Glial reactivity and T cell infiltration in frontotemporal lobar degeneration with tau pathology.

Frontotemporal lobar degeneration with tau (FTLD-tau) is a group of tauopathies that underlie ∼50% of FTLD cases. Identification of genetic risk variants related to innate/adaptive immunity have highlighted a role for neuroinflammation and neuroimmune interactions in FTLD. Studies have shown microglial and astrocyte activation together with T cell infiltration in the brain of THY-Tau22 tauopathy mice. However, this remains to be confirmed in FTLD-tau patients. We conducted a detailed post-mortem study of FTLD-tau cases including 45 progressive supranuclear palsy with clinical frontotemporal dementia, 33 Pick's disease, 12 FTLD-MAPT and 52 control brains to characterize the link between phosphorylated tau (pTau) epitopes and the innate and adaptive immunity. Tau pathology was assessed in the cerebral cortex using antibodies directed against: Tau-2 (phosphorylated and unphosphorylated tau), AT8 (pSer202/pThr205), AT100 (pThr212/pSer214), CP13 (pSer202), PHF1 (pSer396/pSer404), pThr181 and pSer356. The immunophenotypes of microglia and astrocytes were assessed with phenotypic markers (Iba1, CD68, HLA-DR, CD64, CD32a, CD16 for microglia and GFAP, EAAT2, glutamine synthetase and ALDH1L1 for astrocytes). The adaptive immune response was explored via CD4+ and CD8+ T cell quantification and the neuroinflammatory environment was investigated via the expression of 30 inflammatory-related proteins using V-Plex Meso Scale Discovery. As expected, all pTau markers were increased in FTLD-tau cases compared to controls. pSer356 expression was greatest in FTLD-MAPT cases versus controls (P < 0.0001), whereas the expression of other markers was highest in Pick's disease. Progressive supranuclear palsy with frontotemporal dementia consistently had a lower pTau protein load compared to Pick's disease across tau epitopes. The only microglial marker increased in FTLD-tau was CD16 (P = 0.0292) and specifically in FTLD-MAPT cases (P = 0.0150). However, several associations were detected between pTau epitopes and microglia, supporting an interplay between them. GFAP expression was increased in FTLD-tau (P = 0.0345) with the highest expression in Pick's disease (P = 0.0019), while ALDH1L1 was unchanged. Markers of astrocyte glutamate cycling function were reduced in FTLD-tau (P = 0.0075; Pick's disease: P < 0.0400) implying astrocyte reactivity associated with a decreased glutamate cycling activity, which was further associated with pTau expression. Of the inflammatory proteins assessed in the brain, five chemokines were upregulated in Pick's disease cases (P < 0.0400), consistent with the recruitment of CD4+ (P = 0.0109) and CD8+ (P = 0.0014) T cells. Of note, the CD8+ T cell infiltration was associated with pTau epitopes and microglial and astrocytic markers. Our results highlight that FTLD-tau is associated with astrocyte reactivity, remarkably little activation of microglia, but involvement of adaptive immunity in the form of chemokine-driven recruitment of T lymphocytes.

Exploring the concerns of second-degree dental students on entering specialist OMFS training and their attitudes towards the second-degree curriculum.

Within the UK, oral and maxillofacial surgery (OMFS) is a competitive specialty with a rigorous training programme that currently requires dual degrees in both medicine and dentistry. Training in OMFS can present various challenges in terms of finances, length of training, and work-life balance. The current study explores the concerns of second-degree dental students in trying to obtain an OMFS specialty training post, as well as their views on the second-degree curriculum. An online survey was distributed via social media to second-degree dental students across the UK and 51 responses were received. Respondents cited a lack of publications (29%), specialty interviews (29%), and the OMFS logbook (29%) as the primary concerns about securing a higher training post. Eighty-eight per cent felt there were elements of repetition within the second degree for which competencies had already been achieved, and 88% agreed with streamlining the curriculum within the second degree. We propose that the second degree should incorporate ways to build the OMFS ST1/ST3 portfolio as part of a tailored curriculum, removing or condensing the repetitive elements, and instead emphasising areas of concern for trainees such as research, operative experience, and interview guidance. Second-degree students should be provided with mentors with an interest in research and academia to provide guidance and promote early interest in academia.

CD8 Encephalitis in HIV: A Review of This Emerging Entity.

INTRODUCTION: Encephalitis is a life-threatening neurological condition with multiple causes in the setting of Human Immunodeficiency Virus (HIV). CD8 Encephalitis (CD8E) is a newly recognised condition which can present in an acute manner, with pertinent features including classical radiological findings with an intense brain parenchymal infiltration of CD8+ T cells. This review attempted to clarify the symptomatology, distribution and determinants of this condition, as well as to examine its vast unknowns. METHODS: A literature review was undertaken in July 2022, utilising the PubMed and Google Scholar databases. Papers published between 2006-2022 were reviewed. Eighteen papers, totalling 57 patients, were found and analysed. Statistical analysis was undertaken using Chi-squared and Wilcoxon rank-sum tests as appropriate, with p < 0.05 deemed significant. RESULTS: In this review, 57 patients were identified, with a female (61%, 34/56) and Black African (70%, 40/57) preponderance. Females were more likely to present with headache (p = 0.006), and headache was more likely to be present in those who died (p = 0.02). There was no statistically significant association between baseline CD4 count (p = 0.079) and viral load (p = 0.72) with disease outcome. Overall, 77% (41/53) of patients had classical imaging findings, including bilateral gadolinium-enhancing punctate and perivascular white matter lesions. However, many patients (23/57) required a brain biopsy as part of their diagnostic workup. Corticosteroid treatment was commonly prescribed in patients (64%, 35/55) and had a mortality benefit, with an overall survival in this group of 71% (p = 0.0008). In those who died, median survival was 5.5 months. In rare instances, recurrence of the disease was noted, which responded poorly to treatment. DISCUSSION: CD8E represents a new and complex condition with few risk factors identified for its occurrence. The presenting symptoms are broad, but headache appears to be more common in females and more significantly associated with death. Though rare, CD8E is likely under-diagnosed, possibly due to overlapping features with other illnesses and lack of physician experience in its recognition and management. Corticosteroids demonstrate a clear mortality benefit, but more studies are required to determine their optimal dosing and duration, as well as the use of steroid-sparing agents. Further reviews should help to better determine the risk factors for the condition, as well as non-invasive biomarkers, to aid in diagnosis and help to predict poor prognosis and disease recurrence.