Biomarker Changes Precede Symptoms by 20 Years

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Amyloid accumulation. Cross-sectional analysis using florbetapir PET shows that brain amyloid deposits ramp up steeply in AD mutation carriers between the ages of 28 and 38, several years before clinical symptoms appear. Movie courtesy of Adam Fleisher and Lancet Neurology

Evidence keeps building that the first signs of Alzheimer’s disease appear decades before symptoms. In two companion papers in the November 6 Lancet Neurology, theAlzheimer’s Prevention Initiative (API) formally published cross-sectional biomarker data from young adults who carry a presenilin 1 mutation and are destined to develop AD. Researchers led by Eric Reiman at Banner Alzheimer’s Institute, Phoenix, Arizona, and Francisco Lopera, University of Antioquia, Medellin, Colombia, report that mutation carriers show structural and functional brain abnormalities characteristic of AD more than two decades before they are expected to develop cognitive symptoms of the disease. Notably, the changes occur in the presence of high levels of Aβ42, but before there is evidence of amyloid accumulation in the brain. Although it is not yet proven that these results will generalize to late-onset AD, researchers noted the changes are consistent with brain imaging findings in young adults at increased risk for sporadic AD, suggesting the two forms of the disease progress similarly. The researchers saw the first evidence of amyloid deposits about 16 years before the expected symptom onset, in agreement with findings from the Dominantly Inherited Alzheimer Network (DIAN) cohort. Much of these data were previously presented at conferences.

Preclinical Alzheimer disease: identification of cases at risk among cognitively intact older individuals

Hypothetical model of preclinical Alzheimer's disease (AD). According to the proposed model, the group currently defined as 'preclinical AD' is heterogeneous and comprises two subpopulations. Firstly, there is the group of individuals at different stages of preclinical AD defined by the biomarkers indicated in the lower panel of the figure. All of these individuals will progress to dementia, and we call this phase 'presymptomatic AD'. The second group comprises individuals who are positive for amyloid markers and neuronal injury markers, and fall into one of the stages of preclinical AD, based on the current classification. However, this population has efficient active compensatory mechanisms, and remains resistant to dementia (stable asymptomatic cerebral amyloidosis).

Since the first description of the case of Auguste Deter, presented in Tübingen in 1906 by Alois Alzheimer, there has been an exponential increase in our knowledge of the neuropathological, cellular, and molecular foundation of Alzheimer's disease (AD). The concept of AD pathogenesis has evolved from a static, binary view discriminating cognitive normality from dementia, towards a dynamic view that considers AD pathology as a long-lasting morbid process that takes place progressively over years, or even decades, before the first symptoms become apparent, and thus operating in a continuum between the two aforementioned extreme states. Several biomarkers have been proposed to predict AD-related cognitive decline, initially in cases with mild cognitive impairment, and more recently in cognitively intact individuals. These early markers define at-risk individuals thought to be in the preclinical phase of AD. However, the clinical relevance of this preclinical phase remains controversial. The fate of such individuals, who are cognitively intact, but positive for some early AD biomarkers, is currently uncertain at best. In this report, we advocate the point of view that although most of these preclinical cases will evolve to clinically overt AD, some appear to have efficient compensatory mechanisms and virtually never develop dementia. We critically review the currently available early AD markers, discuss their clinical relevance, and propose a novel classification of preclinical AD, designating these non-progressing cases as 'stable asymptomatic cerebral amyloidosis'.

BMC Medicine 2012, 10:127 doi:10.1186/1741-7015-10-127 © 2012 Lazarczyk et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Fluid-Attenuated Inversion Recovery Hypointensity of the Pulvinar Nucleus of Patients with Alzheimer Disease: Its Possible Association with Iron Accumulation as Evidenced by the T2* Map

Difference of fluid-attenuated inversion recovery signal intensity and T2* values of thalamic pulvinar nuclei in Alzheimer disease subject and control subject. There is no discernable hypointensity (A) and T2* shortening (B) of pulvinar nuclei in age-matched control subject. In contrast, white arrows indicate bilateral hypointense pulvinar nuclei relative to remaining thalami in patient with Alzheimer disease (C). Prominent T2* shortening is noted in this patient (arrows) (D).

Objective We hypothesized that prominent pulvinar hypointensity in brain MRI represents the disease process due to iron accumulation in Alzheimer disease (AD). We aimed to determine whether or not the pulvinar signal intensity (SI) on the fluid-attenuated inversion recovery (FLAIR) sequences at 3.0T MRI differs between AD patients and normal subjects, and also whether the pulvinar SI is correlated with the T2^* map, an imaging marker for tissue iron, and a cognitive scale.

Materials and Methods Twenty one consecutive patients with AD and 21 age-matched control subjects were prospectively included in this study. The pulvinar SI was assessed on the FLAIR image. We measured the relative SI ratio of the pulvinar to the corpus callosum. The T2^* values were calculated from the T2^* relaxometry map. The differences between the two groups were analyzed, by using a Student t test. The correlation between the measurements was assessed by the Pearson's correlation test.

Results As compared to the normal white matter, the FLAIR signal intensity of the pulvinar nucleus was significantly more hypointense in the AD patients than in the control subjects (p < 0.01). The pulvinar T2^* was shorter in the AD patients than in the control subjects (51.5 ± 4.95 ms vs. 56.5 ± 5.49 ms, respectively, p = 0.003). The pulvinar SI ratio was strongly correlated with the pulvinar T2^* (r = 0.745, p < 0.001). When controlling for age, only the pulvinar-to-CC SI ratio was positively correlated with that of the Mini-Mental State Examination (MMSE) score (r = 0.303, p < 0.050). Conversely, the pulvinar T2^* was not correlated with the MMSE score (r = 0.277, p = 0.080).

Conclusion The FLAIR hypointensity of the pulvinar nucleus represents an abnormal iron accumulation in AD and may be used as an adjunctive finding for evaluating AD.

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