Molecular imaging in Alzheimer's disease: new perspectives on biomarkers for early diagnosis and drug development

Abstract

Recent progress in molecular imaging has provided new important knowledge for further understanding the time course of early pathological disease processes in Alzheimer's disease (AD). Positron emission tomography (PET) amyloid beta (Aβ) tracers such as Pittsburgh Compound B detect increasing deposition of fibrillar Aβ in the brain at the prodromal stages of AD, while the levels of fibrillar Aβ appear more stable at high levels in clinical AD. There is a need for PET ligands to visualize smaller forms of Aβ, oligomeric forms, in the brain and to understand how they interact with synaptic activity and neurodegeneration. The inflammatory markers presently under development might provide further insight into the disease mechanism as well as imaging tracers for tau. Biomarkers measuring functional changes in the brain such as regional cerebral glucose metabolism and neurotransmitter activity seem to strongly correlate with clinical symptoms of cognitive decline. Molecular imaging biomarkers will have a clinical implication in AD not only for early detection of AD but for selecting patients for certain drug therapies and to test disease-modifying drugs. PET fibrillar Aβ imaging together with cerebrospinal fluid biomarkers are promising as biomarkers for early recognition of subjects at risk for AD, for identifying patients for certain therapy and for quantifying anti-amyloid effects. Functional biomarkers such as regional cerebral glucose metabolism together with measurement of the brain volumes provide valuable information about disease progression and outcome of drug treatment.

Figure 1

Pittsburgh Compound B retention in the brain. Pittsburgh Compound B (¹¹C-PIB) retention in the brain of a healthy control (HC), an Alzheimer patient (AD), patients with mild cognitive impairment (MCI) who later at clinical follow-up converted to AD, and patients with MCI who did not later convert to AD. PIB⁺, high Pittsburgh Compound B retention; PIB^-, low Pittsburgh Compound B retention. Red, high ¹¹C-PIB retention; yellow, medium ¹¹C-PIB retention; blue, low ¹¹C-PIB retention.

Figure 2

Schematic drawing of changes in pathological and functional imaging markers during progression of Alzheimer's disease. Aβ, amyloid beta; AD, Alzheimer's disease; CSF, cerebrospinal fluid; MCI, mild cognitive impairment.

Figure 3

Positron emission tomography measurements, cerebrospinal fluid amyloid beta 1-42 and episodic memory scores. Statistical parametric mapping analysis showing clusters with significant covariance between positron emission tomography measurements versus levels of cerebrospinal fluid (CSF) amyloid beta 1-42 (Aβ_1-42) and episodic memory scores measured by means of Rey Auditory Verbal Learning (RAVLtot) tests, using data from Alzheimer's disease and mild cognitive impairment patients, at threshold P < 0.001, uncorrected for multiple comparisons. (a) Areas with significant covariance between Pittsburgh Compound B (¹¹C-PIB) retention and concentrations of Aβ_1-42 in CSF. (b) Clusters with significant covariance between ¹¹C-PIB retention and scores in RAVLtot tests. (c) Significant clusters of covariance between regional cerebral glucose metabolism (rCMRglc) and scores in RAVLtot tests. Data from [54].

Figure 4

Multi-tracer positron emission tomography concept to study pathological and functional processes in the brain. Multi-positron emission tomography tracer concept applied in drug trials combined with atrophy studies (magnetic resonance imaging (MRI)), cerebrospinal fluid (CSF) biomarkers and cognitive testing. ¹¹C-PMP, acetylcholinesterase; ¹¹C-PIB, amyloid; ¹¹C-deprenyl, astrocytosis; ¹¹C-nicotine, nicotinic receptors; ¹⁸F-FDG, 2-[¹⁸F]-fluoro-2-deoxy-D-glucose metabolism. Red, high activity; yellow, medium activity; blue, low activity.