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Impaired reach-to-grasp kinematics in parkinsonian patients relates to dopamine-dependent, subthalamic beta bursts

Vissani, Matteo; Palmisano, Chiara; Volkmann, Jens; Pezzoli, Gianni; Micera, Silvestro; Isaias, Ioannis U; Mazzoni, Alberto
Excessive beta-band oscillations in the subthalamic nucleus are key neural features of Parkinson's disease. Yet the distinctive contributions of beta low and high bands, their dependency on striatal dopamine, and their correlates with movement kinematics are unclear. Here, we show that the movement phases of the reach-to-grasp motor task are coded by the subthalamic bursting activity in a maximally-informative beta high range. A strong, three-fold correlation linked beta high range bursts, imbalanced inter-hemispheric striatal dopaminergic tone, and impaired inter-joint movement coordination. These results provide new insight into the neural correlates of motor control in parkinsonian patients, paving the way for more informative use of beta-band features for adaptive deep brain stimulation devices.
PMID: 34188058
ISSN: 2373-8057
CID: 4950312

Clinical Outcome and Striatal Dopaminergic Function After Shunt Surgery in Patients With Idiopathic Normal Pressure Hydrocephalus

Todisco, Massimiliano; Zangaglia, Roberta; Minafra, Brigida; Pisano, Patrizia; Trifirò, Giuseppe; Bossert, Irene; Pozzi, Nicoló Gabriele; Brumberg, Joachim; Ceravolo, Roberto; Isaias, Ioannis Ugo; Fasano, Alfonso; Pacchetti, Claudio
OBJECTIVE:To determine changes in clinical features and striatal dopamine reuptake transporter (DAT) density after shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS:I]-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (FP-CIT). Levodopa responsiveness was also evaluated. Patients who did or did not undergo lumboperitoneal shunt were clinically followed up and repeated SPECT after 2 years. RESULTS:< 0.01). CONCLUSIONS:This prospective interventional study highlights the pathophysiological relevance of striatal dopaminergic dysfunction in the motor phenotypic expression of iNPH. Absence of levodopa responsiveness, shunt-responsive parkinsonism, and post-surgery improvement of striatal DAT density are findings that corroborate the notion of a reversible striatal dysfunction in a subset of iNPH patients.
PMID: 33893195
ISSN: 1526-632x
CID: 4852772

Striatal Dopamine Deficit and Motor Impairment in Idiopathic Normal Pressure Hydrocephalus

Pozzi, Nicoló Gabriele; Brumberg, Joachim; Todisco, Massimiliano; Minafra, Brigida; Zangaglia, Roberta; Bossert, Irene; Trifirò, Giuseppe; Ceravolo, Roberto; Vitali, Paolo; Isaias, Ioannis Ugo; Fasano, Alfonso; Pacchetti, Claudio
BACKGROUND:Idiopathic normal pressure hydrocephalus can present with parkinsonism. However, abnormalities of the striatal dopamine reuptake transporter are unclear. OBJECTIVES/OBJECTIVE:To explore presence and features of striatal dopaminergic deficit in subjects with idiopathic normal pressure hydrocephalus as compared to Parkinson's disease (PD) patients and healthy controls. METHODS:I]-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane and single-photon emission computed tomography to quantify the striatal dopamine reuptake transporter binding. All subjects with idiopathic normal pressure hydrocephalus underwent a levodopa (l-dopa) challenge test and magnetic resonance imaging to evaluate ventriculomegaly and white matter changes. Gait, cognition, balance, and continence were assessed with the Idiopathic Normal Pressure Hydrocephalus Rating Scale, and parkinsonism with the motor section of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale. All patients completed a 2-year follow-up. RESULTS:A total of 62% of patients with idiopathic normal pressure hydrocephalus featured a reduced striatal dopamine reuptake transporter binding, which correlated with the severity of parkinsonism but not with features of ventriculomegaly or white matter changes. Unlike PD, this dopaminergic deficit in idiopathic normal pressure hydrocephalus was more symmetric and prominent in the caudate nucleus. CONCLUSIONS:Subjects with idiopathic normal pressure hydrocephalus can present a reduction of striatal dopamine reuptake transporter binding, which is consistent with the severity of parkinsonism and qualitatively differs from that found in PD patients. Longitudinal interventional studies are needed to prove a role for striatal dopamine reuptake transporter deficit in the pathophysiology of idiopathic normal pressure hydrocephalus. © 2020 International Parkinson and Movement Disorder Society.
PMID: 33151012
ISSN: 1531-8257
CID: 4664292

Differential diagnosis of parkinsonism: a head-to-head comparison of FDG PET and MIBG scintigraphy

Brumberg, Joachim; Schröter, Nils; Blazhenets, Ganna; Frings, Lars; Volkmann, Jens; Lapa, Constantin; Jost, Wolfgang H; Isaias, Ioannis U; Meyer, Philipp T
[18F]fluorodeoxyglucose (FDG) PET and [123I]metaiodobenzylguanidine (MIBG) scintigraphy may contribute to the differential diagnosis of neurodegenerative parkinsonism. To identify the superior method, we retrospectively evaluated 54 patients with suspected neurodegenerative parkinsonism, who were referred for FDG PET and MIBG scintigraphy. Two investigators visually assessed FDG PET scans using an ordinal 6-step score for disease-specific patterns of Lewy body diseases (LBD) or atypical parkinsonism (APS) and assigned the latter to the subgroups multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal syndrome. Regions-of-interest analysis on anterior planar MIBG images served to calculate the heart-to-mediastinum ratio. Movement disorder specialists blinded to imaging results established clinical follow-up diagnosis by means of guideline-derived case vignettes. Clinical follow-up (1.7 ± 2.3 years) revealed the following diagnoses: n = 19 LBD (n = 17 Parkinson's disease [PD], n = 1 PD dementia, and n = 1 dementia with Lewy bodies), n = 31 APS (n = 28 MSA, n = 3 PSP), n = 3 non-neurodegenerative parkinsonism; n = 1 patient could not be diagnosed and was excluded. Receiver operating characteristic analyses for discriminating LBD vs. non-LBD revealed a larger area under the curve for FDG PET than for MIBG scintigraphy at statistical trend level for consensus rating (0.82 vs. 0.69, p = 0.06; significant for investigator #1: 0.83 vs. 0.69, p = 0.04). The analysis of PD vs. MSA showed a similar difference (0.82 vs. 0.69, p = 0.11; rater #1: 0.83 vs. 0.69, p = 0.07). Albeit the notable differences in diagnostic performance did not attain statistical significance, the authors consider this finding clinically relevant and suggest that FDG PET, which also allows for subgrouping of APS, should be preferred.
PMID: 33311476
ISSN: 2373-8057
CID: 4722472

Brain metabolic alterations herald falls in patients with Parkinson's disease

Isaias, Ioannis U; Brumberg, Joachim; Pozzi, Nicoló G; Palmisano, Chiara; Canessa, Andrea; Marotta, Giorgio; Volkmann, Jens; Pezzoli, Gianni
Pathophysiological understanding of gait and balance disorders in Parkinson's disease is insufficient and late recognition of fall risk limits efficacious follow-up to prevent or delay falls. We show a distinctive reduction of glucose metabolism in the left posterior parietal cortex, with increased metabolic activity in the cerebellum, in parkinsonian patients 6-8 months before their first fall episode. Falls in Parkinson's disease may arise from altered cortical processing of body spatial orientation, possibly predicted by abnormal cortical metabolism.
PMID: 32162447
ISSN: 2328-9503
CID: 4481612

Vocal cord electromyographic correlates of stridor in multiple system atrophy phenotypes

Todisco, Massimiliano; Alfonsi, Enrico; Isaias, Ioannis Ugo; Zangaglia, Roberta; Minafra, Brigida; Cosentino, Giuseppe; Terzaghi, Michele; Pozzi, Nicoló Gabriele; Manni, Raffaele; Pacchetti, Claudio
INTRODUCTION/BACKGROUND:Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by dysautonomia in combination with parkinsonian and cerebellar signs. Stridor may also occur and it is associated with life-threatening events and poor prognosis. The pathophysiology of stridor in MSA is still debated. OBJECTIVE:To define correlations between diurnal electromyographic (EMG) abnormalities of vocal cord muscles and stridor in MSA phenotypes. METHODS:We recruited 60 patients with "probable" MSA (45 with parkinsonian [MSA-P] and 15 with cerebellar phenotype [MSA-C]). Nocturnal stridor was detected with video-polysomnography, whereas diurnal stridor was clinically noted when present. A diurnal kinesiologic EMG study of the adductor thyroarytenoid and the abductor posterior cricoarytenoid muscles was also performed. RESULTS:Among subjects with nocturnal stridor, MSA-P patients predominantly showed a paradoxical burst-like activation of the adductor thyroarytenoid muscle during inspiration. This dystonic pattern was associated with nocturnal stridor in MSA-P (odds ratio [OR] = 23.64, 95% confidence interval [CI] 3.42-70.77, p < 0.001). Conversely, MSA-C patients with nocturnal stridor mainly had additional neurogenic findings of vocal cord muscles. This dystonic-plus pattern correlated with nocturnal stridor in MSA-C (OR = 17.21, 95% CI 4.17-74.92, p < 0.01). The findings of diurnal stridor paralleled the observations for nocturnal stridor. CONCLUSIONS:The pathophysiology of stridor may differ between MSA phenotypes, possibly related to dysfunctional supranuclear mechanisms in MSA-P (dystonic pattern) and to additional nuclear damage in MSA-C (dystonic-plus pattern).
PMID: 31809947
ISSN: 1873-5126
CID: 4219122

A New Scale to Evaluate Motor Function in Rett Syndrome: Validation and Psychometric Properties

Rodocanachi Roidi, Marina Luisa; Isaias, Ioannis Ugo; Cozzi, Francesca; Grange, Francesca; Scotti, Fabrizia Maria; Gestra, Valentina Francesca; Gandini, Alessandra; Ripamonti, Enrico
BACKGROUND:We aim to describe and psychometrically validate the Rett Syndrome Motor Evaluation Scale, a 25-item ordinal scale examining (loco-)motor function across six sections: standing, sitting, transitions, walking, running, and walking up or downstairs. METHODS:We illustrate the process of item construction and validation, report findings and normative data obtained on a standardization sample of 60 patients with Rett syndrome. We investigate the validity and reliability of the scale and illustrate its psychometric properties using modern multivariate techniques of data analysis. RESULTS:Sixty patients with Rett syndrome were included (all female; mean age 12.45 (S.D. 8.75) years). The multidimensional latent structure of the scale was supported by the results of the confirmatory factor analysis. Rett Syndrome Motor Evaluation Scale showed strong internal consistency reliability as well as excellent inter-rater agreement. The Rett Syndrome Motor Evaluation Scale scores were not predicted by age, but were associated with disease severity, degree of spasticity, and hand dysfunction. We also identified three latent classes with different degrees of impairment. CONCLUSIONS:Rett Syndrome Motor Evaluation Scale is a new, valid, and reliable scale that can be introduced in clinical practice when assessing (loco-)motor function in Rett syndrome.
PMID: 31047758
ISSN: 1873-5150
CID: 3918552

Sit-to-walk performance in Parkinson's disease: A comparison between faller and non-faller patients

Palmisano, Chiara; Brandt, Gregor; Pozzi, Nicoló Gabriele; Leporini, Alice; Maltese, Virginia; Canessa, Andrea; Volkmann, Jens; Pezzoli, Gianni; Frigo, Carlo Albino; Isaias, Ioannis Ugo
BACKGROUND:Falls are one of the main concerns in people with Parkinson's disease, leading to poor quality of life and increased mortality. The sit-to-walk movement is the most frequent postural transition task during daily life and is highly demanding in terms of balance maintenance and muscular strength. METHODS:With the aim of identifying biomechanical variables of high risk of falling, we investigated the sit-to-walk task performed by 9 Parkinson's disease patients with at least one fall episode in the six months preceding this study, 15 Parkinson's disease patients without previous falls, and 20 healthy controls. Motor performance was evaluated with an optoelectronic system and two dynamometric force plates after overnight suspension of all dopaminergic drugs and one hour after consumption of a standard dose of levodopa/benserazide. FINDINGS/RESULTS:Poor trunk movements critically influenced the execution of the sit-to-walk movement in patients with a history of falling. The peak velocity of the trunk in the anterior-posterior direction discriminated faller from non-faller patients, with high specificity and sensitivity in both the medication-off and -on state. INTERPRETATION/CONCLUSIONS:Our results confirm the difficulties in merging consecutive motor tasks in patients with Parkinson's disease. Trunk movements during the sit-to-walk can provide valuable measurements to monitor and possibly predict the risk of falling.
PMID: 30889433
ISSN: 1879-1271
CID: 3748942

Excitability of the supplementary motor area in Parkinson's disease depends on subcortical damage

Casarotto, Silvia; Turco, Francesco; Comanducci, Angela; Perretti, Alessio; Marotta, Giorgio; Pezzoli, Gianni; Rosanova, Mario; Isaias, Ioannis U
BACKGROUND:Cortical dysfunctioning significantly contributes to the pathogenesis of motor symptoms in Parkinson's disease (PD). OBJECTIVE:We aimed at testing whether an acute levodopa administration has measurable and specific cortical effects possibly related to striatal dopaminergic deficit. METHODS:I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane to identify the more affected and the less affected brain side in each patient, according to the dopaminergic innervation loss of the putamen. Cortical excitability changes before and after an acute intake of levodopa were computed and compared between the more and the less affected brain side at the single-patient as well as at the group level. RESULTS:We found that levodopa intake induces a significant increase (P < 0.01) of cortical excitability nearby the supplementary motor area in the more affected brain side, greater (P < 0.025) than in the less affected brain side. Notably, cortical excitability changes nearby the superior parietal lobule were not statistically significant. CONCLUSIONS:These results strengthen the idea that dysfunction of specific cortico-subcortical circuits may contribute to pathophysiology of PD symptoms. Most important, they support the use of navigated TMS/EEG as a non-invasive tool to better understand the pathophysiology of PD.
PMID: 30416036
ISSN: 1876-4754
CID: 3781272

Cortical response to levodopa in Parkinson's disease patients with dyskinesias

Turco, Francesco; Canessa, Andrea; Olivieri, Chiara; Pozzi, Nicoló G; Palmisano, Chiara; Arnulfo, Gabriele; Marotta, Giorgio; Volkmann, Jens; Pezzoli, Gianni; Isaias, Ioannis U
Levodopa-induced dyskinesias are a common and disabling side effect of dopaminergic therapy in Parkinson's disease, but their neural mechanisms in vivo are still poorly understood. Besides striatal pathology, the importance of cortical dysfunction has been increasingly recognized. The supplementary motor area in particular, may have a relevant role in dyskinesias onset given its involvement in endogenously generated actions. The aim of the present study was to investigate the levodopa-related cortical excitability changes along with the emergence of levodopa-induced peak-of-dose dyskinesias in subjects with Parkinson's disease. Thirteen patients without dyskinesias and ten with dyskinesias received 200/50 mg fast-acting oral levodopa/benserazide following overnight withdrawal (12 hr) from their dopaminergic medication. We targeted transcranial magnetic stimulation to the supplementary motor area, ipsilateral to the most dopamine-depleted striatum defined with single-photon emission computed tomography with [123 I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane, and recorded transcranial magnetic stimulation-evoked potentials with high-density electroencephalography before and at 30, 60, and 180 min after levodopa/benserazide intake. Clinical improvement from levodopa/benserazide paralleled the increase in cortical excitability in both groups. Subjects with dyskinesias showed higher fluctuation of cortical excitability in comparison to non-dyskinetic patients, possibly reflecting dyskinetic movements. Together with endogenous brain oscillation, levodopa-related dynamics of brain state could influence the therapeutic response of neuromodulatory interventions.
PMID: 30117212
ISSN: 1460-9568
CID: 3287042