Italian inter-societal consensus for the biomarker-based etiological diagnosis in MCI M. Boccardi1, V. Nicolosi1, C. Festari1, A. Bianchetti2, S. Cappa1, D. Chiasserini3, A. Falini4, U. Guerra5, F. Nobili6, A. Padovani7, G.M. Sancesario8, S.D. Morbelli9, L. Parnetti10, P. Tiraboschi11, C. Muscio11, D. Perani12, F.B. Pizzini13, A. Beltramello14, G. Salvini Porro15, M. Ciaccio16, O. Schillaci17, M. Trabucchi17, F. Tagliavini11, G.B. Frisoni1 1Laboratory of Alzheimer’s Neuroimaging and Epidemiology, IRCCS Fatebenefratelli, Brescia, Italy, 2Medicine and Rehabilitation Department, Istituto Clinico S. Anna, Brescia, Italy, 3Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy, 4Neuroradiology, Università Vita-Salute San Raffaele, Milan, Italy, 5Department of Nuclear Medicine, Poliambulanza Foundation, Brescia, Italy, 6Clinical Neurology, Department of Neuroscience (DINOGMI), University of Genoa, Genoa, Italy, 7Department of Neurology, University of Brescia, Brescia, Italy, 8Fondazione Policlinico Tor Vergata, Rome, Italy, 9University of Genova, Genoa, Italy, 10University of Perugia, Perugia, Italy, 11Division of Neurology V/ Neuropathology, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy, 12Vita-Salute San Raffaele University, Milan, Italy, 13Neuroradiology, Department of Diagnostics and Pathology, Verona University Hospital, Verona, Italy, 14Department of Neuroradiology, General Hospital, Verona, Verona, Italy, 15Federazione Alzheimer Italia, Milan, Italy, 16University of Palermo, Palermo, Italy, 17University of Rome Tor Vergata, Rome, Italy Background and aims: Biomarkers support the etiological diagnosis of neurodegenerative diseases. However, data allowing defining an evidence-based diagnostic procedure for their combined use are lacking. We aim to develop a consensual diagnostic algorithm to guide clinicians’ use. Methods: Dementia experts joined a Delphi procedure on behalf of five Italian Scientific Societies (SINdem, AIP, AIMN, AINR, and SIBioC). Majority was assumed with at least 80% consistent responses. Results: The panelists selected the 2011 NIA-AA criteria as the conceptual framework minimizing false positives and unnecessary biomarker prescription. In seven voting rounds, the panel identified a diagnostic algorithm including: clinical and cognitive assessment, blood examination and MRI with both exclusionary and inclusionary value at baseline. Different examination is then prescribed based on the diagnostic hypothesis: I-123 MIBG cardiac scintigraphy for suspected DLB, FDG-PET for suspected FTLD and low confidence of AD, and CSF, or amyloid-PET as second choice, for suspected AD. Biomarker investigation for AD in older patients with consistent clinical and MRI findings should be considered based on its plausible clinical impact. Conclusion: This is the first consensual algorithm for an etiological biomarker-based diagnosis of dementing neurodegenerative disorders in MCI patients. Although grounded on expert opinion, these recommendations attempt to maximize biomarkers informative value over costs. Disclosure: This work was supported by the Italian Health Ministry grant NET-2011-02346784 and the EU-EFPIA Innovative Medicines Initiative 2 Joint Undertaking grant N° 115952 (AMYPAD).

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a combination of autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor is an additional feature for MSA diagnosis, showing a high diagnostic positive predictive value, and its early occurrence might contribute to shorten survival. A consensus definition of stridor in MSA is lacking, and disagreement persists about its diagnosis, prognosis, and treatment. An International Consensus Conference among experts with methodological support was convened in Bologna in 2017 to define stridor in MSA and to reach consensus statements for the diagnosis, prognosis, and treatment. Stridor was defined as a strained, high-pitched, harsh respiratory sound, mainly inspiratory, occurring only during sleep or during both sleep and wakefulness, and caused by laryngeal dysfunction leading to narrowing of the rima glottidis. According to the consensus, stridor may be recognized clinically by the physician if present at the time of examination, with the help of a witness, or by listening to an audio recording. Laryngoscopy is suggested to exclude mechanical lesions or functional vocal cord abnormalities related to different neurologic conditions. If the suspicion of stridor needs confirmation, drug-induced sleep endoscopy or video polysomnography may be useful. The impact of stridor on survival and quality of life remains uncertain. Continuous positive airway pressure and tracheostomy are both suggested as symptomatic treatment of stridor, but whether they improve survival is uncertain. Several research gaps emerged involving diagnosis, prognosis, and treatment. Unmet needs for research were identified.

Clinical evaluation is of utmost importance in the semeiological description of motor disorders which often require video recording to highlight subtle signs and their subsequent evolution. After reviewing 1858 video recordings, we composed a suitable list of video-documentation maneuvers, classified semeiologically in the form of a "video recording protocol", to guarantee appropriate documentation when filming movement disorders. Aware that our proposed filming protocol is far from being exhaustive, by suggesting a more detailed documenting approach, it could help not only to achieve a better definition of some disorders, but also to guide neurologists towards the correct subsequent examinations. Moreover, it could be an important tool for the longitudinal evaluation of patients and their response to therapy. Finally, video recording is a powerful teaching tool as visual teaching highly improves educational training.

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.

Neurofilament light chain protein (NfL) is a surrogate biomarker of neurodegeneration that has never been systematically tested, either alone or in combination with other biomarkers, in atypical/rapidly progressive neurodegenerative dementias (NDs).

Diagnostic value of CSF biomarkers in the comparison between subjects with ND and control subjects. Table S2. Diagnostic value of CSF biomarkers in the differential diagnosis of prion disease, AD, and FTLD. Figure S1. ROC analysis of CSF biomarkers in the comparison between prion disease and AD. Figure S2. ROC analysis of CSF biomarkers in the comparison between atypical prion disease and other atypical/rapidly progressive NDs. Figure S3. ROC analysis of CSF biomarkers in the comparison between atypical prion disease and atypical/rapidly progressive AD. (DOCX 1967 kb)

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Restless legs syndrome (RLS) typically affects the limbs, but the involvement of other body parts has also been reported. In this essay, we critically review all literature reports of atypical RLS cases with unusual localizations. Applying the updated diagnostic criteria of the International restless legs syndrome study group (IRLSSG), which also consider symptoms localized outside of the lower limbs, a few of these atypical cases reported in the previous literature resulted in a definitive diagnosis of RLS. We also discuss the relationship between RLS and burning mouth syndrome (BMS) or restless genital syndrome (RGS). We conclude clinical sleep specialists should be aware of unusual RLS localizations because they respond to the usual treatment for RLS. All the IRLSSG diagnostic criteria should be applied in every suspected case, in order to establish a correct diagnosis of this disabling but treatable condition.

IntroductionImpaired sleep has been reported as an important nonmotor feature in dystonia, but so far, self-reported complaints have never been compared with nocturnal video-polysomnographic (PSG) recording, which is the gold standard to assess sleep-related disorders.MethodsTwenty patients with idiopathic isolated cervical dystonia and 22 healthy controls (HC) underwent extensive clinical investigations, neurological examination, and questionnaire screening for excessive daytime sleepiness and sleep-related disorders. A full-night video PSG was performed in both patients and HC. An ad hoc montage, adding electromyographic leads over the muscle affected with dystonia, was used.ResultsWhen compared to controls, patients showed significantly increased pathological values on the scale assessing self-reported complaints of impaired nocturnal sleep. Higher scores of impaired nocturnal sleep did not correlate with any clinical descriptors but for a weak correlation with higher scores on the scale for depression. On video-PSG, patients had significantly affected sleep architecture (with decreased sleep efficiency and increased sleep latency). Activity over cervical muscles disappears during all the sleep stages, reaching significantly decreased values when compared to controls both in nonrapid eye movements and rapid eye movements sleep.ConclusionsPatients with cervical dystonia reported poor sleep quality and showed impaired sleep architecture. These features however cannot be related to the persistence of muscle activity over the cervical muscles, which disappears in all the sleep stages, reaching significantly decreased values when compared to HC.

With the advances in neuroimmunology especially due to the discovery of new neuronal antibodies, the recognition of treatable antibody-related movement disorders has recently received much attention. In contrast, the identification and characterisation of movement disorders associated with systemic autoimmune diseases remains a substantially unexplored area. Beyond the classic few associations such as chorea and antiphospholipid syndrome, or ataxia and coeliac disease, movement disorders have been reported in association with several systemic autoimmune diseases, however a clear image of clinical phenotypes, investigations, and treatment outcomes in these conditions has never been drawn. In this review, we analyse data from approximately 300 cases and summarise the epidemiological, clinical and diagnostic features of movement disorders associated with systemic autoimmune diseases, and the available knowledge about treatment and outcomes. We highlight that movement disorders in systemic autoimmune conditions are frequently the only or among a few presenting manifestations and are mostly treatable disorders responding to immunotherapy or dietary modifications. We point out the pertinent combination of clinical features and investigations which can suggest the underlying autoimmune nature of these movement disorders, and thus address the most appropriate treatment.

The differential diagnosis between multiple system atrophy with predominant parkinsonism (MSA-P) and Parkinson’s disease (PD) may be challenging at disease onset. Levodopa responsiveness helps distinguish the two groups, but studies evaluating this issue using objective standardized tests are scanty. We retrospectively examined the extent of levodopa response by an objective kinetic-dynamic test in a series of patients prospectively followed up for a parkinsonian syndrome and eventually diagnosed as MSA-P or PD. Sixteen MSA-P and 31 PD patients under chronic levodopa therapy received a first morning fasting dose of levodopa/benserazide (100/25 mg) or levodopa/carbidopa (125/12.5 or 100/25 mg) and underwent simultaneous serial assessments of plasma levodopa concentration and alternate finger tapping frequency up to 3 h post dosing. The main levodopa pharmacodynamic variables were the maximum percentage increase in tapping frequency over baseline values (ΔTapmax %) and the area under the tapping effect–time curve (AUCTap). Levodopa pharmacokinetics did not show significant differences between MSA-P and PD, whereas both the magnitude and overall extent of levodopa tapping effect were markedly reduced in the MSA-P group (p < 0.001). The combined use of specific cut-off values for both the main pharmacodynamic variables, ΔTapmax % <20 % and AUCTap <1900 [(tapping/min)·min], correctly discriminated 15 out of 16 MSA-P patients from PD patients. A combined estimation of these pharmacodynamic variables after a subacute low levodopa dose may be a simple and practical clinical tool to aid the differential diagnosis between MSA-P and PD.

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. (C) 2015 Elsevier Ltd. All rights reserved.

BACKGROUND:(123) I-meta-iodobenzylguanidine ((123) I-MIBG) myocardial scintigraphy is considered reliable in differentiating idiopathic Parkinson's disease (IPD) from other parkinsonisms, but it is biased by pharmacological treatments. Skin biopsy is not influenced by therapy and has disclosed skin denervation in IPD. Our aims were to compare (123) I-MIBG scintigraphy and skin biopsy findings in IPD and parkinsonisms to (1) verify whether myocardial and skin denervations are linked; (2) explore the simultaneous extent of the autonomic dysfunction. METHODS:We studied 22 IPD and 11 parkinsonism patients by means of (123) I-MIBG scintigraphy and skin biopsies. RESULTS:In the IPD group, both (123) I-MIBG scintigraphy and skin biopsy results were abnormal in 91% of patients, showing concordance in 82% of cases. In parkinsonisms, results of both tests were normal in all patients. CONCLUSION:(1) Skin biopsy and (123) I-MIBG scintigraphy provide comparable results; (2) in IPD, autonomic dysfunctions are often simultaneously widespread at cardiac and skin branches. © 2015 International Parkinson and Movement Disorder Society.

OBJECTIVE:To investigate (1) whether phosphorylated α-synuclein deposits in skin nerve fibers might represent a useful biomarker for idiopathic Parkinson disease (IPD), and (2) the underlying pathogenesis of peripheral neuropathy associated with IPD.METHODS:Twenty-one well-characterized patients with IPD were studied together with 20 patients with parkinsonisms assumed not to have α-synuclein deposits (PAR; 10 patients fulfilling clinical criteria for vascular parkinsonism, 6 for tauopathies, and 4 with parkin mutations) and 30 controls. Subjects underwent nerve conduction velocities from the leg to evaluate large nerve fibers and skin biopsy from proximal (i.e., cervical) and distal (i.e., thigh and distal leg) sites to study small nerve fibers and deposits of phosphorylated α-synuclein considered the pathologic form of α-synuclein.RESULTS:Patients with IPD showed a small nerve fiber neuropathy prevalent in the leg with preserved large nerve fibers. PAR patients showed normal large and small nerve fibers. Phosphorylated α-synuclein was not found in any skin sample in PAR patients and controls, but it was found in all patients with IPD in the cervical skin site. Abnormal deposits were correlated with leg epidermal denervation.CONCLUSIONS:The search for phosphorylated α-synuclein in proximal peripheral nerves is a sensitive biomarker for IPD diagnosis, helping to differentiate IPD from other parkinsonisms. Neuritic inclusions of α-synuclein were correlated with a small-fiber neuropathy, suggesting their direct role in peripheral nerve fiber damage.CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that the presence of phosphorylated α-synuclein in skin nerve fibers on skin biopsy accurately distinguishes IPD from other forms of parkinsonism.

Cellular mechanism leading to Parkinson Disease (PD) is still unknown, but impairment of lysosomal degradation of aberrant proteins seems to play a crucial role. The most known lysosomal disease associated with PD is Gaucher Disease. However, actually a number of different lysosomal disorders have been linked with PD. We report three families with Arylsulphatase A partial deficit in which we can find a high recurrence of parkinsonism among the siblings. The pedigree members show as well some atypical signs and symptoms among the PD spectrum features. Arylsulphatase A plays a crucial role in protein degradation. Even if a possibly casual association cannot be excluded, it can be speculated that Arylsulphatase A partial deficit can act as a cofactor for neurodegeneration in subjects with other genetic or environmental predispositions to PD or to other neurodegenerative disease.

ABSTRACT Background Primary familial brain calcification (PFBC) is a rare autosomal dominant disorder with bilateral calcification of basal ganglia and other cerebral regions, movement disorders, and neuropsychiatric disturbances. So far, three causative genes have been discovered: SLC20A2 , PDGFRB and PDGFB , accounting for approximately 50% of cases. Methods Seven unrelated families with primary brain calcification were recruited to undergo clinical and genetic analysis, including Sanger sequencing of SLC20A2 , PDGFRB, and PDGFB , and copy number analysis of SLC20A2 . Results Mutations in SLC20A 2 have been detected in three families: p.Glu368Glyfs*46, p.Ser434Trp, and p.Thr595Met. Intrafamilial phenotype variability has been observed. In spite of this, we found similar neuroimaging pattern among members of the same family. Conclusions This molecular analysis expands the mutational spectrum of SLC20A2, which remains the major causative gene of primary familial brain calcification, and suggests the existence of disease‐causing mutations in at least another, still unknown gene. © 2014 International Parkinson and Movement Disorder Society