LC3/FtMt Colocalization Patterns Reveal the Progression of FtMt Accumulation in Nigral Neurons of Patients with Progressive Supranuclear Palsy

Mitochondrial ferritin (FtMt) is a mitochondrial iron storage protein associated with neurodegenerative diseases. In patients with progressive supranuclear palsy (PSP), FtMt was shown to accumulate in nigral neurons. Here, we investigated FtMt and LC3 in the post-mortem midbrain of PSP patients to reveal novel aspects of the pathology. Immunohistochemistry was used to assess the distribution and abnormal changes in FtMt and LC3 immunoreactivities. Colocalization analysis using double immunofluorescence was performed, and subcellular patterns were examined using 3D imaging and modeling. In the substantia nigra pars compacta (SNc), strong FtMt-IR and LC3-IR were observed in the neurons of PSP patients. In other midbrain regions, such as the superior colliculus, the FtMt-IR and LC3-IR remained unchanged. In the SNc, nigral neurons were categorized into four patterns based on subcellular LC3/FtMt immunofluorescence intensities, degree of colocalization, and subcellular overlapping. This categorization suggested that concomitant accumulation of LC3/FtMt is related to mitophagy processes. Using the LC3-IR to stage neuronal damage, we retraced LC3/FtMt patterns and revealed the progression of FtMt accumulation in nigral neurons. Informed by these findings, we proposed a hypothesis to explain the function of FtMt during PSP progression.

Differentiating Progressive Supranuclear Palsy and Parkinson's Disease With Head-Mounted Displays

Background: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder that, especially in the early stages of the disease, is clinically difficult to distinguish from Parkinson's disease (PD).Objective: This study aimed at assessing the use of eye-tracking in head-mounted displays (HMDs) for differentiating PSP and PD.Methods: Saccadic eye movements of 13 patients with PSP, 15 patients with PD, and a group of 16 healthy controls (HCs) were measured. To improve applicability in an inpatient setting and standardize the diagnosis, all the tests were conducted in a HMD. In addition, patients underwent atlas-based volumetric analysis of various brain regions based on high-resolution MRI.Results: Patients with PSP displayed unique abnormalities in vertical saccade velocity and saccade gain, while horizontal saccades were less affected. A novel diagnostic index was derived, multiplying the ratios of vertical to horizontal gain and velocity, allowing segregation of PSP from PD with high sensitivity (10/13, 77%) and specificity (14/15, 93%). As expected, patients with PSP as compared with patients with PD showed regional atrophy in midbrain volume, the midbrain plane, and the midbrain tegmentum plane. In addition, we found for the first time that oculomotor measures (vertical gain, velocity, and the diagnostic index) were correlated significantly to midbrain volume in the PSP group.Conclusions: Assessing eye movements in a HMD provides an easy to apply and highly standardized tool to differentiate PSP of patients from PD and HCs, which will aid in the diagnosis of PSP.

Diagnostic Performance of the Magnetic Resonance Parkinsonism Index in Differentiating Progressive Supranuclear Palsy from Parkinson’s Disease: An Updated Systematic Review and Meta-Analysis

Progressive supranuclear palsy (PSP) and Parkinson’s disease (PD) are difficult to differentiate especially in the early stages. We aimed to investigate the diagnostic performance of the magnetic resonance parkinsonism index (MRPI) in differentiating PSP from PD. A systematic literature search of PubMed-MEDLINE and EMBASE was performed to identify original articles evaluating the diagnostic performance of the MRPI in differentiating PSP from PD published up to 20 February 2021. The pooled sensitivity, specificity, and 95% CI were calculated using the bivariate random-effects model. The area under the curve (AUC) was calculated using a hierarchical summary receiver operating characteristic (HSROC) model. Meta-regression was performed to explain the effects of heterogeneity. A total of 14 original articles involving 484 PSP patients and 1243 PD patients were included. In all studies, T1-weighted images were used to calculate the MRPI. Among the 14 studies, nine studies used 3D T1-weighted images. The pooled sensitivity and specificity for the diagnostic performance of the MRPI in differentiating PSP from PD were 96% (95% CI, 87–99%) and 98% (95% CI, 91–100%), respectively. The area under the HSROC curve was 0.99 (95% CI, 0.98–1.00). Heterogeneity was present (sensitivity: I2 = 97.29%; specificity: I2 = 98.82%). Meta-regression showed the association of the magnet field strength with heterogeneity. Studies using 3 T MRI showed significantly higher sensitivity (100%) and specificity (100%) than those of studies using 1.5 T MRI (sensitivity of 98% and specificity of 97%) (p < 0.01). Thus, the MRPI could accurately differentiate PSP from PD and support the implementation of appropriate management strategies for patients with PSP.

Peripapillary retinal nerve fiber layer thinning in patients with progressive supranuclear palsy

Objectives To investigate peripapillary retinal nerve fiber layer (pRNFL) changes in patients with progressive supranuclear palsy (PSP). Methods We included 21 PSP patients (36 eyes) who underwent peripapillary optical coherence tomography (OCT) scans at 2.5 ± 1.3 years of disease, without ophthalmologic co-morbidities. We compared pRNFL thicknesses in PSP eyes with age-matched 22 controls (22 eyes) using generalized estimating equation model adjusting for intra-subject inter-eye correlations, age and sex. We also analyzed the correlation between the pRNFL thickness and clinical severity using Spearman’s correlation. In twelve PSP patients with 3 T brain MRI volumetric scan within 1 year of OCT exam, we investigated the correlation between the pRNFL thickness and brain atrophy using Pearson’s correlation. Results PSP patients had global pRNFL thinning compared to controls (beta = − 6.436, p = 0.025). Global pRNFL thickness correlated with Hoehn & Yahr stages (r = − 0.487, p = 0.025), and nasal pRNFL thinning showed a trend of correlation (uncorrected p < 0.05). Exploratory correlation analysis between global pRNFL thickness and nonmotor items in the PSP rating scale showed a trend toward association with sleep disturbances (uncorrected p = 0.008) and urinary incontinence (uncorrected p = 0.031), although not significant after Bonferroni correction (all 28 items). The patients had significant atrophy in the posterior cingulate cortex, third ventricle, pallidum, and midbrain with reduced midbrain-to-pons ratio, but no correlation was found between pRNFL thickness and brain volumes. Conclusion The pRNFL seems to be affected in PSP, which is more severe with advanced disease stages. Retinal investigation in a larger longitudinal cohort would help elucidate the pathophysiological role of retinal thinning in PSP.