Longitudinal Change in Tau PET in MCI & Alzheimer’s Disease

The typical frequency of Tau PET scanning in Alzheimer's disease (AD) clinical trials can vary depending on the study's design, objectives, and phase of the trial. Most trials conduct an initial Tau PET scan at the beginning of the study (baseline) to assess the participant’s Tau pathology and establish a reference for future scans. For Phase 2 trials, follow-up scans are often conducted annually to assess the progression of tau pathology over time. Larger, long-term phase 3 trials may also have annual or semi-annual Tau PET scans, but some may include scans every 18 to 24 months depending on the study duration and budget. 

Tau PET images processing typically include the following steps:

• Frame-to-frame motion correction
• Image smoothing, either based on a scanner-specific blurring kernel using Hoffman phantom data or using a novel computational method for harmonization of brain PET images spatial resolution without phantoms (see our SPITFIRE Presentation)
• Concatenation of the dynamic PET frames into a static image
• Registration target selection  
• Co-registration to an anatomical MRI
• Mapping to reference space to define anatomically accurate regions-of-interest (ROIs) 

Orthogonal views of a Tau PET scan (left) and 3D T1 anatomical MRI scan (middle); the right column illustrates the overlay of the Tau PET and MRI scans registered to a reference coordinate space. 

Yes, for several reasons, including: (1) amyloid-beta plaques and tau tangles accumulate in the brain at different stages of the disease, so imaging with both radiotracers gives a more complete picture of the disease's progression; (2) since some forms of dementia do not involve amyloid-beta buildup, confirming its presence ensures the participant’s diagnosis is aligned with the study’s inclusion criteria; (3) in trials of anti-amyloid or anti-tau therapies, imaging both misfolded proteins can help evaluate how the treatment affects amyloid clearance and tau pathology progression, which provides a more holistic measure of treatment efficacy; and (4) combining Amyloid and Tau PET data may help identify subgroups of patients with different pathological burdens, which can support a more personalized approach to treatment, tailoring interventions to the specific pathology of each patient. 

Our team and others have shown that reduction of brain glucose metabolism is primarily driven by tau pathology (see our Tau Pathology Presentation). We have also observed that tau pathology is a key driver of cortical atrophy in Alzheimer's disease, with neurofibrillary tangles leading to neuronal death and cortical thickness reduction in regions critical for cognitive function. These relationships underscore tau’s central role in the neurodegenerative process and its link to cognitive impairment.

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Alzheimer's Disease: a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral changes. It is associated with the accumulation of amyloid-beta plaques and tau tangles in the brain, and loss of neurons and synapses in the cerebral cortex and subcortical regions.   

Amyloid-beta (Aβ): a peptide derived from the amyloid precursor protein (APP) that can aggregate to form plaques. 

Brain Atrophy: reduction in volume or thickness of the entire brain or regions of the brain.   

Diffusion Tensor Imaging (DTI): an MRI technique that measures the diffusion and directionality of water, generating mean diffusivity, axial diffusivity, radial diffusivity, and fractional anisotropy metrics.   

Magnetic Resonance Imaging (MRI): a non-invasive imaging modality that uses magnetic fields and radiofrequency (RF) pulses to generate images.   

MCI (Mild Cognitive Impairment): a decline in cognitive function, such as memory, thinking, and reasoning skills, that go beyond normal age-related decline but are not severe enough to interfere significantly with daily life or independent functioning. Patients with MCI have an risk of developing dementia, particularly Alzheimer's disease. 

Neuritic Plaque: amyloid plaque containing dystrophic neurites (degenerating axons and dendrites). 

Neurodegeneration: a complex, multifactorial process resulting in the loss of neurons. 

Neurofibrillary tangles: abnormal accumulations of tau inside neurons. In healthy neurons, tau proteins help stabilize the structure of microtubules. In certain neurodegenerative conditions, such as Alzheimer's disease, tau proteins become hyperphosphorylated, causing them to clump together and form twisted, thread-like structures known as tangles. 

Neuroinflammation: an inflammatory response within the central nervous system (CNS), primarily involving the activation of microglia and astrocytes. This process can be triggered by various factors, including infections, traumatic brain injury, toxic metabolites, and autoimmune diseases.   

Positron Emission Tomography (PET): a non-invasive imaging technique used in medical diagnostics and research to visualize and measure metabolic and molecular processes in the body. PET scans involve the use of a small amount of injected radioactive tracer. The tracer emissions are collected by PET scanner detectors which uses them to create detailed three-dimensional images of the tracer distribution within the body. PET scans are often combined with computed tomography (CT) or magnetic resonance imaging (MRI) to provide both metabolic/molecular and anatomical information, enhancing the accuracy of diagnosis and treatment planning.  

Tau: a protein that plays a crucial role in maintaining the stability and function of neurons in the brain. It is predominantly found in neurons, where it stabilizes microtubules, which are part of the cell's cytoskeleton. Microtubules are essential for maintaining cell shape, enabling intracellular transport, and facilitating cellular division. Hyperphosphorylation of tau is evident in various neurodegenerative diseases, where the abnormally phosphorylated molecules lead to the detachment of tau from the microtubules. These detached tau proteins can aggregate to form insoluble fibrils, known as neurofibrillary tangles. Diseases impacted by tau aggregation are called tauopathies, and include Alzheimer's disease, progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), and corticobasal degeneration (CBD).