Using genetics to enable studies on the prevention of Alzheimer's disease.

Curing Alzheimer's disease (AD) remains an elusive goal; indeed, it may even prove to be impossible, given the nature of the disease. Although modulating disease progression is an attractive target and will alleviate the burden of the most severe stages, this strategy will not reduce the prevalence of the disease itself. Preventing or (as described in this article) delaying the onset of cognitive impairment and AD will provide the greatest benefit to individuals and society by pushing the onset of disease into the later years of life. Because of the high variability in the age of onset of the disease, AD prevention studies that do not stratify participants by age-dependent disease risk will be operationally challenging, being large in size and of long duration. We present a composite genetic biomarker to stratify disease risk so as to facilitate clinical studies in high-risk populations. In addition, we discuss the rationale for the use of pioglitazone to delay the onset of AD in individuals at high risk.

Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response.

BACKGROUND: Treatment of major depression with antidepressants is generally associated with a delay in onset of clinical response. Functional brain correlates of this phenomenon have not been previously characterized. METHODS: Time course of changes in brain glucose metabolism were measured using positron emission tomography in hospitalized unipolar depressed patients treated with fluoxetine. Time-specific and response-specific effects were examined at 1 and 6 weeks of treatment. RESULTS: Changes were seen over time, and characterized by three distinct patterns: 1) common changes at 1 and 6 weeks, 2) reversal of the 1-week pattern at 6 weeks, and 3) unique changes seen only after chronic treatment. Fluoxetine responders and nonresponders, similar at 1 week, were differentiated by their 6-week pattern. Clinical improvement was uniquely associated with limbic and striatal decreases (subgenual cingulate, hippocampus, insula, and pallidum) and brain stem and dorsal cortical increases (prefrontal, parietal, anterior, and posterior cingulate). Failed response was associated with a persistent 1-week pattern and absence of either subgenual cingulate or prefrontal changes. CONCLUSIONS: Chronic treatment and clinical response to fluoxetine was associated with a reciprocal pattern of subcortical and limbic decreases and cortical increases. Reversal in the week-1 pattern at 6 weeks suggests a process of adaptation in specific brain regions over time in response to sustained serotonin reuptake inhibition. The inverse patterns in responders and nonresponders also suggests that failure to induce these adaptive changes may underlie treatment nonresponse.

Differential limbic--cortical correlates of sadness and anxiety in healthy subjects: implications for affective disorders.

BACKGROUND: Affective disorders are associated with comorbidity of depression and anxiety symptoms. Positron emission tomography resting-state studies in affective disorders have generally failed to isolate specific symptom effects. Emotion provocation studies in healthy volunteers have produced variable results, due to differences in experimental paradigm and instructions. METHODS: To better delineate the neural correlates of sad mood and anxiety, this study used autobiographical memory scripts in eight healthy women to generate sadness, anxiety, or a neutral relaxed state in a within-subject design. RESULTS: Sadness and anxiety, when contrasted to a neutral emotional state, engaged a set of distinct paralimbic-cortical regions, with a limited number of common effects. Sadness was accompanied by specific activations of the subgenual cingulate area (BA) 25 and dorsal insula, specific deactivation of the right prefrontal cortex BA 9, and more prominent deactivation of the posterior parietal cortex BAs 40/7. Anxiety was associated with specific activations of the ventral insula, the orbitofrontal and anterior temporal cortices, specific deactivation of parahippocampal gyri, and more prominent deactivation of the inferior temporal cortex BAs 20/37. CONCLUSIONS: These findings are interpreted within a model in which sadness and anxiety are represented by segregated corticolimbic pathways, where a major role is played by selective dorsal cortical deactivations during sadness, and ventral cortical deactivations in anxiety.

Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness.

OBJECTIVE: Theories of human behavior from Plato to Freud have repeatedly emphasized links between emotion and reason, a relationship now commonly attributed to pathways connecting phylogenetically "old" and "new" brain regions. Expanding on this theory, this study examined functional interactions between specific limbic and neocortical regions accompanying normal and disease-associated shifts in negative mood state. METHOD: Regions of concordant functional change accompanying provocation of transient sadness in healthy volunteers and resolution of chronic dysphoric symptoms in depressed patients were examined with two positron emission tomography techniques: [15O]water and [18F]fluorodeoxyglucose, respectively. RESULTS: With sadness, increases in limbic-paralimbic blood flow (subgenual cingulate, anterior insula) and decreases in neocortical regions (right dorsolateral prefrontal, inferior parietal) were identified. With recovery from depression, the reverse pattern, involving the same regions, was seen--limbic metabolic decreases and neocortical increases. A significant inverse correlation between subgenual cingulate and right dorsolateral prefrontal activity was also demonstrated in both conditions. CONCLUSIONS: Reciprocal changes involving subgenual cingulate and right prefrontal cortex occur with both transient and chronic changes in negative mood. The presence and maintenance of functional reciprocity between these regions with shifts in mood in either direction suggests that these regional interactions are obligatory and probably mediate the well-recognized relationships between mood and attention seen in both normal and pathological conditions. The bidirectional nature of this limbic-cortical reciprocity provides additional evidence of potential mechanisms mediating cognitive ("top-down"), pharmacological (mixed), and surgical ("bottom-up") treatments of mood disorders such as depression.

Cingulate function in depression: a potential predictor of treatment response.

The relationship between pretreatment regional cerebral glucose metabolism and eventual antidepressant drug response was measured using positron emission tomography (PET) in hospitalized patients with unipolar depression. Rostral anterior cingulate metabolism uniquely differentiated eventual treatment responders from non-responders. Hypometabolism characterized non-responders when compared with controls, in contrast to responders who were hypermetabolic. Metabolism in no other region discriminated the two groups, nor did associated demographic, clinical or behavioral measures, including motor speed, cognitive performance, depression severity or illness chronicity. Cingulate hypermetabolism may represent an important adaptive response to depression and failure of this response may underlie poor outcome. A critical role for rostral cingulate area 24a/b in the limbic-cortical network involved in abnormal mood states is proposed.

Beta-adrenergic receptor changes in learned helplessness may depend on stress and test parameters.

Behavioral deficits following inescapable stress (learned helplessness) may serve as an animal model of depression. Previous studies using foot-shock stress to induce learned helplessness and a bar-press test for the stress-induced behavioral deficit have found increased beta-adrenergic receptor density in the hippocampus of learned helpless rats. We replicated these experiments using a tail-shock stress and the shuttle-box test. In our experiments, rats that developed learned helplessness after inescapable stress did not demonstrate any significant differences in beta-adrenergic receptor density or affinity in the frontal cortex, cerebellum, or hippocampus compared to the nonhelpless rats, nor to the tested control rats. These results suggest that beta-adrenergic receptor changes in learned helplessness may depend on the specific stress and test procedures used.