Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder characterized by tremors, rigidity, and bradykinesia. This is primarily attributed to loss of nigrostriatal dopaminergic neurons to varying degrees. Many conditions that present similar classic motor symptoms of PD, known as atypical parkinsonian syndromes (APS), have also been identified. These encompass multiple system atrophy (MSA), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), and corticobasal degeneration (CBD). On the other hand, causes of non-neurodegenerative parkinsonism include vascular parkinsonism, drug-induced parkinsonism, and essential tremors. Neuroimaging plays a significant role in discriminating PD from its mimics which may represent a significant challenge in clinical practice. This article aims to review recent developments in imaging technologies, particularly magnetic resonance imaging (MRI) and nuclear medicine imaging techniques, that have the potential to unravel characteristic morphological and metabolic changes in the brain and would aid in the early diagnosis of PD and its differentiation from its potential mimickers.Learning objectivesTo identify the peculiar structural imaging features of atypical parkinsonian syndromes and recognize the role of the current state-of-the-art neuroimaging modalities (particularly MRI and nuclear medicine techniques) in discriminating Parkinson's disease from its mimics.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder that impacts movement and cognition,caused by abnormal tau protein accumulation in the brain. It involves tau aggregation with 4-repeat domains in various brain regions and cell types. PSP is associated with the tau gene (MAPT),which contains recurrent genomic inversion. Evaluate the distribution and clinical impact of MAPT haplotypes on both motor and non-motor features among Tunisian PSP cohort. We conducted a cross-sectional study where we retrospectively review the medical records of all patients diagnosed with PSP, reclassifying them into phenotypes based on the MDS-2017 criteria. The phenotypes were categorized into three subgroups: Richardson's syndrome (PSP-RS), PSP-cortical and PSP-subcortical. We collected data on clinical and neuropsychological assessments, and genotyping for MAPT haplotypes were performed using classic PCR methods, with validation by Sanger sequencing. We included 118 patients, stratifying them into three groups: 44.06% patients with PSP-RS, 31.35% with cortical PSP, and 24.57% with subcortical PSP. Regarding the MAPT genotype, female predominance was observed among H1/H1 carriers (p = 0.0096). For motor features, homozygous H1 carriers developed parkinsonism earlier (p = 0.041), more frequent Freezing of gait (p = 0.028) and vertical supranuclear gaze palsy (p = 0.041),with earlier development of oculomotor signs associated (p = 0.034). In terms of non-motor features, the homozygo0us MAPT genotype was more associated with cognitive impairment than the heterozygous profile (p = 0.0234). Memory impairment as inaugural symptom was more common in homozygous MAPT patients (p = 0.025), as was language impairment (p = 0.011). These findings suggest that PSP is linked to haplotype-dependent increases in 4-repeat (4R) tau mRNA, which may contribute to the pathogenesis of PSP and influence its clinical phenotype.

Progressive supranuclear palsy-Richardson syndrome (PSP-RS) is a sporadic atypical parkinsonian disorder typically resistant to levodopa. While most cases are neurodegenerative, various conditions (genetic, vascular, infectious, or paraneoplastic) can mimic this phenotype, termed PSP-like or PSP mimics. Although paraneoplastic PSP is extremely rare, it is important to recognize because of its potential reversibility. The diagnosis can be particularly challenging, especially when classical tumor markers or imaging fail to identify a clear neoplastic origin. Here, we describe a 39-year-old man with an Anti-Ri-mediated PSP-like syndrome in whom an extensive evaluation, including surgical removal of two suspicious sites (thymus and testis), failed to identify an underlying tumor. The patient presented with rapidly progressive symptoms characteristic of PSP-RS, raising clinical suspicion for a paraneoplastic cause. We also review the literature on paraneoplastic PSP.

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.

Polyneuropathy (PNP) is increasingly recognized as a comorbidity in Parkinson's disease (PD) but its prevalence, clinical features and impact in atypical Parkinsonian syndromes (APS) remain unclear. Understanding PNP in Parkinsonism is crucial for improving patients' mobility, slowing the disability progression and reducing disease burden. This study aims to characterize prevalence, etiology, and clinical relevance of PNP in PD and APS. Consecutive admissions of 104 PD, 52 progressive supranuclear palsy (PSP), and 27 multiple system atrophy (MSA) patients to the Department of Neurology at Hannover Medical School were analyzed. Assessments included Hoehn and Yahr stage, MDS-UPDRS III, electroneurography, PNP related conditions (e.g., diabetes mellitus, vitamin deficiencies), and PD drugs including levodopa equivalence dose (LED). PNP was highly prevalent across all three groups with a prevalence ranging from 37.0% and 47.1%. PD and PSP patients with PNP were older and predominantly male (p < 0.05). They also showed more advanced Hoehn and Yahr stages and higher MDS-UPDRS-III scores (p < 0.05). Sensorimotor axonal, length-dependent peripheral neuropathy was the most frequent presentation. We found no association between PNP and PD medications, and classic risk factors for PNP, such as diabetes mellitus, vitamin B12 deficiency, or chronic alcohol abuse, did not differ significantly between patients with and without PNP. Screening for PNP among patients with Parkinsonism, particularly among older males, is critical to optimize mobility. Further studies to identify the cause of the high prevalence of PNP among this population are needed.