Cues are specific references that support motor performance by improving speed, timing, and amplitude while reducing variability. This study aimed at investigating the effects of external auditory cueing on bradykinesia-related kinematic deficits and their neural correlates during a hand-tapping task in people with Parkinson’s disease (pwPD) and healthy controls (HC). Twenty-six pwPD and 20 HC performed a right hand-tapping fMRI task either in a self-paced condition (NOCue) or following an auditory cue (Cue). Hand-tapping kinematics were objectively quantified using an optical-fiber glove. PwPD showed reduced hand-tapping amplitude and a greater sequence effect on amplitude than HC during NOCue condition. Cueing attenuated the sequence effect on amplitude in pwPD. During the NOCue condition, pwPD showed reduced activity of pallidum/thalamus relative to HC. No group differences emerged during Cue condition. During Cue relative to NOCue condition, pwPD showed higher activity of pallidum, parietal, temporal, sensorimotor, insular, and cerebellar regions, alongside reduced activation in of paracentral gyrus and cerebellum. Higher activity of pallidum correlated with better motor performance and higher positive effects of cueing. Our results demonstrated that auditory cueing reduces bradykinesia in pwPD possibly by facilitating basal ganglia activity and reducing the need of movement programming.

This study aimed to develop and evaluate a spatiotemporal deep-neural-network (stDNN) using resting-state fMRI (rs-fMRI) data to identify brain biomarkers associated with isolated REM sleep behavior disorder (iRBD) and Parkinson’s disease (PD) and to differentiate these conditions from controls. The final sample included 771 subjects, comprising 423 patients with PD, 144 with iRBD, and 204 healthy controls. stDNN model was applied to mean timeseries extracted for each subject from rs-fMRI data. By integrating spatio-temporal features, the network classified subjects based on distinct neural patterns. Model generalizability was assessed using subject-wise k-fold cross-validation. Explainable artificial intelligence (XAI) methods were applied. stDNN achieved balanced accuracy rates of 71.0% in distinguishing controls from PD and up to 71.9% in middle-stage PD cases. It also demonstrated over 80% accuracy in differentiating healthy controls from iRBD. XAI analysis highlighted the involvement of fronto-parietal and temporal regions, including the dorsolateral prefrontal cortex, and anterior temporal gyri, in distinguishing controls from PD. In the comparison with iRBD, key contributing areas included the bilateral superior and medial frontal gyri, dorsolateral prefrontal cortex, parietal and occipital regions (lingual gyri and cuneus). This study demonstrates the potential of stDNN to differentiate between iRBD, PD, and controls using rs-fMRI data.

Abstract Background Anti-amyloid monoclonal antibodies are entering clinical practice for early symptomatic Alzheimer’s disease (AD), but European real-world data on feasibility, safety, and biomarker monitoring remain limited. We report the first year of implementation of lecanemab and donanemab in an Italian tertiary memory center. Methods We conducted a prospective observational real-world cohort study at the Center for Alzheimer’s and Related Diseases of IRCCS Ospedale San Raffaele (Milan, Italy). Twenty-nine treatment courses were administered in patients with early symptomatic AD (lecanemab, n = 9; donanemab, n = 20) under European Medicines Agency–aligned safety monitoring and risk-mitigation protocols. Given the unbalanced treatment groups, results are descriptive and not intended for direct comparison between treatments. Safety surveillance included serial magnetic resonance imaging for amyloid-related imaging abnormalities (ARIA) and systematic recording of infusion-related reactions. Biological monitoring included amyloid positron emission tomography with Centiloid quantification and plasma biomarkers (phosphorylated tau 181 and 217, glial fibrillary acidic protein, neurofilament light chain, and amyloid-β 42/40 ratio) at baseline and follow-up. Baseline comparisons and longitudinal changes were assessed using appropriate parametric or nonparametric statistical methods. Results ARIA were infrequent. In donanemab-treated patients, mildly symptomatic ARIA-E occurred in 10% (2/20) and asymptomatic ARIA-H in 15% (3/20). In lecanemab-treated patients, asymptomatic ARIA-H occurred in 11% (1/9). Infusion-related reactions occurred in 21% (6/29) of treatment courses and were manageable with standardized premedication. Among 11 patients with six-month follow-up, amyloid burden decreased significantly (mean change − 52.4 Centiloids), and 75% of donanemab-treated patients (6/8) and 0% of lecanemab-treated patients reached amyloid positron emission tomography negativity (< 11CL). Plasma phosphorylated tau 181 and glial fibrillary acidic protein showed directional declines, consistent with expected biomarker trajectories under anti-amyloid therapy, while cognitive measures showed no significant change. Conclusions In a structured multidisciplinary framework, lecanemab and donanemab were feasibly implemented with a preliminary favorable early safety profile, substantial amyloid reduction, and measurable plasma biomarker changes in routine practice. This experience supports the feasibility of structured real-world pathways for deployment and monitoring of disease-modifying therapies in European memory clinics, within the limitations of a small cohort and short follow-up.

Gait impairment is a major contributor to activity limitations in people with Parkinson’s disease (pwPD), yet its neural control remains insufficiently understood [1]. To advance understanding of gait alterations and to inform effective rehabilitation strategies, numerous neuroimaging techniques have been employed to investigate the neural substrates of locomotion in neurological conditions, particularly in PD. Functional magnetic resonance imaging (fMRI) studies using gait-related tasks have examined functional activation within specific brain regions during action simulation (i.e., motor imagery or action observation) and movement execution [2, 3, 4]. However, the heterogeneity of fMRI tasks and the variability of study populations have limited the ability to draw definitive conclusions regarding the neural control of gait. The aim of this review is to summarise gait-related fMRI paradigms and quantify convergent brain activation in healthy controls (HC) and PwPD using the Activation Likelihood Estimation (ALE) meta-analysis method [5].

We report our experience adopting high angular resolution diffusion imaging (HARDI) tractography to define the target in the Ventralis Intermedius (Vim) nucleus in patients with essential tremor (ET). Retrospective observational cohort study on 18 consecutive Gamma Knife Stereotactic (GKRS)-thalamotomies. Dento-Rubro-Thalamo-Cortical-tract (DRTT), Cortico-spinal tract (CST) and Medial Lemniscus (ML) were reconstructed and used to adjust the coordinates-based target. The DRTT received a median maximum dose of 116 Gy (IQR 92.8–124.2 Gy) and the median volume receiving > 20 Gy (V20) was 154 mm3 (IQR 63.5-190.2 mm3). The maximum dose to the Vim was 126 Gy (IQR 126.2–127 Gy) and the median volume covered by 100 Gy was 25 mm3 (IQR 23-28-2 mm3), corresponding to the 14.5

The introduction of anti-amyloid monoclonal antibodies has shifted Alzheimer’s disease care from diagnostic clarification alone to the problem of treatment governance. While lecanemab and donanemab have demonstrated amyloid reduction at the group level, routine clinical care raises a different question: how should treatment exposure be managed in individual patients within constrained healthcare systems? We suggest that amyloid positron emission tomography (PET) may support this task by providing a quantitative baseline reference for target engagement and by informing decisions on treatment continuation, switching, or discontinuation during follow-up. However, amyloid reduction on PET should not be equated with proven individual-level clinical benefit, and the potential role of longitudinal PET must be considered alongside unresolved questions regarding safety, treatment burden, feasibility, and health-system capacity. Drawing on real-world experience from a high-volume European memory clinic, we argue that amyloid PET may have an increasingly relevant role within structured anti-amyloid treatment pathways.

Background Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy characterized by clinicopathological heterogeneity. The complex interplay between tau deposition, structural changes, and disease spread are unclear. Objectives To investigate the temporospatial patterns of tau propagation and neurodegeneration using multimodal imaging with MRI and flortaucipir (FTP) PET, and determine relationship with clinical heterogeneity. Methods 150 PSP patients (n = 66 Richardson's syndrome [PSP-RS], n = 26 parkinsonism [PSP-P], n = 25 speech-language [PSP-SL], n = 13 progressive gait freezing (PSP-PGF), n = 10 corticobasal syndrome [PSP-CBS], n = 3 frontal, n = 1 oculomotor and n = 6 postural instability) underwent 3 T-MRI and FTP-PET. Forty-three patients died and underwent autopsy. Subtype and Stage Inference (SuStaIn), an unsupervised machine learning algorithm that separates data-driven disease phenotypes distinguished by diverse temporal progression patterns, was applied to both MRI and FTP-PET W-scores (adjusted for age, sex and scanner, using 102 controls). Longitudinal MRI (n = 76) and FTP (n = 56) data, analysed with linear mixed models, were used to assess regional progression patterns and compared with the machine learning predictions. Results Two subtypes emerged across modalities. Subtype 1 exhibited initial subcortical involvement, mainly included PSP-RS and PSP-P patients and mostly featured PSP pathology, while subtype 2 exhibited early cortical involvement, PSP-SL patients and CBD pathology. FTP-PET stages preceded MRI stages, suggesting tau deposition anticipates atrophy. MRI stages were better in capturing clinical progression and predicting longitudinal disease evolution. Conclusions These findings suggest the existence of subcortical and cortical subtypes of PSP, with distinct clinicopathological features. Tau PET and MRI provide complementary insights into disease progression, with MRI more closely reflecting clinical evolution.

BACKGROUND:Isolated REM sleep behavior disorder (iRBD) is the prodromal phase of α-synucleinopathies. Peripheral inflammation, indexed by the neutrophil-to-lymphocyte ratio (NLR), has been associated with cognitive dysfunctions in established α-synucleinopathies, but its role in prodromal stages remains unclear. Based on this background, we investigated the association between NLR and cognitive performance in individuals with iRBD. METHODS:We analyzed cross-sectional data from 371 individuals with iRBD and 262 controls from the Parkinson's Progression Markers Initiative. Baseline assessments included demographic and clinical variables, NLR derived from peripheral blood counts, and a comprehensive neuropsychological battery. Cross-sectional associations between NLR and cognitive performance were examined using univariate and multivariable linear regression models adjusted for age, sex, education, APOE ε4 status, and motor severity. Longitudinal analyses were conducted in a subgroup of 38 iRBD participants followed for 2-5 years to evaluate the relationship between baseline NLR and changes in cognitive performance over time. RESULTS:At baseline, NLR was inversely associated with long-term verbal memory in the iRBD group, but not in the control group. In the iRBD group, higher NLR was also associated with worsening of visuospatial abilities, processing speed, and semantic fluency over time. CONCLUSION:These findings suggest that peripheral inflammation may be involved in early mechanisms of cognitive vulnerability in iRBD. Further studies are needed to clarify whether this represents an epiphenomenon of the underlying pathology or plays an active role in disease progression.

Status epilepticus (SE) is a critical neurological emergency with mortality rates reaching 15–25

Theory of mind (ToM), the ability to infer others' beliefs (cognitive ToM) and emotions (affective ToM), is compromised in behavioural variant frontotemporal dementia (bvFTD). However, its diagnostic and prognostic value in other frontotemporal dementia (FTD) variants remains underexplored due to limited understanding of the underlying neural mechanisms. This study investigated whether ToM deficits are shared across the frontotemporal dementia spectrum and explored the functional connectivity alterations underlying these disturbances using resting-state functional magnetic resonance imaging. Sixty-seven FTD patients [14 non-fluent variant primary progressive aphasia (nfvPPA), 17 semantic variant primary progressive aphasia (svPPA), 23 bvFTD, 13 right temporal variant frontotemporal dementia (rtvFTD); 34 women; mean age 66.5 ± 7.7 years] and two control groups (48 age-matched healthy controls; 50 young healthy controls) underwent clinical, neuropsychological and brain magnetic resonance imaging assessments. ToM was evaluated in patients using the Story-Based Empathy Task (SET), which includes the Story-Based Empathy Task affective subtest (SET-EA) and the Story-Based Empathy Task cognitive subtest (SET-IA). Resting-state functional connectivity networks were obtained in young healthy controls using seed-based analysis centred on the left medial prefrontal cortex for affective ToM and the right supramarginal gyrus for cognitive ToM. In addition, four large-scale functional networks were reconstructed to reflect disease-specific vulnerability. Functional brain connectivity within all networks was quantified using graph analysis and connectomics, and between-group comparisons were performed on both global and seed-based regional metrics. All patient groups showed similar impairments in affective and cognitive ToM performance. Network analyses revealed two dissociable but interconnected ToM systems. Global metrics of network topology indicated increased path length and reduced nodal strength in both ToM networks, particularly in bvFTD and nfvPPA patients (P < 0.05). Direct seed-based connectivity analyses confirmed widespread functional connectivity reductions from key nodes (e.g. left inferior frontal gyrus, anterior cingulate cortex) in these groups. In contrast, svPPA and rtvFTD cases exhibited relatively preserved functional connectivity within ToM circuits. Correlation analyses revealed associations between cognitive ToM network metrics and global ToM performance, and between functional connectivity in the salience network and behavioural dysfunction. Affective and cognitive ToM abilities are comparably impaired across FTD variants, suggesting that socio-cognitive impairments may represent a core and early feature across the FTD spectrum. Such deficits are mirrored by patterns of functional disconnection within dedicated large-scale networks, with bvFTD and nfvPPA showing the most pronounced disruptions. This study underscores the diagnostic relevance of socio-cognitive markers and highlights their potential as clinical and biomarker targets in future therapeutic interventions.

Background Dysphagia can lead to fatal aspiration pneumonia in progressive supranuclear palsy (PSP). Little is known about the longitudinal progression of dysphagia or whether it differs across PSP clinical variants. Objectives To characterize longitudinal changes in dysphagia across PSP variants and determine relationships with disease severity and rate of atrophy in PSP-related regions. Methods Sixty-one PSP patients were recruited and underwent at least two serial evaluations, comprising neurological and videofluorographic exams, and MRI. Variables-of-interest were the oral and pharyngeal total sum scores (OTSS/PTSS) from the Modified Barium Swallow Impairment Profile, the Penetration Aspiration Scale (PAS), Functional Oral Intake Scale (FOIS), and lingual pressure assessments. Rates of change were compared across PSP variants and related to baseline scores, PSP Rating Scale and regional brain atrophy rates. Results Dysphagia progressed longitudinally, particularly with worsening in OTSS and anterior and posterior lingual pressures. Rate of change in OTSS was fastest in PSP with predominant speech-language disorder. Negative correlations were observed between rates of change and baseline scores for OTSS, PTSS and PAS. Rates of change in lingual pressure measures correlated with rates of change in the PSP Rating Scale. Rate of change in the FOIS correlated with rates of change in OTSS and lingual pressure. Rates of brain atrophy were associated with baseline OTSS, PTSS, and PAS. Conclusions Dysphagia and lingual pressure worsen over time in PSP, with variability in rates of change in the OTSS across PSP variants and evidence that dysphagia is related to rates of atrophy.

Functional motor disorders (FMD) are a common yet often misunderstood group of neurological conditions characterized by abnormal movements, including limb weakness, tremor, dystonia, and gait disturbances. These disorders involve disrupted sensory processing mechanism. Previous studies have shown abnormal prepulse inhibition of the blink reflex (BR) in FMD, but the baseline R2-area, reflecting brainstem excitability and cortical modulation, has not been characterized. This study investigated baseline BR R2-area in patients with FMD compared with healthy controls (HC), its associations with affective and interoceptive factors, and its diagnostic potential when combined with laser-evoked potentials (LEPs). BR responses were recorded in clinically definite patients with FMD (n = 75) and matched HC (n = 75). The R2-component was elicited by supraorbital stimulation and quantified as the area under the curve across ipsilateral, contralateral, and average responses. Associations with with behavioural and interoceptive measures were investigated. LEPs were incorporated into multivariate logistic regression models to assess diagnostic potential. Compared with HC, FMD-patients exhibited a consistent reduction in baseline R2 area. Worst depressive symptoms were associated with larger R2 areas, whereas reduced body awareness was associated with smaller responses, indicating affective and interoceptive influences on brainstem excitability. Baseline R2-metrics, particularly the ipsilateral area, contributed substantially to group discrimination, achieving 71.1

Abstract Background Apolipoprotein E (ApoE) ε4 status informs risk stratification and safety management for anti-amyloid therapies, but genotyping typically requires dedicated procedures, longer turnaround times, and higher costs compared with automated laboratory assays. We evaluated an automated plasma approach for ε4 stratification based on proteotyping, the quantification of isoform-specific ApoE proteins to infer ApoE genotype. Methods We retrospectively included 110 patients (mean age 67.82 ± 10.11 years, 49.1% female) of European ancestry with cognitive impairment across a broad diagnostic spectrum, including 68 AD-spectrum cases, 29 with subjective symptoms, and 16 with other etiologies. ApoE genotyping identified 57 ε4 non-carriers (51.8%), 44 heterozygous carriers (40.0%), and 9 homozygous carriers (8.2%). ApoE4 and total ApoE (PanApoE) were measured on Lumipulse and the ApoE4/PanApoE ratio (ApoE ratio) was derived. Results The ratio showed excellent separation across genotypes in our cohort. For ε4 carrier identification, both the ratio and ApoE4 achieved an AUC of 1.00 (95% CI 1.00–1.00), whereas PanApoE showed poor discrimination (AUC 0.30, 95% CI 0.20–0.40), reflecting lower PanApoE levels in ε4 carriers. The ratio also accurately distinguished heterozygotes from homozygotes (AUC 1.00, 95% CI 1.00–1.00). Conclusions Automated plasma ApoE proteotyping mirrored genetic ε4 status. The ApoE ratio provided complete genotype separation, supporting its use for individual-level stratification. These findings should be interpreted cautiously considering the retrospective single-center design and the limited number of ApoE ε4 homozygotes, and require validation in larger, independent cohorts.

Fatigue is a common and disabling non-motor symptom in Parkinson’s disease (PD), significantly affecting patients’ quality of life. However, it is often underdiagnosed due to its subjective nature and the lack of a clear definition, hindering the development of effective treatments. This study aims to investigate the prevalence of fatigue and its associations with sociodemographic factors, disease severity, levodopa equivalent daily dosage (LEDD) and motor, non-motor, and cognitive symptoms in an Italian cohort of patients with PD. An observational cross-sectional study was carried out in three Italian centers from January to May 2024. One hundred PD patients (H Y ≤ 4) were assessed using validated tools: Parkinson Fatigue Scale (PFS), Fatigue Severity Scale, and Modified Fatigue Impact Scale. Motor and non-motor signs and symptoms, cognitive status, and LEDD were analyzed using non-parametric tests and Spearman’s correlations. Fatigue prevalence was determined based on PFS score ≥ 3.09. Fatigue was present in 36