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Advanced age represents one of the major risk factors for Parkinson's Disease. Recent biomedical studies posit a role for microRNAs, also known to be remodelled during ageing. However, the relationship between microRNA remodelling and ageing in Parkinson's Disease, has not been fully elucidated. Therefore, the aim of the present study is to unravel the relevance of microRNAs as biomarkers of Parkinson's Disease within the ageing framework. We employed Next Generation Sequencing to profile serum microRNAs from samples informative for Parkinson's Disease (recently diagnosed, drug-naïve) and healthy ageing (centenarians) plus healthy controls, age-matched with Parkinson's Disease patients. Potential microRNA candidates markers, emerging from the combination of differential expression and network analyses, were further validated in an independent cohort including both drug-naïve and advanced Parkinson's Disease patients, and healthy siblings of Parkinson's Disease patients at higher genetic risk for developing the disease. While we did not find evidences of microRNAs co-regulated in Parkinson's Disease and ageing, we report that hsa-miR-144-3p is consistently down-regulated in early Parkinson's Disease patients. Moreover, interestingly, functional analysis revealed that hsa-miR-144-3p is involved in the regulation of coagulation, a process known to be altered in Parkinson's Disease. Our results consistently show the down-regulation of hsa-mir144-3p in early Parkinson's Disease, robustly confirmed across a variety of analytical and experimental analyses. These promising results ask for further research to unveil the functional details of the involvement of hsa-mir144-3p in Parkinson's Disease., This work was supported by the Horizon 2020 Framework Programme (Grant number 634821, PROPAG-AGING).

Objective The Bologna motor and non-motor prospective study on parkinsonism at onset (BoProPark) was designed to prospectively characterize motor and non-motor features in patients with a progressive neurodegenerative disease starting with parkinsonism since early disease stage and to investigate their diagnostic and prognostic role in the differential diagnosis of Parkinson’s disease from atypical parkinsonisms. The aim of this paper is to describe the method and population of the BoProPark study. Methods Patients referred to our Department with parkinsonism within 3 years from motor onset were recruited. Secondary causes of parkinsonism were excluded. Each patient underwent a comprehensive evaluation of motor and non-motor symptoms, assessed by means of quantitative, objective instrumental tests in addition to scales and questionnaires. The evaluations were performed at enrolment (T0), after 16 months (T1) and after 5 years (T2). Diagnoses were made according to consensus criteria. Results We recruited 150 patients, with mean age 61.5 ± 9.8 years and mean disease duration 20 ± 9 months. H&Y stage was 1 in 47.3% and 2 in 46.7% of cases. Mean UPDRS-III was 17.7 ± 9.2. Fifty-four patients were on dopaminergic treatment with median levodopa equivalent daily dose (LEDD) of 200 mg. Conclusions We expect that the prospective nature of the BoProPark study as well as the comprehensive, instrumental evaluation of motor and non-motor symptoms in patients with parkinsonism will provide important new insights for both clinical practice and research. Our data could be used for comparison with other cohorts and shared with national and international collaborators to develop new innovative projects.

Background Lack of awareness of cognitive decline (ACD) is common in late-stage Alzheimer’s disease (AD). Recent studies showed that ACD can also be reduced in the early stages. Methods We described different trends of evolution of ACD over 3 years in a cohort of memory-complainers and their association to amyloid burden and brain metabolism. We studied the impact of ACD at baseline on cognitive scores’ evolution and the association between longitudinal changes in ACD and in cognitive score. Results 76.8% of subjects constantly had an accurate ACD (reference class). 18.95% showed a steadily heightened ACD and were comparable to those with accurate ACD in terms of demographic characteristics and AD biomarkers. 4.25% constantly showed low ACD, had significantly higher amyloid burden than the reference class, and were mostly men. We found no overall effect of baseline ACD on cognitive scores’ evolution and no association between longitudinal changes in ACD and in cognitive scores. Conclusions ACD begins to decrease during the preclinical phase in a group of individuals, who are of great interest and need to be further characterized. Trial registration The present study was conducted as part of the INSIGHT-PreAD study. The identification number of INSIGHT-PreAD study (ID-RCB) is 2012-A01731-42.

Background In idiopathic normal pressure hydrocephalus (iNPH), gait and balance impairment is the most frequent symptom, and it is often associated with a higher fall risk. In a prior study, the anterior callosal angle (ACA) was validated as a reliable marker to discriminate iNPH from Alzheimer's disease and healthy controls. However, the potential correlation between the ACA with clinical symptoms and functional outcomes has not been assessed. The objective of this study is to determine the utility of the ACA in predicting gait improvement after ventriculoperitoneal (VP) shunting.Methods Patients with probable iNPH who underwent shunt placement at a single institution were prospectively enrolled from May 2015 to May 2019. Patients were assessed preoperatively and at 6 months postoperatively following a standard clinical and MRI protocol. Callosal angle (CA) and ACA were calculated from 3 T MRI preoperatively and at 6 months postoperatively. CA and ACA were tested for correlation with clinical scores.Results Forty-seven patients with probable INPH who completed 6-month postoperative follow-up were enrolled in the study. Baseline ACA was significantly correlated with preoperative fall risk, gait, and balance impairment assessed with Tinetti POMA scale. Additionally, baseline ACA differentiated patients who experienced improvement at Tinetti POMA scale after surgery.Conclusions The baseline ACA is a useful neuroradiological marker to differentiate patients by fall risk and has significant correlation with the improvement in gait and balance impairment following surgery. This study demonstrated that the ACA may be a complementary tool to the CA in predicting shunt responsiveness in iNPH.

The in vivo differential diagnosis between idiopathic Parkinson's disease (PD) and atypical parkinsonian syndromes (PS), such as multiple system atrophy [MSA with a cerebellar (C) and parkinsonian (P) subtype] and progressive supranuclear palsy - Richardson's Syndrome (PSP-RS) is often challenging. Previous brain MR proton spectroscopy ((1)H-MRS) studies showed biochemical alterations in PS, despite results are conflicting. Cerebellum plays a central role in motor control and its alterations has been already demonstrated in atypical PS. The main aim of this study was to evaluate diagnostic accuracy of cerebellar (1)H-MRS in the differential diagnosis between PD and atypical PS.We obtained (1)H-MRS spectra from the left cerebellar hemisphere of 57 PS (21 PD, and 36 atypical PS) and 14 unaffected controls by using a 1.5 T GE scanner. N-acetyl-aspartate (NAA)/Creatine (Cr), choline-containing compounds (Cho)/Cr, myoinositol (mI)/Cr, and NAA/mI ratios were calculated.NAA/Cr and NAA/mI ratios were significantly lower (p0.01) in atypical PS compared to PD and controls, and in MSA-C compared to PD, MSA-P, PSP-RS and controls. PSP-RS group showed reduced NAA/Cr ratios compared to PD (p0.05) and controls (p0.05), and reduced NAA/mI compared to controls (p0.01). NAA/Cr ratio values higher than 1.016 showed 100% sensitivity and negative predictive value, 62% positive predictive value and 64% specificity in discriminating PD.Cerebellar biochemical alterations detected by using (1)H-MRS could represent an adjunctive diagnostic tool to improve the differential diagnosis of PS.

In the prospect of improved disease management and future clinical trials in Frontotemporal Dementia, it is desirable to share common diagnostic procedures. To this aim, the Italian FTD Network, under the aegis of the Italian Neurological Society for Dementia, has been established. Currently, 85 Italian Centers involved in dementia care are part of the network. Each Center completed a questionnaire on the local clinical procedures, focused on (1) clinical assessment, (2) use of neuroimaging and genetics; (3) support for patients and caregivers; (4) an opinion about the prevalence of FTD. The analyses of the results documented a comprehensive clinical and instrumental approach to FTD patients and their caregivers in Italy, with about 1,000 newly diagnosed cases per year and 2,500 patients currently followed by the participating Centers. In analogy to other European FTD consortia, future aims will be devoted to collect data on epidemiology of FTD and its subtypes and to provide harmonization of procedures among Centers.

Background: One of the hallmarks of the E-synucleinopathies is the degeneration of the autonomic nervous system. Summary: This review discusses the diagnosis and management of cardiovascular autonomic failure within the context of the E-synucleinopathies. In addition, it outlines the utility of various laboratory assessments including cardiovascular reflex tests for the differential diagnoses of these disorders, as well as general disease management strategies. Key Messages: Laboratory investigations assessing the autonomic control of the cardiovascular system are useful in the differential diagnosis of E-synucleinopathies, especially in early stages of disease. Clinical Implications: The characterization of the different features of AF in patients with E-synucleinopathies is challenging because it might help to improve the accuracy of the differential diagnosis between these diseases at onset. Further cardiovascular AF has been demonstrated to have a negative prognostic role in E-synucleinopathies, therefore an early detection of cardiovascular dysautonomia allows to positively impact the disease course guiding the appropriate therapy. i 2014 S. Karger AG, Basel

Many studies have addressed the relation between orthostatic hypotension (OH) and cognitive impairment (CI) in the elderly, in mild cognitive impairment, vascular and neurodegenerative dementias and movement disorders, such as Parkinson’s disease. However, results concerning both the increased coexistence of the two conditions and their causal relationship remain controversial. According to the literature three hypotheses can be formulated on the relation between OH and CI. In neurodegenerative disease, OH and CI may result from a common pathological process which affects areas involved in both cognition and cardiovascular autonomic control. Alternatively, OH may lead to cerebral hypoperfusion which is supposed to play a role in the development of CI. Finally, recent data suggest that CI should probably be considered more a transient symptom of OH than a chronic effect. This study reviews the literature reports on the relationship between OH and CI, and emphasises the need for longitudinal studies designed to investigate this topic.

Objectiveaims of the current study were 1) to evaluate global cognitive function in patients with autonomic failure (AF) of peripheral origin and 2) to investigate the effect of a documented fall in blood pressure (BP) fulfilling the criteria for orthostatic hypotension (OH) on cognitive performances.Methodswe assessed 12 consecutive patients (10 males, 68±7 years old) with pure AF (PAF) or autoimmune autonomic neuropathy (AAN) and 12 age- and gender-matched controls. All patients had no clinical signs of central nervous system involvement and normal brain CT/MRI scan. Cognitive function was assessed on two consecutive days in 3 conditions: on day 1, while sitting, by means of a comprehensive battery of neuropsychological tests; on day 2, while tilted (HUT) and during supine rest (supine) in a randomized manner. BP and heart rate (HR) were continuously recorded non-invasively for the whole duration of the examination.Resultspatients with PAF or AAN displayed a preserved global cognitive function while sitting. However, compared to supine assessment, during HUT patients scored significantly worse during the Trail Making Test A and B, Barrage test, Analogies test, Immediate Visual Memory, Span Forward and Span Backward test. Pathological scores, with regard to Italian normative range values, were observed only during HUT in the Barrage test and in the Analogies test in 3 and 6 patients respectively. On the contrary, in healthy controls, results to neuropsychological tests were not significantly different, during HUT compared to supine rest.Conclusionsthese data demonstrate that patients with PAF and AAN present a normal sitting global cognitive evaluation. However, their executive functions worsen significantly during the orthostatic challenge, possibly because of transient frontal lobes hypoperfusion.

Background and purpose: Treatment of freezing of gait (FoG) and other Parkinson disease (PD) axial symptoms is challenging. Systematic assessments of axial symptoms at progressively increasing levodopa doses are lacking. We sought to analyze the resistance to high levodopa doses of FoG, posture, speech, and altered gait features presenting in daily-ON therapeutic condition. Methods: We performed a pre-/postinterventional study including patients treated with levodopa/carbidopa intestinal gel infusion (LCIG) with disabling FoG in daily-ON condition. Patients were evaluated at their usual LCIG infusion rate (T1), and 1 h after 1.5× (T2) and 2× (T3) increase of the LCIG infusion rate by quantitative outcome measures. The number of FoG episodes (primary outcome), posture, speech, and gait features were objectively quantified during a standardized test by a blinded rater. Changes in motor symptoms, dyskinesia, and plasma levodopa concentrations were also analyzed. Results: We evaluated 16 patients with a mean age of 69 ± 9.4 years and treated with LCIG for a mean of 2.2± 2.1 years. FoG improved in 83.3% of patients by increasing the levodopa doses. The number of FoG episodes significantly decreased (mean=2.3 at T1, 1.7 at T2, 1.2 at T3; p= 0.013). Posture and speech features did not show significant changes, whereas stride length (p= 0.049), turn duration (p= 0.001), and turn velocity (p= 0.024) significantly improved on doubling the levodopa infusion rate. Conclusions: In a short-term evaluation, the increase of LCIG dose can improve "dopa-resistant" FoG and gait issues in most advanced PD patients with overall good control of motor symptoms in the absence of clinically significant dyskinesia.

Background “Impulse Control Disorders” are behavioral conditions (e.g., gambling, hypersexuality), which are increasingly reported as reactions to dopamine agonists in Parkinson's disease. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease focuses only on 6 behaviors. Nonetheless, impulsivity could affect the entire range of human practices. Because of their heterogeneity and undefined boundaries, it is not clear what conditions should be considered as Impulse Control Disorders. This results in poorly standardized scientific literature and underdiagnosis. Objective We aimed to create a comprehensive list of possible manifestations of drug-induced Impulse Control Disorders in Parkinson's disease and test it on pharmacosurveillance data. Methods PubMed was used to identify reviews in English about Impulse Control Disorders in Parkinson's disease. Mentioned conditions were charted and translated to the lexicon of MedDRA, ICD-11, and DSM-5. The relevant MedDRA terms were used to test potential association with dopamine agonists on the FDA Adverse Event Reporting System. Results 50 reviews published between 2001 and 2020 were identified. 66 conditions were collected as possible Impulse Control Disorders. Pathological gambling, shopping, eating and sexuality, dopamine dysregulation syndrome, hobbyism and punding were the most frequently mentioned, together with leisure activities, body-focused compulsivity, disruptive, impulse control and conduct disorders, and substance abuse. All these conditions were disproportionately reported with dopamine agonists, except for substance abuse. Conclusions We defined a potential extended list of ICDs, which, along with its conversion to international taxonomies, can support the identification of drug-induced conditions in pharmacovigilance archives, as well as monitoring processes in clinical practice.

Background Increasing evidence supports the use of plasma biomarkers of neurodegeneration and neuroinflammation to screen and diagnose patients with dementia. However, confirmatory studies are required to demonstrate their usefulness in the clinical setting. Methods We evaluated plasma and cerebrospinal fluid (CSF) samples from consecutive patients with frontotemporal dementia (FTD) (n = 59), progressive supranuclear palsy (PSP) (n = 31), corticobasal syndrome (CBS) (n = 29), dementia with Lewy bodies (DLB) (n = 49), Alzheimer disease (AD) (n = 97), and suspected non-AD physiopathology (n = 51), as well as plasma samples from 60 healthy controls (HC). We measured neurofilament light chain (NfL), phospho-tau181 (p-tau181), and glial fibrillary acid protein (GFAP) using Simoa (all plasma biomarkers and CSF GFAP), CLEIA (CSF p-tau181), and ELISA (CSF NfL) assays. Additionally, we stratified patients according to the A/T/N classification scheme and the CSF α-synuclein real-time quaking-induced conversion assay (RT-QuIC) results. Results We found good correlations between CSF and plasma biomarkers for NfL (rho = 0.668, p < 0.001) and p-tau181 (rho = 0.619, p < 0.001). Plasma NfL was significantly higher in disease groups than in HC and showed a greater increase in FTD than in AD [44.9 (28.1–68.6) vs. 21.9 (17.0–27.9) pg/ml, p < 0.001]. Conversely, plasma p-tau181 and GFAP levels were significantly higher in AD than in FTD [3.2 (2.4–4.3) vs. 1.1 (0.7–1.6) pg/ml, p < 0.001; 404.7 (279.7–503.0) vs. 198.2 (143.9–316.8) pg/ml, p < 0.001]. GFAP also allowed discriminating disease groups from HC. In the distinction between FTD and AD, plasma p-tau181 showed better accuracy (AUC 0.964) than NfL (AUC 0.791) and GFAP (AUC 0.818). In DLB and CBS, CSF amyloid positive (A+) subjects had higher plasma p-tau181 and GFAP levels than A− individuals. CSF RT-QuIC showed positive α-synuclein seeding activity in 96% DLB and 15% AD patients with no differences in plasma biomarker levels in those stratified by RT-QuIC result. Conclusions In a single-center clinical cohort, we confirm the high diagnostic value of plasma p-tau181 for distinguishing FTD from AD and plasma NfL for discriminating degenerative dementias from HC. Plasma GFAP alone differentiates AD from FTD and neurodegenerative dementias from HC but with lower accuracy than p-tau181 and NfL. In CBS and DLB, plasma p-tau181 and GFAP levels are significantly influenced by beta-amyloid pathology.

Objectives The prevalence of neurogenic orthostatic hypotension (NOH, due to cardiovascular autonomic failure) at early stage of Parkinson's disease (PD) is unknown. The aims of this study are to prospectively evaluate in a cohort of PD patients recruited within 3 years from motor onset (1) cardiovascular autonomic functions by means of cardiovascular reflex tests (CRTs) and the occurrence of NOH; (2) the frequency of orthostatic symptoms with a validated questionnaire. Methods We included the first 105 PD patients of the prospective “BoProPark” study. Each patient underwent CRTs (head up tilt test; Valsalva manoeuvre; deep breathing; cold face test and handgrip test) under continuous blood pressure monitoring according to standardized procedures and SCOPA-Aut questionnaire at baseline (T0) and after 16 months (T1). A group of 50 age- and sex-matched controls was used for comparison. Results At T0 (mean age 61 ± 9 years, disease duration 19 ± 9 months) NOH was detected in 4/105 (3.8%) patients, whereas at T1 in 8/105 (7.6%). CRTs responses assessing sympathetic function were impaired at T0 in PD patients compared to controls and progressively worsened at T1. Only 1 patient at T0 and 3 at T1 with NOH reported orthostatic symptoms with low frequency, while the majority of patients reporting these symptoms did not have OH at testing. Conclusions Our prospective study shows that NOH is not common at early PD stage. Asymptomatic mild sympathetic impairment was observed at first evaluation and progressed with disease evolution. Secondary OH may account for the higher prevalence of OH in PD reported so far.

Introduction Idiopathic Normal Pressure Hydrocephalus (iNPH) is a complex and often misdiagnosed syndrome, whose major challenge is to identify which patients will benefit from surgery. Previous studies reported a variability in positive surgery response. The role of tap test(TT) in screening patients suitable for shunting is controversial. The primary aim of this study was to describe the clinical/instrumental features and their longitudinal progression after surgery in iNPH patients. Secondarily, we aimed to investigate the response of the three iNPH domains and the best time of outcome assessment after TT. Methods Patients compatible with iNPH underwent a 3-T-MRI and an inpatients program with TT including standardized clinical evaluations, neuropsychological assessments and instrumental gait analysis pre- and after-(24-h and 72-h) TT. The multidisciplinary team selected candidates for surgery. Patients were evaluated 6- and 12-months after surgery. Results A total of 154 consecutive patients were included from 2015 to 2018, 76 with an iNPH diagnosis (43 underwent surgery, 35 were evaluated after 6-months). Clinical and instrumented quantitative gait measures and urinary symptoms improved over time along with some neuropsychological functions. Concerning pre and post-TT analyses, the three iNPH domains showed a different response after TT, the delayed motor assessment was more appropriate than the early one and the instrumental measures highlighted the motor improvement. Conclusion: iNPH patients improved after surgery, when accurately selected. A multidisciplinary team focused on this disease and a standardized protocol helped in achieving a correct diagnosis and management of iNPH. Our results could impact the management of this disease.

PROPAG-AGEING consortium., A prodromal phase of Parkinson’s disease (PD) may precede motor manifestations by decades. PD patients’ siblings are at higher risk for PD, but the prevalence and distribution of prodromal symptoms are unknown. The study objectives were (1) to assess motor and non-motor features estimating prodromal PD probability in PD siblings recruited within the European PROPAG-AGEING project; (2) to compare motor and non-motor symptoms to the well-established DeNoPa cohort. 340 PD siblings from three sites (Bologna, Seville, Kassel/Goettingen) underwent clinical and neurological evaluations of PD markers. The German part of the cohort was compared with German de novo PD patients (dnPDs) and healthy controls (CTRs) from DeNoPa. Fifteen (4.4%) siblings presented with subtle signs of motor impairment, with MDS-UPDRS-III scores not clinically different from CTRs. Symptoms of orthostatic hypotension were present in 47 siblings (13.8%), no different to CTRs (p = 0.072). No differences were found for olfaction and overall cognition; German-siblings performed worse than CTRs in visuospatial-executive and language tasks. 3/147 siblings had video-polysomnography-confirmed REM sleep behavior disorder (RBD), none was positive on the RBD Screening Questionnaire. 173/300 siblings had, This project has received funding from the European Union’s Horizon 2020 research and innovation program Propag‐Ageing under grant agreement no. 634821.

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

Background Depression is more frequently associated with akinetic-rigid/postural instability gait difficulty subtypes of Parkinson's disease than with tremor-dominant subtype. Objectives The aim of the study is to investigate the frequency of exposure to antidepressant drugs, as proxy of depression, before motor onset according to Parkinson's disease subtypes. Method Based on a historical cohort design, the exposure to antidepressant drugs before Parkinson's disease motor onset was obtained from the drug prescription database and assessed in the resident population of the Local Healthcare Trust of Bologna (443,117 subjects older than 35 years). Diagnosis of Parkinson's disease and subtype (tremor dominant, non-tremor dominant) at onset were recorded by neurologists and obtained from the “ParkLink Bologna” record linkage system. Exposure to antidepressants was compared both to the general population and between the two subtypes. Results From 2006 to 2018, 198 patients had a tremor dominant subtype at onset whereas 450 did not. Comparison with the general population for antidepressant exposure showed an adjusted hazard ratio of 0.86 (95% CI 0.44–1.70) for the tremor dominant subtype and 1.66 (1.16–2.39) for the non-tremor dominant subtype. Comparison of non-tremor dominant with tremor dominant subtypes showed an adjusted odds ratio of 1.86 (1.05–3.95) for antidepressant exposure. Conclusions In our study, non-tremor dominant Parkinson's disease at onset was significantly associated with exposure to antidepressants in comparison to the general population and in comparison with the tremor dominant subtype. These results support the hypothesis of different biological substrates for different Parkinson's disease subtypes even before motor onset.

Introduction: Cognitive decline is not a characteristic feature of multiple system atrophy (MSA), but recent evidence suggests cognitive impairment as an integral part of the disease. We aim to describe the cognitive profile and its progression in a cohort of patients with MSA.Methods: We retrospectively selected patients referred to our department with a clinical diagnosis of MSA who were evaluated at least once a year during the course of the disease and underwent a comprehensive neuropsychological evaluation.Results: At the first evaluation (T0), 37 out of 60 patients (62%) were cognitively impaired, mainly (76%) in attention and executive functioning. Thirteen patients were impaired in one cognitive domain and 24 in more than one cognitive domain. Six out of the 24 had dementia. Twenty patients underwent a follow-up evaluation (T1) after a mean of 16.6 ± 9.3 months from the first evaluation (T0). Eight out of 20 patients were cognitively normal at both T0 and T1. Seven out of 12 patients presented with stable cognitive impairment at T1, while cognitive decline progressed in five patients. Patients with progression in cognitive decline performed significantly worse at T0 than cognitively stable patients. Education was significantly different between patients with and without cognitive impairment. No other differences in demographic and clinical variables and autonomic or sleep disturbances were found. Patients with dementia were older at disease onset and at T0 and had lower education and disease duration at T0 compared to those in other groups.Conclusions: In patients with MSA, we observed three different cognitive profiles: normal cognition, stable selective attention-executive deficits, and progressive cognitive deficits evolving to dementia. The detection of cognitive impairment in patients with suspected MSA suggests the need for comprehensive and longitudinal neuropsychological evaluation.

Background Levodopa-carbidopa intestinal gel (LCIG) treatment has shown variable effect on dyskinesia in Parkinson's disease (PD). Objective To identify PD patients who are likely to have troublesome dyskinesia under LCIG treatment and describe the pharmacokinetic-dynamic profile and dyskinesia phenomenology of those patients. Methods PD patients were assessed for clinical and therapeutic variables, before LCIG treatment (T0) and at last outpatient visit (T1). Sub-groups of patients with and without "troublesome dyskinesia" (UPDRS IV, item 33 ≥2), matched for disease and LCIG treatment duration, underwent a pharmacokinetic-dynamic assessment. Results We included 53 PD patients. After a mean of 51.7 ± 34.1 months of LCIG treatment, "off-time" was significantly reduced, whereas, dyskinesia duration/disability did not change. The multivariate regression model, adjusted for LCIG treatment duration, showed that being female increases the risk of presenting troublesome dyskinesia at T1 (odds ratio [OR] = 9.2; 95% confidence interval [CI] = 2.4-37.4) that was also significantly associated to longer off periods at T1 (OR= 4.4; 95% CI = 1.1-14.3). Female patients showed a higher risk for a higher dyskinesia score at T1 (sum of the items 32 and 33: P = 0.001). Patients with troublesome dyskinesia showed a tendency for a lower motor benefit and the appearance of more severe dyskinesia despite similar levodopa plasma concentration. Conclusion Dyskinesia should be carefully monitored in patients undergoing LCIG, with particular caution for female patients. Whether combined clinical and pharmacodynamic assessments could be helpful to manage patients with troublesome dyskinesia under LCIG treatment needs further evaluation in a larger group of patients.

Objectives To evaluate white matter and cortical changes in patients with parkinsonisms and healthy controls (HC), applying both hypothesis-free and regions of interest (ROI)-based advanced brain MR analyses. Methods Twenty-five patients with Progressive Supranuclear Palsy - Richardson's Syndrome (PSP-RS), nine with cerebellar and nine with parkinsonian Multiple System Atrophy variants (MSA-C and MSA-P), forty-seven with Parkinson's Disease (PD) and twenty-seven HC underwent a 1.5 T brain-MR protocol including high-resolution 3D T1-weighted and 25-direction diffusion tensor imaging sequences. We performed cortical and white matter analysis by using vertex-based cortical thickness evaluation and Tract Based Spatial Statistics (TBSS), followed by a ROI-based cortical thickness analysis and probabilistic tractography of cortico-spinal tract (CST), and middle and superior cerebellar peduncles (MCP and SCP). Results In PSP-RS, both ROIs-based and voxel-wise analyses demonstrated significant thinning of the pre-central cortices and diffuse white matter alterations involving supra- and infratentorial compartments. Along-tract tractography analysis of CST showed a significantly higher MD in PSP-RS vs PD and HC limited to the portion of the tract within the corona radiata. In MSA-C, a predominant involvement of MCPs was evident, while alterations in MCPs in MSA–P and in SCPs in PSP-RS and MSA-C were also present. Conclusion Specific patterns of cortical and white matter changes in atypical parkinsonism patients reflect the neuropathological and clinical features of these disorders. This study shows that quantitative brain MR techniques can detect significant changes that help to elucidate the physiopathology of movement disorders and support their differential diagnosis.

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Disorders of arousal include confusional arousals, sleepwalking and sleep terrors. The diagnosis of disorders of arousal is based on the clinical criteria established in the International Classification of Sleep Disorders, third edition, although the interobserver reliability of these criteria has never been investigated. The aim of this study was to estimate the inter-rater reliability of the diagnostic criteria for disorders of arousal throughout the whole life in order to understand their feasibility in clinical daily activity and in multicenter observational studies. Three raters interviewed 126 subjects (patients complaining of sleep disorders, headache, and healthy subjects), aged 18–80 years, with a standardized questionnaire created by applying the International Diagnostic Criteria for Disorders of Arousal. An “almost perfect” inter-rater reliability for disorders of arousal criteria and the final diagnosis was found among the raters (kappa 0.89 for confusional arousals, 0.87 for sleepwalking, and 0.87 for sleep terrors). The International Classification of Sleep Disorders, Third Edition criteria are adequate for a reliable diagnosis of disorders of arousal. Further validation studies, confirming DOA diagnosis with video polysomnography, are needed to investigate the predictive value of ICSD-3 criteria.

We report the clinical description of an Italian patient with c.638A>G mutation in exon 5 of EIF2B2 gene and a very slow progressive Vanishing White Matter disease phenotype. Infact, in relation to her causative mutation, our patient had an unusual early onset and long course. Furthermore, other than standard MRI examination and spectroscopy study, we report DWI and ADC maps and FA maps reconstruction from DTI in order to describe brain tissue degeneration in vanishing white matter disease.

Slowly progressive aphemia (SPA) is a rare focal degenerative disorder characterized by severe dysarthria, frequent orofacial apraxia, dysprosody, phonetic and phonemic errors without global cognitive deterioration for many years. This condition is caused by a degeneration of anterior frontal lobe regions, mainly of the left frontal operculum. We report a case of SPA with a course of 8 years, evaluated by repeated neuropsychological, conventional, and functional MRI examinations. In our case, neuropsychological examinations showed a progressive impairment of speech articulation including dysprosody, phonetic and phonemic errors, and slight writing errors. No global cognitive deterioration was detected and the patient is still completely autonomous. Morphological and functional investigations showed, respectively, a progressive atrophy and progressive impairment of the left frontal region, confirming the role of the opercular region in determining this rare syndrome. During verbal task generation as the cortical activation of this region gradually decreased, the language articulation worsened.

The objective is to evaluate the prognosis of subjective cognitive complaints (SCC) patients during 4-year follow-up. A prospective study on 92 SCC patients investigating their cognitive, affective and behavioural aspects. SCC patients were classified as having no objective cognitive impairment (NOCI), mild cognitive impairment (MCI), or subtypes of MCI. RESULTS: 43 patients were found to have NOCI and 49 MCI. During the follow-up, 45.5% of NOCI patients remained unchanged, 13.9% were diagnosed as MCI and only one progressed to dementia. Of the MCI patients, 32.3% remained stable, 18.4% became demented and 4% reverted to NOCI. Visual attention, behavioural memory, long-term verbal memory, apathy and caregiver distress, provided independent predictors of progression to dementia.

The burden of migraine strongly increases considering its linkage with other psychiatric, neurological, cardiovascular and cerebrovascular diseases. Migraine is positively associated with many disorders: some are confirmed by several studies whereas others remain uncertain or controversial. The association with some disorders is not simply due to concomitance but it implies a linkage in terms of causality. Highlighting these relationships is important to improve treatment strategies, broaden our knowledge of the pathophysiology and understand if migraine is per se a modifiable risk factor for some disorders.

Migraine has complex relationships with cerebrovascular and cardiovascular disorders but also with cardiac anomalies. Patients affected by migraine with aura have an increased prevalence of right-to-left shunt due to patent foramen ovale or pulmonary arteriovenous malformations. The association between ischemic heart disease, cardiovascular mortality and migraine remains unsettled. The debate focuses on a physiopathological link between migraine and cardiovascular diseases or a higher prevalence of risk factors in migraineurs.

Accelerated long term forgetting (ALF) is a characteristic cognitive aspect in patients affected by temporal lobe epilepsy that is probably due to an impairment of memory consolidation and retrieval caused by epileptic activity in hippocampal and parahippocampal regions. We describe a case of a patient with TLE who showed improvement in ALF and in remote memory impairment after an anterior left temporal pole lobectomy including the uncus and amygdala. Our findings confirm that impairment of hippocampal functioning leads to pathological ALF, whereas restoration of hippocampal functioning brings ALF to a level comparable to that of controls.