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Contact sport and blast-related neuropathology
Published in Helen Whitwell, Christopher Milroy, Daniel du Plessis, Forensic Neuropathology, 2021
Daniel du Plessis, Christopher Milroy
Some caution has been proposed about the role of a tauopathy in CTE (Castellani 2015; Castellani et al. 2015) as clinico-pathological correlation is poor and standard methodology is lacking (Castellani and Perry 2017). Historical and recent evidence suggests that CTE, as it is presented in the literature, might not be pathologically or clinically progressive in a substantial percentage of people. At present, it is not known whether the emergence, course, or severity of clinical symptoms, can be predicted by specific combinations of neuropathologies, thresholds for accumulation of pathology, or regional distributions of pathologies (Iverson et al. 2018).
The advent of subconcussion and chronic traumatic encephalopathy
Published in Brian Sindelar, Julian E. Bailes, Sports-Related Concussion, 2017
A tauopathy is a group of neurodegenerative diseases that are characterized by intracellular or extracellular aggregations of tau within the brain—Alzheimer’s being the most common tauopathy.101 The tau protein is normally found associated with microtubules, a cell structural protein that assists in axonal transport, within the axon of a neuron but is also found in glial cells.102,103 In nonpathological states, tau is phosphorylated (by kinases) and dephosphorylated (by phosphatases) at sites along the length of the protein in order to aid in normal CNS development, but this homeostasis is altered after injury exposure (Figure 9.3).104 Following a pathological insult, the tau protein (soluble form) becomes preferentially hyperphosphorylated at specific sites (associated with development of neurodegenerative disease, see Figure 9.4104), leading to destabilization of the microtubule, and release of the insoluble form of hyperphosphorylated tau. These tau proteins clump together and are moved from the neuron’s axon to the cytoplasm of the neuronal soma, seen histologically as neurofibrillary tangles or neuropil threads104,105 (Figure 9.5). In other neurodegenerative diseases, tau aggregations also occur in oligodendrocytes (affecting maintenance of myelin), astrocytes (potentially altering the blood–brain barrier integrity), and microglial cells (Figure 9.6).103 The specifics regarding tau accumulation based on location and even isoform type, and how this translates to clinical disease in CTE, is still under active investigation.103 Areas of active and future investigation regarding location should include delineation of both anatomic and microscopic locations of abnormal tau. For isoform subtypes, these investigations should determine whether the tau inclusions are 3R and/or 4R tau as well as if there are differences between the neuronal and glial tau inclusions in isoform expression in CTE.
Movement disorders
Published in Henry J. Woodford, Essential Geriatrics, 2022
Corticobasal degeneration (CBD) is a neurodegenerative condition of unknown aetiology. It shares pathological similarities with both PSP and frontotemporal dementia (FTD).121 It is also associated with abnormal tau protein processing (‘tauopathy'). The most common presenting signs are unilateral limb clumsiness or rigidity (‘useless arm'), bradykinesia, ideomotor apraxia, postural imbalance and arm dystonia. Ideomotor apraxia can be demonstrated by asking people to mime activities such as combing their hair or cutting a piece of paper with a pair of scissors. The myoclonus can usually be induced (‘stimulus-sensitive'). Around 50% will develop an ‘alien limb'. This may present as spontaneous limb elevation, uncontrollable reaching for objects or intermanual conflict when performing tasks. This is not specific to CBD and may occur in other neurodegenerative disorders. Cortical sensory signs such as astereognosis (the inability to recognise objects by touch – e.g. keys placed in the hand), agraphaesthesia (the inability to distinguish numbers or letters ‘drawn' on the palm) and reduced two-point discrimination may occur. Approximately one-third of people will have early cognitive impairment.122 There may also be clinical features similar to PSP, such as pseudobulbar palsy and ophthalmic signs. Clinical variants of this condition also exist. It can initially present as a focal cortical degenerative syndrome, for example, primary progressive aphasia, or similarly to FTD. Gait tends to be broad-based and small-stepping.3 Diagnostic accuracy is low (less than 50%) in comparison to autopsy pathology.120 This is probably due to the clinical heterogeneity of CBD and the large degree of overlap both clinically and pathologically between all of the neurodegenerative disorders.122 MRI scanning may demonstrate focal cortical atrophy or atrophy of the corpus callosum in later disease.18
Mixed neuropathology in frontotemporal lobar degeneration
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2020
Catherine Pennington, Luca Marini, Elizabeth Coulthard, Seth Love
Tauopathies are frequently seen as co-existent or incidental pathologies in patients with other forms of neurodegeneration (23,24) but the incidence of mixed pathology in those with a primary tauopathy is understudied. An autopsy series of 33 people with neuropathologically diagnosed CBD found coexisting Alzheimer’s spectrum pathology in 3 cases (25). An archival review of 66 cases of Pick’s disease identified proteinopathy consistent with low or intermediate level probability of AD in 3 cases, and occasional alpha-synuclein immunopositivity (26). In our cohort, most of those with FTLD-tau had no other neuropathology present. Why mixed neuropathology is less frequent in FTLD-tau than FTLD-TDP-43 is unclear; this discrepancy was not explained by age at death, or by an excess of any one particular neuropathology with FTLD-TDP.
Youth Soccer Parents’ Perceptions of Long-Term Effects of Concussion
Published in Developmental Neuropsychology, 2020
Philip Schatz, Mary Corcoran, Anthony P. Kontos, RJ Elbin
CTE is a clinical syndrome akin to a progressive dementia which is first manifested by deteriorations in attention, concentration, and memory, as well as disorientation and confusion, and later-stage symptoms, of lack of insight, poor judgment, and overt dementia (McKee et al., 2009). This deterioration has been described in progressive stages, associated with progressive tauopathy, as a result of repetitive mild traumatic brain injury (McKee et al., 2013). However, the absence of a clear causal relationship between repetitive mild TBI and CTE (Solomon & Zuckerman, 2015), the co-morbidity between CTE and other progressive dementias (Brett et al., 2019), and the shared neuropathology with other progressive diseases (Iverson et al., 2019) have highlighted a clear lack of agreement between the media presentation of CTE and the findings in the scientific literature. It is unclear if educational information regarding concussion also contains information about CTE; only 18% of parents surveyed reported ever having received educational materials from a school or sports program with information about CTE, and 15% were not sure whether they had received materials (Daugherty & Sarmiento, 2018). However, from that same sample, parents whose children play contact sports were more likely to indicate concern that their child would develop CTE as a result of playing sports (37.0%) than parents who do not have children who play contact sports (21.0%) (Daugherty & Sarmiento, 2018).
Alzheimer’s disease: phenotypic approaches using disease models and the targeting of tau protein
Published in Expert Opinion on Therapeutic Targets, 2020
Elisabetta Lauretti, Domenico Praticò
In recent years, tau immunotherapy has made incredible progress, and based on preclinical data, both active immunization and passive immunization have shown promising results. Currently, several clinical trials implementing this approach are being conducted for AD and related tauopathies [96]. Importantly, anti-tau monoclonal antibodies have been proved to enter neurons, likely through clathrin-mediated endocytosis, and to clear extra- and intracellular tau potentially blocking tau spreading [97]. Although there are some concerns about safety, active immunization successfully reduced tau pathology in different tauopathy models. Immunotherapy targeting phospho-tau reduces the extent of aggregated tau and halts the progression of cognitive impairments in P301L mice [98]. Similarly, active immunization with peptide containing phospho-Ser422 epitope reduces tau pathology and improves cognitive functions in the THYTau22 mouse model [99]. Vaccination with fibrillar PHF-tau decreases brain levels of sarkosyl-soluble tau and NFTs in old tau transgenic mice [100]. Finally, immunization with wild-type human tau results in reduced tau pathology and neuroinflammation in rTg4510 tau mice [101].