Search Results (52)

Background: In Parkinson’s disease (PD), a higher prevalence of polyneuropathy (PNP) is increasingly recognized, although the causal association is still under debate. In contrast, PNP in atypical parkinsonian syndromes (APS) has been insufficiently addressed, despite preliminary evidence suggesting elevated prevalence. Methods: Nerve conduction studies were performed on 13 patients with multiple system atrophy (MSA) and 9 patients with progressive supranuclear palsy (PSP) at baseline. PNP was diagnosed according to standard electrophysiological criteria after exclusion of common secondary causes. Comprehensive clinical evaluation included motor and non-motor assessments over two years of follow-up. Results: At baseline, PNP was present in 53.8% of MSA patients and 66.7% of PSP patients. MSA patients with PNP showed greater motor symptom severity (UPDRS III score; p = 0.046) and worse cognitive performance (MoCA; p = 0.044) compared to those without PNP. Over two years, a significant reduction in the tibial nerve amplitude was observed exclusively in MSA patients (p = 0.039), paralleling disease progression. Conclusions: This study provides the first longitudinal evaluation of clinical and electrophysiological PNP progression in MSA and PSP. A high comorbidity of PNP in patients with APS could contribute to motor and sensory impairments in these patients. Our findings indicate that PNP progression may reflect disease progression in MSA. Given the limited sample size, larger-scale longitudinal studies are needed to further investigate biomarker potential of PNP in APS and to clarify differences in peripheral nerve involvement between synucleinopathies and tauopathies. Full article

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation tool for investigating the neurophysiology of different neurological and neuropsychiatric disorders, including Parkinson’s disease (PD) and other parkinsonian syndromes and movement disorders. Briefly, TMS enables targeted stimulation of specific cortical regions through externally applied magnetic pulses, avoiding surgical intervention (as it occurs in deep brain stimulation) and making it a safe, repeatable, and well-tolerated approach. Over the past two decades, extensive research has explored the clinical utility of TMS in PD, with particular emphasis on motor cortex excitability, synaptic plasticity, and functional connectivity, which are central contributors to both motor and non-motor symptoms in PD patients. In addition, repetitive TMS and related stimulation paradigms have been shown to positively modulate cortical plasticity, i.e., the brain’s capacity to reorganize neural circuits, suggesting potential benefits for longer-term non-pharmacological management and rehabilitation protocols. More recently, studies have also investigated the role of TMS in atypical and secondary parkinsonisms, indicating that it may help characterize distinct neurophysiological abnormalities and provide symptomatic improvement in selected patients. This narrative expert review provides a comprehensive summary of TMS applications across the wide spectrum of parkinsonian syndromes, highlighting not only clinical potential, but also methodological limitations and future research directions. Full article

In multiple system atrophy (MSA), the fatal movement disorder, cell populations of the striatum and other subcortical brain regions degenerate, leading to a rapidly progressive, atypical Parkinsonian syndrome. The pathophysiology of neurons and glial cells shows misfolding, aggregation, and increased release of the protein α-synuclein. In addition, neuronal hypoexcitability, a reduction in the activity of the mitochondrial respiratory chain, and a dysregulation of the enzymes involved in the biosynthesis of coenzyme Q10 were observed in human stem-cell models. In this study, untargeted and targeted metabolome analyses were performed with MSA patient-derived GABAergic striatal medium spiny neurons focusing on the citrate cycle and mitochondrial respiratory chain. The results indicate a significant decrease in succinate and ATP as well as an imbalanced NAD⁺/NADH ratio of MSA cell lines compared to matched healthy controls, suggesting alterations in mitochondrial processes which may facilitate neurodegeneration. Full article

Parkinson’s disease (PD) is a multifaceted neurodegenerative disorder characterized by dopaminergic neuronal loss and widespread α-synuclein pathology. Nuclear medicine imaging offers essential in vivo tools for early diagnosis, differential assessment, and monitoring disease progression. This review summarizes key PET and SPECT radiotracers targeting dopaminergic synthesis and transport, vesicular storage, post-synaptic receptors, neuroinflammation, and protein aggregation, highlighting their roles in clinical evaluation and phenotyping. Clinically, these modalities support earlier recognition of PD, distinction from atypical parkinsonian syndromes, and assessment of non-motor involvement. Future directions include the development of selective α-synuclein tracers and multimodal imaging strategies to refine prodromal detection and guide personalized therapeutic interventions. Full article

Background/Objectives: Transferrin is a multi-task protein commonly known for binding iron; however, it is involved in multiple crucial processes, including antimicrobial activity, the growth of different cell types, differentiation, chemotaxis, the cell cycle, and cytoprotection. Vascular cell adhesion molecule 1 (VCAM-1) is a cell surface glycoprotein which participates in inflammation and the trans-endothelial movement of leukocytes. Neither transferrin nor VCAM-1 has been studied in the context of progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS). This study aimed to evaluate the utility of transferrin and VCAM-1 assessment for the in vivo examination of tauopathic atypical Parkinsonian syndromes. Methods: This study included 10 patients with clinically probable PSP-RS, 10 with clinically probable PSP-P, and 8 with probable CBS. Patients’ blood and urine were collected and analyzed. Twenty-four serum samples (from twelve males and twelve females) were obtained from age-matched healthy volunteers. Peripheral blood inflammatory ratios, including the neutrophil-to-lymphocyte ratio, the platelet-to-lymphocyte ratio, the neutrophil-to-monocyte ratio, the neutrophil-to-high-density lipoprotein ratio, and the monocyte-to-high-density lipoprotein ratio, were calculated. VCAM-1 and transferrin concentrations were measured in the serum and urine. The urinary biomarker results are not included in the main analysis due to the absence of a control group. Results: The highest concentrations of transferrin in the serum were observed in patients with PSP-P, followed by PSP-RS and CBS. Statistically significant differences were found between PSP-P and healthy controls (p < 0.0001) and PSP-RS and healthy controls (p < 0.0001). The highest levels of serum VCAM-1 were observed in the PSP-P group. Significant differences were found between PSP-P and healthy controls (p < 0.0001), PSP-P and CBS (p < 0.001), and PSP-RS and healthy controls (p < 0.001). Serum VCAM-1 levels were negatively correlated with the NLR in CBS patients (p < 0.03; r = −0.74). Serum transferrin levels were negatively correlated with the NHR in CBS patients (p < 0.04; r = −0.64). ROC curve analyses were conducted to evaluate the diagnostic utility of serum transferrin and VCAM-1 in distinguishing tauopathic APS patients from controls. Transferrin showed excellent diagnostic performance, with an AUC of 0.975 (95% CI: 0.888–0.999; p < 0.0001), a sensitivity of 96.4%, and a specificity of 95.8% at the optimal cut-off (>503.0). VCAM-1 demonstrated good accuracy, with an AUC of 0.839 (95% CI: 0.711–0.926; p < 0.0001), a sensitivity of 75.0%, and a specificity of 91.7% at the optimal cut-off (>463.9). Conclusions: The obtained results indicate the potential role of transferrin and VCAM-1 in the pathogenesis of tauopathic APSs and highlight the need for further exploration in this field. Full article

Atypical parkinsonian disorders—progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA)—are rare, rapidly progressive neurodegenerative syndromes characterized by distinct molecular pathologies, heterogeneous clinical phenotypes, and limited therapeutic options. Accurate diagnosis remains a major clinical challenge, especially during early and prodromal phases, due to overlap with Parkinson’s disease (PD), phenotypic evolution, and the absence of reliable stand-alone biomarkers. Misclassification delays prognosis, impairs patient care, and hinders clinical trial design. This review synthesizes advances from 2015 to 2025 in clinical, imaging, and biomarker-based diagnosis of PSP, CBD, and MSA. We examine their phenotypic spectra, neuropathological substrates, and epidemiological trends, and critically evaluate the diagnostic performance and translational potential of emerging tools—including quantitative MRI morphometry, second-generation tau and α-synuclein PET ligands, neurophysiological markers such as video-oculography and autonomic testing, and fluid biomarkers such as neurofilament light chain. Persistent diagnostic barriers are identified, from phenotypic mimicry and pathological pleomorphism to the limited specificity of molecular assays and inequitable access to advanced technologies. We propose tiered, multimodal diagnostic algorithms that integrate structured clinical phenotyping with quantitative imaging, molecular diagnostics, systemic risk profiling, and autopsy-linked validation. Such biology-anchored approaches could enable diagnosis years before classical features emerge, improve patient stratification for disease-modifying trials, and lay the foundation for precision medicine in atypical parkinsonian disorders. A paradigm shift from descriptive nosology to mechanistically grounded frameworks is essential to accelerate early intervention and transform the clinical management of these devastating diseases. Full article

Neurodegenerative diseases such as Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD), and α-synucleinopathies—including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)—are characterized by the accumulation of misfolded protein aggregates. Advances in positron emission tomography (PET) imaging have enabled in vivo visualization of these pathologies, particularly tau and α-synuclein fibrils, facilitating early diagnosis and differential classification. Tau PET tracers such as ¹⁸F-florzolotau have demonstrated robust imaging of both AD-type and 4-repeat tauopathies, including atypical parkinsonian syndromes in FTLD such as progressive supranuclear palsy and corticobasal degeneration. Cryo-electron microscopy has elucidated the molecular interactions underlying tracer binding, highlighting hydrophobic grooves in cross-βstructures as binding components commonly present in multiple tau fibril types. For α-synucleinopathies, new tracers with a modified cross-β-binding scaffold, including ¹⁸F-SPAL-T-06 and ¹⁸F-C05-05, have shown promise in detecting MSA-related pathology and, more recently, midbrain pathology in PD and DLB. However, sensitive detection of pathologies in early PD/DLB stages remains a challenge. The integration of high-resolution PET technologies and structurally optimized ligands may enable earlier and more accurate detection of protein aggregates, supporting both clinical decision-making and the development of targeted disease-modifying therapies. Full article

The rare and rapidly progressive neurodegenerative disease multiple system atrophy (MSA) mainly affects the striatum and other subcortical brain regions. In this atypical Parkinsonian syndrome, the protein alpha-synuclein aggregates and misfolds in neurons as well as glial cells and is released in elevated amounts by hypoexcitable neurons. Mitochondrial dysregulation affects the biosynthesis of coenzyme Q10 and the activity of the respiratory chain, as shown in an induced pluripotent stem cell (iPSC) model. Proteome studies of cerebrospinal fluid and brain tissue from MSA patients yielded inconsistent results regarding possible protein changes due to small and combined groups of atypical Parkinsonian syndromes. In this study, we analysed the cellular proteome of MSA patient-derived striatal GABAergic medium spiny neurons. We observed 25 significantly upregulated and 16 significantly downregulated proteins in MSA cell lines compared to matched healthy controls. Various protein types involved in diverse molecular functions and cellular processes emphasise the multifaceted pathomechanisms of MSA. These data could contribute to the development of novel disease-modifying treatment strategies for MSA patients. Full article

Although diagnostic criteria and research are constantly advancing, distinguishing between progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) remains a significant challenge. This difficulty stems from their similar clinical symptoms and the lack of reliable biomarkers. In this work, we present a detailed review of fluorodeoxyglucose (FDG)–positron emission tomography (PET), exploring its potential role in differentiating PSP and CBS, drawing on their established utility in other neurodegenerative diseases. We searched the PubMed database from its inception for original research articles assessing the utility of FDG-PET for the diagnosis or differential diagnosis of PSP and CBS from other neurodegenerative conditions. A total of 91 studies were eligible. These 91 studies were categorized as follows: (a) 20 studies included only patients with PSP, (b) 15 studies included only patients with CBS, (c) 39 studies involved patients with Parkinson’s disease and atypical Parkinsonian disorders, including subgroups of PSP and/or CBS, and (d) 17 studies compared patients with PSP and/or CBS to individuals with Alzheimer’s disease, frontotemporal dementia, or other dementias. Most FDG-PET studies involving PSP and CBS were not specifically designed for these disorders. An additional obstacle lies in the methodological variability across studies. Despite several studies achieving high diagnostic accuracy for PSP and/or CBS with specificity exceeding 90% using FDG-PET, sensitivity remains considerably lower. CBS appears to have a distinct hypometabolic pattern compared to PSP, marked by asymmetry and predominant cortical involvement. CBS more often affects posterior cortical regions (parietal and posterior parts of the frontal cortex, and sometimes temporal and occipital parts) and the thalamus, whereas PSP appears to affect the striatum, frontal cortex, anterior cingulate, and subtentorial structures, typically in a more symmetrical manner. Large, multicenter studies are needed, utilizing standardized imaging and protocols. 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

In addition to axial motor complications such as abnormal posture, instability, falls, and gait variability, neurodegenerative diseases like Parkinsonian syndromes include executive dysfunction, Parkinson’s disease dementia, and neuropsychiatric symptoms. These motor disorders significantly affect mobility, quality of life, and well-being. Recently, physical activity of various intensities monitored both remotely and face-to-face via digital health technologies, mobile platforms, or sensory cues has gained relevance in managing idiopathic and atypical Parkinson’s disease (PD and APD). Remote monitoring solutions, including home-based digital health assessments using semi-structured activities, offer unique advantages. Real-world gait parameters like walking speed can now be continuously assessed with body-worn sensors. Developing effective strategies to slow pathological aging and mitigate neurodegenerative progression is essential. This study presents outcomes of using digital health technologies (DHTs) for remote assessment of motor function, physical activity, and daily living tasks, aiming to reduce disease progression in PD and APD. In addition to wearable inertial sensors, clinical rating scales and digital biomarkers enhance the ability to characterize and monitor motor symptoms. By reviewing recent literature, we identified emerging trends in quantifying and intervening in neurodegeneration using tools that evaluate both remote and face-to-face physical activity. Our findings confirm that DHTs offer accurate detection of motor fluctuations and support clinical evaluations. In conclusion, DHTs represent a scalable, effective strategy for improving the clinical management of PD and APD. Their integration into healthcare systems may enhance patient outcomes, support early intervention, and help delay the progression of both motor and cognitive symptoms in aging individuals. Full article

Background/Objectives: 123I-FP-CIT dopamine transporter imaging is commonly used for the diagnosis of Parkinsonian syndromes in patients whose clinical presentation is atypical. Prolonged immobility, which can be difficult to maintain in this population, is required to perform SPECT acquisition. In this study we aimed to develop a Convolutional Neural Network (CNN) able to predict the outcome of the full examination based on the first acquired projection, and reliably detect normal patients. Methods: All 123I-FP-CIT SPECT performed in our center between June 2017 and February 2024 were included and split between a training and a validation set (70%/30%). An additional 100 SPECT were used as an independent test set. Examinations were labeled by two independent physicians. A VGG16-like CNN model was trained to assess the probability of examination abnormality from the first acquired projection (anterior and posterior view at 0°), taking age into consideration. A threshold maximizing sensitivity while maintaining good diagnostic accuracy was then determined. The model was validated in the independent testing set. Saliency maps were generated to visualize the most impactful areas in the classification. Results: A total of 982 123I-FP-CIT SPECT were retrieved and labelled (training set: 618; validation set: 264; independent testing set: 100). The trained model achieved a sensibility of 98.0% and a negative predictive value of 96.3% (one false negative) while maintaining an accuracy of 75.0%. The saliency maps confirmed that the regions with the greatest impact on the final classification corresponded to clinically relevant areas (basal ganglia and background noise). Conclusions: Our results suggest that this trained CNN could be used to exclude presynaptic dopaminergic loss with high reliability from the first acquired projection. It could be particularly useful in patients with compliance issues. Confirmation with images from other centers will be necessary. Full article

Susceptibility-weighted imaging (SWI) is a magnetic resonance imaging (MRI) sequence sensitive to substances that alter the local magnetic field, such as calcium and iron, allowing phase information to distinguish between them. SWI is a 3D gradient–echo sequence with high spatial resolution that leverages both phase and magnitude effects. The interaction of paramagnetic (such as hemosiderin and deoxyhemoglobin), diamagnetic (including calcifications and minerals), and ferromagnetic substances with the local magnetic field distorts it, leading to signal changes. Neurodegenerative diseases are typically characterized by the progressive loss of neurons and their supporting cells within the neurovascular unit. This cellular decline is associated with a corresponding deterioration of both cognitive and motor abilities. Many neurodegenerative disorders are associated with increased iron accumulation or microhemorrhages in various brain regions, making SWI a valuable diagnostic tool in clinical practice. Suggestive SWI findings are known in Parkinson’s disease, Lewy body dementia, atypical parkinsonian syndromes, multiple sclerosis, cerebral amyloid angiopathy, amyotrophic lateral sclerosis, hereditary ataxias, Huntington’s disease, neurodegeneration with brain iron accumulation, and chronic traumatic encephalopathy. This review will assist radiologists in understanding the technical framework of SWI sequences for a correct interpretation of currently established MRI findings and for its potential future clinical applications. Full article

The role of the intestinal microbiota and its influence on neurodegenerative disorders has recently been extensively explored, especially in the context of Parkinson’s disease (PD). In particular, its role in immunomodulation, impact on inflammation, and participation in the gut–brain axis are under ongoing investigations. Recent studies have revealed new data that could be important for exploring the neurodegeneration mechanisms connected with the gut microbiota, potentially leading to the development of new methods of treatment. In this review, the potential roles of the gut microbiota in future disease-modifying therapies were discussed and the properties of the intestinal microbiota—including its impacts on metabolism and short-chain fatty acids and vitamins—were summarized, with a particular focus on atypical Parkinsonian syndromes. This review focused on a detailed description of the numerous mechanisms through which the microbiota influences neurodegenerative processes. This review explored potentially important connections between the gut microbiota and the evolution and progression of atypical Parkinsonian syndromes. Finally, a description of recently derived results regarding the microbiota alterations in atypical Parkinsonian syndromes in comparison with results previously described in PD was also included. 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