Patterns of Brain Activation in People at Risk for Alzheimer's Disease

Bookheimer, Susan Y.; Strojwas, Magdalena H.; Cohen, Mark S.; Saunders, Ann M.; Pericak‐Vance, Margaret A.; Mazziotta, John C.; Small, Gary W.

doi:10.1056/nejm200008173430701

Cited by 1,162 publications

(987 citation statements)

References 33 publications

Supporting

Mentioning

882

Contrasting

Unclassified

Order By: Relevance

“…They reported reduced activation in ApoE-ɛ4 carriers in bilateral inferotemporal areas that typically subserve visual object processing. In contrast, in another fMRI study, Bookheimer et al (2000) found greater and more widespread activation of the left hippocampal, prefrontal, and parietal regions during a memory task in individuals with the ɛ4 allele than in those with the ɛ3 allele. A pattern of reduced activation in object processing areas and increased activation in pre-frontal cortex is also seen in AD patients and could be indicative of a compensatory response (Grady, Haxby, Horwitz, & Rapoport, 1993;Grady & Parasuraman, 1995).…”

Section: Structural and Functional Neuroimaging Studies In Apoe-ɛ4 Camentioning

confidence: 62%

The apolipoprotein E gene, attention, and brain function.

Parasuraman¹,

Greenwood²,

Sunderland³

2002

Neuropsychology

102

View full text Add to dashboard Cite

The ɛ4 allele of the apolipoprotein E (ApoE) gene is associated with alterations in brain function and is a risk factor for Alzheimer's disease (AD). Changes in components of visuospatial attention with ApoE-ɛ4, aging, and AD are described. Healthy middle-aged adults without dementia who have the ApoE-ɛ4 gene show deficits in spatial attention and working memory that are qualitatively similar to those seen in clinically diagnosed AD patients. The findings support an association between ApoE polymorphism and specific components of visuospatial attention. Molecular mechanisms that may mediate the ApoE-attention link by modulating cholinergic neurotransmission to the posterior parietal cortex are discussed. Studies of attention and brain function in ApoE-ɛ4 carriers without dementia can advance knowledge of the genetics of visual attention, may enhance understanding of the preclinical phase of AD, and may lead to better methods for early AD detection.Apolipoprotein E (ApoE) is an amino acid glycoprotein that is important in lipid storage, transport, and metabolism (Mahley, 1988). Although synthesized mainly in the liver, ApoE is also found in the peripheral and central nervous systems, including the brain. ApoE has long been of interest in medicine, but its importance in neuroscience increased dramatically with the identification of the ɛ4 allele of the ApoE gene on chromosome 19 as a major risk factor for the development of late-onset Alzheimer's disease (AD) in older adults Strittmatter et al., 1993). This discovery led to a growing number of studies examining the role of the ApoE gene in normal brain function and cognition, as well as in disorders such as AD, brain injury, and stroke (Higgins, Large, Rupniak, & Barnes, 1997;Horsburgh, McCarron, White, & Nicol, 2000; J. D. Smith, 2000).Polymorphisms of the ApoE gene are associated with significant alterations in brain morphology (Plassman et al., 1997) and cognitive functioning, including attention (Greenwood, Sunderland, Friz, & Parasuraman, 2000) and memory (Bondi et al., 1995). Studies of ApoE may thus reveal information relevant to the genetics of attention and memory in normal individuals. At the same time, such studies may identify cognitive and neural changes that may be characteristic of preclinical stages of AD. In this article, we review the role of the ApoE gene in normal cognition and in the development of deficits indicative of early AD.Currently, no reliable methods exist for the early detection and treatment of AD. New techniques for preventing, slowing the progression of, and treating AD are being urgently sought. Such efforts would be aided considerably if AD could be detected prior to the clinical diagnosis of AD and before irreversible brain changes occur (Daffner & Scinto, 2000). Postmortem studies show that neuropathological changes occur decades before the onset of NIH Public Access Author ManuscriptNeuropsychology. Author manuscript; available in PMC 2006 January 25. Published in final edited form as:Neuropsychology. 2002 April ; ...

show abstract

Section: Structural and Functional Neuroimaging Studies In Apoe-ɛ4 Camentioning

confidence: 62%

The apolipoprotein E gene, attention, and brain function.

Parasuraman¹,

Greenwood²,

Sunderland³

2002

Neuropsychology

102

View full text Add to dashboard Cite

show abstract

“…Specifically, functional brain imaging studies revealed hippocampal mild abnormalities prior to clinical diagnosis and in the absence of structural brain atrophy, suggesting an altered functional connectivity of hippocampus at early stages of disease [3][4][5] .…”

Section: Discussionmentioning

confidence: 99%

Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease

et al. 2010

View full text Add to dashboard Cite

SummarySynaptic loss is the best pathological correlate of the cognitive decline in Alzheimer's Disease; yet, the molecular mechanisms underlying synaptic failure are unknown. Here we report a non-apoptotic baseline caspase-3 activity in hippocampal dendritic spines, and an enhancement of this activity at the onset of memory decline in the Tg2576-APPswe mouse model of Alzheimer's Disease. We show that, in spines, caspase-3 activates calcineurin which, in turn, triggers dephosphorylation and removal of the GluR1 subunit of AMPA-type receptor from post-synaptic sites. These molecular modifications lead to alterations of glutamatergic synaptic transmission and plasticity, and correlate with spine degeneration and a deficit in hippocampal-dependent memory. Importantly, pharmacological inhibition of caspase-3 activity in Tg2576 mice rescues the observed Alzheimerlike phenotypes. Therefore, we identify a novel caspase-3-dependent mechanism driving synaptic failure and contributing to cognitive dysfunction in Alzheimer's Disease. These findings point to caspase-3 as possible avenues for pharmacological therapy during early disease stages.Episodic hippocampal-dependent memory loss, the earliest clinical sign of Alzheimer's disease, is thought to be due to changes in synaptic function rather than neuronal loss 1,2 . Specifically, functional brain imaging studies revealed hippocampal mild abnormalities prior to clinical diagnosis and in the absence of structural brain atrophy, suggesting an altered functional connectivity of hippocampus at early stages of disease [3][4][5] .Dendritic spines are likely to be the first affected synaptic elements during early cognitive decline 6 . This is supported by several lines of evidence, such as: i) hippocampal spine-mediated plasticity underlies learning and memory 7 ; ii) post-mortem hippocampus from Alzheimer patients shows a significant decrease in dendritic spine density compared to age-matched controls 8 and iii) transgenic 3 mice expressing mutated forms of the amyloid precursor protein (APP), associated with familial Alzheimer's Disease, show age-dependent reductions in spine density, prior to plaque deposition 9 .Nevertheless, the molecular link between APP mutations triggering Alzheimer's Disease, and the occurrence of early spine loss remains elusive. Interestingly, a localized caspase-3 activity, causing synaptic failure, has been observed in vitro 10 , but the molecular mechanism linking caspase-3 activity to synaptic loss is far from being elucidated.Here, we analyzed caspase-3 activity in hippocampal synapses of the Tg2576 transgenic mouse model, harboring the human APPswe mutant allele linked to familial Alzheimer's Disease 11 . These mice develop early synaptic deficits 12 and several neuropathological features at older age, including amyloid plaques and dystrophic neurites 13 . Although Tg2576 mice lack neurofibrillary tangles and significant neuronal loss 14 , there is strong evidence that accumulation of the amyloid-β (Aβ) peptide, derived via APP proteolysis, is r...

show abstract

“…2, except that a memory task was used. Here the task was for the subject to recall the second word of a pair when the first word was pre- sented (13). The memorization process took place before the scans.…”

Section: Modified Roc Curvesmentioning

confidence: 99%

Novel ROC‐type method for testing the efficiency of multivariate statistical methods in fMRI

Nandy

Cordes

2003

Magnetic Resonance in Med

View full text Add to dashboard Cite

The receiver operating characteristic (ROC) method is a useful and popular tool for testing the efficiency of various diagnostic tests applicable to functional MRI (fMRI) data. Typically, the diagnostic tests are applied on simulated and pseudo-human fMRI data, and the area under the ROC curve is used as a measure of the efficiency of the diagnostic test. The effectiveness of such a method depends on how well the simulated data approximate the real data. For multivariate statistical methods, however, this technique is usually inadequate, as the spatial dependence among voxels is ignored for simulated data. In this work a modified ROC method using real fMRI data with a broader scope is proposed. This method can be applied to most fMRI postprocessing techniques, including multivariate analyses such as canonical correlation analysis (CCA). Also, the relationship of the modified ROC method with the conventional ROC method is discussed in detail. The goal of all postprocessing algorithms in functional MRI (fMRI) is to detect signal from a noisy background. It is important to assess the performance of these different methods in terms of accuracy (few false positives (FPs)) and efficiency (few missed positives). The most popular and useful tools for such assessments are methods based on the receiver operating characteristic (ROC) (1). One of the first studies of ROC methods in fMRI was made by Constable et al. (2). These methods require knowledge about the distributions of true signal and noise. If these are already known, ROC curves can be obtained from purely theoretical considerations, and there is no need for data. However, the actual distributions are unknown in most cases (if not always) and it is necessary to obtain data for an estimate of the ROC curve. In conventional ROC methods, the dataset consists of true signal as well as noise, and it must be determined which one is the true signal and which one is not. This information is not normally revealed by real data; therefore, simulated data are required. For any specific postprocessing method, one typically uses simulated or pseudo-human fMRI datasets and plots the ROC curve after the postprocessing algorithm is implemented (3). The area under the ROC curve serves as a measure of the power of a particular postprocessing algorithm.Despite its advantages, the conventional ROC method in its present form is limited in scope. This is most evident in multivariate statistical analysis. The conventional ROC method looks at the time-course of a single voxel and assumes spatial independence among neighboring voxels. This simple assumption enables us to simulate fMRI data in order to implement the ROC methods. However, in real fMRI data the assumption of spatial independence is not valid, and it is necessary to use multivariate statistical methods to take into account the spatial dependence between neighboring voxels. Since we normally have very little information about the nature of spatial dependence, it is difficult to simulate fMRI data that incorporate the spatial de...

show abstract

Patterns of Brain Activation in People at Risk for Alzheimer's Disease

Cited by 1,162 publications

References 33 publications

The apolipoprotein E gene, attention, and brain function.

The apolipoprotein E gene, attention, and brain function.

Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease

Novel ROC‐type method for testing the efficiency of multivariate statistical methods in fMRI

Contact Info

Product

Resources

About