Increased glucosylsphingosine levels and Gaucher disease in GBA1-associated Parkinson's disease.

INTRODUCTION: Gaucher's disease (GD) is caused by biallelic mutations in the GBA1 gene, leading to reduced glucocerebrosidase (GCase) activity and substrate (glucosylceramide and glucosylsphingosine, GlcSph) accumulation. GBA1 variant carriers are at risk of Parkinson's disease (PD), but only those with biallelic mutations cross the threshold of GCase reduction, leading to substrate accumulation and GD. The link between GBA1 mutations, GD and PD is not fully understood. Here we aimed at reporting the results of a large PD population screening with dried blood spot tests for GD. METHODS: We measured GCase activity and GlcSph levels in 1344 PD patients with dried blood spot tests, and performed GBA1 genetic sequencing. RESULTS: While the GCase activity was reduced in GBA1-PD carriers compared to wild type PD, GlcSph was increased in GBA1-PD compared to GBA1-controls, regardless of the underlying type of GBA1 variant. 13.6 % and 0.4 % of PD patients had mono- or biallelic GBA1 mutations respectively. GCase deficiency, lipid accumulation and clinical manifestations of GD was detected in five PD patients with biallelic GBA1 mutations, of whom four had a risk combined with a GD causing variant. CONCLUSIONS: GlcSph appearing higher in PD may represent a reliable biomarker of the disease and deserves to be further investigated. This study highlights the importance of screening PD patients for possible underlying GD, which is a treatable condition that should not be missed. We diagnosed GD cases carrying a "risk" variant in one allele, which is an unprecedented finding deserving further investigation.

Artificial intelligence of imaging and clinical neurological data for predictive, preventive and personalized (P3) medicine for Parkinson Disease: The NeuroArtP3 protocol for a multi-center research study.

BACKGROUND: The burden of Parkinson Disease (PD) represents a key public health issue and it is essential to develop innovative and cost-effective approaches to promote sustainable diagnostic and therapeutic interventions. In this perspective the adoption of a P3 (predictive, preventive and personalized) medicine approach seems to be pivotal. The NeuroArtP3 (NET-2018-12366666) is a four-year multi-site project co-funded by the Italian Ministry of Health, bringing together clinical and computational centers operating in the field of neurology, including PD. OBJECTIVE: The core objectives of the project are: i) to harmonize the collection of data across the participating centers, ii) to structure standardized disease-specific datasets and iii) to advance knowledge on disease's trajectories through machine learning analysis. METHODS: The 4-years study combines two consecutive research components: i) a multi-center retrospective observational phase; ii) a multi-center prospective observational phase. The retrospective phase aims at collecting data of the patients admitted at the participating clinical centers. Whereas the prospective phase aims at collecting the same variables of the retrospective study in newly diagnosed patients who will be enrolled at the same centers. RESULTS: The participating clinical centers are the Provincial Health Services (APSS) of Trento (Italy) as the center responsible for the PD study and the IRCCS San Martino Hospital of Genoa (Italy) as the promoter center of the NeuroartP3 project. The computational centers responsible for data analysis are the Bruno Kessler Foundation of Trento (Italy) with TrentinoSalute4.0 -Competence Center for Digital Health of the Province of Trento (Italy) and the LISCOMPlab University of Genoa (Italy). CONCLUSIONS: The work behind this observational study protocol shows how it is possible and viable to systematize data collection procedures in order to feed research and to advance the implementation of a P3 approach into the clinical practice through the use of AI models.

Parkinsonism may aggravate dysphagia in myotonic dystrophy type 1: two case reports.

Introduction: Weakness of trunk muscles, fatigue and reduced mobility are features of myotonic dystrophy type 1 (DM1) and may also characterize patients with extrapyramidal disorders.Dysphagia is common in DM1 and parkinsonism and can be predominant compared to other symptom, often requiring surgical tratment. Methods: We describe two cases of patients with DM1 and parkinsonism who arrived at our Center for worsening dysphagia and who showed very similar and peculiar clinical features. Case reports: The first patient presented initially at the outpatient clinic reporting a 7 year history of progressive difficulties in swallowing and movement slowness. Neurologic examination showed a general bradykinesia, plastic rigidity of upper limbs, diffuse hypotrophy and deep tendon reflexes weakness. MRI scan of brain and spine was unremarkable, but neurophysiological evaluation revealed diffuse myotonic discharges on distal limb muscles. Genetic testing confirmed DM1 diagnosis (CTG range E1).The second patient, presented with an initial diagnosis of parkinsonism due to a 10 years history of gait impairment, generalized weakness and dysphagia. Due to low back pain a neurophysiological study was performed after 5 years from diagnosis of parkinsonism detecting diffuse myotonic discharges and genetic testing confirmed diagnosis of DM1 (CTG range E2).Percutaneous endoscopic gastrostomy (PEG) was severe and burdensome for both patients.To date, only one case of molecularly confirmed DM1 along with parkinsonism has been described. We have described two cases of DM1 and parkinsonism in which swallowing function has been affected by a synergic effect triggered by both muscle condition and extrapyramidal disease.

Brain 18F-FDG and 18F-Flumetamol PET Imaging of Fragile X-Associated Tremor Ataxia Syndrome.

ABSTRACT: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a rare movement disorder caused by a 55-to-200 CGG-trinucleotide expansion premutation in the FMR1 gene. Core diagnostic criteria are tremor, ataxia, and T2-weighted hyperintensity of the middle cerebellar peduncles on MRI, but FXTAS encompass a broad spectrum of neurological symptoms. FXTAS pathophysiology is largely unknown, and some animal models and neuropathology findings suggest possible overlap with Alzheimer disease. We report the combined PET imaging of a genetically confirmed FXTAS patient, presenting reduced temporal-frontal 18F-FDG uptake, and pathological cortical deposition of amyloid to 18F-flumetamol PET scan. This report may offer clues to FXTAS pathophysiology.

Incremental value of amyloid-PET versus CSF in the diagnosis of Alzheimer's disease.

PURPOSE: To compare the incremental diagnostic value of amyloid-PET and CSF (Aß42, tau, and phospho-tau) in AD diagnosis in patients with mild cognitive impairment (MCI) or mild dementia, in order to improve the definition of diagnostic algorithm. METHODS: Two independent dementia experts provided etiological diagnosis and relative diagnostic confidence in 71 patients on 3 rounds, based on (1) clinical, neuropsychological, and structural MRI information alone; (2) adding one biomarker (CSF amyloid and tau levels or amyloid-PET with a balanced randomized design); and (3) adding the other biomarker. RESULTS: Among patients with a pre-biomarker diagnosis of AD, negative PET induced significantly more diagnostic changes than amyloid-negative CSF at both rounds 2 (CSF 67%, PET 100%, P = 0.028) and 3 (CSF 0%; PET 78%, P < 0.001); PET induced a diagnostic confidence increase significantly higher than CSF on both rounds 2 and 3. CONCLUSIONS: Amyloid-PET should be prioritized over CSF biomarkers in the diagnostic workup of patients investigated for suspected AD, as it provides greater changes in diagnosis and diagnostic confidence. TRIAL REGISTRATION: EudraCT no.: 2014-005389-31.

Toward a Wearable System for Predicting Freezing of Gait in People Affected by Parkinson's Disease.

Some wearable solutions exploiting on-body acceleration sensors have been proposed to recognize Freezing of Gait (FoG) in people affected by Parkinson Disease (PD). Once a FoG event is detected, these systems generate a sequence of rhythmic stimuli to allow the patient restarting the gait. While these solutions are effective in detecting FoG events, they are unable to predict FoG to prevent its occurrence. This paper fills in the gap by presenting a machine learning-based approach that classifies accelerometer data from PD patients, recognizing a pre-FOG phase to further anticipate FoG occurrence in advance. Gait was monitored by three tri-axial accelerometer sensors worn on the back, hip and ankle. Gait features were then extracted from the accelerometer's raw data through data windowing and non-linear dimensionality reduction. A k-nearest neighbor algorithm (k-NN) was used to classify gait in three classes of events: pre-FoG, no-FoG and FoG. The accuracy of the proposed solution was compared to state-of-the-art approaches. Our study showed that: (i) we achieved performances overcoming the state-of-the-art approaches in terms of FoG detection, (ii) we were able, for the very first time in the literature, to predict FoG by identifying the pre-FoG events with an average sensitivity and specificity of, respectively, 94.1% and 97.1%, and (iii) our algorithm can be executed on resource-constrained devices. Future applications include the implementation on a mobile device, and the administration of rhythmic stimuli by a wearable device to help the patient overcome the FoG.

Medial temporal lobe atrophy and posterior atrophy scales normative values.

OBJECTIVES: The medial temporal lobe atrophy (MTA) and the posterior atrophy (PA) scales allow to assess the degree hippocampal and parietal atrophy from magnetic resonance imaging (MRI) scans. Despite reliable, easy and widespread employment, appropriate normative values are still missing. We aim to provide norms for the Italian population. METHODS: Two independent raters assigned the highest MTA and PA score between hemispheres, based on 3D T1-weighted MRI of 936 Italian Brain Normative Archive subjects (age: mean ±â€¯SD: 50.2 ±â€¯14.7, range: 20-84; MMSE>26 or CDR = 0). The inter-rater agreement was assessed with the absolute intraclass correlation coefficient (aICC). We assessed the association between MTA and PA scores and sociodemographic features and APOE status, and normative data were established by age decade based on percentile distributions. RESULTS: Raters agreed in 90% of cases for MTA (aICC = 0.86; 95% CI = 0.69-0.98) and in 86% for PA (aICC = 0.82; 95% CI = 0.58-0.98). For both rating scales, score distribution was skewed, with MTA = 0 in 38% of the population and PA = 0 in 52%, while a score ≥ 2 was only observed in 12% for MTA and in 10% for PA. Median denoted overall hippocampal (MTA: median = 1, IQR = 0-1) and parietal (PA: median = 0, IQR = 0-1) integrity. The 90th percentile of the age-specific distributions increased from 1 (at age 20-59) for both scales, to 2 for PA over age 60, and up to 4 for MTA over age 80. Gender, education and APOE status did not significantly affect the percentile distributions in the whole sample, nor in the subset over age 60. CONCLUSIONS: Our normative data for the MTA and PA scales are consistent with previous studies and overcome their main limitations (in particular uneven representation of ages and missing percentile distributions), defining the age-specific norms to be considered for proper brain atrophy assessment.

Twelve-year Follow-up of A Large Italian Family with Atypical Phenotypes of DYT1-dystonia.

BACKGROUND: A heterozygous mutation in the TOR1A gene (DYT1) accounts for isolated dystonia typically presenting during childhood or adolescence, with initial involvement of one limb, spreading rapidly to other limbs and the trunk, sparing craniocervical muscles. However, atypical phenotypes, regarding age at onset, site of presentation, and spreading have been reported. METHODS AND FINDINGS: In 2006, we described a large Italian family showing atypical phenotypes and intrafamilial clinical variability of DYT1-dystonia. The current article reports on a 12-year follow-up of this family, focusing on disease onset in three previously asymptomatic DYT1 mutation carriers, and the reassessment of initially affected individuals. CONCLUSIONS: The new cases confirm the intrafamilial phenotypic heterogeneity of DYT1-dystonia. Moreover, this case series highlights that symptoms in atypical phenotypes seem not to spread significantly and in the long term, rarely worsen. Prolonged follow-up of DYT1-positive pedigrees may expand the clinical spectrum of DYT1-dystonia.

Tremor induced by Calcineurin inhibitor immunosuppression: a single-centre observational study in kidney transplanted patients.

INTRODUCTION: Tremor is the most frequent and disabling neurological side effect under Calcineurin inhibitor-induced immunosuppression, but no studies have defined its phenomenology, severity, distribution, the impact on quality of life, as well as of other neurological symptoms associated. METHODS: 126 consecutive kidney-transplanted patients, under treatment with Cyclosporin A, Tacrolimus and non-Calcineurin inhibitors, within therapeutic range, were enrolled. Participants underwent a deep neurological examination by two blinded to the treatment raters, and a blood sampling to assess plasmatic immunosuppressant level and nephrological function tests. Tremor and cerebellar signs were scored according to the Fahn-Tolosa-Marin and the SARA scale. Parkinsonism was excluded applying the UPDRS (part III). RESULTS: Tremor was more common and severe in the Tacrolimus group, similar to impairment in ADL. Regardless of treatment, tremor involved both upper and lower limbs and was activated by action, but in about 50% of cases presented in action and rest condition. Plasmatic level of Tacrolimus was higher in patients with tremor than in those without, while cholesterol was significantly lower. Cerebellar and neuropathic signs were overall mild and were not significantly different across the three groups comparing patients with and without tremor. CONCLUSIONS: Non-Calcineurin inhibitors such as Sirolimus have the lowest propensity to induce tremor and with a milder severity, while Calcineurin inhibitors, especially Tacrolimus, the highest, and regardless of the formulation. Plasmatic concentration of Tacrolimus was higher in tremulous patients; further research needs to validate the role of cholesterol plasmatic concentration in predicting the occurrence of tremor in patients on Tacrolimus.

Abnormal nociceptive processing occurs centrally and not peripherally in pain-free Parkinson disease patients: A study with laser-evoked potentials.

BACKGROUND: Several studies documented abnormal nociceptive processing in PD patients. Pain central pathways are accessible by laser-evoked potentials (LEPs). LEPs recording show a N2/P2 complex mostly generated by the anterior cingulate cortex, preceded by an earlier negative component (N1), originating from the opercular cortex. Previous work demonstrated N2/P2 amplitude reduction in PD patients and suggested a centrally-acting pathomechanism for the genesis of pain. However, since a peripheral deafferentation has been recently demonstrated in PD, it is not clear if such LEP abnormalities reflect a mechanism acting centrally or not. OBJECTIVE: To assess whether abnormalities of nociceptive inputs occur at central and/or peripheral level in pain-free PD patients with hemiparkinson using Nd:YAP LEPs. METHODS: We recorded scalp Nd:YAP-LEPs to hand stimulation in 13 pain-free patients with unilateral PD and in 13 healthy subjects. Additionally, we collected laser pain-rating in both groups. RESULTS: PD patients and normal subjects showed comparable N1, N2 and P2 latencies. The N2/P2 amplitude was significantly lower in PD patients than in controls, regardless of the clinically affected side, whereas the N1/P1 amplitude was not different. PD patients had higher pain-rating, indicative of hyperalgesia. CONCLUSIONS: These findings demonstrate that in the PD patients the abnormal processing of pain stimuli occurs at central rather than peripheral level. The co-existence of hyperalgesia and reduced amplitude of the N2/P2 complex, in spite of a normal N1/P1 component, suggests an imbalance between the medial and lateral pain systems. Such a dissociation might explain the genesis of central pain in PD.