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Despite the advances in the understanding of Huntington's disease (HD), there is a need for molecular biomarkers to categorize mutation carriers during the preclinical stage of the disease preceding functional decline. Small RNAs (sRNAs) are a promising source of biomarkers since their expression levels are highly sensitive to pathobiological processes. Here, using an optimized method for plasma extracellular vesicles (EVs) purification and an exhaustive analysis pipeline of sRNA sequencing data, we show that EV‐sRNAs are downregulated early in mutation carriers and that this deregulation is associated with premanifest cognitive performance. Seven candidate sRNAs (tRF‐Glu‐CTC, tRF‐Gly‐GCC, miR‐451a, miR‐21‐5p, miR‐26a‐5p, miR‐27a‐3p and let7a‐5p) were validated in additional subjects, showing a significant diagnostic accuracy at premanifest stages. Of these, miR‐21‐5p was significantly decreased over time in a longitudinal study; and miR‐21‐5p and miR‐26a‐5p levels correlated with cognitive changes in the premanifest cohort. In summary, the present results suggest that deregulated plasma EV‐sRNAs define an early biosignature in mutation carriers with specific species highlighting the progression and cognitive changes occurring at the premanifest stage. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease (HD) is a genetically determined disease with motor, cognitive, and neuropsychiatric disorders. However, the links between clinical progression and disruptions to dynamics in motor and cognitive large‐scale networks are not well established. Objective: To investigate changes in dynamic and static large‐scale networks using an established tool of disease progression in Huntington's disease, the composite Unified Huntington's Disease Rating Scale (cUHDRS). Methods: Sixty‐four mutation carriers were included. Static and dynamic baseline functional connectivity as well as topological features were correlated to 2‐year follow‐up clinical assessments using the cUHDRS. Results: Decline in cUHDRS scores was associated with higher connectivity between frontal default‐mode and motor networks, whereas higher connectivity in posterior, mainly visuospatial regions was associated with a smaller decline in cUHDRS scores. Conclusions: Structural disruptions in HD were evident both in posterior parietal/occipital and frontal motor regions, with reciprocal increases in functional connectivity. However, although higher visuospatial network connectivity was tied to a smaller cUHDRS decline, increased motor and frontal default‐mode connections were linked to a larger cUHDRS decreases. Therefore, divergent functional compensation mechanisms might be at play in the clinical evolution of HD. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease is a neurodegenerative disorder characterized by clinical alterations in the motor, behavioral, and cognitive domains. However, the structure and disruptions to large‐scale brain cognitive networks have not yet been established. Objective: We aimed to profile changes in large‐scale cognitive networks in premanifest and symptomatic patients with Huntington's disease. Methods: We prospectively recruited premanifest and symptomatic Huntington's disease mutation carriers as well as healthy controls. Clinical and sociodemographic data were obtained from all participants, and resting‐state functional connectivity data, using both time‐averaged and dynamic functional connectivity, was acquired from whole‐brain and cognitively oriented brain parcellations. Results: A total of 64 gene mutation carriers and 23 healthy controls were included; 21 patients with Huntington's disease were classified as premanifest and 43 as symptomatic Huntington's disease. Compared with healthy controls, patients with Huntington's disease showed decreased network connectivity within the posterior hubs of the default‐mode network and the medial prefrontal cortex, changes that correlated with cognitive (t = 2.25, P = 0.01) and disease burden scores (t = −2.42, P = 0.009). The salience network showed decreased functional connectivity between insular and supramarginal cortices and also correlated with cognitive (t = 2.11, P = 0.02) and disease burden scores (t = −2.35, P = 0.01). Dynamic analyses showed that network variability was decreased for default‐central executive networks, a feature already present in premanifest mutation carriers (dynamic factor 8, P = 0.02). Conclusions: Huntington's disease shows an early and widespread disruption of large‐scale cognitive networks. Importantly, these changes are related to cognitive and disease burden scores, and novel dynamic functional analyses uncovered subtler network changes even in the premanifest stages. [ABSTRACT FROM AUTHOR]

Background: Minor hallucinations and well-structured hallucinations are considered in the severity continuum of the psychotic spectrum associated with Parkinson's disease. Although their chronological relationship is largely unknown, the spatial patterns of brain atrophy in these 2 forms of hallucinations partially overlap, suggesting they share similar pathophysiological processes. Functional connectivity studies show that disruption of functional networks involved in perception and attention could be relevant in the emergence of well-structured hallucinations. However, functional neuroimaging studies in patients with isolated minor hallucinations are lacking. The objectives of this study were to explore the structural and functional changes underlying minor hallucinations.Methods: We compared patients with (n = 18) and without (n = 14) minor hallucinations using a multimodal structural (gray-matter volume voxel-based morphometry) and functional (seed-to-whole-brain resting-state functional MRI) neuroimaging study.Results: Coincident with previously described structural changes in well-structured hallucinations in Parkinson's disease, patients with minor hallucinations exhibited gray-matter atrophy with significant voxel-wise differences in visuoperceptual processing areas and core regions of the default mode network. Functional connectivity changes consisted of altered connectivity within the default mode network, reduced negative correlation with task-positive network, and aberrant connectivity between posterior regions of the default mode network and visual-processing areas. These changes are in accordance with the attentional networks hypothesis proposed for well-structured hallucinations.Conclusions: Although longitudinal studies are needed to assess the potential role of minor hallucinations as an early clinical biomarker of progression to well-structured hallucinations, the present findings show that the 2 phenomena share similar structural and functional brain correlates. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Cognitive decline is a major disabling feature in Parkinson's disease (PD). Multimodal imaging studies have shown functional disruption in neurocognitive networks related to cognitive impairment. However, it remains unknown whether these changes are related to gray matter loss, or whether they outline network vulnerability in the early stages of cognitive impairment. In this work, we intended to assess functional connectivity and graph theoretical measures and their relation to gray matter loss in Parkinson's disease with mild cognitive impairment (PD‐MCI). We recruited 53 Parkinson's disease patients and classified them for cognitive impairment using Level‐1 Movement Disorders Society‐Task Force Criteria. Voxel‐based morphometry, functional connectivity and graph theoretical measures were obtained on a 3‐Tesla MRI scanner. Loss of gray matter was observed in the default mode network (bilateral precuneus), without a corresponding disruption of functional or graph theoretical properties. However, functional and graph theoretical changes appeared in salience network nodes, without evidence of gray matter loss. Global cognition and executive scores showed a correlation with node degree in the right anterior insula. We also found a correlation between visuospatial scores and right supramarginal gyrus node degree. Our findings highlight the loss of functional connectivity and topological features without structural damage in salience network regions in PD‐MCI. They also underline the importance of multimodal hubs in the transition to mild cognitive impairment. This functional disruption in the absence of gray matter atrophy suggests that the salience network is a key vulnerable system at the onset of mild cognitive impairment in PD. [ABSTRACT FROM AUTHOR]

ABSTRACT Lack of validated data on cutoff scores for mild cognitive impairment (MCI) and sensitivity to change in predementia stages of Parkinson's disease (PD) limit the utility of instruments measuring global cognition as screening and outcome measures in therapeutic trials. Investigators who were blinded to PD-Cognitive Rating Scale (PD-CRS) scores classified a cohort of prospectively recruited, nondemented patients into a PD with normal cognition (PD-NC) group and a PD with MCI (PD-MCI) group using Clinical Dementia Rating (CDR) and the Mattis Dementia Rating Scale-2 (MDRS-2). The discriminative power of the PD-CRS for PD-MCI was examined in a representative sample of 234 patients (145 in the PD-NC group; 89 in the PD-MCI group) and in a control group of 98 healthy individuals. Sensitivity to change in the PD-CRS score (the minimal clinically important difference was examined with the Clinical Global Impression of Change scale and was calculated with a combination of distribution-based and anchor-based approaches) was explored in a 6-month observational multicenter trial involving a subset of 120 patients (PD-NC, 63; PD-MCI, 57). Regression analysis demonstrated that PD-CRS total scores ( P < 0.001) and age ( P = 0.01) independently differentiated PD-NC from PD-MCI. Area under the receiver operating characteristic curve (AUC) analysis (AUC, 0.85; 95% confidence interval, 0.80-0.90) indicated that a score ≤81 of 134 was the optimal cutoff point on the total score for the PD-CRS (sensitivity, 79%; specificity, 80%; positive predictive value, 59%; negative predictive value, 91%). A range of change from 10 to 13 points on the PD-CRS total score was indicative of clinically significant change. These findings suggest that the PD-CRS is a useful tool to identify PD-MCI and to track cognitive changes in nondemented patients with PD. © 2013 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]