PET Imaging of Tau Pathology in Alzheimer’s Disease and Tauopathies

Alzheimer’s disease (AD) is a major public health problem affecting nearly 35 million people worldwide with numbers projected to rise to 115.4 million by 2050. Medicare and Medicaid cost of AD is anticipated to increase fourfold to approximately $ 600 billion in the next 40 years. AD is the only cause of death among the top 10 causes that has no prevention or cure (1, 2). AD causes are not fully known and clinical drug trials have a greater than 90% failure rate. There is an urgent need to find accurate methods of early detection as well as effective therapies before patients with AD develop significant brain damage. Clinical diagnosis of AD remains a challenge since there are no validated tests for an affirmative diagnosis and dozens of conditions can mimic it. Hallmarks of AD brain are numerous neurons with neurofibrillary tangles of paired helical filaments (PHFs), straight filaments, and extracellular deposits of β-amyloid as the major component of senile (neuritic) plaques in the brain. Definitive diagnosis of AD is made only after an autopsy or biopsy. While AD is the most common cause of dementia in the elderly, accounting for approximately 50–70% of cases, many other causes of dementia can mimic and overlap with AD clinical presentation. Vascular dementia, mixed dementia of vascular and Alzheimer’s etiology, dementia with Lewy bodies (DLB), and frontotemporal dementias are some examples with overlapping clinical and diagnostic features. Clinical diagnosis of probable AD is currently made by excluding other causes using history, exam and labs, structural imaging, and cognitive testing. However, their accuracy is suboptimal. For example, a clinical-autopsy correlative study of more than 900 cases seen at leading academic memory centers found that some 40% of patients clinically diagnosed with non-AD dementia had postmortem histopathology consistent with AD (3). Likewise, nearly 30% of patients, who were thought to have AD, clinically do not meet postmortem pathologic criteria for AD (3). In recent clinical drug trials of mild to moderate AD, it is also estimated that about 30% of patients did not have AD pathology thus making it difficult to determine if failures were due to ineffective drug versus diagnostic errors (4). There is a call for the development and integration of pathologic biomarkers into routine clinical evaluation to establish revised diagnostic criteria for clinical and preclinical AD. Such markers may not only assist with an accurate affirmative diagnosis of AD and disease staging, but may also accelerate drug development (5). Molecular imaging, specifically positron emission tomography (PET), is a promising modality for early detection and disease staging in Alzheimer’s patients. Recently approved amyloid PET tracers (e.g., F-18 florbetapir, F-18 flutemetamol) can detect cortical fibrillary β-amyloid (6). A negative amyloid scan substantially decreases the odds of a person having AD and can impact clinical decision making or treatment. In at-risk subjects, a positive amyloid scan is associated with a threefold greater risk of converting to dementia (7). The limitations of amyloid imaging are that amyloid plaques by themselves are insufficient for a positive diagnosis of AD. Thus, the advent of a PET taupathology tracer may serve as a complimentary tool to aid in affirmative diagnosis, as well as in disease staging. Given the number of tau-based therapies being developed, a tau-PET tracer would also allow for a selection of pathology-positive individuals and monitor the effectiveness of therapy.