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Current Understanding of Neurodegenerative Diseases Associated With the Protein Tau

      Abstract

      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.

      Abbreviations and Acronyms:

      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), MRI (magnetic resonance imaging)
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      Learning Objectives: On completion of this article, you should be able to (1) describe how tau biology and pathology relate to specific neurodegenerative diseases; (2) recognize the complex relationship between clinical diagnosis and underlying pathologies and predict pathology on the basis of the presenting clinical syndrome; and (3) summarize the current status of the field in terms of the prion-like hypothesis of tau, the newly available tau positron emission tomography scan that can detect antemortem tau, and what kinds of treatment approaches are currently being tried for primary tauopathies.
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      In their editorial and administrative roles, Karl A. Nath, MBChB, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the content of this program but have no relevant financial relationship(s) with industry.
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      Tauopathy is an umbrella term that subsumes many different entities, all characterized by the abnormal deposition of tau in the brain.
      • Josephs K.A.
      • Hodges J.R.
      • Snowden J.
      • et al.
      Neuropathological background of phenotypical variability in frontotemporal dementia.
      • Arendt T.
      • Stieler J.T.
      • Holzer M.
      Tau and tauopathies.
      • Spillantini M.G.
      • Goedert M.
      • Crowther R.A.
      • Murrell J.R.
      • Farlow M.R.
      • Ghetti B.
      Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments.
      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,
      • Braak H.
      • Braak E.
      Neuropathological staging of Alzheimer-related changes.
      • Hyman B.T.
      • Phelps C.H.
      • Beach T.G.
      • et al.
      National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease.
      Lewy body disease in which α-synuclein is also present,
      • McKeith I.G.
      • Dickson D.W.
      • Lowe J.
      • et al.
      Consortium on DLB
      Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.
      myotonic dystrophy,
      • Spillantini M.G.
      • Tolnay M.
      • Love S.
      • Goedert M.
      Microtubule-associated protein tau, heparan sulphate and alpha-synuclein in several neurodegenerative diseases with dementia.
      subacute sclerosing panencephalitis,
      • Spillantini M.G.
      • Tolnay M.
      • Love S.
      • Goedert M.
      Microtubule-associated protein tau, heparan sulphate and alpha-synuclein in several neurodegenerative diseases with dementia.
      Down syndrome,
      • Bussière T.
      • Hof P.R.
      • Mailliot C.
      • et al.
      Phosphorylated serine422 on tau proteins is a pathological epitope found in several diseases with neurofibrillary degeneration.
      and Niemann-Pick disease type C.
      • Spillantini M.G.
      • Tolnay M.
      • Love S.
      • Goedert M.
      Microtubule-associated protein tau, heparan sulphate and alpha-synuclein in several neurodegenerative diseases with dementia.
      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.
      Current pathological diagnosisType of tauopathy
      Pick disease3R
      Progressive supranuclear palsy4R
      Corticobasal degeneration4R
      Argyrophilic grain disease4R
      Globular glial tauopathies4R
      Aging-related tau astrogliopathy4R
      Chronic traumatic encephalopathy3R+4R
      Primary age-related tauopathy
      This diagnosis now includes the entity previously known as tangle dominant dementia.
      3R+4R
      Parkinsonism-dementia complex of Guam3R+4R
      Postencephalitic parkinsonism3R+4R
      Atypical parkinsonism of Guadeloupe3R+4R
      Diffuse neurofilament tangles with calcification3R+4R
      Frontotemporal dementia and parkinsonism linked to chromosome 173R, 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.

      Tau Biology

      Tau is encoded by the microtubule-associated protein tau gene which is located on chromosome 17q21.
      • Neve R.L.
      • Harris P.
      • Kosik K.S.
      • Kurnit D.M.
      • Donlon T.A.
      Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2.
      • Goedert M.
      • Wischik C.M.
      • Crowther R.A.
      • Walker J.E.
      • Klug A.
      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 is a microtubule-associated protein that functions in the stabilization and assembly of microtubules.
      • Weingarten M.D.
      • Lockwood A.H.
      • Hwo S.Y.
      • Kirschner M.W.
      A protein factor essential for microtubule assembly.
      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.
      • Kempf M.
      • Clement A.
      • Faissner A.
      • Lee G.
      • Brandt R.
      Tau binds to the distal axon early in development of polarity in a microtubule- and microfilament-dependent manner.
      Tau is also found in oligodendrocytes and astrocytes in which its function is similar to its function in neurons.
      • Papasozomenos S.C.
      • Binder L.I.
      Phosphorylation determines two distinct species of Tau in the central nervous system.
      • LoPresti P.
      • Szuchet S.
      • Papasozomenos S.C.
      • Zinkowski R.P.
      • Binder L.I.
      Functional implications for the microtubule-associated protein tau: localization in oligodendrocytes.
      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.
      • Arendt T.
      • Stieler J.T.
      • Holzer M.
      Tau and tauopathies.
      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.
      • Woody R.W.
      • Clark D.C.
      • Roberts G.C.
      • Martin S.R.
      • Bayley P.M.
      Molecular flexibility in microtubule proteins: proton nuclear magnetic resonance characterization.
      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.
      • Uversky V.N.
      What does it mean to be natively unfolded?.
      • Jeganathan S.
      • von Bergen M.
      • Mandelkow E.M.
      • Mandelkow E.
      The natively unfolded character of tau and its aggregation to Alzheimer-like paired helical filaments.
      The binding of tau to microtubules is regulated by the phosphorylation/dephosphorylation equilibrium of tau.
      • Lindwall G.
      • Cole R.D.
      Phosphorylation affects the ability of tau protein to promote microtubule assembly.
      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.
      • Morris M.
      • Knudsen G.M.
      • Maeda S.
      • et al.
      Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice.
      Not all tau sequences are created equal. There are 6 isoforms of tau that are expressed in the adult brain.
      • Goedert M.
      • Spillantini M.G.
      • Jakes R.
      • Rutherford D.
      • Crowther R.A.
      Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease.
      These 6 isoforms are derived from the alternative splicing of 3 N-terminal exons in the tau gene: exon 2, exon 3, and exon 10.
      • Goedert M.
      • Spillantini M.G.
      • Jakes R.
      • Rutherford D.
      • Crowther R.A.
      Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease.
      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.
      • Delacourte A.
      • Sergeant N.
      • Wattez A.
      • Gauvreau D.
      • Robitaille Y.
      Vulnerable neuronal subsets in Alzheimer's and Pick's disease are distinguished by their tau isoform distribution and phosphorylation.
      However, glial pathology in Pick disease is predominantly 4R tau.
      • Hogg M.
      • Grujic Z.M.
      • Baker M.
      • et al.
      The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy.
      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
      • Crary J.F.
      • Trojanowski J.Q.
      • Schneider J.A.
      • et al.
      Primary age-related tauopathy (PART): a common pathology associated with human aging.
      coexisting with argyrophilic grain disease, another tauopathy.
      • Togo T.
      • Sahara N.
      • Yen S.H.
      • et al.
      Argyrophilic grain disease is a sporadic 4-repeat 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.
      • Crary J.F.
      • Trojanowski J.Q.
      • Schneider J.A.
      • et al.
      Primary age-related tauopathy (PART): a common pathology associated with human aging.
      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.
      • Josephs K.A.
      • Murray M.E.
      • Tosakulwong N.
      • et al.
      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
      + = highly suggestive of the underlying primary tauopathy; ± = equivocal; − = argues against the underlying primary tauopathy.
      Specific signs and symptomsAssociation with tauopathy
      Motor
       Vertical supranuclear gaze palsy+
       Axial rigidity+
       Unexplained falls+
       Speech apraxia+
       Limb apraxia±
       Dysarthria±
       Stiffness of muscles±
       Dystonia±
       Action myoclonus±
       Early gait freezing (freezing while trying to walk)±
       Resting tremor
       Ataxia
       Weakness of limb
      Cognitive and behavioral
       Memory loss±
       Behavioral and/or personality change±
       Limb apraxia±
       Spatial/perceptual deficits
      Only rarely associated with a primary tauopathy.
       Aphasia in the absence of speech apraxia_
       Problems with calculations_
       Loss of word or object knowledge_
       Loss of facial recognition_
      Other
       Depression/anxiety±
       Head trauma±
       Constipation±
       Loss of smell±
       Urinary incontinence±
       Orthostatic hypotension
       Fasciculation_
       Rapid eye movement sleep behavior disorder
       Delusions (eg, Capgras and Othello)_
       Visual/auditory/tactile hallucinations_
      a + = highly suggestive of the underlying primary tauopathy; ± = equivocal; − = argues against the underlying primary tauopathy.
      b Only rarely associated with a primary tauopathy.

      Richardson Syndrome

      Richardson syndrome is the classic presenting syndrome suggestive of a pathological diagnosis of progressive supranuclear palsy
      • Williams D.R.
      • de Silva R.
      • Paviour D.C.
      • et al.
      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.
      • Josephs K.A.
      • Duffy J.R.
      • Strand E.A.
      • et al.
      Characterizing a neurodegenerative syndrome: primary progressive apraxia of speech.
      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.
      • Duffy J.R.
      Apraxia of speech in degenerative neurologic disease.
      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).
      • Josephs K.A.
      • Duffy J.R.
      • Strand E.A.
      • et al.
      Syndromes dominated by apraxia of speech show distinct characteristics from agrammatic PPA.
      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.
      • Josephs K.A.
      • Duffy J.R.
      • Strand E.A.
      • et al.
      The evolution of primary progressive apraxia of speech.
      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
      • Armstrong M.J.
      • Litvan I.
      • Lang A.E.
      • et al.
      Criteria for the diagnosis of corticobasal degeneration.
      ; although of all the 3 syndromes discussed, it may be the least specific to an underlying primary tauopathy.
      • Josephs K.A.
      • Hodges J.R.
      • Snowden J.
      • et al.
      Neuropathological background of phenotypical variability in frontotemporal dementia.
      • Ling H.
      • O'Sullivan S.S.
      • Holton J.L.
      • et al.
      Does corticobasal degeneration exist? A clinicopathological re-evaluation.
      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
      • Hassan A.
      • Josephs K.A.
      Alien hand syndrome.
      (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),
      • Rascovsky K.
      • Hodges J.R.
      • Knopman D.
      • et al.
      Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.
      the logopenic variant of primary progressive aphasia (in which patients present with language and other problems affecting naming, word retrieval, working memory, and calculations),
      • Gorno-Tempini M.L.
      • Hillis A.E.
      • Weintraub S.
      • et al.
      Classification of primary progressive aphasia and its variants.
      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).
      • Warrington E.K.
      The selective impairment of semantic memory.
      Other classic clinical syndromes such as dementia with Lewy bodies (in which dementia, parkinsonism, and psychoses occur in any combination)
      • McKeith I.G.
      • Dickson D.W.
      • Lowe J.
      • et al.
      Consortium on DLB
      Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.
      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.
      • McKee A.C.
      • Cairns N.J.
      • Dickson D.W.
      • et al.
      TBI/CTE Group
      The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy.
      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.
      • Borroni B.
      • Gardoni F.
      • Parnetti L.
      • et al.
      Pattern of Tau forms in CSF is altered in progressive supranuclear palsy.
      Others report no association between cerebrospinal fluid tau levels and the presence or absence of an underlying tauopathy.
      • Kuiperij H.B.
      • Verbeek M.M.
      Tau forms in CSF as a reliable biomarker for progressive supranuclear palsy.
      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,
      • Massey L.A.
      • Micallef C.
      • Paviour D.C.
      • et al.
      Conventional magnetic resonance imaging in confirmed progressive supranuclear palsy and multiple system atrophy.
      • Oba H.
      • Yagishita A.
      • Terada H.
      • et al.
      New and reliable MRI diagnosis for progressive supranuclear palsy.
      although this is not a sensitive marker of pathology.
      • Whitwell J.L.
      • Jack Jr., C.R.
      • Parisi J.E.
      • et al.
      Midbrain atrophy is not a biomarker of progressive supranuclear palsy pathology.
      This is sometimes referred to as the hummingbird sign because of a reduction in the anterior-posterior diameter of the midbrain
      • Gröschel K.
      • Kastrup A.
      • Litvan I.
      • Schulz J.B.
      Penguins and hummingbirds: midbrain atrophy in progressive supranuclear palsy.
      (Figure 1). Atrophy, seen as flattening of the superior colliculi, and atrophy of the superior cerebellar peduncles
      • Paviour D.C.
      • Price S.L.
      • Stevens J.M.
      • Lees A.J.
      • Fox N.C.
      Quantitative MRI measurement of superior cerebellar peduncle in progressive supranuclear palsy.
      • Tsuboi Y.
      • Slowinski J.
      • Josephs K.A.
      • Honer W.G.
      • Wszolek Z.K.
      • Dickson D.W.
      Atrophy of superior cerebellar peduncle in progressive supranuclear palsy.
      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,
      • Whitwell J.L.
      • Josephs K.A.
      • Rossor M.N.
      • et al.
      Magnetic resonance imaging signatures of tissue pathology in frontotemporal dementia.
      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.
      • Zalewski N.
      • Botha H.
      • Whitwell J.L.
      • Lowe V.
      • Dickson D.W.
      • Josephs K.A.
      FDG-PET in pathologically confirmed spontaneous 4R-tauopathy variants.
      Atrophy of the midbrain results in a focal signal of hypometabolism in the midbrain (Figure 2) known as the pimple sign.
      • Botha H.
      • Whitwell J.L.
      • Madhaven A.
      • Senjem M.L.
      • Lowe V.
      • Josephs K.A.
      The pimple sign of progressive supranuclear palsy syndrome.
      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
      • Zalewski N.
      • Botha H.
      • Whitwell J.L.
      • Lowe V.
      • Dickson D.W.
      • Josephs K.A.
      FDG-PET in pathologically confirmed spontaneous 4R-tauopathy variants.
      (Figure 2), as well as frontoparietal and caudate hypometabolism occurring together
      • Josephs K.A.
      • Whitwell J.L.
      • Tacik P.
      • et al.
      [18F]AV-1451 tau-PET uptake does correlate with quantitatively measured 4R-tau burden in autopsy-confirmed corticobasal degeneration.
      (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 thumbnail gr1
      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 thumbnail gr2
      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.

      Management of Tauopathies

      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).
      • Cooper A.D.
      • Josephs K.A.
      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.
      • Tilley E.
      • McLoughlin J.
      • Koblar S.A.
      • et al.
      Effectiveness of allied health therapy in the symptomatic management of progressive supranuclear palsy: a systematic review.
      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
      SymptomManagement
      Postural tremorβ-Blockers
      Slowness of movementsDopamine
      Muscle stiffnessDopamine
      Sensitivity to bright lightsWearing dark sun glasses
      Involuntary eye closureBotox
      Neck pain associated with dystoniaBotox
      DroolingBotox of salivary glands
      Trouble with balance and fallsPhysical and occupational therapy
      Trouble swallowingSwallow evaluation
      Choking while eating or drinkingSwallow evaluation
      Dysarthria or apraxia of speechSpeech therapy
      Excessive tearing (lacrimation)Artificial tears multiple times daily
      Difficulty falling or staying asleepProper sleep hygiene and behavioral and pharmacologic management
      Excessive daytime sleepinessCaffeine and proper sleep hygiene
      DepressionAntidepressants
      AnxietyAnxiolytics
      Emotional incontinence (laughs/cries excessively)Antidepressants and dextromethorphan/quinidine (Nuedexta)
      Loss of sex drive (libido)Exercise and antidepressants

      Genetic Factors

      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.
      • Baker M.
      • Litvan I.
      • Houlden H.
      • et al.
      Association of an extended haplotype in the tau gene with progressive supranuclear palsy.
      The inheritance of the H1 haplotype and the H1/H1 genotype in the Western world is a risk factor for the development of a primary tauopathy.
      • Baker M.
      • Litvan I.
      • Houlden H.
      • et al.
      Association of an extended haplotype in the tau gene with progressive supranuclear palsy.
      • Houlden H.
      • Baker M.
      • Morris H.R.
      • et al.
      Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype.
      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.
      • Myers A.J.
      • Pittman A.M.
      • Zhao A.S.
      • et al.
      The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts.
      • Rademakers R.
      • Melquist S.
      • Cruts M.
      • et al.
      High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy.
      This variant has been shown to be associated with an increased deposition of 4R tau isoforms.
      • Myers A.J.
      • Pittman A.M.
      • Zhao A.S.
      • et al.
      The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts.
      • Rademakers R.
      • Melquist S.
      • Cruts M.
      • et al.
      High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy.
      • Kouri N.
      • Murray M.E.
      • Hassan A.
      • et al.
      Neuropathological features of corticobasal degeneration presenting as corticobasal syndrome or Richardson syndrome.
      Interestingly, the H2 haplotype has been suggested to be associated with a protective effect against the development of a primary tauopathy.
      • Caffrey T.M.
      • Joachim C.
      • Wade-Martins R.
      Haplotype-specific expression of the N-terminal exons 2 and 3 at the human MAPT locus.
      A large genome-wide association study of the primary tauopathy progressive supranuclear palsy discovered previously unidentified signals associated with progressive supranuclear palsy,
      • Höglinger G.U.
      • Melhem N.M.
      • Dickson D.W.
      • et al.
      Identification of common variants influencing risk of the tauopathy 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.
      • Klunk W.E.
      • Engler H.
      • Nordberg A.
      • et al.
      Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B.
      Over the past 5 years, many radiotracers have been developed with the intention of selectively detecting tau in the brain.
      • Dani M.
      • Brooks D.J.
      • Edison P.
      Tau imaging in neurodegenerative diseases.
      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).
      • Chien D.T.
      • Bahri S.
      • Szardenings A.K.
      • et al.
      Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807.
      • Xia C.F.
      • Arteaga J.
      • Chen G.
      • et al.
      [(18)F]T807, a novel tau positron emission tomography imaging agent for Alzheimer's disease.
      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.
      • Chien D.T.
      • Bahri S.
      • Szardenings A.K.
      • et al.
      Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807.
      • Lowe V.J.
      • Curran G.
      • Fang P.
      • et al.
      An autoradiographic evaluation of AV-1451 Tau PET in dementia.
      • Sander K.
      • Lashley T.
      • Gami P.
      • et al.
      Characterization of tau positron emission tomography tracer [F]AV-1451 binding to postmortem tissue in Alzheimer's disease, primary tauopathies, and other dementias.
      • Marquié M.
      • Normandin M.D.
      • Vanderburg C.R.
      • et al.
      Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue.
      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.
      • Cho H.
      • Choi J.Y.
      • Hwang M.S.
      • et al.
      Tau PET in Alzheimer disease and mild cognitive impairment.
      • Johnson K.A.
      • Schultz A.
      • Betensky R.A.
      • et al.
      Tau positron emission tomographic imaging in aging and early Alzheimer disease.
      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
      • Josephs K.A.
      • Whitwell J.L.
      • Tacik P.
      • et al.
      [18F]AV-1451 tau-PET uptake does correlate with quantitatively measured 4R-tau burden in autopsy-confirmed corticobasal degeneration.
      • Whitwell J.L.
      • Lowe V.J.
      • Tosakulwong N.
      • et al.
      [18F]AV-1451 tau positron emission tomography in progressive supranuclear palsy.
      • Hammes J.
      • Bischof G.N.
      • Giehl K.
      • et al.
      Elevated in vivo [18F]-AV-1451 uptake in a patient with progressive supranuclear palsy.
      • Smith R.
      • Schain M.
      • Nilsson C.
      • et al.
      Increased basal ganglia binding of 18 F-AV-1451 in patients with progressive supranuclear palsy.
      (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
      • Lowe V.J.
      • Curran G.
      • Fang P.
      • et al.
      An autoradiographic evaluation of AV-1451 Tau PET in dementia.
      • Marquié M.
      • Normandin M.D.
      • Vanderburg C.R.
      • et al.
      Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue.
      (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.
      • Ono M.
      • Sahara N.
      • Kumata K.
      • et al.
      Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies.
      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,
      • Ishiki A.
      • Harada R.
      • Okamura N.
      • et al.
      Tau imaging with [18 F]THK-5351 in progressive supranuclear palsy.
      although binding may be targeting dopamine-related receptors and not tau.
      Figure thumbnail gr3
      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).

      Prion-Like Properties and Propagation of Tau

      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.
      • Clavaguera F.
      • Hench J.
      • Goedert M.
      • Tolnay M.
      Invited review: Prion-like transmission and spreading of tau pathology.
      • Frost B.
      • Diamond M.I.
      Prion-like mechanisms in neurodegenerative diseases.
      More specifically, does tau behave like a prion and can it be transmitted like an infection? The term “prion” was first coined by Prusiner
      • Prusiner S.B.
      Novel proteinaceous infectious particles cause scrapie.
      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
      • Braak H.
      • Braak E.
      Neuropathological staging of Alzheimer-related changes.
      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.
      • Alonso Adel C.
      • Li B.
      • Grundke-Iqbal I.
      • Iqbal K.
      Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity.
      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.
      • Frost B.
      • Jacks R.L.
      • Diamond M.I.
      Propagation of tau misfolding from the outside to the inside of a cell.
      The second was the demonstration that tau when injected into mice may promote tau filamentous aggregation.
      • Clavaguera F.
      • Bolmont T.
      • Crowther R.A.
      • et al.
      Transmission and spreading of tauopathy in transgenic mouse brain.
      The third provided some evidence that tau can jump from cell to cell.
      • Sanders D.W.
      • Kaufman S.K.
      • DeVos S.L.
      • et al.
      Distinct tau prion strains propagate in cells and mice and define different tauopathies.
      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.
      • Hyman B.T.
      Tau propagation, different tau phenotypes, and prion-like properties of tau.

      Treatment Trials and Future Directions

      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,
      • Bensimon G.
      • Ludolph A.
      • Agid Y.
      • Vidailhet M.
      • Payan C.
      • Leigh P.N.
      NNIPPS Study Group
      Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: the NNIPPS study.
      octapeptide NAPVSIPQ,
      • Boxer A.L.
      • Lang A.E.
      • Grossman M.
      • et al.
      AL-108-231 Investigators
      Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial.
      and tideglusib.
      • Tolosa E.
      • Litvan I.
      • Höglinger G.U.
      • et al.
      TAUROS Investigators
      A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy.
      None of these compounds have shown any evidence for efficacy. In addition, many different tau immunotherapies are currently being assessed.
      • Pedersen J.T.
      • Sigurdsson E.M.
      Tau immunotherapy for Alzheimer's disease.
      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.
      • Pedersen J.T.
      • Sigurdsson E.M.
      Tau immunotherapy for Alzheimer's disease.
      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.

      Supplemental Online Material

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