Familial Alzheimer disease: Decreases in CSF A 42 levels precede cognitive decline
Department of Medicine, University of Toronto, Toronto, Ontario, Canada Neurology
(Impact Factor: 8.29).
08/2005; 65(2):323-5. DOI: 10.1212/01.wnl.0000171397.32851.bc
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.
Available from: Christoffer Rosén
- "Another study that included members of the Colombian Alzheimer’s Preventive Initiative Registry found that CSF and plasma Aβ42 levels in young individuals carrying a specific presenilin 1 (PS1) mutation were significantly increased compared to non-carriers more than two decades before estimated MCI onset . Studies on cognitively normal mutation carriers that were closer to the expected onset of AD have found decreased levels of Aβ42 [13,14], increased levels of T-tau and P-tau [13,15], and reduced Aβ42:40 ratio in CSF or increased plasma Aβ42 levels  compared with controls. These studies are thought to constitute models that are applicable to patients with sporadic AD as well. "
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ABSTRACT: The diagnostic guidelines of Alzheimer's disease (AD) have recently been updated to include brain imaging and cerebrospinal fluid (CSF) biomarkers, with the aim of increasing the certainty of whether a patient has an ongoing AD neuropathologic process or not. The CSF biomarkers total tau (T-tau), hyperphosphorylated tau (P-tau) and the 42 amino acid isoform of amyloid β (Aβ42) reflect the core pathologic features of AD, which are neuronal loss, intracellular neurofibrillary tangles and extracellular senile plaques. Since the pathologic processes of AD start decades before the first symptoms, these biomarkers may provide means of early disease detection. The updated guidelines identify three different stages of AD: preclinical AD, mild cognitive impairment (MCI) due to AD and AD with dementia. In this review, we aim to summarize the CSF biomarker data available for each of these stages. We also review results from blood biomarker studies. In summary, the core AD CSF biomarkers have high diagnostic accuracy both for AD with dementia and to predict incipient AD (MCI due to AD). Longitudinal studies on healthy elderly and recent cross-sectional studies on patients with dominantly inherited AD mutations have also found biomarker changes in cognitively normal at-risk individuals. This will be important if disease-modifying treatment becomes available, given that treatment will probably be most effective early in the disease. An important prerequisite for this is trustworthy analyses. Since measurements vary between studies and laboratories, standardization of analytical as well as pre-analytical procedures will be essential. This process is already initiated. Apart from filling diagnostic roles, biomarkers may also be utilized for prognosis, disease progression, development of new treatments, monitoring treatment effects and for increasing the knowledge about pathologic processes coupled to the disease. Hence, the search for new biomarkers continues. Several candidate biomarkers have been found in CSF, and although biomarkers in blood have been harder to find, some recent studies have presented encouraging results. But before drawing any major conclusions, these results need to be verified in independent studies.
Molecular Neurodegeneration 06/2013; 8(1):20. DOI:10.1186/1750-1326-8-20 · 6.56 Impact Factor
Available from: ncbi.nlm.nih.gov
- "Thus, it is not surprising that a deficit in the ability to learn and remember new information (i.e., anterograde amnesia) is the clinical hallmark of AD pathology . However, the amyloid pathology that likely occurs years prior to the onset of symptoms (Morris et al. 1996; Reiman et al. 1996; Moonis et al. 2005; Mintun et al. 2006; Becker et al. 2010; De Meyer et al. 2010) is not particularly abundant in medial temporal lobe, but instead in the regions comprising the " default mode network " (Buckner et al. 2005; Sperling et al. 2009). These changes in the default mode network, comprised of a set of functionally interconnected cortical areas (posterior cingulate, inferior parietal lobule, lateral temporal neocortex, ventromedial and dorsomedial prefrontal cortex) that project heavily to medial temporal lobe structures (Buckner et al. 2008), presage cell death in the hippocampus by years. "
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ABSTRACT: Neuropsychological assessment has featured prominently over the past 30 years in the characterization of dementia associated with Alzheimer disease (AD). Clinical neuropsychological methods have identified the earliest, most definitive cognitive and behavioral symptoms of illness, contributing to the identification, staging, and tracking of disease. With increasing public awareness of dementia, disease detection has moved to earlier stages of illness, at a time when deficits are both behaviorally and pathologically selective. For reasons that are not well understood, early AD pathology frequently targets large-scale neuroanatomical networks for episodic memory before other networks that subserve language, attention, executive functions, and visuospatial abilities. This chapter reviews the pathognomonic neuropsychological features of AD dementia and how these differ from "normal," age-related cognitive decline and from other neurodegenerative diseases that cause dementia, including cortical Lewy body disease, frontotemporal lobar degeneration, and cerebrovascular disease.
Cold Spring Harbor Perspectives in Medicine 04/2012; 2(4):a006171. DOI:10.1101/cshperspect.a006171 · 9.47 Impact Factor
Available from: Olivier Felician
- "L'hypothè se la plus couramment admise pour rendre compte de ce fait serait que le peptide, capté par les plaques sé niles, ne passerait pas dans le LCR (Weller, 2001). Son taux diminuerait avant les premiè res manifestations cliniques de la maladie, comme le suggè rent les e ´ tudes mené es dans les formes familiales de MA, montrant que les taux de Ab42 dans le LCR sont significativement plus bas chez les sujets asymptomatiques porteurs d'une anomalie sur le gè ne de la pré sé niline 1 que chez des sujets sains du mê me a ˆ ge (Moonis et al., 2005). De mê me, le LCR des sujets sains porteurs d'un (ou deux) allè le(s) du gè ne ApoE4 (le principal facteur de susceptibilité gé né tique identifié dans les formes sporadiques de la MA) pré sente un taux de Ab42 diminué , avec un effet dose (valeurs infé rieures chez les homozygotes que chez les hé té rozygotes) (Shaw et al., 2009). "
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ABSTRACT: IntroductionThe diagnosis of Alzheimer's disease (AD) currently relies on clinical criteria that are primarily based on the presence of an amnestic syndrome of the mesial temporal lobe type. In recent years, new diagnostic tools have been developed, such as the possibility of measuring a set of proteins directly involved in the pathophysiological process of AD. A profile suggestive of AD has been defined, characterized by decreased beta-amyloid peptide, combined with increased Tau protein and phopho-Tau.
Revue Neurologique 06/2011; 167(6):474-484. DOI:10.1016/j.neurol.2010.10.007 · 0.66 Impact Factor
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