Publications by authors named "Cristoforo Comi"

94 Publications

Simple Parameters from Complete Blood Count Predict In-Hospital Mortality in COVID-19.

Dis Markers 2021 13;2021:8863053. Epub 2021 May 13.

Università del Piemonte Orientale UPO, Novara, Italy.

Introduction: The clinical course of Coronavirus Disease 2019 (COVID-19) is highly heterogenous, ranging from asymptomatic to fatal forms. The identification of clinical and laboratory predictors of poor prognosis may assist clinicians in monitoring strategies and therapeutic decisions.

Materials And Methods: In this study, we retrospectively assessed the prognostic value of a simple tool, the complete blood count, on a cohort of 664 patients ( 260; 39%, median age 70 (56-81) years) hospitalized for COVID-19 in Northern Italy. We collected demographic data along with complete blood cell count; moreover, the outcome of the hospital in-stay was recorded.

Results: At data cut-off, 221/664 patients (33.3%) had died and 453/664 (66.7%) had been discharged. Red cell distribution width (RDW) ( 10.4; < 0.001), neutrophil-to-lymphocyte (NL) ratio ( 7.6; = 0.006), and platelet count ( 5.39; = 0.02), along with age ( 87.6; < 0.001) and gender ( 17.3; < 0.001), accurately predicted in-hospital mortality. Hemoglobin levels were not associated with mortality. We also identified the best cut-off for mortality prediction: a NL ratio > 4.68 was characterized by an odds ratio for in-hospital mortality (OR) = 3.40 (2.40-4.82), while the OR for a RDW > 13.7% was 4.09 (2.87-5.83); a platelet count > 166,000/L was, conversely, protective (OR: 0.45 (0.32-0.63)).

Conclusion: Our findings arise the opportunity of stratifying COVID-19 severity according to simple lab parameters, which may drive clinical decisions about monitoring and treatment.
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http://dx.doi.org/10.1155/2021/8863053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123088PMC
June 2021

The Impact of the COVID-19 Pandemic on the Cognition of People with Dementia.

Int J Environ Res Public Health 2021 04 18;18(8). Epub 2021 Apr 18.

Neurology Unit, S. Andrea Hospital, Department of Translational Medicine, University of Piemonte Orientale, Corso Abbiate 21, 13100 Vercelli, Italy.

(1) Background: To limit the COVID-19 outbreak, the Italian government implemented social restrictions that may have had psychological and cognitive repercussions on people with dementia. We aimed to analyze cognitive decline during the pandemic year in people evaluated in a memory clinic in northern Italy, the epicenter of COVID-19 spread. (2) Methods: A single-center retrospective study was carried out, including individuals with annual follow-up evaluated in three different years (2020-GROUP, 2019-GROUP, 2018-GROUP). We performed an intergroup comparison of cognitive decline over a one-year follow-up, and an intragroup comparison in the 2020-GROUP to analyze the five-year cognitive decline trajectory, as measured by the MMSE. (3) Results: The 2020-GROUP showed a significant loss of MMSE points per year in the considered follow-up period compared with the 2019-GROUP and 2018-GROUP ( = 0.021). Demographics, clinical features, and the other analyzed variables, including rate of diagnosis, therapy, and comorbidities, did not significantly differ between groups. The five-year cognitive decline trajectory confirmed a significant worsening of cognitive decline between 2019 and 2020 ( < 0.001), while the decrease in MMSE scores was not statistically significant between previous time points. (4) Conclusions: COVID-19 pandemic measures have induced a significant worsening of cognitive decline in people with dementia, needing more careful assistance to minimize the adverse effects of social isolation in case of future lockdowns.
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http://dx.doi.org/10.3390/ijerph18084285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073614PMC
April 2021

Polymorphisms of Dopamine Receptor Genes and Parkinson's Disease: Clinical Relevance and Future Perspectives.

Int J Mol Sci 2021 Apr 6;22(7). Epub 2021 Apr 6.

Centre of Research in Medical Pharmacology, University of Insubria, 21100 Varese, Italy.

Parkinson's disease (PD) is a neurodegenerative disease caused by loss of dopaminergic neurons in the midbrain. PD is clinically characterized by a variety of motor and nonmotor symptoms, and treatment relies on dopaminergic replacement. Beyond a common pathological hallmark, PD patients may present differences in both clinical progression and response to drug therapy that are partly affected by genetic factors. Despite extensive knowledge on genetic variability of dopaminergic receptors (DR), few studies have addressed their relevance as possible influencers of clinical heterogeneity in PD patients. In this review, we summarized available evidence regarding the role of genetic polymorphisms in DR as possible determinants of PD development, progression and treatment response. Moreover, we examined the role of DR in the modulation of peripheral immunity, in light of the emerging role of the peripheral immune system in PD pathophysiology. A better understanding of all these aspects represents an important step towards the development of precise and personalized disease-modifying therapies for PD.
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http://dx.doi.org/10.3390/ijms22073781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038729PMC
April 2021

Potential protective role of ACE-inhibitors and AT1 receptor blockers against levodopa-induced dyskinesias: a retrospective case-control study.

Neural Regen Res 2021 Dec;16(12):2475-2478

Movement Disorders Centre, Neurology Unit, Department of Translational Medicine, University of Piemonte Orientale, Novara; Center of Research in Medical Pharmacology, University of Insubria, Varese, Italy.

Growing evidence has highlighted that angiotensin-converting enzyme (ACE)-inhibitors (ACEi)/AT1 receptor blockers (ARBs) may influence the complex interplay between dopamine and the renin-angiotensin system in the nigrostriatal pathway, thus affecting the development of levodopa-induced dyskinesia in Parkinson's disease (PD). In the present study, we analyzed whether the use of this class of medication was associated with a reduced occurrence of levodopa-induced dyskinesia, using electronically-stored information of idiopathic PD patients enrolled at Novara University Hospital "Maggiore della Carità". We conducted a retrospective case-control study identifying PD patients with dyskinesias (PwD; n = 47) as cases. For each PwD we selected a non-dyskinetic control (NoD), nearly perfectly matched according to sex, Unified Parkinson's Disease Rating Scale (UPDRS) part III score, and duration of antiparkinsonian treatment. Binary logistic regression was used to evaluate whether dyskinesias were associated with ACEi/ARBs use. Ninety-four PD patients were included, aged 72.18 ± 9 years, with an average disease duration of 10.20 ± 4.8 years and 9.04 ± 4.9 years of antiparkinsonian treatment. The mean UPDRS part III score was 18.87 ± 7.6 and the median HY stage was 2. In the NoD group, 25 (53.2%) were users and 22 (46.8%) non-users of ACEi/ARBs. Conversely, in the PwD group, 11 (23.4%) were users and 36 non-users (76.6%) of this drug class (Pearson chi-square = 8.824, P = 0.003). Concerning general medication, there were no other statistically significant differences between groups. After controlling for tremor dominant phenotype, levodopa equivalent daily dose, HY 3-4, and disease duration, ACEi/ARBs use was a significant predictor of a lower occurrence of dyskinesia (OR = 0.226, 95% CI: 0.080-0.636, P = 0.005). Therefore, our study suggests that ACEi/ARBs may reduce levodopa-induced dyskinesia occurrence and, thanks to good tolerability and easy management, represent a feasible choice when dealing with the treatment of hypertension in PD patients. The study was approved by the Ethics Committee of Novara University Hospital "Maggiore della Carità" (CE 65/16) on July 27, 2016.
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http://dx.doi.org/10.4103/1673-5374.313061DOI Listing
December 2021

Telehealth in Neurodegenerative Diseases: Opportunities and Challenges for Patients and Physicians.

Brain Sci 2021 Feb 13;11(2). Epub 2021 Feb 13.

Department of Neurology and ALS Centre, Traslational Medicine, University of Piemonte Orientale, Maggiore della Carità Hospital, 28100 Novara, Italy.

Telehealth, by definition, is distributing health-related services while using electronic technologies. This narrative Review describes the technological health services (telemedicine and telemonitoring) for delivering care in neurodegenerative diseases, Alzheimer's disease, Parkinson's Disease, and amyotrophic lateral Sclerosis, among others. This paper aims to illustrate this approach's primary experience and application, highlighting the strengths and weaknesses, with the goal of understanding which could be the most useful application for each one, in order to facilitate telehealth improvement and use in standard clinical practice. We also described the potential role of the COVID-19 pandemic to speed up this service's use, avoiding a sudden interruption of medical care.
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http://dx.doi.org/10.3390/brainsci11020237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917616PMC
February 2021

Paraneoplastic neuromyelitis optica spectrum disorders: a case series.

Neurol Sci 2021 Jun 28;42(6):2519-2522. Epub 2021 Jan 28.

Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Novara, Italy.

Aquaporin-4 antibody (AQP4-IgG) neuromyelitis optica spectrum disorders (NMOSD) are rare idiopathic autoimmune diseases, presenting with optic neuritis (ON), longitudinally extensive transverse myelitis (LETM), and brainstem syndromes and a prevalence range between 0.5 and 4/100,000. Only 3% to 25% of NMOSD have been described as a paraneoplastic (PN) syndrome (PNNMOSD). Both idiopathic NMOSD (INMOSD) and PNNMOSD cases mostly affect females, but PNNMOSD usually presents with a spinal cord or brainstem involvement in elderly patients. Few cases of both malignancies (for the majority breast or lung cancer) and benign tumors (monoclonal gammopathy) were previously reported. Currently, there is no consensus on treatment approach for PNNMOSD (only surgical removal or surgery combined with chronic immunosuppression). Here, we present a series of three newly diagnosed PNNMOSD cases, who differ from each other for demographic and clinical features, tumor association, long-term treatment, and outcome. We propose that a PN etiology should be considered always whenever a new diagnosis of NMOSD is made, not only in patients over 50 years old or in spinal cord/brainstem lesions presentations. Our findings add to existing evidence and raise awareness on PNNMOSD. We enhance the importance for the clinicians of recognizing tumor symptoms and signs whenever a NMOSD is newly diagnosed.
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http://dx.doi.org/10.1007/s10072-021-05055-yDOI Listing
June 2021

Expanding the genetic spectrum of primary familial brain calcification due to SLC2OA2 mutations: a case series.

Neurogenetics 2021 03 20;22(1):65-70. Epub 2021 Jan 20.

Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.

Primary familial brain calcification (PFBC) is a neurological condition characterized by the presence of intracranial calcifications, mainly involving basal ganglia, thalamus, and dentate nuclei. So far, six genes have been linked to this condition: SLC20A2, PDGFRB, PDGFB, and XPR1 inherited as autosomal-dominant trait, while MYORG and JAM2 present a recessive pattern of inheritance. Patients mainly present with movement disorders, psychiatric disturbances, and cognitive decline or are completely asymptomatic and calcifications may represent an occasional finding. Here we present three variants in SLC20A2, two exonic and one intronic, which we found in patients with PFBC associated to three different clinical phenotypes. One variant is novel and two were already described as variants of uncertain significance. We confirm the pathogenicity of these three variants and suggest a broadening of the phenotypic spectrum associated with mutations in SLC20A2.
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http://dx.doi.org/10.1007/s10048-021-00634-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997821PMC
March 2021

Expression of Transcription Factors in CD4 + T Cells as Potential Biomarkers of Motor Complications in Parkinson's Disease.

J Parkinsons Dis 2021 ;11(2):507-514

Movement Disorders Centre, Neurology Unit, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.

Background: Management of motor complications (MC) represents a major challenge in the long-term treatment of Parkinson's disease (PD) patients. In this context, the role of peripheral adaptive immunity may provide new insights, since neuroinflammatory mechanisms have been proved crucial in the disease.

Objective: The aim of this study was to analyze the transcription factors genes involved in CD4 + T cells development to uncover specific molecular signatures in patients with (PMC) and without (WMC) motor complications.

Methods: mRNA levels of CD4 + T lymphocytes transcription factor genes TBX21, STAT1, STAT3, STAT4, STAT6, RORC, GATA3, FOXP3, and NR4A2 were measured from 40 PD patients, divided into two groups according to motor complications. Also, 40 age- and sex-matched healthy controls were enrolled.

Results: WMC patients had higher levels of STAT1 and NR4A2 (p = 0.004; p = 0.003), whereas in PMC we found higher levels of STAT6 (p = 0.04). Also, a ROC curve analysis confirmed STAT1 and NR4A2 as feasible biomarkers to discriminate WMC (AUC = 0.76, 95%CI 0.59-0.92, p = 0.005; AUC = 0.75, 95%CI 0.58-0.90, p = 0.007). Similarly, STAT6 detected PMC patients (AUC = 0.69, 95%CI 0.52-0.86, p = 0.037).

Conclusion: These results provide evidence of different molecular signatures in CD 4 + T cells of PD patients with and without MC, thus suggesting their potential as biomarkers of MC development.
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http://dx.doi.org/10.3233/JPD-202417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150526PMC
January 2021

The of osteopontin in nervous system diseases: damage repair.

Neural Regen Res 2021 Jun;16(6):1131-1137

Department of Translational Medicine, Neurology Unit, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale, Novara, Italy.

Osteopontin is a broadly expressed pleiotropic protein, and is attracting increased attention because of its role in the pathophysiology of several inflammatory, degenerative, autoimmune, and oncologic diseases. In fact, in the last decade, several studies have shown that osteopontin contributes to tissue damage not only by recruiting harmful inflammatory cells to the site of lesion, but also increasing their survival. The detrimental role of osteopontin has been indeed well documented in the context of different neurological conditions (i.e., multiple sclerosis, Parkinson's, and Alzheimer's diseases). Intriguingly, recent findings show that osteopontin is involved not only in promoting tissue damage (the Yin), but also in repair/regenerative mechanisms (the Yang), mostly triggered by the inflammatory response. These two apparently discordant roles are partly related to the presence of different functional domains in the osteopontin molecule, which are exposed after thrombin or metalloproteases cleavages. Such functional domains may in turn activate intracellular signaling pathways and mediate cell-cell and cell-matrix interactions. This review describes the current knowledge on the Yin and Yang features of osteopontin in nervous system diseases. Understanding the mechanisms behind the Yin/Yang would be relevant to develop highly specific tools targeting this multifunctional protein.
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http://dx.doi.org/10.4103/1673-5374.300328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224140PMC
June 2021

Fatality rate and predictors of mortality in an Italian cohort of hospitalized COVID-19 patients.

Sci Rep 2020 11 26;10(1):20731. Epub 2020 Nov 26.

Department of Translational Medicine, Università del Piemonte Orientale UPO, Via Solaroli 17, 28100, Novara, NO, Italy.

Clinical features and natural history of coronavirus disease 2019 (COVID-19) differ widely among different countries and during different phases of the pandemia. Here, we aimed to evaluate the case fatality rate (CFR) and to identify predictors of mortality in a cohort of COVID-19 patients admitted to three hospitals of Northern Italy between March 1 and April 28, 2020. All these patients had a confirmed diagnosis of SARS-CoV-2 infection by molecular methods. During the study period 504/1697 patients died; thus, overall CFR was 29.7%. We looked for predictors of mortality in a subgroup of 486 patients (239 males, 59%; median age 71 years) for whom sufficient clinical data were available at data cut-off. Among the demographic and clinical variables considered, age, a diagnosis of cancer, obesity and current smoking independently predicted mortality. When laboratory data were added to the model in a further subgroup of patients, age, the diagnosis of cancer, and the baseline PaO/FiO ratio were identified as independent predictors of mortality. In conclusion, the CFR of hospitalized patients in Northern Italy during the ascending phase of the COVID-19 pandemic approached 30%. The identification of mortality predictors might contribute to better stratification of individual patient risk.
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http://dx.doi.org/10.1038/s41598-020-77698-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692524PMC
November 2020

Genetic parkinsonisms and cancer: a systematic review and meta-analysis.

Rev Neurosci 2021 02 5;32(2):159-167. Epub 2020 Nov 5.

Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, 260 Stetson St., Cincinnati, OH45219, USA.

Genes associated with parkinsonism may also be implicated in carcinogenesis, but their interplay remains unclear. We systematically reviewed studies (PubMed 1967-2019) reporting gene variants associated with both parkinsonism and cancer. Somatic variants were examined in cancer samples, whereas germline variants were examined in cancer patients with both symptomatic and asymptomatic (carriers) genetic parkinsonisms. Pooled proportions were calculated with random-effects meta-analyses. Out of 9,967 eligible articles, 60 were included. Of the 28 genetic variants associated with parkinsonism, six were also associated with cancer. In cancer samples, was predominantly associated with gastrointestinal cancers with breast cancer, and with head-and-neck cancers. In asymptomatic carriers, was predominantly associated with gastrointestinal and prostate cancers, with prostate and genitourinary tract cancers, with sarcoma, and deletion with leukemia. In symptomatic genetic parkinsonism, was associated with nonmelanoma skin cancers and breast cancers, and with head-and-neck cancers. Cancer was more often manifested in genetic parkinsonisms compared to asymptomatic carriers. These results suggest that intraindividual genetic contributions may modify the co-occurrence of cancer and neurodegeneration.
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http://dx.doi.org/10.1515/revneuro-2020-0083DOI Listing
February 2021

Kinematic but not clinical measures predict falls in Parkinson-related orthostatic hypotension.

J Neurol 2021 Mar 26;268(3):1006-1015. Epub 2020 Sep 26.

Department of Neurology, Wexner Medical Center, Ohio State University, Columbus, OH, USA.

Objective: We sought to test the hypothesis that technology could predict the risk of falls in Parkinson's disease (PD) patients with orthostatic hypotension (OH) with greater accuracy than in-clinic assessment.

Methods: Twenty-six consecutive PD patients with OH underwent clinical (including home-like assessments of activities of daily living) and kinematic evaluations of balance and gait as well as beat-to-beat blood pressure (BP) monitoring to estimate their association with the risk of falls. Fall frequency was captured by a diary collected prospectively over 6 months. When applicable, the sensitivity, specificity, and diagnostic accuracy were measured using the area under the receiver operating characteristics curve (AUC). Additional in-clinic assessments included the OH Symptom Assessment (OHSA), the OH Daily Activity Score (OHDAS), and the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS).

Results: The prevalence of falls was 53.8% over six months. There was no association between the risk of falls and test of gait and postural stability (p ≥ 0.22) or home-like activities of daily living (p > 0.08). Conversely, kinematic data (waist sway during time-up-and-go, jerkiness, and centroidal frequency during postural sway with eyes-opened) predicted the risk of falls with high sensitivity and specificity (> 80%; AUC ≥ 0.81). There was a trend for higher risk of falls in patients with orthostatic mean arterial pressure ≤ 75 mmHg.

Conclusions: Kinematic but not clinical measures predicted falls in PD patients with OH. Orthostatic mean arterial pressure ≤ 75 mmHg may represent a hemodynamic threshold below which falls become more prevalent, supporting the aggressive deployment of corrective measures.
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http://dx.doi.org/10.1007/s00415-020-10240-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914136PMC
March 2021

Relationship between circulating CD4+ T lymphocytes and cognitive impairment in patients with Parkinson's disease.

Brain Behav Immun 2020 10 17;89:668-674. Epub 2020 Jul 17.

Center of Research in Medical Pharmacology, University of Insubria, Varese, Italy; Center for Research in Neuroscience, University of Insubria, Varese, Italy.

Introduction: Parkinson's disease (PD) is characterized by loss of dopaminergic neurons. Neuroinflammation may represent an important factor in the pathophysiology of PD and recent findings indicate that PD patients present a pro-inflammatory peripheral profile of CD4+ T lymphocytes, which may correlate with motor disability. However, no data are currently available on the relationship between CD4+ T lymphocytes and cognitive function in PD. The aim of our study is to evaluate the relationship between cognitive profile and circulating CD4+ T lymphocyte subsets in PD patients.

Methods: PD patients underwent blood withdrawal and CD4+ T lymphocyte subpopulations, including CD4+ T naïve and memory cells, Th1, Th2, Th17, Th1/17 and T regulatory (Treg) cells were evaluated by flow cytometry. Cognitive evaluation was performed using Addenbrooke Cognitive Examination (ACE-R).

Results: 43 consecutive PD patients (31 males; age [mean ± SD]: 68.9 ± 8.4 years) were enrolled. 14/43 (32.6%) were drug naïve. Based on the ACE-R score, patients were divided in two groups using defined cutoff values. In comparison to patients with normal cognitive profile, patients with cognitive impairment had a higher number of circulating lymphocytes. Moreover, drug naïve patients with a worse cognitive outcome had a lower number of resting Treg and higher number of activated Treg. Furthermore, we found a correlation between pro-inflammatory peripheral immune phenotype and worse cognitive outcome in the ACE-R total and sub-items scores.

Conclusions: In our cohort of PD patients, cognitive impairment was associated with higher number of circulating lymphocytes, and - at least in drug naïve patients - with dysregulation of the Treg compartment. Further studies are needed to assess whether and to what extent peripheral immunity mechanistically contributes to cognitive decline in PD.
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http://dx.doi.org/10.1016/j.bbi.2020.07.005DOI Listing
October 2020

CD4+ T-cell Transcription Factors in Idiopathic REM Sleep Behavior Disorder and Parkinson's Disease.

Mov Disord 2021 01 10;36(1):225-229. Epub 2020 Jul 10.

Center of Research in Medical Pharmacology, University of Insubria, Varese, Italy.

Background: CD4+ T-cell dysregulation occurs in Parkinson's disease (PD); however, it is unknown whether it contributes to PD development. The objective of this study was to investigate transcription factor gene expression in CD4+ T cells in idiopathic rapid eye movement sleep behavior disorder, the strongest risk factor for prodromal PD.

Methods: Expression of transcription factors (TBX21, STAT1, STAT3, STAT4, STAT6, RORC, GATA3, FOXP3, and NR4A2) was measured in CD4+ T cells from 33 polysomnographically confirmed idiopathic rapid eye movement sleep behavior disorder subjects and compared with expression in cells from matched healthy subjects and antiparkinson drugs-naive PD patients.

Results: Compared with healthy subjects, idiopathic rapid eye movement sleep behavior disorder subjects and PD patients had lower TBX21, STAT3, and STAT4, and higher FOXP3 expression. TBX21 expression discriminated healthy subjects from idiopathic rapid eye movement sleep behavior disorder subjects and PD patients, but not idiopathic rapid eye movement sleep behavior disorder subjects with PD.

Conclusions: In idiopathic rapid eye movement sleep behavior disorder subjects CD4+ T cells exhibit a peculiar molecular signature strongly resembling cells from PD patients, suggesting early involvement of peripheral immunity in PD. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28137DOI Listing
January 2021

Cortical visuomotor interactions in Freezing of Gait: A TMS approach.

Neurophysiol Clin 2020 Jul 27;50(3):205-212. Epub 2020 Apr 27.

Department of Translational Medicine, Section of Neurology, University of Piemonte Orientale and "Maggiore della Carità" University Hospital, Novara, Italy.

Objectives: Altered cortical visuomotor integration has been involved in the pathophysiology of freezing of gait (FoG) in parkinsonism. The aim of this study was to assess the connections between the primary visual (V1) and motor (M1) areas with a paired-pulse, twin-coil transcranial magnetic stimulation (TMS) technique in patients with FoG.

Methods: Twelve Parkinson's disease (PD) patients suffering from levodopa-responsive-FoG (off-FoG) were compared with 12 PD patients without FoG and 12 healthy subjects of similar age/sex. In the "off" condition, visuomotor connections (VMCs) were assessed bilaterally. A conditioning stimulus over the V1 phosphene hotspot was followed at interstimulus intervals (ISIs) of 18 and 40ms by a test stimulus over M1, to elicit motor evoked potentials (MEPs) in the contralateral first dorsal interosseous muscle.

Results: Significant (P<0.01), bilateral effects due to VMCs were detected in all three groups, consisting of a MEP suppression at ISI 18 and 40ms. However, in PD patients with FoG, the MEP suppression was significantly (P<0.05) enhanced, both at ISI 18-40ms, in comparison with the other two groups. The phenomenon was limited to the right hemisphere.

Conclusions: PD patients with FoG showed an excessive inhibitory response of the right M1 to inputs travelling from V1 at given ISIs. Right-sided alterations of the cortical visuomotor integration may contribute to the pathophysiology of FoG.
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http://dx.doi.org/10.1016/j.neucli.2020.04.001DOI Listing
July 2020

The TANDEM investigation: efficacy and tolerability of levodopa-carbidopa intestinal gel in (LCIG) advanced Parkinson's disease patients.

J Neural Transm (Vienna) 2020 06 24;127(6):881-891. Epub 2020 Mar 24.

Department of Neuroscience "Rita Levi-Montalcini", University of Torino, Turin, Italy.

The TANDEM investigation was carried out in 17 Italian Movement Disorder centers on behalf of a joint initiative of neurologist members of the Italian Academy for Parkinson's disease and Movement Disorders (LIMPE-DISMOV Academy) and gastroenterologist members of the Italian Society of Digestive Endoscopy (SIED) to evaluate the efficacy and tolerability of levodopa-carbidopa intestinal gel (LCIG) in patients with advanced Parkinson's disease (PD) in routine medical care. Motor scores in "ON" and OFF" state (UPDRS-III), complications of therapy (UPDRS-IV), activities of daily living, sleep disorders and quality of life were evaluated at baseline and at two follow-up assessments (FUV1 and FUV2) within the initial 12-month LCIG treatment. In 159 patients (55% males) with a mean age of 69.1 ± 6.6 years and a diagnosis of PD since 13.6 ± 5.5 years, the UPDRS-III total score (in "OFF") decreased from baseline (45.8 ± 13.2) to FUV1 (41.0 ± 17.4; p < 0.001) and FUV2 (40.5 ± 15.5; p < 0.001), the UPDRS-IV total score decreased from baseline (8.8 ± 2.9) to FUV1 (5.1 ± 3.4; p < 0.001) and FUV2 (5.5 ± 3.2; p < 0.001). The percentage of patients exhibiting freezing, dystonia, gait/walking disturbances, falls, pain and sleep disorders was significantly reduced. Twenty-eight device complications were reported and 11 (6.9%) patients prematurely terminated the study. LCIG after 12-month treatment led to sustained improvement of time spent in "OFF", complications of therapy, PD-associated symptoms and sleep disorders. LCIG tolerability was consistent with the established safety profile of LCIG.
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http://dx.doi.org/10.1007/s00702-020-02175-1DOI Listing
June 2020

Nerve conduction, circulating osteopontin and taxane-induced neuropathy in breast cancer patients.

Neurophysiol Clin 2020 Feb 9;50(1):47-54. Epub 2020 Jan 9.

Department of Translational Medicine, Section of Neurology, University of Piemonte-Orientale, Via Solaroli 17, 28100 Novara, Italy; Department of Neurology, "Maggiore della Carità" University Hospital, Corso-Mazzini 18, 28100 Novara, Italy.

Objective: Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling complication related to taxanes. Underlying mechanisms are not completely understood and no specific treatment exists. We investigated the role of nerve conduction studies (NCS) and of serum osteopontin (OPN) measurement as a means to stratify the risk of developing taxane-induced neuropathy (TIN).

Methods: We enrolled 50 women with breast cancer treated with taxanes (docetaxel or paclitaxel) in a 3-month prospective study. They were evaluated before chemotherapy (time-point T0) and followed up at 1 (T1) and 3 (T2) months with clinical examinations/scales, quality of life (QoL) questionnaires, NCS, and serum OPN dosages.

Results: A reduction of sural and superficial peroneal sensory action potentials was seen at T1, with a progression at T2 (P<0.001). In contrast, a significant impact of neuropathic symptoms on QoL only occurred at T2 (P<0.01). OPN levels at T0 inversely correlated to axonal loss in the sural nerve (T0-T2, P<0.01). OPN levels at T0 were lower in the intermediate and poor outcome patient subgroups, compared to the good outcome subgroup, as specifically defined (P<0.05).

Conclusion: Lower limb NCS changes occurred earlier than the detrimental effects of TIN on patients' QoL. Low serum OPN levels before chemotherapy may represent a novel biomarker of TIN risk.
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http://dx.doi.org/10.1016/j.neucli.2019.12.001DOI Listing
February 2020

Editorial: Peripheral Immunity in Parkinson's Disease: Emerging Role and Novel Target for Therapeutics.

Front Neurol 2019 15;10:1080. Epub 2019 Oct 15.

Laboratory of Neuroimmunology, Fundación Ciencia and Vida, Ñuñoa, Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile.

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http://dx.doi.org/10.3389/fneur.2019.01080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804273PMC
October 2019

TAM Receptor Pathways at the Crossroads of Neuroinflammation and Neurodegeneration.

Dis Markers 2019 15;2019:2387614. Epub 2019 Sep 15.

Neurology Unit, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.

Increasing evidence suggests that pathogenic mechanisms underlying neurodegeneration are strongly linked with neuroinflammatory responses. Tyro3, Axl, and Mertk (TAM receptors) constitute a subgroup of the receptor tyrosine kinase family, cell surface receptors which transmit signals from the extracellular space to the cytoplasm and nucleus. TAM receptors and the corresponding ligands, Growth Arrest Specific 6 and Protein S, are expressed in different tissues, including the nervous system, playing complex roles in tissue repair, inflammation and cell survival, proliferation, and migration. In the nervous system, TAM receptor signalling modulates neurogenesis and neuronal migration, synaptic plasticity, microglial activation, phagocytosis, myelination, and peripheral nerve repair, resulting in potential interest in neuroinflammatory and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Multiple Sclerosis. In Alzheimer and Parkinson diseases, a role of TAM receptors in neuronal survival and pathological protein aggregate clearance has been suggested, while in Multiple Sclerosis TAM receptors are involved in myelination and demyelination processes. To better clarify roles and pathways involving TAM receptors may have important therapeutic implications, given the fine modulation of multiple molecular processes which could be reached. In this review, we summarise the roles of TAM receptors in the central nervous system, focusing on the regulation of immune responses and microglial activities and analysing in vitro and in vivo studies regarding TAM signalling involvement in neurodegeneration.
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http://dx.doi.org/10.1155/2019/2387614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766163PMC
April 2020

The vermiform appendix in Parkinson's disease: At the crossroad of peripheral immunity, the nervous system and the intestinal microbiome.

Autoimmun Rev 2019 Sep 16;18(9):102357. Epub 2019 Jul 16.

Center of Research in Medical Pharmacology, University of Insubria, Via Monte Generoso n. 71, Varese, VA, Italy.

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http://dx.doi.org/10.1016/j.autrev.2019.102357DOI Listing
September 2019

Probiotics May Have Beneficial Effects in Parkinson's Disease: Evidence.

Front Immunol 2019 7;10:969. Epub 2019 May 7.

Neurology Unit, Department of Translational Medicine, Interdisciplinary Research Centre of Autoimmune Diseases, Movement Disorders Centre, University of Piemonte Orientale, Novara, Italy.

Parkinson's disease (PD) is characterized by loss of dopaminergic neurons and intraneuronal accumulation of alpha-synuclein, both in the basal ganglia and in peripheral sites, such as the gut. Peripheral immune activation and reactive oxygen species (ROS) production are important pathogenetic features of PD. In this context, the present study focused on the assessment of effects of probiotic bacterial strains in PBMCs isolated from PD patients vs. healthy controls. 40 PD patients and 40 matched controls have been enrolled. Peripheral blood mononuclear cells (PBMCs) were isolated and co-cultured with a selection of probiotics microorganisms belonging to the and genus. release of the major pro- (Tumor Necrosis Factor-alpha and Interleukin-17A and 6) and anti-inflammatory (Interleukin 4 and 10) cytokines by PBMCs, as well as the production of ROS was investigated. Furthermore, we assessed the ability of probiotics to influence membrane integrity, antagonize the growth of potential pathogen bacteria, such as and and encode tyrosine decarboxylase genes (). All probiotic strains were able to inhibit inflammatory cytokines and ROS production in both patients and controls. The most striking results were obtained in PD subjects with LS01 and which significantly reduced pro-inflammatory and increased the anti-inflammatory cytokines ( < 0.05). Furthermore, most strains determined restoration of membrane integrity and inhibition of and . Finally, we also showed that all the strains do not carry gene, which is known to decrease levodopa bioavailability in PD patients under treatment. Probiotics exert promising results in decreasing pro-inflammatory cytokines, oxidative stress and potentially pathogenic bacterial overgrowth. longitudinal data are mandatory to support the use of bacteriotherapy in PD.
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http://dx.doi.org/10.3389/fimmu.2019.00969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513970PMC
September 2020

K Index is a Reliable Marker of Intrathecal Synthesis, and an Alternative to IgG Index in Multiple Sclerosis Diagnostic Work-Up.

J Clin Med 2019 Apr 2;8(4). Epub 2019 Apr 2.

Institute of Neurology, Department of Transational Medicine, AOU Maggiore della Carità, University of PiemonteOrientale, corso Mazzini 18, 28100 Novara, Italy.

The K free light chain (K) index has been suggested as a reliable marker of intrathecal synthesis,despite the 2017 McDonald criteria for multiple sclerosis (MS) suggesting to "interpret with caution positiveimmunoglobulin G (IgG) index when testing for oligoclonal bands (OB) is negative or not performed". Theaim of this study was to compare the performance of K and IgG indexes for MS diagnosis and OB detectionin a cohort of Italian patients. We enrolled 385 patients (127 MS, 258 non-MS) who had cerebrospinal fluid(CSF) analysis, including isoelectric focusing (IEF), to detect OB in the diagnostic work-up. Albumin, IgGand free light chains were measured by nephelometry and used to calculate IgG and K indexes. Althoughthe two markers were highly related (r = 0.75, r2 = 0.55, p < 0.0001), the K index showed greater sensitivity andnegative predictive value (versus the IgG index) for OB detection (97% versus 48% and 97% versus 71%) andMS diagnosis (96% versus 50% and 98% versus 78%). These results support K index (and not IgG index) as afirst-line marker for MS, followed by IEF, according to a sequential testing approach in CSF analysis.
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http://dx.doi.org/10.3390/jcm8040446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518364PMC
April 2019

Untangling Extracellular Proteasome-Osteopontin Circuit Dynamics in Multiple Sclerosis.

Cells 2019 03 20;8(3). Epub 2019 Mar 20.

Max-Planck-Institute for Biophysical Chemistry, 37077 Göttingen, Germany.

The function of proteasomes in extracellular space is still largely unknown. The extracellular proteasome-osteopontin circuit has recently been hypothesized to be part of the inflammatory machinery regulating relapse/remission phase alternation in multiple sclerosis. However, it is still unclear what dynamics there are between the different elements of the circuit, what the role of proteasome isoforms is, and whether these inflammatory circuit dynamics are associated with the clinical severity of multiple sclerosis. To shed light on these aspects of this novel inflammatory circuit, we integrated in vitro proteasome isoform data, cell chemotaxis cell culture data, and clinical data of multiple sclerosis cohorts in a coherent computational inference framework. Thereby, we modeled extracellular osteopontin-proteasome circuit dynamics during relapse/remission alternation in multiple sclerosis. Applying this computational framework to a longitudinal study on single multiple sclerosis patients suggests a complex interaction between extracellular proteasome isoforms and osteopontin with potential clinical implications.
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http://dx.doi.org/10.3390/cells8030262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468732PMC
March 2019

Holmes tremor caused by a natalizumab-related progressive multifocal leukoencephalopathy: a case report and brief review of the literature.

Neurol Sci 2019 Sep 1;40(9):1943-1945. Epub 2019 Mar 1.

Department of Translational Medicine, Section of Neurology, University of Eastern Piedmont, Novara, Italy.

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http://dx.doi.org/10.1007/s10072-019-03779-6DOI Listing
September 2019

Ultrasonography Monitoring of Optic Nerve Sheath Diameter and Retinal Vessels in Patients with Cerebral Hemorrhage.

J Neuroimaging 2019 05 3;29(3):394-399. Epub 2019 Feb 3.

Department of Neurology, Saarland University Medical Center, Homburg, Germany.

Background And Purpose: Evaluation of the diagnostic accuracy of optic nerve sheath diameter (ONSD) and Doppler indices of central retinal arteries and veins for the detection of increased intracranial pressure (ICP) in intracerebral hemorrhage (ICH) and of the usefulness of a second assessment of these variables in the monitoring of ICH.

Methods: A total of 46 acute ICH patients with (group 1, n = 25) and without (group 2, n = 21) clinical and radiological computed tomography signs of raised ICP and 40 healthy controls were recruited. The median binocular ONSD and Doppler indices of retinal vessels including resistive index (RI) and retinal venous pulsation (RVP) were compared among groups, both at admission and later during ICH monitoring.

Results: Median binocular ONSD showed higher accuracy for the detection of increased ICP (sensitivity and specificity 100%), while Doppler indices were less accurate (sensitivity 48% and specificity 95% for RI; 80% and 62% for RVP). In ICH patients, ONSD was significantly elevated in group 1 both at admission (6.40 mm [interquartile range [IQR] = .70] vs. 4.70 [.40]) and at control time (6.00 [.55] vs. 4.55 [.40]; P < .01), as well as RI (.79 [.11] vs. .77 [.03] and .80 [.06] vs. .75 [.35]; P = .01). RVP was significantly increased in group 1 only at admission (3.20 cm/s [1.05] vs. 2.00 [1.55], P = .02).

Conclusions: Median binocular ONSD evaluation showed higher accuracy for the estimation of elevated ICP compared with Doppler indices of retinal vessels. The ONSD enlargement detected in the early phase of ICH persists at control time.
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http://dx.doi.org/10.1111/jon.12604DOI Listing
May 2019

Post-lumbar puncture headache: an adverse effect in multiple sclerosis work-up.

Neurol Sci 2019 Apr 21;40(4):759-762. Epub 2019 Jan 21.

Neurology Unit, Department of Translational Medicine, AOU Maggiore della Carità and University of Piemonte Orientale, Novara, Italy.

Background: Lumbar puncture (LP) is a safe procedure commonly performed in the diagnostic work-up of multiple sclerosis (MS), and its main adverse event is post-LP headache (PLPH). Predictors for PLPH in MS are not established.

Aims: To describe the occurrence of, and, factors related to PLPH in patients with suspected MS, studied on a daily-basis admission.

Patients And Methods: One hundred patients (70 females) were admitted for a diagnostic LP (standardized with a traumatic 19-G needle), observed for 6 h, and evaluated for adverse events 2 and 7 days later. Descriptive statistics and a multivariate analysis (for PLPH) were performed.

Results: Fifty-seven (57%) patients had PLPH at 48 h, which persisted 1 week in 31, and only two presented beyond the first 2 days. Other adverse events were tinnitus and neck stiffness. None required investigations or was hospitalized. Age was the only predictor for PLPH at day 2, whereas the onset of headache within 48 h and female gender were predictors for PLPH at day 7.

Conclusion: PLPH is a frequent complication of LP performed on daily-basis admission in MS work-up. The maximum onset is within the first 48 h. Age and gender seem the only predictors for the appearance and persistence of PLPH.
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http://dx.doi.org/10.1007/s10072-019-3724-zDOI Listing
April 2019

Exploiting PLGA-Based Biocompatible Nanoparticles for Next-Generation Tolerogenic Vaccines against Autoimmune Disease.

Int J Mol Sci 2019 Jan 8;20(1). Epub 2019 Jan 8.

Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy.

Tolerogenic vaccines are aimed at inhibiting antigen-specific immune responses. Antigen-loaded nanoparticles (NPs) have been recently emerged as ideal tools for tolerogenic vaccination because their composition, size, and capability of loading immunomodulatory molecules can be readily exploited to induce peripheral tolerance. Among polymeric NPs, poly(lactic-co-glycolic acid) (PLGA) NPs have the advantage of currently holding approval for several applications in drug delivery, diagnostics, and other clinical uses by the Food and Drug Administration (FDA). PLGA-NPs are non-toxic and display excellent biocompatibility and biodegradability properties. Moreover, surface functionalization may improve their interaction with biological materials, thereby optimizing targeting and performance. PLGA-NPs are the most extensively studied in pre-clinical model in the field of tolerogenic vaccination. Thus, this review describes their potential applications in the treatment of autoimmune diseases.
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http://dx.doi.org/10.3390/ijms20010204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337481PMC
January 2019

Beta2-Adrenoceptor Agonists in Parkinson's Disease and Other Synucleinopathies.

J Neuroimmune Pharmacol 2020 03 7;15(1):74-81. Epub 2019 Jan 7.

Movement Disorders Centre, Neurology Unit, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.

Evidence supporting the use of β2AR agonists in synucleinopathies is rapidly growing. Findings come from different scientific approaches. Molecular and immunological data suggest that adrenergic stimulation may decrease both α-synuclein (α-syn) deposition and pro-inflammatory/neurotoxic molecules release. Small open label clinical trials including a total number of 25 Parkinson's disease (PD) patients, in which the β2AR agonist salbutamol was added to levodopa, suggest a promising symptomatic benefit. In line with these findings, epidemiological studies investigating the risk of PD development suggest that long term exposure to the agonist salbutamol might be protective, while the antagonist propranolol possibly detrimental. Nonetheless, in both lines of investigation the studies performed so far present important limitations. On the clinical side, large randomized controlled trials are lacking, whereas on the epidemiological side the presence of co-morbid conditions (i.e. smoking and essential tremor) potentially influencing PD risk should taken into consideration. In summary, it is our opinion that β2AR stimulation in synucleinopathies has a rationale and therefore merits further investigation. Graphical Abstract.
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http://dx.doi.org/10.1007/s11481-018-09831-0DOI Listing
March 2020

Antiphospholipid Syndrome and the Neurologist: From Pathogenesis to Therapy.

Front Neurol 2018 26;9:1001. Epub 2018 Nov 26.

Section of Neurology, Department of Translational Medicine University of Eastern Piedmont, Novara, Italy.

Antiphospholipid syndrome (APS) is an autoimmune antibody-mediated condition characterized by thrombotic events and/or pregnancy morbidity in association with persistent positivity to antiphospholipid antibodies (aPL). The nervous system is frequently affected, as intracranial vessels are the most frequent site of arterial pathology. Over the course of years, many other neurological conditions not included in the diagnostic criteria, have been associated with APS. The pathogenic mechanisms behind the syndrome are complex and not fully elucidated. aPL enhance thrombosis, interfering with different pathways. Nevertheless, ischemic injury is not always sufficient to explain clinical features of the syndrome and immune-mediated damage has been advocated. This may be particularly relevant in the context of neurological complications. The reason why only a subgroup of patients develop non-criteria nervous system disorders and what determines the clinical phenotype are questions that remain open. The double nature, thrombotic and immunologic, of APS is also reflected by therapeutic strategies. In this review we summarize known neurological manifestations of APS, revisiting pathogenesis and current treatment options.
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http://dx.doi.org/10.3389/fneur.2018.01001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275383PMC
November 2018
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