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Editorial commentary for jnnp-2016-313476.R1: association between naturally occurring antiamyloid β autoantibodies and medial temporal lobe atrophy in Alzheimer's disease

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Abstract

The pathophysiology of Alzheimer's disease (AD) is thought to involve the accumulation and deposition of amyloid β (Aβ) peptide in the form of plaques. It is well known that decreased cerebrospinal fluid (CSF) Aβ42 concentrations occur early in AD. Besides this, τ protein becomes hyperphosphorylated (P-τ), getting unstable and unable to bind the microtubules and finally disintegrating into neurofibrillary tangles. The neuropathological process leads to a characteristic pattern of brain damage starting in the medial temporal lobe (MTL) that can be viewed and measured with structural MRI. Both CSF biomarkers (Aβ and P-τ) and MTL atrophy have been accepted as biomarkers of AD, supporting the diagnosis of AD even in preclinical stages.1 There is some correlation between MRI findings and CSF biomarkers. On one hand, atrophy of the MTL is a diagnostic marker for AD at the mild cognitive impairment stage, although this is not a such …

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... These data suggest that reduction of Aβ in the periphery is not sufficient to reduce brain Aβ levels and that BACE is not the rate-limiting enzyme for Aβ processing in the brain (Georgievska et al., 2015). Recent research suggests that CSF naturally occurring antibodies against Aβ seem to have a protective effect for AD, while serum naturally occurring antibodies against Aβ do not seem to have any effect (Kimura et al., 2017;Menendez Gonzalez, 2017a). In line with this, Piazza et al. (2013) reported the first evidence about the participation of natural anti-Aβ autoantibodies in cerebral amyloid-related angiopathy (CAA) and the possible elimination mechanism of soluble Aβ in the CSF by antibodies. ...
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Article
Background Naturally occurring autoantibodies against amyloid β (Aβ) peptide exist in the serum and cerebrospinal fluid (CSF) of healthy individuals. Recently, it was reported that administration of intravenous immunoglobulin at the mild cognitive impairment (MCI) stage of Alzheimer's disease (AD) reduces brain atrophy. Objective To examine the association between naturally occurring anti-Aβ autoantibodies and brain atrophy in patients with cognitive impairment. Methods Serum and CSF levels of anti-Aβ autoantibodies and CSF biomarkers were evaluated in 68 patients with cognitive impairment, comprising 44 patients with AD, 19 patients with amnestic MCI and five patients with non-Alzheimer's dementia. The degree of brain atrophy was assessed using the voxel-based specific regional analysis system for AD, which targets the volume of interest (VOI) in medial temporal structures, including the whole hippocampus, entorhinal cortex and amygdala. Results CSF levels of anti-Aβ autoantibodies were inversely correlated with the extent and severity of VOI atrophy, and the ratio of VOI/grey matter atrophy in patients with AD, but not in MCI or non-AD patients. Serum levels of anti-Aβ autoantibodies were not associated with these parameters in any of the patient groups. Conclusions These results indicate that CSF levels of naturally occurring anti-Aβ autoantibodies are inversely associated with the degree of the VOI atrophy in patients with AD. Although the mechanism is unclear, CSF levels of naturally occurring anti-Aβ autoantibodies may be implicated in the progression of atrophy of the whole hippocampus, entorhinal cortex and amygdala, in AD.
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Article
Objective: To capitalize on data from different clinical series to compare sensitivity and specificity of individual biomarkers for predicting mild cognitive impairment (MCI) progression to Alzheimer's disease (AD). Methods: Medial temporal atrophy, cortical hypometabolism, and cerebrospinal fluid biomarkers were assessed in 18 patients with mild cognitive impairment (MCI) with prodromal AD (pAD; conversion time, 26 ± 12 months) and 18 stable MCI (sMCI) patients from the Translational Outpatient Memory Clinic cohort, as well as in 24 pAD patients (conversion time, 36 ± 12 months) and 33 sMCI patients from the Alzheimer's Disease Neuroimaging Initiative cohort. Medial temporal atrophy was measured by manual, semi-automated, and automated hippocampal volumetry; cortical hypometabolism was measured using several indices of AD-related hypometabolism pattern; and cerebrospinal fluid markers were amyloid β (Aβ)42 and total tau protein concentrations. For each biomarker, sensitivity for pAD, specificity for sMCI, and diagnostic accuracy were computed. Results: Sensitivity to predict MCI conversion to AD in the Alzheimer's Disease Neuroimaging Initiative and Translational Outpatient Memory Clinic cohorts was 79% and 94% based on Aβ42, 46% and 28% based on hippocampal volumes, 33% to 66% and 56% to 78% based on different hypometabolism indices, and 46% and 61% based on total tau levels, respectively. Specificity to exclude sMCI was 27% and 50% based on Aβ42, 76% and 94% based on hippocampal volumes, 58% to 67% and 55% to 83% based on different hypometabolism indices, and 61% and 83% based on total tau levels, respectively. Conclusions: Current findings suggest that Aβ42 concentrations and hippocampal volumes may be used in combination to best identify pAD.
Article
Hippocampal atrophy as assessed by magnetic resonance imaging (MRI) and abnormal cerebrospinal fluid (CSF) biomarkers are supportive features for the diagnosis of Alzheimer's disease (AD) and are assumed to be indirect pathological markers of the disease. In AD patients, antemortem MRI hippocampal volumes (HVs) correlate with the density of neurofibrillary tangles (but not with senile plaques) at autopsy suggesting that HVs may better correlate with CSF tau and hyperphosphorylated tau (P-tau) levels than CSF amyloid beta protein (Aβ)(42) level. Here, we tested this hypothesis in a well-defined AD group. Patients were selected according to the New Research Criteria for AD, including specific episodic memory deficit and CSF AD profile (defined as abnormal ratio of Aβ(42):tau). MRI was performed within 6 months of lumbar puncture. HVs were obtained using automated segmentation software. Thirty-six patients were included. Left HV correlated with CSF tau (R = -0.53) and P-tau (R = -0.56) levels. Mean HVs correlated with the CSF P-tau level (R = -0.52). No correlation was found between any brain measurement and CSF Aβ(42) level. The CSF tau and P-tau levels, but not the CSF Aβ(42) level, correlated with HV, suggesting that CSF tau markers reflect the neuronal loss associated with the physiopathological process of AD.
Translational outpatient memory clinic Working Group
  • A Prestia
  • A Caroli
  • K Herholz
Prestia A, Caroli A, Herholz K, et al., Translational outpatient memory clinic Working Group, Alzheimer's Disease Neuroimaging Initiative. Diagnostic accuracy of