Tracking Alzheimerʼs disease in transgenic mice using fluorodeoxyglucose autoradiography

Reiman, Eric M.; Uecker, Anne; González-Lima, Francisco; Minear, Deanna; Chen, Kewei; Callaway, Narriman Lee; Berndt, Jason D.; Games, Dora

doi:10.1097/00001756-200004070-00018

Cited by 60 publications

(46 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Group-only effects in the lateral septum as well as in the cerebellar lobules could also play into the sensorimotor/arousal effects, but they also provide a link to the limbic system and involvement in retention of spatial learning (Hilber et al, 1998), respectively. Cerebellar involvement (as vermis lobules 1-6) was also shared by the PDAPP mice in our initial study (Reiman et al, 2000). Further investigation into this latter effect may be of interest since neither transgenic strain demonstrates amyloid deposition in the cerebellum.…”

Section: Discussionmentioning

confidence: 62%

Age- and transgene-related changes in regional cerebral metabolism in PSAPP mice

2006

Self Cite

View full text Add to dashboard Cite

In parallel to imaging studies in humans with Alzheimer's disease (AD), we have mapped brain metabolic activity in transgenic mouse models of AD. Our aim in both is to provide new surrogate markers of progression to help clarify disease mechanisms and rapidly screen candidate therapeutics. Since previous findings of preferential reductions in posterior cingulate glucose metabolism may have been confounded by morphological abnormalities in previously studied "PDAPP" transgenic mice, we first assessed hippocampal and callosal anatomy in PSAPP (PS1×APP) mice, another transgenic mouse model of AD, and found no major abnormalities. We then used fluorodeoxyglucose (FDG) autoradiography in older and younger PSAPP and wildtype mice to assess the functional state of 56 regions-of-interest across group, age and increasing amyloid load. Reductions in FDG uptake in aged transgenic mice, with significant interactions between group and age, were found in retrosplenial cingulate gyrus, found to be metabolically affected in persons affected by or at risk for AD, and in brain regions known to participate with retrosplenial cingulate in networks contributing to spatial learning deficits found in these animals. Like patients with AD, PSAPP mice have agerelated metabolic reductions in posterior cingulate cortex, a finding that does not appear to be related to morphological abnormalities. If longitudinal studies support these progressive and preferential reductions in retrosplenial metabolism in PSAPP mice, these reductions could provide an indicator of disease progression, help bridge the gap between human and animal studies of AD, and aid in clarification of disease mechanisms and screening of promising treatments.

show abstract

Section: Discussionmentioning

confidence: 62%

Age- and transgene-related changes in regional cerebral metabolism in PSAPP mice

2006

Self Cite

View full text Add to dashboard Cite

show abstract

“…When rodents are maintained in cognitively stimulating environment or on a dietary restriction regimen neurons in their hippocampus are more resistant to death and neurogenesis (the production of new neurons from stem cells) is increased [10][11][12] . Similarly, regular physical exercise enhances hippocampal synaptic plasticity and neurogenesis, and is neuroprotective 22 .…”

Section: Risk Factorsmentioning

confidence: 99%

“…The activities of cytochrome c oxidase, pyruvate dehydrogenase complex and α-ketoglutarate dehydrogenase complex, critical enzymes in energy metabolism, are decreased in brain cells of AD patients 20 . Altered proteolytic processing of APP may contribute to impaired energy metabolism, because brain glucose metabolism is decreased in cognition-related brain regions of APP mutant mice in association with increased amounts of Aβ in their brains 21,22 . Moroever, hypoxic tolerance is significantly decreased in presymptomatic APP mutant mice suggesting an early role for perturbed energy metabolism in the pathogenic action of altered APP processing 23 .…”

Section: Cellular Stress: Renegade Radicals and Power Cutsmentioning

confidence: 99%

Pathways towards and away from Alzheimer's disease

Mattson

2004

Nature

2,758

2,058

View full text Add to dashboard Cite

Slowly, but surely, Alzheimer's disease (AD) patients lose their memory, their cognitive abilities and even their personalities may change dramatically. These changes are due to the progressive dysfunction and death of nerve cells that are responsible for the storage and processing of information. While drugs can temporarily improve memory, at present there are no treatments that can stop or reverse the inexorable neurodegenerative process. But rapid progress towards understanding the cellular and molecular alterations that are responsible for the neuron's demise is increasing optimism that effective preventative and therapeutic strategies are in the offing.Alzheimer's disease (AD) is a neurodegenerative disorder that currently affects nearly 2% of the population in industrialized countries; the risk of AD dramatically increases in individuals beyond the age of 70 and it is predicted that the incidence of AD will triple within the next 50 years (www.alz.org). There can be other causes of memory loss and definitive diagnosis of AD therefore requires postmortem examination of the brain, which must contain sufficient numbers of "plaques" and "tangles" to qualify as AD 1, 2 . Plaques are extracellular deposits of fibrils and amorphous aggregates of amyloid β-peptide (Aβ); diffuse deposits of Aβ are also present in high amounts. Neurofibrillary tangles are intracellular fibrillar aggregates of the microtubule-associated protein tau which exhibit hyperphosphorylation and oxidative modifications. Plaques and tangles are present mainly in brain regions involved in learning and memory and emotional behaviors such as the entorhinal cortex, hippocampus, basal forebrain and amygdala. Brain regions with plaques typically exhibit reduced numbers of synapses, and neurites associated with the plaques are often damaged, suggesting that Aβ damages synapses and neurites. Neurons that employ glutamate or acetylcholine as neurotransmitters appear to be particularly affected, but neurons that produce serotonin and norepinephrine are also damaged. This review focuses on the molecular and cellular abnormalities that occur in the brain in AD, how they result in synaptic dysfunction and cell death, and how they can be counteracted. Central to the disease is altered proteolytic processing of the amyloid precursor protein (APP) resulting in the production and aggregation of neurotoxic forms of Aβ. Neurons that degenerate in AD exhibit increased oxidative damage, impaired energy metabolism and perturbed cellular calcium homeostasis; Aβ appears to be an important instigator of these abnormalities. Genetic and environmental factors can determine one's risk for and an understanding of these risk factors and how they modify the amyloid cascade is leading to the development of interventions for the prevention and treatment of AD that range from changes in diet and lifestyle, to vaccines and drugs.

show abstract

“…cursor protein associated with a form of early-onset Alzheimer's disease (23); and abnormal reductions in thalamic, posterior and anterior cingulate, and hippocampal perfusion in patients with questionable Alzheimer's disease predicted their subsequent conversion to probable Alzheimer's disease (24). The CMRgl declines observed in 4 noncarriers with a reported family history of probable Alzheimer's disease may be related to normal aging, the earliest preclinical stages of Alzheimer's disease, or their combination (15).…”

Section: Discussionmentioning

confidence: 99%

Declining brain activity in cognitively normal apolipoprotein E ɛ4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease

Reiman

Caselli

Chen

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

432

316

View full text Add to dashboard Cite

Cross-sectional positron emission tomography (PET) studies find that cognitively normal carriers of the apolipoprotein E (APOE) 4 allele, a common Alzheimer's susceptibility gene, have abnormally low measurements of the cerebral metabolic rate for glucose (CMRgl) in the same regions as patients with Alzheimer's dementia. In this article, we characterize longitudinal CMRgl declines in cognitively normal 4 heterozygotes, estimate the power of PET to test the efficacy of treatments to attenuate these declines in 2 years, and consider how this paradigm could be used to efficiently test the potential of candidate therapies for the prevention of Alzheimer's disease. We studied 10 cognitively normal 4 heterozygotes and 15 4 noncarriers 50 -63 years of age with a reported family history of Alzheimer's dementia before and after an interval of approximately 2 years. The 4 heterozygotes had significant CMRgl declines in the vicinity of temporal, posterior cingulate, and prefrontal cortex, basal forebrain, parahippocampal gyrus, and thalamus, and these declines were significantly greater than those in the 4 noncarriers. In testing candidate primary prevention therapies, we estimate that between 50 and 115 cognitively normal 4 heterozygotes are needed per active and placebo treatment group to detect a 25% attenuation in these CMRgl declines with 80% power and P ‫؍‬ 0.005 in 2 years. Assuming these CMRgl declines are related to the predisposition to Alzheimer's dementia, this study provides a paradigm for testing the potential of treatments to prevent the disorder without having to study thousands of research subjects or wait many years to determine whether or when treated individuals develop symptoms.

show abstract

Tracking Alzheimerʼs disease in transgenic mice using fluorodeoxyglucose autoradiography

Cited by 60 publications

References 8 publications

Age- and transgene-related changes in regional cerebral metabolism in PSAPP mice

Age- and transgene-related changes in regional cerebral metabolism in PSAPP mice

Pathways towards and away from Alzheimer's disease

Declining brain activity in cognitively normal apolipoprotein E ɛ4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease

Contact Info

Product

Resources

About