Moreover, in two other cases, no immunohistochemistry could be performed because tissue sections detached from the glass slide. The neuropathological diagnosis of PSP was based on the National Institute of Neurological Disorders and Stroke (NINDS) criteria. with a clinical diagnosis of PSP (22 with Richardsons syndrome) and 6 control cases. We quantified the presence of hyperphosphorylated tau, the number of pigmented cells indicative of noradrenergic neurons, Deruxtecan and the percentage of pigmented neurons with tau-positive inclusions. assessment of clinical severity using the PSP rating scale was available within 1.8 (0.9) years for 23 patients. We found an average 49% reduction of pigmented neurons in PSP patients relative to controls. The loss of pigmented neurons correlated with disease severity, even after adjusting for disease duration and the interval between clinical assessment and death. The degree of neuronal loss was negatively?associated with tau-positive inclusions, with an average of 44% of pigmented neurons displaying tau-inclusions. Degeneration and tau pathology in the locus coeruleus are related to clinical heterogeneity of PSP. The noradrenergic deficit in the locus coeruleus is usually a candidate target for pharmacological treatment. Recent developments in ultra-high field magnetic resonance imaging to quantify in vivo structural integrity of the locus coeruleus may provide biomarkers for noradrenergic experimental medicines studies in PSP. examination of the brain. Recently, the Deruxtecan development of high-resolution magnetic resonance imaging (MRI) sequences [44], sensitive to the paramagnetic features of neuromelanin [58], has renewed the interest in developing biomarkers for assessing the in vivo degeneration of the locus coeruleus in neurodegenerative diseases including PSP [7]. However, before these MRI methods can be further developed, it is necessary to quantify the neuronal loss in the LC ex vivo and determine whether this pathology relates to other neuropathological aspects in PSP such as the proportion of tau-positive inclusions, and to clinical severity. Therefore, we quantified the locus coeruleus neuropathology in complementary ways. First, we estimated the total number of pigmented neurons in PSP patients in relation to a group of controls of comparable age. Second, we estimated the number of pigmented neurons in the locus coeruleus that manifested neuronal inclusions comprising aggregated hyperphosphorylated tau. Third, we tested Deruxtecan the correlations between pathological and clinical ratings. We confirm the severe loss of locus coeruleus neuron number, and a high Rabbit Polyclonal to EHHADH rate of tau inclusions [20, 39], with a correlation between disease severity (adjusting for time between latest clinical assessment and death), and the severity of neuronal loss in the locus coeruleus. Materials and methods Brainstem tissue from patients and controls was obtained through the Cambridge Brain Bank at the Cambridge University Hospitals NHS Trust, UK (under the ethically approved protocol for Neurodegeneration Research in Dementia) and normative cognitive data from the PiPPIN cohort (Picks disease and progressive supranuclear palsy prevalence and incidence study [17]). Thirty-one patient donations were received between 2010 and 2017 from patients with a clinical and pathological diagnosis of PSP. The available fixed tissue blocks for two PSP-cases did not include the entire locus coeruleus so for these two we only report their percentage of pigmented neurons positive for tau-inclusions. Moreover, in two other cases, no immunohistochemistry could be performed because tissue sections detached from the glass slide. The neuropathological diagnosis of PSP was based on Deruxtecan the National Institute of Neurological Disorders and Stroke (NINDS) criteria. Clinical diagnoses were made according to the revised MDS 2017 criteria (H?glinger et al., 2017), based on the final clinical review (see Gazzina et al. for details [22]). This led to diagnoses of probable PSP-Richardsons syndrome in clinical and cognitive data for control brain donors were not available. However, we compared the cognitive profile of the PSP patients to a control population of elderly individuals (progressive supranuclear palsy, standard deviation, progressive supranuclear palsy, PSP Richardsons syndrome, Picks disease and progressive supranuclear palsy prevalence and incidence study [17], PSP rating scale, revised Addenbrookes cognitive examination, revised Cambridge Behavioural Inventory, Mini Mental State Examination, standard deviation, clinical.