There is considerable interest in the pathobiology of tau protein, given its potential role in neurodegenerative diseases and aging. Tau is an important microtubule associated protein, required for the assembly of tubulin into microtubules and maintaining structural integrity of axons. Tau has other diverse cellular functions involving signal transduction, cellular proliferation, developmental neurobiology, neuroplasticity, and synaptic activity. Alternative splicing results in tau isoforms with differing microtubule binding affinity, differing representation in pathological inclusions in certain disease states, and differing roles in developmental biology and homeostasis. Tau haplotypes confer differing susceptibility to neurodegeneration. Tau phosphorylation is a normal metabolic process, critical in controlling tau’s binding to microtubules, and is ongoing within the brain at all times. Tau may be hyperphosphorylated, and may aggregate as detectable fibrillar deposits in tissues, in both aging and neurodegenerative disease. The hypothesis that p-tau is neurotoxic has prompted constructs related to isomers, low-n assembly intermediates or oligomers, and the “tau prion”. Human postmortem studies have elucidated broad patterns of tauopathy, with tendencies for those patterns to differ as a function of disease phenotype. However, there is extensive overlap, not only between genuine neurodegenerative diseases, but also between aging and disease. Recent studies highlight uniqueness to pathological patterns, including a pattern attributed to repetitive head trauma, although clinical correlations have been elusive. The diagnostic process for tauopathies and neurodegenerative diseases in general is challenging in many respects, and may be particularly problematic for postmortem evaluation of former athletes and military service members.
SUMMARY OF PURPOSE
The primary purpose of this review is to highlight the complexity of tau in health and disease, and to point out the many uncertainties concerning its role in pathogenesis as well as diagnostic interpretation. It is intended to foster a more circumspect approach to molecular and clinical neuroscience with respect to tau biology, and the avoidance of premature conclusions with respect to: 1) the role of tau phosphorylation as a primary neurotoxic process; and 2) the relationship between tau pathology at autopsy and clinical problems that may have been present during life.
IDENTIFICATION OF TAU AND THE TAU GENE
Tau was initially identified by Weingarten et al. as a heat stable protein factor that would convert 6S dimers of tubulin into 36S rings necessary for microtubule polymerization . They named this factor tau (τ) for its ability to induce tubule formation. Phosphorylation of tau was found to promote a conformational change favoring depolymerization of the tubulin assembly [2–4]. Brion et al. first reported immunohistochemical evidence of tau in paired helical filaments (PHF) in 1985 . Later the same year, Grundke-Iqbal et al.  reported that bovine tau preparations reacted with antibodies to Alzheimer PHF, and that affinity purified antibodies labeled neurofibrillary tangles (NFT) and dystrophic neurites, but not amyloid-β (Aβ) plaques. Neve et al.  subsequently used cDNA clones for tau and mapped the tau gene to 17q21.
The tau gene on chromosome 17q21.31 spans 16 exons of approximately 150 kilobases of genomic DNA. In human brain, alternative splicing of exons 2 and 3 results in three isoforms with either 0, 1, or 2 inserts of 29 amino acids (0N, 1N, 2N) [7–11] (Table 1). Each of the three isoforms may contain 3 repeats (3R) or 4 repeats (4R) of the microtubule binding domain encoded on exon 10, resulting is six isoforms. 1N, 0N, and 2N isoforms comprise 54%, 37%, and 9% of tau in human brain, while 3R and 4R tau species are expressed in roughly equal amounts among 0N, 1N, and 2N tau [12–14]. Expression of tau isoforms is developmentally regulated and tissue specific [9, 15, 16]. In the human fetus, only the shortest isoform (3R, 0N) is expressed, while the same isoform is downregulated in the adult brain. Tau phosphorylation is also developmentally regulated, being high until the end of synaptogenesis, compared to the adult human brain in which only 2–4 mole phosphate are attached per molecule of tau protein .
|Differential regulation of exons 2, 3, and 10 in development and disease (6 isoforms)|
|Regulated 3R and 4R tau with different microtubule binding affinities|
|Two haplotypes (H1 and H2) that confer disease susceptibility|
|Pathogenic mutation causes frontotemporal dementia phenotype|
The developmental shift in isoforms roughly coincides with the formation of synapses . The 3R, 0N isoform that predominates during development shows the least microtubule binding affinity, and switches to a relative increase in 4R tau species over time, suggesting pressure for greater microtubule binding affinity in the developed brain, and perhaps a role for the 3R tau species in neuroplasticity or in response to injury. Increased 3R tau during cellular stress, as well as the persistence of fetal tau in the adult brain , support this concept.
The regulation of tau binding appears to occur by alternative splicing and post-translational modifications. Tau also has a short reaction time with microtubules , which might explain why a protein in such abundance within the axon does not interfere with axonal transport. There is evidence that tau has two binding sites for microtubules. Microtubule binding repeats bind protofilaments at the taxol-binding site of beta-tubulin. The proline-rich region binds a protofilament anchoring the projection domain on the surface of the microtubule .
It is interesting that exon 10 is constitutively expressed in rodents , but is regulated in humans [8, 9]. This may in part underlie human susceptibility to tauopathy compared to rodents. The relative microtubule instability conferred by human 3R tau in response to cellular stress favors a depolymerized phosphorylated species, compared to rodents in which microtubule binding is maintained in a steady state because of constitutive expression of exon 10.
Faulty regulation of exon 10 splicing in humans, and the resulting imbalance of 3R and 4R tau expression, is suggested as a pathogenic basis for human tauopathy . Excessive inclusion of exon 2 and exon 3 has also been reported in gliopathy and spinal cord degeneration , although it remains to be determined whether cell specific expression of exon 2 and exon 3 is the basis for this finding.
Two tau haplotypes, referred to as H1 and H2, occur because of a 900 kb inversion polymorphism [24–26]. The H1 haplotype and the H1/H1 genotype is suggested to be a risk factor for progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease, and idiopathic Parkinson’s disease [24, 27–32]. The H2 haplotype is associated with increased expression of exon 3 in grey matter, suggesting that the inclusion of exon 3 might be protective against neurodegeneration . The H1/H2 genotype confers a greater risk of developing dementia before the age of 45 years in individuals with Down’s syndrome [32, 34].
Normal tau function
The primary function of tau within the brain appears to be the binding of tubulin to promote polymerization and stabilization of microtubules  (Table 2). Tau stabilizes and stiffens microtubules such that it supports the lengthy axon. Interactions with tubulin are dynamic processes with equal binding properties to both polymerized and non-polymerized tubulin, which regulates neurite polarity, axonal sprouting, and neuroplasticity, i.e., morphogenesis, and regulates axonal transport through interactions with motor proteins [35–41]. Microtubule binding confers a conformational change [3, 4], influences other diverse cellular processes [42–45], and interacts with other natively unfolded protein such as TDP-43, FUS, and alpha-synuclein [46–48]. A number of studies suggest alternative functions, including cell cycle regulation via tyrosine kinase, plasma membrane interaction, and synaptic function [42, 43, 46, 49].
|Stabilization of microtubules|
|Actin binding and cytoskeletal integrity|
|Regulating neurite polarity|
|Cell cycle regulation|
|Plasma membrane interaction|
|Synaptic transmission (“synaptic brake”)|
Physiologic tau phosphorylation is therefore integral to life across species as a productive response to a variety of stressors including insulin dysfunction, glucose deprivation, starvation, hypothermia, hibernation, anesthesia, and glucocorticoids, among other conditions [50–57] (Table 3). Physiologic tau phosphorylation may also regulate subcellular localization of tau, which in turn may influence signaling cascades or synaptic function [58, 59]. A number of post-translational modifications apart from phosphorylation also occur which may have functional implications . Among these are O-glycosylation, advanced glycation and the Maillard reaction, ubiquitination, nitration, SUMOylation, prolyl-isomerization, acetylation, and truncation [60–67].
Studies increasingly suggest a role for physiologic tau phosphorylation in synaptic function . Tau is normally present at both pre- and post-synaptic sites , and accumulates as hyperphosphorylated tau at these sites in AD . Whether tau diffuses across the synapse under normal conditions is an open question. Synaptic stimulation nevertheless induces site-specific, subsynaptic tau phosphorylation [70–72]. Tau mRNA has also been identified in axons and at subsynaptic sites, suggesting a role for local translation of tau in maintaining axonal integrity and synaptic function [73, 74]. Tau may also modulate signaling of synaptic neurotransmitter receptors, with post-synaptic tau phosphorylation acting as a “synaptic brake” via a complex and incompletely resolved mechanism. Glycogen synthase kinase 3 beta (GSK3β)-mediated tau phosphorylation, for example, may regulate neurotransmitter receptor endocytosis and negatively influence long term depression [59, 72].
The biology of hibernation is interesting in that tau protein transitions to a PHF-like phosphorylated state, involving epitopes typically related to tau phosphorylation in AD. Yet the phosphorylation state is completely reversible upon arousal from torpor and return to euthermic conditions . This tends to suggest that tau phosphorylation in AD is a reactive phenomenon rather than a primary toxic process, and raises the issue of whether controlled hyperphosphorylation of tau confers cellular protection.
Tau has been shown to bind filamentous actin of dendritic spines as further evidence of its role in cytoskeletal integrity [76, 77]. Other studies have localized tau to the nucleus and the centrosome, in addition to the mitotic spindle microtubules of dividing cells [78–80], suggesting that tau phosphorylation might be involved in nucleus-cytoplasm translocation and cell cycle transition. Tau can also bind DNA, whereas tau phosphorylation may prevent DNA binding [81, 82]. Nucleolar organization and protection of genomic DNA is still another potential function [83, 84]. Tau is found in association with RNA as part of a ribonucleoproteome, complexing with RNA and a variety of proteins [48, 85, 86]. Finally, tau is also expressed in astrocytes and oligodendrocytes, the latter with all six isoforms, although with a lesser degree of microtubule binding [87–89]. Oligodendrocyte tau appears to be involved in microtubule stability during morphogenesis and myelination .
Tau protein phosphorylation and hyperphosphorylation
Normal tau is a highly soluble natively unfolded protein [91–93], which contrasts with hyperphosphorylated p-tau in NFT which is highly insoluble . The latter should be distinguished from physiologic tau phosphorylation, which is an ongoing dynamic process in the brain, and a necessary, tightly regulated process . Phosphorylation regulates interactions involved in subcellular distribution and axonal transport [95, 96], organelle delivery to the somatodendritic compartment , neurotransmitter receptors , apolipoprotein E , Src kinases [49, 100, 101], and Pin1 . Because of its high number of serine and threonine residues, tau protein is an excellent substrate for protein kinases, especially proline-directed kinases such as GSK3β . Tau phosphorylation by cyclin dependent kinases and mitogen activated protein kinases [103–105], emphasize the role of tau metabolism in cellular division and proliferation. Non-proline directed kinases are also involved . GSK3β and cdk5 may play a relatively more prominent role in tau phosphorylation in the human brain . Interconnection of the kinase network, promiscuity of protein kinases, and the tendency of phosphorylation sites to cluster present technical challenges to the study of tau phosphorylation in vivo. The phosphorylation yield at any given site is low and can be difficult to assess. Site directed mutagenesis results in complex alterations in ionic properties, which limits the significance of experimental findings .
Numerous phosphatases dephosphorylate tau in vitro, especially PP2A which is thought to also play a role in vivo . Activity of tau protein phosphatases is further regulated by endogenous inhibitors, which themselves are subject to regulatory phosphorylation , emphasizing the complexity of tau phosphorylation.
The broad property of “hyperphosphorylation” is a hallmark of tau aggregates in AD, numerous other tauopathies, and aging [17, 109, 110]. Many phosphorylation sites occupied in PHF tau may be occupied in the normal brain . In advanced disease, most of the approximately 39 potential AD phosphorylation sites [111, 112] are phosphorylated, with total phosphate content in p-tau pathological aggregates three times that of physiologic tau [17, 113]. One study in transgenic mice reports that pathological hyperphosphorylation is characterized by an increase in the proportion of phosphorylation at given residues, rather than an increase in the total number of phosphorylated residues , suggesting that tau “hyperphosphorylation” reflects an exaggerated physiologic phosphorylation, rather than disorganized phosphorylation at random sites receptive to phosphate groups. Still other studies suggest a role for molecular isomerism catalyzed by proline isomerase, with cis isomers of the Thr231 proline motif of p-tau variously labeling lesional brain tissue in AD and former professional athletes, as well as acutely traumatized murine neurons and axons in acute or recent trauma in humans [114, 115]. Trans isomers of p-tau are said to be “physiological” , although their specific role in the diversity of cellular tau functions is unclear.
It is noteworthy that antibodies used in p-tau analyses in vitro and in vivo react to highly selective epitopes, each with functional and pathological implications. The widely used monoclonal antibody AT8, for example, is used to identify tau phosphorylation at Ser 202, Thr 205, and Ser 208, which in turn identifies a wide spectrum of tau aggregates including the “pre-tangle” in autopsy brain . Pretangle aggregates are not otherwise apparent using histologic dyes such as hematoxylin and eosin, or silver impregnation techniques such as Bielschowsky silver. For this reason, p-tau as identified by AT8 immunohistochemistry may lack any associated pathological alteration (such as a morphologically identifiable NFT). Pathology with a hypothesized link to repetitive traumatic brain injury (TBI) for example is often entirely immunohistochemical, with no tissue reaction that would otherwise suggest that an injury has taken place. This tends to raise questions about p-tau immunoreactivity as an indicator of cell death with repetitive TBI exposure. This may also explain the lack of eloquence regarding p-tau and clinical signs [117–120]. Phosphorylation at Thr 212 and Ser 214, identified in tissues by monoclonal antibody AT100, may be a better indicator of more advanced pathology , less sensitive than AT8 but more specific for pathological aggregates.
Decomposition and associated artifacts are synonymous with postmortem human brain analyses, and may be underappreciated. It is known, for example, that postmortem changes in the phosphorylation state is a dynamic process, with dephosphorylation of p-tau occurring rapidly postmortem, in a site-specific manner [122–128]. P-tau autopsy tissues may preferentially label buried epitopes, i.e., resistant to degradation. The patterns of immunoreactivity in the human brain may therefore be skewed toward postmortem artifact and away from solubility or in vivo biological relevance.
Hyperphosphorylation of tau may result from an imbalance in the activity of tau protein kinases and tau phosphatases, which in turn may be necessary for the formation of pathological fibrils. The conversion of physiologic tau to filamentous tau is believed to be a multi-step processes, with microtubule detachment as the initial step [129–131]. A number of biological mechanisms have been suggested [132–136]. Higher concentrations of tau may also influence conformational changes necessary for fibril formation . Interestingly, 3R tau is said to facilitate twisted paired helical filaments such as those seen in classical AD NFT, while 4R tau has a tendency to assemble into straight filaments such as described in PSP . Whether fibrillar or PHF tau signifies cytotoxicity, versus a productive response to the aging process or cellular stress, remains an open question . Direct experiments verifying a feed-forward pathological cascade are sparse, with some studies showing no correlation between NFT accumulation and length of microtubules . Still other studies demonstrating adduct formation (e.g., advanced glycation, advanced lipid peroxidation), and sequestration of redox active transition metals, may indicate that p-tau aggregation, up to and including PHF tau, is a productive response to cellular stress [140, 141].
Studies in recent years have increasingly implicated soluble, low-n tau assembly intermediates as the toxic or biologically active species [142–149]. The same concept is invoked for Aβ in AD . This again suggests that the most readily identifiable postmortem lesions detected by immunohistochemistry may be the least biologically relevant. In one inducible transgenic model, progression of insoluble tau pathology was noted after suppression of mutated tau gene expression, during the process of functional recovery .
The broad term “tauopathy” was first suggested in 1997 for a familial degenerative tauopathy  and is often used to connote diverse neurodegenerative diseases characterized by p-tau accumulations with various morphologies and clinical correlates (Table 4). To the extent that tauopathy implies the accumulation of p-tau as a rate-limiting factor for disease pathogenesis, the terminology may be unfortunate. A convincing case could be made that p-tau is a disease response, perhaps even a productive disease response [117, 138]. The term “tauopathy” may be subclassified into “primary” tauopathy, in which p-tau accumulation is the major pathological finding, or “secondary” tauopathy, in which some other protein deposit occurs (e.g., Aβ, prion protein) . P-tau in sporadic primary tauopathies may not correlate with neuronal loss in some diseases . Rigorously defined, true primary tauopathies may be limited to frontotemporal lobar degenerations associated with pathogenic mutations of the tau gene (MAPT) on chromosome 17 (FTDP-17) . Like familial AD with APP mutations, the role of tau mutation in the molecular pathology is unclear. Some studies suggest that MAPT mutation causes chromosomal instability and aneuploidy [153, 154], rather than the elaboration of a toxic tau species per se.
|Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)|
|Primary age-related tauopathy|
|Aging-related tau astrogliopathy|
|Progressive supranuclear palsy|
|Argyrophilic grain disease|
|Progressive subcortical gliosis|
|Amyotrophic lateral sclerosis/parkinsonism-dementia complex|
|Diffuse neurofibrillary tangles with calcification|
|Globular glial tauopathy|
|Niemann-Pick disease type C|
|Prion protein cerebral amyloid angiopathy|
|Subacute sclerosing panencephalitis|
|Non-guanamian motor neuron disease with neurofibrillary tangles|
Sporadic tauopathies are currently classified as frontotemporal lobar degeneration-tau (FTLD-tau), which encompasses Pick disease, PSP, and CBD . Interestingly, MAPT remains the most substantial association by genome wide association analysis , and patients with MAPT tau mutation have clinical and pathological features that overlap with PSP and CBD [156, 157]. CBD and PSP clinical phenotypes tend to contain lesions composed mainly of 4R tau, which supports dysfunctional microtubule binding as a factor in neurodegeneration. Pick disease phenotype (the least common of the sporadic FTLD-tau phenotypes), on the other hand, contains lesions comprised of 3R tau. Given the tendencies toward tau isoform specificity in FTLD-tau, it is tempting to suggest specific isoforms as therapeutic targets . Such a construct would require p-tau as inherently toxic, however, which is not established.
The tau prion
Clavaguera et al. first demonstrated the elaboration of tau filaments following injection of wild-type mice with tau derived from P301S transgenes, raising the issue of protein-only transmission of phenotypic characteristics . Relevance to human disease nevertheless requires the presumption that p-tau is neurotoxic in the human brain in vivo, which remains an open question. Conceptualizing the tau prion is challenging, and involves putative processes such as seeding, templating, spread, strain variation, transcellular propagation, trans-synaptic propagation, functional connectivity, selective vulnerability, and prion-like, each with a level of imprecision . Pliability of definition is evident with terms such as “infectious prions”, “non-infectious prions”, “quasi-prions”, and “transcellular prionoids” . The tau prion nevertheless provides a framework for neurodegeneration based on non-mendelian, horizontal transmission of deleterious information, which is at issue in genuine prion disease. Protein-only transmission of phenotypic information in yeast is well-characterized . By the prion analogy, p-tau would template or seed brain tissue, confer adverse biological properties on naÏve tau molecules, and perpetuate an autocatalytic neurodegenerative cascade. Kaufman et al. provide evidence for seeding phenomena and strain variation in tauopathy [163, 164], although their relationship with neurodegeneration in progressive tauopathies is unclear.
There are some limitations of the tau prion concept (Table 5). In an early seminal study by Frost et al., extracellular tau at supraphysiological levels templated intracellular tau in less than 2% of the cells, while the conformationally templated p-tau in cell culture showed little, if any, resemblance to NFT . Guo and Lee used recombinant 4-R tau , which has weak amyloid-like properties in human tauopathies compared to mixed 3R and 4R tau in AD. Sonication is often used to generate neurotoxic species for in vitro analyses, which is not standardized across laboratories. Characteristics of tau fibrils necessary for seeding experiments are poorly defined. Consensus standards for tau seeding in cell culture studies do not exist . Many studies employ mutant tau, which is of doubtful relevance to sporadic disease since MAPT mutations do not occur in the overwhelming majority of human tauopathies. Most studies on tau propagation also utilize truncated tau , mutated or not, rather than full length tau. While reasonable in theory given C-terminally truncated tau in the synapse, it generally ignores the multiple isoforms in humans with variable splicing of the C-terminus and N-terminus. Many studies use recombinant tau rather than tau filaments derived from human disease, raising an issue of biological relevance. Propagation studies that rely on selective expression of specific isoforms do not take into account the fact that expression of 3R and 4R isoforms occurs in all human tauopathies, regardless of whether the predominant form in pathological lesions is 3R, 4R, or a mixture of both . Transgenic constructs relying on conditional expression of tau  may have unaccounted for promiscuity (e.g., expression outside the entorhinal cortex), tau “leakiness,”  or axonal tau mRNA and expression outside the cell body [73, 74].
|Inefficiency of templating in culture|
|Methods for generating neurotoxic species not standardized|
|Fibril characteristics necessary for seeding are poorly defined|
|No consensus standards for tau seeding in culture|
|Relevance of mutant tau|
|Selective isoform expression experimentally versus nonselective expression in vivo|
|Tau expression promiscuity in transgenic animals|
|Axonal (as opposed to perikaryal) expression of tau|
|No natural tauopathy in rodents|
|Phenotypic propagation of neurodegeneration as a function of strain is not demonstrated|
|Does not explain selective vulnerability|
|Contradicted by early appearance of tau in structures with diffuse projections|
Transgenic mice expressing, or overexpressing, a single isoform of wild-type human tau, do not develop tauopathy or neurodegeneration , while various other experimental constructs show tau expression without neurodegeneration [168, 169]. Tau prions have yet to be re-derived and re-injected with phenotypic changes in subsequent passages, separating tau prions from conventional prion disease. It may finally be pointed out that p-tau accumulates initially within neurons of the locus ceruleus, appearing as early as childhood . Since the locus ceruleus is said to be “unsurpassed” among brain regions in the diffuseness of its connections [171, 172], trans-synaptic or transcellular neurodegeneration appears to be limited in the aging process in vivo.
Recent analyses of primary age-related tauopathy (PART)  and aging-related tau astrogliopathy (ARTAG)  have expanded the spectrum age-related p-tau accumulation patterns. PART is, in essence, an accumulation of p-tau within medial temporal lobe and subcortical structures, with little or no Aβ deposition. Clinical symptoms range from no symptoms to mild symptoms involving the memory domain. Most cases previously referred to as “tangle only dementia” or “tangle-predominant senile dementia” are likely within the PART spectrum. It is noteworthy that classic studies of dementia pugilistica (DP) describe neurofibrillary degeneration in a similar distribution , which raises the possibility of coincidental p-tau pathology.
The related condition ARTAG, refers to p-tau accumulation within astrocytes, with a tendency for subpial, subependymal, and perivascular areas, and in subcortical white matter. Like PART, ARTAG has no predictable clinical substrate and overlaps substantially with pathology hypothesized as a substrate for repetitive neurotrauma . PART is said to be primarily neuronal although tau astrogliopathy may co-exist with PART. Interestingly, PART is a mixed 3R/4R tauopathy whereas ARTAG is a 4R tauopathy, suggesting some degree of cell type specificity. This may in part explain why AD is a mixed 3R/4R tauopathy, while PSP and CBD, with an abundance of 4R tau, have prominent glial p-tau accumulation. A recent study of 687 postmortem brains from a spectrum tauopathies suggested variable distribution patterns of ARTAG, and differing pathogenesis possibly related to cerebrospinal fluid circulation or mechanical forces. The clinical significance of these patterns was not studied. The issue of spread among astrocytes was raised but remained speculative .
TBI and tauopathy in athletes and military service members
The relationship between repetitive TBI and neurodegenerative tauopathy has been poorly understood for decades. It remains theoretical and is problematic for a number of reasons  (Table 6). The TBI component of the equation itself presents a significant challenge for study. Mathematical thresholds for parenchymal and vascular injury are impossible to quantify (reviewed in ). TBI repetition is largely undefined, and the role of TBI repetition of whatever extent on injury thresholds or putative tauopathy is unknown. Given myriad conditions associated with p-tau accumulation, as well as the numerous biological processes associated tau phosphorylation, it is nevertheless expected that TBI at some level of severity may stimulate physiologic tau phosphorylation, and even that p-tau inclusions may appear over time following TBI in some instances, for reasons not fully elucidated.
|Neurological signs attributed to early 20th century boxing were not progressive in most cases|
|Index case of DP at autopsy was most likely familial AD in a former boxer|
|Index case of putative DP-like disease in a football player depicted age-related changes |
|Putative disease process is currently defined solely by immunohistochemistry (no clinical correlate required; no neurodegeneration (neuron or axon loss) required)|
|TBI in athletes is inferred from participation; otherwise undefined and impossible to quantitate|
|Athletes in modern case series were neurologically asymptomatic or had known neurodegenerative diseases in most cases|
|National Football League cohort has less cancer, fewer suicides, lower mortality, and better cardiovascular health compared to controls (no evidence of a pervasive, fatal disease related to occupational exposure)|
|Studies suggesting AD risk with mild TBI are inconsistent (no risk or modest risk)|
|AD is not confirmed pathologically in studies showing AD risk with moderate or severe TBI (dementia from structural brain injury in some cases not excluded)|
|No longitudinal data exists demonstrating TBI, latency, clinical neurodegeneration, and neurodegenerative pathology|
TBI-neurodegenerative disease theory began with the investigation of boxers in the early part of the 20th century, some of whom demonstrated neurological signs and a putative condition known in boxing circles as “punch drunk.”  Signs included dysarthria, gait disturbance, tremor, and cognitive impairment, as well as dementia in some cases (later termed ‘dementia pugilistica’ by Millspaugh ). It is important to note that neurotrauma exposure in boxers of this era was extreme [180, 181]. Many hundreds of fights over a lengthy career, with additional exposure in boxer booths and as sparring partners for elite fighters, were commonplace. Medical oversight was limited, with no mandatory exclusion times. Boxers often used light gloves. Little care was taken to match evenly weighted or evenly skilled boxers, and there was little inclination to stop fights short of incapacitating and often multiple TBI of a range of severities. The emergence of neurological manifestations of TBI in this setting is therefore not surprising.
Theoretical constructs suggesting a relationship between TBI and chronic disease have evolved considerably. Concussion-related hemorrhage was suggested by Martland as a pathological substrate for Punch Drunk, but was discarded by the 1940s. Martland included autopsy data of acute TBI in a non-boxer to support his theory, although there was no mention of NFT or other neurodegenerative inclusions. The case itself depicted gross features of diffuse axonal injury, suggesting conflation with severe, acute TBI. Later pathogenic theory by Millspaugh also emphasized acute traumatic injury with no mention of NFT , suggesting some difficulty with an explanation for chronic disease and disease progression. Interestingly, the first report of microscopic neuropathology by Brandenburg and Hallervorden in 1954  indicated in retrospect a case of early-onset, and likely familial autosomal dominant AD, having nothing to do with boxing. The depiction of lesions that could aptly be regarded as “cotton wool” plaques, early-onset dementia, and extensive cerebral amyloid angiopathy suggest presenilin 1 mutation .
In 1973, Corsellis and colleagues  reported neuropathological features in 15 boxers from the early 20th century, most of whom had severe neurologic impairment. The findings included NFT, prominent in the medial temporal lobe and out of proportion to plaque pathology (distinguishing DP from AD), loss of pars compacta neurons of the substantia nigra, scarring of the cerebellar tonsils, and fenestrated cavum septum pellucidi. Thin fornices and atrophy of the mammillary bodies were common in this series. Vascular disease with infarcts and other co-morbidities such as contusions, neurosyphilis, and cavernous malformation were also present. The NFT assumed primary importance, however, eventually placing DP in the lexicon of tauopathies, and solidifying the notion of TBI-induced progressive degenerative tauopathy, perhaps prematurely. Careful examination of the clinical data and neuropathology from historical cases casts doubt on the concept of a progressive AD-like or PD-like neurodegenerative disease, or otherwise progressive degenerative tauopathy following a period of latency, even among early 20th century boxer with extreme levels of neurotrauma exposure .
The Corsellis et al. series was reported prior to the advent of immunohistochemistry (i.e., the concept of tauopathy), although case material from that series was relied upon for later immunohistochemical studies [185–188], likely because of reduced neurotrauma exposure in boxers and few new DP cases. Studies in recent years more often include asymptomatic boxers  (notwithstanding one death from acute TBI), or boxers who became symptomatic from other neurodegenerative diseases [190–193]. Boxing-related neuropathology has also become progressively more subtle, limited to immunohistochemical reactivity in some cases . In essence, there has been a shift in case material from men with unambiguous neurological signs due to head trauma from boxing, to deceased men who happened to have boxed.
Attempts to link TBI to neurodegenerative tauopathy in non-boxers from 2005 forward follow a similar pattern. Subjects either lacked neurological signs attributable to TBI or had other neurodegenerative diseases. Diagnosis instead relies only on brain p-tau interpretation [195, 196]. Identification of p-tau in some cases requires whole brain screening with free-floating immunohistochemistry of 50μm hemispheric sections obtained from a sledge microtome . Given the ubiquity of p-tau with age , the high frequency of p-tau deposits in former American football players is not surprising , nor is the fact that p-tau patterns attributed to TBI are described in people with no history of neurotrauma [198–202]. Data from other athlete cohorts are sparse, but tend to be similar. Autopsy studies of p-tau in former soccer players, for example, describe p-tau in athletes with either no neurological signs , or neurological signs attributable to known neurodegenerative diseases [204–208].
In summary, available scientific evidence does not demonstrate a causal link between athletic participation and progressive neurodegenerative tauopathy in athletes, or for that matter a risk for genuine neurodegenerative disease , either from TBI inferred from athletic participation or athletic participation in general. Such a link would also be in conflict with epidemiological data demonstrating that NFL athletes in particular have better overall health (lower cancer rates, lower mortality, better cardiovascular health), and lower suicide rates , notwithstanding a modest increase in AD and amyotrophic lateral sclerosis (ALS) , which may be explained by the lower mortality. Indeed, the superior overall health of the NFL cohort, combined with the reported high frequency of focal p-tau immunoreactivity, indicate axiomatically that the focal p-tau as described has no clinical impact across the group as a whole.
Military service members
Military service members are vulnerable to TBI because of the nature of armed conflict and military training, and also because of the increased use of improvised explosive devices (IEDs) . Most military service-related TBIs since 2006 have been associated with IED blasts . Case reports and small case series have likewise described focal p-tau immunoreactivity patterns, hypothesized to be due to blast-related TBI sustained in the service [214, 215]. Reports have gone so far as to suggest that post-traumatic stress disorder may share common neurobiological underpinnings with neurodegenerative tauopathy [214–216].
Some studies have suggested that military service-related TBI is a risk for AD specifically. A study of World War II veterans suggested that AD risk was increased in subjects with a history of moderate or severe TBI in a dose dependent fashion, with moderate TBI conferring roughly two-fold risk, and severe TBI conferring a roughly four-fold risk . The study did not find an AD risk with mild TBI, which is in line with one systematic review . However, one recent, large-scale case-control study of US veterans concluded that mild TBI without loss of consciousness conferred a modest risk for dementia as well as AD specifically . The risk was higher in mild TBI with loss of consciousness, and higher still with moderate or severe TBI, again suggesting a dose-dependent relationship between TBI and AD. A recent large cohort study of civilians in Denmark concluded that mild TBI conferred a modest risk for both dementia and AD .
Causal assertions from epidemiological studies remain hypothetical, however. The risks are overall modest as noted. The dose–response relationship between AD and TBI severity is also problematic in that severe TBI causes dementia and reduced life expectancy, while AD increases exponentially after middle age. Small relative risks in this setting may be due to misclassification of TBI-related dementia as AD in subset of cases. For example, Lewin et al.  studied 75 severely head-injured patients and found that patients often had dementia from TBI, with few surviving more than a decade. In another study, of 288,009 hospitalized survivors of TBI, 124,626 developed long-term disability including dementia . Accurately assessing AD risk in this setting may therefore require pathological confirmation (generally not available in large scale epidemiological studies), since moderate and severe TBI often include structural brain damage  (e.g., contusion, laceration, diffuse axonal injury), which may in turn cause “dementia.” To date, no longitudinal study demonstrating the sequence of TBI, a period of latency, clinical neurological deterioration, and autopsy-confirmed AD has been presented. More research is needed before the null hypothesis— that the reported dose-response relationship with service-related TBI and AD is a statistical artifact— can be rejected.
Blast-related TBI has emerged as a major cause of morbidity and mortality in military service. Blasts have been the most common cause of injury in American soldiers since 2006; of the ∼1 million veterans screened for TBI between 2007 and 2015, 8.4% reported TBI, the majority of which were mild and associated with blast . Injury to the brain associated with blasts is heterogeneous . Primary blast injury due to positive and negative pressure waves, secondary injury due to shrapnel, tertiary injury due to acceleration of the head and body across the war theater, and quaternary injury due any downstream pathology, including burns, lung injury, mass effect from brain swelling, ischemic brain injury, etc., are components of the blast injury complex. Neuropathological sequelae of primary blast injury are unclear, although early data suggest astroglial scarring at sites of differing tissue density (gray-white interface, periventricular tissue, perivascular areas, subpial areas) . P-tau proteinopathy was inconsistent in this series, arguing against the hypothesis of blast-induced tauopathy.
Tau immunohistochemistry, TBI, and diagnostic challenges
Given the complexities of tau biology as well as the unproven concept that TBI causes neurodegenerative tauopathy, limitations in the diagnostic process, for which there is a paucity of literature, may not be fully appreciated (Table 8). Pathological assessment and tissue sampling typically involve a multitude of brain regions, the standards for which are variable and evolving. Antibodies in common use for immunohistochemistry react with only one of a large number of candidate epitopes, and may have differing reactivities as a function of epitope, time, and lesion type . Human tissue is limited to postmortem brain, which is by definition partly decomposed and subjected to phosphatase activity as noted above. Epitopes that survive phosphatase activity are amplified by polymers , such that the tissue expression overestimates the true amount of p-tau. Cross reactivity is usually controlled for by omitting the primary antibody rather than by absorption with purified protein. The extent to which p-tau antibodies react with tau epitopes per se in any given case is, strictly speaking, unclear.
Neuropathological assessment by immunohistochemistry is therefore an entirely empirical exercise, permitting no conclusions about the nuances of tau pathobiology. The focus is instead on microscopic morphology [118, 173], which may be misleading as an indicator of disease or neurotoxicity (reviewed in ). P-tau immunohistochemistry also calls attention to selective vulnerability, for which there is no explanation. The questions of why, for example, the neurons of the cerebellar cortex are spared of p-tau even in end-stage neurodegenerative tauopathy, or why the neurons of the locus ceruleus or the basal nucleus of Meynert may accumulate p-tau early in life, separately or together, are unanswered. Factors responsible for AD variants such as limbic predominant AD and hippocampal sparing AD, are similarly elusive .
Added to the diagnostic challenges are limitless morphological variations and patterns of immunoreactivity [75, 173, 227] (Table 7). The NFT, dating to the early 20th century , was the primary lesion of interest until the identification of tau as the major protein component of NFT and the advent of immunohistochemistry. Neuropil threads, dystrophic neurites, and a variety of morphologic p-tau presentations within neurons in AD and FTLD-tau were described subsequently [120, 229]. Various morphological subtypes of glial inclusion are reported in recent literature, including tufted astrocytes, oligodendroglial coiled bodies, astrocytic plaques, globular astroglial inclusions, ramified astrocytes, “equivocal tufted astrocytes,” thorn-shaped astrocytes, and granular or fuzzy astrocytes, each considered somewhat specific among the tauopathies [120, 227, 230–234]. The error rate in distinguishing among these descriptive morphologies, irrespective of clinical correlation, is entirely unknown.
|Flame-shaped neurofibrillary tangle|
|Globus neurofibrillary tangle|
|Equivocal tufted astrocyte|
|Globular astroglial inclusion|
|Poor correlation of p-tau accumulations with clinical signs|
|Frequent lack of detailed TBI history|
|Evolving standards for sampling, immunohistochemistry, and diagnosis|
|Subjectivity in interpreting p-tau accumulations and tissue architecture|
|Broadening spectrum of benign, age-related p-tau patterns|
|Lack of guidelines for assessing vascular disease, metabolic derangements, polypharmacy|
|Unknown error rate between and within neuropathologists|
|Variable clinical characterization of individual cases during life|
|Absence of genetic data|
|Broad public misunderstanding of TBI consequences driven by scientifically naïve media|
|Absence of patient consequences for misdiagnosis at autopsy|
|Vulnerability to ipse dixit interpretation|
Clinical correlations in neurodegenerative proteinopathy are also more limited than may be appreciated . For example, AD proteinopathy cannot predict the level of cognitive dysfunction unless the pathology is end-stage . Decedents with a substantial level of p-tau pathology in their medial temporal memory circuitry are often cognitively normal . In the elderly, proteinopathy is virtually meaningless as a predictor of cognitive function by blinded analysis . Proteinopathy cannot distinguish clinical Parkinson’s disease from the clinical presentation of Lewy body dementia . PSP p-tau pathology may be associated with CBD clinical manifestations, and vice versa. Both PSP and CBD p-tau pathology may occur in patients with the behavioral variant of frontotemporal dementia or primary progressive aphasia . Patients with frontotemporal lobar degeneration may show signs of ALS, and patients with ALS may develop the spectrum of frontotemporal dementia phenotypes , none of which have been shown to correlate with proteinopathy burden with any degree of precision. The presence of neurodegeneration, i.e., neuronal/axonal degeneration, has an inconsistent relationship with p-tau pathology in CBD and PSP . Clinical signs correlate more with neurodegeneration than proteinopathy , suggesting that proteinopathy may be epiphenomenal in some cases. This may explain substantial proteinopathy with intact cognition [118, 170, 173, 236], or the lack of a clinical correlate of p-tau pathology described in former athletes or military service members. There are also few guidelines for assessing metabolic derangements, numerous medications, and microvascular disease , which influence cognition independent of proteinopathy.
Some guidance is available in terms of consensus recommendations [118, 119, 173, 238, 240–242], although these tend to be provisional and subject to repeated modification. Because of the nature of consensus guidelines, i.e., the formal recognition that the science is unresolved, their application in neuropathology tends toward precision (consistency in pathological assessment), rather than accuracy in identifying clinical disease. This is reflected in consensus recommendations for AD, in which the preferred terminology is “Alzheimer’s disease neuropathologic change,” irrespective of clinical findings during life . Similarly, consensus recommendations for frontotemporal lobar degeneration are concerned with patterns of neuropathology rather than clinical subtypes .
Added to the bewildering array of pathological lesions and clinical correlations, is the human element. The breadth of circumstances associated with prospective case material, and interpretation for the sake of diagnosis for interested families, may be considerable. Any given case may present with little or no clinical information, and variably rigorous clinical disease classification during life. The specialization of treating physicians may vary from general family practitioners to neurologists with specific expertise in dementia and movement disorders. Genetic data is often not available. Imaging studies may cloud the diagnostic process by suggesting some conditions over others based on variable image acquisition sequences and soft anatomical data.
The diagnostic process may be even more challenging in the arena of presumed repetitive neurotrauma. TBI history may be absent or incomplete, or inferred from a history of athletic participation or military service. Surviving next-of-kin may believe that recent onset of psychiatric signs is due to sport participation many decades prior. A family may be struggling with an inexplicable neurodegeneration in a family member. They may believe that concussion causes suicidal ideation or neurodegeneration because of scientifically naÏve media reporting [243–245], or they may be unwilling or unable to accept that a family member took his or her own life. Families may demand that certain items appear or not appear on death certificates, or they may be interested in seeking damages from a third party, which may in turn lead to profligate tissue sampling and p-tau immunostaining in an attempt to confirm a desired diagnosis. The diagnostic process further takes place in the autopsy setting, in which misdiagnosis has no impact on the patient. These factors taken together may encourage ipse dixit interpretation, and present major challenges to objective and accurate disease classification.
The foundation for tau toxicity theory dates to Alzheimer’s description of the NFT in 1906. It began in earnest with the identification of tau, a protein co-factor involved in the polymerization of tubulin, as a major protein component of the NFT. Subsequent pathogenic theory, including kinase-phosphatase imbalance, soluble assembly intermediates, and prion-like propagation, is rooted in the concept that pathological lesions represent neurotoxicity. The limiting factor for this neurotoxicity bias may be the light microscope. But for the visible microscopic inclusions, p-tau neurotoxicity theory and the extensive literature that now accompanies it, would not exist. The question nevertheless remains whether neurodegenerative inclusions embody a dynamic, primary etiopathogenesis, or instead downstream epiphenomena that distract from a more fundamental upstream biology.
Investigations from multiple perspectives including molecular, genetic, experimental, pathological, and clinical, indicate complex tau biology that bridges normal metabolic processes, neurodevelopment, healthy aging, and neurodegenerative disease. Normal tau, including tau phosphorylation, is necessary for development, cell cycle activity, synaptic function, and neuroplasticity. P-tau in postmortem brain may tend toward buried epitopes, insolubility, and limited biological meaning. Clinicopathological correlations with inert p-tau inclusions are fraught with imprecision. Neurodegeneration in the true sense, that is degeneration of neurons with an associated tissue reaction, is the better clinical correlate, while p-tau immunoreactivity in the absence of neurodegeneration and clinical signs may be extensive. P-tau neuropathology is ultimately a superficial indicator of tau pathophysiology, and may be misleading in terms of cause and effect.
Uncertainties in the repetitive TBI-tauopathy paradigm are considerable. TBI definitions are widely variable. Thresholds for mechanical tissue injury are impossible to quantify. Human data in athletes are limited to case reports and heterogeneous case series with little to no TBI history other than that inferred from participation. Brain tissue interpretation may require expensive, labor-intensive research methodology that has yet to be validated for diagnostic purposes. The concept of a decades’ long period of latency between TBI exposure and neurodegenerative disease is often asserted, but has not been convincingly demonstrated, even in boxers. P-tau, especially p-tau identified in postmortem brain, is debatable as a driver of clinical disease, and is in part an artifact of postmortem decomposition. Importantly, epidemiological data indicate better overall health in the NFL athlete cohort, compared to the control population, casting doubt on the idea of a pervasive neurodegenerative disease from athletic participation. In former military service members, epidemiological studies of dementia or AD (and associated tauopathy) risk with mild TBI show modest risk or no risk, which essentially precludes causality. The dose-dependent risk of AD with TBI severity is based on large-scale epidemiology with no pathological confirmation of tauopathy. To these uncertainties and contrary data are added the tau prion concept, soluble low-n assembly intermediates, and geometric isomers, making for limitless theoretical possibilities and the potential for constructs more metaphysical than biological.
Finally, the diagnostic process with respect to tauopathy in postmortem brain is problematic. Clinical correlation is poor, standard methodology for postmortem brain examination is lacking, diagnostic error rates are unknown, and there may be external influences that degrade diagnostic accuracy. Such challenges, along with the consequence-free environment of postmortem diagnosis, may risk autopsy confirmation of individual preferences rather than genuine neurodegenerative disease.
Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/18-0721r1).
Weingarten MD , Lockwood AH , Hwo SY , Kirschner MW (1975) A protein factor essential for microtubule assembly. Proc Natl Acad Sci USA 72, 1858–1862.
Cleveland DW , Hwo SY , Kirschner MW (1977) Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J Mol Biol 116, 207–225.
Nishida E , Kotani S , Kuwaki T , Sakai H (1982) Phosphorylation of microtubule-associated proteins controls both microtubule assembly and MAP-actin interaction. In Biological Functions of Microtubules and Related Structures, Sakai H , Mohri H , Borisy G , eds. Academic Press, New York, pp. 285–295.
Lindwall G , Cole RD (1984) Phosphorylation affects the ability of tau protein to promote microtubule assembly. J Biol Chem 259, 5301–5305.
Brion JP , Passareiro H , Nunez J , Flament-Durand J (1985) Mise en evidence immunologique de la proteine tau au niveau des lesions de degenerescence neurofibrillaire de la maladie d'Alzheimer. Arch Biol 95, 229–35.
Grundke-Iqbal I , Iqbal K , Quinlan M , Tung YC , Zaidi MS , Wisniewski HM (1986) Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 261, 6084–6089.
Neve RL , Harris P , Kosik KS , Kurnit DM , Donlon TA (1986) Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule- associated protein 2. Mol Brain Res 1, 271–280.
Goedert M , Spillantini MG , Jakes R , Rutherford D , Crowther RA (1989) Multiple isoforms of human microtubule-associated protein tau: Sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3, 519–526.
Goedert M , Spillantini MG , Potier MC , Ulrich J , Crowther RA (1989) Cloning and sequencing of the cDNA encoding an isoform of microtubule- associated protein tau containing four tandem repeats: Differential expression of tau protein mRNAs in human brain. EMBO J 8, 393–399.
Himmler A (1989) Structure of the bovine tau gene: Alternatively spliced transcripts generate a protein family. Mol Cell Biol 9, 1389–1396.
Andreadis A (2005) Tau gene alternative splicing: Expression patterns, regulation and modulation of function in normal brain and neurodegenerative diseases. Biochim Biophys Acta 1739, 91–103.
Spillantini MG , Goedert M (1998) Tau protein pathology in neurodegenerative diseases. Trends Neurosci 21, 428–433.
Goedert M , Jakes R (1990) Expression of separate iso-forms of human tau protein: Correlation with the tau pattern in brain and effects on tubulin polymerization. EMBO J 9, 4225–4230.
Hong M (1998) Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282, 1914–1917.
Couchie D , Mavilia C , Georgieff IS , Liem RK , Shelanski ML , Nunez J (1992) Primary structure of high molecular weight tau present in the peripheral nervous system. Proc Natl Acad Sci USA 89, 4378–4381.
Nunez J , Fischer I (1997) Microtubule-associated proteins (MAPs) in the peripheral nervous system during development and regeneration. J Mol Neurosci 8, 207–222.
Kopke E , Tung YC , Shaikh S , Del Alonso CA , Iqbal K , Grundke-Iqbal I (1993) Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J Biol Chem 268, 24374–24384.
Simons DJ , Land PW (1987) Early experience of tactile stimulation influences organization of somatic sensory cortex. Nature 326, 694–697.
Janke C , Holzer M , Klose J , Arendt T (1996) Distribution of isoforms of the microtubule-associated protein tau in grey and white matter areas of human brain: A two-dimensional gelelectrophoretic analysis. FEBS Lett 379, 222–226.
Igaev M , Janning D , Sündermann F , Niewidok B , Brandt R , Junge W (2015) A refined reaction-diffusion model of tau-microtubule dynamics and its application in FDAP analysis. Biophys J 107, 2567–2578.
Al-Bassam J , Ozer RS , Safer D , Halpain S , Milligan RA (2002) MAP2 and tau bind longitudinally along the outer ridges of microtubule protofilaments. J Cell Biol 157, 1187–1196.
Kosik KS , Orecchio LD , Bakalis S , Neve RL (1989) Developmentally regulated expression of specific tau sequences. Neuron 2, 1389–1397.
Higuchi M , Ishihara T , Zhang B , Hong M , Andreadis A , Trojanowski JQ , Lee VMY (2002) Transgenic mouse model of tauopathies with glial pathology and nervous system degeneration. Neuron 35, 433–446.
Baker M , Litvan I , Houlden H , Adamson J , Dickson D , Perez-Tur J , Hardy J , Lynch T , Bigio E , Hutton M (1999) Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 8, 711–715.
Cruts M , Rademakers R , Gijselinck I , van der Zee J , Dermaut B , de Pooter T , de Rijk P , Del-Favero J , van Broeckhoven C (2005) Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region. Hum Mol Genet 14, 1753–1762.
Stefansson H , Helgason A , Thorleifsson G , Steinthorsdottir V , Masson G , Barnard J , Baker A , Jonasdottir A , Ingason A , Gudnadottir VG , Desnica N , Hicks A , Gylfason A , Gudbjartsson DF , Jonsdottir GM , Sainz J , Agnarsson K , Birgisdottir B , Ghosh S , Olafsdottir A , Cazier JB , Kristjansson K , Frigge ML , Thorgeirsson TE , Gulcher JR , Kong A , Stefansson K (2005) A common inversion under selection in Europeans. Nat Genet 37, 129–137.
Di Maria E , Tabaton M , Vigo T , Abbruzzese G , Bellone E , Donati C , Frasson E , Marchese R , Montagna P , Munoz DG , Pramstaller PP , Zanusso G , Ajmar F , Mandich P (2000) Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy. Ann Neurol 47, 374–337.
Pastor P , Ezquerra M , Munoz E , Marti MJ , Blesa R , Tolosa E , Oliva R (2000) Significant association between the tau gene A0/A0 genotype and Parkinson's disease. Ann Neurol 47, 242–245.
Togo T , Sahara N , Yen SH , Cookson N , Ishizawa T , Hutton M , De Silva R , Lees A , Dickson DW (2002) Argyrophilic grain disease is a sporadic 4-repeat tauopathy. J Neuropathol Exp Neurol 61, 547–556.
Pittman AM , Myers AJ , Abou-Sleiman P , Fung HC , Kaleem M , Marlowe L , Duckworth J , Leung D , Williams D , Kilford L , Thomas N , Morris CM , Dickson D , Wood NW , Hardy J , Lees AJ , De Silva R (2005) Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration. J Med Genet 42, 837–846.
Cruchaga C , Vidal-Taboada JM , Ezquerra M , Lorenzo E , Martinez-Lage P , Blazquez M , Tolosa E , Pastor P , Gaig C , Marti MJ , Molinuevo JL , Valldeoriola F , Campdelacreu J , Masdeuf JC , Luquin R , Obesof JA , Pastor MA , Riverol M , Rodriguezf MC , Villoslada P , Tunon T , Huerta C , Alvarez V , Calopa M , Erro E , Rojo A , Ruiz J (2009) 5′-upstream variants of CRHR1 and MAPT genes associated with age at onset in progressive supranuclear palsy and cortical basal degeneration. Neurobiol Dis 33, 164–170.
Caffrey TM , Wade-Martins R (2012) The role of MAPT sequence variation in mechanisms of disease susceptibility. Biochem Soc Trans 40, 687–692.
Caffrey TM , Joachim C , Wade-Martins R (2008) Haplotype-specific expression of the N-terminal exons 2 and 3 at the human MAPT locus. Neurobiol Aging 29, 1923–1929.
Jones EL , Margallo-Lana M , Prasher VP , Ballard CG (2008) The extended tau haplotype and the age of onset of dementia in Down syndrome. Dement Geriatr Cogn Disord 26, 199–202.
Drubin DG , Feinstein SC , Shooter EM , Kirschner MW (1985) Nerve growth factor-induced neurite outgrowth in PC12 cells involves the coordinate induction of microtubule assembly and assembly-promoting factors. J Cell Biol 101, 1799–1807.
Hirokawa N , Shiomura Y , Okabe S (1988) Tau proteins: The molecular structure and mode of binding on microtubules. J Cell Biol 107, 1449–1459.
Kempf M , Clement A , Faissner A , Lee G , Brandt R (1996) Tau binds to the distal axon early in development of polarity in a microtubule- and microfilament-dependent manner. J Neurosci 16, 5583–5592.
Liu CWA , Lee G , Jay DG (1999) Tau is required for neurite outgrowth and growth cone motility of chick sensory neurons. Cell Motil Cytoskeleton 43, 232–242.
Takei Y , Teng J , Harada A , Hirokawa N (2000) Defects axonal elongation and neuronal migration in mice with disrupted tau and map1b genes. J Cell Biol 150, 989–1000.
Samsonov A (2004) Tau interaction with microtubules in vivo . J Cell Sci 117, 6129–6141.
Dixit R , Ross JL , Goldman YE , Holzbaur ELF (2008) Differential regulation of dynein and kinesin motor proteins by tau. Science 319, 1086–1089.
Brandt R , Leger J , Lee G (1995) Interaction of tau with the neural plasma membrane mediated by tau's amino-terminal projection domain. J Cell Biol 131, 1327–1340.
Buee L , Bussiere T , Buee-Scherrer V , Delacourte A , Hof PR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Rev 33, 95–130.
Maas T , Eidenmüller J , Brandt R (2000) Interaction of tau with the neural membrane cortex is regulated by phos- phorylation at sites that are modified in paired helical filaments. J Biol Chem 275, 15733–15740.
Fulga TA , Elson-Schwab I , Khurana V , Steinhilb ML , Spires TL , Hyman BT , Feany MB (2007) Abnormal bundling and accumulation of F-actin mediates tau- induced neuronal degeneration in vivo . Nat Cell Biol 9, 139–148.
Jensen PH , Hager H , Nielsen MS , Højrup P , Gliemann J , Jakes R (1999) Alpha-synuclein binds to tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356. J Biol Chem 274, 25481–25489.
Uversky VN (2010) Targeting intrinsically disordered proteins in neurodegenerative and protein dysfunction diseases: Another illustration of the D2concept. Expert Rev Proteomics 7, 543–564.
Gunawardana CG , Mehrabian M , Wang X , Mueller I , Lubambo IB , Jonkman JEN , Wang H , Schmitt-Ulms G (2015) The human tau interactome: Binding to the ribonucleoproteome, and impaired binding of the proline-to-leucine mutant at position 301 (P301L) to chaperones and the proteasome. Mol Cell Proteomics 14, 3000–3014.
Lee G (2005) Tau and src family tyrosine kinases. Biochim Biophys Acta 1739, 323–330.
Wang S , Zhou S lei , Min F yuan , Ma J ju , Shi X jie , Bereczki E , Wu J (2014) mTOR-mediated hyperphosphorylation of tau in the hippocampus is involved in cognitive deficits in streptozotocin-induced diabetic mice. Metab Brain Dis 29, 729–736.
El Khoury NB , Gratuze M , Papon M-A , Bretteville A , Planel E (2014) Insulin dysfunction and Tau pathology. Front Cell Neurosci 8, 22.
Platt TL , Beckett TL , Kohler K , Niedowicz DM , Murphy MP (2016) Obesity, diabetes, and leptin resistance promote tau pathology in a mouse model of disease. Neuroscience 315, 162–174.
Yanagisawa M , Planel E , Ishiguro K , Fujita SC (1999) Starvation induces tau hyperphosphorylation in mouse brain: Implications for Alzheimer’s disease. FEBS Lett 461, 329–333.
Planel E , Miyasaka T , Launey T , Chui D-H , Tanemura K , Sato S , Murayama O , Ishiguro K , Tatebayashi Y , Takashima A (2004) Alterations in glucose metabolism induce hypothermia leading to tau hyperphosphorylation through differential inhibition of kinase and phosphatase activities: Implications for Alzheimer’s disease. J Neurosci 24, 2401–2411.
Le Freche H , Brouillette J , Fernandez-Gomez F-J , Patin P , Caillierez R , Zommer N , Sergeant N , Buee-Scherrer V , Lebuffe G , Blum D , Buee L (2012) Tau phosphorylation and sevoflurane anesthesia: An association to postoperative cognitive impairment. Anesthesiology 116, 779–787.
Whittington RA , Bretteville A , Dickler MF , Planel E (2013) Anesthesia and tau pathology. Prog Neuropsychopharmacol Biol Psychiatry 47, 147–155.
Sotiropoulos I , Catania C , Pinto LG , Silva R , Pollerberg GE , Takashima A , Sousa N , Almeida OFX (2011) Stress acts cumulatively to precipitate Alzheimer’s disease-like tau pathology and cognitive deficits. J Neurosci 31, 7840–7847.
Morris M , Knudsen GM , Maeda S , Trinidad JC , Ioanoviciu A , Burlingame AL , Mucke L (2015) Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice. Nat Neurosci 18, 1183–1189.
Regan P , Whitcomb DJ , Cho K (2017) Physiological and pathophysiological implications of synaptic tau. Neuroscientist 23, 137–151.
Arnold CS , Johnson GV , Cole RN , Dong DL , Lee M , Hart GW (1996) The microtubule-associated protein tau is extensively modified with O-linked N-acetylglucosamine. J Biol Chem 271, 28741–28744.
Smith MA , Taneda S , Richey PL , Miyata S , Yant SD , Sternt D , Sayre LM , Monnier VM , Perry G (1994) Advanced Maillard reaction end products are associated with Alzheimer disease pathology. Neurobiology 91, 5710–5714.
Mori H , Kondo J , Ihara Y (1987) Ubiquitin is a component of paired helical filaments in Alzheimer’s disease. Science 235, 1641–1644.
Dorval V , Fraser PE (2006) Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and a-synuclein. J Biol Chem 281, 9919–9924.
Horiguchi T , Uryu K , Giasson BI , Ischiropoulos H , Light-Foot R , Bellmann C , Richter-Landsberg C , Lee VMY , Trojanowski JQ (2003) Nitration of tau protein is linked to neurodegeneration in tauopathies. Am J Pathol 163, 1021–1031.
Cohen TJ , Guo JL , Hurtado DE , Kwong LK , Mills IP , Trojanowski JQ , Lee VMY (2011) The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat Commun 2, 252.
Nakamura K , Greenwood A , Binder L , Bigio EH , Denial S , Nicholson L , Zhou XZ , Lu KP (2012) Proline isomer-specific antibodies reveal the early pathogenic tau conformation in Alzheimer’s disease. Cell 149, 232–244.
Wischik CM , Novak M , Thøgersen HC , Edwards PC , Runswick MJ , Jakes R , Walker JE , Milstein C , Roth M , Klug A (1988) Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA 85, 4506–4510.
Tai HC , Serrano-Pozo A , Hashimoto T , Frosch MP , Spires-Jones TL , Hyman BT (2012) The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system. Am J Pathol 181, 1426–1435.
Fein JA , Sokolow S , Miller CA , Vinters HV , Yang F , Cole GM , Gylys KH (2008) Co-localization of amyloid beta and tau pathology in Alzheimer’s disease synaptosomes. Am J Pathol 172, 1683–1692.
Kimura T , Whitcomb DJ , Jo J , Regan P , Piers T , Heo S , Brown C , Hashikawa T , Murayama M , Seok H , Sotiropou-los I , Kim E , Collingridge GL , Takashima A , Cho K (2013) Microtubule-associated protein tau is essential for long-term depression in the hippocampus. Philos Trans R Soc B Biol Sci 369, 20130144.
Frandemiche ML , De Seranno S , Rush T , Borel E , Elie A , Arnal I , Lante F , Buisson A (2014) Activity-dependent tau protein translocation to excitatory synapse is disrupted by exposure to amyloid-beta oligomers. J Neurosci 34, 6084–6097.
Regan P , Piers T , Yi J-H , Kim D-H , Huh S , Park SJ , Ryu JH , Whitcomb DJ , Cho K (2015) Tau phosphorylation at serine 396 residue is required for hippocampal LTD. JNeurosci 35, 4804–4812.
Malmqvist T , Anthony K , Gallo JM (2014) Tau mRNA is present in axonal RNA granules and is associated with elongation factor 1A. Brain Res 1584, 22–27.
Aronov S , Aranda G , Behar L , Ginzburg I (2001) Axonal tau mRNA localization coincides with tau protein in living neuronal cells and depends on axonal targeting signal. J Neurosci 21, 6577–6587.
Arendt T , Stieler JT , Holzer M (2016) Tau and tauopathies. Brain Res Bull 126, 238–292.
Moraga DM , Nunez P , Garrido J , Maccioni RB (1993) A T fragment containing a repetitive sequence induces bundling of actin filaments. J Neurochem 61, 979–986.
Hering H , Sheng M (2001) Dentritic spines: Structure, dynamics and regulation. Nat Rev Neurosci 2, 880–888.
Wang Y , Loomis PA , Zinkowski RP , Binder LI (1993) A novel tau transcript in cultured human neuroblastoma cells expressing nuclear tau. J Cell Biol 121, 257–267.
Loomis PA , Howard TH , Castleberry RP , Binder LI (1990) Identification of nuclear tau isoforms in human neuroblastoma cells. Proc Natl Acad Sci USA 87, 8422–8426.
Thurston VC , Pena P , Pestell R , Binder LI (1997) Nucleolar localization of the microtubule-associated protein tau in neuroblastomas using sense and anti-sense transfection strategies. Cell Motil Cytoskeleton 38, 100–110.
Qi H , Cantrelle F-X , Benhelli-Mokrani H , Smet-Nocca C , Buee L , Lippens G , Bonnefoy E , Galas M-C , Landrieu I (2015) Nuclear magnetic resonance spectroscopy characterization of interaction of tau with DNA and its regulation by phosphorylation. Biochemistry 54, 1525–1533.
Camero S , Benitez MJ , Cuadros R , Hernandez F , Avila J , Jimenez JS (2014) Thermodynamics of the interaction between Alzheimer’s disease related tau protein and DNA. PLoS One 9, e104690.
Sjoberg MK (2006) Tau protein binds to pericentromeric DNA: A putative role for nuclear tau in nucleolar organization. J Cell Sci 119, 2025–2034.
Sultan A , Nesslany F , Violet M , Begard S , Loyens A , Talahari S , Mansuroglu Z , Marzin D , Sergeant N , Humez S , Colin M , Bonnefoy E , Buee L , Galas MC (2011) Nuclear tau, a key player in neuronal DNA protection. J Biol Chem 286, 4566–4575.
Ke Y , Dramiga J , Schutz U , Kril JJ , Ittner LM , Schroder H , Götz J (2012) Tau-mediated nuclear depletion and cytoplasmic accumulation of SFPQ in Alzheimer’s and Pick's disease. PLoS One 7, e35678.
Vanderweyde T , Apicco DJ , Youmans-Kidder K , Ash PEA , Cook C , Lummertz da Rocha E , Jansen-West K , Frame AA , Citro A , Leszyk JD , Ivanov P , Abisambra JF , Steffen M , Li H , Petrucelli L , Wolozin B (2016) Interaction of tau with the RNA-binding protein TIA1 regulates tau pathophysiology and toxicity. Cell Rep 15, 1455–1466.
Papasozomenos SC , Binder LI (1987) Phosphorylation determines two distinct species of Tau in the central nervous system. Cell Motil Cytoskeleton 8, 210–226.
LoPresti P , Szuchet S , Papasozomenos SC , Zinkowski RP , Binder LI (1995) Functional implications for the microtubule-associated protein tau: Localization in oligodendrocytes. Proc Natl Acad Sci USA 92, 10369–10373.
Gorath M , Stahnke T , Mronga T , Goldbaum O , RichterLandsberg C (2001) Developmental changes of tau protein and mRNA in cultured rat brain oligodendrocytes. Glia 36, 89–101.
Seiberlich V , Bauer NG , Schwarz L , Ffrench-Constant C , Goldbaum O , Richter-Landsberg C (2015) Downregulation of the microtubule associated protein Tau impairs process outgrowth and myelin basic protein mRNA transport in oligodendrocytes. Glia 63, 1621–1635.
Uversky VN (2002) What does it mean to be natively unfolded? Eur J Biochem 269, 2–12.
Uversky VN (2015) Intrinsically disordered proteins and their (disordered) proteomes in neurodegenerative disorders. Front Aging Neurosci 7, 18.
Jeganathan S , Von Bergen M , Mandelkow EM , Mandelkow E (2008) The natively unfolded character of Tau and its aggregation to Alzheimer-like paired helical filaments. Biochemistry 47, 10526–10539.
Kopeikina KJ , Hyman BJ , Spires-Jones TL (2012) Soluble forms of tau are toxic in Alzheimer’s disease. Transl Neurosci 3, 223–233.
Xia D , Li C , Gotz J (2015) Pseudophosphorylation of tau at distinct epitopes or the presence of the P301L mutation targets the microtubule-associated protein tau to dendritic spines. Biochim Biophys Acta 1852, 913–924.
LaPointe NE , Morfini G , Pigino G , Gaisina IN , Kozikowski AP , Binder LI , Brady ST (2009) The amino terminus of tau inhibits kinesin-dependent axonal transport: Implications for filament toxicity. J Neurosci Res 87, 440–451.
Ebneth A , Godemann R , Stamer K , Illenberger S , Trinczek B , Mandelkow EM , Mandelkow E (1998) Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: Implications for Alzheimer’s disease. J Cell Biol 143, 777–794.
Cardona-Gomez GP , Arango-Davila C , Gallego-Gomez JC , Barrera-Ocampo A , Pimienta H , Garcia-Segura LM (2006) Estrogen dissociates tau and alpha-amino-3-hydroxy-5-methylisoxazole-4- propionic acid receptor subunit in postischemic hippocampus. Neuroreport 17, 1337–1341.
Strittmatter WJ , Saunders AM , Goedert M , Weisgraber KH , Dong LM , Jakes R , Huang DY , Pericak-Vance M , Schmechel D , Roses AD (1994) Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: Implications for Alzheimer disease. Proc Natl Acad Sci USA 91, 11183–11186.
Lee G , Newman ST , Gard DL , Band H , Panchamoorthy G (1998) Tau interacts with src-family non-receptor tyrosine kinases. J Cell Sci 111(Pt 2), 3167–3177.
Bhaskar K , Yen SH , Lee G (2005) Disease-related modifications in tau affect the interaction between Fyn and tau. J Biol Chem 280, 35119–35125.
Smet C , Sambo AV , Wieruszeski JM , Leroy A , Landrieu I , Buee L , Lippens G (2004) The peptidyl prolyl cis/trans-isomerase Pin1 recognizes the phospho-Thr212-Pro213 site on tau. Biochemistry 43, 2032–2040.
Baumann K , Mandelkow EM , Biernat J , Piwnica-Worms Mandelkow E (1993) Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5. FEBS Lett 336, 417–424.
Arendt T , Holzer M , Stobe A , Gartner U , Luth HJ , Brückner MK , Ueberham U (2000) Activated mitogenic signaling induces a process of dedifferentiation in Alzheimer’s disease that eventually results in cell death. Ann N Y Acad Sci 920, 249–255.
Arendt T (2004) Neurodegeneration and plasticity. Int J Dev Neurosci 22, 507–514.
Yoshida H , Goedert M (2006) Sequential phosphorylation of tau protein by cAMP-dependent protein kinase and SAPK4/p38delta or JNK2 in the presence of heparin generates the AT100 epitope. J Neurochem 99, 154–164.
Liu F , Grundke-Iqbal I , Iqbal K , Gong CX (2005) Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci 22, 1942–1950.
Qian W , Shi J , Yin X , Iqbal K , Grundke-Iqbal I , Gong CX , Liu F (2010) PP2A regulates tau phosphorylation directly and also indirectly via activating GSK-3ß. J Alzheimers Dis 19, 1221–1229.
Simic G , Babic Leko M , Wray S , Harrington C , Delalle I , Jovanov-Milosevic N , Bazadona D , Buee L , de Silva R , Giovanni G Di , Wischik C , Hof PR (2016) Tau protein hyperphosphorylation and aggregation in Alzheimer’s disease and other tauopathies, and possible neuroprotective strategies. Biomolecules 6, 2–28.
Noble W , Hanger DP , Miller CCJ , Lovestone S (2013) The importance of tau phosphorylation for neurodegenerative diseases. Front Neurol 4, 83.
Morishima-Kawashima M , Hasegawa M , Takio K , Suzuki M , Yoshida H , Watanabe A , Titani K , Ihara Y (1995) Hyperphosphorylation of tau in PHF. Neurobiol Aging 16, 365–371.
Hanger DP , Byers HL , Wray S , Leung KY , Saxton MJ , Seereeram A , Reynolds CH , Ward MA , Anderton BH (2007) Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. J Biol Chem 282, 23645–23654.
Ksiezak-Reding H , Liu WK , Yen SH (1992) Phosphate analysis and dephosphorylation of modified tau associated with paired helical filaments. Brain Res 597, 209–219.
Kondo A , Shahpasand K , Mannix R , Qiu J , Moncaster J , Chen CH , Yao Y , Lin YM , Driver JA , Sun Y , Wei S , Luo ML , Albayram O , Huang P , Rotenberg A , Ryo A , Goldstein LE , Pascual-Leone A , McKee AC , Meehan W , Zhou XZ , Lu KP (2015) Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature 523, 431–436.
Albayram O , Kondo A , Mannix R , Smith C , Tsai CY , Li C , Herbert MK , Qiu J , Monuteaux M , Driver J , Yan S , Gormley W , Puccio AM , Okonkwo DO , Lucke-Wold B , Bailes J , Meehan W , Zeidel M , Lu KP , Zhou XZ (2017) Cis P-tau is induced in clinical and preclinical brain injury and contributes to post-injury sequelae. Nat Commun 8, 1000.
Bancher C , Brunner C , Lassmann H , Budka H , Jellinger K , Wiche G , Seitelberger F , Grundke-Iqbal I , Iqbal K , Wisniewski HM (1989) Accumulation of abnormally phosphorylated T precedes the formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res 477, 90–99.
Castellani RJ , Lee H-G , Zhu X , Perry G , Smith MA (2008) Alzheimer disease pathology as a host response. J Neuropathol Exp Neurol 67, 523–531.
Crary JF , Trojanowski JQ , Schneider JA , Abisambra JF , Abner EL , Alafuzoff I , Arnold SE , Attems J , Beach TG , Bigio EH , Cairns NJ , Dickson DW , Gearing M , Grinberg LT , Hof PR , Hyman BT , Jellinger K , Jicha GA , Kovacs GG , Knopman DS , Kofler J , Kukull WA , Mackenzie IR , Masliah E , McKee A , Montine TJ , Murray ME , Neltner JH , Santa-Maria I , Seeley WW , Serrano-Pozo A , Shelanski ML , Stein T , Takao M , Thal DR , Toledo JB , Troncoso JC , Vonsattel JP , White CL , Wisniewski T , Woltjer RL , Yamada M , Nelson PT (2014) Primary age-related tauopathy (PART): A common pathology associated with human aging. Acta Neuropathol 128, 755–766.
Montine TJ , Phelps CH , Beach TG , Bigio EH , Cairns NJ , Dickson DW , Duyckaerts C , Frosch MP , Masliah E , Mirra SS , Nelson PT , Schneider JA , Thal DR , Trojanowski JQ , Vinters HV , Hyman BT (2012) National institute on aging-Alzheimer’s association guidelines for the neuropathologic assessment of Alzheimer’s disease: A practical approach. Acta Neuropathol 123, 1–11.
Dickson DW , Kouri N , Murray ME , Josephs KA (2011) Neuropathology of frontotemporal lobar degeneration-tau (FTLD-Tau). J Mol Neurosci 45, 384–389.
Allen B , Ingram E , Takao M , Smith MJ , Jakes R , Virdee K , Yoshida H , Holzer M , Craxton M , Emson PC , Atzori C , Migheli A , Crowther RA , Ghetti B , Spillantini MG , Goedert M (2002) Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci 22, 9340–9351.
Matsuo ES , Shin RW , Billingsley ML , Van deVoorde A , O'Connor M , Trojanowski JQ , Lee VMY (1994) Biopsyderived adult human brain tau is phosphorylated at many of the same sites as Alzheimer’s disease paired helical filament tau. Neuron 13, 989–1002.
Song J , Combs CK , Pilcher WH , Song LY , Utal AK , Coleman PD (1997) Low initial tau phosphorylation in human brain biopsy samples. Neurobiol Aging 18, 475–481.
Wang Y , Zhang Y , Hu W , Xie S , Gong CX , Iqbal K , Liu F (2015) Rapid alteration of protein phosphorylation during postmortem: Implication in the study of protein phosphorylation. Sci Rep 5, 15709.
Oka T , Tagawa K , Ito H , Okazawa H (2011) Dynamic changes of the phosphoproteome in postmortem mouse brains. PLoS One 6, e21405.
Gartner U , Janke C , Holzer M , Vanmechelen E , Arendt T (1998) Postmortem changes in the phosphorylation state of tau-protein in the rat brain. Neurobiol Aging 19, 535–543.
Li J , Gould TD , Yuan P , Manji HK , Chen G (2003) Post-mortem interval effects on the phosphorylation of signaling proteins. Neuropsychopharmacology 28, 1017–1025.
Scharf MT , Mackiewicz M , Naidoo N , O'Callaghan JP , Pack AI (2008) AMP-activated protein kinase phosphorylation in brain is dependent on method of killing and tissue preparation. J Neurochem 105, 833–841.
Kuret J , Chirita CN , Congdon EE , Kannanayakal T , Li G , Necula M , Yin H , Zhong Q (2005) Pathways of tau fibrillization. Biochim Biophys Acta 1739, 167–178.
Mandelkow EM , Mandelkow E (2011) Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb Perspect Biol 3, 1–25.
Ross CA , Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10, S10–S17.
Bramblett GT , Goedert M , Jakes R , Merrick SE , Trojanowski JQ , Lee VMY (1993) Abnormal tau phosphorylation at Ser396in Alzheimer’s disease recapitulates development and contributes to reduced microtubule binding. Neuron 10, 1089–1099.
Yoshida H , Ihara Y (1993) Tau in paired helical filaments is functionally distinct from fetal tau: Assembly incompetence of paired helical filament-tau. J Neurochem 61, 1183–1186.
Schweers O , Mandelkow EM , Biernat J , Mandelkow E (1995) Oxidation of cysteine-322 in the repeat domain of microtubule-associated protein tau controls the in vitro assembly of paired helical filaments. Proc Natl Acad Sci USA 92, 8463–8467.
Liu Q , Lee HG , Honda K , Siedlak SL , Harris PLR , Cash AD , Zhu X , Avila J , Nunomura A , Takeda A , Smith MA , Perry G (2005) Tau modifiers as therapeutic targets for Alzheimer’s disease. Biochim Biophys Acta 1739, 211–215.
King ME , Kan HM , Baas PW , Erisir A , Glabe CG , Bloom GS (2006) Tau-dependent microtubule disassembly initiated by prefibrillar beta-amyloid. J Cell Biol 175, 541–546.
Goedert M , Jakes R , Spillantini MG , Hasegawa M , Smith MJ , Crowther RA (1996) Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature 383, 550–553.
Castellani RJ , Nunomura A , Lee H-G , Perry G , Smith MA (2008) Phosphorylated tau: Toxic, protective, or none of the above. J Alzheimers Dis 14, 377–383.
Cash AD , Aliev G , Siedlak SL , Nunomura A , Fujioka H , Zhu X , Raina AK , Vinters H V , Tabaton M , Johnson AB , Paula-Barbosa M , Aviila J , Jones PK , Castellani RJ , Smith MA , Perry G (2003) Microtubule reduction in Alzheimer’s disease and aging is independent of tau filament formation. Am J Pathol 162, 1623–1627.
Castellani RJ , Harris PL , Sayre LM , Fujii J , Taniguchi N , Vitek MP , Founds H , Atwood CS , Perry G , Smith MA (2001) Active glycation in neurofibrillary pathology of Alzheimer disease: N(epsilon)-(Carboxymethyl) lysine and hexitol-lysine. Free Radic Biol Med 31, 175–180.
Sayre LM , Perry G , Harris PLR , Liu Y , Schubert KA , Smith MA (2000) In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer’s disease: A central role for bound transition metals. J Neurochem 74, 270–279.
Chung CW , Song YH , Kim IK , Yoon WJ , Ryu BR , Jo DG , Woo HN , Kwon YK , Kim HH , Gwag BJ , Mook-Jung IH , Jung YK (2001) Proapoptotic effects of tau cleavage product generated by caspase-3. Neurobiol Dis 8, 162–172.
Fath T , Eidenmuller J , Brandt R (2002) Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer’s disease. J Neurosci 22, 9733–9741.
Santacruz K , Lewis J , Spires T , Paulson J , Kotilinek L , Ingelsson M , Guimaraes A , DeTure M , Ramsden M , McGowan E , Forster C , Yue M , Orne J , Janus C , Mariash A , Kuskowski M , Hyman B , Hutton M , Ashe KH (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476–81.
Shahani N (2006) Tau aggregation and progressive neuronal degeneration in the absence of changes in spine density and morphology after targeted expression of Alzheimer’s disease-relevant tau constructs in organotypic hippocampal slices. J Neurosci 26, 6103–6114.
Brandt R , Gergou A , Wacker I , Fath T , Hutter H (2009) A Caenorhabditis elegans model of tau hyperphosphory- lation: Induction of developmental defects by transgenic overexpression of Alzheimer’s disease-like modified tau. Neurobiol Aging 30, 22–33.
Flach K , Hilbrich I , Schiffmann A , Gartner U , Krüger M , Leonhardt M , Waschipky H , Wick L , Arendt T , Holzer M (2012) Tau oligomers impair artificial membrane integrity and cellular viability. J Biol Chem 287, 43223–43233.
Decker JM , Kriiger L , Sydow A , Zhao S , Frotscher M , Mandelkow E , Mandelkow EM (2015) Pro-aggregant tau impairs mossy fiber plasticity due to structural changes and Ca(++) dysregulation. Acta Neuropathol Commun 3, 23.
Krüger L , Mandelkow EM (2016) Tau neurotoxicity and rescue in animal models of human Tauopathies. Curr Opin Neurobiol 36, 52–58.
Selkoe DJ , Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8, 595–608.
Spillantini MG , Goedert M , Crowther RA , Murrell JR , Farlow MR , Ghetti B (1997) Familial multiple system tauopathy with presenile dementia: A disease with abundant neuronal and glial tau filaments. Proc Natl Acad Sci USA 94, 4113–4118.
Ghetti B , Oblak AL , Boeve BF , Johnson KA , Dickerson BC , Goedert M (2015) Invited review: Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: A chameleon for neuropathology and neuroimaging. Neuropathol Appl Neurobiol 41, 24–46.
Rossi G , Conconi D , Panzeri E , Redaelli S , Piccoli E , Paoletta L , Dalpra L , Tagliavini F (2013) Mutations in MAPT gene cause chromosome instability and introduce copy number variations widely in the genome. J Alzheimers Dis 33, 969–982.
Rossi G , Conconi D , Panzeri E , Paoletta L , Piccoli E , Ferretti MG , Mangieri M , Ruggerone M , Dalpra L , Tagliavini F (2014) Mutations in MAPT give rise to aneuploidy in animal models of tauopathy. Neurogenetics 15, 31–40.
Kouri N , Ross OA , Dombroski B , Younkin CS , Serie DJ , Soto-Ortolaza A , Baker M , Finch NCA , Yoon H , Kim J , Fujioka S , Mclean CA , Ghetti B , Spina S , Cantwell LB , Farlow MR , Grafman J , Huey ED , Ryung Han M , Beecher S , Geller ET , Kretzschmar HA , Roeber S , Gearing M , Juncos JL , Vonsattel JPG , Van Deerlin VM , Grossman M , Hurtig HI , Gross RG , Arnold SE , Trojanowski JQ , Lee VM , Wenning GK , White CL , Hoglinger GU , Müller U , Devlin B , Golbe LI , Crook J , Parisi JE , Boeve BF , Josephs KA , Wszolek ZK , Uitti RJ , Graff-Radford NR , Litvan I , Younkin SG , Wang LS , Ertekin-Taner N , Rademakers R , Hakonarsen H , Schellenberg GD , Dickson DW (2015) Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy. Nat Commun 6, 7247.
Stanford PM , Halliday GM , Brooks WS , Kwok JB , Storey CE , Creasey H , Morris JG , Fulham MJ , Schofield PR (2000) Progressive supranuclear palsy pathology caused by a novel silent mutation in exon 10 of the tau gene: Expansion of the disease phenotype caused by tau gene mutations. Brain 123 (Pt 5), 880–893.
Bugiani O , Murrell JR , Giaccone G , Hasegawa M , Ghigo G , Tabaton M , Morbin M , Primavera A , Carella F , Solaro C , Grisoli M , Savoiardo M , Spillantini MG , Tagliavini F , Goedert M , Ghetti B (1999) Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau. J Neuropathol Exp Neurol 58, 667–677.
Espindola SL , Damianich A , Alvarez RJ , Sartor M , Belforte JE , Ferrario JE , Gallo JM , Avale ME (2018) Modulation of tau isoforms imbalance precludes tau pathology and cognitive decline in a mouse model of tauopathy. Cell Rep 23, 709–715.
Clavaguera F , Bolmont T , Crowther RA , Abramowski S , Frank S , Probst A , Fraser G , Stalder AK , Beibel M , Staufenbiel M , Jucker M , Goedert M , Tolnay M (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11, 909–913.
Lewis J , Dickson DW (2016) Propagation of tau pathology: Hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies. Acta Neuropathol 131, 27–48.
Harbi D , Harrison PM (2014) Classifying prion and prion-like phenomena. Prion 8, 1–5.
Wickner RB , Edskes HK , Bateman DA , Kelly AC , Gorkovskiy A , Dayani Y , Zhou A (2013) Amyloids and yeast prion biology. Biochemistry 52, 1514–1527.
Kaufman SK , Sanders DW , Thomas TL , Ruchinskas AJ , Vaquer-Alicea J , Sharma AM , Miller TM , Diamond MI (2016) Tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo . Neuron 92, 796–812.
Kaufman SK , Thomas TL , Del Tredici K , Braak H , Diamond MI (2017) Characterization of tau prion seeding activity and strains from formaldehyde-fixed tissue. Acta Neuropathol Commun 5, 41.
Frost B , Jacks RL , Diamond MI (2009) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 284, 12845–12852.
Guo JL , Lee VMY (2011) Seeding of normal tau by pathological tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem 286, 15317–15331.
De Calignon A , Polydoro M , Suarez-Calvet M , William C , Adamowicz DH , Kopeikina KJ , Pitstick R , Sahara N , Ashe KH , Carlson GA , Spires-Jones TL , Hyman BT (2012) Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73, 685–697.
Stancu IC , Vasconcelos B , Ris L , Wang P , Villers A , Peeraer E , Buist A , Terwel D , Baatsen P , Oyelami T , Pierrot N , Casteels C , Bormans G , Kienlen-Campard P , Octave JN , Moechars D , Dewachter I (2015) Templated misfolding of tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice. Acta Neuropathol 129, 875–894.
Yoshiyama Y , Higuchi M , Zhang B , Huang SM , Iwata N , Saido TCC , Maeda J , Suhara T , Trojanowski JQ , Lee VMY (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351.
Braak H , Thal DR , Ghebremedhin E , Del Tredici K (2011) Stages of the pathologic process in Alzheimer disease: Age categories from 1 to 100 years. J Neuropathol Exp Neurol 70, 960–969.
Fornicola W , Pelcovits A , Li B-X , Heath J , Perry G , Castellani RJ (2014) Alzheimer disease pathology in middle age reveals a spatial-temporal disconnect between amyloid-ß and phosphorylated tau. Open Neurol J 8, 22–26.
Jones BE (1991) Noradrenergic locus coeruleus neurons: Their distant connections and their relationship to neighboring (including cholinergic and GABAergic) neurons of the central gray and reticular formation. Prog Brain Res 88, 15–30.
Kovacs GG , Ferrer I , Grinberg LT , Alafuzoff I , Attems J , Budka H , Cairns NJ , Crary JF , Duyckaerts C , Ghetti B , Halliday GM , Ironside JW , Love S , Mackenzie IR , Munoz DG , Murray ME , Nelson PT , Takahashi H , Trojanowski JQ , Ansorge O , Arzberger T , Baborie A , Beach TG , Bieniek KF , Bigio EH , Bodi I , Dugger BN , Feany M , Gelpi E , Gentleman SM , Giaccone G , Hatanpaa KJ , Heale R , Hof PR , Hofer M , Hortobágyi T , Jellinger K , Jicha GA , Ince P , Kofler J , Kövari E , Kril JJ , Mann DM , Matej R , McKee AC , McLean C , Milenkovic I , Montine TJ , Murayama S , Lee EB , Rahimi J , Rodriguez RD , Rozemüller A , Schneider JA , Schultz C , Seeley W , Seilhean D , Smith C , Tagliavini F , Takao M , Thal DR , Toledo JB , Tolnay M , Troncoso JC , Vinters HV , Weis S , Wharton SB , White CL , Wisniewski T , Woulfe JM , Yamada M , Dickson DW (2016) Aging-related tau astrogliopathy (ARTAG): Harmonized evaluation strategy. Acta Neuropathol 131, 87–102.
Corsellis JA , Bruton CJ , Freeman-Browne D (1973) The aftermath of boxing. Psychol Med 3, 270–303.
Kovacs GG , Xie SX , Robinson JL , Lee EB , Smith DH , Schuck T , Lee VM-Y , Trojanowski JQ (2018) Sequential stages and distribution patterns of aging-related tau astrogliopathy (ARTAG) in the human brain. Acta Neuropathol Commun 6, 1–19.
Castellani RJ , Perry G (2017) Dementia pugilistica revisited. J Alzheimers Dis 60, 1209–1221.
Castellani RJ , Schmidt CJ (2018) Brain injury biomechanics and abusive head trauma. J Forensic Sci Med 4, 91–100.
Martland HS (1928) Punch drunk. J Am Med Assoc 91, 1103–1107.
Millspaugh JA (1937) Dementia pugilistica. U S Nav Med Bull 35, 297–303.
Roberts A (1969) Brain damage in boxers: A study of prevalance of traumatic encephalopathy among exprofessional boxers, Pitman Medical Scientific Publishing Co., London.
McCrory P , Zazryn T , Cameron P (2007) The evidence for chronic traumatic encephalopathy in boxing. Sport Med 37, 467–476.
Brandenburg W , Hallervorden J (1954) Dementia pugilistica mit anatomischem Befund. Virchows Arch 325, S680–S709.
Crook R , Verkkoniemi A , Perez-Tur J , Mehta N , Baker M , Houlden H , Farrer M , Hutton M , Lincoln S , Hardy J , Gwinn K , Somer M , Paetau A , Kalimo H , Ylikoski R , Poyhonen M , Kucera S , Haltia M (1998) A variant of Alzheimer’s disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med 4, 452–455.
Omalu BI , Dekosky ST , Minster RLIS , Kamboh MI , Hamilton RL , Wecht CH (2005) Chronic traumatic encephalopathy in a National Football League Player. Neurosurgery 57, 128–134.
Roberts GW (1988) Immunohistochemistry of neurofib- rillary tangles in dementia pugilistica and Alzheimer’s disease: Evidence for common genesis. Lancet 332, 1456–1458.
Roberts GW , Allsop D , Bruton C (1990) The occult aftermath of boxing. J Neurol Neurosurg Psychiatry 53, 373–378.
Allsop D , Haga S , Bruton C , Ishii T , Roberts GW (1990) Neurofibrillary tangles in some cases of dementia pugilistica share antigens with amyloid beta-protein of Alzheimer’s disease. Am J Pathol 136, 255–260.
Tokuda T , Ikeda S , Yanagisawa N , Ihara Y , Glenner GG (1991) Re-examination of ex-boxers' brains using immunohistochemistry with antibodies to amyloid ß- protein and tau protein. Acta Neuropathol 82, 280–285.
Geddes JF , Vowles GH , Robinson SF , Sutcliffe JC (1996) Neurofibrillary tangles, but not Alzheimer-type pathology, in a young boxer. Neuropathol Appl Neurobiol 22, 12–16.
Cabot RC , Scully RE , Mark EJ , McNeely WF , Ebeling SH , Drachman DA , Newell KL (1999) Case 12-1999. N Engl J Med 340, 1269–1277.
Schmidt ML , Zhukareva V , Newell KL , Lee VM , Trojanowski JQ (2001) Tau isoform profile and phos- phorylation state in dementia pugilistica recapitulate Alzheimer’s disease. Acta Neuropathol 101, 518–524.
Areza-Fegyveres R , Rosemberg S , Castro RMRPS , Porto CS , Bahia VS , Caramelli P , Nitrini R (2007) Dementia Pugilistica with clinical features of Alzheimer’s disease. Arq Neuropsiquiatr 65, 830–833.
Nowak La , Smith GG , Reyes PF (2009) Dementia in a retired world boxing champion: Case report and literature review. Clin Neuropathol 28, 275–280.
McKee AC , Stern RA , Nowinski CJ , Stein TD , Alvarez VE , Daneshvar DH , Lee H-S , Wojtowicz SM , Hall G , Baugh CM , Riley DO , Kubilus CA , Cormier KA , Jacobs MA , Martin BR , Abraham CR , Ikezu T , Reichard RR , Wolozin BL , Budson AE , Goldstein LE , Kowall NW , Cantu RC (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136, 43–64.
Omalu B , Bailes J , Hamilton RL , Kamboh MI , Hammers J , Case M , Fitzsimmons R (2011) Emerging histomorphologic phenotypes of chronic traumatic encephalopathy in American athletes. Neurosurgery 69, 173–183.
McKee AC , Cairns NJ , Dickson DW , Folkerth RD , Dirk Keene C , Litvan I , Perl DP , Stein TD , Vonsattel JP , Stewart W , Tripodis Y , Crary JF , Bieniek KF , Dams-O'Connor K , Alvarez VE , Gordon WA (2016) The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol 131, 75–86.
Mez J , Daneshvar DH , Kiernan PT , Abdolmohammadi B , Alvarez VE , Huber BR , Alosco ML , Solomon TM , Nowinski CJ , McHale L , Cormier KA , Kubilus CA , Martin BM , Murphy L , Baugh CM , Montenigro PH , Chaisson CE , Tripodis Y , Kowall NW , Weuve J , McClean MD , Cantu RC , Goldstein LE , Katz DI , Stern RA , Stein TD , McKee AC (2017) Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. JAMA 318, 360–370.
Noy S , Krawitz S , Bigio MR Del (2016) Chronic traumatic encephalopathy-like abnormalities in a routine neuropathology service. J Neuropathol Exp Neurol 75, 1145–1154.
Puvenna V , Engeler M , Banjara M , Brennan C , Schreiber P , Dadas A , Bahrami A , Solanki J , Bandyopadhyay A , Morris JK , Bernick C , Ghosh C , Rapp E , Bazarian JJ , Janigro D (2016) Is phosphorylated tau unique to chronic traumatic encephalopathy? Phosphorylated tau in epileptic brain and chronic traumatic encephalopathy. Brain Res 1630, 225–240.
Fournier CN , Gearting M , Upadhyayula SR , Klein M , Glass JD (2015) Head injury does not alter disease progression or neuropathologic outcomes in ALS. Neurology 84, 1788–1795.
Koga S , Dickson DW , Bieniek KF (2016) Chronic traumatic encephalopathy pathology in multiple system atrophy. J Neuropathol Exp Neurol 75, 963–970.
Ling H , Holton JL , Shaw K , Davey K , Lashley T , Revesz T (2015) Histological evidence of chronic traumatic encephalopathy in a large series of neurodegenerative diseases. Acta Neuropathol 130, 891–893.
Geddes JF , Vowles GH , Nicoll JAR , Revesz T (1999) Neuronal cytoskeletal changes are an early consequence of repetitive head injury. Acta Neuropathol 98, 171–178.
Hales C , Neill S , Gearing M , Cooper D , Glass J , Lah J (2014) Late-stage CTE pathology in a retired soccer player with dementia. Neurology 83, 2307–2309.
McKee AC , Daneshvar DH , Alvarez VE , Stein TD (2014) The neuropathology of sport. Acta Neuropathol 127, 2951.
Grinberg LT , Anghinah R , Nascimento CF , Amaro E , Leite RP , Da Graca Martin M , Naslavsky MS , Takada LT , Filho WJ , Pasqualucci CA , Nitrini R (2016) Chronic traumatic encephalopathy presenting as Alzheimer’s disease in a retired soccer player. J Alzheimers Dis 54, 169–174.
Ling H , Morris HR , Neal JW , Lees AJ , Hardy J , Holton JL , Revesz T , Williams DD (2017) Mixed pathologies including chronic traumatic encephalopathy account for dementia in retired association football (soccer) players. Acta Neuropathol 133, 337–352.
Bieniek KF , Ross OA , Cormier KA , Walton RL , Soto-Ortolaza A , Johnston AE , DeSaro P , Boylan KB , Graff-Radford NR , Wszolek ZK , Rademakers R , Boeve BF , McKee AC , Dickson DW (2015) Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank. Acta Neuropathol 130, 877–889.
Casson IR , Viano DC , Haacke EM , Kou Z , LeStrange DG (2014) Is there chronic brain damage in retired NFL players? Neuroradiology, neuropsychology, and neurology examinations of 45 retired players. Sports Health 6, 384–395.
Baron SL , Hein MJ , Lehman E , Gersic CM (2012) Body mass index, playing position, race, and the cardiovascular mortality of retired professional football players. Am J Cardiol 109, 889–896.
Lehman EJ , Hein MJ , Baron SL , Gersic CM (2012) Neurodegenerative causes of death among retired national football league players. Neurology 79, 1970–1974.
Yamamoto S , DeWitt D , Prough D (2018) Impact & blast traumatic brain injury: Implications for therapy. Molecules 23, E245.
DePalma RG , Hoffman SW (2018) Combat blast related traumatic brain injury (TBI): Decade of recognition; promise of progress. Behav Brain Res 340, 102–105.
Omalu B , Hammers JL , Bailes J , Hamilton RL , Kamboh MI , Webster G , Fitzsimmons RP (2011) Chronic traumatic encephalopathy in an Iraqi war veteran with posttraumatic stress disorder who committed suicide. Neurosurg Focus 31, E3.
McKee AC , Robinson ME (2014) Military-related traumatic brain injury and neurodegeneration. Alzheimers Dement 10, S242–S253.
Shively SB , Perl DP (2012) Traumatic brain injury, shell shock, and posttraumatic stress disorder in the military- past, present, and future. J Head Trauma Rehabil 27, 234–239.
Plassman BL , Havlik RJ , Steffens DC , Helms MJ , Newman TN , Drosdick D , Phillips C , Gau BA , Welsh-Bohmer KA , Burke JR , Guralnik JM , Breitner JCS (2000) Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias. Neurology 55, 1158–1166.
Godbolt AK , Cancelliere C , Hincapie CA , Marras C , Boyle E , Kristman VL , Coronado VG , Cassidy JD (2014) Systematic review of the risk of dementia and chronic cognitive impairment after mild traumatic brain injury: Results of the international collaboration on mild traumatic brain injury prognosis. Arch Phys Med Rehabil 95, S245–S256.
Barnes DE , Byers AL , Gardner RC , Seal KH , Boscardin WJ , Yaffe K (2018) Association of mild traumatic brain injury with and without loss of consciousness with dementia in US military veterans. JAMA Neurol 75, 1055–1061.
Fann JR , Ribe AR , Schou Pedersen H , Fenger-Gr0n M , Christensen J , Benros ME , Vestergaard M (2018) Long-term risk of dementia among people with traumatic brain injury in Denmark: A population-based observational cohort study. Lancet Psychiatry 5, 424–431.
Lewin W , Marshall TF , Roberts AH (1979) Long-term outcome after severe head injury. Br Med J 2, 1533–1538.
Sayed N , Culver C , Dams-O'Connor K , Hammond F , Diaz-Arrastia R (2013) Clinical phenotype of dementia after traumatic brain injury. J Neurotrauma 30, 1117–1122.
Shively SB , Horkayne-Szakaly I , Jones RV , Kelly JP , Armstrong RC , Perl DP (2016) Characterisation of interface astroglial scarring in the human brain after blast exposure: A post-mortem case series. Lancet Neurol 15, 944–953.
Augustinack JC , Schneider A , Mandelkow EM , Hyman BT (2002) Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta Neuropathol 103, 26–35.
Buchwalow I , Boecker W , Wolf E , Samoilova V , Tiemann M (2013) Signal amplification in immunohistochemistry: Loose-jointed deformable heteropolymeric HRP conjugates vs. linear polymer backbone HRP conjugates. Acta Histochem 115, 587–594.
Castellani RJ , Perry G (2014) The complexities of the pathology-pathogenesis relationship in Alzheimer disease. Biochem Pharmacol 88, 671–676.
Ahmed Z , Bigio EH , Budka H , Dickson DW , Ferrer I , Ghetti B , Giaccone G , Hatanpaa KJ , Holton JL , Josephs KA , Powers J , Spina S , Takahashi H , White CL , Revesz T , Kovacs GG (2013) Globular glial tauopathies (GGT): Consensus recommendations. Acta Neuropathol 126, 537–544.
Maurer K , Volk S , Gerbaldo H (1997) Auguste D and Alzheimer’s disease. Lancet 349, 1546–1549.
Love S , Saitoh T , Quijada S , Cole GM , Terry RD (1988) Alz-50, ubiquitin and tau immunoreactivity of neurofibrillary tangles, Pick bodies and Lewy bodies. J Neuropathol Exp Neurol 47, 393–405.
Kovacs GG , Rozemuller AJM , van Swieten JC , Gelpi E , Majtenyi K , Al-Sarraj S , Troakes C , Bodi I , King A , Hortobagyi T , Esiri MM , Ansorge O , Giaccone G , Ferrer I , Arzberger T , Bogdanovic N , Nilsson T , Leisser I , Ala-fuzoff I , Ironside JW , Kretzschmar H , Budka H (2013) Neuropathology of the hippocampus in FTLD-Tau with Pick bodies: A study of the BrainNet Europe Consortium. Neuropathol Appl Neurobiol 39, 166–178.
Kovacs GG (2015) Invited review: Neuropathology of tauopathies: Principles and practice. Neuropathol Appl Neurobiol 41, 3–23.
Kovacs GG (2016) Molecular pathological classification of neurodegenerative diseases: Turning towards precision medicine. Int J Mol Sci 17, pii: E189.
Ferrer I , Lopez-Gonzalez I , Carmona M , Arregui L , Dalfo E , Torrejón-Escribano B , Diehl R , Kovacs GG (2014) Glial and neuronal tau pathology in tauopathies: Characterization of disease-specific phenotypes and tau pathology progression. J Neuropathol Exp Neurol 73, 81–97.
Yokoyama Y , Toyoshima Y , Shiga A , Tada M , Kitamura H , Hasegawa K , Onodera O , Ikeuchi T , Someya T , Nishizawa M , Kakita A , Takahashi H (2016) Pathological and clinical spectrum of progressive supranuclear palsy: With special reference to astrocytic tau pathology. Brain Pathol 26, 155–166.
Nelson PT , Alafuzoff I , Bigio EH , Bouras C , Braak H , Cairns NJ , Castellani RJ , Crain BJ , Davies P , Tredici KD , Duyckaerts C , Frosch MP , Haroutunian V , Hof PR , Hulette CM , Hyman BT , Iwatsubo T , Jellinger KA , Jicha GA , Ko vari E , Kukull WA , Leverenz JB , Love S , MacKenzie IR , Mann DM , Masliah E , McKee AC , Montine TJ , Morris JC , Schneider JA , Sonnen JA , Thal DR , Trojanowski JQ , Troncoso JC , Wisniewski T , Woltjer RL , Beach TG (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: A review of the literature. J Neuropathol Exp Neurol 71, 362–381.
Brayne C , Richardson K , Matthews FE , Fleming J , Hunter S , Xuereb JH , Paykel E , Mukaetova-Ladinska EB , Huppert FA , O'Sullivan A , Dening T (2009) Neuropathological correlates of dementia in over-80-year-old brain donors from the population-based Cambridge city over-75s cohort (CC75C) study. J Alzheimers Dis 18, 645–658.
Dickson DW (2018) Neuropathology of Parkinson disease. Parkinsonism Relat Disord 46, S30–S33.
Riedl L , Mackenzie IR , Forstl H , Kurz A , Diehl-Schmid J (2014) Frontotemporal lobar degeneration: Current perspectives. Neuropsychiatr Dis Treat 10, 297–310.
Nelson PT , Trojanowski JQ , Abner EL , Al-Janabi OM , Jicha GA , Schmitt FA , Smith CD , Fardo DW , Wang WX , Kryscio RJ , Neltner JH , Kukull WA , Cykowski MD , Van Eldik LJ , Ighodaro ET (2016) "New old pathologies": AD, PART, and cerebral age-related TDP-43 with sclerosis (CARTS). J Neuropathol Exp Neurol 75, 482–498.
Mackenzie IRA , Neumann M , Bigio EH , Cairns NJ , Alafuzoff I , Kril J , Kovacs GG , Ghetti B , Halliday G , Holm IE , Ince PG , Kamphorst W , Revesz T , Rozemuller AJM , Kumar-Singh S , Akiyama H , Baborie A , Spina S , Dickson DW , Trojanowski JQ , Mann DMA (2009) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: Consensus recommendations. Acta Neuropathol 117, 15–18.
McKeith IG , Boeve BF , Dickson DW , Halliday G , Taylor J-P , Weintraub D , Aarsland D , Galvin J , Attems J , Ballard CG , Bayston A , Beach TG , Blanc F , Bohnen N , Bonanni L , Bras J , Brundin P , Burn D , Chen-Plotkin A , Duda JE , El-Agnaf O , Feldman H , Ferman TJ , Ffytche D , Fujishiro H , Galasko D , Goldman JG , Gomperts SN , Graff-Radford NR , Honig LS , Iranzo A , Kantarci K , Kaufer D , Kukull W , Lee VMY , Leverenz JB , Lewis S , Lippa C , Lunde A , Masellis M , Masliah E , McLean P , Mollenhauer B , Montine TJ , Moreno E , Mori E , Murray M , O'Brien JT , Orimo S , Postuma RB , Ramaswamy S , Ross OA , Salmon DP , Singleton A , Taylor A , Thomas A , Tiraboschi P , Toledo JB , Trojanowski JQ , Tsuang D , Walker Z , Yamada M , Kosaka K (2017) Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology 89, 88–100.
Cairns NJ , Bigio EH , Mackenzie IRA , Neumann M , Lee VMY , Hatanpaa KJ , White CL , Schneider JA , Grinberg LT , Halliday G , Duyckaerts C , Lowe JS , Holm IE , Tolnay M , Okamoto K , Yokoo H , Murayama S , Woulfe J , Munoz DG , Dickson DW , Ince PG , Trojanowski JQ , Mann DMA (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: Consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 114, 5–22.
Webner D , Iverson GL (2016) Suicide in professional American football players in the past 95 years. Brain Inj 30, 1718–1721.
Iverson GL (2016) Suicide and chronic traumatic encephalopathy. J Neuropsychiatry Clin Neurosci 28, 9–16.
Iverson GL (2014) Chronic traumatic encephalopathy and risk of suicide in former athletes. Br J Sports Med 48, 162–164.