Delusions are unfounded yet tenacious beliefs and a symptom of psychotic disorder. Varying degrees of delusional ideation are also found in the healthy population. Here, we empirically validated a neurocognitive model that explains both the formation and the persistence of delusional beliefs in terms of altered perceptual inference. In a combined behavioral and functional neuroimaging study in healthy participants, we used ambiguous visual stimulation to probe the relationship between delusion-proneness and the effect of learned predictions on perception. Delusional ideation was associated with less perceptual stability, but a stronger belief-induced bias on perception, paralleled by enhanced functional connectivity between frontal areas that encoded beliefs and sensory areas that encoded perception. These findings suggest that weakened lower-level predictions that result in perceptual instability are implicated in the emergence of delusional beliefs. In contrast, stronger higher-level predictions that sculpt perception into conformity with beliefs might contribute to the tenacious persistence of delusional beliefs.

Neuronal loss is the ultimate outcome in a variety of neurodegenerative diseases and central nerve system disorders. Understanding the sequelae of events that leads to cell death would provide insight into neuroprotective approaches. We imaged neurons in the living brain of a mouse model of Alzheimer's disease that overexpresses mutant human amyloid precursor protein and presenilin 1 and followed the death of individual neurons in real time. This mouse model exhibited limited neurodegeneration and atrophy, but we were able to identify a small fraction of vulnerable cells that would not have been detectable by using standard approaches. By exploiting a genetically encoded reporter of oxidative stress, we identified susceptible neurons by their increased redox potential. The oxidative stress was most dramatic in neurites near plaques, propagated to cell bodies, and preceded activation of caspases that led to cell death within 24 h. Thus, local oxidative stress surrounding plaques contributes to longrange toxicity and selective neuronal death in Alzheimer's disease.in vivo imaging | reduction-oxidation sensitive GFP A lzheimer's disease (AD) is underscored by neurodegeneration and is the most common form of dementia. The pathological hallmarks of this disease include amyloid plaques, neurofibrillary tangles, and neuronal loss. Early-onset familial AD is caused by genetic mutations of amyloid precursor protein (APP) or presenilin 1 and 2 (PS1 and PS2). Although recent genetic studies have revealed risk factors for late onset AD, the pathogenic pathways for sporadic AD remain largely unknown. The development of mouse models of AD that develop senile plaques similar to those found in AD patients was a critical step in identifying the role of amyloid β (Aβ) on neuronal function. A major disappointment of most of the mouse models is the lack of overt neuronal loss that is a hallmark of the human disease. Many, in fact, have used this lack of neuronal death as evidence that amyloid is not relevant to dementia in AD. We and others (1-4) have identified structural and functional alterations of neurons in the brains of APP mice that implicate amyloid-mediated toxicity, but we have never detected neuronal death. The ability to monitor cell death in an experimental model provides the opportunity to intervene with neuroprotective agents that could be applied to the spectrum of neurodegenerative diseases and CNS disorders.We were able to identify vulnerable cells by quantitatively imaging the redox potential of neurons in the living brain. Our hypothesis was that amyloid-mediated increases in oxidative stress are the initiators of the toxic cascade that leads to cell loss. Accumulating evidence supports a role for oxidative stress in the pathogenesis of neuronal degeneration and death in AD (5-8). The evidence supporting oxidative stress in AD comes largely from postmortem samples and includes increased lipid peroxidation, decreased polyunsaturated fatty acids (9-12), increased protein oxidation (13,14), and DNA oxidation (15, ...

The premature aging hypothesis of alcohol dependence proposes that the neurobiological and behavioural deficits in individuals with alcohol dependence are analogous to those of chronological aging. However, to date no systematic neurobiological evidence for this hypothesis has been provided. To test the hypothesis, 119 alcohol-dependent subjects and 97 age- and gender-matched healthy control subjects underwent structural MRI. Whole-brain grey matter volume maps were computed from structural MRI scans using voxel-based morphometry and parcelled into a comprehensive set of anatomical brain regions. Regional grey matter volume averages served as the basis for cross-regional similarity analyses and a brain age model. We found a striking correspondence between regional patterns of alcohol- and age-related grey matter loss across 110 brain regions. The brain age model revealed that the brain age of age-matched AD subjects was increased by up to 11.7 years. Interestingly, while no brain aging was detected in the youngest AD subjects (20–30 years), we found that alcohol-related brain aging systematically increased in the following age decades controlling for lifetime alcohol consumption and general health status. Together, these results provide strong evidence for an accelerated aging model of AD and indicate an elevated risk of alcohol-related brain aging in elderly individuals.

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