Pittsburgh Compound B Imaging and Prediction of Progression From Cognitive Normality to Symptomatic Alzheimer Disease

Morris, John C.; Roe, Catherine M.; Grant, Elizabeth; Head, Denise; Storandt, Martha; Goate, Alison M.; Fagan, Anne M.; Holtzman, David M.; Mintun, Mark A.

doi:10.1001/archneurol.2009.269

Cited by 449 publications

(342 citation statements)

References 56 publications

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“…Aβ accumulation and deposition in the AD brain can begin 10 y before the appearance of the first symptoms (2, 32). The concept of "preclinical AD" indicates that AD pathologies are present but AD symptoms are not (49,50). Several anti-Aβ therapeutic strategies are being pursued to treat AD; however, it is likely that treatment will need to begin during the preclinical phase to prevent or limit plaque accumulation to be beneficial in reducing the risk of developing AD (51,52).…”

Section: Discussionmentioning

confidence: 99%

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Cirrito

Disabato²,

Restivo³

et al. 2011

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

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300

307

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Aggregation of amyloid-β (Aβ) as toxic oligomers and amyloid plaques within the brain appears to be the pathogenic event that initiates Alzheimer's disease (AD) lesions. One therapeutic strategy has been to reduce Aβ levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate Aβ metabolism. We assessed the ability of serotonin signaling to alter brain Aβ levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) Aβ levels were decreased by 25% following administration of several selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Similarly, direct infusion of serotonin into the hippocampus reduced ISF Aβ levels. Serotonindependent reductions in Aβ were reversed if mice were pretreated with inhibitors of the extracellular regulated kinase (ERK) signaling cascade. Chronic treatment with an SSRI, citalopram, caused a 50% reduction in brain plaque load in mice. To test whether serotonin signaling could impact Aβ plaques in humans, we retrospectively compared brain amyloid load in cognitively normal elderly participants who were exposed to antidepressant drugs within the past 5 y to participants who were not. Antidepressant-treated participants had significantly less amyloid load as quantified by positron emission tomography (PET) imaging with Pittsburgh Compound B (PIB). Cumulative time of antidepressant use within the 5-y period preceding the scan correlated with less plaque load. These data suggest that serotonin signaling was associated with less Aβ accumulation in cognitively normal individuals.microdialysis | selective serotonin reuptake inhibitor antidepressants | late-life depression A myloid-β (Aβ) dysregulation appears to initiate the pathogenesis of Alzheimer's disease (AD) with a cascade of downstream factors that exacerbate and propagate neuronal injury (1). Aβ can accumulate as toxic plaques and soluble oligomers in the brains of individuals with AD a decade or more before the initial symptoms are identified (2). The concentration of Aβ is a critical factor determining if and when it will aggregate into these toxic structures; high concentrations of Aβ are more prone to convert from its normal soluble form into these multimeric conformations (3). Aβ is formed within neurons by sequential cleavage of the amyloid precursor protein (APP) by two enzymes, β-secretase and then γ-secretase. Alternatively, α-secretase can cleave APP within the Aβ sequence, which precludes the peptide from being formed at all. The enzymes and mechanisms that produce Aβ have been well characterized; however, the mechanisms that regulate Aβ production and levels are only partly understood. Understanding the cellular processes that regulate Aβ levels may provide greater insight into disease pathogenesis and suggest new avenues to treat or prevent AD.Synaptic activity is one key regulator of brain Aβ production. Depolarization and subsequent synaptic transmission causes Aβ to be produced presynaptically and then secreted into the brain extracel...

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Section: Discussionmentioning

confidence: 99%

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Cirrito

Disabato²,

Restivo³

et al. 2011

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

Self Cite

300

307

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“…In addition, structural MRI will help to enrich study samples of asymptomatic subjects with positive molecular biomarkers of AD. The presence of amyloid alone does not predict progression to cognitive decline with sufficient accuracy, as only 25% of amyloid positive cognitively healthy subjects progress to MCI or AD within 3 years [166]. Therefore, the presence of hippocampus atrophy together with amyloid positivity will help to select subjects with a high risk of conversion to AD or MCI within a timeframe that is relevant for a clinical trial.…”

Section: Future Directions: Application Of Existing Methods In a New mentioning

confidence: 99%

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Hampel

Lista

Teipel

et al. 2014

Biochemical Pharmacology

102

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Recent advances in understanding the molecular mechanisms underlying various paths toward the pathogenesis of Alzheimer's disease (AD) has begun to provide new insight for interventions to modify disease progression. The evolving knowledge gained from multidisciplinary basic research has begun to identify new concepts for treatments and distinct classes of therapeutic targets; as well as putative disease-modifying compounds that are now being tested in clinical trials. There is a mounting consensus that such disease modifying compounds and/or interventions are more likely to be effectively administered as early as possible in the cascade of pathogenic processes preceding and underlying the clinical expression of AD. The budding sentiment is that "treatments" need to be applied before various molecular mechanisms converge into an irreversible pathway leading to morphological, metabolic and functional alterations that characterize the pathophysiology of AD. In light of this, biological indicators of pathophysiological mechanisms are desired to chart and detect AD throughout the asymptomatic early molecular stages into the prodromal and early dementia phase. A major conceptual development in the clinical AD research field was the recent proposal of new diagnostic criteria, which specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD. This paradigm shift in AD definition, conceptualization, operationalization, detection and diagnosis represents novel fundamental opportunities for the modification of interventional trial designs. This perspective summarizes not only present knowledge regarding biological markers but also unresolved questions on the status of surrogate indicators for detection of the disease in asymptomatic people and diagnosis of AD

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“…Interestingly, many MCI and a significant percentage (30%) of cognitively normal elderly individuals show high brain retention of PIB and low Aβ42 levels in the CSF [34][35]. Further follow-up studies are required to determine if this identifies those individuals that will go on to develop AD, with one recent study supporting this hypothesis [36].…”

Section: Another Promising Approach Is Pet Imaging Employing Ligandsmentioning

confidence: 99%

Ocular Biomarkers for Early Detection of Alzheimer's Disease

Frost

Martins

Kanagasingam

2010

JAD

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Alzheimer's disease (AD) is the most common form of dementia and is characterized clinically by a progressive decline in memory, learning and executive function and neuropathologically by the presence of cerebral amyloid deposits. Despite a century of research, there is still no cure or conclusive pre-mortem diagnosis for the disease. A number of symptom-modifying drugs for AD have been developed, but their efficacy is minimal and short-lived. AD cognitive symptoms arise only after significant, irreversible neural deterioration has occurred, hence there is an urgent need to detect AD early, before the onset of cognitive symptoms. An accurate, early diagnostic test for AD would enable current and future treatments to be more effective, as well as contribute to the development of new treatments.While most AD related pathology occurs in the brain, the disease has also been reported to affect the eye, which is more accessible for imaging than the brain. AD-related proteins exist in the normal human eye and may produce ocular pathology in AD. There is some homology between the retinal and cerebral vasculatures and the retina also contains nerve cells and fibers that form a sensory extension of the brain. The eye is the only place in the body where vasculature or neural tissue is available for non-invasive optical imaging. This article presents a review of current literature on ocular morphology in AD and discusses the potential for an ocular based screening test for AD.

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Pittsburgh Compound B Imaging and Prediction of Progression From Cognitive Normality to Symptomatic Alzheimer Disease

Cited by 449 publications

References 56 publications

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Ocular Biomarkers for Early Detection of Alzheimer's Disease

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