Amyloid Imaging with PET in Early Alzheimer Disease Diagnosis

Chalcone [(E)-1,3-diphenyl-2-propene-1-one], a small molecule with α, β unsaturated carbonyl group is a precursor or component of many natural flavonoids and isoflavonoids. It is one of the privileged structures in medicinal chemistry. It possesses a wide range of biological activities encouraging many medicinal chemists to study this scaffold for its usefulness to oncology, infectious diseases, virology and neurodegenerative diseases including Alzheimer’s disease (AD). Small molecular size, convenient and cost-effective synthesis, and flexibility for modifications to modulate lipophilicity suitable for blood brain barrier (BBB) permeability make chalcones a preferred candidate for their therapeutic and diagnostic potential in AD. This review summarizes and highlights the importance of chalcone and its analogs as single target small therapeutic agents, multi-target directed ligands (MTDLs) as well as molecular imaging agents for AD. The information summarized here will guide many medicinal chemist and researchers involved in drug discovery to consider chalcone as a potential scaffold for the development of anti-AD agents including theranostics.

Alzheimer’s disease (AD) is the most common neurodegenerative disease among the elderly with a progressive decline in cognitive function significantly affecting quality of life. Both the prevalence and emotional and financial burdens of AD on patients, their families, and society are predicted to grow significantly in the near future, due to a prolongation of the lifespan. Several lines of evidence suggest that modifications of risk-enhancing life styles and initiation of pharmacological and non-pharmacological treatments in the early stage of disease, although not able to modify its course, helps to maintain personal autonomy in daily activities and significantly reduces the total costs of disease management. Moreover, many clinical trials with potentially disease-modifying drugs are devoted to prodromal stages of AD. Thus, the identification of markers of conversion from prodromal form to clinically AD may be crucial for developing strategies of early interventions. The current available markers, including volumetric magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebral spinal fluid (CSF) analysis are expensive, poorly available in community health facilities, and relatively invasive. Taking into account its low cost, widespread availability and non-invasiveness, electroencephalography (EEG) would represent a candidate for tracking the prodromal phases of cognitive decline in routine clinical settings eventually in combination with other markers. In this scenario, the present paper provides an overview of epidemiology, genetic risk factors, neuropsychological, fluid and neuroimaging biomarkers in AD and describes the potential role of EEG in AD investigation, trying in particular to point out whether advanced analysis of EEG rhythms exploring brain function has sufficient specificity/sensitivity/accuracy for the early diagnosis of AD.

Molecular imaging techniques using ¹⁸F-fluorodeoxyglucose, amyloid tracers, and, more recently, tau ligands have taken dementia research by storm and undoubtedly improved our understanding of neurodegenerative diseases. The ability to image in vivo the pathological substrates of degenerative diseases and visualize their downstream impact has led to improved models of pathogenesis, better differential diagnosis of atypical conditions, as well as focused subject selection and monitoring of treatment in clinical trials aimed at delaying or preventing the symptomatic phase of Alzheimer's disease. In this article, we present the main molecular imaging techniques used in research and practice. We further summarize the key findings brought about by each technique individually and more recently, as adjuncts to each other. Specific limitations of each imaging modality are discussed, as well as recommendations to overcome them. A nonvalidated clinical algorithm is proposed for earlier and more accurate identification of complex/atypical neurodegenerative diseases.

In two solanezumab trials for mild-to-moderate Alzheimer's disease (AD) dementia, 27% of patients had biomarker confirmation of amyloid status. Of these, approximately 25% of mild patients and approximately 10% of moderate patients were amyloid negative and, as a group, did not exhibit clinical progression typical of AD. This post-hoc analysis describes a statistical surrogate for amyloid status.

Quantile regression was used to examine solanezumab treatment effects at fixed percentiles of varying degrees of clinical progression, with lowest percentiles (minimal progression atypical of AD) and higher percentiles acting as surrogates for amyloid negativity or positivity, respectively.

In mild patients, solanezumab treatment effect was greater in higher percentiles of progression and less in lowest percentiles (AD-atypical). In moderate patients, solanezumab did not show effects across most percentiles.

Results are compatible with design of the ongoing solanezumab EXPEDITION 3 trial that limits patients to those with mild AD dementia and evidence of amyloid pathology.

Antidepressants have modest efficacy in late-life depression (LLD), perhaps because various neurobiologic processes compromise frontolimbic networks required for antidepressant response. We propose that amyloid accumulation is an etiologic factor for frontolimbic compromise that predisposes to depression and increases treatment resistance in a subgroup of older adults. In patients without history of depression, amyloid accumulation during the preclinical phase of Alzheimer disease (AD) may result in the prodromal depression syndrome that precedes cognitive impairment. In patients with early-onset depression, pathophysiologic changes during recurrent episodes may promote amyloid accumulation, further compromise neurocircuitry required for antidepressant response, and increase treatment resistance during successive depressive episodes. The findings that support the amyloid hypothesis of LLD are (1) Depression is a risk factor, a prodrome, and a common behavioral manifestation of AD; (2) amyloid deposition occurs during a long predementia period when depression is prevalent; (3) patients with lifetime history of depression have significant amyloid accumulation in brain regions related to mood regulation; and (4) amyloid deposition leads to neurobiologic processes, including vascular damage, neurodegeneration, neuroinflammation, and disrupted functional connectivity, that impair networks implicated in depression. The amyloid hypothesis of LLD is timely because availability of ligands allows in vivo assessment of amyloid in the human brain, a number of antiamyloid agents are relatively safe, and there is evidence that some antidepressants may reduce amyloid production. A model of LLD introducing the role of amyloid may guide the design of studies aiming to identify novel antidepressant approaches and prevention strategies of AD.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by hallmarks that include an accumulation of amyloid-β peptide (Aβ), inflammation, oxidative stress and synaptic dysfunction, which lead to a decrease in cognitive function. To date, the onset and progression of AD have been associated with pathologies such as hypertension and diabetes. Hypertension, a disease with a high incidence worldwide, is characterized by a chronic increase in blood pressure. Interestingly, this disease has a close relationship to the eating behavior of patients because high Na⁺ intake is a significant risk factor for hypertension. In fact, a decrease in Na⁺ consumption, along with an increase in K⁺ intake, is a primary non-pharmacological approach to preventing hypertension. In the present work, we examined whether an increase in K⁺ intake affects the expression of certain neuropathological markers or the cognitive performance of a murine model of AD. We observed that an increase in K⁺ intake leads to a change in the aggregation pattern of the Aβ peptide, a partial decrease in some epitopes of tau phosphorylation and improvement in the cognitive performance. The recovery in cognitive performance was correlated with a significant improvement in the generation of long-term potentiation. We also observed a decrease in markers related to inflammation and oxidative stress such as glial fibrillary acidic protein (GFAP), interleukin 6 (IL-6) and 4-hydroxynonenal (4-HNE). Together, our data support the idea that changes in diet, such as an increase in K⁺ intake, may be important in the prevention of AD onset as a non-pharmacological therapy.