Maria Antonietta Volontè

Cause and course in a series of patients with sporadic chorea

Abstract.Objective: To identify correlations between clinical and neuroimaging features in sporadic chorea and to explicate the evolution of choreas of differing aetiologies. Methods: We analysed the clinical and neuroimaging data of 51 consecutive cases (17 males, 34 females; age 16–95 years) of sporadic chorea admitted to the neurology departments of two general hospitals from January 1994 to December 1999, and two neurological institutes from January 1997. Six months later the patients were reassessed clinically and those still with chorea (20 cases) were asked to undergo the genetic tests for Huntingtons disease and dentatorubropallidoluysian atrophy. Results: There were 9 cases of focal dyskinesias, 18 of hemichorea, and 24 of generalised chorea; onset was acute in 17, subacute in 27, and insidious in seven. Analysis permitted classification as follows: vascular-related (21 cases); vasculitis (1 case); hypoxia (2 cases); drug-induced (7 cases); AIDS-related (5 cases), borreliosis (1 case); Sydenhams chorea (1 case); hyperglycaemia (2 cases); hyponatraemia (2 cases); Huntingtons disease (HD) (5 cases) and acanthocytosis (1 case). In 3 patients neither etiological factors nor neuroradiological alterations were found. Conclusions: Although a convincing concordance between choreic signs and neuroradiological findings was possible in 4 patients only, it was possible to assign an aetiology in most cases with vascular related causes the most frequent and metabolic factors often participating. Huntingtons disease is not unusual as a cause of sporadic choreas. HIV infection is an emerging cause of chorea and AIDS-related disease should be considered in young patients presenting without a family history of movement disorders. We emphasize the importance of follow-up to identify persistent chorea for which genetic testing is mandatory.

Acute effects of L-dopa on event-related desynchronization in Parkinson's disease.

Abstract. We tested whether dispersible L-dopa has acute effects on event-related desynchronization (ERD) of the mu rhythm in patients with idiopathic Parkinsons disease (IPD). ERD to voluntary movement is delayed in akinetic IPD patients and improves after chronic L-dopa treatment. We evaluated ERD to self-paced finger movement in 14 IPD patients (before and 30–40 min after oral administration of dispersible L-dopa) and in 10 normal subjects. Sensorimotor ERD onset contralateral to movement was significantly delayed in IPD patients compared to normal subjects. This abnormality was no longer significant after L-dopa treatment. We conclude that a single dose of dispersible L-dopa can improve not only motor performance in IPD patients but also the timing of cortical activation of sensorimotor areas during motor programming.

Brain structural and functional connectivity in Parkinson's disease with freezing of gait

To use a multimodal approach to assess brain structural pathways and resting state (RS) functional connectivity abnormalities in patients with Parkinsons disease and freezing of gait (PD‐FoG).

Transcranial magnetic stimulation and silent period in spasmodic torticollis

OBJECTIVE Our objective was to study the corticobulbar projections to neck muscles in cervical dystonia. DESIGN We compared both the motor evoked potentials and the electromyographic silent period after transcranial magnetic stimulation from sternocleidomastoid and trapezius muscles in a group of 13 patients with spasmodic torticollis with those of 20 healthy volunteers. RESULTS With the target muscle at rest, no changes of motor threshold, motor evoked potentials latency, and amplitude were observed in dystonic patients. With facilitation, the mean amplitude of the motor evoked potentials was increased in patients compared with controls, the significant difference being for the trapezius muscle, whereas the latency did not differ between groups. The cortical silent period was significantly shorter in dystonic patients than in healthy subjects in both muscles. The duration of the cortical silent period recorded from the sternocleidomastoid muscle showed a positive correlation with the degree of neurologic disability assessed by Tsuis scale. No abnormalities of both nerve conduction velocity and peripheral silent period by stimulation of accessory nerve were found. CONCLUSIONS These results indicate an impairment of the mechanisms of inhibitory motor control in patients with spasmodic torticollis, which could be the result of a decrease of the basal ganglia inhibitory output over the motor cortex.

Excitatory deep repetitive transcranial magnetic stimulation with H-coil as add-on treatment of motor symptoms in Parkinson's disease: an open label, pilot study.

BACKGROUND Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a potential treatment for Parkinsons disease (PD). H-coils, inducing deeper and wider magnetic fields compared to traditional coils, may be potentially useful in PD, characterized by widespread, bilateral involvement of cortico-subcortical circuits. OBJECTIVE To evaluate the safety of repetitive deep TMS (rDTMS) with H-coil as add-on treatment of motor symptoms in PD. METHODS Twenty-seven PD patients (aged 60.1 ± 6.8 y; PD-duration: 6.3 ± 2.8 y; motor-UPDRS: 39.6 ± 10.1) underwent 12 rDTMS sessions over 4 weeks at excitatory (10 Hz) frequency over primary motor (M1) and bilateral prefrontal (PF) regions. Motor UPDRS off therapy was assessed before and after the last rDTMS session, together with safety records at each treatment session. RESULTS No drop-outs or adverse events were recorded. Motor UPDRS significantly improved after rDTMS (10.8 points average reduction; P < 0.0001). CONCLUSIONS High-frequency rDTMS might be a safe treatment for PD motor symptoms. Further placebo-controlled, randomized studies are warranted.

Pisa syndrome in Parkinson disease: An observational multicenter Italian study

Objective: To estimate the prevalence of Pisa syndrome (PS) in patients with Parkinson disease (PD) and to assess the association between PS and demographic and clinical variables. Methods: In this multicenter cross-sectional study, consecutive outpatients with PD attending 21 movement disorders Italian tertiary centers were enrolled and underwent standardized clinical evaluation. PS was defined as trunk lateral deviation ≥10°. Patients with PD were compared according to the presence of PS for several demographic and clinical variables. Results: Among 1,631 enrolled patients with PD, PS was detected in 143 patients (8.8%, 95% confidence interval 7.4%–10.3%). Patients with PS were older, had lower body mass index, longer disease duration, higher disease stages, and poorer quality of life. Falls were more frequent in the PS group as well as occurrence of “veering gait” (i.e., the progressive deviation toward one side when patient walked forward and backward with eyes closed). Patients with PS received higher daily levodopa equivalent daily dose and were more likely to be treated with combination of levodopa and dopamine agonists. Osteoporosis and arthrosis were significantly the most frequent associated medical conditions in patients with PS. Multiple explanatory variable logistic regression models confirmed the association of PS with the following variables: Hoehn and Yahr stage, ongoing combined treatment with levodopa and dopamine agonist, associated medical conditions, and presence of veering gait. Conclusions: Our results suggest that PS is a relatively frequent and often disabling complication in PD, especially in the advanced disease stages. The association is dependent on a number of potentially relevant demographic and clinical variables.

Axonal damage and loss of connectivity in nigrostriatal and mesolimbic dopamine pathways in early Parkinson's disease

A progressive loss of dopamine neurons in the substantia nigra (SN) is considered the main feature of idiopathic Parkinsons disease (PD). Recent neuropathological evidence however suggests that the axons of the nigrostriatal dopaminergic system are the earliest target of α-synuclein accumulation in PD, thus the principal site for vulnerability. Whether this applies to in vivo PD, and also to the mesolimbic system has not been investigated yet. We used [11C]FeCIT PET to measure presynaptic dopamine transporter (DAT) activity in both nigrostriatal and mesolimbic systems, in 36 early PD patients (mean disease duration in months ± SD 21.8 ± 10.7) and 14 healthy controls similar for age. We also performed anatomically-driven partial correlation analysis to evaluate possible changes in the connectivity within both the dopamine networks at an early clinical phase. In the nigrostriatal system, we found a severe DAT reduction in the afferents to the dorsal putamen (DPU) (η2 = 0.84), whereas the SN was the less affected region (η2 = 0.31). DAT activity in the ventral tegmental area (VTA) and the ventral striatum (VST) were also reduced in the patient group, but to a lesser degree (VST η2 = 0.71 and VTA η2 = 0.31). In the PD patients compared to the controls, there was a marked decrease in dopamine network connectivity between SN and DPU nodes, supporting the significant derangement in the nigrostriatal pathway. These results suggest that neurodegeneration in the dopamine pathways is initially more prominent in the afferent axons and more severe in the nigrostriatal system. Considering PD as a disconnection syndrome starting from the axons, it would justify neuroprotective interventions even if patients have already manifested clinical symptoms.

Brain plasticity in Parkinson’s disease with freezing of gait induced by action observation training

Gait disorders represent a therapeutic challenge in Parkinson’s disease (PD). This study investigated the efficacy of 4-week action observation training (AOT) on disease severity, freezing of gait and motor abilities in PD, and evaluated treatment-related brain functional changes. 25 PD patients with freezing of gait were randomized into two groups: AOT (action observation combined with practicing the observed actions) and “Landscape” (same physical training combined with landscape-videos observation). At baseline and 4-week, patients underwent clinical evaluation and fMRI. Clinical assessment was repeated at 8-week. At 4-week, both groups showed reduced freezing of gait severity, improved walking speed and quality of life. Moreover, AOT was associated with reduced motor disability and improved balance. AOT group showed a sustained positive effect on motor disability, walking speed, balance and quality of life at 8-week, with a trend toward a persisting reduced freezing of gait severity. At 4-week vs. baseline, AOT group showed increased recruitment of fronto-parietal areas during fMRI tasks, while the Landscape group showed a reduced fMRI activity of the left postcentral and inferior parietal gyri and right rolandic operculum and supramarginal gyrus. In AOT group, functional brain changes were associated with clinical improvements at 4-week and predicted clinical evolution at 8-week. AOT has a more lasting effect in improving motor function, gait and quality of life in PD patients relative to physical therapy alone. AOT-related performance gains are associated with an increased recruitment of motor regions and fronto-parietal mirror neuron and attentional control areas.

MRI signatures of the frontotemporal lobar degeneration continuum

Objective. To identify overlapping and unique grey (GM) and white matter (WM) signatures within the frontotemporal lobar degeneration (FTLD) continuum, and discriminate likely FTLD‐TAU and FTLD‐TDP patients using structural and diffusion tensor (DT) magnetic resonance imaging (MRI). Methods. T1‐weighted and DT MRI were collected from 121 subjects: 35 motor neuron disease (MND), 14 behavioral variant of frontotemporal dementia, 12 semantic and 11 nonfluent primary progressive aphasia, 21 progressive supranuclear palsy syndrome patients, and 28 healthy controls. Patterns of GM atrophy were established using voxel‐based morphometry. Tract‐based spatial statistics was used to perform a WM voxelwise analysis of mean diffusivity and fractional anisotropy. Results. In all clinical FTLD phenotypes, the pattern of WM damage was more distributed than that of GM atrophy. All patient groups, with the exception of MND cases with a pure motor syndrome, shared a focal GM atrophy centered around the dorsolateral and medial frontal cortex and a largely overlapping pattern of WM damage involving the genu and body of the corpus callosum and ventral frontotemporal and dorsal frontoparietal WM pathways. Surrounding this common area, phenotype (symptom)‐specific GM and WM regions of damage were found in each group. Conclusions. In the FTLD spectrum, WM disruption is more severe than GM damage. Frontal cortex and WM pathways represent the common target of neurodegeneration in these conditions. The topographic pattern of damage supports a “prion‐like” protein propagation through WM connections as underlying mechanism of the stereotyped progression of FTLD. Hum Brain Mapp 36:2602–2614, 2015.

Ceruloplasmin functional changes in Parkinson's disease-cerebrospinal fluid.

BackgroundCeruloplasmin, a ferroxidase present in cerebrospinal fluid (CSF), plays a role in iron homeostasis protecting tissues from oxidative damage. Its reduced enzymatic activity was reported in Parkinson’s disease (PD) contributing to the pathological iron accumulation. We previously showed that ceruloplasmin is modified by oxidation in vivo, and, in addition, in vitro by deamidation of specific NGR-motifs that foster the gain of integrin-binding function. Here we investigated whether the loss of ceruloplasmin ferroxidase activity in the CSF of PD patients was accompanied by NGR-motifs deamidation and gain of function.ResultsWe have found that endogenous ceruloplasmin in the CSF of PD patients showed structural changes, deamidation of the 962NGR-motif which is usually hidden within the ceruloplasmin structure, and the gain of integrin-binding function. These effects occur owing to the presence of abnormal levels of hydrogen peroxide we detected in the CSF of PD patients. Interestingly, the pathological CSFs environment of PD patients promoted the same modifications in the exogenously added ceruloplasmin, which in turn resulted in loss of ferroxidase-activity and acquisition of integrin-binding properties.ConclusionsWe show that in pathological oxidative environment of PD-CSF the endogenous ceruloplasmin, in addition to loss-of-ferroxidase function, is modified as to gain integrin-binding function. These findings, beside the known role of ceruloplasmin in iron homeostasis, might have important pathogenic implications due to the potential triggering of signals mediated by the unusual integrin binding in cells of central nervous system. Furthermore, there are pharmacological implications because, based on data obtained in murine models, the administration of ceruloplasmin has been proposed as potential therapeutic treatment of PD, however, the observed CSFs pro-oxidant properties raise the possibility that in human the ceruloplasmin-based therapeutic approach might not be efficacious.