Search Results (135)

A novel brain positron emission tomography (PET) radioligand, [¹¹C]HY-2-15, has potential for imaging alpha-synuclein aggregations in multiple system atrophy and misfolded tau proteins in tauopathies, based on its high binding affinity in disease brain tissue homogenates. Here, we demonstrate that [³H]HY-2-15 has the capability to bind to aggregated alpha-synuclein in multiple system atrophy brain and tau aggregations in progressive supranuclear palsy and corticobasal degeneration brain tissues via in vitro autoradiography study. A first-in-human pilot multicenter clinical study recruited a total of 10 subjects including healthy controls and patients with Parkinson’s disease, multiple system atrophy, or progressive supranuclear palsy. The study revealed that [¹¹C]HY-2-15 has a relatively higher specific uptake in the pallidum and midbrain of patients with progressive supranuclear palsy. Total-body scans performed on the PennPET Explorer showed the radiotracer was cleared by renal excretion. However, the rapid metabolism and low brain uptake resulted in a limited signal of [¹¹C]HY-2-15 in brain. Full article

Background/Objectives: Cognitive impairment often occurs in various parkinsonian syndromes. The course of deficits in cognitive functions ranges from mild cognitive decline to severe deterioration. Affected cognitive domains are also variable. The genetic background of patients exhibiting parkinsonism with concomitant cognitive decline is still elusive. A significant part of current research in Parkinson’s disease and other parkinsonian syndromes is targeted towards the genetic aspects of these disorders. The aim of the present review was to summarize existing studies focusing on the investigation of the interplay between genetic data in parkinsonism and associated cognitive symptoms. Methods: A review of English-language articles published between 2000 and 2024 was conducted, focusing on genetic studies of Parkinson’s disease and atypical parkinsonian syndromes with cognitive decline, using the databases PUBMED, SCOPUS, and EMBASE. Results: We have selected a clinical phenotype-wise assessment of parkinsonian conditions with cognitive deficits, including typical or early-onset Parkinson’s disease, dementia with Lewy bodies, Corticobasal Syndrome, Progressive Supranuclear Palsy, and frontotemporal dementia with parkinsonism. Both typical and atypical parkinsonian syndromes with concomitant cognitive decline were explored. Conclusions: Genetic background likely contributes to the heterogeneity of cognitive impairment in parkinsonian syndromes, with specific mutations linked to distinct cognitive symptoms. The integration of genetic data and a more thorough neuropsychological assessment with clinical, imaging, and biomarkers may enhance diagnosis and enable personalized therapies. Full article

The molecular imaging of α-synuclein (α-syn) pathology in Parkinson’s disease (PD) and related movement disorders is a clinically unmet need. The aim of this study was to discover and characterize in vitro a radioligand for imaging α-syn pathology. A library of 78 small molecules was developed and screened using recombinant α-syn fibrils and brain homogenates from Alzheimer’s disease (AD) donors. The selection criteria were as follows: Ki_α-syn < 30 nM, Ki_tau and Ki_A-β > 200 nM. Three compounds, GMC-073 (K_iα-syn: 8 nM), GMC-098 (Ki_α-syn: 9.7 nM), and GMC-058 (Ki_α-syn: 22.5 nM), fulfilled the criteria and were radiolabeled with ³H. [³H]GMC-058 was the only compound with negligible binding in controls, and was further evaluated using tissue microarrays, autoradiography on fresh-frozen brain slices, and in vitro saturation binding assay on brain homogenates. [³H]GMC-058 binding co-localized with α-syn inclusions in Parkinson’s disease (PD) and multiple-system atrophy (MSA), with dense A-β plaques in cerebral amyloid angiopathy and AD and with p-tau inclusions in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Specific binding was highest in PSP and CBD. In vitro K_D was highest in AD (5.4 nM), followed by PSP (41 nM) and CBD (75 nM). The K_D in MSA, PD, and controls was >100 nM. [³H]GMC-058 is a novel radioligand displaying a low affinity for aggregated α-syn in tissue, with an in vitro profile also suitable for detecting tau pathology in 4R tauopathies. Full article

Background: Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disorder characterized by abnormal tau protein aggregation. The MAPT gene encodes for tau protein. The MAPT locus harbors two major haplotypes, H1 and H2, with H1 and its subhaplotypes being associated with an increased risk of PSP. Methods: In this study, we genotyped rs8070723 in a cohort of 73 PSP patients, including 47 PSP Richardson Syndrome (PSP-RS) and 27 PSP variants (vPSP), and 93 age-matched healthy controls (HC) from Southern Italy. Results: Haplotype analysis identified H1 and H2 haplotypes that conferred a risk (OR, 2.620; 95% CI, 1.399–5.140; p = 0.0035) and a protective effect (OR, 0.370; 95% CI, 0.196–0.695; p = 0.0015), respectively. In addition, we genotyped five MAPT variants (rs1467967, rs242557, rs3785883, rs2471738, and rs7521) that, together with rs8070723, defined H1 subhaplotypes. We identified 18 distinct MAPT H1 subhaplotypes, among which H1j displayed a nominally significant reduced risk of PSP (OR, 0.201; 95% CI, 0.044–0.915; p = 0.0265). Conclusions: These findings reinforce the role of MAPT genetic variation in PSP pathogenesis and highlight the potential impact of haplotype diversity on disease susceptibility. Full article

Background/Objectives: Progressive supranuclear palsy (PSP) is an atypical Parkinsonian disorder characterized by Parkinsonism with gait imbalance, vertical gaze palsy, and frontal cognitive dysfunction. Though digital health technologies (DHTs) are widely used both clinically and in research as outcome measures, there is a lack of consistency applied to these devices and their resulting metrics. This scoping review aims to identify efforts taken to validate wearable DHTs for use in PSP, identify gaps in research, and discuss the steps needed to expand their use and acceptance as primary trial endpoints. Methods: In this scoping review, we conducted a search of the MEDLINE database to examine the use of DHTs as outcome measures in Progressive Supranuclear Palsy. Results: A total of 17 publications were identified and reviewed. Included articles evaluated the use of DHT to measure lower extremity function/gait, balance, upper extremity function, and speech. Conclusions: Our scoping review highlights the importance of standardization of DHT metrics by thorough assessment of their content validity, reliability, construct validity, responsiveness, and discriminant validity. Efforts must be taken to ensure DHTs capture clinically relevant, patient-centered outcome measures that are comparable to conventional rating scales, that consistently discriminate disease progression. Incorporation of DHTs as clinical trial endpoints has the potential to encourage clinical research and to advance patient care. Full article

We have previously shown that neuromodulatory actions on astrocytes can elicit metabotropic glutamate- and N-methyl-D-aspartate receptor-dependent tonic changes in excitability in the mesopontine region. Although in vitro experiments explored robust effects, the in vivo significance of our findings remained unknown. In this project, chronic chemogenetic activation of mesopontine astrocytes and its actions on movement, circadian activity, acoustic startle and spatial memory were tested. The control group of young adult male mice where mesopontine astrocytes expressed only the mCherry fluorescent tag was compared to the group expressing the hM3D(Gq) chemogenetic actuator. Chronic chemogenetic astrocyte activation reduced the amplitude of the acoustic startle reflex and increased the locomotion speed in the resting period. Gait alterations were also demonstrated but no change in the spatial memory was explored. As a potential background of these findings, chronic astrocytic activation decreased the cholinergic neuronal number to 54% and reduced the non-cholinergic neuronal number to 76% of the control. In conclusion, chronic astrocytic activation and the consequential decrease in the neuronal number led to disturbances in movement and circadian activity resembling brainstem-related symptoms of progressive supranuclear palsy, raising the possibility that astrocytic overactivation is involved in the pathogenesis of this disease. Full article

Tau protein plays a pivotal role in maintaining neuronal structure and function through its regulation of microtubule stability and neuronal polarity. Encoded by the MAPT gene, Tau exists in multiple isoforms due to alternative mRNA splicing, with differential expression in the central and peripheral nervous systems. In healthy neurons, tau mRNA is selectively localized and translated in axons, a process tightly regulated by untranslated regions (UTRs) and RNA-binding proteins such as HuD and FMRP. Pathologically, Tau undergoes hyperphosphorylation, misfolding, and aggregation, which contribute to neurodegeneration in a range of disorders collectively known as tauopathies. Alzheimer’s disease (AD) is the most prevalent tauopathy, where abnormal Tau accumulation in the temporal and frontal lobes correlates with cognitive decline and behavioral symptoms. Other tauopathies, including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Frontotemporal Dementia with Parkinsonism (FTDP-17), and Pick’s disease, are distinguished by the predominance of specific Tau isoforms (3R or 4R), cellular distribution, and affected brain regions. Notably, astroglial tauopathies highlight the pathological role of Tau accumulation in glial cells, expanding the understanding of neurodegeneration beyond neurons. Despite advances in imaging biomarkers (e.g., Tau-PET) and molecular diagnostics, effective disease-modifying therapies for tauopathies remain elusive. Ongoing research targets Tau through immunotherapies, splicing modulators, kinase inhibitors, and antisense oligonucleotides, aiming to mitigate Tau pathology and its deleterious effects. Understanding the multifaceted roles of Tau in neuronal and glial contexts is critical for developing future therapeutic strategies against tauopathies. Full article

Progressive supranuclear palsy (PSP) is a neurodegenerative disease, classified as an atypical Parkinsonian syndrome, that has been pathologically and clinically defined. The histopathological aspects of the disease include tufted astrocytes, while the clinical features involve oculomotor dysfunction, postural instability, akinesia, cognitive impairment, and language difficulties. Although PSP is generally considered a sporadic disease, interest is growing in its genetics, with contemporary research focusing on familial backgrounds and neuroinflammation. Indeed, microglial activation and other inflammatory mechanisms of PSP pathogenesis have been extensively analyzed using genetic examinations to identify the factors impacting neurodegeneration. As such, this review aims to elaborate on recent findings in this field. Full article

Introduction: Neurodegenerative diseases like progressive supranuclear palsy (PSP) present challenges concerning their diagnosis. Neuroimaging using magnetic resonance (MRI) may add diagnostic value. However, modern techniques such as volumetric assessment using Voxel-Based Morphometry (VBM), although proven to be more accurate and superior compared to MRI, have not gained popularity among scientists in the investigation of neurological disorders due to their higher cost and time-consuming applications. Conventional brain MRI methods may present a quick, practical, and easy-to-use imaging rating tool for the differential diagnosis of PSP. The purpose of this study is to evaluate a string of existing visual MRI rating scales and signs regarding their impact for the diagnosis of PSP. Materials and Methods: The population study consisted of 30 patients suffering from PSP and 72 healthy controls. Each study participant underwent a brain MRI, which was subsequently examined by two independent researchers in a double-blinded fashion. Fifteen visual rating scales and signs were evaluated, including pontine atrophy, cerebellar atrophy, midbrain atrophy, aqueduct of Sylvius enlargement, cerebellar peduncle hyperintensities, enlargement of the fourth ventricle (100% sensitivity and 71% specificity) and left temporal lobe atrophy (97% sensitivity and 78% specificity). Conclusions: Enlargement of the Sylvius aqueduct, enlargement of the fourth ventricle and atrophy of both temporal lobes together with the presence of morning glory and hummingbird signs can be easily and quickly distinguished and identified by an experienced radiologist without involving any complex analysis, making them useful tools for PSP diagnosis. MRI visual scale measurements could be added to the diagnostic criteria of PSP and may serve as an alternative to highly technical and more sophisticated quantification methods. Full article

Background: Research has associated chronic inflammation with the evolution of neurological and psychiatric disorders. Neurodegenerative diseases, including Parkinson’s Disease (PD), Alzheimer’s Disease (AD), and less common ones such as Progressive Supranuclear Palsy (PSP), are commonly linked to depression. However, the pathomechanisms and the role of neuroinflammation in these disorders remain unclear; therefore, interest is increasing in easily accessible inflammatory morphological assessments of blood samples, such as the neutrophil-to-lymphocyte ratio (NLR), the neutrophil-to-monocyte ratio (NMR), and the neutrophil-to-hemoglobin ratio (N/HGBR). Methods: The authors analyzed 15 age-matched controls and 21 patients with PSP; the PSP group was additionally divided into 11 patients without depression (PSP) and 10 with depression (Beck Depression Inventory [BDI] ≥ 14) (PSP-D). Results: In the PSP-D group, the level of N/HGBR was significantly lower than in the controls (p = 0.01), but there were no significant differences in any other neutrophil-derived parameters or comparisons of morphological blood assessment. Patients with PSP-D exhibited a marginally significant decrease in neutrophil levels compared to the controls. Conclusions: This is the first study highlighting the possible significance of peripheral inflammatory factors in patients with PSP affected by depression. It highlights possible tendencies in the area of non-specific inflammatory markers and suggests their relation to affective disorders in PSP. Full article

Background and Objectives: Despite ongoing research and evolving diagnostic criteria, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) remain notoriously difficult to differentiate, largely due to their overlapping clinical presentations and the absence of definitive biomarkers. Materials and Methods: We provide a comprehensive review of cerebrospinal fluid (CSF) biomarkers, which have proven valuable in the diagnosis of other neurodegenerative conditions, and their application to PSP and CBS. Results: The most promising results derive from a combination of biomarkers associated with Parkinson’s disease, Alzheimer’s disease, and neurofilament light chain. Furthermore, CSF proteomics analysis offers valuable insights into the pathogenesis of PSP and CBS and could also contribute to accurate diagnosis. Conclusions: CSF biomarkers hold significant potential for improving the differential diagnosis of PSP and CBS. A stepwise combination approach—starting with CSF α-synuclein and neurofilament light chain, followed by amyloid-β42 and total and phosphorylated tau—may provide clinicians with a practical framework for distinguishing PSP and CBS from other neurodegenerative disorders. To advance this field, future efforts should prioritize large-scale, multicenter studies employing standardized methodologies to enhance the validity and reproducibility of biomarker-based diagnostics. Importantly, considering the frequent pathological overlap between PSP and CBS, future studies would greatly benefit from pathology-confirmed cohorts to ensure diagnostic accuracy and to better delineate biomarker profiles across these challenging conditions. Full article

Progressive Supranuclear Palsy (PSP) is an atypical Parkinsonism, pathologically described as a four-repeat tauopathy. The contemporary criteria for diagnosis of PSP indicate akinesia, oculomotor dysfunction, postural instability, and language/cognitive impairment as core symptoms. Among these features, the first two are linked to PSP—Parkinsonism predominant (PSP-P). PSP-P is the second most common subtype of PSP, following PSP—Richardson’s syndrome (PSP-RS), and is associated with a more gradual deterioration, beneficial course, and longer life expectancy after diagnosis. It is also problematic in terms of clinical evaluation, as this entity may overlap with Parkinson’s disease (PD) in early stages and with other atypical Parkinsonisms in more advanced stages. The evolution in understanding PSP and the possible progress in care and therapy of the disease leads to the necessity of finding optimal examination methods with sufficient sensitivity and specificity. In this context, PSP-P seems a crucial point. The goal of this narrative review is to provide an overview of the possibilities provided by Magnetic Resonance Imaging (MRI) assessments in terms of PSP-P and analyze their strengths and weaknesses. Full article

Astrocytes have multiple crucial roles, including maintaining brain homeostasis and synaptic function, performing phagocytic clearance, and responding to injury and repair. It has been suggested that astrocyte performance is progressively impaired with aging, leading to imbalances in the brain’s internal milieu that eventually impact neuronal function and lead to neurodegeneration. Until now, most evidence of astrocytic dysfunction in aging has come from experiments done with whole tissue homogenates, astrocytes collected by laser capture, or cell cultures derived from animal models or cell lines. In this study, we used postmortem-derived whole cells sorted with anti-GFAP antibodies to compare the unbiased, whole-transcriptomes of human astrocytes from control, older non-impaired individuals and subjects with different neurodegenerative diseases, such as Parkinson’s disease (PD), Alzheimer’s disease (ADD), and progressive supranuclear palsy (PSP). We found hundreds of dysregulated genes between disease and control astrocytes. In addition, we identified numerous genes shared between these common neurodegenerative disorders that are similarly dysregulated; in particular, UBC a gene for ubiquitin, which is a protein integral to cellular homeostasis and critically important in regulating function and outcomes of proteins under cellular stress, was upregulated in PSP, PD, and ADD when compared to control. Full article

Background: Lee Silverman Voice Treatment-BIG (LB) was developed for Parkinson’s disease patients to improve patients’ movement amplitude and accuracy through large movements and enhance movements through self-awareness and recalibration. This study aimed to review studies on LB for neurological diseases other than Parkinson’s disease and examine its potential as an intervention tool. Method: The main search databases included Google Scholar, PubMed, and ScienceDirect. ‘Neurological disease’, ‘LSVT-BIG’, ‘Treatment or Rehabilitation’, ‘Intervention’, and ‘Therapy’ were used as search keywords until December 2024, and eight articles were finally selected. Results: As a result of analyzing eight studies, there were four studies on stroke (all conducted by occupational therapists) and four studies on other diseases, including two studies on progressive supranuclear palsy, one study on idiopathic normal pressure hydrocephalus, and one study on Huntington’s disease (all conducted by physical therapists). Conclusions: LB had a positive effect on improving physical function and overall motor control in patients with neurological diseases other than Parkinson’s disease, indicating its potential as an intervention tool. In the future, studies that have high-level evidence-based study designs and complement small sample sizes are needed to demonstrate the effectiveness of LB. Full article

Background/Objectives: Atypical parkinsonisms are a group of diseases with significant obstacles in the context of efficient methods of examination and understanding pathomechanisms. This is associated with the overlaps in clinical manifestation. One of the hypotheses regarding the mechanism leading to neurodegeneration in this group is related to inflammation. Methods: Authors examined 18 patients with Multiple System Atrophy—Parkinsonism Predominant (MSA-P), 15 with Progressive Supranuclear Palsy—Richardson’s Syndrome (PSP-RS) and 15 with PSP—Parkinsonism Predominant (PSP-P) (disease duration: 3–6 years) using neutrophil-to-lymphocyte-ratio, platelet-to-lymphocyte ratio and high-density lipoprotein (HDL)-derived inflammatory ratios, e.g., neutrophil to high-density lipoprotein cholesterol ratio (NHR), lymphocyte to high-density lipoprotein cholesterol ratio (LHR) and platelet to high-density lipoprotein cholesterol ratio (PHR). The potential differences between the groups were examined using one-way ANOVA, with Tukey’s HSD test. Results: The comparison revealed significant differences between PSP-RS and MSA-P in NHR (p = 0.0224). The levels of the parameters were more increased in MSA-P. No other significant differences were found. Conclusions: The possible significance of HDL in the context of brain–blood barrier permeability is a repeatedly highlighted feature of neurodegenerative diseases. The outcome of this pilot study may suggest that the evaluation of inflammatory processes should be performed with the indication of subtypes of PSP, as the character of pathomechanisms likely differs. Full article