Imaging Techniques in Alzheimer's Disease: A Review of Applications in Early Diagnosis and Longitudinal Monitoring

Abstract

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting many individuals worldwide with no effective treatment to date. AD is characterized by the formation of senile plaques and neurofibrillary tangles, followed by neurodegeneration, which leads to cognitive decline and eventually death.

Introduction: In AD, pathological changes occur many years before disease onset. Since disease-modifying therapies may be the most beneficial in the early stages of AD, biomarkers for the early diagnosis and longitudinal monitoring of disease progression are essential. Multiple imaging techniques with associated biomarkers are used to identify and monitor AD.

Aim: In this review, we discuss the contemporary early diagnosis and longitudinal monitoring of AD with imaging techniques regarding their diagnostic utility, benefits and limitations. Additionally, novel techniques, applications and biomarkers for AD research are assessed.

Findings: Reduced hippocampal volume is a biomarker for neurodegeneration, but atrophy is not an AD-specific measure. Hypometabolism in temporoparietal regions is seen as a biomarker for AD. However, glucose uptake reflects astrocyte function rather than neuronal function. Amyloid-β (Aβ) is the earliest hallmark of AD and can be measured with positron emission tomography (PET), but Aβ accumulation stagnates as disease progresses. Therefore, Aβ may not be a suitable biomarker for monitoring disease progression. The measurement of tau accumulation with PET radiotracers exhibited promising results in both early diagnosis and longitudinal monitoring, but large-scale validation of these radiotracers is required. The implementation of new processing techniques, applications of other imaging techniques and novel biomarkers can contribute to understanding AD and finding a cure.

Conclusions: Several biomarkers are proposed for the early diagnosis and longitudinal monitoring of AD with imaging techniques, but all these biomarkers have their limitations regarding specificity, reliability and sensitivity. Future perspectives. Future research should focus on expanding the employment of imaging techniques and identifying novel biomarkers that reflect AD pathology in the earliest stages.

Keywords: Alzheimer’s disease; MRI; PET; amyloid-β; early diagnosis; imaging techniques; longitudinal monitoring; tau.

Figure 1

The Alzheimer’s disease continuum with corresponding pathological changes, biomarkers and clinical diagnosis. Figure adapted from Yoshiyama et al. [21].

Figure 6

Tau spreading pattern in each Braak stage. Spreading pattern of tau throughout the brain from Braak stage I-II to stage III-IV (limbic regions) and stage V-VI (isocortical areas). Figure adapted from Goedert [145] and created with www.BioRender.com (accessed on 11 February 2021).

Figure 2

Regions affected by Alzheimer’s disease. Figure created with www.BioRender.com (accessed on 12 February 2021).

Figure 3

Neuroimages of the healthy versus the Alzheimer’s disease (AD) brain. Neuroimaging with (a) structural MRI, (b) FDG-PET, (c) amyloid-PET with PiB and (d) tau PET with ¹⁸F-AV1451 in both healthy and AD brains. Figure created with www.BioRender.com (accessed on 14 February 2021).

Figure 4

Accumulation of amyloid-β in AD. Figure adapted from Patterson et al. [89] and created with www.BioRender.com (accessed on 16 November 2020).

Figure 5

Tau protein aggregation leads to formation of neurofibrillary tangles in AD. (a) Role of tau protein in healthy brain; (b) role of tau protein in Alzheimer’s disease brain. NFT: neurofibrillary tangles; PHF: paired helical filaments. Figure adapted from “Pathology of Alzheimer’s Disease”, by BioRender.com (2020). Retrieved from https://app.biorender.com/biorender-templates (accessed on 16 November 2020).

Figure 7

AD leads to hippocampal atrophy and ventricle enlargement. Healthy brain (left) versus AD brain (right). AD leads to decreased hippocampal volume, shrinkage of cerebral cortex and ventricle enlargement. MTA: medial temporal lobe atrophy; MTA = 0: no atrophy in medial temporal lobe; MTA = 4: severe volume loss of hippocampus. Figure created with www.BioRender.com (accessed on 14 February 2021).

Figure 8

Spreading pattern of amyloid-β accumulation throughout the brain. Amyloid-β accumulation starts in frontal areas and spreads to other regions as disease progresses, leading to a plateau in amyloid-β as disease progresses. Figure adapted from Goedert [145] and created with www.BioRender.com (accessed on 11 February 2021).