Search

Background: Recent evidence suggests that the failure of the glymphatic system - the brain's waste clearance system, which is active during sleep - plays a key role in the pathophysiology of Alzheimer's Disease (AD). Glymphatic function can be investigated using serial MRIs after intrathecal gadobutrol injection. This technique can reveal the health of the glymphatic system, but has not yet been used in participants with cognitive impairment due to AD., Case Report: This report describes the sleep and gadobutrol tracer clearance patterns of four participants diagnosed with mild to moderate cognitive impairment with evidence of AD pathology (pathological levels of Ab and p-tau in cerebrospinal fluid). We performed polysomnography and MRI studies before tracer injection and MRI scans at 1.5-2 h, 5-6 h, and 48 h after injection. Despite participants reporting no sleep problems, polysomnography revealed that all participants had moderate to severe sleep disturbances, including reduced sleep efficiency during the study and obstructive sleep apnea. Severe side-effects related to tracer administration were observed, impeding the completion of the protocol in two participants. Participants who finished the protocol displayed delayed and persistent tracer enrichment in the cortex and white matter, even 48 h after injection. These outcomes have not been observed in previous studies in participants without AD., Conclusion: The findings suggest that brains with sleep impairment and AD pathology have poor glymphatic function, and therefore cannot clear the contrast tracer efficiently. This is likely to have caused the severe side effects in our participants, that have not been reported in healthy individuals. Our results may therefore represent the only available data acquired with this technique in participants with AD pathology., (© 2023. The Author(s).)

To fabricate optical components with surface layers compatible with high-power laser applications that may operate as antireflective coatings, polarization rotators, or harness physical anisotropy for other uses, metasurfaces are becoming an appealing candidate. In this study, large-beam (1.05 cm diameter) 351-nm laser-induced damage testing was performed on an all-glass metasurface structure composed of cone-like features with a subwavelength spacing of adjacent features. These structures were fabricated on untreated fused silica glass and damage tested, as were structures that were fabricated on fused silica glass that experienced a preliminary etching process to remove the surface Beilby layer that is characteristic of polished fused silica. The laser-induced damage onset for structures on untreated fused silica glass was 19.3 J ⋅ c m -2 , while the sample that saw an initial pretreatment etch exhibited an improved damage onset of 20.4 J ⋅ c m -2 , only 6% short of the reference pretreated glass damage onset of 21.7 J ⋅ c m -2 . For perspective, the National Ignition Facility operational average fluence at this wavelength and pulse length is about 10 J / c m 2 . At a fluence of 25.5 J ⋅ c m -2 , the reference (pretreated) fused silica initiated 5.2 damage sites per m m 2 , while the antireflective metasurface sample with a preliminary etching process treatment initiated 9.8 damage sites per m m 2 . These findings demonstrate that substrate-engraved metasurfaces are compatible with high energy and power laser applications, further broadening their application space.

Introduction: Degeneration of cortical cholinergic projections from the nucleus basalis of Meynert (NBM) is characteristic of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), whereas involvement of cholinergic projections from the pedunculopontine nucleus (PPN) to the thalamus is less clear., Methods: We studied both cholinergic projection systems using a free water-corrected diffusion tensor imaging (DTI) model in the following cases: 46 AD, 48 DLB, 35 mild cognitive impairment (MCI) with AD, 38 MCI with Lewy bodies, and 71 controls., Results: Free water in the NBM-cortical pathway was increased in both dementia and MCI groups compared to controls and associated with cognition. Free water along the PPN-thalamus tract was increased only in DLB and related to visual hallucinations. Results were largely replicated in an independent cohort., Discussion: While NBM-cortical projections degenerate early in AD and DLB, the thalamic cholinergic input from the PPN appears to be more selectively affected in DLB and might associate with visual hallucinations., Highlights: Free water in the NBM-cortical cholinergic pathways is increased in AD and DLB. NBM-cortical pathway integrity is related to overall cognitive performance. Free water in the PPN-thalamus cholinergic pathway is only increased in DLB, not AD. PPN-thalamus pathway integrity might be related to visual hallucinations in DLB., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Birefringent materials-which are highly needed in high power laser systems-may be limited in usage due to the laser-induced damage threshold of traditional birefringent materials. This work reports here on all-glass metasurfaces, fabricated by angled etching through sacrificial metal nanoparticle (NP) etching masks, for generation of effective birefringence in the formed layer. As a result, a fused silica metasurface, monolithic to the underlying substrate, is demonstrated to exhibit a birefringence of 6.57° under 375 nm illumination. Full-wave analysis shows a good agreement with the measurement and presents potential paths forward to increasing the effective metasurface birefringence. This is the first demonstration, to the best of knowledge, of an etching technique to obtain the resulting tilted pillar-like nanofeatures. The anisotropy of the metasurface nanoelements along the two window in-plane major axes presents different effective paths for the two polarizations and thus generates birefringence in a nonbirefringent material. Additionally, the imparted anisotropy lends itself to manipulation of physical properties of the surface as well, with metasurface feature orientation suppressing water flow along one principal axis and giving rise to water flow steering capabilities., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Objectives: Structural imaging of the cholinergic basal forebrain may provide a biomarker for cholinergic system integrity that can be used in motor and non-motor outcome studies in Parkinson's disease. However, no prior studies have validated these structural metrics with cholinergic nerve terminal in vivo imaging in Parkinson's disease. Here, we correlate cholinergic basal forebrain morphometry with the topography of vesicular acetylcholine transporter in a large Parkinson's sample., Methods: [ 18 F]-Fluoroethoxybenzovesamicol vesicular acetylcholine transporter positron emission tomography was carried out in 101 non-demented people with Parkinson's (76.24% male, mean age 67.6 ± 7.72 years, disease duration 5.7 ± 4.4 years). Subregional cholinergic basal forebrain volumes were measured using magnetic resonance imaging morphometry. Relationships were assessed via volume-of-interest based correlation analysis., Results: Subregional volumes of the cholinergic basal forebrain predicted cholinergic nerve terminal loss, with most robust correlations occurring between the posterior cholinergic basal forebrain and temporofrontal, insula, cingulum, and hippocampal regions, and with modest correlations in parieto-occipital regions. Hippocampal correlations were not limited to the cholinergic basal forebrain subregion Ch1-2. Correlations were also observed in the striatum, thalamus, and brainstem., Interpretation: Cholinergic basal forebrain morphometry is a robust predictor of regional cerebral vesicular acetylcholine transporter bindings, especially in the anterior brain. The relative lack of correlation between parieto-occipital binding and basal forebrain volumes may reflect the presence of more diffuse synaptopathy in the posterior cortex due to etiologies that extend well beyond the cholinergic system. ANN NEUROL 2023;93:991-998., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Parkinson's disease (PD) is an idiopathic disease of the central nervous system characterized by both motor and non-motor symptoms. It is the second most common neurodegenerative disease. Magnetic resonance imaging (MRI) can reveal underlying brain changes associated with PD., Objective: In this study, structural connectivity and white matter networks were analyzed by diffusion MRI and graph theory in a cohort of patients with PD and a cohort of healthy controls (HC) obtained from the Parkinson's Progression Markers Initiative (PPMI) database in a cross-sectional analysis. Furthermore, we investigated longitudinal changes in the PD cohort over 36 months., Result: Compared with the control group, participants with PD showed lower structural connectivity in several brain areas, including the corpus callosum, fornix, and uncinate fasciculus, which were also confirmed by a large effect-size. Additionally, altered connectivity between baseline and after 36 months was found in different network paths inside the white matter with a medium effect-size. Network analysis showed trends toward lower network density in PD compared with HC at baseline and after 36 months, though not significant after correction. Significant differences were observed in nodal degree and strength in several nodes., Conclusion: In conclusion, altered structural and network metrics in several brain regions, such as corpus callosum, fornix, and cingulum were found in PD, compared to HC. We also report altered connectivity in the PD group after 36 months, reflecting the impact of both PD pathology and aging processes. These results indicate that structural and network metrics might yield insight into network reorganization that occurs in PD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bergamino, Keeling, Ray, Macerollo, Silverdale and Stokes.)

Free-water imaging can predict and monitor dopamine system degeneration in people with Parkinson's disease. It can also enhance the sensitivity of traditional diffusion tensor imaging (DTI) metrics for indexing neurodegeneration. However, these tools are yet to be applied to investigate cholinergic system degeneration in Parkinson's disease, which involves both the pedunculopontine nucleus and cholinergic basal forebrain. Free-water imaging, free-water-corrected DTI and volumetry were used to extract structural metrics from the cholinergic basal forebrain and pedunculopontine nucleus in 99 people with Parkinson's disease and 46 age-matched controls. Cognitive ability was tracked over 4.5 years. Pearson's partial correlations revealed that free-water-corrected DTI metrics in the pedunculopontine nucleus were associated with performance on cognitive tasks that required participants to make rapid choices (behavioural flexibility). Volumetric, free-water content and DTI metrics in the cholinergic basal forebrain were elevated in a sub-group of people with Parkinson's disease with evidence of cognitive impairment, and linear mixed modelling revealed that these metrics were differently associated with current and future changes to cognition. Free water and free-water-corrected DTI can index cholinergic degeneration that could enable stratification of patients in clinical trials of cholinergic interventions for cognitive decline. In addition, degeneration of the pedunculopontine nucleus impairs behavioural flexibility in Parkinson's disease, which may explain this region's role in increased risk of falls., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

To fabricate high-precision and accurate optics relative to the optical design surface, a high level of deterministic control of material removal (i.e., the tool influence function, TIF) during subaperture tool polishing is required. In this study, a detailed analysis of the pressure distribution, which is a key component of the TIF, has been performed using finite element analysis to couple together solid mechanics and fluid dynamics. Modeling experimental parameters of recently published work reveals that, when considering tool deformation, which in turn influences the fluid film thickness between the tool and workpiece, the effective pressure profile has a flat-top distribution. This flat-top pressure profile differs from the parabolic pressure distributions predicted by Hertzian mechanics. Moreover, the shear contribution is shown here to be a key contributor to material removal, inducing the removal at the periphery of the contact edge and even outside the generally accepted contact area. Finally, the simulated fluid velocities provide evidence of mixed-mode contact polishing, supporting recent experimental findings that also suggest that onset of hydroplaning contributions lead to material removal drop-off.

Patients who have dementia with Lewy bodies and Alzheimer's disease show early degeneration of the cholinergic nucleus basalis of Meynert. However, how white matter projections between the nucleus basalis of Meynert and the cortex are altered in neurodegenerative disease is unknown. Tractography of white matter pathways originating from the nucleus basalis of Meynert was performed using diffusion-weighted imaging in 46 patients with Alzheimer's disease dementia, 48 with dementia with Lewy bodies, 35 with mild cognitive impairment with Alzheimer's disease, 38 with mild cognitive impairment with Lewy bodies and 71 control participants. Mean diffusivity of the resulting pathways was compared between groups and related to cognition, attention, functional EEG changes and dementia conversion in the mild cognitive impairment groups. We successfully tracked a medial and a lateral pathway from the nucleus basalis of Meynert. Mean diffusivity of the lateral pathway was higher in both dementia and mild cognitive impairment groups than controls (all P < 0.03). In the patient groups, increased mean diffusivity of this pathway was related to more impaired global cognition (β = -0.22, P = 0.06) and worse performance on an attention task (β = 0.30, P = 0.03). In patients with mild cognitive impairment, loss of integrity of both nucleus basalis of Meynert pathways was associated with increased risk of dementia progression [hazard ratio (95% confidence interval), medial pathway: 2.51 (1.24-5.09); lateral pathway: 2.54 (1.24-5.19)]. Nucleus basalis of Meynert volume was reduced in all clinical groups compared to controls (all P < 0.001), but contributed less strongly to cognitive impairment and was not associated with attention or dementia conversion. EEG slowing in the patient groups as assessed by a decrease in dominant frequency was associated with smaller nucleus basalis of Meynert volumes (β = 0.22, P = 0.02) and increased mean diffusivity of the lateral pathway (β = -0.47, P = 0.003). We show that degeneration of the cholinergic nucleus basalis of Meynert in Alzheimer's disease and dementia with Lewy bodies is accompanied by an early reduction in integrity of white matter projections that originate from this structure. This is more strongly associated with cognition and attention than the volume of the nucleus basalis of Meynert itself and might be an early indicator of increased risk of dementia conversion in people with mild cognitive impairment., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Visuospatial impairment in Parkinson's disease (PD) heralds the onset of a progressive dementia syndrome and might be associated with cholinergic dysfunction. It remains unclear however, whether degeneration of the cholinergic basal forebrain is directly related to cognitive decline, or whether relationships between this region and cognitive function are mediated by closely related brain structures such as those in the medial temporal lobe. To evaluate relationships between structure of the cholinergic basal forebrain, medial temporal lobe and cognition, 27 PD patients without dementia and 20 controls underwent neuropsychological assessment and MRI. Volumes of the cholinergic basal forebrain nuclei, the entorhinal cortex, the hippocampus and its subfields were measured. Regression models utilised basal forebrain and hippocampal volumetric measures to predict cognitive performance. In PD, visuospatial memory (but not verbal memory or executive function) was correlated with hippocampal volume, particularly CA2-3, and basal forebrain subregion Ch1-2, but not Ch4. In addition, hippocampal volume was correlated with Ch1-2 in PD. The relationship between Ch1-2 and visuospatial memory was mediated by CA2-3 integrity. There were no correlations between cognitive and volumetric measures in controls. Our data imply that the integrity of the cholinergic basal forebrain is associated with subregional hippocampal volume. Additionally, a relationship between visuospatial function and cholinergic nuclei does exist, but is fully mediated by variations in hippocampal structure. These findings are consistent with the recent hypothesis that forebrain cholinergic system degeneration results in cognitive deficits via cholinergic denervation, and subsequent structural degeneration, of its target regions., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cholinergic degeneration is a key feature of dementia in neurodegenerative conditions including Alzheimer's disease (AD) and Parkinson's disease (PD). Quantitative electro-encephalography (EEG) metrics are altered in both conditions from early stages, and recent research in people with Lewy body and AD dementia suggests these changes may be associated with atrophy in cholinergic basal forebrain nuclei (cBF). To determine if these relationships exist in predementia stages of neurodegenerative conditions, we studied resting-state EEG and in vivo cBF volumes in 31 people with PD (without dementia), 21 people with mild cognitive impairment (MCI), and 21 age-matched controls. People with PD showed increased power in slower frequencies and reduced alpha reactivity compared to controls. Volumes of cholinergic cell clusters corresponding to the medial septum and vertical and horizontal limb of the diagonal band, and the posterior nucleus basalis of Meynert, correlated positively with; alpha reactivity in people with PD (p< 0.01); and pre-alpha power in people with MCI (p< 0.05). These results suggest that alpha reactivity and pre-alpha power are related to changes in cBF volumes in MCI and PD without dementia., (Copyright © 2021. Published by Elsevier Inc.)

Neurodegeneration leads to redistribution of processing, which is reflected in a reorganisation of the structural connectome. This might affect its vulnerability to structural damage. Cortical acetylcholine allows favourable adaptation to pathology within the memory circuit. However, it remains unclear if it acts on a broader scale, affecting reconfiguration of whole-brain networks. To investigate the role of the cholinergic basal forebrain (CBFB) in strategic lesions, twenty patients with mild cognitive impairment (MCI) and twenty elderly controls underwent magnetic resonance imaging. Whole-brain tractograms were represented as network graphs. Lesions of individual nodes were simulated by removing a node and its connections from the graph. The impact of simulated lesions was quantified as the proportional change in global efficiency. Relationships between subregional CBFB volumes, global efficiency of intact connectomes and impacts of individual simulated lesions of network nodes were assessed. In MCI but not controls, larger CBFB volumes were associated with efficient network topology and reduced impact of hippocampal, thalamic and entorhinal lesions, indicating a protective effect against the global impact of simulated strategic lesions. This suggests that the cholinergic system shapes the configuration of the connectome, thereby reducing the impact of localised damage in MCI., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: This qualitative study examined fiscal and administrative (i.e., pre- and post-award grants process) barriers and facilitators to community-engaged research among stakeholders across 4 Clinical and Translational Science Awards (CTSA) institutions., Method: A purposive sample of 24 key informants from 3 stakeholder groups-community partners, academic researchers, and research administrators-from the CTSA institutions at the University of North Carolina at Chapel Hill, Medical University of South Carolina, Vanderbilt University Medical Center, and Yale University participated. Semistructured interviews were conducted in March-July 2018, including questions about perceived challenges and best practices in fiscal and administrative processes in community-engaged research. Transcribed interviews were independently reviewed and analyzed using the Rapid Assessment Process to facilitate key theme and quote identification., Results: Community partners were predominantly Black, academic researchers and research administrators were predominantly White, and women made up two-thirds of the overall sample. Five key themes were identified: level of partnership equity, partnership collaboration and communication, institutional policies and procedures, level of familiarity with varying fiscal and administrative processes, and financial management expectations. No stakeholders reported best practices for the institutional policies and procedures theme. Cross-cutting challenges included communication gaps between stakeholder groups; lack of or limits in supporting community partners' fiscal capacity; and lack of collective awareness of each stakeholder group's processes, procedures, and needs. Cross-cutting best practices centered on shared decision making and early and timely communication between all stakeholder groups in both pre- and post-award processes., Conclusions: Findings highlight the importance of equitable processes, triangulated communication, transparency, and recognizing and respecting different financial management cultures within community-engaged research. This work can be a springboard used by CTSA institutions to build on available resources that facilitate co-learning and discussions between community partners, academic researchers, and research administrators on fiscal readiness and administrative processes for improved community-engaged research partnerships., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Association of American Medical Colleges.)

Background: Gait disturbance is an early, disabling feature of Parkinson's disease (PD) that is typically refractory to dopaminergic medication. The cortical cholinergic system, originating in the nucleus basalis of Meynert of the basal forebrain, has been implicated. However, it is not known if degeneration in this region relates to a worsening of disease-specific gait impairment., Objective: To evaluate associations between sub-regional cholinergic basal forebrain volumes and longitudinal progression of gait impairment in PD., Methods: 99 PD participants and 47 control participants completed gait assessments via an instrumented walkway during 2 minutes of continuous walking, at baseline and for up to 3 years, from which 16 spatiotemporal characteristics were derived. Sub-regional cholinergic basal forebrain volumes were measured at baseline via MRI and a regional map derived from post-mortem histology. Univariate analyses evaluated cross-sectional associations between sub-regional volumes and gait. Linear mixed-effects models assessed whether volumes predicted longitudinal gait changes., Results: There were no cross-sectional, age-independent relationships between sub-regional volumes and gait. However, nucleus basalis of Meynert volumes predicted longitudinal gait changes unique to PD. Specifically, smaller nucleus basalis of Meynert volume predicted increasing step time variability (P = 0.019) and shortening swing time (P = 0.015); smaller posterior nucleus portions predicted shortening step length (P = 0.007) and increasing step time variability (P = 0.041)., Conclusions: This is the first study to demonstrate that degeneration of the cortical cholinergic system predicts longitudinal progression of gait impairments in PD. Measures of this degeneration may therefore provide a novel biomarker for identifying future mobility loss and falls. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Purpose of Review: This paper aims to review novel trends in cholinergic neuroimaging in Alzheimer and Lewy body parkinsonian disorders., Recent Findings: The spectrum of cholinergic imaging is expanding with the availability of spatially more precise radioligands that allow assessment of previously less recognized subcortical and cortical structures with more dense cholinergic innervation. In addition, advances in MRI techniques now allow quantitative structural or functional assessment of both the cholinergic forebrain and the pedunculopontine nucleus, which may serve as non-invasive prognostic predictors. Multimodal imaging approaches, such as PET-MRI or multiligand PET offer new insights into the dynamic and interactive roles of the cholinergic system at both local and larger-scale neural network levels., Summary: Our understanding of the heterogeneous roles of the cholinergic system in age-related diseases is evolving. Multimodal imaging approaches that provide complimentary views of the cholinergic system will be necessary to shed light on the impact of cholinergic degeneration on regional and large-scale neural networks that underpin clinical symptom manifestation in neurodegeneration., Competing Interests: Conflict of Interest The authors declare no competing interests. The authors have received research funding support from the National Institutes of Health, Department of Veterans Affairs, the Michael J. Fox Foundation and the Wellcome Trust.

Many optical applications that could potentially benefit from the design flexibility provided by the metasurface approach are being prohibited by the limited scalability of the fabrication and the robustness of the end-result structures when using a resonant meta-elements-based approach. An alternative demonstrated approach with superior scalability and robustness is substrate-engraved metasurfaces, based on medium mixing homogenization, yet it suffers from very limited optical response. Here we propose advancing this approach by coupling the metasurface with buried etalon layers, leading to enhancement in the optical response. A transfer matrix analysis is used to study the parameter space, predicting that the patterned reflectance values range of a beam shaper could be raised from only 4% to 30% when the metasurface is engraved in silica, and even up to 66% when engraved into higher-index oxides. Using the method proposed here, the phase difference range across the metasurface could be increased by 0.4 radians beyond the range achievable by a metasurface engraved in silica and could reach even higher values when embedded in higher-index materials. Full-wave numerical simulations are used to demonstrate a cylindrical metareflector and a metalens, further validating the analysis.

Background: There is an urgent need to identify individuals at risk of postural instability and gait difficulties, and the resulting propensity for falls, in Parkinson's disease., Objectives: Given known relationships between posture and gait and degeneration of the cholinergic pedunculopontine nucleus, we investigated whether metrics of pedunculopontine nucleus microstructural integrity hold independent utility for predicting future postural instability and gait difficulties and whether they could be combined with other candidate biomarkers to improve prognostication of these symptoms., Methods: We used stereotactic mapping of the pedunculopontine nucleus and diffusion tensor imaging to extract baseline pedunculopontine nucleus diffusivity metrics in 147 participants with Parkinson's disease and 65 controls enrolled in the Parkinson's Progression Markers Initiative. We also recorded known candidate markers of posture and gait changes: loss of caudate dopamine and CSF β-amyloid 1-42 levels at baseline; as well as longitudinal progression motor symptoms over 72-months., Results: Survival analyses revealed that reduced dopamine in the caudate and increased axial diffusivity in the pedunculopontine nucleus incurred independent risk of postural instability and gait difficulties. Binary logistic regression and receiver operating characteristics analysis in 117 participants with complete follow-up data at 60 months revealed that only pedunculopontine nucleus microstructure provided more accurate discriminative ability for predicting future postural instability and gait difficulties than clinical and demographic variables alone., Conclusion: Dopaminergic and cholinergic loss incur independent risk for future postural instability and gait difficulties, and pedunculopontine nucleus microstructure can be used to prognosticate these symptoms from early Parkinson's disease stages. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

Latent biomarkers are quantities that strongly relate to patient's disease diagnosis and prognosis, but are difficult to measure or even not directly observable. The objective of this study was to develop, analyze and validate new priors for Bayesian inference of such biomarkers. Theoretical analysis revealed a relationship between the estimates inferred from the model and the true values of measured quantities, and the impact of the priors. This led to a new prior encoding scheme that incorporates objectively measurable domain knowledge, i.e. by performing two measurements with a reference method, which imply scale of the prior distribution. Second, priors on parameters of systematic error are non-informative, which enables biomarker estimation from a set of different quantities. Analysis showed that the volume of nucleus basalis of Meynert, which is reduced in early stages of Alzheimer's dementia and Parkinson's disease, is inter-related and could be inferred from compartmental brain volume measurements performed on routine clinical MR scans. Another experiment showed that total lesion load, associated to future disability progression in multiple sclerosis patients, could be inferred from lesion volume measurements based on multiple automated MR scan segmentations. Besides, figures of merit derived from the estimates could, without comparing against reference gold standard segmentations, identify the best performing lesion segmentation method. The proposed new priors substantially simplify the application of Bayesian inference for latent biomarkers and thus open an avenue for clinical implementation of new biomarkers, which may ultimately advance the evidence-based medicine.

Optical performance of anti-reflective random meta-surfaces are studied numerically for coherent beam propagation systems, such as lasers. A methodology for the modeling of such optics performance is developed and applied to study the reflectivity and laser beam quality degradation. These quantitative metrics and design considerations highlight that reducing the size of the meta-surface period much below the light wavelength is not necessarily required.

A key challenge for metasurface research is locally controlling at will the nanoscale geometric features on meter-scale apertures. Such a technology is expected to enable large aperture meta-optics and revolutionize fields such as long-range imaging, lasers, laser detection and ranging (LADAR), and optical communications. Furthermore, these applications are often more sensitive to light-induced and environmental degradation, which constrains the possible materials and fabrication process. Here, we present a relatively simple and scalable method to fabricate a substrate-engraved metasurface with locally printed index determined by induced illumination, which, therefore, addresses both the challenges of scalability and durability. In this process, a thin metal film is deposited onto a substrate and transformed into a mask via local laser-induced dewetting into nanoparticles. The substrate is then dry-etched through this mask, and selective mask removal finally reveals the metasurface. We show that masking by the local nanoparticle distribution, and, therefore, the local index, is dependent on the local light-induced dewetting temperature. We demonstrate printing of a free-form pattern engraved into a fused silica glass substrate using a laser raster scan. Large-scale spatially controlled engraving of metasurfaces has implications on other technological fields beyond optics, such as surface fluidics, acoustics, and thermomechanics.

The reducing environment in the eye lens diminishes with age, leading to significant oxidative stress. Oxidation of lens crystallin proteins is the major contributor to their destabilization and deleterious aggregation that scatters visible light, obscures vision, and ultimately leads to cataract. However, the molecular basis for oxidation-induced aggregation is unknown. Using X-ray crystallography and small-angle X-ray scattering, we describe the structure of a disulfide-linked dimer of human γS-crystallin that was obtained via oxidation of C24. The γS-crystallin dimer is stable at glutathione concentrations comparable to those in aged and cataractous lenses. Moreover, dimerization of γS-crystallin significantly increases the protein's propensity to form large insoluble aggregates owing to non-cooperative domain unfolding, as is observed in crystallin variants associated with early-onset cataract. These findings provide insight into how oxidative modification of crystallins contributes to cataract and imply that early-onset and age-related forms of the disease share comparable development pathways., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Individual differences in memory during aging are associated with the microstructure of the fornix, a bidirectional tract connecting the hippocampus with the diencephalon, basal forebrain and cortex. To investigate the origin of alterations in fornix microstructure, measurement of hippocampal subfield volumes was combined with diffusion MRI and cognitive evaluation in a new sample of 31 healthy human participants aged 50-89 years. The fornix, uncinate and parahippocampal cingulum were reconstructed using diffusion MRI tractography. Episodic memory was assessed with free and cued verbal recall, visual recognition and paired associate learning tests. Recall performance was associated with fornix microstructure and hippocampal subfield volumes. Subiculum and CA1 volumes remained positively associated with fornix microstructure when controlling for other volumes. Subiculum volume was also associated with fornix microstructure independent of age. Regression analyses showed that subiculum-fornix associations explained more variation in recall than that of CA1-fornix associations. In a multivariable regression model, age and subiculum volume were independent predictors of free recall whilst fornix microstructure and CA1 volume were not. These results suggest that age-related changes in a network that includes the subiculum and fornix are important in cognitive change in healthy aging. These results match anatomical predictions concerning the importance of hippocampal - diencephalic projections for memory.

Heterogeneity in small heat shock proteins (sHsps) spans multiple spatiotemporal regimes-from fast fluctuations of part of the protein, to conformational variability of tertiary structure, plasticity of the interfaces, and polydispersity of the inter-converting, and co-assembling oligomers. This heterogeneity and dynamic nature of sHsps has significantly hindered their structural characterization. Atomic coordinates are particularly lacking for vertebrate sHsps, where most available structures are of extensively truncated homomers. sHsps play important roles in maintaining protein levels in the cell and therefore in organismal health and disease. HspB2 and HspB3 are vertebrate sHsps that are found co-assembled in neuromuscular cells, and variants thereof are associated with disease. Here, we present the structure of human HspB2/B3, which crystallized as a hetero-tetramer in a 3:1 ratio. In the HspB2/B3 tetramer, the four α-crystallin domains (ACDs) assemble into a flattened tetrahedron which is pierced by two non-intersecting approximate dyads. Assembly is mediated by flexible "nuts and bolts" involving IXI/V motifs from terminal regions filling ACD pockets. Parts of the N-terminal region bind in an unfolded conformation into the anti-parallel shared ACD dimer grooves. Tracts of the terminal regions are not resolved, most likely due to their disorder in the crystal lattice. This first structure of a full-length human sHsp heteromer reveals the heterogeneous interactions of the terminal regions and suggests a plasticity that is important for the cytoprotective functions of sHsps., (Copyright © 2018. Published by Elsevier Ltd.)

Purpose of Review: Although the cholinergic hypothesis of dementia provided a successful paradigm for the development of new drugs for dementia, this hypothesis has waned in popularity. Cholinergic brain imaging may provide novel insights into the viability of this hypothesis., Recent Findings: Cholinergic receptor and forebrain volumetric studies suggest an important role of the cholinergic system in maintaining brain network integrity that may deteriorate with cognitive decline in Alzheimer disease (AD) and Lewy body disorders (LBD). Bidirectional changes in regional receptor expression may suggest the presence of compensatory responses to neurodegenerative injury. Cholinergic system changes are more complex in LBD because of additional subcortical degenerations compared to AD. Cholinergic-dopaminergic interactions affect attentional, verbal learning and executive functions, and impairments in these two transmitter systems may jointly increase the risk of dementia in Parkinson disease., Summary: The cholinergic hypothesis is evolving from a primary focus on memory toward expanded cognitive functions modulated by regionally more complex and interactive brain networks. Cholinergic network adaptation may serve as a novel research target in neurodegeneration., Competing Interests: Disclosure No potential conflicts of interest relevant to this article were reported.

See Gratwicke and Foltynie (doi:10.1093/brain/awx333) for a scientific commentary on this article.Cognitive impairments are a prevalent and disabling non-motor complication of Parkinson's disease, but with variable expression and progression. The onset of serious cognitive decline occurs alongside substantial cholinergic denervation, but imprecision of previously available techniques for in vivo measurement of cholinergic degeneration limit their use as predictive cognitive biomarkers. However, recent developments in stereotactic mapping of the cholinergic basal forebrain have been found useful for predicting cognitive decline in prodromal stages of Alzheimer's disease. These methods have not yet been applied to longitudinal Parkinson's disease data. In a large sample of people with de novo Parkinson's disease (n = 168), retrieved from the Parkinson's Progressive Markers Initiative database, we measured cholinergic basal forebrain volumes, using morphometric analysis of T1-weighted images in combination with a detailed stereotactic atlas of the cholinergic basal forebrain nuclei. Using a binary classification procedure, we defined patients with reduced basal forebrain volumes (relative to age) at baseline, based on volumes measured in a normative sample (n = 76). Additionally, relationships between the basal forebrain volumes at baseline, risk of later cognitive decline, and scores on up to 5 years of annual cognitive assessments were assessed with regression, survival analysis and linear mixed modelling. In patients, smaller volumes in a region corresponding to the nucleus basalis of Meynert were associated with greater change in global cognitive, but not motor scores after 2 years. Using the binary classification procedure, patients classified as having smaller than expected volumes of the nucleus basalis of Meynert had ∼3.5-fold greater risk of being categorized as mildly cognitively impaired over a period of up to 5 years of follow-up (hazard ratio = 3.51). Finally, linear mixed modelling analysis of domain-specific cognitive scores revealed that patients classified as having smaller than expected nucleus basalis volumes showed more severe and rapid decline over up to 5 years on tests of memory and semantic fluency, but not on tests of executive function. Thus, we provide the first evidence that volumetric measurement of the nucleus basalis of Meynert can predict early cognitive decline. Our methods therefore provide the opportunity for multiple-modality biomarker models to include a cholinergic biomarker, which is currently lacking for the prediction of cognitive deterioration in Parkinson's disease. Additionally, finding dissociated relationships between nucleus basalis status and domain-specific cognitive decline has implications for understanding the neural basis of heterogeneity of Parkinson's disease-related cognitive decline., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Amyloid fibril formation occurs from a wide range of peptides and proteins and is typically associated with a loss of protein function and/or a gain of toxic function, as the native structure of the protein undergoes major alteration to form a cross β-sheet array. It is now well recognised that some amyloid fibrils have a biological function, which has led to increased interest in the potential that these so-called functional amyloids may either retain the function of the native protein, or gain function upon adopting a fibrillar structure. Herein, we investigate the molecular chaperone ability of α-crystallin, the predominant eye lens protein which is composed of two related subunits αA- and αB-crystallin, and its capacity to retain and even enhance its chaperone activity after forming aggregate structures under conditions of thermal and chemical stress. We demonstrate that both eye lens α-crystallin and αB-crystallin (which is also found extensively outside the lens) retain, to a significant degree, their molecular chaperone activity under conditions of structural change, including after formation into amyloid fibrils and amorphous aggregates. The results can be related directly to the effects of aging on the structure and chaperone function of α-crystallin in the eye lens, particularly its ability to prevent crystallin protein aggregation and hence lens opacification associated with cataract formation., Competing Interests: The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Deamidation of Glu147 in human αA-crystallin is common in aged cataractous lenses (Hains and Truscott, Invest. Ophthalmol. Vis. Sci. 2010, 51, 3107). Accordingly, this modification may have a causative effect in cataract. αA-crystallin is a small heat-shock molecular chaperone protein that prevents aggregation of proteins and is the principal defence against crystallin unfolding and aggregation in the ageing lens. Deamidated Q147E αA-crystallin was structurally characterised using a variety of spectroscopic and biophysical methods, including NMR, circular dichroism and fluorescence spectroscopy and dynamic light scattering. The effect of Glu147 deamidation on αA-crystallin in vitro chaperone ability was determined for a variety of aggregating proteins. Compared to the wild type protein, Q147E αA-crystallin generally exhibited slightly reduced chaperone ability and a small loss of overall structure in its central α-crystallin domain while also showing significantly enhanced thermal stability and a tendency to form slightly larger oligomers. As αA-crystallin is the major lens protein, even a small loss of function could combine with other sources of age-related damage to the crystallins to contribute to lens opacification., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Sustaining collaborations between community-based organization leaders and academic researchers in community-engaged research (CEnR) in the service of decreasing health inequities necessitates understanding the collaborations from an inter-organizational perspective. We assessed the perspectives of community leaders and university-based researchers conducting community-engaged research in a medium-sized city with a history of community-university tension. Our research team, included experts in CEnR and organizational theory, used qualitative methods and purposeful, snowball sampling to recruit local participants and performed key informant interviews from July 2011-May 2012. A community-based researcher interviewed 11 community leaders, a university-based researcher interviewed 12 university-based researchers. We interviewed participants until we reached thematic saturation and performed analyses using the constant comparative method. Unifying themes characterizing community leaders and university-based researchers' relationships on the inter-organizational level include: 1) Both groups described that community-engaged university-based researchers are exceptions to typical university culture; 2) Both groups described that the interpersonal skills university-based researchers need for CEnR require a change in organizational culture and training; 3) Both groups described skepticism about the sustainability of a meaningful institutional commitment to community-engaged research 4) Both groups described the historical impact on research relationships of race, power, and privilege, but only community leaders described its persistent role and relevance in research relationships. Challenges to community-academic research partnerships include researcher interpersonal skills and different perceptions of the importance of organizational history. Solutions to improve research partnerships may include transforming university culture and community-university discussions on race, power, and privilege.

Here we report on direct evidence of a correlation between hydrogen-to-water oxidation on mesoporous Pt/TiO 2 nanocomposites at room temperature and the conversion of surface-released chemical energy into a stationary electrical current. The Pt phase of this heterojunction device is an electrically continuous 15 nm thick mesh deposited onto a mesoporous TiO 2 substrate fabricated with a plasma electrolytic oxidation process. The H 2 O turnover frequency approaches an asymptotic value associated with the saturation of the Pt/TiO 2 interface as the concentration of hydrogen gas is increased. In situ measurements of the reaction-induced current concurrently with mass spectrometry measurements illuminate the polarity switch of the reaction current (from thermionic emission to a reverse steady-state flow) simultaneously with the production of water. Furthermore, a concentration-dependent value of 5 min is measured as the time constant for the adsorption of the initial addition of H 2 and H 2 O formation and desorption.

Objectives: The aim of this systematic review was to identify from in vitro studies the effect of endodontic access on the fracture resistance and damage around the access cavity of all-ceramic crowns., Data: The articles identified were screened by two reviewers according to inclusion and exclusion criteria. The reference lists of articles advanced to second round screening were hand searched to identify additional potential articles. The risk of bias for the articles was independently performed by two reviewers., Sources: An electronic search was conducted on PubMed/Medline, Web of Science, Scopus and Embase databases with no limitations., Study Selection: 383 articles were identified, of which, eight met the inclusion criteria and formed the basis of this systematic review. Factors investigated in the selected articles included the, presence of microcracks at the access cavity, repair protocol, ceramic type, crown fabrication method, luting agent and grit size of the diamond bur. The risk of bias was deemed to be high for three, medium for two and low for three of the reviewed studies. The high level of heterogeneity across the studies precluded meta-analyses., Conclusion: Based on the currently available scientific evidence, a 'best practice' protocol with regard to improving the fracture resistance of endodontically accessed and repaired all-ceramic crowns cannot be conclusively identified. However, some key factors which potentially impact on the fracture resistance of endodontically accessed and repaired all-ceramic crowns have been isolated. Cautious clinical interpretation of these factors is concluded for the maintenance of the crown as a permanent restoration., Clinical Significance: Key factors which impact on the fracture resistance of endodontically accessed and repaired all-ceramic crowns have been isolated from in vitro studies. Cautious clinical interpretation of these factors is advised for the maintenance of the crown as a permanent restoration., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Detection of amyloid growth is commonly carried out by measurement of solution turbidity, a low-cost assay procedure based on the intrinsic light scattering properties of the protein aggregate. Here, we review the biophysical chemistry associated with the turbidimetric assay methodology, exploring the reviewed literature using a series of pedagogical kinetic simulations. In turn, these simulations are used to interrogate the literature concerned with in vitro drug screening and the assessment of amyloid aggregation mechanisms., Competing Interests: Compliance with ethical standards Conflict of interests Ran Zhao declares that he has no conflict of interest. Masatomo So declares that he has no conflict of interest. Hendrik Maat declares that he has no conflict of interest. Nicholas J. Ray declares that he has no conflict of interest. Fumio Arisaka declares that he has no conflict of interest. Yuji Goto declares that he has no conflict of interest. John A. Carver declares that he has no conflict of interest. Damien Hall declares that he has no conflict of interest. Ethical approval This article does not contain any studies with human participants or animals performed byany of the authors.

Background: Cataract formation is often attributed to the build-up of post-translational modifications in the crystallin proteins of the eye lens. One such modification, the deamidation of N76 in human γS-crystallin to D76, is highly correlated with age-related cataract (Hooi et al. Invest. Ophthalmol. Vis. Sci. 53 (2012) 3554-3561). In the current work, this modification has been extensively characterised in vitro., Methods: Biophysical characterisation was performed on wild type and N76D γS-crystallins using turbidity measurements to monitor aggregation, intrinsic fluorescence and circular dichroism spectroscopy to determine the folded state and NMR spectroscopy for identifying local changes in structure. Protein mass was determined using SEC-MALLS and analytical ultracentrifugation methods., Results: Relative to the wild type protein, deamidation at N76 in γS-crystallin causes an increase in the thermal stability and resistance to thermally induced aggregation alongside a decrease in stability to denaturants, a propensity to aggregate rapidly once destabilised and a tendency to form a dimer. We ascribe the apparent increase in thermal stability upon deamidation to the formation of dimer which prevents the unfolding of the inherently less stable monomer., Conclusions: Deamidation causes a decrease in stability of γS-crystallin but this is offset by an increased tendency for dimer formation., General Significance: Deamidation at N76 in human γS-crystallin likely has a combinatorial effect with other post-translational crystallin modifications to induce age-related cataract. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease., (Copyright © 2015 Elsevier B.V. All rights reserved.)

There have been many works analyzing thermionic currents and chemicurrents generated on various electrolyte-free metal/semiconductor nanostructures. More recently, the chemicurrent phenomenon was reported for mesoporous Pt/semiconductor systems adept at converting surface-released chemical energy into a stationary electrical signal at room-temperature conditions. The present work points out the existence of an entire class of such surface-driven functional nanosystems. Here, the reaction current generation of Pt/ZrO2 systems was studied at room temperature under exposure to oxyhydrogen environments for mesoporous zirconia; this nanostructure was capable of the continuous oxidation of hydrogen, producing a long-standing stationary current. Synthesis parameters during the anodization process were manipulated to control sample pore density and the average pore diameter. Deposited via wide-angle PVD sputtering, the Pt phase forms an electrically continuous topographical nanomesh layer, and thus the Pt/ZrO2/gas interface is regulated through the manipulation of zirconia porosity. We observed reaction current enhancements with increasing porosity due to the lengthening of the Pt/ZrO2 interface. The most porous sample was significantly more sensitive to initial hydrogen additions, pointing toward the spillover of positive ionic charge across the Pt/ZrO2 interface as the origin of the observed electromotive force.

This review examines both recent and historical literature related to the biophysical chemistry of the proteins in the ageing eye, with a particular focus on cataract development. The lens is a vital component of the eye, acting as an optical focusing device to form clear images on the retina. The lens maintains the necessary high transparency and refractive index by expressing crystallin proteins in high concentration and eliminating all large cellular structures that may cause light scattering. This has the consequence of eliminating lens fibre cell metabolism and results in mature lens fibre cells having no mechanism for protein expression and a complete absence of protein recycling or turnover. As a result, the crystallins are some of the oldest proteins in the human body. Lack of protein repair or recycling means the lens tends to accumulate damage with age in the form of protein post-translational modifications. The crystallins can be subject to a wide range of age-related changes, including isomerisation, deamidation and racemisation. Many of these modification are highly correlated with cataract formation and represent a biochemical mechanism for age-related blindness.

The fornix and hippocampus are critical to recollection in the healthy human brain. Fornix degeneration is a feature of aging and Alzheimer's disease. In the presence of fornix damage in mild cognitive impairment (MCI), a recognized prodrome of Alzheimer's disease, recall shows greater dependence on other tracts, notably the parahippocampal cingulum (PHC). The current aims were to determine whether this shift is adaptive and to probe its relationship to cholinergic signaling, which is also compromised in Alzheimer's disease. Twenty-five human participants with MCI and 20 matched healthy volunteers underwent diffusion MRI, behavioral assessment, and volumetric measurement of the basal forebrain. In a regression model for recall, there was a significant group × fornix interaction, indicating that the association between recall and fornix structure was weaker in patients. The opposite trend was present for the left PHC. To further investigate this pattern, two regression models were generated to account for recall performance: one based on fornix microstructure and the other on both fornix and left PHC. The realignment to PHC was positively correlated with free recall but not non-memory measures, implying a reconfiguration that is beneficial to residual memory. There was a positive relationship between realignment to PHC and basal forebrain gray matter volume despite this region demonstrating atrophy at a group level, i.e., the cognitive realignment to left PHC was most apparent when cholinergic areas were relatively spared. Therefore, cholinergic systems appear to enable adaptation to injury even as they degenerate, which has implications for functional restoration., (Copyright © 2015 Ray et al.)

The control of impulse behavior is a multidimensional concept subdivided into separate subcomponents, which are thought to represent different underlying mechanisms due to either disinhibitory processes or poor decision-making. In patients with Parkinson's disease (PD), dopamine-agonist (DA) therapy has been associated with increased impulsive behavior. However, the relationship among these different components in the disease and the role of DA is not well understood. In this imaging study, we investigated in PD patients the effects of DA medication on patterns of brain activation during tasks testing impulsive choices and actions. Following overnight withdrawal of antiparkinsonian medication, PD patients were studied with a H2 ((15)) O PET before and after administration of DA (1 mg of pramipexole), while they were performing the delay discounting task (DDT) and the GoNoGo Task (GNG). We observed that pramipexole augmented impulsivity during DDT, depending on reward magnitude and activated the medial prefrontal cortex and posterior cingulate cortex and deactivated ventral striatum. In contrast, the effect of pramipexole during the GNG task was not significant on behavioral performance and involved different areas (i.e., lateral prefrontal cortex). A voxel-based correlation analysis revealed a significant negative correlation between the discounting value (k) and the activation of medial prefrontal cortex and posterior cingulate suggesting that more impulsive patients had less activation in those cortical areas. Here we report how these different subcomponents of inhibition/impulsivity are differentially sensitive to DA treatment with pramipexole influencing mainly the neural network underlying impulsive choices but not impulsive action., (Copyright © 2013 Wiley Periodicals, Inc.)

Objectives: It is proposed that a non-uniform rational B-spline (NURBS) based solid geometric model of a ceramic crown would be a flexible and quick approach to virtually simulate root canal access cavities. The computation of strain components orthogonal to surface flaws generated during the drilling would be an appropriate way of comparing different access cavity configurations., Methods: A μCT scan is used to develop a full 3D NURBS geometric solid model of a ceramic crown. Three different access cavity configurations are created virtually in the geometric model and there are then imported into proprietary finite element software. A linear analysis of the each crown is carried out under appropriate in vivo loading and the results are post-processed to carry out a quantitative comparison of the three configurations, Results: The geometric model is shown to be a flexible and quick way of simulation access cavities. Preliminary indications are that post processed strain results from the finite element analysis are good comparators of competing access cavity configurations., Significance: The generation of geometric solid models of dental crowns from μCT scans is a flexible and efficient methodology to simulate a number of access cavity configurations. Furthermore, advanced post-processing of the primary finite element analysis results is worthwhile as preliminary results indicate that improved quantitative comparisons between different access cavity configurations are possible., (Copyright © 2013 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.)

Established substance addictions and impulse control disorders (ICDs) such as pathological gambling share similar underlying neurobiology, and recent data extends these commonalities to the risk factors that increase an individuals' susceptibility to develop such behaviours. In Parkinson's disease (PD), impulse control disorders (ICDs) are increasingly recognised to develop after patients begin dopamine (DA) restoration therapy, in particular DA agonists. In both the PD and non-PD population, more impulsive individuals are at increased risk for impulse control disorders. Here, we review the neuroimaging data confirming the connection between addiction and ICDs, and revealing how DA agonists might cause specific alterations of basal ganglia and cortical function that vary as a function of an individuals' propensity for impulsivity.

Impulse control disorders such as pathological gambling (PG) are a serious and common adverse effect of dopamine (DA) replacement medication in Parkinson's disease (PD). Patients with PG have increased impulsivity and abnormalities in striatal DA, in common with behavioural and substance addictions in the non-PD population. To date, no studies have investigated the role of extrastriatal dopaminergic abnormalities in PD patients with PG. We used the PET radiotracer, [11C] FLB-457, with high-affinity for extrastriatal DA D2/3 receptors. 14 PD patients on DA agonists were imaged while they performed a gambling task involving real monetary reward and a control task. Trait impulsivity was measured with the Barratt Impulsivity Scale (BIS). Seven of the patients had a history of PG that developed subsequent to DA agonist medication. Change in [11C] FLB-457 binding potential (BP) during gambling was reduced in PD with PG patients in the midbrain, where D2/D3 receptors are dominated by autoreceptors. The degree of change in [11C] FLB-457 binding in this region correlated with impulsivity. In the cortex, [11C] FLB-457 BP was significantly greater in the anterior cingulate cortex (ACC) in PD patients with PG during the control task, and binding in this region was also correlated with impulsivity. Our findings provide the first evidence that PD patients with PG have dysfunctional activation of DA autoreceptors in the midbrain and low DA tone in the ACC. Thus, altered striatal and cortical DA homeostasis may incur vulnerability for the development of PG in PD, linked with the impulsive personality trait., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Patients with Parkinson's disease (PD) often develop a spectrum of cognitive symptoms that can evolve into dementia. Dopamine (DA) replacement medications, though improving motor symptoms, can exert both positive and negative effects on cognitive ability, depending on the severity of the disease and the specific skill being tested. By considering the behavioral and clinical aspects of disease- and treatment-mediated changes in cognition alongside the pathophysiology of PD, an understanding of the factors that govern the heterogeneous expression of cognitive impairment in PD is beginning to emerge. Here, we review the neuroimaging studies revealing the neural correlates of cognitive changes after DA loss and DA replacement as well as those that may accompany the conversion from milder stages of cognitive impairment to frank dementia., (Copyright © 2012 Movement Disorder Society.)

The subthalamic nucleus (STN) is a key node in the network that supports response inhibition. It is suggested that the STN rapidly inhibits basal ganglia activity, to pause motor output during conflict until an appropriate motor plan is ready. Here, we recorded neural activity during a Stroop task from deep brain stimulation electrodes implanted in the human STN. We intended to determine whether cognitive psychological phenomena such as the Stroop effect can be explained via mechanisms of response inhibition involving the STN, or whether higher cognitive centers are alone responsible. We show stimulus-driven desychronization in the beta band (15-35 Hz) that lasts throughout the verbal response, in keeping with the idea that beta-band synchrony decreases to allow motor output to occur. During incongruent trials--in which response times were elongated due to the Stroop effect--a resynchronization was seen in the beta band before response. Crucially, in the incongruent trials during which the participant was unable to withhold the prepotent response, this resynchronization occurred after response onset. We suggest that this beta-band resynchronization pauses the motor system until conflict can be resolved.