Tau Imaging Gives New Insights into Alzheimer’s Disease
Alzheimer’s disease (AD) is the leading cause of dementia in the elderly, accounting for 60–80% of cases, and is the only one of the top 10 global causes of death that cannot be prevented or cured.1 It is characterised by the accumulation of β-amyloid (Αβ) and tau proteins.2 Although the main focus of AD research has been the Αβ protein, human post-mortem studies have found that neurodegeneration and cognitive decline in AD is more closely associated with tau neurofibrillary tangles than with Αβ plaques.3 Tau is a microtubule-associated protein that is essential for neuronal stability and transport of axonal nutrients. In neurodegenerative diseases, abnormal hyperphosphorylation causes tau proteins to aggregate in neurofibrillary tangles in the brain, known as tautopathies.4 Although the importance of tau in the pathology of AD has long been recognised, the only way of measuring tau has been cerebrospinal fluid (CSF) measurement, which requires a painful spinal tap and does not provide information about the spatial distribution of tau.5
Recently, effective ways to image tau have been developed using positron emission tomography (PET) radiotracers. The most advanced tracer to date is 18F-AV-1451, also known as T807, and three recent publications have demonstrated its utility in the imaging of tau. In a study published in May, Brier et al. compared PET 18F-AV-1451 images of 36 cognitively normal individuals to those of 10 patients with mild AD. Tau deposition in the temporal lobe of the brain more closely tracked dementia status and was a better predictor of cognitive performance than Aβ deposition in any region of the brain.6
In June, Smith et al reported a study of PET imaging with 18F-AV-1451 in three patients harbouring a mutation in the MAPT gene, which encodes tau. Two patients with short disease duration showed 18F-AV-1451 uptake, mainly in the hippocampus and adjacent temporal lobe regions. One patient died after 26 years of disease duration. Pre-mortem, 18F-AV-1451 uptake was seen in the temporal and frontal lobes, as well as in the basal ganglia. This showed a strong correlation with tau pathology determined in post-mortem brain sections.7
In an article published in July, Wang et al. further investigated the utility of PET imaging using 18F-AV-1451.8 The study involved 59 participants, 64% of whom were male with a median age 76 years. Of these, 42 had undergone lumbar puncture and been designated as Aβ-positive or -negative based on the concentration of Aβ in their CSF. The standardised uptake value ratio (SUVR) was used to measure tau, using a cut-off of 1.19 in the AD cortical signature regions. This technique distinguished participants with AD from those who were cognitively normal. A fraction of cognitively normal people who tested positive for Aβ had SUVRs above the cut-off, suggesting they might be on the verge of conversion to AD The authors suggested that tau imaging may be useful for clinical staging of AD, a proposal that has also been made in a separate article published this month.9 The presence of tau in cerebrospinal fluid (CSF) may indicate disease in the preclinical stage, and volumetric magnetic resonance imaging (MRI) indicates clinical disease, but tau in cortical signature regions was elevated in both the preclinical and clinical stage. Therefore tau imaging can detect a wider range of AD neurodegeneration than CSF measurements or volumetric MRI.8
The researchers also investigated the relationships between Aβ plaques, tau deposition, and brain volume. They found that cortical tau was elevated in the presence of Αβ. In addition, elevated tau was associated with volume loss in the hippocampus and AD cortical signature regions of the brain. The researches proposed that Αβ may initiate a pathogenic cascade that transforms tau to a more toxic form that kills neurons in the hippocampus and spreads to the cortical regions to which it then spreads.
These findings represent an important breakthrough in AD research. The combination of tau and Αβ imaging could enable earlier diagnosis of AD leading to earlier treatment; at present, diagnosis occurs at a stage where brain function is already diminished. In the next decade, tau imaging is likely to be at the forefront of neurological research. In addition to AD, tautopathies are also found in some variants of frontotemporal lobe degeneration, Down's syndrome, Guam Parkinsonism-dementia complex, frontotemporal dementia with parkinsonism linked to chromosome-17, progressive supranuclear palsy, corticobasal degeneration, and traumatic brain injury.10 PET tau imaging will be useful clinically, in differential diagnosis and as a biomarker of disease progression, and also in research, where it will guide the selection of appropriate patients and monitoring of efficacy in clinical trials.
Comparison of PET scans of Abeta and tau proteins in Alzheimer’s disease
The top images show PET scans of cognitively normal individuals. Images across the bottom show scans of patients with mild AD. The difference between scans of healthy people and scans of patients with mild AD is more marked in the images that measure tau, suggesting tau protein build-up in the brain is a better marker of AD symptoms than Αβ. Reproduced with permission from the owner, Matthew R Brier. Original source:
1. Alzheimer's Association, 2016 Alzheimer's disease facts and figures, http://www.alz.org/documents_custom/2016-facts-and-figures.pdf Accessed 9 August 2016.
2. Masters CL, Cappai R, Barnham KJ, et al., Molecular mechanisms for Alzheimer's disease: implications for neuroimaging and therapeutics, J Neurochem, 2006;97:1700-25.
3. Arriagada PV, Growdon JH, Hedley-Whyte ET, et al., Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease, Neurology, 1992;42:631-9.
4. Spillantini MG, Goedert M, Tau pathology and neurodegeneration, Lancet Neurol, 2013;12:609-22.
5. Blennow K, Cerebrospinal fluid protein biomarkers for Alzheimer's disease, NeuroRx, 2004;1:213-25.
6. Brier MR, Gordon B, Friedrichsen K, et al., Tau and Abeta imaging, CSF measures, and cognition in Alzheimer's disease, Sci Transl Med, 2016;8:338ra66.
7. Smith R, Puschmann A, Scholl M, et al., 18F-AV-1451 tau PET imaging correlates strongly with tau neuropathology in MAPT mutation carriers, Brain, 2016; epub ahead of print.
8. Wang L, Benzinger TL, Su Y, et al., Evaluation of Tau Imaging in Staging Alzheimer Disease and Revealing Interactions Between beta-Amyloid and Tauopathy, JAMA Neurol, 2016; epub ahead of print.
9. Jack CR, Jr., Bennett DA, Blennow K, et al., A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers, Neurology, 2016;87:539-47.
10. Lee VM, Goedert M, Trojanowski JQ, Neurodegenerative tauopathies, Annu Rev Neurosci, 2001;24:1121-59.