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Acta Neuropathologica Communications Nov 2023Tau seed amplification assays (SAAs) directly measure the seeding activity of tau and would therefore be ideal biomarkers for clinical trials targeting seeding-competent...
Tau seed amplification assays (SAAs) directly measure the seeding activity of tau and would therefore be ideal biomarkers for clinical trials targeting seeding-competent tau in Alzheimer's disease (AD). However, the precise relationship between tau seeding measured by SAA and the levels of pathological forms of tau in the AD brain remains unknown. We developed a new tau SAA based on full-length 0N3R tau with sensitivity in the low fg/ml range and used it to characterize 103 brain samples from three independent cohorts. Tau seeding clearly discriminated between AD and control brain samples. Interestingly, seeding was absent in Progressive Supranuclear Palsy (PSP) putamen, suggesting that our tau SAA did not amplify 4R tau aggregates from PSP brain. The specificity of our tau SAA for AD brain was further supported by analysis of matched hippocampus and cerebellum samples. While seeding was detected in hippocampus from Braak stages I-II, no seeding was present in AD cerebellum that is devoid of tau inclusions. Analysis of 40 middle frontal gyrus samples encompassing all Braak stages showed that tau SAA seeding activity gradually increased with Braak stage. This relationship between seeding activity and the presence of tau inclusions in AD brain was further supported by robust correlations between tau SAA results and the levels of phosphorylated tau212/214, phosphorylated tau181, aggregated tau, and sarkosyl-insoluble tau. Strikingly, we detected tau seeding in the middle frontal gyrus already at Braak stage II-III, suggesting that tau SAA can detect tau pathology earlier than conventional immunohistochemical staining. In conclusion, our data suggest a quantitative relationship between tau seeding activity and pathological forms of tau in the human brain and provides an important basis for further development of tau SAA for accessible human samples.
Topics: Humans; Alzheimer Disease; tau Proteins; Brain; Supranuclear Palsy, Progressive; Cerebellum
PubMed: 37964332
DOI: 10.1186/s40478-023-01676-w -
Investigative Ophthalmology & Visual... Oct 2023The purpose of this study was to explore the cortical deficits of patients with acquired concomitant esotropia (AACE) using the resting-state functional magnetic...
PURPOSE
The purpose of this study was to explore the cortical deficits of patients with acquired concomitant esotropia (AACE) using the resting-state functional magnetic resonance imaging (rs-fMRI) technique.
METHODS
Rs-fMRI signals from 25 patients with AACE and 25 matched controls were collected. The repeated-measures analysis of variance (RM-ANOVA) test and two-sample t-test were used to investigate statistical differences of the amplitudes of low-frequency fluctuation (ALFF) signals and correlation analysis was performed to validate the relationship of signal change and clinical features.
RESULTS
The AACE group showed decreased ALFF in both hemispheres symmetrically (t = 0.38, P = 0.71), with peak t in both middle occipital gyrus. The ALFF signal from the upper left inferior frontal gyrus was negatively correlated with the age of onset (r = 0.62, P = 0.0008), and the ALFF signal from the right superior temporal gyrus was negatively correlated with the near work hours (r = 0.63, P = 0.0008). The ALFF signal in the left fusiform gyrus was positively correlated with both near (r = 0.48, P = 0.01) and far (r = 0.44, P = 0.03) deviation, whereas it was only positively correlated with far deviation (r = 0.44, P = 0.03) in the right. Besides, the age of onset and the near work hour were independent factors of signal changes.
CONCLUSIONS
Using the ALFF signal of rs-fMRI, we found functional deficits in the primary visual cortex and dorsal pathway in patients with AACE. There were functional changes in the fusiform gyrus, and the greater the deviation angle, the higher the changing level. These findings reveal the association of AACE and the visual center, giving us more clues about the treatment of AACE.
Topics: Humans; Esotropia; Acute Disease; Analysis of Variance; Occipital Lobe; Visual Cortex
PubMed: 37902746
DOI: 10.1167/iovs.64.13.46 -
Journal of Parkinson's Disease 2024
Topics: Humans; Supranuclear Palsy, Progressive
PubMed: 38160366
DOI: 10.3233/JPD-230301 -
Journal of Neurology May 2024The cause of downbeat nystagmus (DBN) remains unknown in a substantial number of patients ("idiopathic"), although intronic GAA expansions in FGF14 have recently been...
OBJECTIVES
The cause of downbeat nystagmus (DBN) remains unknown in a substantial number of patients ("idiopathic"), although intronic GAA expansions in FGF14 have recently been shown to account for almost 50% of yet idiopathic cases. Here, we hypothesized that biallelic RFC1 expansions may also represent a recurrent cause of DBN syndrome.
METHODS
We genotyped the RFC1 repeat and performed in-depth phenotyping in 203 patients with DBN, including 65 patients with idiopathic DBN, 102 patients carrying an FGF14 GAA expansion, and 36 patients with presumed secondary DBN.
RESULTS
Biallelic RFC1 AAGGG expansions were identified in 15/65 patients with idiopathic DBN (23%). None of the 102 GAA-FGF14-positive patients, but 2/36 (6%) of patients with presumed secondary DBN carried biallelic RFC1 expansions. The DBN syndrome in RFC1-positive patients was characterized by additional cerebellar impairment in 100% (15/15), bilateral vestibulopathy (BVP) in 100% (15/15), and polyneuropathy in 80% (12/15) of cases. Compared to GAA-FGF14-positive and genetically unexplained patients, RFC1-positive patients had significantly more frequent neuropathic features on examination and BVP. Furthermore, vestibular function, as measured by the video head impulse test, was significantly more impaired in RFC1-positive patients.
DISCUSSION
Biallelic RFC1 expansions are a common monogenic cause of DBN syndrome.
Topics: Humans; Replication Protein C; Male; Female; Middle Aged; Phenotype; Adult; Nystagmus, Pathologic; Aged; DNA Repeat Expansion; Fibroblast Growth Factors; Young Adult; Bilateral Vestibulopathy
PubMed: 38381176
DOI: 10.1007/s00415-024-12229-z -
Acta Neuropathologica Communications Nov 2023The development of novel treatments for Progressive Supranuclear Palsy (PSP) is hindered by a knowledge gap of the impact of neurodegenerative neuropathology on brain...
The development of novel treatments for Progressive Supranuclear Palsy (PSP) is hindered by a knowledge gap of the impact of neurodegenerative neuropathology on brain structure and function. The current standard practice for measuring postmortem tau histology is semi-quantitative assessment, which is prone to inter-rater variability, time-consuming and difficult to scale. We developed and optimized a tau aggregate type-specific quantification pipeline for cortical and subcortical regions, in human brain donors with PSP. We quantified 4 tau objects ('neurofibrillary tangles', 'coiled bodies', 'tufted astrocytes', and 'tau fragments') using a probabilistic random forest machine learning classifier. The tau pipeline achieved high classification performance (F1-score > 0.90), comparable to neuropathologist inter-rater reliability in the held-out test set. Using 240 AT8 slides from 32 postmortem brains, the tau burden was correlated against the PSP pathology staging scheme using Spearman's rank correlation. We assessed whether clinical severity (PSP rating scale, PSPRS) score reflects neuropathological severity inferred from PSP stage and tau burden using Bayesian linear mixed regression. Tufted astrocyte density in cortical regions and coiled body density in subcortical regions showed the highest correlation to PSP stage (r = 0.62 and r = 0.38, respectively). Using traditional manual staging, only PSP patients in stage 6, not earlier stages, had significantly higher clinical severity than stage 2. Cortical tau density and neurofibrillary tangle density in subcortical regions correlated with clinical severity. Overall, our data indicate the potential for highly accurate digital tau aggregate type-specific quantification for neurodegenerative tauopathies; and the importance of studying tau aggregate type-specific burden in different brain regions as opposed to overall tau, to gain insights into the pathogenesis and progression of tauopathies.
Topics: Humans; Supranuclear Palsy, Progressive; tau Proteins; Bayes Theorem; Reproducibility of Results; Tauopathies; Brain
PubMed: 37946288
DOI: 10.1186/s40478-023-01674-y -
Parkinsonism & Related Disorders Oct 2023Distinguishing Parkinson's disease (PD) from Progressive supranuclear palsy (PSP) at early disease stages is important for clinical trial enrollment and clinical...
INTRODUCTION
Distinguishing Parkinson's disease (PD) from Progressive supranuclear palsy (PSP) at early disease stages is important for clinical trial enrollment and clinical care/prognostication.
METHODS
We recruited 21 participants with PSP(n = 11) or PD(n = 10) with reliable caregivers. Standardized passage reading, counting, and sustained phonation were recorded on the BioDigit Home tablet (BioSensics LLC, Newton, MA USA), and speech features from the assessments were analyzed using the BioDigit Speech platform (BioSensics LLC, Newton, MA USA). An independent t-test was performed to compare each speech feature between PSP and PD participants. We also performed Spearman's correlations to evaluate associations between speech measures and clinical scores (e.g., PSP rating scales and MoCA). In addition, the model's performance in classifying PSP and PD was evaluated using Rainbow passage reading analysis.
RESULTS
During Rainbow passage reading, PSP participants had a significantly slower articulation rate (2.45(0.49) vs 3.60(0.47) words/minute), lower speech-to-pause ratio (2.33(1.08) vs 3.67(1.18)), intelligibility dynamic time warping (DTW, 0.26(0.19) vs 0.53(0.26)), and similarity DTW (0.43(0.27) vs 0.67(0.13)) compared to PD participants. PSP participants also had longer pause times (17.24(5.47) vs 8.45(3.13) sec) and longer total signal times (52.44(6.67) vs (36.67(6.73) sec) when reading the passage. In terms of the phonation 'a', PSP participants showed a significant higher spectral entropy, spectral centroid, and spectral spread compared to PD participants and no differences were found for phonation 'e'. PD participants had more accurate reverse number counts than PSP participants (14.89(3.86) vs 7.36(4.67)). PSP Rating Scale (PSPRS) dysarthria (r = 0.79, p = 0.004) and bulbar item scores (r = 0.803, p = 0.005) were positively correlated with articulation rate in reverse number counts. Correct reverse number counts were positively correlated with total Montreal Cognitive Assessment scores (r = 0.703, p = 0.016). Machine learning models using passage reading-derived measures obtained an AUC of 0.93, and the sensitivity/specificity in correctly classifying PSP and PD participants were 0.95 and 0.90, respectively.
CONCLUSION
Our study demonstrates the feasibility of differentiating PSP from PD using a digital health technology platform. Further multi-center studies are needed to expand and validate our initial findings.
Topics: Humans; Parkinson Disease; Supranuclear Palsy, Progressive; Speech; Dysarthria; Sensitivity and Specificity
PubMed: 37678101
DOI: 10.1016/j.parkreldis.2023.105835 -
Scientific Reports Nov 2023Heterophoria is a common type of binocular fusion disorder that consists of a latent eye misalignment with potential consequences on daily activities such as reading or...
Heterophoria is a common type of binocular fusion disorder that consists of a latent eye misalignment with potential consequences on daily activities such as reading or working on a computer (with CVS). Crowding, a type of contextual modulation, can also impair reading. Our recent studies found an abnormal pattern of low-level visual processing with larger perceptive fields (PF) in heterophoria. The PF is the fundamental processing unit of human vision and both masking and crowding depend on its size. We investigated how heterophoria would impact the PF's size via a lateral masking experiment and consequently affect the foveal crowding at different letter-spacings (the crowding zone). More specifically, we explored the relationship between crowding, lateral masking, the PF's size, and the amount of heterophoria. The binocular horizontal PF's size was larger with heterophoric subjects, in agreement with our previous study. We found a stronger crowding and an extended crowding zone associated with slower response times; this shows that the processing of letter identification under both crowded and uncrowded conditions requires more processing effort in heterophoric individuals. In agreement with previous studies, we found a correlation between the crowding zone and the PF's size; each was strongly correlated with the amount of phoria. These findings resemble those involving the PF size and the extended crowding found at the fovea in amblyopia and young children. We suggest that these findings could help explain the inter-observers' variability found in the masking literature, and the reading difficulties often encountered in subjects with high heterophoria.
Topics: Child; Humans; Child, Preschool; Visual Acuity; Perceptual Masking; Visual Perception; Amblyopia; Strabismus; Malocclusion; Pattern Recognition, Visual
PubMed: 37935803
DOI: 10.1038/s41598-023-46291-w -
Sensors (Basel, Switzerland) May 2024In this study, we propose a deep learning-based nystagmus detection algorithm using video oculography (VOG) data to diagnose benign paroxysmal positional vertigo (BPPV)....
In this study, we propose a deep learning-based nystagmus detection algorithm using video oculography (VOG) data to diagnose benign paroxysmal positional vertigo (BPPV). Various deep learning architectures were utilized to develop and evaluate nystagmus detection models. Among the four deep learning architectures used in this study, the CNN1D model proposed as a nystagmus detection model demonstrated the best performance, exhibiting a sensitivity of 94.06 ± 0.78%, specificity of 86.39 ± 1.31%, precision of 91.34 ± 0.84%, accuracy of 91.02 ± 0.66%, and an -score of 92.68 ± 0.55%. These results indicate the high accuracy and generalizability of the proposed nystagmus diagnosis algorithm. In conclusion, this study validates the practicality of deep learning in diagnosing BPPV and offers avenues for numerous potential applications of deep learning in the medical diagnostic sector. The findings of this research underscore its importance in enhancing diagnostic accuracy and efficiency in healthcare.
Topics: Humans; Deep Learning; Algorithms; Benign Paroxysmal Positional Vertigo; Nystagmus, Pathologic; Video Recording; Male; Female; Neural Networks, Computer; Middle Aged
PubMed: 38894208
DOI: 10.3390/s24113417 -
Investigative Ophthalmology & Visual... Nov 2023Perception of the motion quartet (MQ) alternates between horizontal and vertical motion, with a bias toward vertical motion. This vertical bias has been explained by the...
PURPOSE
Perception of the motion quartet (MQ) alternates between horizontal and vertical motion, with a bias toward vertical motion. This vertical bias has been explained by the dominance of intrahemispheric processing. In albinism, each hemisphere receives input from both visual hemifields owing to enhanced crossing of the optic nerves at the optic chiasm. This might affect the perception of the ambiguous MQ and particularly the vertical bias.
METHODS
The effect of optic nerve misrouting in persons with albinism and nystagmus (PWA, n = 14) on motion perception for MQ was compared with healthy controls (HC; n = 11) and with persons with nystagmus in the absence of optic nerve misrouting (PWN; n = 12). We varied the ratio of horizontal and vertical distances of MQ dots (aspect ratio [AR]) between 0.75 and 1.25 and compared the percentages of horizontal and vertical motion percepts as a function of AR between groups.
RESULTS
For HC, the probability of vertical motion perception increased as a sigmoid function with increasing AR exhibiting the expected vertical percept bias (mean, 58%; median, 54%; vertical motion percepts). PWA showed a surprisingly strong horizontal bias independent of the AR with a mean of 11% (median, 10%) vertical motion percepts. The PWN was in between PWA and HC, with a mean of 34% (median, 47%) vertical perception. Nystagmus alone is unlikely to explain this pattern of results because PWA and PWN had comparable fixation stabilities.
CONCLUSIONS
The strong horizontal bias observed in PWA and PWN might partly result from the horizontal nystagmus. The even stronger horizontal bias in PWA indicates that the intrahemispherical corepresentation of both visual hemifields may play an additional role. The altered perception of the MQ in PWA opens opportunities to (i) understand the interplay of stability and plasticity in altered visual pathway conditions and (ii) identify visual pathway abnormalities with a perception-based test using the MQ.
Topics: Humans; Albinism; Motion Perception; Nystagmus, Pathologic; Optic Chiasm; Optic Nerve
PubMed: 38015177
DOI: 10.1167/iovs.64.14.39 -
Medicina (Kaunas, Lithuania) Sep 2023: Progressive supranuclear palsy (PSP) is a neurodegenerative disease, a tauopathy, which results in a wide clinical spectrum of neurological symptoms. The diagnosis is...
: Progressive supranuclear palsy (PSP) is a neurodegenerative disease, a tauopathy, which results in a wide clinical spectrum of neurological symptoms. The diagnosis is mostly based on clinical signs and neuroimaging; however, possible biomarkers for screening have been under investigation, and the role of the gut microbiome is unknown. The aim of our study was to identify potential blood biomarkers and observe variations in the gut microbiome within a PSP discordant monozygotic twin pair. : Anthropometric measurements, neuropsychological tests, and the neurological state were evaluated. Blood was collected for metabolic profiling and for the detection of neurodegenerative and vascular biomarkers. Both the gut microbiome and brain MRI results were thoroughly examined. : We found a relevant difference between alpha-synuclein levels and moderate difference in the levels of MMP-2, MB, Apo-A1, Apo-CIII, and Apo-H. With respect to the ratios, a small difference was observed for ApoA1/SAA and ApoB/ApoA1. Using a microbiome analysis, we also discovered a relative dysbiosis, and the MRI results revealed midbrain and frontoparietal cortical atrophy along with a reduction in overall brain volumes and an increase in white matter lesions in the affected twin. : We observed significant differences between the unaffected and affected twins in some risk factors and blood biomarkers, along with disparities in the gut microbiome. Additionally, we detected abnormalities in brain MRI results and alterations in cognitive functions.
Topics: Humans; Supranuclear Palsy, Progressive; Neurodegenerative Diseases; Magnetic Resonance Imaging; Risk Factors; Biomarkers
PubMed: 37893413
DOI: 10.3390/medicina59101696