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The tauopathies: Neuroimaging characteristics and emerging experimental therapies

Abstract The tauopathies are a heterogeneous group of neurodegenerative disorders in which the prevailing underlying disease process is intracellular deposition of abnormal misfolded tau protein. Diseases often categorized as tauopathies include progressive supranuclear palsy, chronic traumatic encephalopathy, corticobasal degeneration, and frontotemporal lobar degeneration. Tauopathies can be classified through clinical assessment, imaging findings, histologic validation, or molecular biomarkers tied to the underlying disease mechanism. Many tauopathies vary in their clinical presentation and overlap substantially in presentation, making clinical diagnosis of a specific primary tauopathy difficult. Anatomic imaging findings are also rarely specific to a single tauopathy, and when present may not manifest until well after the point at which therapy may be most impactful. Molecular biomarkers hold the most promise for patient care and form a platform upon which emerging diagnostic and therapeutic applications could be developed. One of the most exciting developments utilizing these molecular biomarkers for assessment of tau deposition within the brain is tau‐PET imaging utilizing novel ligands that specifically target tau protein. This review will discuss the background, significance, and clinical presentation of each tauopathy with additional attention to the pathologic mechanisms at the protein level. The imaging characteristics will be outlined with select examples of emerging imaging techniques. Finally, current treatment options and emerging therapies will be discussed. This is by no means a comprehensive review of the literature but is instead intended for the practicing radiologist as an overview of a rapidly evolving topic.


INTRODUCTION
Tauopathies are a heterogeneous group of neurodegenerative disorders (NDs) in which the primary underlying disease process is intracel-more comprehensively in other publications. [5][6][7] Additional NDs such as Alzheimer disease (AD) are associated with heterogeneous protein deposition, which includes abnormal deposition of tau; however, this heterogeneity raises controversy as to the true role of tau. 8 Therefore, AD will not be discussed in this review except where comparisons are made.
Normal tau is a microtubule-associated protein essential for the stability and formation of microtubules and is predominantly found within axons. [9][10][11] Neuronal bodies, dendrites, astrocytes, and oligodendrocytes have also been observed to contain tau protein. 12,13 Tau exists in an unfolded state physiologically; however, it can form aggregates when abnormally hyperphosphorylated. [14][15][16] This hyperphosphorylated state is thought to lead to abnormal interactions with microtubules, resulting in microtubule dysfunction and aggregate formation, a hallmark of primary tauopathies. Recent research suggests that pathologic tau aggregates can induce tau pathology in adjacent cells, resulting in prion-like propagation. [17][18][19][20][21] One pitfall of the radiology literature is a potential bias toward classifying NDs based on imaging characteristics, which are rarely specific to a single neurodegenerative disease. While imaging findings can correlate with disease progression, they may not have fully manifested when a given therapy would be most impactful. The point in the disease course at which a patient presents can dramatically influence classification. Additionally, lack of the full clinical picture at the reading station could potentially reduce sensitivity for subtle imaging findings, which may have been best appreciated with specific imaging protocols. A common example is qualitative MRI evaluation of brain atrophy without utilizing quantitative volumetric assessment of subregional brain volumes, which requires specialized software.
Atrophy can be subtle early in the disease course, making reliable quantitative assessment difficult until late in the disease course, at which time disease modifying treatments may not be an option.
Pathologic/histologic verification remains the gold standard, but biopsy is invasive and prone to complications, and postmortem tissue acquisition after death is not useful to the patient. Autopsy results have shown the clinical diagnoses are often inaccurate. 22,23 Tracking symptoms and imaging patterns over time may allow for more accurate diagnosis.
Characterization of the neurodegenerative diseases by underlying molecular mechanism allows for a molecular biomarker approach to classification, facilitating development of more specific and sensitive imaging biomarkers and therapy targets. 24 Identifying aberrations years before they clinically manifest allows for early diagnosis and offers targeted therapy options, which include small molecule drugs, antibodies, and cell therapies.
This review is by no means a comprehensive evaluation of the literature and instead is meant for the radiologist as an overview of a rapidly evolving topic. The background, significance, and clinical presentation of each disease will be discussed, highlighting the difficulty in discerning various overlapping diseases ( Table 1). The underlying pathologic mechanisms that lead to tauopathies will be outlined at the protein level along with available and emerging imaging techniques.
Finally, current treatment options and emerging therapies will be reviewed.

Background, significance, and clinical presentation
PSP is a neurodegenerative disease initially described by Richardson in 1963 with the clinical syndrome of supranuclear vertical ophthalmoplegia, pseudobulbar palsy, and dementia. 25 The classic presentation of PSP is often referred to as Richardson's syndrome and consists of dementia, supranuclear vertical ophthalmoplegia, and postural instability with falls. [26][27][28][29] PSP typically presents in the seventh decade and has a male predilection. 26,27 The prevalence of PSP ranges from 5 to 6 cases per 100,000 people in the United States. 30 Median survival from disease onset is just under 6 years with pneumonia being the most common cause of death. 26,29 While uncommon, PSP can impose a significant economic cost to patients, their caregivers, and society with one study suggesting an annual cost of up to 2.7 million euros in the European Union alone. 31 Richardson's syndrome is the classic clinical presentation of PSP, although significant symptom heterogeneity makes a definitive diagnosis clinically difficult. PSP can present with Parkinsonism and be misdiagnosed as idiopathic Parkinson's disease (PD). 26,27 Clinical features that may help differentiate PSP from PD include vertical supranuclear gaze palsy, early postural instability, falls, rapidly progressive disease, and Parkinsonism with poor response to levodopa. 26,28 No specific PSP laboratory tests are clinically available, although studies utilizing the Real-Time Quaking-Induced Conversion (RT-QuIC) assay are showing great promise for distinguishing the various proteinopathies. The test specific to the tauopathies is being referred to as the 4 tau (4T) RT-QuIC assay. [32][33][34] The assay takes advantage of the protein seeding mechanism, amplifying miniscule amounts of the abnormal CSF protein to detectable levels ( Figure 1).

Underlying pathologic mechanism
Neuropathologically, PSP is characterized by neuronal loss and gliosis with deposition of abnormal tau aggregates predominantly within the basal ganglia, subthalamic nucleus, substantia nigra, and pons. [35][36][37] An additional hallmark feature is the presence of taupositive inclusions within astrocytes, referred to as glial fibrillary tangles or tufted astrocytes. 37,38 Macroscopically, PSP is associated with marked volume loss of the midbrain, superior cerebellar peduncle, and subthalamic nucleus with loss of pigment within the substantia nigra. 37,39 PSP is classified as a 4R tauopathy due to the fact that the deposited tau aggregates predominantly consist of tau isoforms containing four repeats within the microtubulebinding domain. 37,40,41 The anatomic distribution of abnormal tau deposition has been shown to correlate with clinical presentation ( Figure 2).

Imaging characteristics and emerging imaging techniques
While no imaging features are entirely specific to any one primary tauopathy, certain features suggestive of PSP can be helpful in making the diagnosis. Midbrain atrophy is one of those features, but can also be seen in association with conditions such as PD and CBD. Certain features of the midbrain atrophy may help increase the specificity of anatomic imaging findings. Marked midbrain atrophy resulting in a decreased AP diameter has been referred to as the "hummingbird" sign when viewed in the sagittal plane ( Figure 3A). 42 Additionally, the superior surface of the midbrain is typically flat or concave in those with PSP, as compared to convex in healthy patients. 43 Atrophic concavity of the lateral midbrain tegmentum has also been described in PSP, termed the "morning glory" sign ( Figure 5). 44 A reduced midbrainto-pons diameter ratio (below 0.52) measured on midsagittal images has also been found to have sensitivity and specificity in pathologically proven cases of PSP ( Figure 3A). 45 Finally, the ratio of the midbrain to pons areas as measured on midsagittal images has been shown to have predictive value for early death from PSP with a cutoff value of 0.12 ( Figure 3B). 46 A more advanced MRI measurement system known as the MR Parkinsonism index (MRPI) has shown to be helpful in differentiating PSP from PD ( Figure 4). 47 54 Beta-amyloid PET imaging, a F I G U R E 1 4 tau real-time quaking-induced conversion (4T RT-QuIC) assay for tauopathy detection. The patient tissue sample with suspected abnormal tau protein is delivered into a solution containing many copies of the normal recombinant tau protein. The solution is placed on a shaker for 1 minute followed by 1 minute of incubation. If abnormal tau protein is present, the normal recombinant tau proteins will become misfolded and propagate the misfolding pattern thus causing a significant amplification. The fluorescent probe will bind only the misfolded proteins and therefore the amplified signal can be detected using a fluorimeter. Normal negative controls do not fluoresce technique used to noninvasively assess amyloid deposition in patients with AD, is of little use in PSP as it is not associated with abnormal amyloid deposition.
Perhaps the most exciting modality in development for assessment of tau deposition within the brain is tau-PET imaging utilizing novel ligands that specifically target tau protein. (also known as flortaucipir) in the basal ganglia, thalamus, midbrain, subthalamic nuclei, and cerebellar dentate nuclei when compared to healthy control patients ( Figure 6). 54 [64][65][66] Due to these limitations, other potential PET agents specific for tau have been investigated, including 18 F-THK5105 and 18 F-THK5117. [67][68][69] While these agents were found to show uptake in typical areas of tau deposition primarily in patients with AD, they also had some issues with "off-target" binding, particularly within the subcortical white matter. In order to decrease this nonspecific binding, the chemical structure of 18 F-THK5117 was modified in order to create F I G U R E 2 Abnormal tau seeding and propagation. The normal tau protein (top) converts to a misfolded tau protein and starts aggregating and altering the conformation of neighboring tau proteins. The larger oligomer unit forms fibrils that then build into disorganized aggregates. The aggregates can spread interneuronally across the synapse to begin the process of destruction in neighboring neurons. Beginning locally in a given part of the brain, the disease spreads to more distant parts of the brain to induce the neurodegenerative disease (shown on the bottom). This is shown progressing from the darker blue color in the brainstem to the lightest blue color in the more distal cortical regions of the cerebrum 18 F-THK-5351. 70 18 F-THK-5351 demonstrated higher binding affinity for neurofibrillary tangles and has less white matter binding, making it more sensitive for abnormal tau protein. 70 There is also evidence that 18 F-THK-5351 binds to abnormal tau protein within the basal ganglia and brainstem in patients with PSP. 71 Potential limitations to imaging with 18 F-THK-5351 include offtarget binding within the basal ganglia, which has been demonstrated to an extent, similar to and possibly greater than that of [ 18 F]AV-1451. 72 There is also evidence that 18 F-THK-5351 may bind to monoamine oxidase B (MAO-B) within the brain in addition to pathologic tau, potentially confounding examinations showing increased uptake of the radiotracer. 73,74 Further research into these agents is ongoing in order to fully realize their potential in imaging tau deposition in PSP as well as other tauopathies.

Background, significance, and clinical presentation
CTE is a progressive neurodegenerative condition characterized by abnormal deposition of hyperphosphorylated tau protein in patients who have experienced repetitive brain trauma. 75 79 Additionally, a recent study demonstrated an increased risk of death secondary to neurodegenerative disease in a cohort of former soccer players with a hazard ratio >5. 80 It has been shown that there are two main presentation patterns in patients with CTE: one in relatively younger patients (average age 51) presenting mainly with mood and behavioral disturbances, and one in somewhat older patients (average age 69) presenting mainly with cognitive impairment. 81 The severity of patient symptoms appears to correlate with the number of traumatic brain injuries suffered as well as the duration of the patient's engagement in the sport/activity. 75 It should be noted that some patients have reported symptoms of CTE as young as 25 years of age. 75

Underlying pathologic mechanism
On gross pathology, CTE has been classically described as having the following features: diffuse cerebral atrophy, thinning of the corpus callosum, cavum septum pellucidum with fenestrations, enlarged lateral and third ventricles, and cerebellar scarring. 82 Marked atrophy of the hippocampi, amygdala, and entorhinal cortex can be seen within increasing disease severity. Other gross pathological features that may be observed include atrophy of the thalami, mamillary bodies, brainstem, and olfactory bulbs as well as pallor of the substantia nigra and locus ceruleus. 75 Microscopically, CTE typically shows irregular, dense and may include additional cortical findings including myoclonus, alien limb phenomenon, cortical sensory loss, and basal ganglia findings such as bradykinesia and tremor. 91 The clinical presentation of CBD can vary widely and may appear quite different from the classic CBS presentation. The term CBD is now reserved for the pathologic diagnosis characterized by tau-positive neuronal and glial lesions within a characteristic distribution. 92 CBD typically occurs in the fifth to seventh decades and has no sex predilection. 93,94 The prevalence of CBD has been estimated at 4.9-7.3 cases per 100,000. 95 Disease duration after diagnosis ranges from 2 to 12 years with an average of 6.6 years. 94,96 As with several other neurodegenerative diseases, pneumonia has been cited as the most frequent cause of death.
The clinical diagnosis of CBD is challenging owing to the marked symptom heterogeneity. There have been four primary phenotypes of CBD identified: classic CBS, nonfluent variant of primary F I G U R E 7 Former football player presented in his mid-40s with mild early atrophy and clinical concern for chronic traumatic encephalopathy (CTE). The objective of this figure is to depict the nonspecific findings of CTE via brain MRI early on. In this patient, there is mild enlargement of the lateral (white arrows) and third ventricles with notable thinning of the septum pellucidum and corpus callosum (red arrows). There was also mild nonspecific atrophy of the mesial temporal structures. Molecular image has great potential to better diagnosis CTE in this early stage progressive aphasia, frontal behavioral-spatial syndrome, and a primary PSP syndrome. 97 The American Academy of Neurology has devised a set of consensus criteria for the diagnosis of probable and possible CBD. 97 CBD is noted to be refractory to treatment with levodopa. As with PSP, there are currently no laboratory tests available that specifically diagnose CBD.

Underlying pathologic mechanism
The neuropathologic diagnosis of CBD is based primarily upon the histopathologic findings. Gross pathologic findings are helpful but not critical to making the diagnosis. Subtle findings include volume loss and thinning of the cortical gyri predominantly within the parasagittal peri-Rolandic distribution, most often involving the superior frontal gyrus. 92 The temporal and occipital lobes are less often involved. 6On histopathology, CBD is characterized by tau-reactive lesions within neurons and glial cells within the cortex and striatum.
Additionally, neuronal loss is often seen in focal cortical regions and the substantia nigra. 92 One other histopathological feature often considered a hallmark of CBD is the "astrocytic plaque." 98 Like PSP, CBD is also classified as a 4R tauopathy. 41 CBD can demonstrate FDG hypometabolism within the frontal and parietal cortices, as well as the thalami and caudate nuclei. [103][104][105][106] The degree of hypometabolism is typically contralateral to the more clinically affected side, mirroring reported anatomic imaging findings ( Figure 8). Regional differences in hypometabolism between CBD and other tauopathies may be helpful in distinguishing between diagnoses. 106 As with PSP, beta-amyloid PET imaging is unlikely to be of value in the diagnosis of CBD as the disease is not associated with abnormal amyloid deposition. Beta-amyloid PET can help identify underlying AD in those presenting with CBS, and may have an important clinical impact as treatments become more widely available. 107 Visuospatial and functional symptoms tend to be more severe in beta-

Background, significance, and clinical presentation
FTLD is a generic umbrella term referring to progressive degeneration of the frontal and temporal lobes. The condition was first described in 1892 by Arnold Pick and was referred to as Pick's disease, although today that term is now only utilized for a very specific syndrome/pathology. FTLD is recognized to produce three distinct clinical syndromes (  114,115,124 The clinical diagnosis of FTLD syndromes can be challenging due to the possibility of symptom overlap with other primary tauopathies such as PSP and CBD. bvFTD is the most common of the FTLD syndromes and typically presents with changes in behavior, personality, and impaired executive functioning. 113,124,125 Patients with bvFTD also frequently appear apathetic and unmotivated; however, memory function is usually preserved. Patients with SD typically present with a characteristic syndrome of progressive loss of knowledge of word meanings. Patients will forget the meaning of common words, facts, or even people and may experience impaired objected recognition (visual associative agnosia). 113,124,126,127 SD patients will typically speak fluently; however, the spoken words may not make any sense. 113,124 PNFA will present with effortful, nonfluent speech as well as agrammatism. These patients often have troubles comprehending complex sentences, although single word comprehension is usually preserved, helping to distinguish PNFA from SD. 113,124,127 Patients with advanced PNFA may also develop the behavioral changes and impaired executive functioning seen with bvFTD. Of note, PSP, CBS, and motor neuron diseases such as amyotrophic lateral sclerosis also have underlying FTLD pathology. Lack of reliable laboratory and imaging biomarkers has made the diagnosis of FTLD primarily clinical and there have been several consensus criteria developed to aid evaluation. 113,128 Underlying pathologic mechanism FTLD shows atrophy of the frontal and/or temporal lobes on gross pathology, although each variant classically has a somewhat distinct pattern of volume loss. The parietal lobes can occasionally be affected but the occipital lobes are almost never involved. bvFTD will classically show symmetric atrophy of the frontal lobes and occasionally the right temporal lobe. 113,124 SD, on the other hand, classically shows asymmetric atrophy and cortical thinning of the anterior inferior temporal lobes, usually greater on the left side. 113,124,126,127,129 In cases of SD where right temporal lobe atrophy is greater, patients tend to present with prosopagnosia. 124,129,130 PNFA classically shows asymmetric left frontal and perisylvian atrophy. 114,124,127,131 On microscopic evaluation, there is classically cortical microvacuolation and neuronal loss, predominantly within layer II along with gliosis and myelin loss within the underlying white matter. 114,115,132 FTLD can also be divided into two broad categories based on the presence or absence of tau inclusions. A form of tau-negative FTLD with ubiquitin positive inclusions, previously referred to as FTLD-U, is the most common form of FTLD comprising around 60% of cases. 124,133,134 The predominant protein implicated in this condition has been found to be TAR DNA-binding protein 43 (TDP-43). 135,136 There are several tauopathies that may underlie FTLD-associated syndromes, of which Pick's disease (a form of bvFTD) is often considered the prototype syndrome. The typical pathology underlying Pick's disease is a 3R tauopathy with characteristic spherical depositions of abnormal tau protein within the hippocampi, basal ganglia, and the superficial neocortical layers of the frontal and temporal lobes. 114,115,137,138 The tauopathies underlying both PSP and CBD may also produce clinical syndromes associated with FTLD, making diagnostic differentiation between these syndromes quite difficult. An additional tauopathy that may be seen with FTLD syndromes is associ- corresponding with the gross pathology of the underlying FTLD syndrome ( Figure 10). 149,150 The parietal lobes may be involved later in the disease process, with the occipital lobes rarely involved.
The patterns of hypometabolism on 18 F-FDG-PET have also been shown to fairly reliably distinguish FTLD from AD, one of the main clinical diagnostic differential considerations. 151 FTLD typically shows no beta-amyloid deposition on beta-amyloid PET imaging with some reported positive cases thought to be potentially secondary to underlying AD mimicking FTLD symptoms. 152,153 In terms of tau-specific PET agents, [ 164,165 Riluzole has also been studied and has not been shown to have significant benefits on survival or disease progression in PSP. 166 As previously mentioned, tau is a microtubule-associated protein that is critical for microtubule stability. Under pathologic conditions, however, tau can become abnormally hyperphosphorylated, leading to decreased stability of microtubules as well as formation of toxic aggregates of hyperphosphorylated tau. Therefore, more novel approaches to disease-modifying therapy target tau phosphorylation, kinase inhibition, and microtubule stabilization, among others. Davunetide is a peptide that inhibits tau phosphorylation and promotes microtubule stability and it was hypothesized that it may be beneficial in tauopathy patients. A trial of davunetide in patients with PSP, however, found no benefits. 167 An additional Phase 2 trial of tideglusib, an inhibitor of a kinase contributing to tau hyperphos-phorylation, also showed no benefit in patients with PSP. Early-stage trials for other medications including an additional microtubule stabilizer (TPI-287) and an inhibitor of tau acetylation (salsalate) are also ongoing. 161 The more recently described "prion hypothesis" of tauopathies may also provide a potential target for therapies. This theory also holds that in order for the pathologic intracellular tau aggregates to propagate to neighboring cells, they must first enter the extracellular space and then be internalized by the adjacent cell. [168][169][170][171] Evidence suggests that the pathway of propagation of pathologic tau aggregates may proceed via functional synaptic neuronal connections rather than direct spatial proximity. 168  Gene-targeting therapies such as this are currently being employed in the therapy of spinal muscular atrophy and Duchenne muscular dystrophy and have even been evaluated for potential treatment in Huntington's disease. 174,175 Other compounds targeting tau aggregation and phosphorylation have also been studied in patients with AD. TRx0237, a form of methylene blue, is a tau aggregation inhibitor that is currently undergoing a Phase 2/3 trial in early-stage AD patients, although several previously performed trials did not demonstrate efficacy. 24,161,176 The tyrosine kinase inhibitor nilotinib has been shown to reduce levels of tau in neurodegenerative diseases, 177 and is currently undergoing Phase 2 trials in patients with AD and PD. 161

CONCLUSION
Modern medicine is benefitting greatly from the shift away from histologic/pathologic diagnosis toward noninvasive yet highly specific forms of diagnosis, including imaging. Molecular imaging provides a key stepping-stone for not only permitting more specific disease diagnoses, but it also holds great potential for personalized monitoring of the disease progression or therapeutic effect of therapies through the duration of the disease. While the neurodegenerative diseases in general and tauopathies, in particular, have struggled to find significant disease-modifying treatments, coevolution of molecular imaging with therapies will be key to the future of combatting these often devastating and debilitating diseases.