Familial Alzheimer disease: Decreases in CSF A 42 levels precede cognitive decline
ABSTRACT CSF amyloid beta-peptide 42 (A beta(42)) levels in presymptomatic subjects with pathogenic mutations in the PS1 gene are significantly lower than in an age-matched control group. Consequently, in these subjects, there is a window of opportunity estimated as at least 4 to 12 years to evaluate the ability of any putative prophylactic therapy to decrease, arrest, or reverse abnormalities in A beta(42) metabolism many years before clinical symptoms of Alzheimer disease are otherwise likely to occur.
SourceAvailable from: Kuniaki Kiuchi[Show abstract] [Hide abstract]
ABSTRACT: Subjective cognitive impairment may be a very early at-risk period of the continuum of dementia. However, it is difficult to discriminate at-risk states from normal aging. Thus, detection of the early pathological changes in the subjective cognitive impairment period is needed. To elucidate these changes, we employed diffusion tensor imaging and volumetry analysis, and compared subjective cognitive impairment with normal, mild cognitive impairment and Alzheimer's disease. The subjects in this study were 39 Alzheimer's disease, 43 mild cognitive impairment, 28 subjective cognitive impairment and 41 normal controls. There were no statistically significant differences between the normal control and subjective cognitive impairment groups in all measures. Alzheimer's disease and mild cognitive impairment had the same extent of brain atrophy and diffusion changes. These results are consistent with the hypothetical model of the dynamic biomarkers of Alzheimer's disease.PLoS ONE 08/2014; 9(8):e104007. DOI:10.1371/journal.pone.0104007 · 3.53 Impact Factor
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ABSTRACT: Presenilins play essential roles in memory formation, synaptic function, and neuronal survival. Mutations in the Presenilin-1 (PSEN1) gene are the major cause of familial Alzheimer's disease (FAD). How PSEN1 mutations cause FAD is unclear, and pathogenic mechanisms based on gain or loss of function have been proposed. Here, we generated Psen1 knockin (KI) mice carrying the FAD mutation L435F or C410Y. Remarkably, KI mice homozygous for either mutation recapitulate the phenotypes of Psen1(-/-) mice. Neither mutation altered Psen1 mRNA expression, but both abolished γ-secretase activity. Heterozygosity for the KI mutation decreased production of Aβ40 and Aβ42, increased the Aβ42/Aβ40 ratio, and exacerbated Aβ deposition. Furthermore, the L435F mutation impairs hippocampal synaptic plasticity and memory and causes age-dependent neurodegeneration in the aging cerebral cortex. Collectively, our findings reveal that FAD mutations can cause complete loss of Presenilin-1 function in vivo, suggesting that clinical PSEN mutations produce FAD through a loss-of-function mechanism. Copyright © 2015 Elsevier Inc. All rights reserved.Neuron 03/2015; 85(5):967-81. DOI:10.1016/j.neuron.2015.02.010 · 15.98 Impact Factor
Article: Biomarkers of AD[Show abstract] [Hide abstract]
ABSTRACT: with a sensitivity of 95% and a specificity of 87% . Bateman et al., analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging and CSF and blood tests. Concentrations of amyloid-beta Aβ42in the CSF appeared to decline 25 years before expected symptomonset. Aβ deposition, as measured by PET with the use of Pittsburgh compound B (PIB), was detected 15 years before expected symptomonset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptomonset. They found that autosomal dominant Alzheimer's disease was associated with a several pathophysiological changes over decades in CSF biomarkers of AD . CSF or blood plasma remain the most promising sources for AD biomarkers as compared to brain tissue. Blood Biomarkers CSF limits the ability to access DNA and RNA, In contrast blood's biomarkers provide a rich source of genetic materials and proteomic species for investigations. Several data indicate that miRNAs are deregulated in brain, CSF, and in blood, therefore they might be used as biomarkers in the diagnosis of AD. Kiddle et al., used Soma Logic's SOMA scan proteomics technology, they were able to conduct a large-scale replication study for 94 of the 163 candidate biomarkers from 21 published studies in plasma samples. Nine of the 94 previously reported candidates were associated to AD phenotype. These proteins may be considered as a biomarker set for further investigations . Lin Tan et al., investigated the potential role of serum miRNAs as diagnostic biomarkers for AD. They indicated that serum miR-125b may serve as a useful noninvasive biomarker for AD . Leidinger et al., revealed the involvement of 12 miRNAs in AD. They differentiated between AD and controls with an accuracy of 93%, a specificity of 95% and a sensitivity of 92% . Galimberti et al., demonstrated that cell-free miR-125b serum levels are decreased in serum from patients with AD as compared with non-inflammatory neurological controls with an accuracy of 82% . Blood is an attractive source for biomarkers due to minimal discomfort to the patient. Unfortunately the sensitivity and specificity of blood biomarkers remain lower than those from CSF. Ray et al., found 18 signaling proteins in blood plasma that can beused to classify Alzheimer patients from control subjects with 90% accuracy and to identify patients who had mild cognitive impairment that progressed to AD 2–6 years later . Lundstrom et al., revealed the alteration of blood plasma IgG Fc glycans in AD which can discriminate cognitively normal (CN) subjects from those with MCI and AD, with a sensitivity of 89.3% and a specificity of 79.1% .