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Background The efficacy of subthalamic stimulation on axial signs of Parkinson's disease (PD) is debated in the literature. This study delves into the dynamic interplay of gait and posture, specifically probing their nuanced response to subthalamic stimulation and levodopa. Methods We used wearable sensor technology to examine alterations in the spatiotemporal parameters of gait and posture in individuals with PD before and 6 months after subthalamic deep brain stimulation (STN‐DBS) surgery. Thirty‐three subjects with PD were evaluated in two pre‐operative and four post‐operative conditions comprising OFF/ON medication and stimulation states. Standardized response mean (SRM) values were calculated to assess treatment responsiveness. Results Significant improvements in spatiotemporal gait parameters, including speed, stride length, cadence, and turning, were observed following STN‐DBS surgery. Quantitatively, stimulation outperformed levodopa in enhancing gait speed, stride length, and turning, as indicated by SRM. Levodopa moderately improved stride time variability and asymmetry, while stimulation alone demonstrated limited efficacy. Postural parameters exhibited minimal change following STN‐DBS, although stimulation showed a slight benefit in certain postural aspects. Conclusion Our findings suggest positive effects of stimulation and levodopa on gait and postural parameters, with STN‐DBS demonstrating superior efficacy in enhancing gait speed, stride length, and turning. However, gait variability remains unaddressed by current therapies, highlighting the need for novel treatments targeting regions beyond the basal ganglia.

Neurofilament light chain (NfL) and α-synuclein oligomeric seeds (α-syn-s) are promising biomarkers for patients with parkinsonism. We assessed their performance in discriminating Parkinson disease (PD) from atypical parkinsonisms (APDs) and evaluated the association between NfL levels and clinical measures of disease severity. We measured NfL in cerebrospinal fluid (CSF) and/or plasma by immunoassays and α-syn-s in CSF by real-time quaking-induced conversion (RT-QuIC) in patients with PD (n = 153), multiple system atrophy (MSA) (n = 80), progressive supranuclear palsy/cortico-basal syndrome (PSP/CBS) (n = 58), dementia with Lewy bodies (n = 64), isolated REM-sleep behaviour disorder (n = 19), and isolated autonomic failure (n = 30). Measures of disease severity included disease duration, UPDRS-III score, Hoehn and Yahr stage, orthostatic hypotension, MMSE score, and CSF amyloid-beta profile. Both CSF NfL (cNfL) and plasma NfL (pNfL) levels were markedly elevated in APDs, and allowed differentiation with PD (vs. APDs, cNfL AUC 0.96; pNfL AUC 0.95; vs. MSA cNfL AUC 0.99; pNfL AUC 0.97; vs. PSP/CBS cNfL AUC 0.94; pNfL AUC 0.94). RT-QuIC detected α-syn-s in 91.4% of PD, but only 2.5% of APDs (all MSA). In PD/PDD, motor scales significantly correlated with cNfL levels. Although pNfL and both cNfL and α-syn-s accurately distinguished PD from APDs, the combined assessment of CSF markers provided a higher diagnostic value (PD vs. APDs AUC 0.97; vs. MSA AUC 0.97; vs. PSP/CBS AUC 0.99) than RT-QuIC alone (p = 0.047 vs. APDs; p = 0.002 vs MSA; p = 0.007 vs PSP/CBS), or cNfL alone (p = 0.011 vs. APDs; p = 0.751 vs MSA; p = 0.0001 vs. PSP/CBS). The results support the use of these assays in specialised clinics.

Dementia with Lewy Bodies (DLB) is characterized by motor and cognitive deficits that often overlap with other neurodegenerative disorders, complicating its diagnosis. This study combined linear mixed-effects modeling and machine learning to investigate key parameters of pointing movements, saccadic behavior, and superior parietal lobule (SPL) volumetry in differentiating DLB patients from controls. DLB patients exhibited distinct motor impairments, including increased movement times, greater pointing errors, and spatially modulated deficits in pointing accuracy. Saccadic analysis revealed prolonged saccade latencies, larger amplitudes, and pervasive hypermetria, with notable spatial asymmetries in accuracy and amplitude. Specifically, reduced hypermetria for upward-directed saccades suggests direction-specific modulation in DLB, highlighting potential disruptions in visuomotor pathways. Brain volumetric analysis demonstrated significant volumetric loss of SPL, particularly in the left hemisphere, further implicating this region in the visuospatial and motor deficits observed in DLB. Interestingly, an inverse relationship between SPL volumetry and task performance was found, more evident for hand-related parameters. The integration of behavioral, saccadic, and volumetric data revealed that a combined approach highlights the complementary contributions of motor, oculomotor, and neural changes in distinguishing patients from controls. This study provides novel insights into the visuomotor and neural substrates underlying DLB and emphasizes the importance of adopting a multimodal approach to its diagnosis. The results go beyond traditional visuospatial assessments, offering a robust framework for the identification of DLB-specific biomarkers. Future research should explore the generalizability of this combined model across other neurodegenerative conditions to refine diagnostic tools and improve patient outcomes.

The clinical diagnosis of synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), is challenging, especially at an early disease stage, due to the heterogeneous and often non-specific clinical manifestations. The discovery of reliable specific markers for synucleinopathies would consequently be of great aid to the diagnosis and management of these disorders. Real-Time Quaking-Induced Conversion (RT-QuIC) is an ultrasensitive technique that has been previously used to detect self-templating amyloidogenic proteins in the cerebrospinal fluid (CSF) and other biospecimens in prion disease and synucleinopathies. Using a wild-type recombinant α-synuclein as a substrate, we applied RT-QuIC to a large cohort of 439 CSF samples from clinically well-characterized, or post-mortem verified patients with parkinsonism or dementia. Of significance, we also studied patients with isolated REM sleep behavior disorder (iRBD) ( n  = 18) and pure autonomic failure (PAF) ( n  = 28), representing clinical syndromes that are often caused by a synucleinopathy, and may precede the appearance of parkinsonism or cognitive decline. The results show that our RT-QuIC assay can accurately detect α-synuclein seeding activity across the spectrum of Lewy Body (LB)-related disorders (LBD), including DLB, PD, iRBD, and PAF, with an overall sensitivity of 95.3%. In contrast, all but two patients with MSA showed no α-synuclein seeding activity in the applied experimental setting. The analysis of the fluorescence response reflecting the amount of α-synuclein seeds revealed no significant differences between the clinical syndromes associated with LB pathology. Finally, the assay demonstrated 98% specificity in a neuropathological cohort of 101 cases lacking LB pathology. In conclusion, α-synuclein RT-QuIC provides an accurate marker of synucleinopathies linked to LB pathology and may have a pivotal role in the early discrimination and management of affected patients. The finding of no α-synuclein seeding activity in MSA seems to support the current view that MSA and LBD are associated with different conformational strains of α-synuclein.

Our previous findings indicate that A2A and D2 receptors are co-expressed on adult rat striatal astrocytes and on the astrocyte processes, and that A2A-D2 receptor–receptor interaction can control the release of glutamate from the processes. Functional evidence suggests that the receptor–receptor interaction was based on heteromerization of native A2A and D2 receptors at the plasma membrane of striatal astrocyte processes. We here provide biochemical and biophysical evidence confirming that receptor–receptor interaction between A2A and D2 receptors at the astrocyte plasma membrane is based on A2A-D2 heteromerization. To our knowledge, this is the first direct demonstration of the ability of native A2A and D2 receptors to heteromerize on glial cells. As striatal astrocytes are recognized to be involved in Parkinson’s pathophysiology, the findings that adenosine A2A and dopamine D2 receptors can form A2A-D2 heteromers on the astrocytes in the striatum (and that these heteromers can play roles in the control of the striatal glutamatergic transmission) may shed light on the molecular mechanisms involved in the pathogenesis of the disease.

Neurofilament light chain protein (NfL) is a valuable biomarker for the differential diagnosis between Parkinson’s disease (PD) and atypical parkinsonian disorders (APD). Here, we compared the performance of four cerebrospinal fluid (CSF) and three plasma NfL immunoassays in 253 PD and 265 APD. We measured NfL by ELISA in CSF and by SiMoA, CLEIA, and ELLA in both CSF and plasma. Additionally, we assessed Lewy body pathology by CSF α-synuclein real-time quaking-induced conversion assay (α-syn-RT-QuIC). In each biofluid, the tested assays showed comparable precision; however, CSF NfL showed higher diagnostic accuracy than plasma NfL for discriminating PD from APD (AUC range 0.966–0.974 vs 0.917–0.924). Combining CSF NfL and α-syn-RT-QuIC increased diagnostic accuracy. These results confirm the high diagnostic value of NfL in patients with parkinsonism, even when different assays are used. Combining CSF NfL and α-syn-RT-QuIC provides the highest accuracy, followed by CSF NfL and plasma NfL.

Background and purpose Levodopa (LD) is the main treatment for parkinsonism, but its use may be limited by a potential hypotensive effect. Methods We evaluated the cardiovascular effect of LD performing head‐up tilt test (HUTT) before and 60 min after 100/25 mg LD/dopa‐decarboxylase inhibitor (pre‐LD vs. post‐LD HUTT) in 164 patients with parkinsonism on chronic LD treatment. Features predictive of LD‐induced orthostatic hypotension (OH) were assessed by logistic regression analysis. Results Basal supine blood pressure (BP) and heart rate (HR) decreased after LD. During post‐LD HUTT, BP drop and HR increase were significantly greater than at pre‐LD HUTT. Thirty‐eight percent of patients had OH at post‐LD HUTT compared to 22% of patients presenting OH at pre‐LD HUTT (p < 0.001). Risk factors for LD‐induced/worsened OH were pre‐LD OH (odds ratio [OR] = 36, 95% confidence interval [CI] = 10–131), absence of overshoot at Valsalva maneuver (OR = 9, 95% CI = 4–20), and pathological Valsalva ratio (OR = 6, 95% CI = 2–15). Conclusions LD administration caused/worsened hypotension in both supine and orthostatic conditions. Patients with cardiovascular autonomic failure had a higher risk of developing LD‐induced OH. In clinical practice, LD‐induced OH could represent a red flag for cardiovascular autonomic failure.

The brain controls the heart directly through the sympathetic and parasympathetic branches of the autonomic nervous system, which consists of multi-synaptic pathways from myocardial cells back to peripheral ganglionic neurons and further to central preganglionic and premotor neurons. Cardiac function can be profoundly altered by the reflex activation of cardiac autonomic nerves in response to inputs from baro-, chemo-, nasopharyngeal and other receptors as well as by central autonomic commands, including those associated with stress, physical activity, arousal and sleep. In the clinical setting, slowly progressive autonomic failure frequently results from neurodegenerative disorders, whereas autonomic hyperactivity may result from vascular, inflammatory or traumatic lesions of the autonomic nervous system, adverse effects of drugs and chronic neurological disorders. Both acute and chronic manifestations of an imbalanced brain-heart interaction have a negative impact on health. Simple, widely available and reliable cardiovascular markers of the sympathetic tone and of the sympathetic-parasympathetic balance are lacking. A deeper understanding of the connections between autonomic cardiac control and brain dynamics through advanced signal and neuroimage processing may lead to invaluable tools for the early detection and treatment of pathological changes in the brain-heart interaction.

Clinical evaluation is of utmost importance in the semeiological description of motor disorders which often require video recording to highlight subtle signs and their subsequent evolution. After reviewing 1858 video recordings, we composed a suitable list of video-documentation maneuvers, classified semeiologically in the form of a “video recording protocol”, to guarantee appropriate documentation when filming movement disorders. Aware that our proposed filming protocol is far from being exhaustive, by suggesting a more detailed documenting approach, it could help not only to achieve a better definition of some disorders, but also to guide neurologists towards the correct subsequent examinations. Moreover, it could be an important tool for the longitudinal evaluation of patients and their response to therapy. Finally, video recording is a powerful teaching tool as visual teaching highly improves educational training.

Objective To disclose the nature of cognitive deficits in a cohort of patients with idiopathic autonomic failure (IAF) by exploring the relation among cognitive functions, cardiovascular autonomic failure (AF) and clinical progression to another α‐synucleinopathy (phenoconversion). Methods We retrospectively identified all patients with a clinical diagnosis of IAF who underwent a comprehensive neuropsychological evaluation, clinical examination and cardiovascular autonomic tests from the IAF‐BO cohort. Brain magnetic resonance imaging (MRI) studies and cerebrospinal fluid (CSF) analysis, including neurofilament light chain (NfL), Alzheimer disease core biomarkers, and α‐synuclein seeding activity were further evaluated when available. Correlations among cognitive functions, clinical features, cardiovascular AF, cerebral white matter hyperintensities (WMH) load, and CSF biomarkers were estimated using Spearman correlation coefficient. Results Thirteen out of 30 (43%) patients with IAF displayed cognitive deficits (CI) mainly concerning executive functioning. Seven out of 30 (23%) met the criteria for mild cognitive impairment (MCI). The diagnosis of CI and MCI was not associated with phenoconversion or autonomic function parameters, including duration and severity of neurogenic orthostatic hypotension, presence and severity of supine hypertension, and nocturnal dipper profile. Twenty patients underwent a brain MRI and CSF analysis. MCI was related to WMH load (r = 0.549) and NfL levels (r = 0.656), while autonomic function parameters were not associated with either WMH or NfL levels. Interpretation Cardiovascular AF and phenoconversion, underlying the spreading of neurodegeneration to the central nervous system, were not independent drivers of cognitive dysfunction in IAF. We identified WMH load and NfL levels as potential biomarkers of the neural network disruption associated with cognitive impairment in patients with IAF.