Search Results (107)

Parkinsonian syndromes comprise overlapping neurodegenerative and non-degenerative disorders, making aetiological diagnosis difficult, while existing procedural guidance does not fully integrate tracer-specific biology with clinical decision-making, multimodal strategies, and emerging quantitative and pathology-directed biomarkers. This review synthesises evidence on the molecular targets, radiopharmaceutical characteristics, biological interpretation, and clinical applications of dopaminergic single-photon emission computed tomography (SPECT) and positron emission tomography (PET), focusing on the dopamine transporter (DAT), aromatic L-amino acid decarboxylase (AADC), vesicular monoamine transporter type 2 (VMAT2), dopamine D₂/D₃ receptors, differential diagnosis, semiquantification, kinetic modelling, and artificial intelligence-assisted interpretation. The evidence confirms that DAT SPECT with [¹²³I]ioflupane ([¹²³I]FP-CIT) remains the most established method for demonstrating or arguing against presynaptic nigrostriatal dysfunction, but an abnormal result cannot establish aetiology, and a normal result can redirect evaluation towards non-degenerative mimics; target-specific PET provides complementary biological information, although availability, standardisation, and prospective validation remain limiting. By additionally integrating genetic and prodromal applications, question-driven multimodal imaging, emerging acquisition approaches, α-synuclein imaging and seed amplification assays, and contemporary biological staging frameworks, this review extends procedural guidance and positions dopaminergic imaging as a targeted functional biomarker selected according to the unresolved clinical question rather than as a stand-alone disease label. Full article

Background/Objectives: Progressive supranuclear palsy (PSP) and Parkinson’s disease (PD) share several clinical manifestations, which may complicate differential diagnosis. The aim of this study was to evaluate whether automated volumetric measurements of the pallidum and ventral diencephalon can differentiate PSP from PD. Methods: Thirty-two patients were included, comprising 20 patients with PD and 12 patients with PSP. All participants underwent 3-T brain magnetic resonance imaging. Automated segmentation and volumetric analysis were performed using the vol2Brain pipeline. Absolute and normalized volumes of the pallidum and ventral diencephalon were compared between groups. Receiver operating characteristic (ROC) analysis was used to assess diagnostic performance. Results: Patients with PSP demonstrated lower pallidal and ventral diencephalic volumes than patients with PD. Differences were observed for both absolute and normalized volumetric measurements (all p ≤ 0.002). Total pallidal volume showed the highest diagnostic performance, with an area under the ROC curve (AUC) of 0.958, sensitivity of 85%, and specificity of 100%. Total ventral diencephalon volume also differentiated PSP from PD, yielding an AUC of 0.829, seNsitivity of 70%, and specificity of 92%. Conclusions: Pallidal and ventral diencephalic volumes differed between patients with PSP and PD. Automated measurements of pallidal and ventral diencephalic volumes may complement conventional MRI findings in patients with parkinsonian syndromes. Further studies are needed to validate these findings in larger cohorts. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder of motor function, while at advanced stages it includes memory deficits and neuropsychiatric conditions. It is characterized primarily by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and reduced dopamine levels in the striatum. Accumulating evidence highlights the role of polyphenols against oxidative stress and neuroinflammatory processes, underlying key factors of PD pathogenesis. The present study used a rotenone rat model to determine the involvement of inflammatory cytokines in the basal ganglia, hippocampus, basolateral amygdala, and prefrontal cortex and to evaluate the potential of black Corinthian currant, a fruit abundant in antioxidant polyphenols, to attenuate brain inflammatory responses. Rotenone is known to trigger oxidative stress by inhibiting mitochondrial complex I and thus induce dopaminergic neurodegeneration, further amplified by inflammation. Our findings clearly demonstrated that rotenone treatment resulted in significant increases in pro-inflammatory cytokines as well as MAO-B expression within the rat brain motor and limbic regions. Importantly, dietary supplementation with black Corinthian currant mitigated rotenone-induced overexpression of IL-1β, TNFα, and MAO-B. Moreover, double immunofluorescence suggested the microglial localization of these inflammatory markers in SNpc. Overall, our data highlight the neuroprotective potential of dietary Corinthian currant polyphenols, modulating glial-mediated neuroinflammation in a rotenone PD model. Full article

Introduction: Adult-onset Alexander disease (AOAD) is a rare astrocytopathy linked to the glial fibrillary acidic protein (GFAP) gene, which is known for its clinical heterogeneity and common misdiagnosis. In adults, it may present with bulbar dysfunction, pyramidal signs, ataxia, dysautonomia, cognitive decline, or parkinsonism, which often mimics atypical parkinsonian syndromes like multiple system atrophy (MSA). The purpose of this case series was to define practical clinical, radiological, and genetic cues for suspecting AOAD in adults with atypical parkinsonism, autonomic dysfunction, or paroxysmal focal symptoms, particularly when genetic findings are inconclusive. Case Presentation: Four patients, aged 40 to 59 years, had progressive and varied neurological symptoms, like gait disturbance, lower limb weakness, dysarthria, dysphagia, autonomic dysfunction, parkinsonism, cognitive decline, and paroxysmal focal deficits. Initial diagnoses were parkinsonian syndrome, stroke, transient ischemic attack (TIA), and MSA. Diagnostic Assessment and Intervention: Brain magnetic resonance imaging (MRI) in all patients showed characteristic lower brainstem abnormalities, particularly atrophy of the medulla oblongata and upper cervical spinal cord, consistent with the “tadpole sign.” GFAP sequencing identified one likely pathogenic variant (p.Arg70Trp) and three variants of uncertain significance: p.Glu122_Arg124del, p.Met415Ile, and p.Glu195Val. Management was mainly symptomatic; one patient showed significant motor improvement after repetitive transcranial magnetic stimulation (rTMS). Conclusions: AOAD should be considered in adults with parkinsonism-plus syndromes or unexplained combinations of bulbar symptoms, pyramidal signs, autonomic dysfunction, and cognitive decline. Recognizing the tadpole sign on MRI may improve diagnostic accuracy, particularly when genetic results are inconclusive. Full article

Background: Mutations in the FBXO7 gene (PARK15) cause an autosomal recessive, early-onset neurodegenerative disorder typically presenting as Parkinsonian-Pyramidal Syndrome (PPS). Despite its recognition, the high phenotypic variability often delays diagnosis. Here, we report a novel Italian family and synthesize data from all published cases to date, offering an updated clinical and molecular overview of the disease. Methods: We performed clinical and molecular characterization of a newly identified family. Furthermore, we conducted a systematic literature review (from 2008 to 2026) to aggregate clinical, genetic, and geographic data of all reported PARK15 cases. Results: Two siblings presented with a complex phenotype including early-onset parkinsonism, cognitive decline, psychiatric symptoms, and aphasia-type speech disorders. Genetic analyses identified two novel likely pathogenic variants: a missense substitution in the UBL domain (p.Ile74Met) and a frameshift indel (p.Val233GlufsTer8). The literature review (incorporating clinical data from Europe, Asia, and South America) confirms a high prevalence of postural instability (87.5%), bradykinesia (83.3%), and pyramidal signs (~60%). We observed a distinct distribution of variants: missense mutations cluster in the N-terminal UBL and F-box domains, while truncating variants are more common in the C-terminal region. Discussion: Our findings expand the FBXO7 mutational landscape and underscore the “atypical” clinical markers, such as pyramidal signs and cognitive decline, that distinguish PARK15 from other recessive forms of parkinsonism like PARK2 and PARK6. The dual role of FBXO7 in mitochondrial quality control and proteasomal assembly suggests a broad disruption of cellular homeostasis. These observations refine genotype–phenotype correlations and may guide variant interpretation in routine diagnostic settings. Full article

Neurodegenerative diseases are among the most consequential disorders of later life, not only because of their increasing prevalence, rising from approximately 1–2% at age 65 to over 30% by age 85, but also because they develop within the broader clinical context of ageing, multimorbidity, frailty, and polypharmacy. In older adults, these conditions rarely present as isolated and static diagnostic entities; rather, they unfold as dynamic clinical trajectories involving the progressive interaction of cognitive decline, behavioural-neuropsychiatric symptoms, and extrapyramidal-motor dysfunction. In this review, we propose a trajectory-based framework for the interpretation and management of major neurodegenerative disorders in later life, including Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease and Parkinson’s disease dementia, dementia with Lewy bodies, and vascular cognitive impairment. Building on a conceptual model organized around three major symptom spheres: cognitive, behavioural-neuropsychiatric, and extrapyramidal-motor, we argue that each disorder can be understood according to the relative predominance and temporal evolution of these domains. Alzheimer’s disease is typically cognition-led, frontotemporal dementia behaviour-led, and Parkinsonian syndromes motor-led, whereas dementia with Lewy bodies shows early multidomain convergence across all three spheres simultaneously. Vascular and mixed dementias follow more heterogeneous trajectories shaped by lesion burden, network disruption, and copathology. This framework has direct implications for diagnosis, prognostic stratification, and treatment selection, because interventions targeting one sphere may destabilize another and generate prescription cascades, delirium, or functional decline. We further discuss how biomarker-based diagnosis, disease-modifying therapies, non-pharmacological interventions, multidisciplinary care, deprescribing strategies, and palliative planning can be integrated within a trajectory-based approach. Interpreting neurodegeneration through clinical trajectories rather than diagnostic labels alone offers a more realistic and therapeutically useful model for precision geriatric neurology across the full course of disease. Full article

Background/Objectives: Imaging of both cardiac sympathetic denervation and nigrostriatal dopaminergic degeneration can support the diagnosis of Parkinson’s disease (PD). However, their temporal relationship and combined diagnostic value remain unclear. This review addresses (1) whether nigrostriatal degeneration and cardiac sympathetic denervation are correlated in PD and (2) the comparative and combined diagnostic accuracy of striatal dopaminergic and cardiac sympathetic imaging in PD. Methods: We searched PubMed (October 2025) for studies assessing both a striatal dopaminergic and a cardiac sympathetic imaging biomarker in the same PD cohort, supplemented by citation chaining. Diagnostic accuracy studies were evaluated using QUADAS-2. Results: Nineteen studies met the inclusion criteria. Ten studies examined within-subject associations; six reported significant correlations ranging from weak to strong (ρ ~0.2–0.8). Two studies observed a significant correlation for the akinetic-rigid subtype but not for the tremor-dominant subtype of PD. Ten studies compared diagnostic accuracies, five of which used pre-defined thresholds and consistently found higher sensitivity for [¹²³I]FP-CIT SPECT (78–100%) compared to [¹²³I]MIBG scintigraphy (65–82%), but higher specificity for [¹²³I]MIBG (range 75–100%) than for [¹²³I]FP-CIT (range 11–73%). Adding [¹²³I]MIBG scintigraphy to [¹²³I]FP-CIT SPECT generally increased specificity but had inconsistent effects on overall accuracy. QUADAS-2 revealed substantial risks of patient selection bias, data-driven thresholds, and limited blinding. Conclusions: Reported correlations between nigrostriatal dopaminergic degeneration and cardiac sympathetic denervation in PD are inconsistent, likely reflecting both methodological heterogeneity and real variation between phenotypes. There may be a stronger correlation in the akinetic-rigid phenotype. Dopaminergic imaging is more sensitive in early PD, while cardiac sympathetic imaging is more specific for differentiating PD from atypical Parkinsonian syndromes. However, study designs greatly restrict the generalizability of reported diagnostic accuracies. Full article

Diagnosis of atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), rely on clinical criteria that often result in misclassification or delayed confirmation. Cerebrospinal fluid (CSF) metabolomics offers the potential to identify disease-specific biochemical “fingerprints”. The aim of the study is to identify CSF metabolomic biomarkers that distinguish PSP and MSA from each other and from non-neurodegenerative controls. Targeted mass spectrometry-based metabolomics was performed on CSF samples from 30 patients with MSA, 41 with PSP, and 30 age- and sex-matched non-neurodegenerative controls. Global metabolomic profiles showed no clear group separation. Both PSP and MSA showed elevated gut-derived metabolites p-cresyl sulfate and deoxycholic acid versus controls. In PSP, decreased cortisone and increased hexosylceramide d18:1/24:1 were observed, whereas in MSA, dihydroxyphenylalanine was elevated alongside homoarginine and creatinine. In the direct comparison of APS, levels of α-aminoadipic acid were increased in PSP compared to MSA. Pathway analysis highlighted disrupted glycerophospholipid metabolism in both APS disorders. Distinct metabolite panels mainly combining membrane-associated lipids, gut-derived and neurotransmitter-related metabolites demonstrated high diagnostic accuracy for distinguishing PSP and MSA from control groups (AUC = 0.95 for PSP and AUC = 0.98 for MSA), while a separate panel showed moderate performance in differentiating PSP from MSA (AUC = 0.85). Distinct but partially overlapping CSF metabolomic profiles characterize PSP and MSA. These metabolomic fingerprints highlight gut–brain axis involvement, alterations in cell membrane-related lipid metabolism, and disease-specific changes in neurotransmitter-related metabolites. Further, a panel of these metabolites showed strong potential as diagnostic biomarkers. 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

Parkinson’s disease (PD) is a heterogeneous clinical syndrome representing the final stage of a complex and long-lasting neurodegenerative process that involves not only dysfunction of the dopaminergic system but also impairments in other neurotransmitter systems. The diversity of the clinical presentation of PD, together with the existence of Parkinsonian syndromes and atypical Parkinsonism—such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB)—has important implications for rehabilitation outcomes and underscores the need for individualized, stage-dependent therapeutic approaches. Juggling is a complex motor activity that integrates cognitive, visuomotor, and balance processes, requiring a high level of concentration, precision, and motor adaptation. In recent years, there has been growing interest in this form of activity as a potential tool for supporting neuroplasticity, cognitive functions, and neurological rehabilitation. The aim of this review was to summarize current scientific evidence on the effects of juggling training on cognitive functions, visuomotor coordination, and balance, as well as to discuss the potential benefits of combining it with controlled hypoxia in patients with Parkinson’s disease (PD). This narrative review additionally considers how disease heterogeneity and stage of progression may influence the effectiveness of such multimodal interventions. This paper reviews the literature concerning the neurophysiological basis of learning to juggle and the mechanisms of brain plasticity, including increases in gray matter volume, improvements in white matter integrity, and reorganization of neuronal networks in motor and associative regions. Attention is drawn to the synergistic potential of combining juggling training with exposure to moderate, controlled hypoxia, which may induce an adaptive response involving the transcription factor HIF-1α, enhance the expression of brain-derived neurotrophic factor (BDNF), and promote angiogenesis and mitochondrial biogenesis. Although juggling and hypoxia are not directly related to training stimuli, both interventions activate overlapping and complementary neuroplastic pathways, providing a conceptual rationale for their parallel consideration and potential integration within future rehabilitation protocols. Juggling delivers task-specific motor–cognitive learning, whereas hypoxia may amplify molecular plasticity signaling, potentially enhancing responsiveness to motor interventions, particularly in patients at early stages of PD when compensatory mechanisms and neuroplastic capacity are relatively preserved. Findings from existing studies suggest that juggling under controlled hypoxic conditions may represent an innovative, safe, and multimodal form of training that supports both cognitive and motor components. Such effects may be particularly relevant in patients at early stages of PD, when compensatory mechanisms and neuroplastic potential are relatively preserved. Such an intervention may contribute to improvements in balance, attention, executive functions, and cognitive flexibility, which is particularly relevant in the context of rehabilitation for patients with neurodegenerative diseases. Importantly, to date, no randomized clinical trials have directly examined juggling performed under controlled hypoxic conditions in PD. Therefore, the present concept should be regarded as translational and exploratory, integrating evidence from juggling-induced neuroplasticity and hypoxia-related physiological adaptations. In this context, the proposed approach represents a proof-of-concept framework for future multimodal interventions rather than an established therapeutic strategy. Available evidence suggests that combining complex sensorimotor skill training with physiological modulation of the internal environment may constitute a novel direction in PD rehabilitation, extending beyond conventional exercise-based models. Despite promising reports, further well-designed clinical studies are needed to determine the optimal training parameters (frequency, intensity, duration, and degree of hypoxia), to evaluate the long-term sustainability of therapeutic effects, and to account for the heterogeneity of PD and related Parkinsonian disorders. Full article

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

Background/Objectives: Clinical differentiation between Parkinson’s disease (PD) and atypical parkinsonism (AP) remains complex. Current diagnostic procedures helpful in their distinction lack specificity, making non-invasive tools like optical coherence tomography (OCT) crucial in evaluating possible retinal changes as potential biomarkers. Our study examined the thickness of the ganglion cell inner plexiform layer complex (GCIPL), peripapillary retinal nerve fiber layer (RNFL) and macular segments in individuals with PD, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and healthy controls (HC). The objective of our study was to determine if OCT analyses can effectively discriminate PD patients from HC and whether retinal thickness can distinguish typical PD patients from those with AP. Methods: Research was an observational, cross-sectional study. Multiple retinal layers measured with OCT of PD and AP patients were compared with age- and sex-matched HC. An intergroup assessment was conducted. Results: Patients with PD and PSP exhibit a thinner GCIPL compared to HC, with no difference observed in the MSA group. GCIPL thickness between investigational groups does not differentiate between PD and AP. The RNFL and central macula thickness were statistically significantly reduced in all patient groups compared to HC. The RNFL was thinner in PSP compared to PD. Nearly all inner and outer macular segments were thinner in the investigational groups compared to HC. The preservation of outer nasal segments distinguished HC from both typical and AP. Patients with PSP and PD differed in the thickness of all macular segments, being thinner in PSP patients. Conclusions: Thickness of multiple retinal layers and macular regions might serve as a distinguishing feature between PD, AP and HC. Full article

REM sleep behavior disorder (RBD) represents a prodromal manifestation of Parkinson’s disease (PD), reflecting the breakdown of inhibitory networks extending from the brainstem to the cortex. This review synthesizes pathological, physiological, and behavioral evidence to illustrate how early α-synuclein pathology disrupts REM-sleep atonia and motor automaticity through degeneration of pontomedullary and cholinergic–inhibitory circuits. The resulting failure of inhibitory precision links nocturnal REM sleep without atonia to daytime gait and postural abnormalities, framing RBD as a dynamic systems disorder rather than a purely sleep-related phenomenon. By examining this continuum across neurophysiological, behavioral, and clinical domains, the review highlights current knowledge gaps, particularly regarding the temporal dynamics of degeneration and compensation. It further integrates multimodal biomarkers that capture these transitions in vivo and discusses therapeutic strategies aimed at preserving inhibitory network integrity and delaying phenoconversion to overt Parkinsonian syndromes. Full article