Publications by authors named "Maria Sofia Cotelli"

51 Publications

Spread of segmental/multifocal idiopathic adult-onset dystonia to a third body site.

Parkinsonism Relat Disord 2021 06 12;87:70-74. Epub 2021 May 12.

IRCCS Mondino Foundation, Pavia, Italy; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.

Background: Adult-onset focal dystonia can spread to involve one, or less frequently, two additional body regions. Spread of focal dystonia to a third body site is not fully characterized.

Materials And Methods: We retrospectively analyzed data from the Italian Dystonia Registry, enrolling patients with segmental/multifocal dystonia involving at least two parts of the body or more. Survival analysis estimated the relationship between dystonia features and spread to a third body part.

Results: We identified 340 patients with segmental/multifocal dystonia involving at least two body parts. Spread of dystonia to a third body site occurred in 42/241 patients (17.4%) with focal onset and 10/99 patients (10.1%) with segmental/multifocal dystonia at onset. The former had a greater tendency to spread than patients with segmental/multifocal dystonia at onset. Gender, years of schooling, comorbidity, family history of dystonia/tremor, age at dystonia onset, and disease duration could not predict spread to a third body site. Among patients with focal onset in different body parts (cranial, cervical, and upper limb regions), there was no association between site of focal dystonia onset and risk of spread to a third body site.

Discussion And Conclusion: Spread to a third body site occurs in a relative low percentage of patients with idiopathic adult-onset dystonia affecting two body parts. Regardless of the site of dystonia onset and of other demographic/clinical variables, focal onset seems to confer a greater risk of spread to a third body site in comparison to patients with segmental/multifocal dystonia at onset.
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http://dx.doi.org/10.1016/j.parkreldis.2021.04.022DOI Listing
June 2021

Exposure to gamma tACS in Alzheimer's disease: A randomized, double-blind, sham-controlled, crossover, pilot study.

Brain Stimul 2021 May-Jun;14(3):531-540. Epub 2021 Mar 21.

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy; Neurology Unit, Department of Neurological and Vision Sciences, ASST Spedali Civili, Brescia, Italy. Electronic address:

Objective: To assess whether exposure to non-invasive brain stimulation with transcranial alternating current stimulation at γ frequency (γ-tACS) applied over Pz (an area overlying the medial parietal cortex and the precuneus) can improve memory and modulate cholinergic transmission in mild cognitive impairment due to Alzheimer's disease (MCI-AD).

Methods: In this randomized, double-blind, sham controlled, crossover pilot study, participants were assigned to a single 60 min treatment with exposure to γ-tACS over Pz or sham tACS. Each subject underwent a clinical evaluation including assessment of episodic memory pre- and post-γ-tACS or sham stimulation. Indirect measures of cholinergic transmission evaluated using transcranial magnetic stimulation (TMS) pre- and post-γ-tACS or sham tACS were evaluated.

Results: Twenty MCI-AD participants completed the study. No tACS-related side effects were observed, and the intervention was well tolerated in all participants. We observed a significant improvement at the Rey auditory verbal learning (RAVL) test total recall (5.7 [95% CI, 4.0 to 7.4], p < 0.001) and long delayed recall scores (1.3 [95% CI, 0.4 to 2.1], p = 0.007) after γ-tACS but not after sham tACS. Face-name associations scores improved during γ-tACS (4.3 [95% CI, 2.8 to 5.8], p < 0.001) but not after sham tACS. Short latency afferent inhibition, an indirect measure of cholinergic transmission evaluated with TMS, increased only after γ-tACS (0.31 [95% CI, 0.24 to 0.38], p < 0.001) but not after sham tACS.

Conclusions: exposure to γ-tACS over Pz showed a significant improvement of memory performances, along with restoration of intracortical connectivity measures of cholinergic neurotransmission, compared to sham tACS.
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http://dx.doi.org/10.1016/j.brs.2021.03.007DOI Listing
March 2021

Classification accuracy of TMS for the diagnosis of mild cognitive impairment.

Brain Stimul 2021 Mar-Apr;14(2):241-249. Epub 2021 Jan 13.

Neurology Unit, Department of Clinial and Experimental Sciences, University of Brescia, Italy. Electronic address:

Objective: To evaluate the performance of a Random Forest (RF) classifier on Transcranial Magnetic Stimulation (TMS) measures in patients with Mild Cognitive Impairment (MCI).

Methods: We applied a RF classifier on TMS measures obtained from a multicenter cohort of patients with MCI, including MCI-Alzheimer's Disease (MCI-AD), MCI-frontotemporal dementia (MCI-FTD), MCI-dementia with Lewy bodies (MCI-DLB), and healthy controls (HC). All patients underwent TMS assessment at recruitment (index test), with application of reference clinical criteria, to predict different neurodegenerative disorders. The primary outcome measures were the classification accuracy, precision, recall and F1-score of TMS in differentiating each disorder.

Results: 160 participants were included, namely 64 patients diagnosed as MCI-AD, 28 as MCI-FTD, 14 as MCI-DLB, and 47 as healthy controls (HC). A series of 3 binary classifiers was employed, and the prediction model exhibited high classification accuracy (ranging from 0.72 to 0.86), high precision (0.72-0.90), high recall (0.75-0.98), and high F1-scores (0.78-0.92), in differentiating each neurodegenerative disorder. By computing a new classifier, trained and validated on the current cohort of MCI patients, classification indices showed even higher accuracy (ranging from 0.83 to 0.93), precision (0.87-0.89), recall (0.83-1.00), and F1-scores (0.85-0.94).

Conclusions: TMS may be considered a useful additional screening tool to be used in clinical practice in the prodromal stages of neurodegenerative dementias.
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http://dx.doi.org/10.1016/j.brs.2021.01.004DOI Listing
October 2021

Guillain-Barré syndrome and COVID-19: an observational multicentre study from two Italian hotspot regions.

J Neurol Neurosurg Psychiatry 2021 07 6;92(7):751-756. Epub 2020 Nov 6.

Unit of Neurology, ASST Valcamonica, Esine (Bs), Italy.

Objective: Single cases and small series of Guillain-Barré syndrome (GBS) have been reported during the SARS-CoV-2 outbreak worldwide. We evaluated incidence and clinical features of GBS in a cohort of patients from two regions of northern Italy with the highest number of patients with COVID-19.

Methods: GBS cases diagnosed in 12 referral hospitals from Lombardy and Veneto in March and April 2020 were retrospectively collected. As a control population, GBS diagnosed in March and April 2019 in the same hospitals were considered.

Results: Incidence of GBS in March and April 2020 was 0.202/100 000/month (estimated rate 2.43/100 000/year) vs 0.077/100 000/month (estimated rate 0.93/100 000/year) in the same months of 2019 with a 2.6-fold increase. Estimated incidence of GBS in COVID-19-positive patients was 47.9/100 000 and in the COVID-19-positive hospitalised patients was 236/100 000. COVID-19-positive patients with GBS, when compared with COVID-19-negative subjects, showed lower MRC sum score (26.3±18.3 vs 41.4±14.8, p=0.006), higher frequency of demyelinating subtype (76.6% vs 35.3%, p=0.011), more frequent low blood pressure (50% vs 11.8%, p=0.017) and higher rate of admission to intensive care unit (66.6% vs 17.6%, p=0.002).

Conclusions: This study shows an increased incidence of GBS during the COVID-19 outbreak in northern Italy, supporting a pathogenic link. COVID-19-associated GBS is predominantly demyelinating and seems to be more severe than non-COVID-19 GBS, although it is likely that in some patients the systemic impairment due to COVID-19 might have contributed to the severity of the whole clinical picture.
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http://dx.doi.org/10.1136/jnnp-2020-324837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650204PMC
July 2021

Motor and Sensory Features of Cervical Dystonia Subtypes: Data From the Italian Dystonia Registry.

Front Neurol 2020 26;11:906. Epub 2020 Aug 26.

Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy.

Cervical dystonia (CD) is one of the most common forms of adult-onset isolated dystonia. Recently, CD has been classified according to the site of onset and spread, in different clinical subgroups, that may represent different clinical entities or pathophysiologic subtypes. In order to support this hypothesis, in this study we have evaluated whether different subgroups of CD, that clinically differ for site of onset and spread, also imply different sensorimotor features. Clinical and demographic data from 842 patients with CD from the Italian Dystonia Registry were examined. Motor features (head tremor and tremor elsewhere) and sensory features (sensory trick and neck pain) were investigated. We analyzed possible associations between motor and sensory features in CD subgroups [focal neck onset, no spread (FNO-NS); focal neck onset, segmental spread (FNO-SS); focal onset elsewhere with segmental spread to neck (FOE-SS); segmental neck involvement without spread (SNI)]. In FNO-NS, FOE-SS, and SNI subgroups, head tremor was associated with the presence of tremor elsewhere. Sensory trick was associated with pain in patients with FNO-NS and with head tremor in patients with FNO-SS. The frequent association between head tremor and tremor elsewhere may suggest a common pathophysiological mechanism. Two mechanisms may be hypothesized for sensory trick: a gating mechanism attempting to reduce pain and a sensorimotor mechanism attempting to control tremor.
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http://dx.doi.org/10.3389/fneur.2020.00906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493687PMC
August 2020

Clinical Presentation and Outcomes of Severe Acute Respiratory Syndrome Coronavirus 2-Related Encephalitis: The ENCOVID Multicenter Study.

J Infect Dis 2021 01;223(1):28-37

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Background: Several preclinical and clinical investigations have argued for nervous system involvement in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Some sparse case reports have described various forms of encephalitis in coronavirus disease 2019 (COVID-19) disease, but very few data have focused on clinical presentations, clinical course, response to treatment, and outcomes.

Methods: The SARS-CoV-2 related encephalopaties (ENCOVID) multicenter study included patients with encephalitis with full infectious screening, cerebrospinal fluid (CSF), electroencephalography (EEG), and magnetic resonance imaging (MRI) data and confirmed SARS-CoV-2 infection recruited from 13 centers in northern Italy. Clinical presentation and laboratory markers, severity of COVID-19 disease, response to treatment, and outcomes were recorded.

Results: Twenty-five cases of encephalitis positive for SARS-CoV-2 infection were included. CSF showed hyperproteinorrachia and/or pleocytosis in 68% of cases whereas SARS-CoV-2 RNA by reverse-transcription polymerase chain reaction resulted negative. Based on MRI, cases were classified as acute demyelinating encephalomyelitis (ADEM; n = 3), limbic encephalitis (LE; n = 2), encephalitis with normal imaging (n = 13), and encephalitis with MRI alterations (n = 7). ADEM and LE cases showed a delayed onset compared to the other encephalitis cases (P = .001) and were associated with previous, more severe COVID-19 respiratory involvement. Patients with MRI alterations exhibited worse response to treatment and final outcomes compared to those with other encephalitis.

Conclusions: SARS-CoV-2 infection is associated with a wide spectrum of encephalitis characterized by different clinical presentation, response to treatment, and outcomes.
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http://dx.doi.org/10.1093/infdis/jiaa609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543535PMC
January 2021

The impact of COVID-19 on health status of home-dwelling elderly patients with dementia in East Lombardy, Italy: results from COVIDEM network.

Aging Clin Exp Res 2020 Oct 12;32(10):2133-2140. Epub 2020 Sep 12.

IPS Cardinal Gusmini, Vertova (Bergamo), Italy.

Background: COVID-19 outbreak has led to severe health burden in the elderly. Age, morbidity and dementia have been associated with adverse outcome.

Aims: To evaluate the impact of COVID-19 on health status in home-dwelling patients.

Methods: 848 home-dwelling outpatients with dementia contacted from April 27 to 30 and evaluated by a semi-structured interview to evaluate possible health complication due to COVID-19 from February 21 to April 30. Age, sex, education, clinical characteristics (including diagnosis of dementia) and flu vaccination history were obtained from previous medical records. Items regarding change in health status and outcome since the onset of the outbreak were collected. COVID-19 was diagnosed in patients who developed symptoms according to WHO criteria or tested positive at nasal/throat swab if hospitalized. Unplanned hospitalization, institutionalization and mortality were recorded.

Results: Patients were 79.7 years old (SD 7.1) and 63.1% were females. Ninety-five (11.2%) patients developed COVID-19-like symptoms. Non COVID-19 and COVID-19 patients differed for frequency of diabetes (18.5% vs. 37.9%, p < 0.001), COPD (7.3% vs. 18.9%, p < 0.001), and previous flu vaccination (56.7% vs. 37.9%, p < 0.001). Diabetes and COPD were positively associated with COVID-19, whereas higher dementia severity and flu vaccination showed an inverse association. Among COVID-19 patients, 42 (44.2%) were hospitalized while 32 (33.7%) died. Non COVID-19 patients' hospitalization and mortality rate were 1.9% and 1.2%, respectively. COVID-19 and COPD were significantly associated with the rate of mortality.

Discussion/conclusions: A high proportion of adverse outcome related to COVID-19 was observed in home-dwelling elderly patients with dementia. Active monitoring though telehealth programs would be useful particularly for those at highest risk of developing COVID-19 and its adverse outcomes.
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http://dx.doi.org/10.1007/s40520-020-01676-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486591PMC
October 2020

Demographic and clinical determinants of neck pain in idiopathic cervical dystonia.

J Neural Transm (Vienna) 2020 10 26;127(10):1435-1439. Epub 2020 Aug 26.

IRCCS Neuromed, Pozzilli, Italy.

Cervical dystonia is associated with neck pain in a significant proportion of cases, but the mechanisms underlying pain are largely unknown. In this exploratory study, we compared demographic and clinical variables in cervical dystonia patients with and without neck pain from the Italian Dystonia Registry. Univariable and multivariable logistic regression analysis indicated a higher frequency of sensory trick and a lower educational level among patients with pain.
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http://dx.doi.org/10.1007/s00702-020-02245-4DOI Listing
October 2020

Association between treatment with colchicine and improved survival in a single-centre cohort of adult hospitalised patients with COVID-19 pneumonia and acute respiratory distress syndrome.

Ann Rheum Dis 2020 10 30;79(10):1286-1289. Epub 2020 Jul 30.

Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Lombardia, Italy.

Objectives: The outbreak of COVID-19 posed the issue of urgently identifying treatment strategies. Colchicine was considered for this purpose based on well-recognised anti-inflammatory effects and potential antiviral properties. In the present study, colchicine was proposed to patients with COVID-19, and its effects compared with 'standard-of-care' (SoC).

Methods: In the public hospital of Esine, northern Italy, 140 consecutive inpatients, with virologically and radiographically confirmed COVID-19 admitted in the period 5-19 March 2020, were treated with 'SoC' (hydroxychloroquine and/or intravenous dexamethasone; and/or lopinavir/ritonavir). They were compared with 122 consecutive inpatients, admitted between 19 March and 5 April 2020, treated with colchicine (1 mg/day) and SoC (antiviral drugs were stopped before colchicine, due to potential interaction).

Results: Patients treated with colchicine had a better survival rate as compared with SoC at 21 days of follow-up (84.2% (SE=3.3%) 63.6% (SE=4.1%), p=0.001). Cox proportional hazards regression survival analysis showed that a lower risk of death was independently associated with colchicine treatment (HR=0.151 (95% CI 0.062 to 0.368), p<0.0001), whereas older age, worse PaO2/FiO2, and higher serum levels of ferritin at entry were associated with a higher risk.

Conclusion: This proof-of-concept study may support the rationale of use of colchicine for the treatment of COVID-19. Efficacy and safety must be determined in controlled clinical trials.
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http://dx.doi.org/10.1136/annrheumdis-2020-217712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509521PMC
October 2020

Effortful speech with distortion of prosody following SARS-CoV-2 infection.

Neurol Sci 2020 Dec 27;41(12):3767-3768. Epub 2020 Jul 27.

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Piazza Spedali Civili 1, 25125, Brescia, Italy.

Coronavirus disease 2019 (COVID-19) infection has the potential for targeting the central nervous system, and several neurological symptoms have been reported in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We describe a 48-year-old Caucasian woman with SARS-CoV-2 infection followed by the onset of word finding difficulties, effortful speech along with prosody distortion, in the context of spared semantic and syntactic abilities. The clinical picture, perceived as foreign accent syndrome (FAS), was not associated with structural and functional imaging changes or neurophysiological assessment abnormalities. We suggest that FAS, herein perceived as a regional accent syndrome, should be considered a possible additional neurological manifestation of SARS-CoV-2.
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http://dx.doi.org/10.1007/s10072-020-04603-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384723PMC
December 2020

Neurotransmitter imbalance dysregulates brain dynamic fluidity in frontotemporal degeneration.

Neurobiol Aging 2020 10 11;94:176-184. Epub 2020 Jun 11.

Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. Electronic address:

Frontotemporal degeneration (FTD) is characterized by reduced global brain flexibility along with GABAergic/glutamatergic neurotransmitter deficits. We aimed to assess the relationship between dynamical properties of time-varying whole-brain network connectivity as well as static large-scale networks and neurotransmitter imbalance using resting-state functional MRI and transcranial magnetic stimulation (TMS) in sixty-six patients with FTD. We assessed GABAergic and glutamatergic neurotransmission by TMS, considering short- and long-interval intracortical inhibition and intracortical facilitation, and large-scale networks connectivity as well as four indexes of meta-state dynamic fluidity: (1) number of distinct meta-states, (2) number of switches from one meta-state to another, (3) span of the realized meta-states, and (4) total distance traveled in the state space. No significant correlations between TMS parameters and large-scale networks connectivity were observed. However, we observed a significant correlation between short-interval intracortical inhibition-intracortical facilitation and four meta-states (all indexes p < 0.02, false discovery rate-corrected). This study suggests that neurotransmitter imbalance dysregulates brain dynamic fluidity, linking microscopic and macroscopic changes in FTD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.05.017DOI Listing
October 2020

Transcranial stimulation in frontotemporal dementia: A randomized, double-blind, sham-controlled trial.

Alzheimers Dement (N Y) 2020 27;6(1):e12033. Epub 2020 May 27.

Neurology Unit Department of Clinical and Experimental Sciences University of Brescia Brescia Italy.

Introduction: Frontotemporal dementia (FTD) is a progressive disease for which no curative treatment is currently available. We aimed to determine whether transcranial direct current stimulation (tDCS) can modulate intracortical connectivity and improve cognition in symptomatic FTD patients and presymptomatic FTD subjects.

Methods: We performed a double-blind, randomized, sham-controlled trial with anodal tDCS or sham stimulation over the left prefrontal cortex in 70 participants (15 presymptomatic and 55 symptomatic FTD).

Results: We observed a significant increase of intracortical connectivity (short interval intracortical inhibition and facilitation) and improvement in clinical scores and behavioral disturbances in both symptomatic FTD patients and presymptomatic carriers after real tDCS but not after sham stimulation.

Discussion: A 2-weeks' treatment with anodal left prefrontal tDCS improves symptoms and restores intracortical inhibitory and excitatory circuits in both symptomatic FTD patients and presymptomatic carriers. tDCS might represent a promising future therapeutic and rehabilitative approach in patients with FTD.
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http://dx.doi.org/10.1002/trc2.12033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253155PMC
May 2020

Expanding the role of education in frontotemporal dementia: a functional dynamic connectivity (the chronnectome) study.

Neurobiol Aging 2020 09 29;93:35-43. Epub 2020 Apr 29.

Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. Electronic address:

In the present study, we aim at investigating whether education modulates dynamical properties of time-varying whole-brain network connectivity (the chronnectome) in frontotemporal dementia (FTD) at a given level of symptom severity. Dynamic connectivity parameters were evaluated in 128 patients with FTD using independent component analysis, sliding-time window correlation, and k-means approach to resting state-magnetic resonance imaging data. We evaluated the relationship between education, a proxy measure of cognitive reserve, and 4 indexes of metastate dynamic connectivity: (1) the number of distinct metastates a patient passes through, (2) the number of switches from one metastate to another, (3) the span of the realized metastates, and (4) the total distance traveled in the state space. We found a significant inverse correlation between years of education and the 4 indexes of metastate dynamic fluidity (all p-values ≤ 0.03, false discovery rate-corrected). This study suggests that patients with FTD with higher education but comparable clinical severity show more global functional brain impairment, suggesting that patients with higher cognitive reserve can cope with more global brain fluidity reduction.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.04.021DOI Listing
September 2020

Does acute peripheral trauma contribute to idiopathic adult-onset dystonia?

Parkinsonism Relat Disord 2020 02 13;71:40-43. Epub 2020 Jan 13.

Neurology Department, Asti Hospital, Asti, Italy.

Background: Acute peripheral trauma is a controversial risk factor for idiopathic dystonia.

Materials And Methods: We retrospectively analyzed data from the Italian Dystonia Registry regarding the occurrence of acute peripheral trauma severe enough to require medical attention in 1382 patients with adult-onset idiopathic dystonia and 200 patients with acquired adult-onset dystonia.

Results: Patients with idiopathic and acquired dystonia showed a similar burden of peripheral trauma in terms of the number of patients who experienced trauma (115/1382 vs. 12/200, p = 0.3) and the overall number of injuries (145 for the 1382 idiopathic patients and 14 for the 200 patients with secondary dystonia, p = 0.2). Most traumas occurred before the onset of idiopathic or secondary dystonia but only a minority of such injuries (14 in the idiopathic group, 2 in the acquired group, p = 0.6) affected the same body part as that affected by dystonia. In the idiopathic group, the elapsed time between trauma and dystonia onset was 8.1 ± 9.2 years; only six of the 145 traumas (4.1%) experienced by 5/1382 idiopathic patients (0.36%) occurred one year or less before dystonia onset; in the acquired dystonia group, the two patients experienced prior trauma to the dystonic body part 5 and 6 years before dystonia development.

Discussion And Conclusion: Our data suggest that the contribution of peripheral acute trauma to idiopathic dystonia is negligible, if anything, and likely involves only a small subset of patients.
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http://dx.doi.org/10.1016/j.parkreldis.2020.01.002DOI Listing
February 2020

Classification Accuracy of Transcranial Magnetic Stimulation for the Diagnosis of Neurodegenerative Dementias.

Ann Neurol 2020 03 23;87(3):394-404. Epub 2020 Jan 23.

Department of Clinical and Experimental Sciences, Center for Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy.

Objective: Transcranial magnetic stimulation (TMS) has been suggested as a reliable, noninvasive, and inexpensive tool for the diagnosis of neurodegenerative dementias. In this study, we assessed the classification performance of TMS parameters in the differential diagnosis of common neurodegenerative disorders, including Alzheimer disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD).

Methods: We performed a multicenter study enrolling patients referred to 4 dementia centers in Italy, in accordance with the Standards for Reporting of Diagnostic Accuracy. All patients underwent TMS assessment at recruitment (index test), with application of reference clinical criteria, to predict different neurodegenerative disorders. The investigators who performed the index test were masked to the results of the reference test and all other investigations. We trained and tested a random forest classifier using 5-fold cross-validation. The primary outcome measures were the classification accuracy, precision, recall, and F1 score of TMS in differentiating each neurodegenerative disorder.

Results: A total of 694 participants were included, namely 273 patients diagnosed as AD, 67 as DLB, and 207 as FTD, and 147 healthy controls (HC). A series of 3 binary classifiers was employed, and the prediction model exhibited high classification accuracy (ranging from 0.89 to 0.92), high precision (0.86-0.92), high recall (0.93-0.98), and high F1 scores (0.89-0.95) in differentiating each neurodegenerative disorder.

Interpretation: TMS is a noninvasive procedure that reliably and selectively distinguishes AD, DLB, FTD, and HC, representing a useful additional screening tool to be used in clinical practice. Ann Neurol 2020;87:394-404.
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http://dx.doi.org/10.1002/ana.25677DOI Listing
March 2020

Neurophysiological Correlates of Positive and Negative Symptoms in Frontotemporal Dementia.

J Alzheimers Dis 2020 ;73(3):1133-1142

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Background: The neural correlates of behavioral symptoms in frontotemporal dementia (FTD) are still to be elucidated. Neurotransmitter abnormalities could be correlated to the pathophysiology of negative and positive symptoms in FTD.

Objective: To evaluate if the imbalance between inhibitory and excitatory cortical circuits, evaluated with transcranial magnetic stimulation (TMS), correlate with the magnitude of negative and positive symptoms, as measured by Frontal Behavioral Inventory (FBI) scores, in patients with FTD.

Methods: Paired-pulse TMS was used to investigate the activity of different intracortical circuits in 186 FTD patients (130 bvFTD, 35 avPPA, 21 svPPA). We applied short interval intracortical inhibition (SICI - GABAAergic transmission), intracortical facilitation (ICF - glutamatergic transmission), long interval intracortical inhibition (LICI - GABABergic transmission), and short latency afferent inhibition (SAI - cholinergic transmission). Linear and stepwise multiple regression analysis were used to determine the contribution of each neurophysiological measures to the total variance of FBI scores.

Results: At the stepwise multivariate analysis, we observed a significant negative correlation between FBI-A scores (negative symptoms) and ICF (β = -0.57, p < 0.001, adjusted R2 = 0.32). For FBI-B scores (positive symptoms), we observed a significant positive correlation for SICI (β = 0.84, p < 0.001, adjusted R2 = 0.56). Significant correlations were observed for single items of the FBI-A score with ICF and FBI-B scores with SICI, with a medium-large size effect for several items.

Conclusions: The present study shows that the imbalance between inhibitory and excitatory intracortical circuits, evaluated with TMS, correlated with the magnitude of negative and positive symptoms in FTD, respectively.
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http://dx.doi.org/10.3233/JAD-190986DOI Listing
May 2021

TMS for staging and predicting functional decline in frontotemporal dementia.

Brain Stimul 2020 Mar - Apr;13(2):386-392. Epub 2019 Nov 22.

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. Electronic address:

Objective: To evaluate if transcranial magnetic stimulation (TMS) measures correlate with disease severity and predict functional decline in frontotemporal dementia (FTD) phenotypes.

Methods: Paired-pulse TMS was used to investigate the activity of different intracortical circuits in 171 FTD patients (122 bvFTD, 31 avPPA, 18 svPPA) and 74 healthy controls. Pearson's correlations were used to analyze the association between TMS measures and disease severity, while multiple regression analysis was used to identify the best clinical or neurophysiological measure to predict functional decline at 12 months.

Results: We observed significant strong correlations between TMS measures [short interval intracortical inhibition-facilitation (SICI-ICF) and long interval intracortical inhibition (LICI)], and disease severity (evaluated with the FTLD-CDR) (all r > 0.5, p < 0.005). SICI-ICF, short interval intracortical facilitation (SICF) and LICI were also significant predictors of functional decline, evaluated as the change in FTLD-CDR scores at 12 months (all p < 0.005), while at the stepwise multiple regression analysis, SICI was the best predictor of disease progression, accounting for 72.5% of the variation in FTLD-CDR scores at 12 months (adjusted R = 0.72, p < 0.001).

Conclusions: The present study has shown that the dysfunction of inhibitory and facilitatory intracortical circuits, evaluated with TMS, correlates with disease severity and progression, accurately predicting functional decline at 12 months, better than any other investigated marker.
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http://dx.doi.org/10.1016/j.brs.2019.11.009DOI Listing
August 2020

Transcranial magnetic stimulation and amyloid markers in mild cognitive impairment: impact on diagnostic confidence and diagnostic accuracy.

Alzheimers Res Ther 2019 12 1;11(1):95. Epub 2019 Dec 1.

Centre for Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, Clinica Neurologica, University of Brescia, P.le Spedali Civili, 1, 25100, Brescia, Italy.

Background: The development of diagnostic tools capable of accurately identifying the pathophysiology of mild cognitive impairment (MCI) has become a crucial target considering the claim that disease-modifying treatments should be administered as early as possible in the disease course. Transcranial magnetic stimulation (TMS) protocols have demonstrated analytical validity in discriminating different forms of dementia; however, its value in daily clinical practice in MCI subjects is still unknown.

Objective: To evaluate the clinical value of TMS compared to amyloid markers on diagnostic confidence and accuracy in MCI subjects, considering clinicians' expertise.

Methods: One hundred seven MCI subjects were included and classified as MCI-Alzheimer disease (MCI-AD), MCI-frontotemporal dementia (MCI-FTD), MCI-dementia with Lewy bodies (MCI-DLB), or MCI-other in a three-step process based on (i) demographic, clinical, and neuropsychological evaluation (clinical work-up); (ii) clinical work-up PLUS amyloidosis markers or clinical work-up PLUS TMS measures; and (iii) clinical work-up PLUS both markers. Two blinded neurologists with different clinical expertise were asked to express a diagnostic confidence for each MCI subgroup, and ROC curve analyses were performed at each step.

Results: The addition of TMS markers to clinical work-up significantly increased the diagnostic confidence for MCI-AD (p = 0.003), MCI-FTD (p = 0.044), and MCI-DLB (p = 0.033) compared to clinical work-up alone, but not for MCI-other (p > 0.05). No significant differences between the add-on effect of TMS and the add-on effect of amyloid markers to clinical work-up were observed (p > 0.732), while the diagnostic confidence further increased when both markers were available. The greater the clinical expertise, the greater the flexibility in considering alternative diagnosis, and the greater the ability to modify diagnostic confidence with TMS and amyloid markers.

Conclusions: TMS in addition to routine clinical assessment in MCI subjects has a significant effect on diagnostic accuracy and confidence, comparable to well-established biomarkers of amyloidosis.
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http://dx.doi.org/10.1186/s13195-019-0555-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886207PMC
December 2019

Acute venous thrombosis of inferior cerebellar vein, case report.

Neurol Sci 2020 May 22;41(5):1283-1284. Epub 2019 Nov 22.

Neurology Unit, Azienda Socio Sanitaria Territoriale "Valcamonica", Esine, Brescia, Italy.

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http://dx.doi.org/10.1007/s10072-019-04148-zDOI Listing
May 2020

Cortico-spinal tDCS in ALS: A randomized, double-blind, sham-controlled trial.

Brain Stimul 2019 Sep - Oct;12(5):1332-1334. Epub 2019 Jun 8.

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.brs.2019.06.011DOI Listing
June 2019

Stimulation over the cerebellum with a regular figure-of-eight coil induces reduced motor cortex inhibition in patients with progressive supranuclear palsy.

Brain Stimul 2019 Sep - Oct;12(5):1290-1297. Epub 2019 May 24.

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. Electronic address:

Objective: To determine whether motor cortex inhibition by stimulation over the cerebellum with a figure-of eight coil (MISC8) may be reduced in patients with Progressive Supranuclear Palsy (PSP).

Methods: Paired pulse TMS was used to evaluate MISC8, in patients with different forms of parkinsonism and dementia. The primary outcome measures were sensitivity and specificity of motor cortex inhibition, derived from receiver operator curve analysis, in discriminating PSP from other neurodegenerative disorders.

Results: A total of 150 participants met inclusion criteria. According to clinical criteria, the study population included 19 PSP, 26 Parkinson's disease, 25 dementia with Lewy bodies, 15 corticobasal syndrome, 25 frontotemporal dementia and 15 Alzheimer's disease patients, and 25 healthy controls. PSP patients were characterized by a specific impairment of MISC8 (0.99 ± 0.08) compared to the healthy control group and to other neurodegenerative disorders (mean range = 0.63-0.80, all p-values<0.001). Using the best cut-off index, MISC8 differentiated PSP from other diagnoses with an overall sensitivity of 100%, a specificity of 94%, and an accuracy of 97%.

Conclusions: TMS is a non-invasive procedure which reliably distinguishes PSP from other neurodegenerative disorders. MISC8 could represent a useful additional diagnostic tool to be used in clinical practice.
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http://dx.doi.org/10.1016/j.brs.2019.05.017DOI Listing
January 2020

Clinical and biomarker changes in presymptomatic genetic frontotemporal dementia.

Neurobiol Aging 2019 04 7;76:133-140. Epub 2019 Jan 7.

Department of Clinical and Experimental Sciences, Neurology Unit, University of Brescia, Brescia, Italy. Electronic address:

Presymptomatic carriers of GRN and C9orf72 mutations, the most frequent genetic causes of frontotemporal lobar degeneration, represent the optimal target population for the development of disease-modifying drugs. Preclinical biomarkers are needed to monitor the effect of therapeutic interventions in this population. We assessed clinical, functional, and neurophysiological measures in 113 GRN or C9orf72 carriers and in 73 noncarrier first-degree relatives. For 73 patients, follow-up longitudinal data were available. Differences between carriers and noncarriers were assessed using linear mixed-effects models. We observed that biological changes and intracortical facilitation transmission abnormalities significantly antecede the emergence of clinical symptoms of at least 3 decades. These are followed by intracortical inhibition transmission deficits, detected approximately 2 decades before expected symptom onset and then followed by an increase of white matter lesions, structural brain atrophy, and cognitive impairment. These results highlight how several biomarkers can show different aspects and rates of decline, possibly correlated with the underlying physiopathological process, that arise decades before the onset of clinical symptoms.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.12.018DOI Listing
April 2019

Transcranial direct current stimulation enhances theory of mind in Parkinson's disease patients with mild cognitive impairment: a randomized, double-blind, sham-controlled study.

Transl Neurodegener 2019 7;8. Epub 2019 Jan 7.

3Neuropsychology Unit, IRCCS Istituto Centro San Giovanni di Dio - Fatebenefratelli, Brescia, Italy.

Background: Parkinson's Disease (PD) with mild cognitive impairment (MCI) (PD-MCI) represents one of the most dreaded complications for patients with PD and is associated with a higher risk of developing dementia. Although transcranial direct current stimulation (tDCS) has been demonstrated to improve motor and non-motor symptoms in PD, to date, no study has investigated the effects of tDCS on Theory of Mind (ToM), i.e., the ability to understand and predict other people's behaviours, in PD-MCI.

Methods: In this randomized, double-blind, sham-controlled study, we applied active tDCS over the medial frontal cortex (MFC) to modulate ToM performance in twenty patients with PD-MCI. Twenty matched healthy controls (HC) were also enrolled and were asked to perform the ToM task without receiving tDCS.

Results: In the patients with PD-MCI, i) ToM performance was worse than that in the HC, ii) ToM abilities were poorer in those with fronto-executive difficulties, and iii) tDCS over the MFC led to significant shortening of latency for ToM tasks.

Conclusions: We show for the first time that active tDCS over the MFC enhances ToM in patients with PD-MCI, and suggest that non-invasive brain stimulation could be used to ameliorate ToM deficits observed in these patients.
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http://dx.doi.org/10.1186/s40035-018-0141-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322239PMC
January 2019

The impact of transcranial magnetic stimulation on diagnostic confidence in patients with Alzheimer disease.

Alzheimers Res Ther 2018 09 18;10(1):94. Epub 2018 Sep 18.

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Background: Cholinergic dysfunction is a key abnormality in Alzheimer disease (AD) that can be detected in vivo with transcranial magnetic stimulation (TMS) protocols. Although TMS has clearly demonstrated analytical validity, its clinical utility is still debated. In the present study, we evaluated the incremental diagnostic value, expressed in terms of diagnostic confidence of Alzheimer disease (DCAD; range 0-100), of TMS measures in addition to the routine clinical diagnostic assessment in patients evaluated for cognitive impairment as compared with validated biomarkers of amyloidosis.

Methods: One hundred twenty patients with dementia were included and scored in terms of DCAD in a three-step assessment based on (1) demographic, clinical, and neuropsychological evaluations (clinical work-up); (2) clinical work-up plus amyloid markers (cerebrospinal fluid or amyloid positron emission tomographic imaging); and (3) clinical work-up plus TMS intracortical connectivity measures. Two blinded neurologists were asked to review the diagnosis and diagnostic confidence at each step.

Results: TMS measures increased the discrimination of DCAD in two clusters (AD-like vs FTD-like) when added to the clinical and neuropsychological evaluations with levels comparable to established biomarkers of brain amyloidosis (cluster distance of 55.1 for clinical work-up alone, 76.0 for clinical work-up plus amyloid markers, 80.0 for clinical work-up plus TMS). Classification accuracy for the "gold standard" diagnosis (dichotomous - AD vs FTD - variable) evaluated in the three-step assessment, expressed as AUC, increased from 0.82 (clinical work-up alone) to 0.98 (clinical work-up plus TMS) and to 0.99 (clinical work-up plus amyloidosis markers).

Conclusions: TMS in addition to routine assessment in patients with dementia has a significant effect on diagnosis and diagnostic confidence that is comparable to well-established amyloidosis biomarkers.
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http://dx.doi.org/10.1186/s13195-018-0423-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145195PMC
September 2018

Transcranial direct current stimulation combined with cognitive training for the treatment of Parkinson Disease: A randomized, placebo-controlled study.

Brain Stimul 2018 Nov - Dec;11(6):1251-1262. Epub 2018 Jul 18.

Neuropsychology Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy. Electronic address:

Background: A number of non-motor symptoms occurs in Parkinson Disease (PD), cognitive decline and mood disturbances representing the most prevalent. Recent studies reported that cognitive training could potentially help to attenuate cognitive deficits in patients with PD and several researches demonstrated a beneficial effect of active transcranial Direct Current Stimulation (tDCS) over the left dorsolateral prefrontal cortex (anode over left dorsolateral prefrontal cortex, cathode over right supraorbital area) on cognitive deficits and mood disturbances.

Objective: To investigate the effects of active tDCS combined with computerized cognitive training on cognition and mood disturbances in PD patients.

Methods: Twenty-two patients with PD were assigned to either active tDCS plus computerized cognitive training (CCT) or sham tDCS plus CCT groups. Each patient underwent two weeks' treatment of daily application of tDCS for 25 minutes during CCT focalized on functions related with prefrontal cortex. Each patient was evaluated at baseline, after treatment and at 3-month follow-up.

Results: A significant reduction of depressive symptoms was observed in the active tDCS group from baseline to post-treatment assessment and from baseline to 3-month follow-up. An improvement in cognitive performances, referring more specifically to language, attentional and executive functions, was observed in both groups post-treatment and at follow-up. However, phonemic verbal fluency showed significant greater changes from baseline in the active tDCS group.

Conclusions: We concluded that cognitive training along with active tDCS is a useful combined approach in the management of mood and cognitive dysfunctions in PD.
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http://dx.doi.org/10.1016/j.brs.2018.07.046DOI Listing
May 2019

Diagnosis of Mild Cognitive Impairment Due to Alzheimer's Disease with Transcranial Magnetic Stimulation.

J Alzheimers Dis 2018 ;65(1):221-230

Department of Clinical and Experimental Sciences, Neurology Unit, University of Brescia, Brescia, Italy.

Background: Considering the increasing evidence that disease-modifying treatments for Alzheimer's disease (AD) must be administered early in the disease course, the development of diagnostic tools capable of accurately identifying AD at early disease stages has become a crucial target. In this view, transcranial magnetic stimulation (TMS) has become an effective tool to discriminate between different forms of neurodegenerative dementia.

Objective: To determine whether a TMS multi-paradigm approach can be used to correctly identify mild cognitive impairment (MCI) due to AD (AD MCI).

Methods: A sample of 69 subjects with MCI were included and classified as AD MCI or MCI unlikely due to AD (non-AD MCI) based on 1) extensive neurological and neuropsychological evaluation, 2) MRI imaging, and 3) cerebrospinal fluid analysis or/and amyloid PET imaging. A paired-pulse TMS multi-paradigm approach assessing short interval intracortical inhibition-facilitation (SICI-ICF), dependent on GABAergic and glutamatergic intracortical circuits, respectively, and short latency afferent inhibition (SAI), dependent on cholinergic circuits, was performed.

Results: We observed a significant impairment of SAI and unimpaired SICI and ICF in AD MCI as compared to non-AD MCI. According to ROC curve analysis, the SICI-ICF / SAI index differentiated AD MCI from non-AD MCI with a specificity of 87.9% and a sensitivity of 94.4%.

Conclusions: The assessment of intracortical connectivity with TMS could aid in the characterization of MCI subtypes, correctly identifying AD pathophysiology. TMS can be proposed as an adjunctive, non-invasive, inexpensive, and time-saving screening tool in MCI differential diagnosis.
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http://dx.doi.org/10.3233/JAD-180293DOI Listing
July 2019

Recent neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC.

F1000Res 2018 15;7:194. Epub 2018 Feb 15.

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa, 11, 25123 Brescia BS, Italy.

Niemann-Pick disease type C (NPC) is a rare autosomal recessive lysosomal storage disorder with extensive biological, molecular, and clinical heterogeneity. Recently, numerous studies have tried to shed light on the pathophysiology of the disease, highlighting possible disease pathways common to other neurodegenerative disorders, such as Alzheimer's disease and frontotemporal dementia, and identifying possible candidate biomarkers for disease staging and response to treatment. Miglustat, which reversibly inhibits glycosphingolipid synthesis, has been licensed in the European Union and elsewhere for the treatment of NPC in both children and adults. A number of ongoing clinical trials might hold promise for the development of new treatments for NPC. The objective of the present work is to review and evaluate recent literature data in order to highlight the latest neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC pathophysiology. Furthermore, ongoing developments in disease-modifying treatments will be briefly discussed.
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http://dx.doi.org/10.12688/f1000research.12361.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814740PMC
February 2018

Trauma and amyotrophic lateral sclerosis: a european population-based case-control study from the EURALS consortium.

Amyotroph Lateral Scler Frontotemporal Degener 2018 02 24;19(1-2):118-125. Epub 2017 Oct 24.

a Laboratorio di Malattie Neurologiche , IRCCS-Istituto Mario Negri , Milano , Italy.

Objectives: To assess the association between amyotrophic lateral sclerosis (ALS) and previous traumatic events, age of trauma, and site of injury.

Methods: A population-based case-control study was performed in five European countries (Italy, Ireland, France, United Kingdom, Serbia). Newly diagnosed ALS patients and matched controls were interviewed to collect relevant demographic factors and exposures. Key clinical features at diagnosis were collected in ALS patients. Trauma was any accidental event causing an injury. Injuries were dated and classified according to cause, severity, type, site, and complications. All exposures were censored five years before symptoms onset. Risks were computed as odds ratios (OR) with 95% confidence intervals (CI) using univariate and multivariate conditional logistic regression models.

Results: Five hundred and seventy-five ALS patients and 1150 controls were interviewed. Disabling traumatic events predominated in the cases (OR 1.54 (95% CI 1.24-1.92)) and maintained significance after adjustment, with a significant gradient. A history of 2 + head injuries was associated with an almost three-fold increased risk of ALS. The risk was almost two-fold when trauma occurred at age 35-54 years. Site of injury was uneventful.

Conclusions: Traumatic events leading to functional disability or confined to the head are risk factors for ALS. Traumatic events experienced at age 35-54 years carry the highest risk.
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http://dx.doi.org/10.1080/21678421.2017.1386687DOI Listing
February 2018
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