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Correspondence: Address to Keith A. Josephs, MD, MST, MSc, Divisions of Movement Disorders and Behavioral Neurology, College of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
Primary tauopathies are a group of neurodegenerative diseases in which tau is believed to be the major contributing factor of the neurodegenerative process. In primary tauopathies, there is a disassociation between tau (a microtubule-associated protein) and microtubules as a result of tau hyperphosphorylation. This disassociation between tau and microtubules results in tau fibrillization and inclusion formation as well as in microtubule dysfunction. There are different clinical syndromes associated with different primary tauopathies, and some clinical syndromes can be associated with multiple primary tauopathies. Hence, although some clinical syndromes are highly specific and almost diagnostic of a primary tauopathy, many are not, making it difficult to diagnose a primary tauopathy. Recently, radioligands that bind to tau and can be combined with positron emission tomography to detect fibrillary tau antemortem have been developed, although preliminary data suggest that these ligands may not be sensitive in detecting tau associated with many primary tauopathies. Another recent advancement in the field is evidence suggesting that tau may exhibit properties similar to those of prions, although infective transmission has not been shown. There have been a few clinical trials targeting tau and microtubule dysfunction, although none have had any disease-modifying effects. Understanding tau biology is critical to the development of pharmacological agents that could have disease-modifying effects on primary tauopathies.
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Many entities subsumed under the umbrella term tauopathy are diseases that can have varying clinical presentations, some of which can overlap between diseases, resulting in a complex web of clinical syndromes and tauopathy-associated diseases. Some primary tauopathies do not have a clinically defined presentation, and some are considered age related. Table 1 provides a list of age-related tauopathies and diseases that are currently considered primary tauopathies. For those considered diseases, the abnormal tau is thought to account for the primary underlying neurodegenerative process. All diseases that are considered primary tauopathies have in common the abnormal deposition of aggregated tau in the brain. There are other diseases in which tau deposition can be observed, but for one reason or another, tau either coexists with another protein or is not considered to be associated with the primary neurodegenerative process. Diseases in the latter category include Alzheimer disease in which β-amyloid is also present,
Tau can be detected at autopsy with immunohistochemical techniques that use specific antibodies that recognize different epitopes of tau. One of the most recent advances in the field has been the development of radioligands that can detect tau in the brain in vivo via positron emission tomography. In this review, I will discuss tau biology, clinical and pathological diagnosis of primary tauopathies, and recent advances in research related to primary tauopathies.
Table 1List of Entities Considered Primary Tauopathies
3R = tau isoform with 3 repeats in the microtubule-binding domain; 4R = tau isoform with 4 repeats in the microtubule-binding domain; 3R+4R = mixed 3 and 4 repeat tau isoforms.
This diagnosis now includes the entity previously known as tangle dominant dementia.
3R+4R
Parkinsonism-dementia complex of Guam
3R+4R
Postencephalitic parkinsonism
3R+4R
Atypical parkinsonism of Guadeloupe
3R+4R
Diffuse neurofilament tangles with calcification
3R+4R
Frontotemporal dementia and parkinsonism linked to chromosome 17
3R, 4R, or 3R+4R
a 3R = tau isoform with 3 repeats in the microtubule-binding domain; 4R = tau isoform with 4 repeats in the microtubule-binding domain; 3R+4R = mixed 3 and 4 repeat tau isoforms.
b This diagnosis now includes the entity previously known as tangle dominant dementia.
Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2.
Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau.
Microtubules are important for axonal transport and for maintaining the structural integrity of the cell. In the adult brain, tau is located within neurons, predominantly within axons.
The tau amino acid sequence can essentially be divided into 4 compartments: the N-terminal domain, a proline-rich domain, a microtubule-binding domain, and the C-terminal domain.
The N-terminal domain is important to provide spacing between the microtubules. The proline-rich domain is important in cell signaling and interactions with protein kinases. The microtubule-binding domain is important for binding to the microtubule. The C-terminal domain is important in regulating microtubule polymerization. The binding of tau to the microtubule is extremely important. In fact, binding can induce tau conformational change.
In its normal form, tau is unfolded and phosphorylated whereas its abnormal form, found in the brains of patients with primary tauopathies, is characterized by hyperphosphorylated and aggregated tau that has a β-pleated sheet conformation.
It is currently thought that hyperphosphorylation of tau results in a loss of tau interaction with microtubules, leading to microtubule dysfunction and impaired axonal transport as well as to tau fibrillization. Recently, it has been suggested that the primary problem with hyperphosphorylated tau results from an increase in the proportion of tau sequences that are phosphorylated, as opposed to an increase in the number of phosphorylated epitopes on each tau sequence.
Three of the 6 isoforms are due to the splicing in of exon 10, whereas the other 3 isoforms are a result of the splicing out of exon 10. The splicing in of exon 10 results in isoforms with 4 repeated microtubule-binding domains, whereas the splicing out of exon 10 results in isoforms with 3 repeated microtubule-binding domains. This is important because although the healthy human brain consists of equal amounts of tau with 3 and 4 repeated microtubule-binding domains, some primary tauopathies are characterized by a predominance of isoforms with 4 repeated microtubule-binding domains (4R tauopathies), some by a predominance of isoforms with 3 repeated microtubule-binding domains (3R tauopathies), and some by an approximately equal mix of isoforms with 3 and 4 repeated microtubule-binding domains (3R+4R tauopathies) (Table 1).
Pathological Diagnosis of Primary Tauopathies
The pathological diagnosis of a primary tauopathy is complex. It depends not only on the immunohistochemical demonstration of abnormal tau deposition in the brain but also on the presence or absence and amount of other non-tau proteins in the brain, the distribution of the abnormal tau that is deposited, and the morphological characteristics of the tau in different regions of the brain. Furthermore, diagnosis may depend on the predominant tau isoform that is present, although this is not always straightforward. For example, Pick disease is typically thought of as a 3R primary tauopathy because neuronal tau in Pick disease is primarily 3R tau.
Hence, one has to be careful when sampling tissue for biochemical tau analyses for diagnosis. It should also be stressed that although we consider these diseases to be primary tauopathies, in most instances there are pathologies present in addition to the primary tau pathology. In some instances, 3 or more pathologies may coexist. It is not uncommon, for example, to have a primary tauopathy such as progressive supranuclear palsy or primary age-related tauopathy
In some instances there may be β-amyloid deposition in addition to the primary tauopathy, which may not necessarily signify Alzheimer disease. Furthermore, protein pathology may be accompanied by vascular pathology. It is, therefore, not surprising that the clinical phenotypes do not always match perfectly with what one expects on the basis of pathological diagnosis that tends to focus on the so-called leading pathology.
Age-Related Tauopathies
Before discussing diseases that are considered primary tauopathies, it is worth mentioning that the presence of tau and hence a tauopathy is not always considered a disease process. Three age-related tauopathies are worth further discussion: argyrophilic grain disease, primary age-related tauopathy, and aging-related tau astrogliopathy. Argyrophilic grain disease, as the name implies, indicates that its presence is not normal or solely due to aging. Argyrophilic grain disease is characterized by the presence of silver-positive grain–like structures identified primarily in the medial temporal lobe. To date, there is no definitive clinical feature associated with the presence of this pathology. Hence, it remains to determine whether argyrophilic grain disease is truly a neurodegenerative disease. The term primary age-related tauopathy was recently coined.
It refers to the presence of tau deposition in neurons within limbic structures of the brain in the absence of, or minimal presence of, β-amyloid deposition. Primary age-related tauopathy is considered by most, although not all, distinct from Alzheimer disease. Recently, it was found that primary age-related tauopathy is associated with subtle cognitive slowing and executive dysfunction as well as atrophy of the left anterior hippocampus.
Tau aggregation influences cognition and hippocampal atrophy in the absence of beta-amyloid: a clinico-imaging-pathological study of primary age-related tauopathy (PART).
Hence, it appears that this pathology may not truly be indicative of tau deposition solely from normal aging. Unlike primary age-related tauopathy in which tau is deposited in neurons, aging-related tau astrogliopathy is characterized by tau deposition in astrocytes. Currently, there is no clinical correlate of aging-related tau astrogliopathy.
Clinical Diagnosis of Diseases Considered Primary Tauopathies
Without specific biomarkers, it is difficult to make a diagnosis that is 100% predictive of an underlying tauopathy. Table 2 provides a list of common presenting signs and symptoms and whether their presence is suggestive of an underlying tauopathy. As can be seen, most signs and symptoms by themselves are not going to be helpful in predicting an underlying tauopathy with any degree of certainty. Instead, it has become clear that recognition of a profile or constellation of signs and symptoms is more helpful than linking a specific sign or symptom in predicting an underlying tauopathy. This profile or constellation of signs and symptoms is better known as a syndrome. Hence, to best predict an underlying tauopathy, in the absence of a specific biomarker, we have now come to rely on the recognition of specific syndromes that are highly suggestive of a tauopathy. The following 3 syndromes are highly suggestive of, although not pathognomonic for, a tauopathy diagnosis: Richardson syndrome, primary progressive apraxia of speech, and corticobasal syndrome.
Table 2List of Clinical Signs and Symptoms and Their Association With an Underlying Tauopathy
Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism.
and hence suggestive of an underlying primary tauopathy. This syndrome is characterized by the insidious onset and progression of gait and balance problems leading to unexplained falls. Typically, patients with Richardson syndrome will have additional symptoms present at onset, including sensitivity to bright light, dizziness, a hoarse raspy voice, neck stiffness, an unusual facial appearance with the eyebrows elevated, and a general slowing down of movements. Patients may be described as having a loss of general interest in people about them or apathy. Resting tremor and loss of memory are not present, arguing against a diagnosis of Parkinson disease and Alzheimer disease, respectively. Neurological examination reveals the presence of executive dysfunction (evidence of disorganization and poor planning) and a relatively symmetric akinetic rigid syndrome. There is a loss of postural reflexes, axial rigidity (neck and trunk rigidity), and loss of, or slowness of, vertical eye movements to commands but relatively preserved eye movements with the dolls eye maneuver (supranuclear gaze palsy). Treatment with high doses of carbidopa or levodopa (>600 mg) and similar agents are typically unhelpful with an absence of any clinically meaningful response.
Primary Progressive Apraxia of Speech
Primary progressive apraxia of speech is also characterized by an insidious onset and worsening of symptoms over time.
The main clinical features are slow effortful speech sometimes associated with difficulty articulating words, leading to the production of either distorted sounds or the substitution of normal sounds with distorted sounds or speech output with lengthened intersegment durations between syllables, words, or phrases.
Sometimes one may observe groping movements of the tongue and mouth and multiple trials to produce the intended sounds. Currently, 2 variants of primary progressive apraxia of speech are recognized: a phonetic variant in which articulatory errors dominate (type 1) and a prosodic variant in which a slowed speech output is typical (type 2).
Language characteristics including syntax, grammar, comprehension, and naming are intact. Hence, the patient easily understands spoken and written sentences and word meaning. Over time primary progressive apraxia of speech evolves, and after 6 to 7 years many patients develop features that begin to look more like Richardson syndrome.
In other patients, aphasia develops and progressively gets worse in the absence of features typical of Richardson syndrome. Regardless, eventually all patients with primary progressive apraxia of speech become mute, although communication by other means such as writing, gesticulating, typing, texting, or signing remains in intact.
Corticobasal Syndrome
The corticobasal syndrome is the third syndrome that is also strongly associated with an underlying tauopathy
The corticobasal syndrome is characterized by the presence of asymmetric clinical features that suggest a combination of cortical and subcortical (basal ganglia) pathologies. Cortical dysfunction can manifest as the alien limb phenomenon
(in which the patient has lost control over a limb) attributed to involvement of sensory motor cortices and connections. Patients may personify their limb and sometimes will refer to their limb as “my little friend.” Another typical feature is the presence of limb apraxia in which the patient may not be able to perform a task that previously could be performed in the absence of motor weakness. For example, a patient may not know how to use a screw driver to drive a screw having done so for decades before. Some patients may manifest unwanted movements of other body parts (eg, opening and closing of the mouth with alternating movements of the hand) and may have cortical sensory loss and agraphesthesia (difficulty recognizing a number or a letter that is traced in the palm of the hand). Myoclonus (quick involuntary jerks) and dystonia (abnormal posturing) may be observed. Basal ganglia–related features must also be present and may include asymmetric limb rigidity and/or akinesia (decreased speed of movement), with little significant or sustained improvement from levodopa therapy. Although not always present, cortical dysfunction of the frontal and temporal lobes may manifest as executive dysfunction, behavioral or personality change, or aphasia (language impairment).
Other Clinical Features and Syndromes
Other clinical syndromes can also be associated with a primary tauopathy. However, many of these other clinical syndromes are less specific and hence are equally likely, or even more likely, to be associated with another neurodegenerative process in which tau is not considered the primary problem. These include the behavioral variant of frontotemporal dementia (in which patients present with behavioral and personality change),
the logopenic variant of primary progressive aphasia (in which patients present with language and other problems affecting naming, word retrieval, working memory, and calculations),
and semantic dementia (in which patients present with a loss of object knowledge, eg, not knowing that a zebra has stripes or that a carrot is orange in color).
are rarely associated with a primary tauopathy. One clinical feature that merits further discussion is that of head trauma. Chronic head trauma has been associated with the primary tauopathy and chronic traumatic encephalopathy. This pathology was recently characterized as the accumulation of the abnormal tau in neurons and glial cells that are located predominantly around small blood vessels at the depths of cortical sulci and in an irregular pattern.
Currently, there are many unanswered questions about chronic traumatic encephalopathy, and other than head injury “at some point in time,” there is little clinical data associated with this primary tauopathy.
Clinically Available Diagnostic Tests
At the present time, there is no clinically available test that is specific to an underlying tauopathy. There are, however, some tests that may be more suggestive of any underlying tauopathy than do others that are worth discussing. There are no blood tests that can determine whether a patient has an underlying tauopathy. Some studies have suggested that measuring tau levels, total tau levels, and phosphorylated tau levels in the cerebrospinal fluid may provide support for an underlying tauopathy.
In contrast, neuroimaging modalities may provide some help when considering a diagnosis of a tauopathy. There are a handful of clinically useful findings on magnetic resonance imaging (MRI) and on molecular imaging that, although not specific, can provide some help in making a diagnosis of a tauopathy. Magnetic resonance imaging head scan is typically performed to exclude the presence of structural lesions that could account for presenting syndromes suggestive of an underlying tauopathy. However, MRI also reveals anatomical patterns of involvement that are somewhat useful in diagnosing a tauopathy. One such feature is the presence of midbrain atrophy, particularly in the absence of atrophy of the pons,
are also strongly associated with, and hence suggestive of, the presence of an underlying tauopathy. Striking atrophy (referred to as knife-edge atrophy) of the frontal and temporal lobes on MRI (Figure 1) can be a feature of Pick disease,
and hence when this characteristic pattern of atrophy is present, it is suggestive of an underlying 3R tauopathy. Asymmetric frontoparietal atrophy (Figure 1) is somewhat suggestive of the underlying corticobasal degeneration pathology. In addition to MRI, [18F]fluorodeoxyglucose positron emission tomography may provide clues to the presence of an underlying tauopathy.
In addition, sometimes there is a subtle hypometabolic track between the midbrain and the cerebellum, likely reflecting atrophy of the superior cerebellar peduncles that may also be present (Figure 2). Other features suggestive of an underlying tauopathy include focal hypometabolism of the lateral premotor and supplementary motor cortices
(Figure 2). It must be pointed out, however, that all the abnormalities discussed relating to MRI or [18F]fluorodeoxyglucose positron emission tomography are less than 100% sensitive and specific for diagnosing an underlying primary tauopathy.
Figure 1T1-weighted magnetic resonance imaging features suggestive of an underlying primary tauopathy include the hummingbird sign resulting from atrophy of the dorsal midbrain and preserved pons (A, bottom image), suggestive of progressive supranuclear palsy; asymmetric parietal atrophy (right greater than left), suggestive of corticobasal degeneration (B, bottom image); and striking atrophy of the prefrontal cortex and anterior temporal lobe with secondary ventricular enlargement (worse on the left), suggestive of Pick disease (C, bottom image). Top images are normal magnetic resonance imaging scans for comparison.
Figure 2[18F]Fluorodeoxyglucose positron emission tomography scan using the CortexID Suite software (GE Healthcare) reveals mild hypometabolism of the left posterior frontal cortex, bilateral supplemental motor cortices, midbrain, superior cerebellar peduncle, and right cerebellum in a patient with Richardson syndrome (top row) and mild hypometabolism in bilateral posterior frontal cortices and right supplemental motor cortex in a patient with primary progressive apraxia of speech (bottom row), suggestive of an underlying primary tauopathy.
At present, there are no disease-modifying therapies for treating tauopathies. Treatment of tauopathies focuses on alleviating or ameliorating symptoms for which treatment exists. Unfortunately, many symptoms and signs, albeit debilitating, are untreatable. Medications are ineffective to ameliorate parkinsonism, and hence patients do not typically respond to dopamine-targeted treatments. Management is complex, however, and one has to target whatever symptom is most bothersome to patients and their careers. For example, a patient with an underlying tauopathy and a Richardson syndrome presentation may be most bothered by bright lights (photosensitivity).
Photophobia, visual hallucinations, and REM sleep behavior disorder in progressive supranuclear palsy and corticobasal degeneration: a prospective study.
Management would simply be having the patient wear dark sun glasses that prevent exposure to bright light. Hence, management of photosensitivity is not specific to photosensitivity in tauopathies but photosensitivity in general. Because almost any symptom can be associated with an underlying tauopathy, detailed and specific management of each and every symptom and sign is beyond the scope of this review. Table 3 provides a list of symptoms commonly observed in the primary tauopathy and general guidance on management of such symptoms. Some symptoms that are typically encountered in tauopathies that may respond relatively well to pharmacological treatments include depression, anxiety, myoclonus, pathological crying/laughing, and insomnia. Others including vertigo, diplopia (double vision), dystonia, parkinsonism, poor appetite, and weight loss are difficult to treat and may not respond to any available treatment. There are also nonpharmacological options that should be offered to patients with suspected tauopathy.
Physical therapy for gait and balance problems is useful to prevent a faster decline in motor function but will not reverse any loss of function. Speech therapy is helpful in patients with progressive apraxia of speech, and a swallow evaluation is critical for any patient who is having trouble swallowing. A simple maneuver such as tucking the chin when swallowing can help reduce the risk of aspiration. Patients who are mute can benefit from the usage of devices that allow communication in the absence of marked to severe aphasia or motor dysfunction of the limbs, which typically can occur later in the disease course.
Table 3List of Symptoms That Commonly Occur in Primary Tauopathies and Associated Management Likely to Provide Some Benefit
Symptom
Management
Postural tremor
β-Blockers
Slowness of movements
Dopamine
Muscle stiffness
Dopamine
Sensitivity to bright lights
Wearing dark sun glasses
Involuntary eye closure
Botox
Neck pain associated with dystonia
Botox
Drooling
Botox of salivary glands
Trouble with balance and falls
Physical and occupational therapy
Trouble swallowing
Swallow evaluation
Choking while eating or drinking
Swallow evaluation
Dysarthria or apraxia of speech
Speech therapy
Excessive tearing (lacrimation)
Artificial tears multiple times daily
Difficulty falling or staying asleep
Proper sleep hygiene and behavioral and pharmacologic management
Excessive daytime sleepiness
Caffeine and proper sleep hygiene
Depression
Antidepressants
Anxiety
Anxiolytics
Emotional incontinence (laughs/cries excessively)
Antidepressants and dextromethorphan/quinidine (Nuedexta)
There is some evidence that primary tauopathies may have genetic links. The chromosomal region containing the microtubule-associated protein tau gene includes 2 major haplotypes—H1 and H2—which are essentially defined by linkage disequilibrium between several polymorphisms over the entire gene.
Linkage disequilibrium fine-mapping analysis has further revealed an association between primary tauopathies and the microtubule-associated protein tau H1c haplotype, which is a variant of the H1 haplotype.
A large genome-wide association study of the primary tauopathy progressive supranuclear palsy discovered previously unidentified signals associated with progressive supranuclear palsy,
although none have been subsequently shown to have any relevance.
Recent Advances in Tau Research
Tau Positron Emission Tomography
The determination of whether a patient has one of the primary tauopathies typically occurs at the time of autopsy after the patient has died. Recently, however, there has been a development of in vivo positron emission tomography radiotracers that allows the detection of tau in the brain in vivo. Previously, there were only tracers that allowed the in vivo detection of β-amyloid.
Unfortunately, because of many unwanted adverse effects and other problems with these tracers such as toxic metabolites, many of these tracers have not been successfully translated into research. Of the tracers that have been tested, 1 tracer that has been successfully integrated into research is [18F]AV-1451 (a type of ligand that selectively binds to tau).
Autoradiographic studies have found that [18F]AV-1451 selectively binds to tau; does not bind to other proteins such as β-amyloid, α-synuclein, and others; and is safe for human studies.
Characterization of tau positron emission tomography tracer [F]AV-1451 binding to postmortem tissue in Alzheimer's disease, primary tauopathies, and other dementias.
Many studies have now found that AV-1451 can detect 3R+4R tau isoforms and hence is a good biomarker to study Alzheimer disease, which is characterized by the presence of 3R+4R tau.
Unfortunately, AV-1451 does not look as promising to detect isolated 3R or 4R tau. There is relatively little observed binding to tau in primary tauopathies compared with Alzheimer disease
(Figure 3). Furthermore, there appears to be off-target binding in the basal ganglia, midbrain, and elsewhere with AV-1451, regions that are critically involved in 4R tauopathies
(Figure 3). Therefore, AV-1451 may not be a good biomarker for primary tauopathies. Two other tau tracers have also been used in research. Unfortunately, none of them have proven to be superior to AV-1451 for studying primary tauopathies. Having said that, PBB3 (a type of ligand that selectively binds to tau) may have the ability to detect a wider range of primary tauopathies because of more robust binding to 4R tau isoforms.
The second tau tracer THK5351 (a type of ligand that selectively binds to tau) has also been used in patients suspected of having an underlying primary tauopathy with results similar to those of AV-1451,
although binding may be targeting dopamine-related receptors and not tau.
Figure 3[18F]AV-1451 tau positron emission tomography shows minimal uptake in a normal (control) patient (top row); mild-moderate uptake in the dentate nucleus of the cerebellum, midbrain, and basal ganglia in a patient with progressive supranuclear palsy (PSP); a primary 4R tauopathy (middle row); and striking uptake in the cortex in a patient with typical Alzheimer disease (AD), a 3R+4R tauopathy, for comparison (bottom row).
Over the past decade, one area of tau research that has dominated the field is whether tau has prion-like properties and can propagate from cell to cell and beyond.
in 1982 to describe the infectious transmissibility of a proteinaceous particle. The concept of tau being prion-like may date to the idea that tau, in the form of neurofibrillary tangles, has a stereotypic pattern of spread throughout the brain in Alzheimer disease when the Braak staging scheme
was published. This staging scheme, although developed from cross-sectional analysis, suggests that tau first deposits in the transentorhinal cortex before spreading to the hippocampus proper and then in multimodal and unimodal cortices. Adding fuel to the fire was the demonstration that hyperphosphorylated tau could recruit or seed normal tau to assemble into filamentous aggregates.
More recently, 3 important areas of study have been published that further promotes this idea. The first provided some evidence that extracellular tau may be able to enter cells and promote tau aggregation inside the cell.
This notion of prion-like behavior of tau is contentious, however, given the lack of transmission like an infection, with many researchers opposing the notion that the behavior of tau mirrors that of the prion proteins of spongiform encephalopathy.
There are many different approaches being directed at treating tauopathies. These approaches include stabilizing microtubules, decreasing hyperphosphorylated tau, inhibiting protein kinases, inhibiting aggregation of tau fibrils, and enhancing intracellular tau degradation. Four different agents have been tested so far in human phase I to III trials, including methylene blue, riluzole,
Such immunotherapies involve both active and passive live attenuated vaccine approaches, with antibodies being developed that target full-length tau, tau fragments, or specific epitopes of tau.
Two areas of active tauopathy research that will likely define the near future are the continued development of biomarkers that can detect in vivo tau and the development of compounds or antibodies for clinical trials that target tau. In addition, one would expect the continued development of mouse models to better represent primary tauopathies and genetic studies to identify genetic influences that either account for disease or provide a model to study disease. Most of these research endeavors will likely focus on Alzheimer disease, given the higher prevalence of this disease, growing elderly population, heightened awareness, financial burden to society, and potential financial gains associated with discoveries, although there is some research that is now focused on primary tauopathies, particularly progressive supranuclear palsy. Focusing on primary tauopathies is critical, as it is unclear whether any biomarker- or treatment-developed targeting non–primary tauopathies such as Alzheimer disease will also be equally applicable to primary tauopathies.
Conclusion
Primary tauopathies represent a group of pathological entities in which most, but not all, are considered a type of neurodegenerative disease. All primary tauopathies are associated with the deposition of the abnormal hyperphosphorylated tau protein. There are a few clinical features that are highly suggestive of an underlying primary tauopathy, but there are no perfect clinical or neuroimaging biomarkers that are able to accurately and robustly detect and differentiate the different types of primary tauopathies. Basic research related to primary tauopathies include mouse and fly models as well as studies at the cellular level, with some researchers suggesting that tauopathies are prion-like diseases. At present there are no disease-modifying treatments, although clinical trials have begun to focus more on primary tauopathies.
Acknowledgments
I acknowledge Jennifer L. Whitwell, PhD (Department of Radiology, Mayo Clinic, Rochester, MN), for creating and providing Figure 1, Figure 2, Figure 3.
Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2.
Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau.
Tau aggregation influences cognition and hippocampal atrophy in the absence of beta-amyloid: a clinico-imaging-pathological study of primary age-related tauopathy (PART).
Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism.
Photophobia, visual hallucinations, and REM sleep behavior disorder in progressive supranuclear palsy and corticobasal degeneration: a prospective study.
Characterization of tau positron emission tomography tracer [F]AV-1451 binding to postmortem tissue in Alzheimer's disease, primary tauopathies, and other dementias.
Grant Support: The work was supported by grants R01 NS89757 , R01 AG037491 , and R21 NS94684 from the National Institutes of Health .
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