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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).

Background and purpose: The patterns of long-term risk of SARS-CoV-2 infection, hospitalization for COVID-19, and related death are uncertain in people with Parkinson disease (PD) or parkinsonism (PS). The aim of the study was to quantify these risks compared to a control population cohort, during the period March 2020–May 2021, in Bologna, Northern Italy. Methods: ParkLink Bologna cohort (759 PD, 192 PS) and controls (9226) anonymously matched (ratio=1:10) for sex, age, district, and comorbidity were included. Data were analysed in the whole period and in the two different pandemic waves (March–May 2020 and October 2020–May 2021). Results: Adjusted hazard ratio of SARS-CoV-2 infection was 1.3 (95% confidence interval [CI] = 1.04–1.7) in PD and 1.9 (95% CI=1.3–2.8) in PS compared to the controls. The trend was detected in both the pandemic waves. Adjusted hazard ratio of hospitalization for COVID-19 was 1.1 (95% CI=0.8–1.7) in PD and 1.8 (95% CI=0.97–3.1) in PS. A higher risk of hospital admission was detected in PS only in the first wave. The 30-day mortality risk after hospitalization was higher (p= 0.048) in PS (58%) than in PD (19%) and controls (26%). Conclusions: Compared with controls, after adjustment for key covariates, people with PD and PS showed a higher risk of SARS-CoV-2 infection throughout the first 15 months of the pandemic. COVID-19 hospitalization risk was increased only in people with PS and only during the first wave. This group of patients was burdened by a very high risk of death after infection and hospitalization.

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 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.

Objectives To report the results of a national survey aimed at quantifying the current level of diffusion of Levodopa/carbidopa intestinal gel (LCIG) in Italy. Methods Sixty Parkinson's Disease (PD) specialists in Italy were invited to complete a survey covering issues on clinical and practical aspects of LCIG therapy. Results Clinical features of 905 patients were collected retrospectively. The majority of centres reported the use of a multidisciplinary team, biochemistry testing, neurophysiological and neuropsychological tests before and after treatment, in addition to caregivers' training and patient's follow as outpatients. Most centres (60%) used internal guidelines for patient selection. The overall rate of adverse events was 55.1%. Weight loss, chronic polyneuropathy and stoma infection were the most frequently reported. 40% of centres used replacement therapy with Vitamin B12 and Folic acid from the start of LCIG and continued this for the duration of treatment. The rate of discontinuation was of 25.7% overall, with 9.5% of cases occurring in the first year. The main causes of withdrawal were device-related complications, disease progression (comorbidity, severe dementia) and caregiver and/or patient dissatisfaction. Conclusions In Italy LCIG infusion is managed in a uniform manner at a clinical, practical and organizational level even though the selection criteria are not standardized through the country. The high percentage of patients remaining on treatment in the short- and long-term follow-up confirms effectiveness of treatment, careful follow-up, and appropriate patient and caregivers training.

Background: The onset of multiple system atrophy (MSA) before age 40 years is referred to as “young-onset MSA.” We identified clinical and pathological characteristics that might help with its early diagnosis and distinction from young-onset Parkinson's disease and late-onset MSA. Methods: We reviewed the available clinical and pathological features in cases that fulfilled consensus criteria for diagnosis of probable MSA or had autopsy confirmed MSA with an onset before age 40 years and compared the clinical features with 16 autopsy confirmed cases with young-onset Parkinson's disease and a large published series of late-onset MSA from the European MSA Study Group. Results: We identified 22 patients with young-onset MSA, 8 of whom had available pathology. The mean age of onset was 36.7 years (standard deviation 2.3). Levodopa-induced dyskinesia was more common, whereas myoclonus and pyramidal signs were less common in young-onset Parkinson's disease when compared with young-onset MSA. Dystonia, levodopa responsiveness, levodopa-induced dyskinesia, and pyramidal signs were more common (P

Background\ud Functional motor disorders (FMDs) are abnormal movements that are significantly altered by distractive maneuvers and are incongruent with movement disorders seen in typical neurological diseases.\ud \ud Objective\ud The objectives of this article are to (1) describe the clinical manifestations of FMDs, including nonmotor symptoms and occurrence of other functional neurological disorders (FND); and (2) to report the frequency of isolated and combined FMDs and their relationship with demographic and clinical variables.\ud \ud Methods\ud For this multicenter, observational study, we enrolled consecutive outpatients with a definite diagnosis of FMDs attending 25 tertiary movement disorders centers in Italy. Each patient underwent a detailed clinical evaluation with a definition of the phenotype and number of FMDs (isolated, combined) and an assessment of associated neurological and psychiatric symptoms.\ud \ud Results\ud Of 410 FMDs (71% females; mean age, 47 ± 16.1 years) the most common phenotypes were weakness and tremor. People with FMDs had higher educational levels than the general population and frequent nonmotor symptoms, especially anxiety, fatigue, and pain. Almost half of the patients with FMDs had other FNDs, such as sensory symptoms, nonepileptic seizures, and visual symptoms. Patients with combined FMDs showed a higher burden of nonmotor symptoms and more frequent FNDs. Multivariate regression analysis showed that a diagnosis of combined FMDs was more likely to be delivered by a movement disorders neurologist. Also, FMD duration, pain, insomnia, diagnosis of somatoform disease, and treatment with antipsychotics were all significantly associated with combined FMDs.\ud \ud Conclusions\ud Our findings highlight the need for multidimensional assessments in patients with FMDs given the high frequency of nonmotor symptoms and other FNDs, especially in patients with combined FMDs.

Background Depression is considered one of the prodromal symptoms of Parkinson's disease (PD) along with sleep disorders, hyposmia and constipation. Prodromal symptoms refer to the stage wherein early motor symptoms and signs allowing a diagnosis of PD are not yet present. The objective of this study was to investigate the association between the use of antidepressants, as indirect measure of depression, and subsequent PD onset, clinically diagnosed, in the Local Health Trust of Bologna, Italy. Methods Historical cohort study with use of antidepressants as exposure and PD onset as outcome. The cohort considered consisted of inhabitants of Bologna aged ≥35 years in 2005; those who had used antidepressants in the previous 3 years were excluded. Subjects were followed up from 2006 and until PD onset, migration out of Bologna, death or end of the study period (2017), whichever came first. “The ParkLink Bologna” system was used to detect disease onset. “ParkLink Bologna” is a research study including patients with a clinical diagnosis of PD residing in Bologna. Residents that used antidepressants for at least 180 consecutive days within 1 year were considered exposed. Hazard ratios (HR) and 95% confidence interval (CI) were estimated with Cox proportional hazards models, using exposure as time-dependent variable and adjusting for potential confounders: age, gender, use of medical care and comorbidities. Results From 2006 to 2017 199,093 person-years were exposed and 4,286,470 not exposed. Fifty-one subjects with PD were identified in the exposed group and 556 subjects in the non-exposed showing an association of adjusted HR = 1.7 (CI 1.3–2.3). The association was stronger for males (HR 2.2, CI 1.5–3.2) compared to females (HR 1.2, CI 0.8–1.9), for subjects ≤65 years of age (HR 2.4, CI 1.6–3.6) vs. >65 years (HR 1.3, CI 0.8–1.9) and for those with less comorbidities. Age and gender were confounders in the associations between antidepressant use and PD onset. Conclusions The use of antidepressants as indirect measure of depression is associated with the subsequent development of PD. Our findings confirm that depression may precede the onset of motor symptoms in PD. The association is stronger for younger subjects, who are males and with fewer comorbidities.

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 The degree of involvement of the autonomic nervous system in progressive supranuclear palsy (PSP) has been investigated in several studies, often providing conflicting results. There is a need for a better characterization of autonomic dysfunction in PSP, to enhance our understanding of this highly disabling neurodegenerative disease including patients’ needs and possibly be of value for clinicians in the differential diagnosis among Parkinsonian syndromes. Methods We applied a systematic methodology to review existing literature on Pubmed regarding autonomic nervous system involvement in PSP. Results PSP reported quite frequently symptoms suggestive of autonomic dysfunction in all domains. Cardiovascular autonomic testing showed in some cases a certain degree of impairment (never severe). There was some evidence suggesting bladder dysfunction particularly in the storage phase. Dysphagia and constipation were the most common gastrointestinal symptoms. Instrumental tests seemed to confirm sudomotor and pupillomotor disturbances. Conclusions PSP patients frequently reported visceral symptoms, however objective testing showed that not always these reflected actual autonomic impairment. Further studies are needed to better delineate autonomic profile and its prognostic role in PSP.

STUDY OBJECTIVES: To describe clinical and video-polysomnographic features of disorders of arousal (DoA) in older adults. METHODS: Four consecutive male patients with nocturnal motor behaviors underwent a clinical interview, neurologic examination, laboratory tests, brain magnetic resonance imaging, and nocturnal in-laboratory or 24- to 48-hour home video polysomnography. The patients repeated an evaluation after 6 months of follow-up, including a 48-hour home video polysomnography in 2 patients. RESULTS: The patients were aged 65-72 years, and 1 patient has Parkinson disease. Sleep-related behavioral episodes had begun from 12-55 years before our observation. Three patients presented with a positive family history for DoA. Sleep motor episodes were described as suddenly raising the head or trunk, sitting in bed, screaming, speaking, gesturing, and sleepwalking (in 1 patient). When questioned, all patients seemed confused, rarely reporting any dream-like content. We recorded 25 DoA episodes of different intensity and complexity arising from nonrapid eye movement sleep. The semiology of the episodes was similar to that described in younger patients, consisting of sleep terrors and confusional arousals. All patients presented with physiological rapid eye movement sleep muscle atonia. Medication therapy reduced the frequency of the episodes in 2/4 patients. CONCLUSIONS: DoA may begin in adulthood and persist or arise in older adults, sometimes causing sleep-related injuries. Motor patterns of DoA in older adults are similar to those of younger patients. A combined clinical examination and video polysomnography recording are crucial in establishing a definitive diagnosis of nocturnal motor behavior in all older adults and especially in those affected by neurodegenerative diseases. CITATION: Loddo G, Fragiacomo F, Mainieri G, etal. Disorders of arousal in 4 older men: evidence from clinical practice. J Clin Sleep Med. 2022;18(1):129-136.

© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes., Background and purpose: Disorders of the autonomic nervous system (ANS) are common conditions, but it is unclear whether access to ANS healthcare provision is homogeneous across European countries. The aim of this study was to identify neurology-driven or interdisciplinary clinical ANS laboratories in Europe, describe their characteristics and explore regional differences. Methods: We contacted the European national ANS and neurological societies, as well as members of our professional network, to identify clinical ANS laboratories in each country and invite them to answer a web-based survey. Results: We identified 84 laboratories in 22 countries and 46 (55%) answered the survey. All laboratories perform cardiovascular autonomic function tests, and 83% also perform sweat tests. Testing for catecholamines and autoantibodies are performed in 63% and 56% of laboratories, and epidermal nerve fiber density analysis in 63%. Each laboratory is staffed by a median of two consultants, one resident, one technician and one nurse. The median (interquartile range [IQR]) number of head-up tilt tests/laboratory/year is 105 (49-251). Reflex syncope and neurogenic orthostatic hypotension are the most frequently diagnosed cardiovascular ANS disorders. Thirty-five centers (76%) have an ANS outpatient clinic, with a median (IQR) of 200 (100-360) outpatient visits/year; 42 centers (91%) also offer inpatient care (median 20 [IQR 4-110] inpatient stays/year). Forty-one laboratories (89%) are involved in research activities. We observed a significant difference in the geographical distribution of ANS services among European regions: 11 out of 12 countries from North/West Europe have at least one ANS laboratory versus 11 out of 21 from South/East/Greater Europe (p = 0.021). Conclusions: This survey highlights disparities in the availability of healthcare services for people with ANS disorders across European countries, stressing the need for improved access to specialized care in South, East and Greater Europe.

Objective\ud We aimed to describe the prevalence and clinical-demographical features of patients with functional gait disorders (FGDs) and to compare them to patients with functional motor disorders (FMDs) without FGDs (No-FGDs).\ud \ud Methods\ud In this multicenter observational study, we enrolled patients with a clinically definite diagnosis of FMDs in 25 tertiary movement disorders centers in Italy. Each subject with FMDs underwent a comprehensive clinical assessment, including screening for different subtypes of functional gait disorders. Multivariate regression models were implemented in order to estimate the adjusted odds ratio (OR; 95% confidence interval) of having FGDs in relation to sociodemographic and clinical characteristics.\ud \ud Results\ud Out of 410 FMDs, 26.6% (n = 109) of patients exhibited FGDs. The most frequent FGDs were slow gait (n = 43, 39.4%), astasia-abasia (n = 26, 23.8%), and knee buckling (n = 24, 22%). They exhibited single FGDs in 51.4% (n = 56) or complex FGDs (more than one type of FGDs) in 48.6% (n = 53) of cases. On multivariate regression analysis, the presence of FGDs was more likely associated with older age (OR 1.03, 95% CI 1.01–1.04), functional visual symptoms (OR 2.19, 95% CI 1.08–4.45), and the diagnosis of somatic symptoms disorder (OR 2.97, 95% CI 1.08–8.17). FGDs were also more likely to undergo physiotherapy (OR 1.81, 95% CI 1.08–3.03).\ud \ud Conclusions\ud People with FMDs may present with different and overlapping types of FGDs, which may occur in older age. The association of FGDs with functional visual symptoms and somatic symptoms disorder opens up to new avenues to the understanding of the neural mechanisms of these disorders.

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.

A higher frequency of motor and breathing sleep-related disorders in multiple system atrophy (MSA) populations is reported. REM sleep behaviour disorder (RBD) is one of the most robust markers of an underlying alpha-synucleinopathy. Although a large corpus of literature documented the higher prevalence of RBD in MSA, few studies have systematically investigated the prevalence of RBD as mode of disease onset and its role in disease progression. Moreover, there has been increasing interest in phenoconversion into synucleinopathies of cohorts of patients with isolated RBD (iRBD). Finally, some studies investigated RBD as predictive factor of conversion in isolated autonomic failure, a synucleinopathy presenting with autonomic failure as the sole clinical manifestation that could convert to a manifest central nervous system synucleinopathy. As the field of neurodegenerative disorders moves increasingly towards developing disease-modifying therapies, detecting individuals in the prodromal stage of these synucleinopathies becomes crucial. The aims of this review are to summarise (1) the prevalence of RBD during the course of MSA and as presenting feature of MSA (iRBD), (2) the RBD features in MSA, (3) MSA progression and prognosis in the subgroup of patients with RBD predating disease onset, and (4) the prevalence of MSA conversion in iRBD cohorts. Moreover, we summarise previous results on the role of RBD in the context of isolated autonomic failure as marker of phenoconversion to other synucleinopathies and, in particular, to MSA.

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.

Myorhythmia is a hyperkinetic movement disorder characterized by slow, repetitive, rhythmic, cranial and limb contractions, typically disappearing during sleep. Infectious, autoimmune or vascular lesions involving brainstem or diencephalic structures are the most common etiologies.1 Anti-IgLON5 disease was originally reported as a progressive neurological syndrome characterized by a preeminent sleep disorder, variably associated with bulbar dysfunctions, gait instability, oculomotor abnormalities and cognitive decline.2, 3 Since initial descriptions, several hyperkinetic movement disorders have been described, including oro-facial myorhythmia in few cases.4, 5 We describe a case of anti-IgLON5 disease-related myorhythmia involving both facial and limb muscles, persisting during physiological and pathological sleep.

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.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a combination of autonomic failure plus cerebellar syndrome and/or parkinsonism. Dysphagia is a frequent and disabling symptom in MSA and its occurrence within 5 years of motor onset is an additional diagnostic feature. Dysphagia can lead to aspiration pneumonia, a recognized cause of death in MSA. Guidelines for diagnosis and management of dysphagia in MSA are lacking. An International Consensus Conference among experts with methodological support was convened in Bologna to reach consensus statements for the diagnosis, prognosis, and treatment of dysphagia in MSA. Abnormalities of the oral and pharyngeal phases of swallowing, esophageal dysfunction and aspiration occur in MSA and worsen as the disease progresses. According to the consensus, dysphagia should be investigated through available screening questionnaires and clinical and instrumental assessment (videofluoroscopic study or fiberoptic endoscopic evaluation of swallowing and manometry) at the time of MSA diagnosis and periodically thereafter. There is evidence that dysphagia is associated with poor survival in MSA, however effective treatments for dysphagia are lacking. Compensatory strategies like diet modification, swallowing maneuvers and head postures should be applied and botulinum toxin injection may be effective in specific conditions. Percutaneous endoscopic gastrostomy may be performed when there is a severe risk of malnutrition and pulmonary complications, but its impact on survival is undetermined. Several research gaps and unmet needs for research involving diagnosis, prognosis, and treatment were identified.

Introduction Functional motor disorders (FMDs) are usually categorized according to the predominant phenomenology; however, it is unclear whether this phenotypic classification mirrors the underlying pathophysiologic mechanisms. Objective To compare the characteristics of patients with different FMDs phenotypes and without co-morbid neurological disorders, aiming to answer the question of whether they represent different expressions of the same disorder or reflect distinct entities. Methods Consecutive outpatients with a clinically definite diagnosis of FMDs were included in the Italian registry of functional motor disorders (IRFMD), a multicenter data collection platform gathering several clinical and demographic variables. To the aim of the current work, data of patients with isolated FMDs were extracted. Results A total of 176 patients were included: 58 with weakness, 40 with tremor, 38 with dystonia, 23 with jerks/facial FMDs, and 17 with gait disorders. Patients with tremor and gait disorders were older than the others. Patients with functional weakness had more commonly an acute onset (87.9%) than patients with tremor and gait disorders, a shorter time lag from symptoms onset and FMDs diagnosis (2.9 ± 3.5 years) than patients with dystonia, and had more frequently associated functional sensory symptoms (51.7%) than patients with tremor, dystonia and gait disorders. Patients with dystonia complained more often of associated pain (47.4%) than patients with tremor. No other differences were noted between groups in terms of other variables including associated functional neurological symptoms, psychiatric comorbidities, and predisposing or precipitating factors. Conclusions Our data support the evidence of a large overlap between FMD phenotypes.

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.

Introduction: Cardiac [123I]metaiodobenzylguanidine scintigraphy (123I-MIBG) is considered a useful test in differentiating multiple system atrophy (MSA) and Lewy body disorders (LBD), including idiopathic Parkinson's disease (IPD), dementia with Lewy bodies (DLB) and pure autonomic failure (PAF). The detection of skin nerve phosphorylated α-synuclein (p-α-syn) deposits could be an alternative marker in vivo. We sought to compare 123I-MIBG scintigraphy and skin biopsy findings in α-synucleinopathies. Methods: We studied 54 patients (7 DLB, 21 IPD, 13 PAF, 13 MSA) who underwent 123I-MIBG scintigraphy and skin biopsy to evaluate cardiac innervation and skin p-α-syn deposition, respectively. Results: Cardiac denervation was observed in 90.5% IPD, 100% DLB and PAF and in none of the MSA patients (P < 0.0001) whereas p-α-syn deposits were detected in all DLB and PAF, in 95.2% of IPD and 69.2% of MSA patients (P = 0.02). However, the analysis of skin structures disclosed a different distribution of the deposits in somatic subepidermal plexus and autonomic fibers among groups, showing that p-α-syn deposits rarely affected the autonomic fibers in MSA as opposed to LBD. Studying the p-α-syn deposition in autonomic nerves, concordance among I123-MIBG scintigraphy and skin biopsy results was observed in 100% of DLB and PAF, 95.2% IPD and 92.3% MSA patients. I123-MIBG scintigraphy and autonomic p-α-syn deposits analysis both showed a sensitivity of 97.5% and a specificity of 100% and 92.3%, respectively, in distinguishing LBD and MSA. Conclusion: Skin biopsy and 123-MIBG scintigraphy can be considered alternative tests for the differential diagnosis of IPD, PAF and DLB versus MSA.

Background: Subthalamic deep brain stimulation (STN-DBS) effects may decrease with Parkinson’s disease (PD) progression. There is no indication if, when, and how to consider the interruption of DBS treatment in late-stage PD. The objective of the current study was to investigate the percentage of “poor stimulation responders” among late-stage PD patients for elaborating an algorithm to decide whether and when DBS discontinuation may be considered. Methods: Late-stage PD patients (Hoehn Yahr stage ≥4 and Schwab and England Scale

Background and purpose\ud The aims of this study were to describe the clinical manifestations of functional motor disorders (FMDs) coexisting with other neurological diseases (“comorbid FMDs”), and to compare comorbid FMDs with FMDs not overlapping with other neurological diseases (“pure FMDs”).\ud \ud Methods\ud For this multicenter observational study, we enrolled outpatients with a definite FMD diagnosis attending 25 tertiary movement disorder centers in Italy. Each patient with FMDs underwent a detailed clinical assessment including screening for other associated neurological conditions. Group comparisons (comorbid FMDs vs. pure FMDs) were performed in order to compare demographic and clinical variables. Logistic regression models were created to estimate the adjusted odds ratios (95% confidence intervals) of comorbid FMDs (dependent variable) in relation to sociodemographic and clinical characteristics (independent variables).\ud \ud Results\ud Out of 410 FMDs, 21.7% of patients (n = 89) had comorbid FMDs. The most frequent coexisting neurological diseases were migraine, cerebrovascular disease and parkinsonism. In the majority of cases (86.5%), FMDs appeared after the diagnosis of a neurological disease. Patients with comorbid FMDs were older, and more frequently had tremor, non‐neurological comorbidities, paroxysmal non‐epileptic seizures, major depressive disorders, and benzodiazepine intake. Multivariate regression analysis showed that diagnosis of comorbid FMDs was more likely associated with longer time lag until the final diagnosis of FMD, presence of tremor and non‐neurological comorbidities.\ud \ud Conclusions\ud Our findings highlight the need for prompt diagnosis of FMDs, given the relatively high frequency of associated neurological and non‐neurological diseases.

Background In the current consensus diagnostic criteria, the diagnosis of probable multiple system atrophy (MSA) is based solely on clinical findings, whereas neuroimaging findings are listed as aid for the diagnosis of possible MSA. There are overlapping phenotypes between MSA-parkinsonian type and Parkinson's disease, progressive supranuclear palsy, and dementia with Lewy bodies, and between MSA-cerebellar type and sporadic adult-onset ataxia resulting in a significant diagnostic delay and misdiagnosis of MSA during life. Objectives In light of an ongoing effort to revise the current consensus criteria for MSA, the Movement Disorders Society Multiple System Atrophy Study Group performed a systematic review of original articles published before August 2019. Methods We included articles that studied at least 10 patients with MSA as well as participants with another disorder or control group for comparison purposes. MSA was defined by neuropathological confirmation, or as clinically probable, or clinically probable plus possible according to consensus diagnostic criteria. Results We discuss the pitfalls and benefits of each diagnostic test and provide specific recommendations on how to evaluate patients in whom MSA is suspected. Conclusions This systematic review of relevant studies indicates that imaging and autonomic function tests significantly contribute to increasing the accuracy of a diagnosis of MSA.

Parkinson disease (PD) is characterized by a clear beneficial motor response to levodopa (LD) treatment. However, with disease progression and longer LD exposure, drug-related motor fluctuations usually occur. Recognition of the individual relationship between LD concentration and its effect may be difficult, due to the complexity and variability of the mechanisms involved. This work proposes an innovative procedure for the automatic estimation of LD pharmacokinetics and pharmacodynamics parameters, by a biologically-inspired mathematical model. An original issue, compared with previous similar studies, is that the model comprises not only a compartmental description of LD pharmacokinetics in plasma and its effect on the striatal neurons, but also a neurocomputational model of basal ganglia action selection. Parameter estimation was achieved on 26 patients (13 with stable and 13 with fluctuating LD response) to mimic plasma LD concentration and alternate finger tapping frequency along four hours after LD administration, automatically minimizing a cost function of the difference between simulated and clinical data points. Results show that individual data can be satisfactorily simulated in all patients and that significant differences exist in the estimated parameters between the two groups. Specifically, the drug removal rate from the effect compartment, and the Hill coefficient of the concentration-effect relationship were significantly higher in the fluctuating than in the stable group. The model, with individualized parameters, may be used to reach a deeper comprehension of the PD mechanisms, mimic the effect of medication, and, based on the predicted neural responses, plan the correct management and design innovative therapeutic procedures.

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.

We aimed to assess the intrasubject reproducibility of a technology-based levodopa (LD) therapeutic monitoring protocol administered in supervised versus unsupervised conditions in patients with Parkinson's disease (PD). The study design was pilot, intrasubject, single center, open and prospective. Twenty patients were recruited. Patients performed a standardized monitoring protocol instrumented by an ad hoc embedded platform after their usual first morning LD dose in two different randomized ambulatory sessions: one under a physician's supervision, the other self-administered. The protocol is made up of serial motor and non-motor tests, including alternate finger tapping, Timed Up and Go test, and measurement of blood pressure. Primary motor outcomes included comparisons of intrasubject LD subacute motor response patterns over the 3-h test in the two experimental conditions. Secondary outcomes were the number of intrasession serial test repetitions due to technical or handling errors and patients' satisfaction with the unsupervised LD monitoring protocol. Intrasubject LD motor response patterns were concordant between the two study sessions in all patients but one. Platform handling problems averaged 4% of total planned serial tests for both sessions. Ninety-five percent of patients were satisfied with the self-administered LD monitoring protocol. To our knowledge, this study is the first to explore the potential of unsupervised technology-based objective motor and non-motor tasks to monitor subacute LD dosing effects in PD patients. The results are promising for future telemedicine applications.

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.

Purpose: Patients suffering from cardiovascular autonomic failure often develop neurogenic supine hypertension (nSH), i.e., high blood pressure (BP) in the supine position, which falls in the upright position owing to impaired autonomic regulation. A committee was formed to reach consensus among experts on the definition and diagnosis of nSH in the context of cardiovascular autonomic failure. Methods: As a first and preparatory step, a systematic search of PubMed-indexed literature on nSH up to January 2017 was performed. Available evidence derived from this search was discussed in a consensus expert round table meeting in Innsbruck on February 16, 2017. Statements originating from this meeting were further discussed by representatives of the American Autonomic Society and the European Federation of Autonomic Societies and are summarized in the document presented here. The final version received the endorsement of the European Academy of Neurology and the European Society of Hypertension. Results: In patients with neurogenic orthostatic hypotension, nSH is defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, measured after at least 5 min of rest in the supine position. Three severity degrees are recommended: mild, moderate and severe. nSH may also be present during nocturnal sleep, with reduced-dipping, non-dipping or rising nocturnal BP profiles with respect to mean daytime BP values. Home BP monitoring and 24-h-ambulatory BP monitoring provide relevant information for a customized clinical management. Conclusions: The establishment of expert-based criteria to define nSH should standardize diagnosis and allow a better understanding of its epidemiology, prognosis and, ultimately, treatment.

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.

Objective To evaluate whether a battery of cardiovascular autonomic tests (Ewing's battery, EB) performed with a new integrated instrumental approach is useful in differentiating multiple system atrophy with predominant parkinsonism (MSA-P) from Parkinson's disease (PD) at an early stage. Methods We retrospectively analyzed EB tests of all the patients (n = 99) with a parkinsonian syndrome referred to our clinic who performed EB during the first diagnostic workup and were subsequently evaluated at least once a year until a final diagnosis of MSA-P (n = 34) or PD (n = 65). Thirty-eight controls matched for age and sex were included. EB consisted of head-up tilt test (HUTT), Valsalva manoeuvre (VM), deep breathing, and sustained handgrip whose correct execution and results were checked and obtained automatically. Results were compared between groups. Discriminant analysis was performed to identify MSA-P or PD patients. Results Orthostatic hypotension was found in 22 MSA-P and 3 PD patients. Cardiovascular reflexes indices were significantly more affected in MSA-P compared to PD and controls. EB presented a 91% sensitivity and 94% specificity in the differentiation of MSA-P and PD. HUTT + VM presented a 91% sensitivity and 92% specificity. Conclusions Our results suggest that EB or HUTT + VM performed with an integrated instrumental approach and analyzed with the discriminant procedure may distinguish MSA-P from PD at an early stage and might improve the accuracy of current diagnostic criteria. However, a validation in separate samples and prospective studies is needed.

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.

INTRODUCTION: The exact clinical and prognostic significance and the therapeutic implications of asystole induced by head-up tilt test are still a matter of debate. METHODS: We assessed, by means of a semi-structured interview, the long-term outcome of cardioinhibitory syncope in all the patients who presented a tilt-induced sinus arrest of more than 3 s in our Autonomic Unit between 1996 and 2010. CONCLUSIONS: Although syncopal recurrences were common, tilt-induced asystole did not imply a poor prognosis in terms of death or major therapeutic procedures.

The anxious hitting sleeper.

We investigated the prevalence of nocturnal eating (sleep-related eating disorder-SRED or night-eating syndrome-NES) in patients with restless legs syndrome (RLS). One hundred RLS patients living in Emilia-Romagna (Northern Italy) and 100 matched controls randomly selected from the general population received two telephone interviews, and were investigated for socio-demographic characteristics, general health status, and presence of nocturnal eating. Additionally, subjects underwent interviews for psychopathological traits [by means of the Eating Disorder Inventory-2 (EDI-2), the Maudsley Obsessive-Compulsive Inventory (MOCI), the Beck Depression Inventory (BDI)], excessive daytime sleepiness (EDS), and subjective sleep quality. Compared with controls, RLS patients had more frequently pathological MOCI scores (24% versus 10%, P = 0.03), used significantly more drugs for concomitant diseases and had more nocturnal sleep impairment and EDS. SRED was more prevalent in RLS patients than controls (SRED: 33% versus 1%, P < 0.001). Medication use and pathological MOCI scores were more prevalent in RLS patients with SRED than among RLS patients without SRED. Use of dopaminergic or hypnotic drugs for RLS was not correlated with the presence of SRED. We demonstrate an association between RLS and SRED. Prospective studies are needed to establish the mechanisms underlying such association and whether it is causal.

Objective Reflex Syncope (RS) is a self-limited loss of consciousness due to systemic arterial hypotension resulting from widespread vasodilatation and/or bradycardia. Higher neural centres have been implicated in the pathophysiology of RS, particularly in blood/injury phobic patients. We investigated interictal central autonomic functions in non-phobic RS subjects compared to non-phobic controls evaluating their central and cardiovascular responses to emotional stimuli. Methods Cardiovascular responses to Valsalva Manoeuvre (VM), Deep Breathing (DB) and during presentation of 108 slides selected from the International Affective Picture System were assessed in 20 non-phobic RS subjects and 20 controls. Slide onset visual event-related potentials (ERPs) were also computed. Results No significant difference in cardiovascular responses and ERP amplitude were found in non-phobic RS subjects and controls at rest, in response to VM and DB or during picture presentation. Conclusions Non-phobic patients with RS not only have a normal interictal autonomic control of the cardiovascular system but also a normal modulation and adaptation of central and cardiovascular response to emotional processing, in our experimental setting. Significance Non-phobic patients with RS present normal interictal central and cardiovascular responses. Autonomic dysfunction observed in phobic RS patients could be related to mechanisms underlying the phobia itself rather than the mechanisms causing RS.

Summary: Purpose: To describe the semiologic features of aggressive behaviors observed in human epileptic seizures with particular reference to the act of biting a conspecific. Methods: We analyzed the biting behavior (BB) and other aggressive gestures occurring in a group of 11 patients retrospectively selected from >1,000 patients subjected to videoEEG/SEEG monitoring for presurgical evaluation of drugresistant seizures. Results: Patients displaying BB showed (a) a male sex predominance, (b) heterogeneous etiologies and lesion locations, and (c) seizures involving the frontotemporal regions of both hemispheres. The act of biting was a rapid motor action, lasting ∼600 ms, occurring in the context of strong emotional arousal, fear, and anger, with various bodily gestures with aggressive connotation. BB was mainly a “reflexive” behavior, in that biting acts were evoked (both during and after seizures) by actions of people in close contact with the patient. The sole intrusion of the examiner’s hand in the space near the patient’s face was effective in triggering BB. Rarely, self-directed or object-directed biting acts were not triggered by external stimuli. Intracranial data (SEEG) obtained in one subject showed that the amygdala/hippocampal region plus the orbitomedial prefrontal cortex had to be involved by ictal activity to observe BB. Conclusions: Anatomic and electrophysiologic data in our patients suggest that a model of dual—temporal and frontal— dysfunction could account for the occurrence of ictal/postictal BB. Behavioral data suggest also that BB and related aggressive gestures can be considered as the emergence of instinctive behaviors with an adaptative significance of defense of the peripersonal space. Ke yW ords: Epilepsy—Aggression— Biting—Peripersonal space—Prefrontal cortex.

Central pattern generators (CPGs) are genetically determined neuronal aggregates in the mesencephalon, pons and spinal cord subserving innate motor behaviours essential for survival (feeding, locomotion, reproduction etc.). In higher primates CPGs are largely under neocortical control. We describe how certain motor events observed in parasomnias and epileptic seizures could have similar features and resemble motor behaviours, which can be the expression of the same CPG. Both epilepsy and sleep can lead to a temporary loss of control of neomammalian cortex that facilitates through a common platform (arousal) the emergences of stereotyped inborn fixed action patterns. Therefore we suggest that, independently from the nature of the trigger, be it a seizure or a parasomnia, the same CPGs can be involved, “caught up”, leading to a common motor semiology (the “Carillon theory”).