We assessed cerebrospinal fluid (CSF) levels of tau and other biomarkers of neurodegenerative disease. CSF tau levels vary widely in reports of frontotemporal dementia (FTD). CSF samples were assayed for tau, amyloid beta1-42 (A1-42), and the isoprostane 8,12-iso-iPF2a-VI (iP) prospectively in 64 patients with FTD, retrospectively in 26 autopsied cases with FTD or Alzheimer's disease (AD), and in 13 healthy seniors. To validate our observations in vivo, we correlated CSF tau levels with cortical atrophy in 17 FTD patients using voxel-based morphometry analyses of high-resolution magnetic resonance imaging. CSF levels of tau, Abeta1-42, and iP differed significantly in FTD compared with AD. Individual patient analyses showed that 34% of FD patients had significantly low levels of CSF tau, although this was never seen in AD. A discriminant analysis based on CSF levels of tau, Abeta1-42, and iP was able to classify 88.5% of these patients in a manner that corresponds to their clinical or autopsy diagnosis. Magnetic resonance imaging studies showed that CSF tau levels correlate significantly with right frontal and left temporal cortical atrophy, brain regions known to be atrophic in patients with autopsy-proved FTD. We conclude that CSF tau levels are significantly reduced in many patients with FTD.
"In our series, no cases of clinical non-AD could be switched to AD based on completely consistently pathological AD biomarkers. Interpretation of biomarkers is complicated by the fact that biomarkers of neuronal injury and amyloid dysfunction are also found in other neurodegenerative diseases like frontotemporal lobe degeneration , Parkinson's disease dementia , dementia with Lewy bodies , or vascular dementia . This highlights the impact of a good clinical assessment with a distinct tentative diagnosis despite the vast heterogeneity and overlapping clinical presentations of these neurodegenerative disorders. "
[Show abstract][Hide abstract] ABSTRACT: Background:
Biomarkers of neuronal injury and amyloid pathology play a pivotal role in the diagnosis of Alzheimer's disease (AD). The degree of AD biomarker congruence is still unclear in clinical practice.
Diagnosis of AD with regard to the congruence of the clinical diagnosis and different biomarkers.
In this prospective cross-sectional observational study, 54 patients with mild cognitive impairment or dementia due to AD or not due to AD were investigated. Biomarkers of neuronal injury were medial temporal lobe atrophy (MTA) on magnetic resonance imaging (MRI) and tau concentration in the cerebrospinal fluid (CSF). CSF Aβ1-42 and amyloid-targeting positron emission tomography (PET) were considered as biomarkers of amyloid pathology.
Forty cases were diagnosed as AD and 14 cases were diagnosed as non-AD based on clinical and routine MRI assessment. AD cases had higher MTA scores, higher levels of CSF tau and lower levels of CSF Aβ1 - 42, and higher amyloid load on PET compared to the non-AD group. In the AD group, completely consistently pathological biomarkers were found in 32.5% , non-pathological in 5% . In 62.5% the findings were inconsistent. Congruence of biomarkers was 67.5% for neuronal injury and for amyloid dysfunction, respectively. In two patients, clinical diagnosis switched to non-AD due to completely consistent non-pathological biomarker findings. The criteria of the international working group were met in 75.0% .
Surprisingly, the number of completely congruent biomarkers was relatively low. Interpretation of AD biomarkers is complicated by multiple biomarker constellations. However, the level of biomarker consistency required to reliably diagnose AD remains uncertain.
"Therefore, there is an urgent need for objective diagnostic tests of AD onset and progression. AD biomarkers based on imaging and body fluid analytes have been proposed and the combined detection of three well recognized CSF biomarkers: Aβ1-42, total tau and phosphorylated tau (p-tau) reach high sensitivity and specificity for AD prediction (Grossman et al., 2005; Jack et al., 2010; Mulder et al., 2010; Petersen et al., 2010). However, a significant limitation to these methods is represented by their costs, availability and invasiveness that impede their routine use especially for the diagnosis of asymptomatic early stages of AD. "
[Show abstract][Hide abstract] ABSTRACT: Alzheimer disease (AD) is the most common form of dementia among the elderly and is characterized by progressive loss of memory and cognition. These clinical features are due in part to the increase of reactive oxygen and nitrogen species that mediate neurotoxic effects. The up-regulation of the heme oxygenase-1/biliverdin reductase-A (HO-1/BVR-A) system is one of the earlier events in the adaptive response to stress. HO-1/BVR-A reduces the intracellular levels of pro-oxidant heme and generates equimolar amounts of the free radical scavengers biliverdin-IX alpha (BV)/bilirubin-IX alpha (BR) as well as the pleiotropic gaseous neuromodulator carbon monoxide (CO) and ferrous iron. Two main and opposite hypotheses for a role of the HO-1/BVR-A system in AD propose that this system mediates neurotoxic and neuroprotective effects, respectively. This apparent controversy was mainly due to the fact that for over about 20years HO-1 was the only player on which all the analyses were focused, excluding the other important and essential component of the entire system, BVR. Following studies from the Butterfield laboratory that reported alterations in BVR activity along with decreased phosphorylation and increased oxidative/nitrosative post-translational modifications in the brain of subjects with AD and amnestic mild cognitive impairment (MCI) subjects, a debate was opened on the real pathophysiological and clinical significance of BVR-A. In this paper we provide a review of the main discoveries about the HO/BVR system in AD and MCI, and propose a mechanism that reconciles these two hypotheses noted above of neurotoxic and the neuroprotective aspects of this important stress responsive system.
Neurobiology of Disease 10/2013; 62. DOI:10.1016/j.nbd.2013.09.018 · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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 (Aβ(1-42)) 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 Aβ(1-42) levels can accurately distinguish FTLD from AD, with a high t-tau to Aβ(1-42) 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.
Camilla N Clark, Jennifer M Nicholas, Elizabeth Gordon, Hannah L Golden, Miriam H Cohen, Felix J Woodward, Kirsty Macpherson, Catherine F Slattery, Catherine J Mummery, Jonathan M Schott, Jonathan D Rohrer, Jason D Warren
Nagaendran Kandiah, Vivian Wang, Xuling Lin, Mei Mei Nyu, Linda Lim, Adeline Ng, Shahul Hameed, Hwee Lin Wee
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