Search Results (39)

Mild behavioral impairment (MBI) is a clinical syndrome characterized by the late-life onset and persistence of neuropsychiatric symptoms (NPSs), representing a change from longstanding behavior or personality and considered a potential prodrome of neurodegenerative disease. MBI is classified into five domains: decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, and psychotic symptoms. In this narrative review, we synthesize clinical, neuroanatomical, and molecular evidence linking MBI to the spectrum of tauopathies, including Alzheimer’s disease (AD), frontotemporal spectrum disorders (FTSDs), and primary four-repeat tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Emerging evidence suggests that early behavioral symptoms associated with MBI may reflect the selective vulnerability of frontolimbic, salience, default mode, and frontostriatal networks to tau-mediated neurodegeneration. Mechanistically, converging findings support roles for tau-related synaptic dysfunction, including synaptotoxic soluble tau species, cytoskeletal and axonal transport disruption, monoaminergic neurotransmitter imbalance in brainstem systems, and neuroinflammatory and glial pathways. We also highlight genotype-related behavioral profiles in genetic frontotemporal lobar degeneration and discuss how scalable blood-based biomarkers, including neurofilament light chain, glial fibrillary acidic protein, and plasma phospho-tau species, may complement MBI-based phenotyping for differential diagnosis and prognostic stratification in clinical research. Full article

The Benson Complex Figure Test (BCFT) is a neuropsychological tool designed to assess visuospatial construction and visual memory with lower complexity than traditional tests. This study evaluated its ability to differentiate between major dementia subtypes. In a retrospective cross-sectional analysis of 1428 participants from a Greek third-age day center (healthy participants [Controls]; patients diagnosed with Alzheimer’s disease dementia [ADD], Lewy body dementia [LBD], Frontotemporal dementia [FTD: behavioral variant (BV), non-fluent variant (NFV), semantic variant (SV)], Corticobasal dementia [CBD], Parkinson’s disease dementia [PDD], and mixed Cardiovascular dementia with Alzheimer’s disease [CVD/AD]), all participants completed the BCFT and the Mini-Mental State Examination (MMSE). Multinomial logistic regression, adjusted for age, sex, and education, revealed distinct BCFT profiles across dementia subtypes. Patients with CBD showed significantly lower copy scores than those with ADD (p = 0.006). The FTD-NFV group exhibited superior memory scores compared to all other dementia subtypes (p < 0.001). Poorer BCFT recognition performance was strongly associated with diagnoses of ADD (OR = 0.39, p = 0.012), FTD-BV (OR = 0.22, p = 0.025), and PDD (OR = 0.26, p < 0.001). Classification accuracy was highest for controls and ADD (sensitivity > 89%) but low for rarer subtypes (<25%), partly reflecting sample size limitations. In conclusion, the BCFT captures distinct visuospatial and memory profiles across dementia syndromes, supporting its potential utility in differential diagnosis, particularly for common subtypes such as ADD. Its simpler design may facilitate assessment in older adults, although validation in larger and more balanced cohorts is required for rarer dementias. Full article

Transcranial sonography is one of the methods of examination used in atypical parkinsonian syndromes. The assessment is not indicated in the diagnostic criteria of entities in this group e.g., Progressive Supranuclear Palsy, Corticobasal Degeneration, Multiple System Atrophy and Dementia with Lewy Bodies. Atypical parkinsonisms are a group of diseases affected by diverse pathologies including alpha-synuclein or tau among others. Recently broader attention was brought to less common atypical parkinsonisms as Perry syndrome. Atypical parkinsonisms are related to poor response to levodopa treatment, rapid deterioration and unfavorable prognosis. Additionally, the entities often overlap in terms of clinical manifestation, especially in the early stages. Though atypical parkinsonisms are affected by the lack of possibility of obtaining definite in vivo diagnosis, growing interest is associated to supplementary evaluations including neuroimaging. Among these methods could be mentioned magnetic resonance imaging, positron emission tomography, single photon emission computed tomography and transcranial sonography. Transcranial sonography is associated with high accessibility and low cost. The goal of this paper is to highlight the strengths and weaknesses of transcranial sonography in the examination of atypical parkinsonisms. Full article

The “Neuroimaging and Pathology Biomarkers in Parkinson’s Disease” course held on 12–13 September 2025 in Milan, Italy, convened an international faculty to review state-of-the-art biomarkers spanning neurotransmitter dysfunction, protein pathology and clinical translation. Here, we synthesize the four themed sessions and highlights convergent messages for diagnosis, stratification and trial design. The first session focused on neuroimaging markers of neurotransmitter dysfunction, highlighting how positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) provided complementary insights into dopaminergic, noradrenergic, cholinergic and serotonergic dysfunction. The second session addressed in vivo imaging of protein pathology, presenting recent advances in PET ligands targeting α-synuclein, progress in four-repeat tau imaging for progressive supranuclear palsy and corticobasal syndromes, and the prognostic relevance of amyloid imaging in the context of mixed pathologies. Imaging of neuroinflammation captures inflammatory processes in vivo and helps study pathophysiological effects. The third session bridged pathology and disease mechanisms, covering the biology of α-synuclein and emerging therapeutic strategies, the clinical potential of seed amplification assays and skin biopsy, the impact of co-pathologies on disease expression, and the “brain-first” versus “body-first” model of pathological spread. Finally, the fourth session addressed disease progression and clinical translation, focusing on imaging predictors of phenoconversion from prodromal to clinically overt stages of synucleinopathies, concepts of neural reserve and compensation, imaging correlates of cognitive impairment, and MRI approaches for atypical parkinsonism. Biomarker-informed pharmacological, infusion-based, and surgical strategies, including network-guided and adaptive deep brain stimulation, were discussed as examples of how multimodal biomarkers may inform personalized management. Across all sessions, the need for harmonization, longitudinal validation, and pathology-confirmed outcome measures was consistently emphasized as essential for advancing biomarker qualification in multicentre research and clinical practice. 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

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

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

Background/Objectives: Multiple system atrophy (MSA) presents a challenging diagnosis due to its clinical overlap with other neurodegenerative disorders, especially other α-synucleinopathies. The main purpose of this systematic review and meta-analysis was to assess neurofilament light chain (NfL) differences in the CSF and blood of patients with MSA versus the healthy control group (HC), patients with Parkinson’s disease (PD) and patients with Lewy body dementia (LBD). Secondarily, the diagnostic metrics of CSF and circulating NfL in MSA versus HC, PD, LBD, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) were discussed. Methods: MEDLINE and EMBASE were thoroughly searched for relevant case-control studies. Standardized mean differences (SMDs) were calculated separately for CSF and blood NfL per comparison. Statistical heterogeneity was assessed based on the Q and I^2 statistics. Results: Twenty-five relevant studies were retrieved. Quantitative syntheses revealed elevated CSF and circulating NfL levels in individuals with MSA versus HC [SMD = 1.80 (95%CI = 1.66, 1.94) and SMD = 2.00 (95%CI = 1.36, 2.63), respectively] versus PD [SMD = 1.65 (95%CI = 1.26, 2.03) and SMD = 1.63 (95%CI = 0.84, 2.43), respectively] as well as versus LBD [SMD = 1.17, (95%CI = 0.71, 1.63) and SMD = 0.65 (95%CI = 0.30, 1.00), respectively]. Diagnostic accuracy was outstanding for CSF and blood NfL in MSA versus HC and PD, and it was moderate in MSA versus LBD. On the other hand, it was suboptimal in MSA vs. PSP and CBD. Conclusions: Both CSF and circulating NfL levels are elevated in MSA compared to HC, PD and LBD. To achieve optimal diagnostic properties, further work is required in the standardization of processes and the establishment of reference NfL intervals and/or thresholds. Full article

Multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) are the most common atypical parkinsonism (AP) syndromes. They are clinically characterized by varying combinations of levodopa-poorly responsive parkinsonism, motor, cerebellar, and other signs. They are associated with a wide spectrum of non-motor symptoms, including prominent cognitive impairment such as global cognitive deficits, memory, executive, attentional, visuospatial, language, and non-verbal reasoning dysfunctions. Within the APs, their cognitive functioning is distributed along a continuum from MSA with the least impaired cognitive profile (similar to Parkinson’s disease) to PSP and CBD with the greatest decline in global cognitive and executive domains. Although their pathological hallmarks are different—MSA α-synucleinopathy, CBD, and PSP 4-repeat tauopathies—cognitive dysfunctions in APs show both overlaps and dissimilarities. They are often preceding and anticipate motor dysfunctions, finally contributing to reduced quality of life of patients and caregivers. The present paper will review the current evidence of the prevalence and type of cognitive impairment in these AP syndromes, their neuroimaging, pathogenic backgrounds, and current management options based on extensive literature research. Cognitive dysfunctions in APs are due to disruption of prefronto-subcortical and striato-thalamo-cortical circuitries and multiple essential brain networks. This supports the concept that they are brain network disorders due to complex pathogenic mechanisms related to the basic proteinopathies that are still poorly understood. Therefore, the pathophysiology and pathogenesis of cognitive impairment in APs deserve further elucidation as a basis for early diagnosis and adequate treatment of these debilitating comorbidities. Full article

Background/Objectives: Atypical parkinsonian syndromes (APSs) are a group of neurodegenerative disorders that differ from idiopathic Parkinson’s disease (IPD) in their clinical presentation, underlying pathology, and response to treatment. APSs include conditions such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and dementia with Lewy bodies (DLB). These disorders are characterized by a combination of parkinsonian features and additional symptoms, such as autonomic dysfunction, supranuclear gaze palsy, and asymmetric motor symptoms. Many hypotheses attempt to explain the causes of neurodegeneration in APSs, including interactions between environmental toxins, tau or α-synuclein pathology, oxidative stress, microglial activation, and vascular factors. While extensive research has been conducted on APSs, there is a limited understanding of the symmetry in these diseases, particularly in MSA. Neuroimaging studies have revealed metabolic, structural, and functional abnormalities that contribute to the asymmetry in APSs. The asymmetry in CBS is possibly caused by a variable reduction in striatal D2 receptor binding, as demonstrated in single-photon emission computed tomography (SPECT) examinations, which may explain the disease’s asymmetric manifestation and poor response to dopaminergic therapy. In PSP, clinical dysfunction correlates with white matter tract degeneration in the superior cerebellar peduncles and corpus callosum. MSA often involves atrophy in the pons, putamen, and cerebellum, with clinical symmetry potentially depending on the symmetry of the atrophy. The aim of this review is to present the study findings on potential symmetry as a tool for determining potential neuropsychological disturbances and properly diagnosing APSs to lessen the misdiagnosis rate. Methods: A comprehensive review of the academic literature was conducted using the medical literature available in PubMed. Appropriate studies were evaluated and examined based on patient characteristics and clinical and imaging examination outcomes in the context of potential asymmetry. Results: Among over 1000 patients whose data were collected, PSP-RS was symmetrical in approximately 84% ± 3% of cases, with S-CBD showing similar results. PSP-P was symmetrical in about 53–55% of cases, while PSP-CBS was symmetrical in fewer than half of the cases. MSA-C was symmetrical in around 40% of cases. It appears that MSA-P exhibits symmetry in about 15–35% of cases. CBS, according to the criteria, is a disease with an asymmetrical clinical presentation in 90–99% of cases. Similar results were obtained via imaging methods, but transcranial sonography produced different results. Conclusions: Determining neurodegeneration symmetry may help identify functional deficits and improve diagnostic accuracy. Patients with significant asymmetry in neurodegeneration may exhibit different neuropsychological symptoms based on their individual brain lateralization, impacting their cognitive functioning and quality of life. Full article

(1) Background: Frontotemporal lobar degeneration (FTLD) is a generic term which refers to multiple pathologies, including FTLD-tau. The most common FTLD-tau diseases are Pick’s disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). These diseases share four major syndromes: behavioral variant frontotemporal dementia (bvFD), Richardson syndrome (RS), corticobasal syndrome (CBS) and non-fluent agrammatic primary progressive aphasia (nfa-PPA). The primary aim of this meta-analysis was to examine the diagnostic performance of CSF total (t-tau) and phosphorylated (p-tau) protein in bvFTD, RS, CBS, nfa-PPA and pathologically or genetically defined tauopathy. (2) Methods: A systematic review and meta-analysis was performed on all studies with >10 subjects in a bvFTD/RS/CBS/nfa-PPA group and control group and available data on CSF t-tau or p-tau (mean, SD). Cohen’s d was used to quantify the effect size of each study (3) Results: The PSP/tauopathy patients exhibited decreased levels of CSF p-tau compared to the control subjects. The CBS/bvFTD/nfa-PPA cohorts exhibited an increase in t-tau compared to the control groups. (4) Conclusions: Tauopathies may exhibit an inherent decrease in CSF p-tau. The admixture of AD patients in FTD cohorts and high heterogeneity among studies on rare diseases are significant confounding factors in FTLD studies. Full article

Parkinsonism may be a clinical manifestation of a wide range of disease entities, and still poses a great diagnostic challenge. In an attempt to provide further insight into the differential diagnosis of PD versus progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), and Lewy body dementia (LBD), several biomarkers have been investigated, yielding inconclusive results, OCT being among them. The present review aims to explore the potential diagnostic value of evaluating retinal parameters through OCT implementation among patients presenting with a Parkinsonian syndrome, with an emphasis on effective differentiation between distinct syndromes. Having reviewed all the available literature published within the last decade, neurodegeneration seems to be paralleled with degeneration and alterations of the retina that may be quantified by OCT. Specific patterns of structural changes within the retina may provide valuable information on the underlying pathology, thus highlighting the role of OCT as a diagnostic tool within this group of patients. Although still not utilized in clinical practice, OCT, if further explored and validated, may significantly enhance overall Parkinsonism care. Full article