No abstract

Fibrillar amyloid-beta (A␤) is found in the brains of many cognitively normal older people. Whether or not this reflects a predisposition to Alzheimer's disease (AD) is unknown. We used Pittsburgh Compound B (PiB) PET to characterize the relationship between fibrillar A␤ burden and this predisposition in cognitively normal older people at 3 mean levels of genetic risk for AD. Dynamic PiB PET scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest (ROIs) were used to characterize and compare cerebral-to-cerebellar PIB distribution volume ratios, reflecting fibrillar A␤ burden, in 28 cognitively normal persons (mean age, 64 years) with a reported family history of AD and 2 copies, 1 copy, and no copies of the apolipoprotein E (APOE) 4 allele. The 8 4 homozygotes, 8 heterozygotes, and 12 noncarriers did not differ significantly in terms of age, sex, or cognitive scores. Fibrillar A␤ was significantly associated with APOE 4 carrier status and 4 gene dose in AD-affected mean cortical, frontal, temporal, posterior cingulate-precuneus, parietal, and basal ganglia ROIs, and was highest in an additional homozygote who had recently developed mild cognitive impairment. These findings suggest that fibrillar A␤ burden in cognitively normal older people is associated with APOE 4 gene dose, the major genetic risk factor for AD. Additional studies are needed to track fibrillar A␤ accumulation in persons with different kinds and levels of AD risk; to determine the extent to which fibrillar A␤, alone or in combination with other biomarkers and risk factors, predicts rates of cognitive decline and conversion to clinical AD; and to establish the role of fibrillar A␤ imaging in primary prevention trials.apolipoprotein E ͉ Pittsburgh Compound B PET

The ‘Vascular Depression’ hypothesis posits that cerebrovascular disease may predispose, precipitate, or perpetuate some geriatric depressive syndromes. This hypothesis stimulated much research that has improved our understanding of the complex relationships between late-life depression (LLD), vascular risk factors, and cognition. Succinctly, there are well-established relationships between late-life depression, vascular risk factors, and cerebral hyperintensities, the radiological hallmark of vascular depression. Cognitive dysfunction is common in late-life depression, particularly executive dysfunction, a finding predictive of poor antidepressant response. Over time, progression of hyperintensities and cognitive deficits predicts a poor course of depression and may reflect underlying worsening of vascular disease. This work laid the foundation for examining the mechanisms by which vascular disease influences brain circuits and influences the development and course of depression. We review data testing the vascular depression hypothesis with a focus on identifying potential underlying vascular mechanisms. We propose a disconnection hypothesis, wherein focal vascular damage and white matter lesion location is a crucial factor influencing neural connectivity that contributes to clinical symptomatology. We also propose inflammatory and hypoperfusion hypotheses, concepts that link underlying vascular processes with adverse effects on brain function that influence the development of depression. Testing such hypotheses will not only inform the relationship between vascular disease and depression but also provide guidance on the potential repurposing of pharmacological agents that may improve late-life depression outcomes.

The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-␤ protein is an initiating event in Alzheimer's disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n ϭ 5) and symptomatic (n ϭ 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n ϭ 2) were studied with PiB-PET imaging and compared with sporadic AD subjects (n ϭ 12) and controls from the general population (n ϭ 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35-49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.

HIV͞AIDS infection is the fourth leading cause of death worldwide, and one in every 100 adults aged 15-49 years is HIV-infected. Forty percent of AIDS patients suffer from neurological symptoms, but the selective profile of damage caused by HIV in the brain is not well understood. Here, we report 3D maps revealing how AIDS affects the human cerebral cortex, identifying the most vulnerable regions and where deficits link with cognitive decline and immunesystem suppression. With high-resolution brain MRI scans, we created composite maps of cortical gray-matter thickness in 26 AIDS patients and 14 healthy controls to establish the selective pattern of brain deficits in AIDS. In AIDS, primary sensory, motor, and premotor cortices were 15% thinner. Thinner frontopolar and language cortex correlated with immune system deterioration measured through blood levels of CD4 ؉ T lymphocytes. Prefrontal and parietal tissue loss correlated with cognitive͞motor deficits. T cell depletion and cognitive impairment are, therefore, associated with specific 3D brain-deficit patterns visualized with MRI. These quantitative MRI-based maps reveal that HIV selectively damages the cortex. They provide an approach to gauge the impact of AIDS on the living brain and show that the brain is still vulnerable to infection even when patients are receiving antiretroviral therapy.brain ͉ MRI ͉ disease ͉ T cell ͉ immunity