BACKGROUND: Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are progressive neurodegenerative syndromes characterised by Parkinsonism with additional features including cognitive dysfunction, falls, and oculomotor abnormalities. Understanding the epidemiology of these conditions is critical to planning for future service provision.
METHODS: We conducted a systematic review of studies reporting incidence and prevalence of CBS and PSP. A search of the PubMed and EMBASE data bases was conducted from their date of inception to 13th July 2021. Meta-analysis of studies sharing similar methodologies was carried out to generate estimated pooled prevalence and incidence.
RESULTS: We found 32 studies meeting our criteria for inclusion. There were 20 studies with data on prevalence and 12 with incidence data of PSP. Prevalence of CBS was reported in eight studies while seven studies reported incidence. Reported estimates of prevalence for PSP ranged from 1.00 (0.9-1.1) to 18 (8-28) per 100,000 while prevalence rates for CBS ranged from 0.83 (0.1-3.0) to 25 (0-59). Incidence rates for PSP and CBS respectively ranged from 0.16 (0.07-0.39) to 2.6 per 100,000 person-years and 0.03 (0-0.18) to 0.8 (0.4-1.3) per 100,000 person-years. A random effects model meta-analysis of studies with similar methodologies yielded a pooled prevalence estimate for PSP of 6.92 (4.33-11.06, I2 = 89%, τ2 = 0.3907) and 3.91 (2.03-7.51, I2 = 72%, τ2 = 0.2573) per 100,000 for CBS.
CONCLUSIONS: Studies of the epidemiology of PSP and CBS report highly heterogeneous findings. There is a need for further studies using rigorous phenotyping and the most recent diagnostic criteria to understand the true burden of these conditions.

In the last decades, numerous post-mortem case series have documented chronic traumatic encephalopathy (CTE) in former contact-sport athletes, though reports of CTE pathology in former soccer players are scarce. This study presents a clinicopathological case of a former professional soccer player with young-onset dementia. The patient experienced early onset progressive cognitive decline and developed dementia in his mid-50 s, after playing soccer for 12 years at a professional level. While the clinical picture mimicked Alzheimer\'s disease, amyloid PET imaging did not provide evidence of elevated beta-amyloid plaque density. After he died in his mid-60 s, brain autopsy showed severe phosphorylated tau (p-tau) abnormalities fulfilling the neuropathological criteria for high-stage CTE, as well as astrocytic and oligodendroglial tau pathology in terms of tufted astrocytes, thorn-shaped astrocytes, and coiled bodies. Additionally, there were TAR DNA-binding protein 43 (TDP-43) positive cytoplasmic inclusions in the frontal lobe and hippocampus, and Amyloid Precursor Protein (APP) positivity in the axons of the white matter. A systematic review of the literature revealed only 13 other soccer players with postmortem diagnosis of CTE. Our report illustrates the complex clinicopathological correlation of CTE and the need for disease-specific biomarkers.

Tauopathy refers to a group of progressive neurodegenerative diseases, including frontotemporal lobar degeneration and Alzheimer\'s disease, which correlate with the malfunction of microtubule-associated protein Tau (MAPT) due to abnormal hyperphosphorylation, leading to the formation of intracellular aggregates in the brain. Despite extensive efforts to understand tauopathy and develop an efficient therapy, our knowledge is still far from complete. To find a solution for this group of devastating diseases, several animal models that mimic diverse disease phenotypes of tauopathy have been developed. Rodents are the dominating tauopathy models because of their similarity to humans and established disease lines, as well as experimental approaches. However, powerful genetic animal models using Drosophila, zebrafish, and C. elegans have also been developed for modeling tauopathy and have contributed to understanding the pathophysiology of tauopathy. The success of these models stems from the short lifespans, versatile genetic tools, real-time in-vivo imaging, low maintenance costs, and the capability for high-throughput screening. In this review, we summarize the main findings on mechanisms of tauopathy and discuss the current tauopathy models of these non-rodent genetic animals, highlighting their key advantages and limitations in tauopathy research.

Traumatic brain injury (TBI) constitutes one of the strongest environmental risk factors for several progressive neurodegenerative disorders of cognitive impairment and dementia that are characterized by the pathological accumulation of hyperphosphorylated tau (p-Tau). It has been questioned whether mouse closed-head TBI models can replicate human TBI-associated tauopathy. We conducted longitudinal histopathological characterization of a mouse closed head TBI model, with a focus on pathological features reported in human TBI-associated tauopathy. Male C57BL/6 J mice were subjected to once daily TBI for 5 consecutive days using a weight drop paradigm. Histological analyses (AT8, TDP-43, pTDP-43, NeuN, GFAP, Iba-1, MBP, SMI-312, Prussian blue, IgG, βAPP, alpha-synuclein) were conducted at 1 week, 4 weeks, and 24 weeks after rTBI and compared to sham operated controls. We conducted a systematic review of the literature for mouse models of closed-head injury focusing on studies referencing tau protein assessment. At 1-week post rTBI, p-Tau accumulation was restricted to the corpus callosum and perivascular spaces adjacent to the superior longitudinal fissure. Progressive p-Tau accumulation was observed in the superficial layers of the cerebral cortex, as well as in mammillary bodies and cortical perivascular, subpial, and periventricular locations at 4 to 24 weeks after rTBI. Associated cortical histopathologies included microvascular injury, neuroaxonal rarefaction, astroglial and microglial activation, and cytoplasmatic localization of TDP-43 and pTDP-43. In our systematic review, less than 1% of mouse studies (25/3756) reported p-Tau using immunostaining, of which only 3 (0.08%) reported perivascular p-Tau, which is considered a defining feature of chronic traumatic encephalopathy. Commonly reported associated pathologies included neuronal loss (23%), axonal loss (43%), microglial activation and astrogliosis (50%, each), and beta amyloid deposition (29%). Our novel model, supported by systematic review of the literature, indicates progressive tau pathology after closed head murine TBI, highlighting the suitability of mouse models to replicate pertinent human histopathology.

The misfolding of proteins such as the prion protein, α-synuclein, and tau represents a key initiating event for pathogenesis of most common neurodegenerative disorders, and its presence correlates with infectivity. To date, the diagnosis of these disorders mainly relied on the recognition of clinical symptoms when neurodegeneration was already at an advanced phase. In recent years, several efforts have been made to develop new diagnostic tools for the early diagnosis of prion diseases. The real-time quaking-induced conversion (RT-QuIC) assay, an in vitro assay that can indirectly detect very low amounts of PrPSc aggregates, has provided a very promising tool to improve the early diagnosis of human prion diseases. Over the decade since RT-QuIC was introduced, the diagnosis of not only prion diseases but also synucleinopathies and tauopathies has greatly improved. Therefore, in our study, we summarize the current trends and knowledge of RT-QuIC assays, as well as discuss the diagnosis of neurodegenerative diseases using RT-QuIC assays, which have been updated in recent years.

Astrocytes with intracellular accumulations of misfolded phosphorylated tau protein have been observed in advanced-stage chronic traumatic encephalopathy (CTE) and in other neurodegenerative conditions. There is a growing awareness that astrocytic tau inclusions are also relatively common in the brains of persons over 70 years of age-affecting approximately one-third of autopsied individuals. The pathologic hallmarks of aging-related tau astrogliopathy (ARTAG) include phosphorylated tau protein within thorn-shaped astrocytes (TSA) in subpial, subependymal, perivascular, and white matter regions, whereas granular-fuzzy astrocytes are often seen in gray matter. CTE and ARTAG share molecular and histopathologic characteristics, suggesting that trauma-related mechanism(s) may predispose to the development of tau astrogliopathy. There are presently few experimental systems to study the pathobiology of astrocytic-tau aggregation, but human studies have made recent progress. For example, leucotomy (also referred to as lobotomy) is associated with a localized ARTAG-like neuropathology decades after the surgical brain injury, suggesting that chronic brain injury of any type may predispose to later life ARTAG. To examine this idea in a different context, we report clinical and pathologic features of two middle-aged men who came to autopsy with large (> 6 cm in greatest dimension) arachnoid cysts that had physically displaced and injured the subjects\' left temporal lobes through chronic mechanical stress. Despite the similarity of the size and location of the arachnoid cysts, these individuals had dissimilar neurologic outcomes and neuropathologic findings. We review the evidence for ARTAG in response to brain injury, and discuss how the location and molecular properties of astroglial tau inclusions might alter the physiology of resident astrocytes. These cases and literature review point toward possible mechanism(s) of tau aggregation in astrocytes in response to chronic brain trauma.

Anti-IgLON5 disease is a rare neurodegenerative tauopathy that displays heterogeneity in clinical spectrum, disease course, cerebrospinal fluid (CSF) findings, and variable response to immunotherapy. Sleep disorders, bulbar dysfunction, and gait abnormalities are common presenting symptoms, and conventional brain MRI scanning is often unrevealing.
To provide a comprehensive overview of the literature and to assess the frequency of symptoms, MRI findings, and treatment response in patients with IgLON5 autoimmunity in the serum and CSF or restricted to serum.
We examined a 65-year-old woman with bulbar-onset IgLON5 disease with serum-restricted antibodies, and we also performed a systematic review of all confirmed cases reported in the English literature.
We identified 93 patients, included our case. Clinical data were obtained in 58 subjects, in whom the most frequent symptoms were sleep-disordered breathing, dysphagia, parasomnias, dysarthria, limb or gait ataxia, stridor or vocal cord paresis, movement disorders, and postural instability. Distinct MRI alterations were identified in 12.5% of cases, as opposed to unspecific or unremarkable changes in the remaining patients. T2-hyperintense non-enhancing signal alterations involving the hypothalamus and the brainstem tegmentum were observed only in the present case. Inflammatory CSF was found in half of the cases and serum-restricted antibodies in 4 patients. Treatment with immunosuppressant or immunomodulatory drugs led to sustained clinical response in 19/52 patients.
Anti-IgLON5 autoimmunity should be considered in patients with sleep disorders, bulbar syndrome, autonomic involvement, and movement disorders, and high-field brain MRI can be of diagnostic help.

Anti-IgLON5 disease is a rare disorder characterized by a heterogeneous myriad of symptoms that may include sleep disorders, bulbar dysfunction, gait problems, movement disorders, cognitive impairment, oculomotor abnormalities, and nervous system hyperexcitability. Its physiopathology remains unknown, with a combination of both autoimmune and neurodegenerative findings.
We describe clinical, cerebrospinal fluid (CSF), and ioflupane single-photon emission computed tomography (SPECT) findings of a positive case of anti-IgLON5 disease mimicking probable progressive supranuclear palsy (PSP). We performed a literature review of previous publications reporting on anti-IgLON5 disease and ioflupane SPECT.
We report the case of a 66-year-old male who met clinical criteria for probable PSP, in whom ioflupane SPECT showed an alteration of the left presynaptic dopaminergic pathway. However, the presence of atypical neurological symptoms for PSP led to further complementary tests, and IgLON5 antibodies were detected in CSF. According to our literature review, ioflupane SPECT findings have been previously described in only three other patients with anti-IgLON5 disease, with a reduced uptake in the striatum in two of them.
Ioflupane SPECT abnormalities, though scarcely described, are not uncommon in anti-IgLON5 disease. They could be related to nigrostriatal dopaminergic degeneration in the context of the tauopathy component of the disease, but further case descriptions are necessary.

Tau is a predominantly neuronal protein that is normally bound to microtubules, where it acts to modulate neuronal and axonal stability. In humans, pathological forms of tau are implicated in a range of diseases that are collectively known as tauopathies. Kinases and phosphatases are responsible for maintaining the correct balance of tau phosphorylation to enable axons to be both stable and labile enough to function properly. In the early stages of tauopathies, this balance is interrupted leading to dissociation of tau from microtubules. This leaves microtubules prone to damage and phosphorylated tau prone to aggregation. Initially, phosphorylated tau forms oligomers, then fibrils, and ultimately neurofibrillary tangles (NFTs). It is widely accepted that the initial soluble oligomeric forms of tau are probably the most pathologically relevant species but there is relatively little quantitative information to explain exactly what their toxic effects are at the individual neuron level. Electrophysiology provides a valuable tool to help uncover the mechanisms of action of tau oligomers on synaptic transmission within single neurons. Understanding the concentration-, time-, and neuronal compartment-dependent actions of soluble tau oligomers on neuronal and synaptic properties are essential to understanding how best to counteract its effects and to develop effective treatment strategies. Here, we briefly discuss the standard approaches used to elucidate these actions, focusing on the advantages and shortcomings of the experimental procedures. Subsequently, we will describe a new approach that addresses specific challenges with the current methods, thus allowing real-time toxicity evaluation at the single-neuron level.

Chronic traumatic encephalopathy (CTE) has become a topic of considerable interest in recent years, with wide-ranging implications for athletes, military members, and other groups exposed to frequent concussive or subconcussive head trauma. The condition has been subject to intensive neuropathological characterization by various groups, with assessment methodologies and staging criteria proposed. Clinical characterization of symptoms has also been performed, but has not yet been definitively formalized. While efforts are underway to develop in vivo markers of tauopathies including CTE, these remain experimental at this time, necessitating postmortem analysis for definitive diagnosis. The putative link between development of cognitive and behavioral dysfunction and neuropathological findings of CTE may prompt requests for postmortem assessment in the forensic setting. Here, we review current concepts in CTE research, describe histopathological findings in CTE, and describe methodologies for pathological assessment of CTE which may be useful to the forensic pathologist.