Niki S.M. Schoonenboom

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

Objective: 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. Methods: 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. Results: 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%. Conclusion: 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.

CSF biomarker levels in early and late onset Alzheimer's disease

OBJECTIVE To compare CSF levels of beta-amyloid 1-42 (Abeta(1-42)), total tau (tau) and tau phosphorylated at threonine 181 (ptau-181) between AD patients and controls according to age. METHODS 248 AD patients (48% men) and 127 controls (51% men, 22 volunteers and 105 subjective complainers) underwent lumbar puncture. Both patients and controls were divided into a young (<65 years) and old (>or=65 years) group. RESULTS All three biomarkers showed main effects of diagnosis (p<0.001). There was an interaction between diagnosis and age for all three biomarkers (p<0.05), as old controls had lower Abeta(1-42) and higher (p)tau than young controls (Abeta(1-42) 699+/-250 versus 866+/-191pg/ml, tau 408+/-245 versus 243+/-102pg/ml, ptau-181 60+/-28 versus 42+/-15pg/ml), but there was no difference according to age among AD patients (Abeta(1-42) 451+/-178 versus 425+/-146pg/ml, tau 741+/-460 versus 798+/-467pg/ml, ptau-181 91+/-42 versus 91+/-41pg/ml). CONCLUSION We found that the older control group had lower Abeta(1-42) and higher (p)tau compared to the younger control group. This suggests that older individuals may have AD pathology, even in the absence of objective cognitive impairment.

Longitudinal changes of CSF biomarkers in memory clinic patients

Objective: In Alzheimer disease (AD), longitudinal changes of beta-amyloid1-42 (Aβ1-42), tau, and phosphorylated tau at threonine 181 (ptau-181) in CSF have been reported in small studies only. We evaluated the natural course of CSF biomarkers in patients with AD, subjective complaints, and mild cognitive impairment (MCI). Methods: One hundred five patients (50 AD, 38 MCI, 17 subjective complaints) underwent two lumbar punctures, with a mean interval of 21 ± 9 months. CSF levels of Aβ1-42, tau, and ptau-181 were measured. Results: CSF Aβ1-42 and tau levels showed main effects for both diagnosis and time (all p < 0.05), with average increases of 47 ± 72 and 49 ± 143 pg/mL. The interaction terms were not significant, which implies a similar time effect for all diagnostic groups. CSF ptau-181 levels showed a main effect for diagnosis (p = 0.01) but not for time (p = 0.27, increase of 1.0 ± 12 pg/mL). Conclusion: Levels of CSF beta-amyloid1-42 and tau but not phosphorylated tau at threonine 181 increased over time in this memory clinic patient cohort with comparable change in all diagnostic groups. The cross-sectional difference between diagnostic groups, however, exceeded by far the longitudinal changes within individuals, suggesting that these biomarkers are not sensitive as markers of disease progression.

Amyloid β 38, 40, and 42 species in cerebrospinal fluid: More of the same?

Various C‐terminally truncated amyloid β peptides (Aβ) are linked to Alzheimers disease (AD) pathogenesis. Cerebrospinal fluid (CSF) concentrations of Aβ38, Aβ40, and Aβ42 were measured by enzyme‐linked immunosorbent assay in 30 patients with AD and 26 control subjects. CSF Aβ42 levels was decreased in patients with AD, whereas CSF Aβ38 and Aβ40 levels were similar in patients with AD and control subjects. All three Aβ peptides were interrelated, particularly CSF Aβ38 and Aβ40. Diagnostic accuracy of CSF Aβ42 concentrations was not improved by applying the ratios of CSF Aβ42 to Aβ38 or Aβ40. Ann Neurol 2005;58:139–142

Inflammatory markers in AD and MCI patients with different biomarker profiles

OBJECTIVE The aim of this study was to demonstrate the involvement of the inflammatory proteins IL-6, ACT and CRP early in the pathology process of AD in patients with mild cognitive impairment (MCI) and AD. METHODS IL-6, ACT, CRP, Abeta42, phospho-tau (p-tau) and total tau concentrations in serum and CSF of 145 patients with probable AD and 67 patients with MCI were measured by sandwich ELISA. MCI patients were characterized as high- respectively low-risk MCI according to their Abeta42/tau risk profile. RESULTS CSF and serum CRP levels were significantly higher in MCI compared to AD patients after adjustment for age, ApoE epsilon4 genotype and cardiovascular diseases (p<0.01). This difference remained present in patients with a low-risk biomarker profile for AD after adjustment for abovementioned covariates. CSF IL-6 levels were also significantly higher in MCI patients with a low-risk CSF profile. CONCLUSIONS These findings suggest that inflammatory processes might be involved in early stages of AD, even before Abeta and tau changes are present in CSF of MCI patients.

CSF and MRI markers independently contribute to the diagnosis of Alzheimer's disease

BACKGROUND Decreased amyloid beta (1-42) (Abeta42) and increased (phosphorylated) tau in cerebrospinal fluid (CSF) are considered to be a reflection of plaques, tangles, and neuronal degeneration in Alzheimers disease (AD). Atrophy of the medial temporal lobe (MTA) on magnetic resonance imaging (MRI) reflects neuronal loss in this area. OBJECTIVE To compare diagnostic accuracy of CSF biomarkers and MTA in AD versus controls. METHODS Abeta42, tau and tau phosphorylated at threonine 181 (Ptau-181) were measured in CSF from 61 AD patients and 32 controls by sandwich enzyme-linked immunosorbent assay. A CSF biomarker profile for AD was constructed. MTA was rated visually on MRI. RESULTS When AD patients and controls were evaluated separately, no correlations were present between the CSF markers and MTA score. Both MTA and CSF biomarker profile were independently associated with the diagnosis AD (MTA: OR (95% CI)=28 (3-239); CSF biomarker profile: OR (95% CI)=57 (13-262)). Among individuals younger than 65 years old and without MTA 60% suffered AD, and the finding of an abnormal CSF biomarker profile was limited to AD patients only. CONCLUSIONS MTA and CSF biomarkers seem to be of incremental value for the diagnosis AD. CSF analysis is most sensitive in the absence of MTA, and especially among early-onset AD patients.

Intrathecal chemokine levels in Alzheimer disease and frontotemporal lobar degeneration

Amyloid beta (Aβ)1–42 deposition into the brain is considered a crucial pathogenetic step during Alzheimer disease (AD) development, as it originates a cascade of events leading to irreversible neuronal damage.1 Conversely, frontotemporal lobar degeneration (FTLD) is characterized by intracellular deposition of abnormally phosphorylated tau protein responsible for neuronal death.2 Immunoreactivity for a number of chemokines and for their related receptors has been demonstrated in resident cells of the CNS.3 Some of them have been proposed as candidate genes for AD,4 and increased levels have been found in CSF from patients with AD,5 whereas no information on chemokines in FTLD is available at present. Interferon-γ-inducible protein-10 (IP-10), monocyte chemotactic protein-1 (MCP-1), and interleukin-8 (IL-8) levels were evaluated in CSF from 32 patients with probable AD (11 men and 21 women; mean age at onset: 62.1 ± 8.0 years), 24 with FTLD (frontotemporal dementia [FTD] = 17; progressive aphasia [PA] = 5; semantic dementia [SD] = 2; 9 men and 15 women; mean age at onset: 61.5 ± 1.6 years). …

CSF Neurofilaments in Frontotemporal Dementia Compared with Early Onset Alzheimer’s Disease and Controls

Background: Frontotemporal dementia (FTD) is pathologically heterogeneous, sometimes revealing intraneuronal inclusions of neurofilaments. We therefore measured CSF neurofilament profiles in patients with FTD, patients with early onset Alzheimer’s disease (EAD) and healthy control subjects to explore the discriminative potential of CSF neurofilaments compared with the existing CSF biomarkers amyloid-β(1–42), tau and tau phosphorylated at threonine-181. Methods: CSF levels of light chain, heavy chain and hyperphosphorylated heavy chain neurofilaments (NfL, t-NfH and P-NfH) were compared between 17 subjects with FTD, 20 with EAD and 25 cognitively healthy controls. Results: A subgroup of FTD patients had remarkably high CSF levels of both NfL and NfH. The degree of NfH phosphorylation was increased in FTD compared to both other groups. The levels of CSF NfL were significantly higher in EAD compared to controls. Conclusion: Differences in CSF biomarker profiles might reflect differential involvement of neurofilaments and tau in FTD and EAD. The subgroup of FTD patients with high CSF neurofilament levels may have a different neuropathological substrate and future studies addressing this specific issue are needed.

Cerebrospinal fluid tau levels in frontotemporal dementia

tients, as measured by comparing preand postconditions. The effect was still observable 30 minutes from the baseline evaluation, but not after 45 minutes and 60 minutes. Only one patient presented a transient bradykinesia worsening immediately after 1Hz rTMS (Fig). Based on the assumption that 1Hz rTMS causes a transient depression of excitability at the cortical level, we propose that overactivity of the SMA plays an essential role in choreic symptoms in HD. Studies with repeated rTMS sessions could evaluate possible long-lasting beneficial effects of 1Hz rTMS in HD patients.

Alzheimer's biomarkers in daily practice (ABIDE) project: Rationale and design

The Alzheimers biomarkers in daily practice (ABIDE) project is designed to translate knowledge on diagnostic tests (magnetic resonance imaging [MRI], cerebrospinal fluid [CSF], and amyloid positron emission tomography [PET]) to daily clinical practice with a focus on mild cognitive impairment (MCI)