Subjective Cognitive Complaints in Parkinson's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Subjective cognitive complaints (SCCs) in Parkinson's disease (PD) are reported frequently, but their prevalence and association with changes on objective testing are not fully known. OBJECTIVE: We aimed to determine the prevalence, clinical correlates, and predictive value of SCCs in PD. METHODS: We conducted a systematic review and meta-analysis. From 204 abstracts, we selected 31 studies (n = 3441 patients), and from these, identified the prevalence, clinical features, associations with neuropsychiatric symptoms, and predictive values of SCCs in PD. RESULTS: The meta-analysis showed an SCC prevalence of 36%. This prevalence, however, was significantly moderated by study heterogeneity regarding female sex, disease severity, levodopa equivalent daily dosage, exclusion from the overall sample of patients with objective cognitive impairment, and measurement instrument. SCC prevalence did not differ between de novo and treated PD patients. SCCs were weakly and negligibly associated with cognitive changes on objective testing in cross-sectional studies. However, in cognitively healthy patients, SCCs had a risk ratio of 2.71 for later cognitive decline over a mean follow-up of 3.16 years. Moreover, SCCs were moderately related to co-occurring symptoms of depression, anxiety, or apathy and were more strongly related to these neuropsychiatric symptoms than objective cognitive functioning. CONCLUSION: Our analyses suggest that SCCs in patients with and without objective cognitive impairment are frequent, occurring in more than one third of PD patients. Establishing uniform measurement instruments for identifying PD-related SCCs is critical to understand their implications. Even in cases lacking evidence of objective cognitive impairment and where SCCs might reflect underlying neuropsychiatric symptoms, the possibility of later cognitive deterioration should not be excluded. Therefore, SCCs in PD patients warrant close monitoring for opportunities for targeted and effective interventions. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Altered domain-specific striatal functional connectivity in patients with Parkinson's disease and urinary symptoms.

BACKGROUND: In this study, we aimed at investigating the possible association of urinary symptoms with whole-brain MRI resting-state functional connectivity (FC) alterations from distinct striatal subregions in a large cohort of early PD patients. METHODS: Seventy-nine drug-naive PD patients (45 PD-urinary+/34 PD-urinary-) and 38 healthy controls (HCs) were consecutively enrolled. Presence/absence of urinary symptoms were assessed by means of the Nonmotor Symptom Scale - domain 7. Using an a priori connectivity-based domain-specific parcellation, we defined three ROIs (per each hemisphere) for different striatal functional subregions (sensorimotor, limbic and cognitive) from which seed-based FC voxel-wise analyses were conducted over the whole brain. RESULTS: Compared to PD-urinary-, PD-urinary+ patients showed increased FC between striatal regions and motor and premotor/supplementary motor areas as well as insula/anterior dorsolateral PFC. Compared to HC, PD-urinary+ patients presented decreased FC between striatal regions and parietal, insular and cingulate cortices. CONCLUSIONS: Our findings revealed a specific pattern of striatal FC alteration in PD patients with urinary symptoms, potentially associated to altered stimuli perception and sensorimotor integration even in the early stages. These results may potentially help clinicians to design more effective and tailored rehabilitation and neuromodulation protocols for PD patients.

Phosphorylated α-synuclein in skin Schwann cells: a new biomarker for multiple system atrophy.

Multiple system atrophy (MSA) is characterized by accumulation of phosphorylated α-synuclein (p-syn) as glial cytoplasmic inclusions in the brain and a specific biomarker for this disorder is urgently needed. We aimed at investigating if p-syn can also be detected in skin Remak non-myelinating Schwann cells (RSCs) as Schwann cell cytoplasmic inclusions (SCCi) and may represent a reliable clinical biomarker for MSA. This cross-sectional diagnostic study evaluated skin p-syn in 96 patients: 46 with probable MSA (29 with parkinsonism type MSA and 17 with cerebellar type MSA), 34 with Parkinson's disease (PD) and 16 with dementia with Lewy bodies (DLB). We also included 50 healthy control subjects. Patients were recruited from five different medical centres. P-syn aggregates in skin sections were stained by immunofluorescence, followed by analyses with confocal microscopy and immuno-electron microscopy. All analyses were performed in a blinded fashion. Overall, p-syn aggregates were found in 78% of MSA patients and 100% of patients with PD/DLB, whereas they could not be detected in controls. As for neuronal aggregates 78% of MSA patients were positive for p-syn in somatic neurons, whereas all PD/DLB patients were positive in autonomic neurons. When analysing the presence of p-syn in RSCs, 74% of MSA patients were positive, whereas no such SCCi could be observed in PD/DLB patients. Analyses by immuno-electron microscopy confirmed that SCCi were only found in cases with MSA and thus absent in those with PD/DLB. In conclusion, our findings demonstrate that (i) fibrillar p-syn in RSCs is a pathological hallmark of MSA and may be used as a specific and sensitive disease biomarker; (ii) in Lewy body synucleinopathies (PD/DLB) only neurons contain p-syn deposits; and (iii) the cell-specific deposition of p-syn in the skin thus mirrors that of the brain in many aspects and suggests that non-myelinated glial cells are also involved in the MSA pathogenesis.

Real-world use of Safinamide in motor fluctuating Parkinson's disease patients in Italy.

INTRODUCTION: Safinamide is a recent antiparkinsonian drug that modulates both dopaminergic and glutamatergic systems with positive effects on motor and nonmotor symptoms of Parkinson's disease (PD). Here, we aimed to describe the efficacy and safety of safinamide in the Italian PD patients in real-life conditions. METHODS: We performed a sub-analysis of the Italian cohort of the SYNAPSES study, a multi-country, multi-center, retrospective-prospective cohort observational study, designed to investigate the use of safinamide in routine clinical practice. Patients received for the first time a treatment with safinamide and were followed up for 12 months. The analysis was conducted on the overall population and in subgroups of interest: i) patients > 75 years, ii) patients with relevant comorbidities and iii) patients affected by psychiatric symptoms. RESULTS: Italy enrolled 616/1610 patients in 52 centers, accounting for 38% of the entire SYNAPSES cohort. Of the patients enrolled, 86.0% were evaluable at 12 months, with 23.3% being > 75 years, 42.4% with psychiatric conditions and 67.7% with relevant comorbidities. Safinamide was effective on motor symptoms and fluctuations as measured through the Unified PD rating scale III and IV scores, and on the total score, without safety issues in none of the subgroups considered. CONCLUSION: The SYNAPSES data related to Italian patients confirms the good safety profile of safinamide even in special groups of patients. Motor fluctuations and motor impairment improved at the follow-up suggesting the significant role of safinamide in managing motor symptoms in PD patients.

Fading of brain network fingerprint in Parkinson's disease predicts motor clinical impairment.

The clinical connectome fingerprint (CCF) was recently introduced as a way to assess brain dynamics. It is an approach able to recognize individuals, based on the brain network. It showed its applicability providing network features used to predict the cognitive decline in preclinical Alzheimer's disease. In this article, we explore the performance of CCF in 47 Parkinson's disease (PD) patients and 47 healthy controls, under the hypothesis that patients would show reduced identifiability as compared to controls, and that such reduction could be used to predict motor impairment. We used source-reconstructed magnetoencephalography signals to build two functional connectomes for 47 patients with PD and 47 healthy controls. Then, exploiting the two connectomes per individual, we investigated the identifiability characteristics of each subject in each group. We observed reduced identifiability in patients compared to healthy individuals in the beta band. Furthermore, we found that the reduction in identifiability was proportional to the motor impairment, assessed through the Unified Parkinson's Disease Rating Scale, and, interestingly, able to predict it (at the subject level), through a cross-validated regression model. Along with previous evidence, this article shows that CCF captures disrupted dynamics in neurodegenerative diseases and is particularly effective in predicting motor clinical impairment in PD.

Memory Phenotypes In Early, De Novo Parkinson's Disease Patients with Mild Cognitive Impairment.

BACKGROUND: Memory deficits in mild cognitive impairment related to Parkinson's disease (PD-MCI) are quite heterogeneous, and there is no general agreement on their genesis. OBJECTIVES: To define memory phenotypes in de novo PD-MCI and their associations with motor and non-motor features and patients' quality of life. METHODS: From a sample of 183 early de novo patients with PD, cluster analysis was applied to neuropsychological measures of memory function of 82 patients with PD-MCI (44.8%). The remaining patients free of cognitive impairment were considered as a comparison group (n = 101). Cognitive measures and structural magnetic resonance imaging-based neural correlates of memory function were used to substantiate the results. RESULTS: A three-cluster model produced the best solution. Cluster A (65.85%) included memory unimpaired patients; Cluster B (23.17%) included patients with mild episodic memory disorder related to a "prefrontal executive-dependent phenotype"; Cluster C (10.97%) included patients with severe episodic memory disorder related to a "hybrid phenotype," where hippocampal-dependent deficits co-occurred with prefrontal executive-dependent memory dysfunctions. Cognitive and brain structural imaging correlates substantiated the findings. The three phenotypes did not differ in terms of motor and non-motor features, but the attention/executive deficits progressively increased from Cluster A, through Cluster B, to Cluster C. This last cluster had worse quality of life compared to others. CONCLUSIONS: Our results demonstrated the memory heterogeneity of de novo PD-MCI, suggesting existence of three distinct memory-related phenotypes. Identification of such phenotypes can be fruitful in understanding the pathophysiological mechanisms underlying PD-MCI and its subtypes and in guiding appropriate treatments. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Resting-state network connectivity changes in drug-naive Parkinson's disease patients with probable REM sleep behavior disorder.

Epidemiological studies have shown that Parkinson's disease (PD) patients with probable REM sleep behavior disorder (pRBD) present an increased risk of worse cognitive progression over the disease course. The aim of this study was to investigate, using resting-state functional MRI (RS-fMRI), the functional connectivity (FC) changes associated with the presence of pRBD in a cohort of newly diagnosed, drug-naive and cognitively unimpaired PD patients compared to healthy controls (HC). Fifty-six drug-naïve patients (25 PD-pRBD+ and 31 PD-pRBD-) and 23 HC underwent both RS-fMRI and clinical assessment. Single-subject and group-level independent component analysis was used to analyze intra- and inter-network FC differences within the major large-scale neurocognitive networks, namely the default mode (DMN), frontoparietal (FPN), salience (SN) and executive-control (ECN) networks. Widespread FC changes were found within the most relevant neurocognitive networks in PD patients compared to HC. Moreover, PD-pRBD+ patients showed abnormal intrinsic FC within the DMN, ECN and SN compared to PD-pRBD-. Finally, PD-pRBD+ patients showed functional decoupling between left and right FPN. In the present study, we revealed that FC changes within the most relevant neurocognitive networks are already detectable in early drug-naïve PD patients, even in the absence of clinical overt cognitive impairment. These changes are even more evident in PD patients with RBD, potentially leading to profound impairment in cognitive processing and cognitive/behavioral integration, as well as to fronto-striatal maladaptive compensatory mechanisms.

Emerging drugs for the preventive treatment of migraine: a review of CGRP monoclonal antibodies and gepants trials.

INTRODUCTION: Migraine is a leading cause of years lived with disability and preventive strategies represent a mainstay to reduce health-related disability and improve quality of life of migraine patients. Until a few years ago, migraine prevention was based on drugs developed for other clinical indications and relocated in the migraine therapeutic armamentarium, characterized by unfavorable tolerability profiles. The advent of monoclonal antibodies against Calcitonin Gene-Related Peptide (CGRP) and gepants, CGRP receptor antagonists, has been a turning point in migraine prevention owing to advantageous efficacy, safety and tolerability profiles.Nevertheless, while in an ideal scenario a drug characterized by significant greater efficacy and tolerability compared to existing therapeutic strategies should be adopted as a first-line treatment, cost-effectiveness analyses available for monoclonal antibodies against CGRP pathway tend to limit their administration to more severe migraine phenotypes. AREAS COVERED: The present narrative review aims to provide a critical appraisal of phase II and III CGRP-mAbs and gepants trials to analyze their use in clinical practice. EXPERT OPINION: Despite monoclonal antibodies against CGRP pathway and gepants can be undoubtedly considered top-of-the-range treatments, there are still issues deserving to be addressed in the coming years as the risk of off-target effects as well as their economic sustainability based on the considerable migraine burden.

Infodemiology of cluster headache seasonality: A proof of concept by a Google Trends analysis.

BACKGROUND: Cluster headache is commonly reported to follow an annual pattern with a peak in the spring and a second peak in autumn. Patients with headache frequently use search engines, such as Google, to look for terms related to their disease, creating trend data that can be analyzed with Google Trends. Indeed, Google Trends has been used for surveillance studies and can provide indirect estimates of the burden of diseases and symptoms. The present cross-sectional study investigated the seasonality of searches for "cluster headache" in the northern and southern hemispheres using 10 years of Google Trends data. METHODS: The term "cluster headache" or its translation in the 10 most spoken languages in the world was searched on Google Trends to obtain relative search volumes (from 0 to 100), in order to compare variations in searches across periods. Twenty-eight countries were selected according to the following criteria: (1) a relative search volume of >40 for the term for cluster headache; and (2) a population of at least 5 million inhabitants. For statistical purposes, countries were grouped in relation to hemisphere (northern or southern). Relative search volumes were extracted from January 2012 to January 2022 and analyzed according to two subgroups based on meteorological seasons (summer and winter vs. spring and autumn). RESULTS: A seasonal trend for in searches for cluster headache was found worldwide exhibiting higher relative search volumes in spring and autumn compared with summer and winter (17 [0, 39] vs. 13 [0, 37]; p = 0.016). CONCLUSION: Higher search volumes for the term during the meteorological seasons of spring and autumn clearly reflect a circannual pattern of cluster headache occurrence, representing new evidence for its seasonality.

Olfactory Loss and Brain Connectivity after COVID-19: Structural Follow-Up at One Year.

The structural connectivity from the primary olfactory cortex to the main secondary olfactory areas was previously reported as relatively increased in the medial orbitofrontal cortex in a cohort of 27 recently SARS-CoV-2-infected (COV+) subjects, of which 23/27 had clinically confirmed olfactory loss, compared to 18 control (COV-) normosmic subjects, who were not previously infected. To complement this finding, here we report the outcome of an identical high angular resolution diffusion MRI analysis on follow-up data sets collected in 18/27 COV+ subjects (10 males, mean age ± SD: 38.7 ± 8.1 years) and 10/18 COV- subjects (5 males, mean age ± SD: 33.1 ± 3.6 years) from the previous samples who repeated both the olfactory functional assessment and the MRI examination after ~1 year. By comparing the newly derived subgroups, we observed that the increase in the structural connectivity index of the medial orbitofrontal cortex was not significant at follow-up, despite 10/18 COV+ subjects were still found hyposmic after ~1 year from SARS-CoV-2 infection. We concluded that the relative hyperconnectivity of the olfactory cortex to the medial orbitofrontal cortex could be, at least in some cases, an acute or reversible phenomenon linked to the recent SARS-CoV-2 infection with associated olfactory loss.

Migraine Treatment: Towards New Pharmacological Targets.

Migraine is a debilitating neurological condition affecting millions of people worldwide. Until a few years ago, preventive migraine treatments were based on molecules with pleiotropic targets, developed for other indications, and discovered by serendipity to be effective in migraine prevention, although often burdened by tolerability issues leading to low adherence. However, the progresses in unravelling the migraine pathophysiology allowed identifying novel putative targets as calcitonin gene-related peptide (CGRP). Nevertheless, despite the revolution brought by CGRP monoclonal antibodies and gepants, a significant percentage of patients still remains burdened by an unsatisfactory response, suggesting that other pathways may play a critical role, with an extent of involvement varying among different migraine patients. Specifically, neuropeptides of the CGRP family, such as adrenomedullin and amylin; molecules of the secretin family, such as pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP); receptors, such as transient receptor potential (TRP) channels; intracellular downstream determinants, such as potassium channels, but also the opioid system and the purinergic pathway, have been suggested to be involved in migraine pathophysiology. The present review provides an overview of these pathways, highlighting, based on preclinical and clinical evidence, as well as provocative studies, their potential role as future targets for migraine preventive treatment.

Arterial spin labeling MRI applied to migraine: current insights and future perspectives.

INTRODUCTION: Advanced neuroimaging techniques have extensively contributed to elucidate the complex mechanisms underpinning the pathophysiology of migraine, a neurovascular disorder characterized by episodes of headache associated with a constellation of non-pain symptoms. The present manuscript, summarizing the most recent progresses of the arterial spin labelling (ASL) MRI techniques and the most significant findings from ASL studies conducted in migraine, is aimed to clarify how ASL investigations are contributing to the evolving insight on migraine pathophysiology and their putative role in migraine clinical setting. ASL techniques, allowing to quantitatively demonstrate changes in cerebral blood flow (CBF) both during the attacks and in the course of interictal period, could represent the melting point between advanced neuroimaging investigations, conducted with pure scientific purposes, and conventional neuroimaging approaches, employed in the diagnostic decision-making processes. MAIN BODY: Converging ASL evidences have demonstrated that abnormal CBF, exceeding the boundaries of a single vascular territory, with biphasic trend dominated by an initial hypoperfusion (during the aura phenomenon but also in the first part of the headache phase) followed by hyperperfusion, characterizes migraine with aura attack and can represent a valuable clinical tool in the differential diagnosis from acute ischemic strokes and epileptic seizures. Studies conducted during migraine without aura attacks are converging to highlight the involvement of dorsolateral pons and hypothalamus in migraine pathophysiology, albeit not able to disentangle their role as "migraine generators" from mere attack epiphenomenon. Furthermore, ASL findings tend to support the presence of perfusion abnormalities in brain regions known to be involved in aura ignition and propagation as well as in areas involved in multisensory processing, in both patients with migraine with aura and migraine without aura. CONCLUSION: Although ASL studies have dramatically clarified quality and timing of perfusion abnormalities during migraine with aura attacks, the same cannot be said for perfusion changes during migraine attacks without aura and interictal periods. Future studies with more rigorous methodological approaches in terms of study protocol, ASL technique and sample selection and size are mandatory to exploit the possibility of better understanding migraine pathophysiology and identifying neuroimaging biomarkers of each migraine phase in different migraine phenotypes.

Olfactory loss and brain connectivity after COVID-19.

To address the impact of COVID-19 olfactory loss on the brain, we analyzed the neural connectivity of the central olfactory system in recently SARS-CoV-2 infected subjects with persisting olfactory impairment (hyposmia). Twenty-seven previously SARS-CoV-2 infected subjects (10 males, mean age ± SD 40.0 ± 7.6 years) with clinically confirmed COVID-19 related hyposmia, and eighteen healthy, never SARS-CoV-2 infected, normosmic subjects (6 males, mean age ± SD 36.0 ± 7.1 years), were recruited in a 3 Tesla MRI study including high angular resolution diffusion and resting-state functional MRI acquisitions. Specialized metrics of structural and functional connectivity were derived from a standard parcellation of olfactory brain areas and a previously validated graph-theoretic model of the human olfactory functional network. These metrics were compared between groups and correlated to a clinical index of olfactory impairment. On the scanning day, all subjects were virus-free and cognitively unimpaired. Compared to control, both structural and functional connectivity metrics were found significantly increased in previously SARS-CoV-2 infected subjects. Greater residual olfactory impairment was associated with more segregated processing within regions more functionally connected to the anterior piriform cortex. An increased neural connectivity within the olfactory cortex was associated with a recent SARS-CoV-2 infection when the olfactory loss was a residual COVID-19 symptom. The functional connectivity of the anterior piriform cortex, the largest cortical recipient of afferent fibers from the olfactory bulb, accounted for the inter-individual variability in the sensory impairment. Albeit preliminary, these findings could feature a characteristic brain connectivity response in the presence of COVID-19 related residual hyposmia.

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.

Do demographic and clinical features and comorbidities affect the risk of spread to an additional body site in functional motor disorders?

The aim of this study is to assess changes in the body distribution and the semeiology of functional motor disorder (FMD) in patients who reported only one or more than one body site affected at FMD onset. Data were obtained from the Italian Registry of Functional Motor Disorders, which included patients with a diagnosis of clinically definite FMDs. The relationship between FMD features and spread to other body sites was estimated by multivariate Cox regression analysis. We identified 201 (49%) patients who reported only one body site affected at FMD onset and 209 (51%) who reported multiple body sites affected at onset. FMD spread from the initial site to another site in 43/201 (21.4%) patients over 5.7 ± 7.1 years in those with only one site affected at FMD onset; FMD spread to an another body site in 29/209 (13.8%) over 5.5 ± 6.5 years. The spread of FMD was associated with non-motor functional symptoms and psychiatric comorbidities only in the patients with one body site affected at FMD onset. Our findings provide novel insight into the natural history of FMD. The number of body sites affected at onset does not seem to have a consistent influence on the risk of spread. Furthermore, our findings suggest that psychiatric comorbidities and non-motor functional symptoms may predict the spread of FMD symptoms, at least in patients with one body site affected at onset.

Functional connectivity changes in complex migraine aura: beyond the visual network.

BACKGROUND AND PURPOSE: Although the majority of migraine with aura (MwA) patients experience simple visual aura, a discrete percentage also report somatosensory, dysphasic or motor symptoms (the so-called complex auras). The wide aura clinical spectrum led to an investigation of whether the heterogeneity of the aura phenomenon could be produced by different neural correlates, suggesting an increased visual cortical excitability in complex MwA. The aim was to explore whether complex MwA patients are characterized by more pronounced connectivity changes of the visual network and whether functional abnormalities may extend beyond the visual network encompassing also the sensorimotor network in complex MwA patients compared to simple visual MwA patients. METHODS: By using a resting-state functional magnetic resonance imaging approach, the resting-state functional connectivity (RS-Fc) of both visual and sensorimotor networks in 20 complex MwA patients was compared with 20 simple visual MwA patients and 20 migraine without aura patients. RESULTS: Complex MwA patients showed a significantly higher RS-Fc of the left lingual gyrus, within the visual network, and of the right anterior insula, within the sensorimotor network, compared to both simple visual MwA and migraine without aura patients (p < 0.001). The abnormal right anterior insula RS-Fc was able to discriminate complex MwA patients from simple aura MwA patients as demonstrated by logistic regression analysis (area under the curve 0.83). CONCLUSION: Our findings suggest that higher extrastriate RS-Fc might promote cortical spreading depression onset representing the neural correlate of simple visual aura that can propagate to sensorimotor regions if an increased insula RS-Fc coexists, leading to complex aura phenotypes.

Validation of new diagnostic criteria for fatigue in patients with Parkinson disease.

BACKGROUND AND PURPOSE: Although disabling fatigue is common in Parkinson disease (PD), available consensus-based diagnostic criteria have not yet been empirically validated. The aim of this study was to evaluate the clinimetric properties of the criteria. METHODS: A sample of outpatients with PD was evaluated for demographic, clinical, behavioral, and cognitive features. Fatigue was diagnosed according to the new diagnostic criteria and was rated by means of the Parkinson Fatigue Scale (PFS) and Fatigue Severity Scale (FSS). Acceptability, concurrent and discriminant validity, and interrater reliability were evaluated with binary logistic regression analyses and Cohen kappa (κ). RESULTS: Of 241 included patients, 17 (7.1%) met the diagnostic criteria for PD-related fatigue. Eight of nine symptoms described in Section A of the diagnostic criteria occurred in >50% of patients with fatigue. Acceptability (missing data = 0.8%) of the criteria was good, as was their concurrent validity with the PFS (odds ratio = 3.65) and FSS (odds ratio = 3.63). The discriminant validity of fatigue criteria with other PD-related behavioral and cognitive features was good (odds ratio < 1.68). The interrater reliability was excellent (κ = 0.92). CONCLUSIONS: This is the first study to test the clinimetric properties of case definition diagnostic criteria for PD-related fatigue. Our results suggest that current diagnostic criteria may be useful in both clinical practice and research. Future longitudinal studies should examine their long-term stability.

Criteria for identification of advanced Parkinson's disease: the results of the Italian subgroup of OBSERVE-PD observational study.

BACKGROUND: Frequency of Advanced Parkinson's Disease (APD) and its clinical characteristics are still not well defined. Here, we aimed to assess APD prevalence in the Italian OBSERVE-PD cohort, as well as treatment eligibility to device-aided therapies (DAT), and to compare the APD clinical judgment with the established Delphi criteria. METHODS: This sub-group analysis of the OBSERVE-PD study was performed on patients enrolled by 9 Movement Disorders centers in Italy. Motor and non-motor symptoms, PD characteristics, activities of daily living, and quality of life were assessed. Patient eligibility for DAT, response to current PD treatments, referral process, and the concordance between APD physician's judgment and Delphi criteria were also assessed. RESULTS: According to physician's judgment, 60 out of 140 patients (43%) had APD. The correlation between physician's judgment and the overall APD Delphi criteria was substantial (K = 0.743; 95%CI 0.633-0.853), mainly driven by a discrete concordance found for the presence of ≥ 2 h of daily OFF time, presence of troublesome dyskinesia, ≥ 5 times daily oral levodopa dosing, and activities of daily living limitation. Forty-four (73%) APD patients were considered eligible to DAT but only 18 of them (41%) used these therapies, while most patients, independently from their eligibility, continued to use 3-5 oral daily medications, due to fear of invasive solutions and need to have a longer time to decide. CONCLUSION: APD was frequent in the Italian OBSERVE-PD population. DAT in the eligible APD population proved to be underused, in spite of unsatisfactory symptoms control with oral medications in 67% of patients.

Cluster headache pathophysiology: What we have learned from advanced neuroimaging.

BACKGROUND: Although remarkable progress has been achieved in understanding cluster headache (CH) pathophysiology, there are still several gaps about the mechanisms through which independent subcortical and cortical brain structures interact with each other. These gaps could be partially elucidated by structural and functional advanced neuroimaging investigations. OBJECTIVE: Although we are aware that substantial achievements have come from preclinical, neurophysiological, and biochemical experiments, the present narrative review aims to summarize the most significant findings from structural, microstructural, and functional neuroimaging investigations, as well as the consequent progresses in understanding CH pathophysiological mechanisms, to achieve a comprehensive and unifying model. RESULTS: Advanced neuroimaging techniques have contributed to overcoming the peripheral hypothesis that CH is of cavernous sinus pathology, in transitioning from the pure vascular hypothesis to a more comprehensive trigeminovascular model, and, above all, in clarifying the role of the hypothalamus and its connections in the genesis of CH. CONCLUSION: Altogether, neuroimaging findings strongly suggest that, beyond the theoretical model of the "pain matrix," the model of the "neurolimbic pain network" that is accepted in migraine research could also be extended to CH. Indeed, although the hypothalamus' role is undeniable, the genesis of CH attacks is complex and seems to not be just the result of a single "generator." Cortical-hypothalamic-brainstem functional interconnections that can switch between out-of-bout and in-bout periods, igniting the trigeminovascular system (probably by means of top-down mechanisms) and the consensual trigeminal autonomic reflexes, may represent the "neuronal background" of CH.

Effects of safinamide on non-motor, cognitive, and behavioral symptoms in fluctuating Parkinson's disease patients: a prospective longitudinal study.

INTRODUCTION: Parkinson's disease (PD) patients in chronic levodopa treatment may experience motor and non-motor fluctuations, which may affect their quality of life. Safinamide is a new monoamine oxidase B inhibitor, also exerting a non-dopaminergic effect, recently approved as add-on therapy in fluctuating PD patients. METHODS: We performed a longitudinal prospective study in a cohort of 20 fluctuating PD patients, to test whether safinamide 50 mg may improve non-motor, cognitive, and behavioral symptoms over a 6-month treatment period. At each timepoint, clinical features were assessed by means of validated PD-specific scales. Neuropsychological assessment was performed by exploring all five cognitive domains. RESULTS: Compared to baseline, significant improvement was found in PD patients at 6-month follow-up in items investigating interest (p = 0.02), motivation (p = 0.02), and urinary disturbances (p = 0.03). Moreover, neuropsychiatric assessment showed a significant decrease in fatigue and apathy scores (p = 0.02 and p = 0.01, respectively). Motor assessment revealed a significant reduction in the total wake-up time spent in OFF state (p = 0.01). Follow-up neuropsychological evaluation did not reveal any change compared to baseline. CONCLUSIONS: Our data reveal that, along with motor fluctuation improvement, treatment with safinamide 50 mg may significantly decrease non-motor symptom burden in PD patients. Interestingly, non-dopaminergic mechanisms, such as glutamatergic overdrive, have been demonstrated to play a role in many pathways underlying these symptoms. Thus, we hypothesize that the neurotransmitter receptor-binding profile of safinamide may explain our findings.