MicroRNAs in Parkinson's disease: a systematic review and diagnostic accuracy meta-analysis.

Current clinical tests for Parkinson's disease (PD) provide insufficient diagnostic accuracy leading to an urgent need for improved diagnostic biomarkers. As microRNAs (miRNAs) are promising biomarkers of various diseases, including PD, this systematic review and meta-analysis aimed to assess the diagnostic accuracy of biofluid miRNAs in PD. All studies reporting data on miRNAs expression in PD patients compared to controls were included. Gene targets and significant pathways associated with miRNAs expressed in more than 3 biofluid studies with the same direction of change were analyzed using target prediction and enrichment analysis. A bivariate model was used to calculate sensitivity, specificity, likelihood ratios, and diagnostic odds ratio. While miR-24-3p and miR-214-3p were the most reported miRNA (7 each), miR-331-5p was found to be consistently up regulated in 4 different biofluids. Importantly, miR-19b-3p, miR-24-3p, miR-146a-5p, and miR-221-3p were reported in multiple studies without conflicting directions of change in serum and bioinformatic analysis found the targets of these miRNAs to be associated with pathways important in PD pathology. Of the 102 studies from the systematic review, 15 studies reported sensitivity and specificity data on combinations of miRNAs and were pooled for meta-analysis. Studies (17) reporting sensitivity and specificity data on single microRNA were pooled in a separate meta-analysis. Meta-analysis of the combinations of miRNAs (15 studies) showed that biofluid miRNAs can discriminate between PD patients and controls with good diagnostic accuracy (sensitivity = 0.82, 95% CI 0.76-0.87; specificity = 0.80, 95% CI 0.74-0.84; AUC = 0.87, 95% CI 0.83-0.89). However, we found multiple studies included more males with PD than any other group therefore possibly introducing a sex-related selection bias. Overall, our study captures key miRNAs which may represent a point of focus for future studies and the development of diagnostic panels whilst also highlighting the importance of appropriate study design to develop representative biomarker panels for the diagnosis of PD.

Reproducibility and repeatability of magnetic resonance imaging in dementia.

PURPOSE: Individualised predictive models of cognitive decline require disease-monitoring markers that are repeatable. For wide-spread adoption, such markers also need to be reproducible at different locations. This study assessed the repeatability and reproducibility of MRI markers derived from a dementia protocol. METHODS: Six participants were scanned at three different sites with a 3T MRI scanner. The protocol employed: T1-weighted (T1w) imaging, resting state functional MRI (rsfMRI), arterial spin labelling (ASL), diffusion-weighted imaging (DWI), T2-weighted fluid attenuation inversion recovery (FLAIR), T2-weighted (T2w) imaging, and susceptibility weighted imaging (SWI). Participants were scanned repeatedly, up to six times over a maximum period of five years. One participant was also scanned a further three times on sequential days on one scanner. Fifteen derived metrics were computed from the seven different modalities. RESULTS: Reproducibility (coefficient of variation; CoV, across sites) was best for T1w derived grey matter, white matter and hippocampal volume (CoV < 1.5%), compared to rsfMRI and SWI derived metrics (CoV, 19% and 21%). For a given metric, long-term repeatability (CoV across time) was comparable to reproducibility, with short-term repeatability considerably better. CONCLUSIONS: Reproducibility and repeatability were assessed for a suite of markers calculated from a dementia MRI protocol. In general, structural markers were less variable than functional MRI markers. Variability over time on the same scanner was comparable to variability measured across different scanners. Overall, the results support the viability of multi-site longitudinal studies for monitoring cognitive decline.

Forward and backward spatial recall in Parkinson's disease and matched controls: A 1-year follow-up study.

Patients with Parkinson's disease (PD) exhibit a domain-general visuospatial dysfunction; however, no previous study has examined changes over time in forward and backward spatial recall in PD against controls. To evaluate changes in short-term (STM) and working memory (WM) dysfunction in PD, the current study assessed performance on a computer-modified version of the Corsi Block-Tapping Test (forward and backward recall) at two-time points 1 year apart, while simultaneously exploring associations with potentially relevant demographic and clinical variables. We enrolled 38 patients with PD and 38 controls matched for age, sex, and Montreal Cognitive Assessment (MoCA) total scores. Linear mixed-effects models analyzed the primary measured variables (forward and backward scores). At baseline, the dysfunction effect sizes were as follows: forward recall (-0.45, 95% CI [-0.90, 0.01]) and backward recall (-0.26, 95% CI [-0.71, 0.19]). At follow-up, patients exhibited substantially greater difficulties in backward recall (-0.65, 95% CI [-1.18, -0.13]) compared to the baseline assessment, whereas the forward dysfunction effect size remained almost the same (-0.43, 95% CI [-0.94, 0.09]). Age (p = .005, f = 0.35) and total scores on MoCA (p = .017, f = 0.18), irrespective of group and recall condition, were significant predictors of spatial block scores. The pattern of dysfunction effect sizes indicates that, in contrast to forward recall, backward recall dysfunction in PD worsened 1-year after the baseline assessment, presumably reflecting the progression of PD-related visuospatial WM dysfunction.

Plasma microRNA vary in association with the progression of Alzheimer's disease.

INTRODUCTION: Early intervention in Alzheimer's disease (AD) requires the development of an easily administered test that is able to identify those at risk. Focusing on microRNA robustly detected in plasma and standardizing the analysis strategy, we sought to identify disease-stage specific biomarkers. METHODS: Using TaqMan microfluidics arrays and a statistical consensus approach, we assessed plasma levels of 185 neurodegeneration-related microRNA, in cohorts of cognitively normal amyloid ß-positive (CN-Aß+), mild cognitive impairment (MCI), and Alzheimer's disease (AD) participants, relative to their respective controls. RESULTS: Distinct disease stage microRNA biomarkers were identified, shown to predict membership of the groups (area under the curve [AUC] >0.8) and were altered dynamically with AD progression in a longitudinal study. Bioinformatics demonstrated that these microRNA target known AD-related pathways, such as the Phosphoinositide 3-kinase (PI3K-Akt) signalling pathway. Furthermore, a significant correlation was found between miR-27a-3p, miR-27b-3p, and miR-324-5p and amyloid beta load. DISCUSSION: Our results show that microRNA signatures alter throughout the progression of AD, reflect the underlying disease pathology, and may prove to be useful diagnostic markers.

Spatial variation of perfusion MRI reflects cognitive decline in mild cognitive impairment and early dementia.

Cerebral blood flow (CBF) measured with arterial spin labelling (ASL) magnetic resonance imaging (MRI) reflects cerebral perfusion, related to metabolism, and arterial transit time (ATT), related to vascular health. Our aim was to investigate the spatial coefficient of variation (sCoV) of CBF maps as a surrogate for ATT, in volunteers meeting criteria for subjective cognitive decline (SCD), amnestic mild cognitive impairment (MCI) and probable Alzheimer's dementia (AD). Whole-brain pseudo continuous ASL MRI was performed at 3 T in 122 participants (controls = 20, SCD = 44, MCI = 45 and AD = 13) across three sites in New Zealand. From CBF maps that included all grey matter, sCoV progressively increased across each group with increased cognitive deficit. A similar overall trend was found when examining sCoV solely in the temporal lobe. We conclude that sCoV, a simple to compute imaging metric derived from ASL MRI, is sensitive to varying degrees of cognitive changes and supports the view that vascular health contributes to cognitive decline associated with Alzheimer's disease.

Computerized testing in Parkinson's disease: Performance deficits in relation to standard clinical measures.

OBJECTIVE: This study assessed deficits associated with Parkinson's disease (PD) at two time points separated by 1 year using a computerized neuropsychological battery, and determined interrelationships with conventional clinical measures of cognitive functioning (Montreal Cognitive Assessment; MoCA) and motor impairment (Part III of the Unified PD Rating Scale; UPDRS), as well as other factors known to influence cognitive dysfunction in PD. METHOD: Participants included 37 with PD and 47 controls. Linear mixed-effects models were developed for each computerized task. RESULTS: Results showed that the PD group performed worse than controls on all of the computerized tasks at both time points. In contrast, MoCA scores differed between PD and controls only at follow-up. However, the MoCA detected decline over the year in the PD group, whereas only one of the computerized tasks did. In both groups, higher MoCA scores predicted better performance on some but not all of the computerized tasks. Surprisingly, UPDRS-rated motor impairment did not predict performance on any of the computerized tasks, and aside from older age, which predicted poorer performance on all but one task, the other factors-education, affective and impulsivecompulsive symptoms, sleep quality, dopaminergic medication-generally had no relationship with performance on the computerized tasks. CONCLUSIONS: The presence of performance deficits for all of the computerized tasks in the PD group compared to controls, but not for the MoCA at initial testing, indicates that the computerized battery was better able to detect deficits. However, in contrast to the MoCA, the current results call into question the suitability of the computerized battery as measured here for tracking decline.

Computerised mirror therapy with Augmented Reflection Technology for early stroke rehabilitation: clinical feasibility and integration as an adjunct therapy.

PURPOSE: New rehabilitation strategies for post-stroke upper limb rehabilitation employing visual stimulation show promising results, however, cost-efficient and clinically feasible ways to provide these interventions are still lacking. An integral step is to translate recent technological advances, such as in virtual and augmented reality, into therapeutic practice to improve outcomes for patients. This requires research on the adaptation of the technology for clinical use as well as on the appropriate guidelines and protocols for sustainable integration into therapeutic routines. Here, we present and evaluate a novel and affordable augmented reality system (Augmented Reflection Technology, ART) in combination with a validated mirror therapy protocol for upper limb rehabilitation after stroke. METHOD: We evaluated components of the therapeutic intervention, from the patients' and the therapists' points of view in a clinical feasibility study at a rehabilitation centre. We also assessed the integration of ART as an adjunct therapy for the clinical rehabilitation of subacute patients at two different hospitals. RESULTS: The results showed that the combination and application of the Berlin Protocol for Mirror Therapy together with ART was feasible for clinical use. This combination was integrated into the therapeutic plan of subacute stroke patients at the two clinical locations where the second part of this research was conducted. CONCLUSIONS: Our findings pave the way for using technology to provide mirror therapy in clinical settings and show potential for the more effective use of inpatient time and enhanced recoveries for patients. Implications for Rehabilitation Computerised Mirror Therapy is feasible for clinical use Augmented Reflection Technology can be integrated as an adjunctive therapeutic intervention for subacute stroke patients in an inpatient setting Virtual Rehabilitation devices such as Augmented Reflection Technology have considerable potential to enhance stroke rehabilitation.

Visual dependency and dizziness after vestibular neuritis.

Symptomatic recovery after acute vestibular neuritis (VN) is variable, with around 50% of patients reporting long term vestibular symptoms; hence, it is essential to identify factors related to poor clinical outcome. Here we investigated whether excessive reliance on visual input for spatial orientation (visual dependence) was associated with long term vestibular symptoms following acute VN. Twenty-eight patients with VN and 25 normal control subjects were included. Patients were enrolled at least 6 months after acute illness. Recovery status was not a criterion for study entry, allowing recruitment of patients with a full range of persistent symptoms. We measured visual dependence with a laptop-based Rod-and-Disk Test and severity of symptoms with the Dizziness Handicap Inventory (DHI). The third of patients showing the worst clinical outcomes (mean DHI score 36-80) had significantly greater visual dependence than normal subjects (6.35° error vs. 3.39° respectively, p = 0.03). Asymptomatic patients and those with minor residual symptoms did not differ from controls. Visual dependence was associated with high levels of persistent vestibular symptoms after acute VN. Over-reliance on visual information for spatial orientation is one characteristic of poorly recovered vestibular neuritis patients. The finding may be clinically useful given that visual dependence may be modified through rehabilitation desensitization techniques.

Visual and proprioceptive interaction in patients with bilateral vestibular loss.

Following bilateral vestibular loss (BVL) patients gradually adapt to the loss of vestibular input and rely more on other sensory inputs. Here we examine changes in the way proprioceptive and visual inputs interact. We used functional magnetic resonance imaging (fMRI) to investigate visual responses in the context of varying levels of proprioceptive input in 12 BVL subjects and 15 normal controls. A novel metal-free vibrator was developed to allow vibrotactile neck proprioceptive input to be delivered in the MRI system. A high level (100 Hz) and low level (30 Hz) control stimulus was applied over the left splenius capitis; only the high frequency stimulus generates a significant proprioceptive stimulus. The neck stimulus was applied in combination with static and moving (optokinetic) visual stimuli, in a factorial fMRI experimental design. We found that high level neck proprioceptive input had more cortical effect on brain activity in the BVL patients. This included a reduction in visual motion responses during high levels of proprioceptive input and differential activation in the midline cerebellum. In early visual cortical areas, the effect of high proprioceptive input was present for both visual conditions but in lateral visual areas, including V5/MT, the effect was only seen in the context of visual motion stimulation. The finding of a cortical visuo-proprioceptive interaction in BVL patients is consistent with behavioural data indicating that, in BVL patients, neck afferents partly replace vestibular input during the CNS-mediated compensatory process. An fMRI cervico-visual interaction may thus substitute the known visuo-vestibular interaction reported in normal subject fMRI studies. The results provide evidence for a cortical mechanism of adaptation to vestibular failure, in the form of an enhanced proprioceptive influence on visual processing. The results may provide the basis for a cortical mechanism involved in proprioceptive substitution of vestibular function in BVL patients.

Lack of effect of the apolipoprotein E ε4 genotype on cognition during healthy aging.

BACKGROUND: The apolipoprotein E (APOE) ε4 genotype is associated with an increased risk of Alzheimer's disease. In community surveys, older adults with this genotype have been found to have lower scores on neuropsychological tests than those who do not. It is possible that this is the consequence of subclinical changes in cognition in those persons who later develop dementia. The aim of this research was to determine whether the effect of APOE genotype on cognition would remain if those who subsequently became demented were retrospectively removed from the analysis of the baseline test data from a sample of healthy adults. METHOD: A sample of 241 nondemented persons over the age of 65 for whom APOE genotyping was available were administered a range of neuropsychological tests at baseline and were followed up 10 years later. RESULTS: Significant differences between the ε4-present and ε4-absent groups were found for the delayed recall trial of the Rey Auditory Verbal Learning Test and the Trail Making Test. When those participants known to have developed dementia during the follow-up period were excluded from the analysis of the baseline data these differences disappeared. A total of 113 nondemented survivors from the original sample were retested, and no difference was found in the rate of decline on any measure between the ε4-present and ε4-absent groups. CONCLUSIONS: It is likely that the reported effect of the ε4 APOE genotype on cognition is the consequence of the ε4-present group containing persons whose cognition is subtly affected by the early stages of a dementing process. It is also unlikely that the presence of the ε4 allele by itself leads to a significantly accelerated rate of cognitive decline in the nondemented elderly.

Vestibular perceptual thresholds to angular rotation in acute unilateral vestibular paresis and with galvanic stimulation.

Studies of compensation of injury to the human vestibular system have, in the main, focused on the vestibular-ocular reflex. Probing vestibular perception allows more of the sensory pathway to be assessed. We present a novel paradigm for simultaneously testing vestibular perceptual and nystagmic thresholds to angular acceleration around an earth vertical axis. The perceptual thresholds can be modulated asymmetrically in normal subjects by DC galvanic stimulation with the head flexed in the roll plane, as expected from the main torsional plane of action of the galvanic stimulus. The perceptual and nystagmic thresholds were bilaterally elevated in acute vestibular neuritis, a unilateral condition, possibly due to central suppression of vestibular input. The degree of asymmetry in thresholds was small in comparison with the large caloric asymmetry present in the patients, indicating a relatively preserved capacity for near-threshold performance of the non-damaged labyrinth both in the "on" and "off" directions.