in suspected cases of Creutzfeldt–Jakob disease in the 10-year period, we calculated a stable and high specificity of 14-3-3 that ranged from 0.91 to 0.95 per year (B). The total 14-3-3 specificity for Creutzfeldt–Jakob disease during the observed time period was 0.92. When compared with all patients with definite diagnoses only, the specificity was slightly lower (0.90).
Influence of 14-3-3 specificity by differential diagnosis
The overall test specificity varied with respect to differential diagnosis. A lower 14-3-3 specificity was observed in discrimination to acute neurological events (82–87%), a high 14-3-3 specificity was obtained in neurodegenerative diseases (95–97%) and non-neurological conditions (91–97%) ( and ).
Protein 14-3-3 specificity stratified by differential diagnosis (this includes total number of 14-3-3 tests in all countries all years). See also .
Protein 14-3-3 specificity stratified by differential diagnosis (this includes total number of 14-3-3 tests in all countries all years)