Some New and Unexpected Tauopathies in Movement Disorders

Tauopathies are a heterogeneous group of neurodegenerative disorders sharing the neuropathologic hallmark of neuronal and/or glial accumulation of tau (Table 1). They can have genetic, toxic, autoimmune, or environmental bases, although in most cases, the etiology remains unknown. Recent years have seen increasing numbers of movement disorders subsumed under the umbrella of “tauopathies.” Herein we review these entities from clinical, etiological, and pathomechanistic standpoints and conclude by discussing the difficulties in interpreting the relevance of tau deposition in these disorders. Indeed, as the number of disparate disorders bearing tau pathology increases, the less likely it becomes that tau is the primary instigator or mediator of disease in all. Moreover, the recognition of a number of aging-related tauopathies (aging-related tau astrogliopathy; primary age related tauopathy), sometimes in patients without clinical deficits, further supports the theory that on occasion, tau deposition may be a late or secondary phenomenon or may merely reflect processes associated with normal aging and life insults.


Brief Overview of Tau
Tau is a critical microtubule-associated protein subserving varied functions ranging from maintenance of cytoskeletal architecture and axonal transport to neurite polarization and DNA protection. 3 A total of 6 tau isoforms exist, generated through alternate splicing of exons 2, 3, and 10 of the MAPT gene on chromosome 17; inclusion or exclusion of exon 10 produces tau with either 3 (3R) or 4 (4R) microtubule-binding domains, the normal 1:1 ratio of which can become skewed in various disease states. 3 In disease, tau becomes misfolded and physiochemically abnormal and accumulates as insoluble inclusions in neurons and/or glia, the neuropathologic detection of which denotes the condition as a "tauopathy." Recent evidence has uncovered "prion-like" cell-to-cell tau propagation along the neuro-anatomic connectome and strain-specific tau pathologic inclusions and seeding characteristics. [3][4][5] In addition to the division into primary (where tau is considered the sole and/or primary mediator of neurodegeneration) and secondary (where tau coexists with other pathology) forms, diseasespecific signatures for each tauopathy exist based on which cell types bear inclusions (neurons, glia, or both), their morphological appearances and anatomic distribution, and the ratio of 3R:4R tau. 3,6 Herein we discuss recent movement disorder additions to the field of tauopathies. Deciding which disorders to include was difficult, as some subjectivity exists regarding what constitutes a "new" or "unexpected" finding. We tried to focus on disorders that would be of interest to practicing clinicians and group these according to likely disease pathomechanisms. become less prominent, parkinsonism and dystonia appear, and dementia progresses. 7 Neuropathology shows widespread Alzheimer-like tau pathology throughout the cortex, basal ganglia, brainstem, and cerebellum. 8 The notable absence of alpha-synuclein pathology helps to differentiate BPAN from other neurodegenerative disorders with brain iron accumulation, particularly phospholipase A2 group VIassociated neurodegeneration and mitochondrial membrane protein associated neurodegeneration, while tau anatomic distribution is quite distinct from that seen in Alzheimer's disease (AD). 7 Adenylate Cyclase 5 (ADCY5)-Related Dyskinesia ADCY5-related dyskinesia is a childhood-onset choreodystonic movement disorder caused by mutations in the ADCY5 family of striatal-specific enzymes, which convert ATP to the second messenger cyclic adenosine monophosphate. 9 Associated symptoms may include axial hypotonia, limb hypertonia, cognitive impairment, depression, attention-deficit hyperactivity disorder, and psychosis. Oculomotor apraxia and nocturnal ballistic bouts may be seen. 10 Neuropathologic features of the disorder have yet to be clearly defined. Recently, the first neuropathological examination of a patient with a genetically confirmed (p.M1029K) ADCY5 gene mutation who died at the age of 46 years was reported. 11 This showed widespread (mixed 3R/4R) tau pathology, including neurofibrillary tangles, neuritic tau, and glial tau deposition involving the cerebral cortex, midbrain, thalamus, and hippocampus. Sulcal perivascular astroglial tau inclusions were identified, raising questions about whether this could have represented chronic traumatic encephalopathy pathology from severe choreodystonic head movements, but the pathology was not typical for this disorder. 11 Benign Hereditary Chorea (BHC) Type 2 Most BHC syndromes result from mutations in either the thyroid transcription factor 1 (TITF1) 12 or ADCY5 genes. 13 BHC type 2, the rarest benign chorea syndrome, was described in 2007 in 2 Japanese families with adult-onset dominantly inherited progressive chorea and mapped to chromosome 8q 21.3-q23.3. 14 Neuropathological findings in a single case of BHC type 2 included presence of neurofibrillary tangles and threads and 4R immunoreactive tufted astrocytes (a hallmark feature of progressive supranuclear palsy) affecting the cortex, basal ganglia, brainstem, and cerebellum. 15 Of note, the reported patient was 83 years old at the time of death, hence it remains to be seen if tau pathology in BHC is a specific feature or rather a concomitant age-related pathology or unrelated primary tauopathy.

Autosomal Dominant Spinocerebellar Ataxias (SCAs)
SCAs are dominantly inherited degenerative disorders characterized principally by progressive ataxia, often accompanied by extracerebellar symptoms including parkinsonism, pyramidal signs, retinal degeneration, and peripheral neuropathy. 16 Tau deposition has been reported in both SCA 11 (1 patient, age at death uncertain but >77 years) and SCA 31 (1 patient, aged 76 years). [16][17][18] In the former, neurofibrillary tangles, neuropil threads, and tau-positive neurites involved various brainstem regions and the basal ganglia. 17 In the latter, tau may simply represent coincidental AD pathology. 18 Huntington's Disease (HD) HD is a dominantly inherited neurodegenerative disorder classically producing the triad of cognitive decline, psychiatric symptoms, and hyperkinetic movements. 19 Expansion of the CAG trinucleotide repeat in the huntingtin (HTT) gene elongates the protein's polyglutamine tract, causing misfolding, aggregation, and impairment of various cellular processes. 19 Along with other misfolded proteins, such as alpha-synuclein and TAR DNA binding protein-43, tau deposition is increasingly recognized as a feature of HD neuropathology, taking the form of neurofibrillary tangles predominantly in medial temporal lobes as well as nuclear tau rods (Lucas rods). 20,21 Tau pathology, which may be responsible for the development of cognitive symptoms in HD, 21 increases with increasing disease stage, suggesting a direct role for mutant HTT in formation of insoluble tau. 20

Autoimmune Disorders
Anti-IgLON5 Disease Anti-IgLON5 disease is a nonparaneoplastic antibody-associated disorder classically presenting in the sixth to seventh decade of life with disordered sleep (parasomnias, obstructive sleep apnea, stridor, hypoventilation), cognitive decline, bulbar symptoms, and ataxia. Parkinsonism, sometimes assuming a progressive supranuclear palsy-like phenotype, can be present, as can chorea. 22 The rate of progression is slow, at times decades from diagnosis until death. Response to immunotherapy may be seen. 23 Neuropathologic findings in the disorder were considered relatively homogeneous, showing almost exclusively neuronal 3Rtau and 4R-tau deposition primarily in the brainstem tegmentum and hypothalamus, following a cranio-caudal gradient to the level of the cervical spinal cord. 22 However, the recent report of a case of symptomatic anti-IGLON5 disease without brainstem tau pathology questions the pathogenic role of tau in this disorder. 24

Idiopathic/Environmentally Mediated Disorders Progressive Ataxia and Palatal Tremor (PAPT)
The PAPT syndrome is characterized by palatal tremor along with progressive cerebellar signs 25 ; cerebellar atrophy and hypertrophic olivary degeneration are frequent neuroimaging findings. PAPT is classified as either "sporadic" or "familial." 25 Familial PAPT is usually a consequence of adult-onset Alexander's disease, although rarer causes include autosomal dominant SCA type 20 and DNA polymerase gamma (POLG) mutations. 25 "Sporadic" PAPT subsumes the nonfamilial conditions, including celiac disease and cerebrotendinous xanthomatosis, although most cases remain idiopathic.
Two separate reports (on 3 patients, aged 75, 80, and 89 years at the time of autopsy) have identified tau deposits in idiopathic PAPT. Its distribution differed, but generally comprised somatodendritic inclusions in the inferior olives, nigra, locus coeruleus, red nucleus, and thalami alongside cortical and/or hippocampal tau pathology that was interpreted as an incidental finding related to aging. 26,27 Globular Glial Tauopathies (GGT) The GGT are rare 4R-tauopathies characterized neuropathologically by widespread globular glial inclusions. 28 Various neuropathologic subtypes of GGT have been defined: • Type I GGT classically presents with fronto-temporal dementia, reflecting predominant fronto-temporal distribution of pathology. • Type II GGT generally demonstrate prominent pyramidal involvement, reflecting motor cortex pathology with corticospinal tract degeneration. • Type III GGT is essentially a combination of types I and II, exhibiting combined involvement of the motor cortex and frontotemporal regions and consequent symptomatic overlap.
GGT types II and III may demonstrate extrapyramidal features and can be misdiagnosed as either progressive supranuclear palsy or corticobasal syndrome, sometimes with "typical" neuroimaging. 29,30 Clinical clues in these cases include prominent upper motor neuron signs, with most cases essentially representing primary lateral sclerosis overlap syndromes. 29,30 Tau strains in GGT demonstrate unique, potent seeding characteristics that appear to be a primary driver of the neurodegenerative process. 31

Traumatic Brain Injury Producing Secondary Dystonia
A single case report of a 78-year-old male patient demonstrated tau pathology potentially underlying the development of secondary dystonia following focal traumatic brain injury. Neuropathology, in addition to chronic traumatic encephalopathylike tau deposition in the frontal cortex (the likely site of impact), and histologic evidence of PART, showed evidence of focal right basal ganglia neuronal and glial tau deposition, likely accounting for left hand dystonia. 32 The report in question should, however, be interpreted with caution, especially given the self-confessed clinical uncertainties about the diagnosis of dystonia. 32 Nodding Syndrome (NS) NS is an enigmatic epidemic neurologic disorder affecting children in East Africa. 33 Joining other geographical clusters of tauopathy such as Guadeloupean parkinsonism and parkinsonism-dementia complex of Guam, the disorder manifests between 3 and 18 years of age with stereotyped head drops, seizures, neurocognitive regression, and slow, inexorable progression until death. 33 Its etiology is uncertain. Theories include intentional poisoning of water sources, exposure to chemicals, neurotropic viruses, and parainfectious autoimmune disorders. 34 Recent neuropathologic examination of 5 patients who had died of NS showed neuronal tau deposition (pretangles and neuropil threads) predominantly in the cortical and brainstem regions, with relative sparing of basal ganglia. 35 However, epilepsy is one of the clinical features of NS, and given that tau pathology is well known to occur in long-standing epileptics, 36 it could be that the observed changes are secondary to poorly controlled seizures.

Discussion
Fundamentally, all tauopathies are characterized by deposition of physio-chemically abnormal, misfolded tau within neurons and/or glia. The upstream pathophysiologic abnormalities leading to such conformational changes are vast. They include alterations in amino acid sequences within the MAPT gene, altered transcription, multiple posttranslational influences (but especially hyperphosphorylation), head trauma, ischemia, and oxidative stress. Therefore, although classifying disorders together according to their neuropathologic similarities is informative, it can convey the wrong message that these diseases all function in similar ways and that disease modification can be applied using a "one size fits all" approach. This is incorrect, and perhaps may be one reason for the disappointing results obtained thus far from disease-modification treatment trials in tauopathies.
With new diseases come new insights about disease mechanisms. Nowhere is this more true than with the new and unexpected tauopathies. Although many of the disorders described previously reflect experience from small numbers of cases and therefore need to be replicated, studying these offers great potential to further our understanding of disease physiology and disclose novel disease-modifying treatment targets.
The aforementioned disorders may critically affect tau structure at various levels. For example, ADCY5 mutations influence cyclic adenosine monophosphate production; in turn, cyclic adenosine monophosphate-dependent protein kinases regulate (among other things) tau phosphorylation and exon 10 splicing. 37 In BPAN, defective autophagy likely impairs clearance of proteins, including tau. 38 Moreover, iron dyshomeostasis in this disorder may influence tau phosphorylation and aggregation. 39 Posttraumatic dystonia, similar to chronic traumatic encephalopathy, reflects the fact that head trauma and shear forces can influence tau folding. 40 The SCA 11 gene product TTBK2 encodes a kinase that putatively phosphorylates tau and tubulin proteins. SCA 31 affects the BEAN gene, coding for a protein that marks defective tau for subsequent degradation. In HD, mutant HTT protein can promote tau hyperphosphorylation and disrupt normal tau splicing, shifting the balance in favor of 4R-tau isoforms. 21 Anti-IGLON5 disease, and possibly NS, offer an opportunity to study the interplay of autoimmunity with later neurodegeneration.
Furthermore, these cases illustrate the importance of untangling what truly represents a tauopathy. Should scant amounts of tau deposition be enough to merit classification of a disorder as a tauopathy and to ascribe disease initiation and/or progression to the observed neuropathologic inclusions? How well defined and reproduced should the neuropathology be to merit this definition? Should there always be a corresponding clinical syndrome? Could tau in some cases be an innocent bystander or a reflection of normal aging?
Further systematic clinical, neuropathologic, and molecular characterization of tauopathies is needed to address these questions and hopefully concomitantly allow the development of targeted disease-modifying therapies.

Acknowledgments
We thank Professor John Hardy for his critical review of this article.