Cerebral noradrenergic activity modulates physiological functions of behaviour, cognition, movement, arousal and sleep. This review aims to provide an accurate summary of the current knowledge on the involvement of the noradrenergic system in Parkinson’s Disease (PD) and its clinical correlations based on neuroimaging studies. Studies in PD highlight neuromelanin MRI signal loss in the locus coeruleus (LC), and positron emission tomography shows noradrenergic denervation across subcortical and cortical areas. More severe phenotypes of PD, manifesting with cognitive decline, apathy, REM sleep behaviour disorder and autonomic dysfunction, are associated with more severe noradrenergic dysfunction. Conversely more preserved noradrenergic transmission is common in tremulous PD. Furthermore, noradrenergic dysfunction, is also involved in transient motor manifestations such as tremor and freezing of gait. Recent neuroimaging advances greatly expanded the knowledge about noradrenergic dysfunction pathophysiology in PD. However, pharmacological treatment of its several associated manifestations is still lacking and needs further investigation.

Most genetic variants contributing to complex diseases reside in the noncoding genome. While common variants uncovered by genome-wide association studies often fail to explain much of the observed heritability of these diseases, rare variants often have higher effect sizes and cumulatively explain a larger portion of heritability. However, rare variants, particularly rare noncoding variants, have remained under-characterized largely due to the difficulties of accurately predicting variant functionality at scale, given that each individual carries an average of ~10,000 rare variants. Here, we generated multi-omic data from >3.3 million nuclei sampled from five brain regions across a cohort of 80 individuals with Parkinson's disease (PD) and 21 neurologically normal control individuals with matched 30x whole-genome sequencing. We use this data to identify cell type-specific features of PD, map cell type-specific chromatin accessibility and expression quantitative trait loci, and train machine learning models to predict the effect of variants on gene regulation. We identify rare noncoding variants statistically associated with sporadic PD and extend our approaches to predict drivers of familial PD of unknown genetic origin. Our results underscore the significance of rare noncoding variants in complex diseases and provide a roadmap for applying similar approaches in other disease systems.

Diagnosing Atypical Parkinsonian Syndromes (APS) may be challenging due to overlapping clinical features of Parkinson’s disease (PD), and the lack of pathognomonic diagnostic tests. Fluid biomarkers can be useful tools that make it easier to identify and track different APS. Objectives: this narrative review aim to update the current state of fluid biomarker research in APS and their potential implications in clinical practice. A comprehensive literature search was conducted in PubMed and Scopus using the following terms: “Aβ42 amyloid beta with 42 amino acids’’, “ alpha-synuclein’’, “Atypical Parkinsonian Syndromes’’, “corticobasaldegeneration’’, “C reactive protein’’, “cerebrospinal fluid’’, “dementia with Lewy bodies’’, “multiple system atrophy’’, “neurofilament light, oligomericαsyn, phosphorylated α –syn’’, “tau phosphorylated at threonine 181’’, “progressive supranuclear palsy’’, “Seeding Amplification Assay’’, “t-tau; total tau”. The lack of high-affinity α-syn antibodies and ligands may contribute to α-syn’s low efficacy as a diagnostic biomarker of APS. Cerebrospinal fluid (CSF) biomarkers reflecting Alzheimer pathology, axonal damage (neurofilament light chain) add valuable diagnostic and prognostic information in the neurochemical characterization of APS. Inflammatoryand microRNAs markers need to be further validated before their clinical use. Seeding Amplification Assays (SAA), despite their high sensitivity and specificity, are at this point used only as a research tool, and they are not quantitative or reflective of disease severity. Biomarker research for early identification and prognosis of APS patients requires multicenter collaboration, validation, and AI-based diagnostics, despite immature biological classification systems.

OBJECTIVE:This study aims to evaluate our experience in the diagnosis of hereditary ataxias (HAs), to analyze data from a real-world scenario. STUDY DESIGN:This is a retrospective, cross-sectional, descriptive study conducted at a single Italian adult neurogenetic outpatient clinic, in 147 patients affected by ataxia with a suspicion of hereditary forms, recruited from November 1999 to February 2024. A stepwise approach for molecular diagnostics was applied: targeted gene panel (TP) next-generation sequencing (NGS) and/or clinical exome sequencing (CES) were performed in the case of inconclusive first-line genetic testing, such as short tandem repeat expansions (TREs) testing for most common spinocerebellar ataxias (SCA1-3, 6-8,12,17, DRPLA), other forms [Fragile X-associated tremor/ataxia syndrome (FXTAS), Friedreich ataxia (FRDA) and mitochondrial DNA-related ataxia, RFC1-related ataxia/CANVAS] or inconclusive phenotype-guided specific single gene sequencing. RESULT:A definitive diagnosis was reached in 36.7% of the cases. TREs testing was diagnostic in 30.4% of patients. The three most common TREs ataxias were FRDA (36.1%), SCA2 (27.8%), and RFC1-related ataxia/CANVAS (11.1%). In five patients, the molecular diagnosis was achieved by single gene sequencing and causative mutations were identified in POLG (2), SACS (1), DARS2 (1), MT-ATP6 (1). Of 94 patients with a suspicion of HAs of indeterminate genetic origin, 68 underwent new molecular evaluation using the NGS approach. In 28 of these cases, CES was performed after the TP sequencing resulted negative. In 13 patients, the diagnosis was achieved by NGS approach. In 7 of these 13 patients, the diagnosis was made by CES. Genes mutations identified as causative of HAs were found in SPG7 (4), SACS (1), CACNA1A (1), CACNA1G (1), EEF2 (1), PRKCG (1), KCNC3 (1), ADCK3 (1), SYNE1 (1), ITPR1 (1). A positive family history of ataxia and early onset of symptoms were associated with a higher likelihood of obtaining a definite diagnosis. CONCLUSION:The molecular diagnosis of HAs remains a significant challenge for neurologists. Our data indicate that, in most cases, a diagnosis of HA can be established through first line genetic testing, particularly TREs testing. However, for patients with a clinical diagnosis of HA who do not achieve a molecular diagnosis through initial genetic tests, the use of NGS proves to be a valuable tool, providing a definitive diagnosis in approximately 20% of cases. Therefore, when feasible in clinical practice, integrating NGS testing, especially exome sequencing, into the diagnostic decision-making process for unsolved cases is crucial.

BACKGROUND AND OBJECTIVES:Idiopathic normal pressure hydrocephalus (iNPH) is characterized by gait disturbance, cognitive decline, and urinary incontinence and may include parkinsonism. The underlying mechanism of parkinsonism in iNPH-whether neurodegenerative or mechanical-remains unclear. This study aimed to assess nigrostriatal integrity in iNPH patients with parkinsonism using dopaminergic transporter imaging (DAT-SPECT) and nigrosome MRI. METHODS:This prospective study was conducted at the Movement Disorders Clinic, Santa Chiara Hospital, Pisa University, from 2021 to 2023. Inclusion criteria for the iNPH group included the following: (1) clinical diagnosis of probable iNPH per the 2021 Japanese Society Guidelines and (2) parkinsonism per United Kingdom Parkinson's Disease Society Brain Bank criteria. An equal number of patients with Parkinson disease (PD), matched for age and sex, served as a comparison group. All participants underwent DAT-SPECT and 3T MRI within 1 month. Statistical analyses included the Student t test or Fisher-Pitman permutation tests for continuous variables and χ2 tests for categorical variables. Multiple linear regression (adjusted for age and sex) compared DAT binding between groups. Pearson correlation assessed relationships between striatal DAT binding and parkinsonism in patients with iNPH evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III. RESULTS:A total of 20 patients with iNPH (mean age 75.4 ± 5.1 years, 65% female) and 20 patients with PD (mean age 74 ± 3.7 years, 55% female) were included. Reduced striatal DAT binding was observed in 45% of patients with iNPH, with none exhibiting nigrosome loss. Conversely, all patients with PD showed both reduced DAT binding and nigrosome loss (p < 0.001). After adjusting for age and sex, patients with iNPH exhibited significantly higher putaminal and caudate DAT binding than patients with PD (right putamen: β = -0.644, p < 0.001; left putamen: β = -0.659, p < 0.001; right caudate: β = -0.429, p = 0.006; left caudate: β = -0.391, p = 0.016), with an elevated putaminal/caudate ratio (p = 0.012). In patients with iNPH, striatal DAT binding negatively correlated with motor severity (left: r = -0.626, p = 0.004; right: r = -0.425, p = 0.07). DISCUSSION:Findings suggest that parkinsonism in iNPH may stem from mechanical disruption of the nigrostriatal pathway rather than neurodegeneration, as indicated by preserved nigrosome integrity despite reduced DAT binding. Limitations include the small sample size and lack of postsurgical follow-up data.

Two Parkinson’s disease subtypes—“Brain-First” and “Body-First”—have been proposed based on putative sites of onset. We examined whether “Body-First” markers relate to more symmetric striatal [123I]-FP-CIT uptake and whether imaging could discriminate the subtypes. In a retrospective cohort of 158 de novo PD patients imaged at diagnosis and followed for six years, patients were classified as “Body-First” if baseline REM sleep behavior disorder, constipation, or neurogenic orthostatic hypotension was present. DaTQUANT provided semiquantitative metrics; a radiomics-based classifier was also trained on DAT-SPECT images. Neither asymmetry indices nor other DaTQUANT measures differed between groups (all p > 0.05). Radiomics showed poor discrimination (AUC ≈ 0.46). Clinically, “Body-First” patients displayed a more adverse course, with higher MCI prevalence and greater MMSE decline and neuropsychiatric burden, whereas motor severity and complications were comparable between groups. These data suggest DAT-SPECT—conventional or radiomics-enhanced—does not separate proposed subtypes at diagnosis, although “Body-First” features forecast worse non-motor progression.

Background: Elevated levels of prokineticin-2 (PK2), regarded as a protein involved in modulating immune/inflammatory responses, have been detected in the substantia nigra, serum, and olfactory neurons of Parkinson's disease (PD) patients. Of note, emerging evidence suggests that gut alterations, including dysbiosis and enteric inflammation, play a role in PD via the gut-brain axis. Objectives: Our goal was to investigate the expression of PK2 in colonic biopsies of PD patients. Methods: Mucosal biopsies from the descending colon were obtained in 11 PD patients and five asymptomatic subjects. Biopsy samples were processed for PK2 immunofluorescence and western blot. Results: We revealed an increased PK2 expression in colonic mucosa from PD patients in the early stages compared to controls. In addition, we found that PK2 was expressed by activated enteric glial cells and macrophages. Conclusions: PK2 is highly expressed within neurogenic/inflammatory cells of colonic mucosa from early PD patients, suggesting a potential role of PK2 in gut inflammation, especially in the early stages of PD. (c) 2024 International Parkinson and Movement Disorder Society.

BACKGROUND:Family history of Parkinson's disease (PD) is a common finding in PD patients. However, a few studies have systematically examined this aspect. OBJECTIVES:We investigated the family history of PD patients, comparing demographic and clinical features between familial PD (fPD) and sporadic PD (sPD). METHODS:A cross-sectional study enrolling 2035 PD patients was conducted in 28 Italian centers. Clinical data and family history up to the third degree of kinship were collected. RESULTS:Family history of PD was determined in 21.9% of patients. fPD patients had earlier age at onset than sporadic patients. No relevant differences in the prevalence of motor and nonmotor symptoms were detected. Family history of mood disorders resulted more prevalently in the fPD group. CONCLUSIONS:fPD was found to recur more frequently than previously reported. Family history collection beyond the core family is essential to discover disease clusters and identify novel risk factors for PD.

Background VPS16 pathogenic variants have been recently associated with inherited dystonia. Most patients affected by dominant VPS16-related disease display early-onset isolated dystonia with prominent oromandibular, bulbar, cervical, and upper limb involvement, followed by slowly progressive generalization.Cases We describe six newly reported dystonic patients carrying VPS16 mutations displaying unusual phenotypic features in addition to dystonia, such as myoclonus, choreoathetosis, pharyngospasm and freezing of gait. Response to bilateral Globus Pallidus Internus Deep Brain Stimulation (GPi-DBS) is reported in three of them, associated with significant improvement of dystonia but only minor effect on other hyperkinetic movements. Moreover, five novel pathogenic/likely pathogenic variants are described.Conclusions This case collection expands the genetic and clinical spectrum of VPS16-related disease, prompting movement disorder specialists to suspect mutations of this gene not only in patients with isolated dystonia.

α-Synuclein (α-syn), a pathological hallmark of PD, is emerging as a bridging element at the crossroads between neuro/immune-inflammatory responses and neurodegeneration in PD. Several evidence show that pathological α-syn accumulates in neuronal and non-neuronal cells (i.e., neurons, microglia, macrophages, skin cells, and intestinal cells) in central and peripheral tissues since the prodromal phase of the disease, contributing to brain pathology. Indeed, pathological α-syn deposition can promote neurogenic/immune-inflammatory responses that contribute to systemic and central neuroinflammation associated with PD. After providing an overview of the structure and functions of physiological α-syn as well as its pathological forms, we review current studies about the role of neuronal and non-neuronal α-syn at the crossroads between neuroinflammation and neurodegeneration in PD. In addition, we provide an overview of the correlation between the accumulation of α-syn in central and peripheral tissues and PD, related symptoms, and neuroinflammation. Special attention was paid to discussing whether targeting α-syn can represent a suitable therapeutical approach for PD.

BACKGROUND:Primary mitochondrial diseases (PMDs) are the most common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. They can result from mutations in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). These disorders are multisystemic and mainly affect high energy-demanding tissues, such as muscle and the central nervous system (CNS). Among many clinical features of CNS involvement, parkinsonism is one of the most common movement disorders in PMDs. METHODS:This review provides a pragmatic educational overview of the most recent advances in the field of mitochondrial parkinsonism, from pathophysiology and genetic etiologies to phenotype and diagnosis. RESULTS:mtDNA maintenance and mitochondrial dynamics alterations represent the principal mechanisms underlying mitochondrial parkinsonism. It can be present in isolation, alongside other movement disorders or, more commonly, as part of a multisystemic phenotype. Mutations in several nuclear-encoded genes (ie, POLG, TWNK, SPG7, and OPA1) and, more rarely, mtDNA mutations, are responsible for mitochondrial parkinsonism. Progressive external opthalmoplegia and optic atrophy may guide genetic etiology identification. CONCLUSION:A comprehensive deep-phenotyping approach is needed to reach a diagnosis of mitochondrial parkinsonism, which lacks distinctive clinical features and exemplifies the intricate genotype-phenotype interplay of PMDs.

Older age at onset and baseline caudate dopaminergic denervation are recognized risk factors for cognitive impairment in Parkinson's disease (PD), posing challenges in identifying their relative contribution to cognitive outcomes. The objective of this study was to assess the distinct contribution of age at onset and baseline caudate dopaminergic binding to the early cognitive deficits in PD patients. We examined the relationship between baseline dopaminergic striatal dysfunction (measured using [ 123 I]-FP-CIT SPECT), age at disease onset and neuropsychological performance in 128 drug-naive PD patients, utilizing putaminal and caudate binding values of 77 healthy controls (HC) for a comparative exploration of age-dependent loss of DAT availability. Additionally, we investigated whether age at onset and DAT binding value of the caudate could independently predict cognitive changes over a median of 7-year follow-up. [ 123 I]-FP-CIT-SPECT binding values had a significant negative correlation with age in both PD and HC, but in PD, aging was linked with a steeper slope for the caudate than the putamen. Older age at onset and lower caudate uptake were associated with worse global cognitive function and performance in specific neuropsychological tests at baseline and demonstrated to be significant independent predictors of cognitive dysfunction at follow-up. Our findings confirm a differential age effect on [ 123 I]-FP-CIT binding in the striatal subregions of de novo PD patients. Notably, we found less age-related attrition of dopaminergic binding in the putamen than in the caudate, reflecting likely the superimposition of putaminal compensatory mechanisms and an increased predisposition of old onset PD patients to develop cognitive disturbances.

Background: This is a retrospective longitudinal study comparing 374 patients with Parkinson’s disease (PD) who were treated in centers offering a specialized program of enhanced rehabilitation therapy in addition to expert outpatient care to 387 patients with PD, who only received expert outpatient care at movement disorders centers in Italy. Methods: The data are from subjects recruited in the Parkinson’s Outcome Project (POP) at six Italian centers that are part of a multicenter collaboration for care quality improvement (the Fresco Network). The effects were measured with a baseline and a follow-up clinical evaluation of the Timed-Up-and-Go test (TUG), Parkinson’s Disease Questionnaire (PDQ-39), and Multidimensional Caregiver Strain Index (MCSI), the number of falls and hospitalizations for any cause. We used a generalized linear mixed model with the dependent variables being the response variable, which included the covariates demographics, evaluation, and treatment variables. Results: We found that the subjects who underwent specialized enhanced rehabilitation had a better motor outcome over time than those who were managed by expert neurologists but had participated in community programs for exercise and other allied health interventions. The greatest effects were seen in patients in the early stages of the disease with a high amount of vigorous exercise per week in the last six months. Similar effects were seen for PDQ39, MCSI, the number of falls, and hospitalization. Conclusions: Long-term benefits to motor function and the quality of life in patients with PD and burden reduction in their caregivers can be achieved through a systematic program of specialized enhanced rehabilitation interventions.

Myoclonus-dystonia (MD) is a syndrome characterized by subcortical myoclonus and milder dystonia. The main causative gene is the epsilon sarcoglycan gene (SGCE), but other genes may be involved. Response to medications is variable, with poor tolerability limiting their use. We present the case of a patient with severe myoclonic jerks and mild dystonia since childhood. At first neurological visit at the age of 46 years old, she presented brief myoclonic jerks predominating in the upper limbs and neck, mild at rest and elicited by action, posture and tactile stimulus. Myoclonus was accompanied by mild neck and right arm dystonia. Neurophysiological tests suggested subcortical origin of myoclonus, brain MRI was unremarkable. Myoclonus-dystonia was diagnosed, and genetic testing identified a novel mutation in SGCE gene (c.907delC) in heterozygosis. Over time she assumed a large variety of anti-epileptics without beneficial effect on myoclonus and low tolerability. Add-on treatment with Perampanel was started, with a beneficial effect. No adverse events were reported. Perampanel is the first selective non-competitive AMPA receptor antagonist approved in add-on for focal and generalized tonic–clonic seizures. To our knowledge, this is the first trial of Perampanel in MD. We presented the case of a patient with MD due to SGCE mutation who was treated with Perampanel with beneficial effects. We propose Perampanel as a novel treatment for myoclonus in MD.

Alpha-synuclein (α-syn) aggregates are the hallmark pathological inclusions of Parkinson’s disease (PD). Even though its mechanisms of action are still unclear, multiple pathways of cellular dysfunction in models of α-syn toxicity have been described, and it is acknowledged that buildup of the misfolded α-syn aggregates hinders cell communication, causing neuronal degeneration. Encouraging preliminary evidence showed a significant lowering of α-syn plasma levels and cerebrospinal fluid penetration of monoclonal antibodies against α-syn. Moreover, passive immunotherapy offers the opportunity to deliver directly precise concentrations of monoclonal antibodies without requiring an immune response to generate an antibody response. Two similarly designed phase II trials using different humanized anti-α-syn antibodies were recently reported. Both multicenter, randomized, double-blinded trials recruiting patients with early-stage PD (Hoehn and Yahr stage <3) with abnormal dopamine transporter (DaT) scans demonstrated a good safety profile, but neither met the primary or secondary end points, represented by the change in the Movement Disorder Society– sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) total score and changes in DaT imaging over a 52-week period, respectively. However, there was the suggestion of a slower progression with the lower dose on the MDS-UPDRS Part III in the PASADENA study, which led to the launch of a phase IIb study. There is a strong scientific rationale in targeting aggregated forms of α-syn. Indeed, the identification of mutations in the α-syn gene leading to PD and the evidence of α-syn aggregates as a major component of Lewy bodies support the hypothesis that α-syn is a key player in the disease. Nevertheless, several mechanisms have been implicated in PD pathogenesis and not all could be linked to α-syn toxicity. PARK2 and LRRK2-related PD may occur independently of α-syn aggregation, and insights from late-onset familial parkinsonism suggest that Lewy bodies might more likely be a consequence than a cause of parkinsonism. In addition, because nigral neuronal loss has been demonstrated to occur before the presence of α-syn, neither the MDS-UPDRS Part III or DaT imaging may be fully appropriate to reflect α-syn toxicity. Finally, both the full extent of the physiological function for α-syn and the nature of its toxic species have yet to be elucidated. In this context, the positive results in secondary end points of antibodies against the C terminus of α-syn in the PASADENA study are encouraging and could suggest a more efficacious target engagement. This, along with using a longer time window to assess the primary end point in future α-syn antibody trials-perhaps on late manifestations such as dementia incidence-might be a worthwhile future step needed to test whether passive immunotherapy targeting α-syn can be clinically useful.

Locus coeruleus (LC) is the main noradrenergic nucleus of the brain, and degenerates early in Parkinson's disease (PD). The objective of this study is to test whether degeneration of the LC is associated with orthostatic hypotension (OH) in PD. A total of 22 cognitively intact PD patients and 52 age-matched healthy volunteers underwent 3 T magnetic resonance (MRI) with neuromelanin-sensitive T1-weighted sequences (LC-MRI). For each subject, a template space-based LC-MRI was used to calculate LC signal intensity (LC contrast ratio-LCCR) and the estimated number of voxels (LCVOX) belonging to LC. Then, we compared the LC-MRI parameters in PD patients with OH (PDOH+) versus without OH (PDOH-) (matched for sex, age, and disease duration) using one-way analysis of variance followed by multiple comparison tests. We also tested for correlations between subject's LC-MRI features and orthostatic drop in systolic blood pressure (SBP). PDOH- and PDOH+ did not differ significantly (p > 0.05) based on demographics and clinical characteristics, except for blood pressure measurements and SCOPA-AUT cardiovascular domain (p < 0.05). LCCR and LCVOX measures were significantly lower in PD compared to HC, while no differences were observed between PDOH- and PDOH+. Additionally, no correlation was found between the LC-MRI parameters and the orthostatic drop in SBP or the clinical severity of autonomic symptoms (p > 0.05). Conversely, RBD symptom severity negatively correlated with several LC-MRI parameters. Our results failed to indicate a link between the LC-MRI features and the presence of OH in PD but confirmed a marked alteration of LC signal in PD patients.