Higher T-tau Research Articles

Diagnostic value of cerebrospinal fluid tau, neurofilament, and progranulin in definite frontotemporal lobar degeneration

BackgroundWe explored the diagnostic performance of cerebrospinal fluid (CSF) biomarkers in allowing differentiation between frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD), as well as between FTLD pathological subtypes.MethodsCSF levels of routine AD biomarkers (phosphorylated tau (p-tau181), total tau (t-tau), and amyloid-beta (Aβ)1–42) and neurofilament proteins, as well as progranulin levels in both CSF and serum were quantified in definite FTLD (n = 46), clinical AD (n = 45), and cognitively healthy controls (n = 20). FTLD subgroups were defined by genetic carrier status and/or postmortem neuropathological confirmation (FTLD-TDP: n = 34, including FTLD-C9orf72: n = 19 and FTLD-GRN: n = 9; FTLD-tau: n = 10).ResultsGRN mutation carriers had significantly lower progranulin levels compared to other FTLD patients, AD, and controls. Both t-tau and p-tau181 were normal in FTLD patients, even in FTLD-tau. Aβ1–42 levels were very variable in FTLD. Neurofilament light chain (Nf-L) was significantly higher in FTLD compared with AD and controls. The reference logistic regression model based on the established AD biomarkers could be improved by the inclusion of CSF Nf-L, which was also important for the differentiation between FTLD and controls. Within the FTLD cohort, no significant differences were found between FTLD-TDP and FTLD-tau, but GRN mutation carriers had higher t-tau and Nf-L levels than C9orf72 mutation carriers and FTLD-tau patients.ConclusionsThere is an added value for Nf-L in the differential diagnosis of FTLD. Progranulin levels in CSF depend on mutation status, and GRN mutation carriers seem to be affected by more severe neurodegeneration.

Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease.

Background:Abnormal insulin signaling in the brain has been linked to Alzheimer’s disease (AD).Objective:To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-β and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype.Methods:From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-β1-42, total (t-)Tau, and phosphorylated (p-)Tau.Results:CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient –0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE ɛ4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029).Conclusion:Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ4 genotype when assessing the role of insulin.

The predictive value of T-tau and AB1-42 levels in idiopathic normal pressure hydrocephalus

BackgroundIdiopathic normal pressure hydrocephalus (INPH) has no reliable biomarker to assist in the selection of patients who could benefit from ventriculo-peritoneal (VP) shunt insertion. The neurodegenerative markers T-tau and Aβ1-42 have been found to successfully differentiate between Alzheimer’s disease (AD) and INPH and therefore are candidate biomarkers for prognosis and shunt response in INPH. The aim of this study was to test the predictive value of cerebrospinal fluid (CSF) T-tau and Aβ1-42 for shunt responsiveness. In particular, we pay attention to the subset of INPH patients with raised T-tau, who are often expected to be poor surgical candidates.MethodsSingle-centre retrospective analysis of probable INPH patients with CSF samples collected from 2006 to 2016. Index test: CSF levels of T-tau and Aβ1-42. Reference standard: postoperative outcome. ROC analysis assessed the predictive value.ResultsA total of 144 CSF samples from INPH patients were analysed. Lumbar T-tau was a good predictor of post-operative mobility (AUROC 0.80). The majority of patients with a co-existing neurodegenerative disease responded well, including those with high T-tau levels.ConclusionINPH patients tended to exhibit low levels of CSF T-tau, and this can be a good predictor outcome. However levels are highly variable between individuals. Raised T-tau and being shunt-responsive are not mutually exclusive, and such patients ought not necessarily be excluded from having a VP shunt. A combined panel of markers may be a more specific method for aiding selection of patients for VP shunt insertion. This is the most comprehensive presentation of CSF samples from INPH patients to date, thus providing further reference values to the current literature.

Levels of amyloid-beta-42 and CSF pressure are directly related in patients with Alzheimer's disease.

Experimental data suggest that the cerebrospinal fluid (CSF) dynamic is involved in the clearance of beta-amyloid, a key event in the pathogenesis of Alzheimer's disease (AD). At this regard no evidence still exists in vivo. In this study we explored the relationships between CSF pressure and AD pathology, as measured with CSF core biomarkers. We enrolled 16 patients with probable AD and 21 controls, collecting demographics, clinical data, CSF opening pressure and CSF levels of beta-amyloid-42 fragment (Aβ42), total-tau (t-tau), phosphorylated-tau-181 (p-tau), albumin and albumin ratio. Differences between the groups were calculated with non-parametric tests, while correlations among all parameters were separately calculated with Spearman's test in each group. The groups significantly differed in biomarkers' concentration with lower Aβ42, and higher t-tau and p-tau in AD patients. Moreover, CSF pressure was significantly lower in AD group (11.0±2.8 vs. 13.3±3.0mmHg, p<0.05) and directly correlated with Aβ42 levels (R=0.512; p<0.05), but not with other biomarkers or parameters. No significant correlations emerged for biomarkers in control group. AD patients exhibit low CSF pressure whose values are directly and selectively related to CSF Aβ42 levels. This interesting correlation may confirm in vivo the association between CSF dynamic and beta-amyloid metabolism occurring in AD.

Cerebrospinal fluid biomarkers for Alzheimer's disease in Down syndrome

Down syndrome (DS), present in nearly six million people, is associated with an extremely high risk to develop Alzheimer's disease (AD). Amyloid-β and tau pathology are omnipresent from age 40 years onward, but clinical symptoms do not appear in all DS individuals. Dementia diagnostics is complex in this population, illustrating the great need for predictive biomarkers. Although blood biomarkers have not yet proven useful, cerebrospinal fluid (CSF) biomarkers (low amyloid-β42, high t-tau, and high p-tau) effectively contribute to AD diagnoses in the general population and are increasingly used in clinical practice. Surprisingly, CSF biomarkers have been barely evaluated in DS. Breaking the taboo on CSF analyses would finally allow for the elucidation of its utility in (differential) diagnoses and staging of disease severity. A sensitive and specific biomarker profile for AD in DS would be of paramount importance to daily care, adaptive caregiving, and specific therapeutic interventions.

PRESENILE- VS LATE-ONSET BEHAVIORAL FRONTO-TEMPORAL LOBAR DEGENERATION (BVFTLD): CLINICAL, RADIOLOGICAL, AND BIOLOGICAL COMPARISON

Late-onset behavioral fronto-temporal lobar degeneration (bvFTLD, >65 years) are clinically and radiologically different from presenile-onset cases (Baborie, Arch Neurol. 2012). BvFTLD diagnostic criteria show low sensitivity for late-onset cases, and Alzheimer’s disease (AD) is the main misdiagnosis. Cerebrospinal fluid (CSF) biomarkers could help in this differential diagnosis (Marelli, DADM 2015), although co-pathology cannot be excluded in older subjects. At present, no data are available about CSF biomarkers in late- vs presenile-onset bvFTLD. A retrospective study (2007-2015) on 41 subjects with possible or probable bvFTLD (Rascovsky, Brain 2011); 17/41 (41%) had onset after and 24/41 (59%) before 65 years. We compared clinical, radiological, and CSF data at the initial valuation. Late-onset bvFTLD (mean age at onset: 70±3 years; probable bvFTLD=59%) and presenile-onset bvFTLD (mean age at onset 59±5 years; probable bvFTLD=71%) had comparable mean disease duration at initial examination (3±3 years) and mean follow up duration (5±3 vs 5±4 years). MRI examination confirmed more frequent hippocampal atrophy (47% vs 21%) and less lobar atrophy (18% vs 58%) in late-onset bvFTLD; this was clinically correlated to more frequent hippocampal memory deficit (53% vs 12.5%). TEP-FDG or SPECT-HMPAO imaging detected focal hypometabolism/hypoperfusion in 53% vs 62.5% of the patients. Unexpectedly, no differences were found in CSF abeta1-42 (1097±276 vs 1034±236), T-tau (289±214 vs 231±100), P-tau (40±17 vs 37±15), and IATI index (2±0.6 vs 2±0.6); the ratio T-tau/abeta1-42 (0.26±0.16 vs 0.23±0.10) and P-tau/abeta1-42 (0.04±0.01 vs 0.04±0.01) were not different, either. In each group three subjects had high T-tau or P-Tau and one subject low abeta1-42. Late-onset bvFTLD is not rare in clinical practice; we confirmed more hippocampal and global atrophy compared to presenile-onset bvFTLD, clinically correlated to more frequent hippocampal memory loss. TEP-FDG and SPECT-HMPAO focal alterations were equally represented. Since no differences were found in CSF biomarkers, the differences between late- and presenile-onset bvFTLD could not be explained by co-existing AD pathology in older patients. They could instead be due to hippocampal sclerosis, known to be associated to FTLD. These data suggest the potential interest of CSF and metabolic markers in the differential diagnosis of late-onset bv-FTLD vs AD.

High tau levels in cerebrospinal fluid predict nursing home placement and rapid progression in Alzheimer's disease.

BackgroundIncreased concentrations of cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau, as well as decreased amyloid-β 42 peptide, are biomarkers of Alzheimer’s disease (AD) pathology, but few studies have shown an association with AD progression rate. We hypothesized that high CSF tau, as a marker of ongoing neurodegeneration, would predict a more aggressive course of AD, using time to nursing home placement (NHP) as the main outcome.MethodsOur sample inlcuded 234 patients with mild cognitive impairment (MCI) due to AD (n = 134) or mild to moderate AD (n = 100) who underwent lumbar puncture at a memory clinic and were followed for 2–11 years (median 4.9 years).ResultsIndividuals with CSF t-tau in the highest quartile (≥900 ng/L) had a higher ratio of NHP, both in the total cohort and in patients with MCI only (adjusted HR 2.17 [95 % CI 1.24–3.80]; HR 2.37 [95 % CI 1.10–5.09], respectively), than the lowest quartile. The association between high t-tau levels and future steep deterioration was confirmed in analyses with conversion to moderate dementia (HR 1.66; 95 % CI 1.08–2.56), rapid decline in Mini Mental State Examination score (≥4-point drop/12 months), and dying in severe dementia as outcomes.ConclusionsTo our knowledge, this is the first study to show that high CSF t-tau levels predict early NHP and conversion to moderate dementia in an AD cohort. Selecting patients with high CSF t-tau, indicating more aggressive neurodegeneration and steeper decline, for AD immunotherapy trials might increase the possibility of showing contrast between active treatment and placebo.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-016-0191-0) contains supplementary material, which is available to authorized users.

Cerebrospinal Fluid Alzheimer's Disease Biomarkers in Cerebral Amyloid Angiopathy-Related Inflammation.

Decreased cerebrospinal fluid (CSF) amyloid-β 1-40 (Aβ40) and amyloid-β 1-42 (Aβ42) and increased total and phosphorylated tau (t-tau, p-tau) concentrations have been described in cerebral amyloid angiopathy (CAA). Our aim was to analyze these biomarkers in patients with CAA-related inflammation (CAA-I). We prospectively recruited nine patients with acute phase CAA-I fulfilling Chung criteria. CSF was analyzed for t-tau, p-tau, Aβ42, and Aβ40. Data were compared to controls (n = 14), patients with Alzheimer's disease (AD, n = 42), CAA (n = 10), and primary angiitis of the central nervous system (PACNS, n = 3). For the CAA-I group, statistically significant differences were: lower Aβ42 (p = 0.00053) compared to the control group; lower t-tau (p = 0.018), p-tau (p < 0.001), and Aβ40 (p < 0.001) compared to AD; lower Aβ42 (p = 0.027) compared to CAA; lower Aβ42 (p = 0.012) compared to PACNS. Nearly significantly lower Aβ40 (p = 0.051) and higher t-tau (p = 0.051) were seen in CAA-I compared to controls. CSF biomarkers profile similar to that of CAA was observed in CAA-I (with even lower levels of Aβ42 compared to CAA). Based on our findings, high p-tau seems more specific for AD, whereas low Aβ42 differentiates CAA-I from CAA, PACNS, and controls, and low Aβ40 differentiates CAA-I from AD.

Performance of Cerebrospinal Fluid Biomarkers of Alzheimer Disease in a Memory Clinic in Norway.

Although Alzheimer disease (AD) remains a clinical diagnosis, biomarkers are in use to support the diagnosis. Three cerebrospinal biomarkers, amyloid-β (Aβ), total tau (T-tau), and phospho tau (P-tau), reflect neuropathologic changes observed in AD patients. The aim of this study was to explore the performance of the cerebrospinal fluid biomarkers used in a memory clinic setting. We included 205 patients who had been through a standardized examination including lumbar puncture. Diagnoses were made blind to the results of the spinal fluid analyses. By combining low Aβ and high T-tau or P-tau values, the sensitivity was 31.9% and the specificity was 92.5% when comparing patients with AD with other patients. In receiver operating characteristic analyses, the AUC for the Aβ was 0.78 (SE=0.04; 95% CI, 0.7-0.85), for T-tau 0.80 (SE=0.03; 95% CI, 0.73-0.86), and for P-tau 0.76 (SE=0.04; 95% CI, 0.69-0.83). A significant difference was found between the sexes, with higher values of Aβ among younger men (under 65 y of age) with AD [799.8 (SD=317.2) vs. 558.9 (SD=123.5) for women, P-value=0.003]. The present study found a lower performance of the biomarkers than reported previously.

The effect of white matter hyperintensities on neurodegeneration in mild cognitive impairment

IntroductionIt is unclear whether white matter hyperintensities (WMHs), magnetic resonance imaging markers of small-vessel cerebrovascular disease, promote neurodegeneration and associated clinical decline in Alzheimer's disease (AD), or simply co-occur with recognized pathogenic processes. MethodsIn 169 patients with mild cognitive impairment, followed for 3 years, we examined the association of (1) baseline regional WMH and cerebral spinal fluid–derived t-tau (total tau) with entorhinal cortex atrophy rates, as a marker of AD-related neurodegeneration, and conversion to AD; and (2) baseline regional WMH with change in t-tau level. ResultsIn participants with low baseline t-tau, higher regional WMH volumes were associated with faster entorhinal cortex atrophy. Higher parietal WMH volume predicted conversion to AD in those with high t-tau. Higher parietal and occipital WMH volumes predicted increasing t-tau. DiscussionWMHs affect AD clinical and pathologic processes both directly and interacting with tau.

CSF biomarkers for Alzheimer’s pathology and the effect size of APOE ɛ4

New research and clinical criteria for Alzheimer's disease (AD) have recently been proposed, which include biomarker information on Alzheimer's plaque and tangle pathology, or AD-typical structural brain changes, as supporting or essential elements of an AD diagnosis.1, 2, 3 In a large group of patients with both genetic and cerebrospinal fluid (CSF) biomarker data, we here show that biomarker-assisted diagnosis-making almost doubles the effect size of the association between the ɛ4 variant of the apolipoprotein E (APOE) gene and AD. We included clinically diagnosed patients with either AD dementia (n=309) or mild cognitive impairment (MCI) due to AD (n=287), cognitively normal controls (n=251) and patients with MCI who remained stable over at least 2 years (n=399) or developed dementias other than AD (n=99) (Table 1, Supplementary Material). All had APOE ɛ2/ɛ3/ɛ4 genotypes and results on the CSF biomarkers total tau (T-tau), phosphorylated tau (P-tau) and the 42-amino-acid isoform of amyloid-β (Aβ42) determined. These CSF biomarkers reflect the core elements of Alzheimer's pathology4 and are strongly associated with AD in cross-sectional as well as longitudinal follow-up studies (Supplementary Material).5, 6 AD dementia and MCI-AD patients were first pooled into one clinical AD group (n=596) and compared with all remaining categories that were designated non-AD (n=749). A positive APOE ɛ4 carrier status (one or two ɛ4 alleles) was overrepresented in the AD group and yielded an odds ratio (OR) of 4.45 (95% confidence interval (CI) 3.52–5.62) for a clinical diagnosis of AD at inclusion or follow-up (Figure 1). This OR is similar to the AlzGene meta-analysis of APOE (3.68, 95% CI 3.30–4.11, www.alzgene.org/meta.asp?geneID=83, November 2012 freeze). Similarly, we tested the association of APOE ɛ4 with AD, comparing the 596 AD patients with the 251 cognitively normal controls, which resulted in an OR of 6.35 (95% CI 4.59–8.80). Figure 1 Odds ratios for a positive APOE ɛ4 carrier status based on (A) clinical diagnosis, comparing patients with clinical AD with dementia at inclusion or follow-up (n=596) versus all other diagnostic groups (n=749), (B) clinical diagnosis, comparing ... Disregarding the clinical diagnoses and subgrouping all subjects into amyloid-positive, defined as CSF Aβ42 <546 ng l−1 (n=779), and amyloid-negative, defined as CSF Aβ42 ⩾546 ng l−1 (n=563) (see Supplementary Material for details on cut-point determination), gave an OR for APOE ɛ4 as high as 6.27 (95% CI 4.93–7.98). Dichotomizing the material according to CSF T-tau or P-tau did not change the ORs as compared with clinical diagnosis only (Figure 1). Even though the OR for the ratio P-tau/Aβ42 (6.50 (95% CI 5.07–8.35)) was slightly higher than for Aβ42 alone, the difference was not statistically significant. We also compared patients, again disregarding the clinical diagnoses, who had a complete CSF biomarker signature indicative of AD, that is, low Aβ42 and both high T-tau and P-tau (n=438, see Supplementary Material for a detailed description of the signature), with subjects with a negative CSF biomarker pattern (n=414). The biomarker diagnosis strengthened the association to APOE ɛ4; the OR increased from 4.45 (95% CI 3.52–5.62) in pure clinical diagnosis to 7.66 (95% CI 5.65–10.39) in patients classified on the basis of biomarker data alone. Finally, ORs were calculated on subjects having both a clinical diagnosis and a concordant complete biomarker profile (n(AD)=324; n(control)=155). This approach resulted in an even stronger association of APOE ɛ4 with AD (OR 10.4, 95% CI 6.65–16.3). Similar effects were seen when comparing non-carriers with ɛ4 heterozygotes and homozygotes across the different diagnostic groups (Figure 1, Supplementary Material). These results have several important implications. First, APOE ɛ4 appears as strongly associated with amyloid pathology as clinical AD. Second, clinical criteria that incorporate biomarker information on Alzheimer's pathology give a stronger association with APOE ɛ4 than clinical diagnosis alone. This is compatible with the presumed higher diagnostic accuracy of the revised clinical approach,1, 2, 3 and has also been seen in a series of neuropathologically verified AD cases and controls.7 Third, the approach of combining clinical with biomarker data may increase the power of genetic association studies, as well as the potential to provide insights into the mechanistic pathways through which genetic risk factors may exert their effects.

Cerebrospinal fluid biomarkers for differentiation of frontotemporal lobar degeneration from Alzheimer's disease

Accurate ante mortem diagnosis in frontotemporal lobar degeneration (FTLD) is crucial to the development and implementation of etiology-based therapies. Several neurodegenerative disease-associated proteins, including the major protein constituents of inclusions in Alzheimer's disease (AD) associated with amyloid-beta (Aβ1−42) plaque and tau neurofibrillary tangle pathology, can be measured in cerebrospinal fluid (CSF) for diagnostic applications. Comparative studies using autopsy-confirmed samples suggest that CSF total-tau (t-tau) and Aβ1−42 levels can accurately distinguish FTLD from AD, with a high t-tau to Aβ1−42 ratio diagnostic of AD; however, there is also an urgent need for FTLD-specific biomarkers. These analytes will require validation in large autopsy-confirmed cohorts and face challenges of standardization of within- and between-laboratory sources of error. In addition, CSF biomarkers with prognostic utility and longitudinal study of CSF biomarker levels over the course of disease are also needed. Current goals in the field include identification of analytes that are easily and reliably measured and can be used alone or in a multi-modal approach to provide an accurate prediction of underlying neuropathology for use in clinical trials of disease modifying treatments in FTLD. To achieve these goals it will be of the utmost importance to view neurodegenerative disease, including FTLD, as a clinicopathological entity, rather than exclusively a clinical syndrome.

Use of cerebrospinal fluid biomarker analysis for improving Alzheimer's disease diagnosis in a non-specialized setting.

Low levels of amyloid-beta42 (Abeta42) and high total-tau (t-tau) or phosphorylated-tau (p181-tau) levels in cerebrospinal fluid (CSF) were shown to be characteristic for Alzheimer's disease (AD) patients and for mildly cognitively impaired (MCI) or non-demented individuals who will progress to AD. The goal of this study was to evaluate the benefit of CSF biomarker testing in a setting with no specialized dementia centers, in order to improve the accuracy of AD diagnosis and to identify individuals with incipient AD. Using ELISA assay we analyzed CSF Abeta42, t-tau and p181-tau levels among clinically diagnosed non-demented individuals, AD patients and individuals with uncertain dementia (n=36). CSF cut-off values of low Abeta42 (less than or equal to 530 pg/mL) and high t-tau (less than or equal to 350 pg/mL) or p181-tau (less than or equal to 52 pg/mL) were used to identify individuals with AD/MCI-CSF profile, regardless of clinical diagnosis. APOE genotyping was performed using PCR-RFLP method. In accord with previous studies we detected significantly decreased levels of CSF Abeta42 and increased tau and p181-tau levels in clinically diagnosed AD group vs. non-demented controls. CSF profiling identified individuals with a typical AD/MCI-CSF pattern in clinically referred non-demented group (9 percent) and among patients with uncertain dementia (41.7 percent). APOE epsilon4-allele was associated with the CSF biomarker changes typical for AD. This study shows that in a non-specialized setting CSF biomarker testing may be used as a screening tool for improving the accuracy of AD diagnosis and for predicting individuals with incipient Alzheimer's disease who need to receive further clinical follow-up.

CSF Biomarkers Correlate with Cerebral Blood Flow on SPECT in Healthy Elderly

Background: The preclinical patterns of biological markers for Alzheimer’s disease (AD) in vivo need further exploration. The aim of this study was therefore to investigate CSF biomarkers, regional cerebral blood flow (rCBF) and cognitive performance in cognitively healthy older individuals. Method: Within a 2-week period, 32 cognitively healthy older individuals underwent CSF analysis, rCBF measurement and cognitive testing. The CSF was analysed for β-amyloid_1–42 (Aβ42), total tau protein (T-tau) and hyperphosphorylated tau protein (P-tau). The rCBF results were analysed with statistical parametric mapping to investigate rCBF covariance with the other measurements. Results: High CSF P-tau and T-tau levels correlated with decreased rCBF in the right superior posterior medial frontal lobe whereas high CSF P-tau levels also correlated with increased rCBF in the left fronto-temporal border zone area. No significant covariance was seen between rCBF and CSF Aβ42. Neither CSF P-tau and T-tau levels nor rCBF in the current right frontal and left posterior locations were associated with cognitive performance. Conclusions: Our findings suggest a possible correlation between tau pathology and blood flow abnormalities in individuals without any overt cognitive symptoms. An association with AD development is possible but other explanatory mechanisms cannot be excluded.

Alzheimer's disease with normal CSF biomarkers.

Background/objectives: Alzheimer’s disease (AD) is currently diagnosed clinically using defined symptomatic diagnostic criteria. Pathological levels of CSF-biomarkers, high T-tau, P-tau and low Ab42 have been associated with AD however definition of cut off values differ. New diagnostic criteria that include the pathological CSF biomarkers have been suggested. How many AD patients in a routine clinical population have normal levels of the CSF biomarkers as defined by clinically defined cut-offs? Methods: Out-patients (n=151) with the clinical diagnosis of dementia as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th ed (DSM-IV) and probable or possible AD, according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and related Disorders Association (NINCDS-ADRDA, 1984), were included in this study. The number of symptoms according to these criteria and the levels of the CSF biomarkers Aβ42, T-tau and P-tau were evaluated at baseline. The patients received cholinesterase inhibitor (ChEI) treatment and were assessed with cognitive tests (MMSE, ADAS-cog) longitudinally for up to three years. Short-term ChEI-response was measured as cognitive change after 2 and 6 months of treatment. Long-term outcome was expressed as MMSE and ADAS-cog change per month. Pathological levels of CSF biomarkers were defined as in clinical routine; T-tau > 450 ng/l, P-tau > 60 ng/l and aβ42 < 400 ng/l. Results: In 15 % of the patients all three CSF biomarkers were normal. At baseline these patients had fewer symptoms (NINCDS-ADRDA), higher MMSE score, but then displayed the same rate of longitudinal cognitive decline as patients with pathological biomarkers. Furthermore, patients with normal CSF biomarkers did not differ in age of onset, duration of disease, IADL or ADAS-cog at baseline, completion rate or short-term response to treatment compared to those with pathological CSF biomarkers. Conclusion: Alzheimer’s disease with normal CSF displays the same cognitive short-term response to ChEI-treatment and clinical long-term outcome as patients with pathological CSF. These findings must be considered when defining future diagnostic criteria for AD. (Less)

Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort

To determine how amyloid β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) levels in CSF behave in a large cohort of patients with different types of dementia. Baseline CSF was collected from 512 patients with Alzheimer disease (AD) and 272 patients with other types of dementia (OD), 135 patients with a psychiatric disorder (PSY), and 275 patients with subjective memory complaints (SMC). Aβ42, t-tau, and p-tau (at amino acid 181) were measured in CSF by ELISA. Autopsy was obtained in a subgroup of 17 patients. A correct classification of patients with AD (92%) and patients with OD (66%) was accomplished when CSF Aβ42 and p-tau were combined. Patients with progressive supranuclear palsy had normal CSF biomarker values in 90%. Patients with Creutzfeldt-Jakob disease demonstrated an extremely high CSF t-tau at a relatively normal CSF p-tau. CSF AD biomarker profile was seen in 47% of patients with dementia with Lewy bodies (DLB), 38% in corticobasal degeneration (CBD), and almost 30% in frontotemporal lobar degeneration (FTLD) and vascular dementia (VaD). PSY and SMC patients had normal CSF biomarkers in 91% and 88%. Older patients are more likely to have a CSF AD profile. Concordance between clinical and neuropathologic diagnosis was 85%. CSF markers reflected neuropathology in 94%. CSF Aβ42, t-tau, and p-tau are useful in differential dementia diagnosis. However, in DLB, FTLD, VaD, and CBD, a substantial group exhibit a CSF AD biomarker profile, which requires more autopsy confirmation in the future.

Biomarcadores en líquido cefalorraquídeo de pacientes con enfermedad de Alzheimer prodrómica

Introduction: The prodromal Alzheimers disease (AD) is a new concept that include an amnesic mild cognitive impairment (MCI- a) and alterations in some complementary tests. Objective: To test the presence of alterations in the cerebrospinal fluid (CSF) bio- markers in our MCI-a patients who developed AD in the first year after the lumbar puncture. Method: 24 control subjects and 36 MCI-a patients were included from the local hospital memory cli- nic. Using INNO-BIA Alzbio-3 reagents from Innogenetics, we quantified CSF Aβ1-42, T-tau and P-tau181p proteins, and calcu- lated the ratios T-tau / Aβ1-42 y P-tau 181p / Aβ1-42. This project was approved by the local Ethical Committee. Results: One year after the lumbar puncture, 14 MCI patients (38%) developed AD. These patients showed lower Aβ1-42 protein levels (285.37 ± 73.36 vs. 365.21 ± 112.53 pg/ml, p < 0.02) and higher T-tau protein (88.3 ± 40.82 vs. 53.21 ± 23.38 pg/ml, p < 0.002), P-tau 181p protein (66.44 ± 23.87 vs. 31.25 ± 13.74 pg/ml, p< 0.02 ), T-tau / Aβ1-42 ratio (0.34 ± 0.19 vs. 0.15 ± 0.08, p < 0.001 ) and P-tau 181p / Aβ1-42 ratio (0.25 ± 0.12 vs. 0.09 ± 0.06, p < 0.0001) than the control subjects. Conclusion: In our experience, as the recent literature, it exist the very clear alterations of CSF biomarkers in patients with prodromal AD. (Alzheimer. Real Invest Demenc. 2011;49:19-25)

Alzheimer's disease markers, hypertension, and gray matter damage in normal elderly

It is not well known whether Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers are associated with brain damage in cognitively normal elderly. The combined influence of CSF biomarkers and hypertension (HTN) on the gray matter (GM) is also not well described. One hundred fifteen cognitively healthy subjects (mean age 62.6 ± 9.5%, 62% women) received clinical assessment, a high resolution magnetic resonance imaging (MRI), and a lumbar puncture. The CSF levels of total tau (t-tau), hyperphosphorylated tau (p-tau231), amyloid beta (Aβ42/Aβ40), p-tau231/Aβ42, and t-tau/Aβ42 were dichotomized as “high” and “low” based on accepted cut off values. Statistical parametric mapping was used to examine MRI scans for regional GM density, studied as a function of the CSF markers, HTN, and combination of both. Global and medial temporal lobe (MTL) GM was also assessed. Voxel based morphometry revealed that higher t-tau was associated with lower GM density in the precunei. Subjects with higher p-tau231 and p-tau231/Aβ42 had less GM in temporal lobes. Low Aβ42/Aβ40 was related to less GM in the thalami, caudate, and midbrain. Subjects with hypertension showed more GM atrophy in the cerebellum, occipital, and frontal regions. Simultaneous presence of elevated CSF AD biomarkers and HTN was associated with more GM atrophy than either marker individually, but no interaction effects were identified. In conclusion, in normal elderly CSF tau markers were associated predominantly with lower GM estimates in structures typically affected early in the AD process. In this presymptomatic stage when no cognitive impairment is present, AD biomarkers and HTN have additive effects on gray matter damage.

Decreased CSF Transferrin in sCJD: A Potential Pre-Mortem Diagnostic Test for Prion Disorders

Sporadic Creutzfeldt-Jakob-disease (sCJD) is a fatal neurodegenerative condition that escapes detection until autopsy. Recently, brain iron dyshomeostasis accompanied by increased transferrin (Tf) was reported in sCJD cases. The consequence of this abnormality on cerebrospinal-fluid (CSF) levels of Tf is uncertain. We evaluated the accuracy of CSF Tf, a ‘new’ biomarker, as a pre-mortem diagnostic test for sCJD when used alone or in combination with the ‘current’ biomarker total-tau (T-tau). Levels of total-Tf (T-Tf), isoforms of Tf (Tf-1 and Tf-β2), and iron saturation of Tf were quantified in CSF collected 0.3–36 months before death (duration) from 99 autopsy confirmed sCJD (CJD+) and 75 confirmed cases of dementia of non-CJD origin (CJD-). Diagnostic accuracy was estimated by non-parametric tests, logistic regression, and receiver operating characteristic (ROC) analysis. Area under the ROC curve (AUC), sensitivity, specificity, positive and negative predictive values (PV), and likelihood ratios (LR) of each biomarker and biomarker combination were calculated. We report that relative to CJD-, CJD+ cases had lower median CSF T-Tf (125,7093 vs. 217,7893) and higher T-tau (11530 vs. 1266) values. AUC was 0.90 (95% confidence interval (CI), 0.85–0.94) for T-Tf, and 0.93 (95% CI, 0.89–0.97) for T-Tf combined with T-tau. With cut-offs defined to achieve a sensitivity of ∼85%, T-Tf identified CJD+ cases with a specificity of 71.6% (95% CI, 59.1–81.7), positive LR of 3.0 (95% CI, 2.1–4.5), negative LR of 0.2 (95% CI, 0.1–0.3), and accuracy of 80.1%. The effect of patient age and duration was insignificant. T-Tf combined with T-tau identified CJD+ with improved specificity of 87.5% (95%CI, 76.3–94.1), positive LR of 6.8 (95% CI, 3.5–13.1), negative LR of 0.2 (95% CI, 0.1–0.3), positive-PV of 91.0%, negative-PV of 80.0%, and accuracy of 86.2%. Thus, CSF T-Tf, a new biomarker, when combined with the current biomarker T-tau, is a reliable pre-mortem diagnostic test for sCJD.

CSF-Tau and CSF-Aβ1–42 in Posterior Cortical Atrophy

Objective: Our purpose was to measure Aβ_1–42, T-tau and P-tau₁₈₁ in the cerebrospinal fluid (CSF) of patients with posterior cortical atrophy (PCA), a presenile dementia likely to represent a variant of Alzheimer’s disease (AD). Methods: CSF samples from 34 subjects including 9 patients with PCA, 11 age-matched patients with AD and 14 age-matched cognitively healthy controls were analyzed using commercially available ELISA kits. Results: The Aβ_1–42, T-tau and P-tau₁₈₁ levels in PCA patients differed significantly (p < 0.02) from those in healthy controls but were indistinguishable from subjects with a clinical diagnosis of AD. Conclusion: High T-tau and P-tau₁₈₁ and low Aβ_1–42 levels in PCA – typically observed in AD – indicate that the underlying pathology of PCA is usually AD. If these findings are replicated in PCA patients with autopsy-confirmed AD neuropathology, PCA patients may be eligible for disease-modifying AD treatments.