Annamaria Vallelunga

Identification of circulating microRNAs for the differential diagnosis of Parkinson's disease and Multiple System Atrophy

Background: Parkinsons disease (PD) is a progressive neurodegenerative disorder which may be misdiagnosed with atypical conditions such as Multiple System Atrophy (MSA), due to overlapping clinical features. MicroRNAs (miRNAs) are small non-coding RNAs with a key role in post-transcriptional gene regulation. We hypothesized that identification of a distinct set of circulating miRNAs (cmiRNAs) could distinguish patients affected by PD from MSA and healthy individuals. Results. Using TaqMan Low Density Array technology, we analyzed 754 miRNAs and found 9 cmiRNAs differentially expressed in PD and MSA patients compared to healthy controls. We also validated a set of 4 differentially expressed cmiRNAs in PD and MSA patients vs. controls. More specifically, miR-339-5p was downregulated, whereas miR-223*, miR-324-3p, and mir-24 were upregulated in both diseases. We found cmiRNAs specifically deregulated in PD (downregulation of miR-30c and miR-148b) and in MSA (upregulation of miR-148b). Finally, comparing MSA and PD, we identified 3 upregulated cmiRNAs in MSA serum (miR-24, miR-34b, miR-148b). Conclusions. Our results suggest that cmiRNA signatures discriminate PD from MSA patients and healthy controls and may be considered specific, non-invasive biomarkers for differential diagnosis.

Brain volume changes in Parkinson's disease and their relationship with cognitive and behavioural abnormalities

Cognitive and behavioral abnormalities are frequent in Parkinsons disease (PD) but their anatomical correlates are still uncertain. We assessed a cohort of 59 PD patients with and without impulse control disorders (PD-ICDs and PD-CNTR) with magnetic resonance imaging and a comprehensive neuropsychological battery. Thirty-five PD patients presented ICDs according to DSM-IV criteria and Minnesota Impulsive Disorders Interview. We found areas of significant brain atrophy in the middle and superior frontal gyrus in the whole cohort of 59 PD patients vs. healthy controls but there were no morphometric changes in PD-ICDs vs. PD-CNTR. This was consistent with cognitive findings of relatively preserved function in PD-ICDs with the exception for slower performance in the Trail Making Test B-A suggesting difficulties to maintain goal-directed tasks and suppress irrelevant responses. Voxel Based Morphometric regression analysis (VBM) carried out using TMTB-A as independent factor showed a negative gray matter correlation between high TMTB-A scores and left middle frontal cortex, right posterior cingulate area, anterior cingulate and supplementary motor area bilaterally. Our results suggest that PD is characterized by an overall loss of gray matter in pre-frontal regions. However, the contribution of these changes to the development of ICDs is marginal.

Patterns of cortical thickness associated with impulse control disorders in Parkinson's disease.

Previous functional neuroimaging studies in Parkinsons disease (PD) patients with impulse control disorders (ICDs) demonstrated dysfunction of the reward network, although the extent of anatomical changes is unclear. The aim of this study was to measure brain cortical thickness and subcortical volumes, and to assess their relationship with presence and severity of symptoms, in PD patients with and without ICDs. We studied 110 PD patients (N = 58 with ICDs) and 33 healthy controls (all negative for ICDs) who underwent an extensive neurological, neuropsychological, and behavioral assessment as well as structural 1.5 Tesla magnetic resonance imaging (MRI). Between‐group differences in brain cortical thickness and subcortical volumes, assessed with the FreeSurfer 5.1 tool, were analyzed. In patients with ICDs, we found significant cortical thinning in fronto‐striatal circuitry, specifically in the right superior orbitofrontal, left rostral middle frontal, bilateral caudal middle frontal region, and corpus callosum, as well as volume reduction in the right accumbens and increase in the left amygdala. Finally, we observed a positive association relationship between severity of impulsive symptoms and left rostral middle frontal, inferior parietal, and supramarginal areas. These results support the involvement of both reward and response inhibition networks in PD patients with ICDs. Moreover, their severity is associated with alterations in brain regions linked with reward and top‐down control networks. Increased understanding of the mechanisms underlying impulsive and compulsive behaviors might help improve therapeutic strategies for these important disorders.

Cognitive profiling of Parkinson disease patients with mild cognitive impairment and dementia

BACKGROUND Prevalence of mild cognitive impairment (MCI) and dementia in Parkinson disease (PD) is variable because different classification criteria are applied and there is lack of consensus about neuropsychological tests and cut-off used for cognitive profiling. Given the important therapeutic consequences for patient management, we aimed at identifying suitable diagnostic cognitive tests and respective screening cut-off values for MCI and dementia in PD (PDD). METHODS We evaluated 105 PD patients using an extensive neuropsychological battery categorized as PD without cognitive impairment (PD-CNT) (35%), PD-MCI (47%) and PDD (18%) based on established criteria and calculated Receiver Operating Characteristic (ROC) curves. RESULTS We found different sensitivity and specificity among neuropsychological tests in detecting PD-MCI and PDD. In particular performance in attention/set shifting, verbal memory and language abilities, discriminated both PD-MCI and PDD from PD-CNT. Abilities involved mainly in semantic retrieval mechanisms discriminated PD-CNT from PD-MCI but also PD-MCI from PDD. Finally deficits in executive and visual-spatial abilities were only affected in PDD. CONCLUSION Our data point to an independent and different load of each test in defining different PD cognitive statuses. These findings can help selection of appropriate cognitive batteries in longitudinal studies and definition of stage-specific therapeutic targets.

Mechanisms and therapeutic applications of electromagnetic therapy in Parkinson’s disease

Electromagnetic therapy is a non-invasive and safe approach for the management of several pathological conditions including neurodegenerative diseases. Parkinson’s disease is a neurodegenerative pathology caused by abnormal degeneration of dopaminergic neurons in the ventral tegmental area and substantia nigra pars compacta in the midbrain resulting in damage to the basal ganglia. Electromagnetic therapy has been extensively used in the clinical setting in the form of transcranial magnetic stimulation, repetitive transcranial magnetic stimulation, high-frequency transcranial magnetic stimulation and pulsed electromagnetic field therapy which can also be used in the domestic setting. In this review, we discuss the mechanisms and therapeutic applications of electromagnetic therapy to alleviate motor and non-motor deficits that characterize Parkinson’s disease.

Mechanisms and therapeutic effectiveness of pulsed electromagnetic field therapy in oncology

Cancer is one of the most common causes of death worldwide. Available treatments are associated with numerous side effects and only a low percentage of patients achieve complete remission. Therefore, there is a strong need for new therapeutic strategies. In this regard, pulsed electromagnetic field (PEMF) therapy presents several potential advantages including non‐invasiveness, safety, lack of toxicity for non‐cancerous cells, and the possibility of being combined with other available therapies. Indeed, PEMF stimulation has already been used in the context of various cancer types including skin, breast, prostate, hepatocellular, lung, ovarian, pancreatic, bladder, thyroid, and colon cancer in vitro and in vivo. At present, only limited application of PEMF in cancer has been documented in humans. In this article, we review the experimental and clinical evidence of PEMF therapy discussing future perspectives in its use in oncology.

Role of proteoglycans and glycosaminoglycans in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is an inherited fatal X-linked myogenic disorder with a prevalence of 1 in 3500 male live births. It affects voluntary muscles, and heart and breathing muscles. DMD is characterized by continuous degeneration and regeneration cycles resulting in extensive fibrosis and a progressive reduction in muscle mass. Since the identification of a reduction in dystrophin protein as the cause of this disorder, numerous innovative and experimental therapies, focusing on increasing the levels of dystrophin, have been proposed, but the clinical improvement has been unsatisfactory. Dystrophin forms the dystrophin-associated glycoprotein complex and its proteins have been studied as a promising novel therapeutic target to treat DMD. Among these proteins, cell surface glycosaminoglycans (GAGs) are found almost ubiquitously on the surface and in the extracellular matrix (ECM) of mammalian cells. These macromolecules interact with numerous ligands, including ECM constituents, adhesion molecules and growth factors that play a crucial role in muscle development and maintenance. In this article, we have reviewed in vitro, in vivo and clinical studies focused on the functional role of GAGs in the pathophysiology of DMD with the final aim of summarizing the state of the art of GAG dysregulation within the ECM in DMD and discussing future therapeutic perspectives.

ApoE ε4 Allele Related Alterations in Hippocampal Connectivity in Early Alzheimer’s Disease Support Memory Performance

BACKGROUND Whether the presence of the Apolipoprotein E ε4 allele modulates hippocampal connectivity networks in abnormal ageing has yet to be fully clarified. OBJECTIVE Allele-dependent differences in this pattern of functional connectivity were investigated in patients with very mild neurodegeneration of the Alzheimers type, carriers and non-carriers of the ε4 allele. METHOD A seed-based connectivity approach was used. The two groups were similar in demographics, volumetric measures of brain structure, and cognitive profiles. RESULTS ε4-carriers had increased connectivity between the seed area in the left hippocampus and 1) a left insular/lateral prefrontal region and 2) the contralateral right parietal cortex. Moreover, hippocampus- to-parietal connectivity in the group of ε4 carriers was positively associated with memory performance, indicating that the between-group difference reflects compensatory processes. Retrospective analyses of functional connectivity based on patients from the ADNI initiative confirmed this pattern. CONCLUSION We suggest that increased connectivity with areas external to the Default Mode Network (DMN) reflects both compensatory recruitment of additional areas, and pathological interwining between the DMN and the salience network as part of a global ε4-dependent circuital disruption. These differences indicate that the ε4 allele is associated with a more profound degree of DMN network breakdown even in the prodromal stage of neurodegeneration.

Physical rehabilitation modulates microRNAs involved in multiple sclerosis: a case report

This study shows that neuromuscular taping improves gait, balance, pain and ability to walk and conduct daily activities in a multiple sclerosis patient. It is the first study to identify a panel of miRNAs modulated throughout rehabilitation using neuromuscular taping in a multiple sclerosis patient.

PATTERNS OF HIPPOCAMPUS FUNCTIONAL CONNECTIVITY IN APOE ɛ4 CARRIERS WITH MILD COGNITIVE IMPAIRMENT

P2-211 PATTERNS OF HIPPOCAMPUS FUNCTIONAL CONNECTIVITY IN APOE ε4 CARRIERS WITH MILD COGNITIVE IMPAIRMENT Matteo De Marco, Francesca Meneghello, Annamaria Vallelunga, Davide Duzzi, Cristina Pilosio, Jessica Rigon, Annalena Venneri, University of Sheffield, Sheffield, United Kingdom; IRCCS Fondazione Ospedale San Camillo, Venice, Italy; IRCCS Ospedale San Camillo, Venice, Italy; University of Sheffield, Sheffield, South Yorkshire, United Kingdom. Contact e-mail: m.demarco@sheffield.ac.uk