Tauopathies & Rare Diseases Imaging for Clinical Trials

Tauopathies are a group of neurodegenerative disorders characterized by abnormal accumulation of tau protein in the brain, leading to neuronal dysfunction and atrophy. Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia (FTD), and corticobasal degeneration are examples of tauopathies.

Rare diseases are often also called orphan diseases. The FDA Orphan Drug Act defines a rare disease as a condition that affects less than 200,000 people in the United States. 

Many rare diseases that affect the brain have characteristic findings that can be seen with MRI, such as atrophy, developmental structural abnormalities (e.g. thin corpus callosum), and white matter abnormalities, all of which can get progressively worse over time and possibly stabilize or improve with a treatment.

It can be difficult to recruit people with rare diseases to participate in clinical trials due to multiple factors. Imaging can be used as a biomarker to improve the likelihood of observing a treatment effect in a small population in a relatively short period of time.​

Coughlin, D.G., Litvan, I. Progressive supranuclear palsy: Advances in diagnosis and management. Parkinsonism Relat. Disord., 73: 105-116, 2020; doi: 10.1016/j.parkreldis.2020.04.014

Dickson, D. W., Bergeron, C., Chin, S. S., Duyckaerts, C., Horoupian, D., Ikeda, K., Jellinger, K., Lantos, P. L., Lippa, C. F., Mirra, S. S., Tabaton, M., Vonsattel, J. P., Wakabayashi, K., Litvan, I. Office of rare diseases neuropathologic criteria for corticobasal degeneration. J. Neuropathol. Exp. Neurol., 61: 935–946, 2002; doi: 10.1093/jnen/61.11.935 

Gröschel, K., Kastrup, A., Litvan, I., Schulz, J.B. Penguins and hummingbirds: midbrain atrophy in progressive supranuclear palsy. Neurology, 66: 949-950, 2006; doi: 10.1212/01.wnl.0000203342.77115.bf 

Hogan, D.B., Jetté, N., Fiest, K.M., Roberts, J.I., Pearson, D., Smith, E.E., Roach, P., Kirk, A., Pringsheim, T., Maxwell, C.J. The prevalence and incidence of frontotemporal dementia: a systematic review. Can. J. Neurol. Sci., 43: S96-S109, 2016; doi: 10.1017/cjn.2016.25 

Ichikawa-Escamilla, E., Velasco-Martínez, R.A., Adalid-Peralta, L. Progressive Supranuclear Palsy Syndrome: An Overview. IBRO Neurosci. Rep., 16:598-608, 2024; doi: 10.1016/j.ibneur.2024.04.008 

Leroy, M., Bertoux, M., Skrobala, E., Mode, E., Adnet-Bonte, C., Le Ber, I., Bombois, S., Cassagnaud, P., Chen, Y., Deramecourt, V., Lebert, F., Mackowiak, M.A., Sillaire, A.R., Wathelet, M., Pasquier, F., Lebouvier, T., Méotis network. Characteristics and progression of patients with frontotemporal dementia in a regional memory clinic network. Alz. Res. Therapy., 13: 19, 2021; doi: 10.1186/s13195-020-00753-9 

Page, I., Gaillard, F. Descriptive neuroradiology: beyond the hummingbird. Pract. Neurol., 20: 463-471, 2020; doi: 10.1136/practneurol-2020-002526

Quattrone, A., Morelli, M., Nigro, S., Quattrone, A., Vescio, B., Arabia, G., Nicoletti, G., Nisticò, R., Salsone, M., Novellino, F., Barbagallo, G., Le Piane, E., Pugliese, P., Bosco, D., Vaccaro, M.G., Chiriaco, C., Sabatini, U., Vescio, V., Stanà, C., Rocca, F., Gullà, D., Caracciolo, M. A new MR imaging index for differentiation of progressive supranuclear palsy-parkinsonism from Parkinson's disease. Parkinsonism Relat. Disord., 54: 3-8, 2018; doi: 10.1016/j.parkreldis.2018.07.016 

Biomarker: a measurable indicator of a biological state or condition. Biomarkers are often used in medicine and research to detect or monitor the presence, progress, or severity of a disease, as well as to assess the effectiveness of a treatment.  

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

Cognitive Decline: a decrease in cognitive function, including memory, thinking, and reasoning skills. ​ 

Corticobasal Degeneration: a rare neurodegenerative disease which presents as an atypical parkinsonian syndrome. Corticobasal Degeneration involves the cerebral cortex and the basal ganglia. Corticobasal Degeneration is often misdiagnosed as Progressive Supranuclear Palsy due to their similar symptoms. Both Progressive Supranuclear Palsy and Corticobasal Degeneration are considered tauopathies with abnormal accumulations of the tau protein in the brain.  

Deep Learning: a subset of machine learning techniques that use neural networks with many layers (deep neural networks) to analyze complex patterns in data​ 

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.   

Frontotemporal Dementia (FTD): a group of neurodegenerative disorders characterized by progressive damage to the frontal and/or temporal lobes of the brain. This damage leads to a variety of symptoms that can include changes in personality, behavior, and language abilities. FTD is distinct from other types of dementia, such as Alzheimer's disease, in that it often affects younger individuals (typically between the ages of 45 and 65) and presents with early and prominent changes in social behavior, executive function, and language, rather than memory loss. The three main subtypes of FTD are Behavioral variant FTD (bvFTD), Non-fluent variant primary progressive aphasia (nfvPPA) and Semantic variant primary progressive aphasia (svPPA). 

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

Magnetic Resonance Spectroscopy (MRS): specifically, proton (1H) MRS, is a non-invasive imaging modality that uses magnetic fields and radiofrequency (RF) pulses to measure the chemical composition of tissues in the body, particularly in the brain. Unlike conventional Magnetic Resonance Imaging (MRI), which generates detailed images of tissue structures, proton (1H) MRS focuses on detecting and quantifying specific biochemical compounds, known as metabolites, within a volume of interest.  

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

Neuroimaging: the process of generating images of structural and functional components within the nervous system, utilizing such techniques as MRI and PET imaging. ​ 

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

Parkinson's Disease (PD): a neurodegenerative disease that is characterized by: (a) movement-related (motor) symptoms, including resting tremor, bradykinesia, rigidity, and postural instability, related to the loss of dopaminergic neurons in the substantia nigra; and (b) non-motor symptoms including anxiety, depression, apathy, hallucinations, constipation, orthostatic hypotension, sleep disorders, hyposmia/anosmia, and cognitive impairment.  ​ 

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.  

Progressive Supranuclear Palsy: a neurodegenerative disease that falls under the category of atypical parkinsonian syndromes. The classic presentation of Progressive Supranuclear Palsy includes symptoms involving walking, balance, eye movements, and swallowing. In addition to these motor symptoms, non-motor signs, such as behavioral changes and executive dysfunction, are also common. The prevalence of Progressive Supranuclear Palsy varies, with estimates ranging from 1.4 to 8.3 individuals per 100,000 (Ichikawa-Escamilla, 2024).  

Region-of-Interest (ROI): a specific subset of data identified within an image. For volumetric analysis, the ROIs correspond to neuroanatomical structures and parcellated features.   ​ 

Single Photon Emission Computed Tomography (SPECT): a nuclear medicine imaging technique that provides three-dimensional information about the distribution of radioactive tracers in the body. Similar to PET scanning, SPECT is a non-invasive imaging technique used in medical diagnostics and research to visualize and measure metabolic and molecular processes in the body. SPECT scans involve the use of a small amount of injected radioactive tracer, where commonly used tracers include technetium-99m, iodine-123, and thallium-201. The tracer emissions are collected by SPECT scanner detectors, which uses them to create detailed three-dimensional images of the tracer distribution within the body.   ​ 

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, frontotemporal dementia (FTD), and corticobasal degeneration.