Faculty Bibliography

In Alzheimer disease (AD) patients, early memory dysfunction is associated with glucose hypometabolism and neuronal loss in the hippocampus. Double transgenic (Tg) mice co-expressing the M146L presenilin 1 (PS1) and K670N/M671L, the double 'Swedish' amyloid precursor protein (APP) mutations, are a model of AD amyloid-beta deposition (Abeta) that exhibits earlier and more profound impairments of working memory and learning than single APP mutant mice. In this study we compared performance on spatial memory tests, regional glucose metabolism, Abeta deposition, and neuronal loss in APP/PS1, PS1, and non-Tg (nTg) mice. At the age of 2 months no significant morphological and metabolic differences were detected between 3 studied genotypes. By 8 months, however, APP/PS1 mice developed selective impairment of spatial memory, which was significantly worse at 22 months and was accompanied by reduced glucose utilization in the hippocampus and a 35.8% dropout of neurons in the CA1 region. PS1 mice exhibited a similar degree of neuronal loss in CA1 but minimal memory deficit and no impairment of glucose utilization compared to nTg mice. Deficits in 22 month APP/PS1 mice were accompanied by a substantially elevated Abeta load, which rose from 2.5% +/- 0.4% at 8 months to 17.4% +/- 4.6%. These findings implicate Abeta or APP in the behavioral and metabolic impairments in APP/PS1 mice and the failure to compensate functionally for PS1-related hippocampal cell loss

The presence of amyloid-beta (Abeta) plaques in the brain is a hallmark pathological feature of Alzheimer's disease (AD). Transgenic mice overexpressing mutant amyloid precursor protein (APP), or both mutant APP and presenilin-1 (APP/PS1), develop Abeta plaques similar to those in AD patients, and have been proposed as animal models in which to test experimental therapeutic approaches for the clearance of Abeta. However, at present there is no in vivo whole-brain imaging method to detect Abeta plaques in mice or men. A novel method is presented to detect Abeta plaques in the brains of transgenic mice by magnetic resonance microimaging (muMRI). This method uses Abeta1-40 peptide, known for its high binding affinity to Abeta, magnetically labeled with either gadolinium (Gd) or monocrystalline iron oxide nanoparticles (MION). Intraarterial injection of magnetically labeled Abeta1-40, with mannitol to transiently open the blood-brain barrier (BBB), enabled the detection of many Abeta plaques. Furthermore, the numerical density of Abeta plaques detected by muMRI and by immunohistochemistry showed excellent correlation. This approach provides an in vivo method to detect Abeta in AD transgenic mice, and suggests that diagnostic MRI methods to detect Abeta in AD patients may ultimately be feasible

Signal abnormalities on magnetic resonance imaging (MRI) T2-weighted images (T2WI) have been described in patients with Creutzfeldt-Jakob disease; however, the pathology underlying these findings remains to be fully described. We investigated the time-course of signal alterations in a murine model of prion disease using in vivo 9.4 Tesla micro magnetic resonance imaging (muMRI). The topography of muMRI signal changes was correlated with the accumulation of proteinase resistant PrP(Sc) in corresponding brain sections. Increased signal intensity on T2WI was observed in the septum and in the hippocampus of presymptomatic mice 120 days post infection (dpi). Mildly symptomatic animals (150 dpi) and animals with apparent neurological deficit (180 dpi) had a greater increase of signal intensity on T2WI in the septum and the hippocampus; in addition, abnormalities in the cortex and in the thalamus were found. Neuropathological evaluation demonstrated accumulation of PrP(Sc) and astrogliosis but only minimal or no spongiform changes in structures where abnormal signal was detected. These observations suggest that early pathological changes related to the accumulation of PrP(Sc) may be detectable in presymptomatic subjects using MRI systems with higher magnetic field strength