Brain Dynamics Complexity as a Signature of Cognitive Decline in Parkinson's Disease.

BACKGROUND: Higuchi's fractal dimension (FD) captures brain dynamics complexity and may be a promising method to analyze resting-state functional magnetic resonance imaging (fMRI) data and detect the neuronal interaction complexity underlying Parkinson's disease (PD) cognitive decline. OBJECTIVES: The aim was to compare FD with a more established index of spontaneous neural activity, the fractional amplitude of low-frequency fluctuations (fALFF), and identify through machine learning (ML) models which method could best distinguish across PD-cognitive states, ranging from normal cognition (PD-NC), mild cognitive impairment (PD-MCI) to dementia (PDD). Finally, the aim was to explore correlations between fALFF and FD with clinical and cognitive PD features. METHODS: Among 118 PD patients age-, sex-, and education matched with 35 healthy controls, 52 were classified with PD-NC, 46 with PD-MCI, and 20 with PDD based on an extensive cognitive and clinical evaluation. fALFF and FD metrics were computed on rs-fMRI data and used to train ML models. RESULTS: FD outperformed fALFF metrics in differentiating between PD-cognitive states, reaching an overall accuracy of 78% (vs. 62%). PD showed increased neuronal dynamics complexity within the sensorimotor network, central executive network (CEN), and default mode network (DMN), paralleled by a reduction in spontaneous neuronal activity within the CEN and DMN, whose increased complexity was strongly linked to the presence of dementia. Further, we found that some DMN critical hubs correlated with worse cognitive performance and disease severity. CONCLUSIONS: Our study indicates that PD-cognitive decline is characterized by an altered spontaneous neuronal activity and increased temporal complexity, involving the CEN and DMN, possibly reflecting an increased segregation of these networks. Therefore, we propose FD as a prognostic biomarker of PD-cognitive decline. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Validation of the Italian version of the Parkinson's Disease- Cognitive Functional Rating Scale.

A key distinguishing factor between mild cognitive impairment (MCI) and dementia in Parkinson's disease (PD) lies in the notable decrease in functioning due to cognitive impairment. The Parkinson's Disease-Cognitive Functional Rating Scale (PD-CRFS) was developed to assess functional limitations caused by cognitive impairment, while reducing the influence of motor impairment. The aim of this multicenter study was to (i) validate the Italian version of the PD-CFRS in PD, (ii) determine optimal cut-off scores for detecting MCI and dementia in PD, (iii) compare its performances with the most established functional assessment tool (IADL). Six hundred and sixty nine PD participants were recruited from 4 Italian Movement Disorders centers (Venice, Milan, Gravedona, and Salerno). They underwent Level-II cognitive evaluation, which resulted in 282 PD-NC, 310 PD-MCI, and 77 PDD. The PD-CFRS's psychometric and clinimetric properties, applicability, and responsiveness were analyzed. The PD-CFRS showed high acceptability. Floor and ceiling effects were acceptable. It also displayed strong internal consistency (Cronbach's α = 0.738), and test-retest reliability (ICC = .854). The PD-CFRS demonstrated higher coefficient of variation to detect dysfunction in PD-MCI patients in comparison to the IADL scale (PD-CFRS 96% vs IADL 22.5%). Convergent validity with the IADL was r = - 0.638 and - 0.527 in males and females, respectively. PD-CFRS total score negatively correlated with global cognition (MoCA corrected score r = - 0.61; p < 0.001). A cut-off score > 6.5 identified PDD with a sensitivity of 90% and specificity of 88% (AUC = .959). A cut-off value of > 1 detected PD-MCI with a sensitivity of 68% and specificity of 69% (AUC = .695). The Italian version of the PD-CFRS demonstrated to be an easy, valid and reliable tool that properly captures functional impairment due to cognitive decline in PD. It also proved to be particularly effective in the advanced stages of PD, and would be a useful support for the diagnosis of PD-MCI and PDD.

Clinical, cognitive, and morphometric profiles of progressive supranuclear palsy phenotypes.

The International Parkinson's and Movement Disorder Society (MDS) criteria for progressive supranuclear palsy (PSP) have broadened the clinical spectrum of the disease and established phenotypic characterization according to the predominant manifestation at onset. The objective of this study is to describe clinical/cognitive and imaging features of a monocentric cohort of PSP patients, highlighting different patterns of functional disability according to the assigned phenotype. We retrospectively reviewed clinical/imaging data of 53 PSP patients diagnosed with probable PSP according to the MDS criteria and 40 age/sex-matched healthy controls (HCs). Neurological/neuropsychological assessments were performed using standardized scales, as well as comprehensive magnetic resonance imaging (MRI) morphometric measurements. In our cohort, there were 24/53 PSP-RS (Richardson's syndrome), 13/53 PSP-P (Parkinsonism), 7/53 PSP-PGF (Progressive gait freezing), and 9/53 PSP-Cog (Cognitive impairment). PSP-Cog presented the worst motor profiles, the highest percentages of dementia and impaired functional autonomy; 4/9 PSP-Cog and 2/7 PSP-PGF died. PSP-P had the lowest motor/cognitive burden. All MRI parameters had good discriminative efficacy vs. HCs, with P/M 2.0 discriminating PSP-PGF from PSP-RS and PSP-Cog. We highlighted discrete clinical and imaging patterns that best characterize different PSP phenotypes. PSP-Cog and PSP-PGF/RS manifest greater incidence of dementia and motor disability, respectively, while PSP-P has a more benign course. The identification of different phenotypes may be the expression of different progression patterns requiring tailored approaches in terms of follow-up and treatment. These findings support the concept of discrete patterns of Tau pathology within the PSP spectrum and encourage research for phenotype-specific outcome measures.

Development and Validation of Automated Magnetic Resonance Parkinsonism Index 2.0 to Distinguish Progressive Supranuclear Palsy-Parkinsonism From Parkinson's Disease.

BACKGROUND: Differentiating progressive supranuclear palsy-parkinsonism (PSP-P) from Parkinson's disease (PD) is clinically challenging. OBJECTIVE: This study aimed to develop an automated Magnetic Resonance Parkinsonism Index 2.0 (MRPI 2.0) algorithm to distinguish PSP-P from PD and to validate its diagnostic performance in two large independent cohorts. METHODS: We enrolled 676 participants: a training cohort (n = 346; 43 PSP-P, 194 PD, and 109 control subjects) from our center and an independent testing cohort (n = 330; 62 PSP-P, 171 PD, and 97 control subjects) from an international research group. We developed a new in-house algorithm for MRPI 2.0 calculation and assessed its performance in distinguishing PSP-P from PD and control subjects in both cohorts using receiver operating characteristic curves. RESULTS: The automated MRPI 2.0 showed excellent performance in differentiating patients with PSP-P from patients with PD and control subjects both in the training cohort (area under the receiver operating characteristic curve [AUC] = 0.93 [95% confidence interval, 0.89-0.98] and AUC = 0.97 [0.93-1.00], respectively) and in the international testing cohort (PSP-P versus PD, AUC = 0.92 [0.87-0.97]; PSP-P versus controls, AUC = 0.94 [0.90-0.98]), suggesting the generalizability of the results. The automated MRPI 2.0 also accurately distinguished between PSP-P and PD in the early stage of the diseases (AUC = 0.91 [0.84-0.97]). A strong correlation (r = 0.91, P < 0.001) was found between automated and manual MRPI 2.0 values. CONCLUSIONS: Our study provides an automated, validated, and generalizable magnetic resonance biomarker to distinguish PSP-P from PD. The use of the automated MRPI 2.0 algorithm rather than manual measurements could be important to standardize measures in patients with PSP-P across centers, with a positive impact on multicenter studies and clinical trials involving patients from different geographic regions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Asymmetric Dopamine Transporter Loss Affects Cognitive and Motor Progression in Parkinson's Disease.

BACKGROUND: Asymmetric hemispheric loss of dopaminergic neurons is one of the characteristic features of Parkinson's disease (PD). However, it is still debated if right or left asymmetry differently affects cognitive and motor progression. OBJECTIVES: The objective of this study was to investigate, for the first time, the relevance of dopamine transporter (DAT) asymmetry on cognitive and motor manifestations at onset and at 4-year progression in drug-naïve PD. METHODS: From the Parkinson's Progression Markers Initiative multicenter cohort, we identified 249 right-handed patients with PD with baseline asymmetry greater than 20% in putamen DAT binding at single-photon emission computed tomography. A predominant putamen asymmetry was found on the left in 143 patients (PD-left), and on the right side in 106 patients (PD-right); we compared them with 196 healthy controls. Patients were followed longitudinally (2-year and 4-year visits), examining their clinical, cognitive, and imaging data. RESULTS: At baseline, the PD-left group showed worse performance on the Symbol Digit Modality Test, an attention and processing-speed test, and lower cerebrospinal fluid ß-amyloid levels than the PD-right group. These differences were maintained at follow-up, declining over time in both groups. By contrast, the PD-right group showed greater motor impairment at baseline, which increased over 4 years. Striatal DAT binding decreased over time in both groups, but the PD-right group showed a steeper decline, particularly during the first 2-year follow-up. Putaminal asymmetry assessed at baseline was maintained over time. CONCLUSIONS: These findings suggest that hemispheric asymmetric dopaminergic denervation influences PD cognitive and motor performance as well as progression. Predominant right hemisphere nigrostriatal dopaminergic loss is associated with greater motor severity, whereas more pronounced left hemisphere denervation affects cognitive manifestations at onset and their progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A New MRI Measure to Early Differentiate Progressive Supranuclear Palsy From De Novo Parkinson's Disease in Clinical Practice: An International Study.

BACKGROUND: Enlargement of the third ventricle has been reported in atypical parkinsonism. We investigated whether the measurement of third ventricle width could distinguish Parkinson's disease (PD) from progressive supranuclear palsy (PSP). METHODS: We assessed a new MR T1-weighted measurement (third ventricle width/internal skull diameter) in a training cohort of 268 participants (98 PD, 73 PSP, 98 controls from our center) and in a testing cohort of 291 participants (82 de novo PD patients and 133 controls from the Parkinson's Progression Markers Initiative, 76 early-stage PSP from an international research group). PD diagnosis was confirmed after a 4-year follow-up. Diagnostic performance of the third ventricle/internal skull diameter was assessed using receiver operating characteristic curve with bootstrapping; the area under the curve of the training cohort was compared with the area under the curve of the testing cohort using the De Long test. RESULTS: In both cohorts, third ventricle/internal skull diameter values did not differ between PD and controls but were significantly lower in PD than in PSP patients (P < 0.0001). In PD, third ventricle/internal skull diameter values did not change significantly between baseline and follow-up evaluation. Receiver operating characteristic analysis accurately differentiated PD from PSP in the training cohort (area under the curve, 0.94; 95% CI, 91.1-97.6; cutoff, 5.72) and in the testing cohort (area under the curve, 0.91; 95% CI, 87.0-97.0; cutoff,: 5.88), validating the generalizability of the results. CONCLUSION: Our study provides a new reliable and validated MRI measurement for the early differentiation of PD and PSP. The simplicity and generalizability of this biomarker make it suitable for routine clinical practice and for selection of patients in clinical trials worldwide. © 2020 International Parkinson and Movement Disorder Society.

Automated MRI Classification in Progressive Supranuclear Palsy: A Large International Cohort Study.

BACKGROUND: The Magnetic Resonance Parkinsonism Index is listed as one of the most reliable imaging morphometric markers for diagnosis of progressive supranuclear palsy (PSP). However, the use of this index in diagnostic workup has been limited until now by the low generalizability of published results because of small monocentric patient cohorts, the lack of data validation in independent patient series, and manual measurements used for index calculation. The objectives of this study were to investigate the generalizability of Magnetic Resonance Parkinsonism Index performance validating previously established cutoff values in a large international cohort of PSP patients subclassified into PSP-Richardson's syndrome and PSP-parkinsonism and to standardize the use of the automated Magnetic Resonance Parkinsonism Index by providing a web-based platform to obtain homogenous measures around the world. METHODS: In a retrospective international multicenter study, a total of 173 PSP patients and 483 non-PSP participants were enrolled. A web-based platform (https://mrpi.unicz.it) was used to calculate automated Magnetic Resonance Parkinsonism Index values. RESULTS: Magnetic Resonance Parkinsonism Index values showed optimal performance in differentiating PSP-Richardson's syndrome and PSP-parkinsonism patients from non-PSP participants (93.6% and 86.5% of accuracy, respectively). The Magnetic Resonance Parkinsonism Index was also able to differentiate PSP-Richardson's syndrome and PSP-parkinsonism patients in an early stage of the disease from non-PSP participants (90.1% and 85.9%, respectively). The web-based platform provided the automated Magnetic Resonance Parkinsonism Index calculation in 94% of cases. CONCLUSIONS: Our study provides the first evidence on the generalizability of automated Magnetic Resonance Parkinsonism Index measures in a large international cohort of PSP-Richardson's syndrome and PSP-parkinsonism patients. The web-based platform enables widespread applicability of the automated Magnetic Resonance Parkinsonism Index to different clinical and research settings. © 2020 International Parkinson and Movement Disorder Society.

Differences in cognitive profiles between Lewy body and Parkinson's disease dementia.

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) not only differ for the time of onset of cognitive deficits but also present variability in affected functions which are relevant in understanding underlying pathology. Cognitive performance of two global cognitive screening scales, the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), as well as of a neuropsychological test battery, was evaluated in 18 DLB and 21 PDD patients. Feasibility for each cognitive test was investigated. Both MMSE and MoCA are feasible assessments in PDD and DLB patients. MoCA was more sensitive in discriminating groups as higher number of DLB patients showed pathological performances on the Digit Span Forward subitem (p = 0.049). The Stroop test in PDD and the Trail Making Tests-A and B, and the Benton's judgment of line orientation tests in both groups were considered not feasible. Among feasible cognitive tests in at least one group, Rey-Osterrieth complex figure test copy (p = 0.013) and semantic fluency (p = 0.038) are sensitive in discriminating DLB from PDD cognitive profile. Trail Making Tests-A and B, the Benton's judgment of line orientation and the Stroop tests are not feasible for assessing patients with frank dementia. Longitudinal studies should not include those tasks to reduce the risk of missing data once disease progresses and dementia develops. DLB patients present more severe and widespread cognitive dysfunction than PDD, particularly in attentive, visuospatial, and language domains.

Dynamic functional connectivity changes associated with dementia in Parkinson's disease.

Dynamic functional connectivity captures temporal variations of functional connectivity during MRI acquisition and it may be a suitable method to detect cognitive changes in Parkinson's disease. In this study, we evaluated 118 patients with Parkinson's disease matched for age, sex and education with 35 healthy control subjects. Patients with Parkinson's disease were classified with normal cognition (n = 52), mild cognitive impairment (n = 46), and dementia (n = 20) based on an extensive neuropsychological evaluation. Resting state functional MRI and a sliding-window approach were used to study the dynamic functional connectivity. Dynamic analysis suggested two distinct connectivity 'States' across the entire group: a more frequent, segregated brain state characterized by the predominance of within-network connections, State I, and a less frequent, integrated state with strongly connected functional internetwork components, State II. In Parkinson's disease, State I occurred 13.89% more often than in healthy control subjects, paralleled by a proportional reduction of State II. Parkinson's disease subgroups analyses showed the segregated state occurred more frequently in Parkinson's disease dementia than in mild cognitive impairment and normal cognition groups. Further, patients with Parkinson's disease dementia dwelled significantly longer in the segregated State I, and showed a significant lower number of transitions to the strongly interconnected State II compared to the other subgroups. Our study indicates that dementia in Parkinson's disease is characterized by altered temporal properties in dynamic connectivity. In addition, our results show that increased dwell time in the segregated state and reduced number of transitions between states are associated with presence of dementia in Parkinson's disease. Further studies on dynamic functional connectivity changes could help to better understand the progressive dysfunction of networks between Parkinson's disease cognitive states.

Characteristics and progression of cognitive deficits in progressive supranuclear palsy vs. multiple system atrophy and Parkinson's disease.

Cognitive impairment is frequent in progressive supranuclear palsy (PSP) and less common in multiple system atrophy (MSA), but characteristics and progression compared with Parkinson's disease (PD) need to be properly defined. We evaluated 35 PSP with Richardson's syndrome (PSP-RS), 30 MSA as well as 65 age-, sex-, and education-matched PD with an extensive clinical and neuropsychological assessment, allowing Level II cognitive diagnosis. Eighteen PSP, 12 MSA and 30 PD had a second evaluation between 12 and 18 months (mean 15 months) after the first assessment. PSP performance at Montreal Cognitive Assessment (MoCA), verbal fluencies (phonemic and semantic tasks), Stroop test (Error and Time), Digit Span Sequencing (DSS), incomplete letters of Visual Object and Space Perception (VOSP) and Benton's Judgment of Line Orientation (JLO) performance were significantly poorer at baseline compared to PD and MSA. Executive, language and visuospatial abilities declined longitudinally in PSP, but not in PD and MSA. After 1.5 year, 16% of PSP converted to dementia. Our study provides evidence that cognitive progression is more severe and rapid in PSP-RS than PD and MSA. Further, we observed that MoCA, verbal fluency (particularly semantic), DSS and Benton's JLO are valuable tests to detect cognitive progression in PSP-RS and may be proposed as possible biomarker to assess efficacy of disease modification strategies.

Brain structural profile of multiple system atrophy patients with cognitive impairment.

Current consensus diagnostic criteria for multiple system atrophy (MSA) consider dementia a non-supporting feature, although cognitive impairment and even frank dementia are reported in clinical practice. Mini-Mental State Examination (MMSE) is a commonly used global cognitive scale, and in a previous study, we established an MSA-specific screening cut-off score <27 to identify cognitive impairment. Finally, MSA neuroimaging findings suggest the presence of structural alterations in patients with cognitive deficits, although the extent of the anatomical changes is unclear. The aim of our multicenter study is to better characterize anatomical changes associated with cognitive impairment in MSA and to further investigate cortical and subcortical structural differences versus healthy controls (HC). We examined retrospectively 72 probable MSA patients [50 with normal cognition (MSA-NC) and 22 cognitively impaired (MSA-CI) based on MMSE <27] and compared them to 36 HC using gray- and white-matter voxel-based morphometry and fully automated subcortical segmentation. Compared to HC, MSA patients showed widespread cortical (bilateral frontal, occipito-temporal, and parietal areas), subcortical, and white-matter alterations. However, MSA-CI showed only focal volume reduction in the left dorsolateral prefrontal cortex compared with MSA-NC. These results suggest only a marginal contribution of cortical pathology to cognitive deficits. We believe that cognitive dysfunction is driven by focal fronto-striatal degeneration in line with the concept of "subcortical cognitive impairment".

Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) performance in progressive supranuclear palsy and multiple system atrophy.

To determine if Montreal Cognitive Assessment (MoCA) is more sensitive than the commonly used Mini-Mental State Examination (MMSE) in detecting cognitive abnormalities in patients with probable progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) compared with Parkinson's disease (PD). In this multicenter observational study, MMSE and MoCA were administered in a random order to 130 patients: 35 MSA, 30 PSP and 65 age, and education and gender matched-PD. We assessed between-group differences for MMSE, MoCA, and their subitems. Receiver-operating characteristic (ROC) curves were calculated. The mean MMSE was higher than the mean MoCA score in each MSA (27.7 ± 2.4 vs. 22.9 ± 3.0, p < 0.0001), PSP (26.0 ± 2.9 vs. 18.2 ± 3.9, p < 0.0001), and PD (27.3 ± 2.0 vs. 22.3 ± 3.5, p < 0.0001). MoCA total score as well as its letter fluency subitem differentiated PSP from MSA and PD with high specificity and moderate sensitivity. More specifically, a cut-off score of 7 F-words or less per minute would support a diagnosis of PSP (PSP vs. PD: 86 % specificity, 70 % sensitivity; PSP vs. MSA: 71 % specificity, 70 % sensitivity). By contrast, MMSE presented an overall ceiling effect for most subitems, except for the pentagon scores, where PSP did less well than MSA or PD patients. These preliminary results suggest that PSP and MSA, similar to PD patients, may present normal MMSE and reduced MoCA performance. Overall, MoCA is more sensitive than MMSE in detecting cognitive impairment in atypical parkinsonism and together with verbal fluency would be a useful test to support PSP diagnosis.

Do Old Errors Always Lead to New Truths? A Randomized Controlled Trial of Errorless Goal Management Training in Brain-Injured Patients.

Both errorless learning (EL) and Goal Management Training (GMT) have been shown effective cognitive rehabilitation methods aimed at optimizing the performance on everyday skills after brain injury. We examine whether a combination of EL and GMT is superior to traditional GMT for training complex daily tasks in brain-injured patients with executive dysfunction. This was an assessor-blinded randomized controlled trial conducted in 67 patients with executive impairments due to brain injury of non-progressive nature (minimal post-onset time: 3 months), referred for outpatient rehabilitation. Individually selected everyday tasks were trained using 8 sessions of an experimental combination of EL and GMT or via conventional GMT, which follows a trial-and-error approach. Primary outcome measure was everyday task performance assessed after treatment compared to baseline. Goal attainment scaling, rated by both trainers and patients, was used as secondary outcome measure. EL-GMT improved everyday task performance significantly more than conventional GMT (adjusted difference 15.43, 95% confidence interval [CI] [4.52, 26.35]; Cohen's d=0.74). Goal attainment, as scored by the trainers, was significantly higher after EL-GMT compared to conventional GMT (mean difference 7.34, 95% CI [2.99, 11.68]; Cohen's d=0.87). The patients' goal attainment scores did not differ between the two treatment arms (mean difference 3.51, 95% CI [-1.41, 8.44]). Our study is the first to show that preventing the occurrence of errors during executive strategy training enhances the acquisition of everyday activities. A combined EL-GMT intervention is a valuable contribution to cognitive rehabilitation in clinical practice.

Gender differences in the effects of emotion induction on intertemporal decision-making.

'Good things come to those who wait' is a popular saying, which goes along with numerous daily life decisions requiring trade-offs between immediate-small and later-larger rewards; however, some individuals have a tendency to prefer sooner rewards while discounting the value of delayed rewards, known as delay discounting. The extant literature indicates that emotions and gender can modulate intertemporal choices, but their interplay remains hitherto poorly investigated. Here, 308 participants were randomized to different conditions, inducing distinct emotions-fear, joy, a neutral state-through standardized movie clips, and then completed a computerized delay discounting task for hypothetical money rewards. Following the induction of fear, women discount the future steeper than men, thus preferring immediate-smaller rewards rather than larger-delayed ones. Also, women were more prone to choose immediate rewards when in a fearful condition than when in a positive state of joy/happiness. By contrast, men were unaffected by their emotional state when deciding on monetary rewards. Our findings provide evidence that fear can trigger different intertemporal choices according to gender, possibly reflecting the adoption of different evolutionary strategies.

Attitudes Toward the Adoption of Remote Patient Monitoring and Artificial Intelligence in Parkinson's Disease Management: Perspectives of Patients and Neurologists.

OBJECTIVE: Early detection of Parkinson's Disease (PD) progression remains a challenge. As remote patient monitoring solutions (RMS) and artificial intelligence (AI) technologies emerge as potential aids for PD management, there's a gap in understanding how end users view these technologies. This research explores patient and neurologist perspectives on AI-assisted RMS. METHODS: Qualitative interviews and focus-groups were conducted with 27 persons with PD (PwPD) and six neurologists from Finland and Italy. The discussions covered traditional disease progression detection and the prospects of integrating AI and RMS. Sessions were recorded, transcribed, and underwent thematic analysis. RESULTS: The study involved five individual interviews (four Italian participants and one Finnish) and six focus-groups (four Finnish and two Italian) with PwPD. Additionally, six neurologists (three from each country) were interviewed. Both cohorts voiced frustration with current monitoring methods due to their limited real-time detection capabilities. However, there was enthusiasm for AI-assisted RMS, contingent upon its value addition, user-friendliness, and preservation of the doctor-patient bond. While some PwPD had privacy and trust concerns, the anticipated advantages in symptom regulation seemed to outweigh these apprehensions. DISCUSSION: The study reveals a willingness among PwPD and neurologists to integrate RMS and AI into PD management. Widespread adoption requires these technologies to provide tangible clinical benefits, remain user-friendly, and uphold trust within the physician-patient relationship. CONCLUSION: This study offers insights into the potential drivers and barriers for adopting AI-assisted RMS in PD care. Recognizing these factors is pivotal for the successful integration of these digital health tools in PD management.

The pharmacological management of the behavioral aspects of Parkinson's disease: an update.

INTRODUCTION: Behavioural symptoms are common manifestations of Parkinson's disease and include depression, anxiety, impulse control disorders, hallucinations, psychosis, and cognitive dysfunction. They remain inadequately addressed in many patients despite their relevance for quality of life and disability. This applies also to impulse control disorders where the most common approach in recent literature is to refrain from using dopamine agonists without consideration about their potential benefit on motor complications. AREAS COVERED: We conducted a narrative review searching for articles on behavioral symptoms in Parkinson disease and selected those which included involved neurotransmitters such as dopamine, noradrenaline, serotonin, acetylcholine. We specifically focused our search on open-label and randomized double-blind studies and biomarkers which could best characterize these clinical manifestations. EXPERT OPINION: Management of Parkinson disease behavioural manifestations lacks clear guidelines and standardized protocols beside general suggestions of dose adjustments in dopamine replacement therapy and use of antidepressants or antipsychotic drugs with little consideration of patients' age, sex, comorbidities, and motor status. We suggest a pragmatic approach which includes education of affected patients and caring people, dealing with complex cases by experienced multidisciplinary teams, use of cognitive behavioural therapy, and psychological counselling to complement drug treatment.

The effectiveness of an immersive virtual reality and telemedicine-based cognitive intervention on prospective memory in Parkinson's disease patients with mild cognitive impairment and healthy aged individuals: design and preliminary baseline results of a placebo-controlled study.

Introduction: Prospective memory (PM) impairments have been extensively documented in individuals with Parkinson's disease associated with mild cognitive impairment (PD-MCI) and in those with healthy aging. Considering how PM failure decreases individuals' quality of life and functional independence in the activities of daily living, training to enhance this ability could be a prior target of intervention. Objective: Here, we aimed to present the study protocol and preliminary results of a novel immersive virtual reality (IVR) and telemedicine-based (TM) cognitive intervention focused on executive abilities (i.e., planning, shifting, and updating) to improve PM functioning in PD-MCI patients and healthy elderly individuals. Methods: Outcome measures, collected before, immediately after and 2 months after the intervention, included: (1) pre-post training changes in objective cognitive functioning, evaluated with tests assessing executive functions and PM; (2) pre-post training changes in subjective perception of memory functioning, psychiatric symptoms, autonomy in daily living and quality of life, evaluated using the appropriate scales; (3) usability, feasibility and users' compliance with the proposed IVR and telemedicine program. The efficacy of this intervention compared to an active control condition is currently being evaluated in a randomized, double-blind controlled trial, which will be conducted on 30 eligible PD-MCI patients and 30 older adults. Results: Preliminary results concerning between-group comparisons of demographic and neuropsychological screening data show a good balance among the intervention groups considered in this study. The results also suggest good levels of usability, feasibility and acceptability, thus supporting the notion that our intervention can be used to promote cognitive functioning, even in people with cognitive decline. Conclusion: Considering the relatively low costs and easy accessibility to this program, it could prove valuable in primary prevention initiatives and early cognitive rehabilitation for dementia risk reduction.

Biomarkers of aging in frailty and age-associated disorders: State of the art and future perspective.

According to the Geroscience concept that organismal aging and age-associated diseases share the same basic molecular mechanisms, the identification of biomarkers of age that can efficiently classify people as biologically older (or younger) than their chronological (i.e. calendar) age is becoming of paramount importance. These people will be in fact at higher (or lower) risk for many different age-associated diseases, including cardiovascular diseases, neurodegeneration, cancer, etc. In turn, patients suffering from these diseases are biologically older than healthy age-matched individuals. Many biomarkers that correlate with age have been described so far. The aim of the present review is to discuss the usefulness of some of these biomarkers (especially soluble, circulating ones) in order to identify frail patients, possibly before the appearance of clinical symptoms, as well as patients at risk for age-associated diseases. An overview of selected biomarkers will be discussed in this regard, in particular we will focus on biomarkers related to metabolic stress response, inflammation, and cell death (in particular in neurodegeneration), all phenomena connected to inflammaging (chronic, low-grade, age-associated inflammation). In the second part of the review, next-generation markers such as extracellular vesicles and their cargos, epigenetic markers and gut microbiota composition, will be discussed. Since recent progresses in omics techniques have allowed an exponential increase in the production of laboratory data also in the field of biomarkers of age, making it difficult to extract biological meaning from the huge mass of available data, Artificial Intelligence (AI) approaches will be discussed as an increasingly important strategy for extracting knowledge from raw data and providing practitioners with actionable information to treat patients.