Roberta Biundo

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.

Validation of the Italian version of the Movement Disorder Society--Unified Parkinson's Disease Rating Scale.

The Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) has been available in English since 2008. As part of this process, the MDS-UPDRS organizing team developed guidelines for development of official non-English translations. We present here the formal process for completing officially approved non-English versions of the MDS-UPDRS and specifically focus on the first of these versions in Italian. The MDS-UPDRS was translated into Italian and tested in 377 native-Italian speaking PD patients. Confirmatory and exploratory factor analyses determined whether the factor structure for the English-language MDS-UPDRS could be confirmed in data collected using the Italian translation. To be designated an ‘Official MDS translation,’ the Comparative Fit Index (CFI) had to be ≥0.90 relative to the English-language version. For all four parts of the Italian MDS-UPDRS, the CFI, in comparison with the English-language data, was ≥0.94. Exploratory factor analyses revealed some differences between the two datasets, however these differences were considered to be within an acceptable range. The Italian version of the MDS-UPDRS reaches the criterion to be designated as an Official Translation and is now available for use. This protocol will serve as outline for further validation of this in multiple languages.

Cognitive and MRI correlates of orthostatic hypotension in Parkinson’s disease

Orthostatic hypotension (OH) is a frequent nonmotor feature of Parkinson’s disease (PD), and its occurrence has been associated with cognitive impairment. The underlying mechanism could be mediated by development of cerebrovascular disease induced by chronic or episodic hypoperfusion, but the extent of brain vascular load in PD patients with OH has never been investigated. This study aimed to assess the relationship between OH and cognitive function in PD patients and to investigate the contribution of brain vascular lesions. Forty-eight PD patients underwent a tilt table test (TT) to assess supine and orthostatic blood pressure as well as an extensive neuropsychological evaluation to evaluate cognitive function. Brain magnetic resonance imaging was acquired in 44/48 patients and analyzed by a visual semiquantitative scale. Twenty-three patients presented OH at TT (13/23 were symptomatic), and 25 did not. There were no differences in motor severity or disease duration between patients with and without OH. In patients with OH we found significantly worse cognitive performance in specific tasks, such as sustained attention, visuospatial and verbal memory, compared with patients without OH. However, there were no differences in vascular burden between the two groups. Our study confirms that there is an association between OH and selective cognitive deficits in PD, but rebuts the hypothesis that this is underlined by the development of cerebrovascular disease.

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.

Anatomical Correlates of Cognitive Functions in Early Parkinson's Disease Patients

Background Cognitive deficits may occur early in Parkinsons disease (PD) but the extent of cortical involvement associated with cognitive dysfunction needs additional investigations. The aim of our study is to identify the anatomical pattern of cortical thickness alterations in patients with early stage PD and its relationship with cognitive disability. Methods We recruited 29 PD patients and 21 healthy controls. All PD patients performed an extensive neuropsychological examination and 14 were diagnosed with mild cognitive impairment (PD-MCI). Surface-based cortical thickness analysis was applied to investigate the topographical distribution of cortical and subcortical alterations in early PD compared with controls and to assess the relationship between cognition and regional cortical changes in PD-MCI. Results Overall PD patients showed focal cortical (occipital-parietal areas, orbito-frontal and olfactory areas) and subcortical thinning when compared with controls. PD-MCI showed a wide spectrum of cognitive deficits and related significant regional thickening in the right parietal-frontal as well as in the left temporal-occipital areas. Conclusion Our results confirm the presence of changes in grey matter thickness at relatively early PD stage and support previous studies showing thinning and atrophy in the neocortex and subcortical regions. Relative cortical thickening in PD-MCI may instead express compensatory neuroplasticity. Brain reserve mechanisms might first modulate cognitive decline during the initial stages of PD.

Grey Matter Changes in Cognitively Impaired Parkinson's Disease Patients

Background Cortical changes associated with cognitive decline in Parkinsons disease (PD) are not fully explored and require investigations with established diagnostic classification criteria. Objective We used MRI source-based morphometry to evaluate specific differences in grey matter volume patterns across 4 groups of subjects: healthy controls (HC), PD with normal cognition (PD-NC), PD with mild cognitive impairment (MCI-PD) and PD with dementia (PDD). Methods We examined 151 consecutive subjects: 25 HC, 75 PD-NC, 29 MCI-PD, and 22 PDD at an Italian and Czech movement disorder centre. Operational diagnostic criteria were applied to classify MCI-PD and PDD. All structural MRI images were processed together in the Czech centre. The spatial independent component analysis was used to assess group differences of local grey matter volume. Results We identified two independent patterns of grey matter volume deviations: a) Reductions in the hippocampus and temporal lobes; b) Decreases in fronto-parietal regions and increases in the midbrain/cerebellum. Both patterns differentiated PDD from all other groups and correlated with visuospatial deficits and letter verbal fluency, respectively. Only the second pattern additionally differentiated PD-NC from HC. Conclusion Grey matter changes in PDD involve areas associated with Alzheimer-like pathology while fronto-parietal abnormalities are possibly an early marker of PD cognitive decline. These findings are consistent with a non-linear cognitive progression in PD.

Default mode network links to visual hallucinations: A comparison between Parkinson's disease and multiple system atrophy

Studying default mode network activity or connectivity in different parkinsonisms, with or without visual hallucinations, could highlight its roles in clinical phenotypes’ expression. Multiple system atrophy is the archetype of parkinsonism without visual hallucinations, variably appearing instead in Parkinsons disease (PD). We aimed to evaluate default mode network functions in multiple system atrophy in comparison with PD.

Cognitive decline in Parkinson’s disease: the complex picture

Mild cognitive impairment (PD-MCI) and dementia (PDD) are among the most frequent non-motor symptoms in Parkinson’s disease (PD). PD-MCI is six times more likely than age-matched controls to develop dementia and the PDD prevalence is 80% after 15–20 years of disease. Therefore, research has focused on the identification of early dementia biomarkers including specific cognitive at-risk profiles hoping to implement therapeutic interventions when they are most likely to be efficacious. However, given the heterogeneous neuropathological, neurochemical, and neuropsychological nature of cognitive deficits, definition of a comprehensive cognitive model of PDD is a challenge. Evidence from neuroimaging studies using different methods and techniques suggests that in addition to degeneration of the dopaminergic system, other mechanisms have a role including β-amyloid and tau deposition, and that specific cognitive scales could help identifying a malignant profile. Prospective studies combining neuroimaging techniques and specific cognitive tests are required to define the interplay between the various neurodegenerative processes and the contribution of structural disconnection in brain functional networks, heralding the development of dementia in PD.