The Challenges of Tau Imaging

Victor L Villemagne; Shozo Furumoto; Michelle Fodero-Tavoletti; Ryuichi Harada; Rachel S Mulligan; Yukitsuka Kudo; Colin L Masters; Kazuhiko Yanai; Chistopher C Rowe; Nobuyuki Okamura

Disclosures

Future Neurology. 2012;7(4):409-421. 

In This Article

Abstract and Introduction

Abstract

In vivo imaging of tau pathology will provide new insights into tau deposition in the human brain, thus facilitating research into causes, diagnosis and treatment of major dementias, such as Alzheimer's disease, or some variants of frontotemporal lobar degeneration, in which tau plays a role. Tau imaging poses several challenges, some related to the singularities of tau aggregation, and others related to radiotracer design. Several groups around the world are working on the development of imaging agents that will allow the in vivo assessment of tau deposition in aging and in neurodegeneration. Development of a tau imaging tracer will enable researchers to noninvasively examine the degree and extent of tau pathology in the brain, quantify changes in tau deposition over time, evaluate its relation to cognition and assess the efficacy of anti-tau therapy.

Introduction

Alzheimer's disease (AD), the leading cause of dementia in the elderly, is an irreversible, progressive neurodegenerative disorder clinically characterized by memory loss and cognitive decline,[1] leading invariably to death, usually within 7–10 years after diagnosis. AD accounts for 50–70% of dementia cases,[2] followed by frontotemporal lobar degeneration (FTLD), which is responsible for 10–20% of cases.[3,4] At present, patients exhibiting signs of dementia are diagnosed based on clinical and neuropsychological examination; however, FTLD is a syndrome that can be clinically difficult to distinguish from AD, especially in the early stages of the disease. To date, definitive diagnosis of these neurodegenerative conditions can only be established after post-mortem examination of the human brain.

Genetic, pathological, biochemical and cellular evidence implicating the amyloid precursor protein and its proteolytic product β-amyloid (Aβ) as being central to AD etiology still remains contentious.[5] Human post-mortem studies have shown that while soluble Aβ oligomers and the density of neurofibrillary tangles (NFTs) strongly correlate with neurodegeneration and cognitive deficits, the density of Aβ insoluble plaques does not,[6–11] and Aβ burden, as assessed by PET, does not strongly correlate with cognitive impairment in AD patients.[12,13] Cortical NFTs are not observed in cognitively unimpaired individuals, in contrast to Aβ plaques, which appear abundantly in some nondemented people;[12,14–16] higher brain Aβ burden is typically seen in hereditary forms of cerebral amyloid angiopathy, without accompanying NFT formation. The lack of a strong association between Aβ deposition and measures of cognition, synaptic activity and neurodegeneration in AD, in addition to the evidence of Aβ deposition in a high percentage of asymptomatic healthy controls, suggests that Aβ is an early and necessary, although not sufficient, cause for cognitive decline in AD.[17] This points to the involvement of other downstream mechanisms, such as NFT formation, leading to synaptic failure and eventually neuronal loss.

The physiological function of tau is to bind to tubulin to stabilize microtubules, which is critical for the axonal support of neurons. Based on the number of tubulin-binding repeats within the protein, six tau isoforms have been identified.[18] While the underlying mechanisms leading to tau hyperphosphorylation, misfolding and aggregation remain unclear, tau aggregation and deposition follows a stereotyped spatiotemporal pathway both at the intraneuronal level[19,20] as well as in its topographical and neuroanatomical distribution in the brain.[21–25] Mutations have been identified within the tau gene (MAPT) leading to frontotemporal dementia with parkinsonism linked to chromosome-17,[26] providing solid evidence that tau malfunction triggers neurodegeneration and dementia.

Neurodegenerative diseases characterized by pathological tau accumulation are termed 'tauopathies'. Along with AD and some variants of FTLD, other tauopathies include Down's syndrome, Guam parkinsonism–dementia complex, dementia pugilistica, frontotemporal dementia with parkinsonism linked to chromosome-17, corticobasal degeneration (CBD), progressive supranuclear palsy and chronic traumatic encephalopathy.[24,27–30] While these conditions share tau immunoreactivity in post-mortem analysis, they can be composed of different tau isoforms and show distinct histopathological and ultrastructural differences.[28,31] For example, a diversity of tau deposits can be recognized histologically in these diseases, either as NFTs, neuropil or glial threads, Pick bodies, dystrophic neurites in plaques, astrocytic plaques or coiled bodies, among others.[24,28]

The notion that tau deregulation could be a key mediator of neurodegeneration[26,32–34] has stimulated the development of therapeutics for the treatment of AD and non-AD tauopathies. Inhibition of abnormal tau hyperphosphorylation, its aggregation or direct stabilization of microtubules, appears to be a promising therapeutic strategy that may cure or retard the development of these diseases.[35–43] Given that these treatments are currently being developed, a noninvasive method of determining both the tau load and its regional cerebral patterns would not only assist in the early and differential diagnosis of AD and non-AD tauopathies, but also facilitate monitoring the efficacy of such new treatments.

Modern molecular imaging procedures may overcome the need for a neuropathological examination of brain tissues by noninvasively identifying the underlying pathology of these diseases, rather than relying solely on clinical symptoms and neuropsychological assessments. In recent years, considerable effort has been focused on imaging agents for the early diagnosis of neurodegenerative diseases such as AD. So far, the main focus has been placed on the development of novel Aβ ligands that are permitting early detection of Aβ deposition.[12,44] Among these tracers, 18F-FDDNP was claimed to not only bind to Aβ deposits but to also bind to NFTs.[45] Furthermore, in vitro studies using tracer concentrations similar to those achieved during a PET scan (~1 nM) showed that 18F-FDDNP failed to bind to NFTs and that it binds weakly to Aβ plaques.[46] Therefore, the development of a selective and specific imaging agent for tau imaging is critical for developing a more profound understanding of the pathophysiology of AD, FTLD and other neurodegenerative conditions, but will also lead to improvements in differential diagnostic accuracy and also accelerate treatment discovery and monitoring of therapeutics.

Tau imaging poses several challenges, some related to tau aggregation and deposition and others related to radiotracer design (Box 1).

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