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Background: Using 11C‐(R)‐PK11195‐PET, we found increased microglia activation in isolated REM sleep behavior disorder (iRBD) patients. Their role remains to be clarified. Objectives: The objective is to assess relationships between activated microglia and progression of nigrostriatal dysfunction in iRBD. Methods: Fifteen iRBD patients previously scanned with 11C‐(R)‐PK11195 and 18F‐DOPA‐PET underwent repeat 18F‐DOPA‐PET after 3 years. 18F‐DOPA Ki changes from baseline were evaluated with volumes‐of‐interest and voxel‐based analyses. Results: Significant 18F‐DOPA Ki reductions were found in putamen and caudate. Reductions were larger and more widespread in patients with increased nigral microglia activation at baseline. Left nigral 11C‐(R)‐PK11195 binding at baseline was a predictor of 18F‐DOPA Ki reduction in left caudate (coef = −0.0426, P = 0.016). Conclusions: Subjects with increased baseline 11C‐(R)‐PK11195 binding have greater changes in nigrostriatal function, suggesting a detrimental rather than protective effect of microglial activation. Alternatively, both phenomena occur in patients with prominent nigrostriatal dysfunction without a causative link. The clinical and therapeutic implications of these findings need further elucidation. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Major depressive disorder is one of the most prevalent mental health disorders, posing a global socioeconomic burden. Conventional antidepressant treatments have a slow onset of action, and 30% of patients show no clinically significant treatment response. The recently approved fast‐acting antidepressant S‐ketamine, an N‐methyl‐D‐aspartate receptor antagonist, provides a new approach for treatment‐resistant patients. However, knowledge of S‐ketamine's mechanism of action is still being established. Depressed human subjects have lower striatal dopamine transporter (DAT) availability compared to healthy controls. Rodent studies report increased striatal dopamine concentration in response to acute ketamine administration. In vivo [18F]FE‐PE2I ([18F]‐(E)‐N‐(3‐iodoprop‐2‐enyl)‐2β‐carbofluoroethoxy‐3β‐(4′‐methyl‐phenyl) nortropane) positron emission tomography (PET) imaging of the DAT has not previously been applied to assess the effect of acute subanesthetic S‐ketamine administration on DAT availability. We applied translational in vivo [18F]FE‐PE2I PET imaging of the DAT in healthy female rats to evaluate whether an acute subanesthetic intraperitoneal dose of 15 mg/kg S‐ketamine alters DAT availability. We also performed [3H]GBR‐12935 autoradiography on postmortem brain sections. We found no effect of acute S‐ketamine administration on striatal DAT binding using [18F]FE‐PE2I PET or [3H]GBR‐12935 autoradiography. This negative result does not support the hypothesis that DAT changes are associated with S‐ketamine's rapid antidepressant effects, but additional studies are warranted. [ABSTRACT FROM AUTHOR]

The pathophysiological development of Alzheimer's disease (AD) begins in the brain years before the onset of clinical symptoms. The accumulation of beta‐amyloid (Aβ) is thought to be the first cortical pathology to occur. Carrying one apolipoprotein E (APOE) ε4 allele increases the risk of developing AD at least 2–3 times and is associated with earlier Aβ accumulation. Although it is difficult to identify Aβ‐related cognitive impairment in early AD with standard cognitive tests, more sensitive memory tests may be able to do this. We sought to examine associations between Aβ and performance on three tests within three subdomains of memory, verbal, visual, and associative memory, to elucidate which of these tests were sensitive to Aβ‐related cognitive impairment in at‐risk subjects. 55 APOE ε4 carriers underwent MRI, 11C‐Pittsburgh Compound B (PiB) PET, and cognitive testing. A composite cortical PiB SUVR cut‐off score of 1.5 was used to categorise subjects as either APOE ε4 Aβ+ or APOE ε4 Aβ−. Correlations were carried out using cortical surface analysis. In the whole APOE ε4 group, we found significant correlations between Aβ load and performance on verbal, visual, and associative memory tests in widespread cortical areas, the strongest association being with performance on associative memory tests. In the APOE ε4 Aβ+ group, we found significant correlations between Aβ load and performance of verbal and associative, but not visual, memory in localised cortical areas. Performance on verbal and associative memory tests provides sensitive markers of early Aβ‐related cognitive impairment in at‐risk subjects. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Capillary dysfunction, characterized by disturbances in capillary blood flow distribution, might be an overlooked factor in the development of Alzheimer's disease (AD). This study investigated microvascular blood flow in preclinical and prodromal AD individuals. METHODS: Using dynamic susceptibility contrast magnetic resonance imaging and positron emission tomography, we examined alterations in microvascular circulation and levels of Aβ deposition in two independent cohorts of APOE ε4 carriers. RESULTS: Capillary dysfunction was elevated in both prodromal and preclinical AD individuals compared to age‐matched controls. Additionally, the prodromal group exhibited higher levels of capillary dysfunction compared to the preclinical group. DISCUSSION: These findings suggest that capillary dysfunction can be detected at the preclinical stage of AD and indicates a worsening of capillary dysfunction throughout the AD continuum. Understanding the interaction between capillary dysfunction and Aβ could provide insights into the relationship between cardiovascular risk factors and the development of AD. Highlights: Alzheimer's disease (AD) is associated with disturbances in microvascular circulation.Capillary dysfunction can be detected in preclinical AD.As cognitive symptoms progress in prodromal AD, capillary dysfunction worsens.Capillary dysfunction may impede the clearance of beta‐amyloid (Aβ).Capillary dysfunction might contribute to the development of AD. [ABSTRACT FROM AUTHOR]

Background: Reduced cortical acetylcholinesterase activity, as measured by 11C‐donepezil positron emission tomography (PET), has been reported in patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD). However, its progression and clinical implications have not been fully investigated. Here, we explored the relationship between longitudinal changes in brain acetylcholinesterase activity and cognitive function in iRBD. Methods: Twelve iRBD patients underwent 11C‐donepezil PET at baseline and after 3 years. PET images were interrogated with statistical parametric mapping (SPM) and a regions of interest (ROI) approach. Clinical progression was assessed with the Movement Disorder Society‐Unified Parkinson's Disease Rating Scale‐Part III (MDS‐UPDRS‐III). Cognitive function was rated using the Mini‐Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). Results: From baseline to follow‐up, the mean 11C‐donepezil distribution volume ratio (DVR) decreased in the cortex (p = 0.006), thalamus (p = 0.013), and caudate (p = 0.013) ROI. Despite no significant changes in the group mean MMSE or MoCA scores being observed, individually, seven patients showed a decline in their scores on these cognitive tests. Subgroup analysis showed that only the subgroup of patients with a decline in cognitive scores had a significant reduction in mean cortical 11C‐donepezil DVR. Conclusions: Our results show that severity of brain cholinergic dysfunction in iRBD patients increases significantly over 3 years, and those changes are more severe in those with a decline in cognitive test scores. [ABSTRACT FROM AUTHOR]

Background: Patients with Lewy body diseases exhibit variable degrees of cortical and subcortical hypometabolism. However, the underlying causes behind this progressive hypometabolism remain unresolved. Generalized synaptic degeneration may be one key contributor. Objective: The objective of this study was to investigate whether local cortical synaptic loss is proportionally linked to the magnitude of hypometabolism in Lewy body disease. Method: Using in vivo positron emission tomography (PET) we investigated cerebral glucose metabolism and quantified the density of cerebral synapses, as measured with [18F]fluorodeoxyglucose ([18F]FDG) PET and [11C]UCB‐J, respectively. Volumes‐of‐interest were defined on magnetic resonance T1 scans and regional standard uptake value ratios‐1 values were obtained for 14 pre‐selected brain regions. Between‐group comparisons were conducted at voxel‐level. Results: We observed regional differences in both synaptic density and cerebral glucose consumption in our cohorts of non‐demented and demented patients with Parkinson's disease or dementia with Lewy bodies compared to healthy subjects. Additionally, voxel‐wise comparisons showed a clear difference in cortical regions between demented patients and controls for both tracers. Importantly, our findings strongly suggested that the magnitude of reduced glucose uptake exceeded the magnitude of reduced cortical synaptic density. Conclusion: Here, we investigated the relationship between in vivo glucose uptake and the magnitude of synaptic density as measured using [18F]FDG PET and [11C]UCB‐J PET in Lewy body patients. The magnitude of reduced [18F]FDG uptake was greater than the corresponding decline in [11C]UCB‐J binding. Therefore, the progressive hypometabolism seen in Lewy body disorders cannot be fully explained by generalized synaptic degeneration. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Gait impairments are characteristic motor manifestations and significant predictors of poor quality of life in Parkinson's disease (PD). Neuroimaging biomarkers for gait impairments in PD could facilitate effective interventions to improve these symptoms and are highly warranted. Objective: The aim of this study was to identify neural networks of discrete gait impairments in PD. Methods: Fifty‐five participants with early‐stage PD and 20 age‐matched healthy volunteers underwent quantitative gait assessment deriving 12 discrete spatiotemporal gait characteristics and [18F]‐2‐fluoro‐2‐deoxyglucose‐positron emission tomography measuring resting cerebral glucose metabolism. A multivariate spatial covariance approach was used to identify metabolic brain networks that were related to discrete gait characteristics in PD. Results: In PD, we identified two metabolic gait‐related covariance networks. The first correlated with mean step velocity and mean step length (pace gait network), which involved relatively increased and decreased metabolism in frontal cortices, including the dorsolateral prefrontal and orbital frontal, insula, supplementary motor area, ventrolateral thalamus, cerebellum, and cuneus. The second correlated with swing time variability and step time variability (temporal variability gait network), which included relatively increased and decreased metabolism in sensorimotor, superior parietal cortex, basal ganglia, insula, hippocampus, red nucleus, and mediodorsal thalamus. Expression of both networks was significantly elevated in participants with PD relative to healthy volunteers and were not related to levodopa dosage or motor severity. Conclusions: We have identified two novel gait‐related brain networks of altered glucose metabolism at rest. These gait networks could serve as a potential neuroimaging biomarker of gait impairments in PD and facilitate development of therapeutic strategies for these disabling symptoms. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Summary: Objective: Imaging activated glutamate N‐methyl‐D‐aspartate receptor ion channels (NMDAR‐ICs) using positron emission tomography (PET) has proved challenging due to low brain uptake, poor affinity and selectivity, and high metabolism and dissociation rates of candidate radioligands. The radioligand [18F]GE‐179 is a known use‐dependent marker of NMDAR‐ICs. We studied whether interictal [18F]GE‐179 PET would detect foci of abnormal NMDAR‐IC activation in patients with refractory focal epilepsy. Methods: Ten patients with refractory focal epilepsy and 18 healthy controls had structural magnetic resonance imaging (MRI) followed by a 90‐min dynamic [18F]GE‐179 PET scan with simultaneous electroencephalography (EEG). PET and EEG findings were compared with MRI and previous EEGs. Standard uptake value (SUV) images of [18F]GE‐179 were generated and global gray matter uptake was measured for each individual. To localize focal increases in uptake of [18F]GE‐179, the individual SUV images were interrogated with statistical parametric mapping in comparison to a normal database. Additionally, individual healthy control SUV images were compared with the rest of the control database to determine their prevalence of increased focal [18F]GE‐179 uptake. Results: Interictal [18F]GE‐179 PET detected clusters of significantly increased binding in eight of 10 patients with focal epilepsy but none of the controls. The number of clusters of raised [18F]GE‐179 uptake in the patients with epilepsy exceeded the focal abnormalities revealed by the simultaneously recorded EEG. Patients with extensive clusters of raised [18F]GE‐179 uptake showed the most abnormal EEGs. Significance: Detection of multiple foci of abnormal NMDAR‐IC activation in 80% of our patients with refractory focal epilepsy using interictal [18F]GE‐179 PET could reflect enhanced neuronal excitability due to chronic seizure activity. This indicates that chronic epileptic activity is associated with abnormal NMDAR ion channel activation beyond the initial irritative zones. [18F]GE‐179 PET could be a candidate marker for identifying pathological brain areas in patients with treatment‐resistant focal epilepsy. [ABSTRACT FROM AUTHOR]

The central cholinergic system includes the basal forebrain nuclei, mainly projecting to the cortex, the mesopontine tegmental nuclei, mainly projecting to the thalamus and subcortical structures, and other groups of projecting neurons and interneurons. This system regulates many functions of human behavior such as cognition, locomotion, and sleep. In Parkinson's disease (PD), disruption of central cholinergic transmission has been associated with cognitive decline, gait problems, freezing of gait (FOG), falls, REM sleep behavior disorder (RBD), neuropsychiatric manifestations, and olfactory dysfunction. Neuropathological and neuroimaging evidence suggests that basal forebrain pathology occurs simultaneously with nigrostriatal denervation, whereas pathology in the pontine nuclei may occur before the onset of motor symptoms. These studies have also detailed the clinical implications of cholinergic dysfunction in PD. Degeneration of basal forebrain nuclei and consequential cortical cholinergic denervation are associated with and may predict the subsequent development of cognitive decline and neuropsychiatric symptoms. Gait problems, FOG, and falls are associated with a complex dysfunction of both pontine and basal forebrain nuclei. Olfactory impairment is associated with cholinergic denervation of the limbic archicortex, specifically hippocampus and amygdala. Available evidence suggests that cholinergic dysfunction, alongside failure of the dopaminergic and other neurotransmitters systems, contributes to the generation of a specific set of clinical manifestations. Therefore, a "cholinergic phenotype" can be identified in people presenting with cognitive decline, falls, and RBD. In this review, we will summarize the organization of the central cholinergic system and the clinical correlates of cholinergic dysfunction in PD. [ABSTRACT FROM AUTHOR]

Background: Patients with Parkinson's disease (PD) often develop dementia, but the underlying substrate is incompletely understood. Generalized synaptic degeneration may contribute to dysfunction and cognitive decline in Lewy body dementias, but in vivo evidence is lacking.Objective: The objective of this study was to assess the density of synapses in non-demented PD (nPD) subjects (N = 21), patients with PD-dementia or Dementia with Lewy bodies (DLB) (N = 13), and age-matched healthy controls (N = 15).Method: Using in vivo PET imaging and the novel synaptic-vesicle-glycoprotein 2A (SV2A) radioligand [11C]UCB-J, SUVR-1 values were obtained for 12 pre-defined regions. Volumes-of-interest were defined on MRI T1 scans. Voxel-level between-group comparisons of [11C]UCB-J SUVR-1 were performed. All subjects underwent neuropsychological assessment. Correlations between [11C]UCB- J PET and domain-specific cognitive functioning were examined.Results: nPD patients only demonstrated significantly reduced SUVR-1 values in the substantia nigra (SN) compared to HC. DLB/PDD patients demonstrated reduced SUVR-1 values in SN and all cortical VOIs except for the hippocampus and amygdala. The voxel-based analysis supported the VOI results. Significant correlation was seen between middle frontal gyrus [11C]UCB-J SUVR-1 and performance on tests of executive function.Conclusion: Widespread cortical reduction of synaptic density was documented in a cohort of DLB/PDD subjects using in vivo [11C]UCB-J PET. Our study confirms previously reported synaptic loss in SN of nPD patients. [11C]UCB-J binding in selected cortical VOIs of the DLB/PDD patients correlated with their levels of cognitive function across relevant neuropsychological domains. These findings suggest that the loss of synaptic density contributes to cognitive impairment in nPD and DLB/PDD. © 2021 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Glucocerebrosidase gene mutations are a common genetic risk factor for Parkinson's disease. They exhibit incomplete penetrance. The objective of the present study was to measure microglial activation and dopamine integrity in glucocerebrosidase gene mutation carriers without Parkinson's disease compared to controls. Methods: We performed PET scans on 9 glucocerebrosidase gene mutation carriers without Parkinson's disease and 29 age‐matched controls. We measured microglial activation as 11C‐(R)‐PK11195 binding potentials, and dopamine terminal integrity with 18F‐dopa influx constants. Results: The 11C‐(R)‐PK11195 binding potential was increased in the substantia nigra of glucocerebrosidase gene carriers compared with controls (Student t test; right, t = −4.45, P = 0.0001). Statistical parametric mapping also localized significantly increased 11C‐(R)‐PK11195 binding potential in the occipital and temporal lobes, cerebellum, hippocampus, and mesencephalon. The degree of hyposmia correlated with nigral 11C‐(R)‐PK11195 regional binding potentials (Spearman's rank, P = 0.0066). Mean striatal 18F‐dopa uptake was similar to healthy controls. Conclusions: In vivo 11C‐(R)‐PK11195 PET imaging detects neuroinflammation in brain regions susceptible to Lewy pathology in glucocerebrosidase gene mutation carriers without Parkinson's. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Activated microglia is present in both Alzheimer's subjects (AD) and mild cognitive impairment (MCI) subjects and can be visualised by both pathological evaluation and in‐vivo imaging studies. It has been established that neuroinflammation plays a vital role in Alzheimer's trajectory and disruption in structural and functional connectivity is also a key event in Alzheimer's disease. However, the mechanism by which microglial activation influence brain structural and functional connectivity remains to be elucidated. 11C‐PBR28 PET is a marker of translocator protein (TSPO) reflecting microglial activation and 18F‐Flutematemol PET is a marker of amyloid deposition. Method: 25 amnestic MCI and 17 healthy controls (HC) were recruited and underwent T1‐weighted, diffusion tensor and resting‐state functional MRI, 11C‐PBR28 and 18F‐Flutemetamol PET scans. 11C‐PBR28 and 18F‐Flutemetamol scans were analysed using target‐to‐cerebellar ratio. Tract‐Based Spatial Statistics was performed on DTI scans. RS‐fMRI scans were analysed using medial prefrontal cortex (MPFC) as a seed. The relationship between tracer uptake and structural integrity of white matter tracts or brain functional connectivity with MPFC was analysed using linear regression corrected for age and gender. Result: MCI cohort showed significantly decreased functional connectivity between MPFC and posterior cingulate and precuneous regions. Cortical 11C‐PBR28 uptake but not 18F‐Flutemetamol was negatively correlated with FA in the corpus callosum, bilateral inferior frontal‐occipital fasciculi and inferior longitudinal fasciculi. MPFC 11C‐PBR28 uptake was correlated with increased MPFC functional connectivity to anterior frontal regions and reduced connectivity to posterior frontal, temporal, parietal and cingulate regions; while frontal amyloid load was correlated with reduced MPFC connectivity with frontal and temporal cortices. Regression analysis with both 18F‐Flutemetamol and 11C‐PBR28 demonstrated that MPFC 11C‐PBR28 was significantly associated MPFC connectivity with posterior frontal, parietal and cingulate regions. Conclusion: The findings suggest that MPFC microglial activation is associated with increased functional connectivity with the nearby regions and decreased connectivity with the distal regions to MPFC in MCI subjects. Findings from DTI analysis showed negative correlation with structural integrity of the long fibre tracts which are connecting distal regions. These findings suggest that neuroinflammation is involved in the structural and functional connectivity disruption and probably remodelling in AD trajectory. [ABSTRACT FROM AUTHOR]

Background: To investigate whether neuroinflammation and β‐amyloid (Aβ) deposition influence brain structural and functional connectivity in Alzheimer's spectrum, we conducted a cross‐sectional multimodal imaging study and interrogated the associations between imaging biomarkers of neuroinflammation, Aβ deposition, brain connectivity and cognition. Method: 58 participants (25 MCI, 16 AD dementia and 17 healthy controls) were recruited and scanned with 11C‐PBR28 and 18F‐flutemetamol PET, T1‐weighted, diffusion tensor and resting‐state functional MRI. Brain structural and functional connectivity were assessed by global white matter integrity and functional topology metrics, while neuroinflammation and Aβ deposition were evaluated by 11C‐PBR28 and 18F‐flutemetamol uptake, respectively. Changes of the biomarkers were compared between diagnostic groups and robust regression analyses at both voxel and regional level were performed on Aβ positive patients, who were considered to be representative of Alzheimer's continuum. Result: Increased 11C‐PBR28 and 18F‐flutemetamol uptake, decreased FA values, impaired small‐worldness and local efficiency of functional network were observed in the AD cohort. In Aβ‐positive patients, cortical 11C‐PBR28 uptake correlated with decreased structural integrity and network local efficiency independent of 18F‐flutemetamol uptake and cortical thickness. Network structural integrity and cortical thickness correlated with functional metrics, including small‐worldness and local efficiency, which were all associated with cognition. Conclusion: Our findings suggest that cortical neuroinflammation may lead to disruption of structural and functional brain network independent of amyloid deposition and cortical atrophy, which in turn can lead to cognitive impairment in AD. [ABSTRACT FROM AUTHOR]

Histopathology differentiates TV from EDV, as TV would be expected to demonstrate hyphae and spores in the stratum corneum.1,2 Flat warts can have a similar clinical and histologic appearance to EDV. A 11-year-old girl with human immunodeficiency virus (HIV) was evaluated by pediatric dermatology for the evaluation of a chronic rash present for at least 5 years. Clinicopathologic correlation with examination and histology findings in the setting of HIV infection favored a diagnosis of EDV. [Extracted from the article]

Background and Purpose: In vivo detection of β-amyloid (Aβ) plaques in Alzheimer's disease (AD) is now possible with 11 C-PiB positron emission tomography (PET). Conventionally, a cortical:cerebellar PiB uptake ratio threshold of 1.4-1.5 has been used to categorize at-risk subjects as "amyloid-positive" and "amyloid-negative." It has been suggested that this threshold is too conservative and may miss early amyloid pathology. We investigated the relationship between conventional and lower baseline 11 C-PiB PET thresholds for raised amyloid load and the subsequent clinical and radiological progression of mild cognitive impairment (MCI) cases longitudinally.Methods: We serially determined the cortical amyloid load with 11 C-PiB PET of 44 MCI subjects over 2 years and compared findings with those for 12 healthy controls (HC) and 5 AD cases.Results: Twenty-four subjects were classified as normal at baseline with mean cortical PiB standard uptake value ratios (SUVR) between 1.2 and 1.5. Their cognitive status remained stable over time. Three of these cases increased their amyloid load above a threshold of 1.5 over 2 years. Twenty-seven "raised amyloid" MCI cases with baseline cortical SUVRs above 1.5, showed deteriorating cognition. Note that 50% of these cases converted clinically to AD during the follow-up period.Conclusion: Use of a PiB SUVR threshold of >1.5 for raised amyloid missed 14.3% of MCI cases who likely had Thal stage 1 or 2 pathology and showed a progressive amyloid increase over 2 years. Lowering the threshold for abnormality to 1.3 abolished all false negatives but resulted in 75% of HCs being falsely diagnosed as raised amyloid subjects. [ABSTRACT FROM AUTHOR]

Background: The pattern and role of microglial activation in multiple system atrophy is largely unclear. The objective of this study was to use [11 C](R)-PK11195 PET to determine the extent and correlation of activated microglia with clinical parameters in MSA patients.Methods: Fourteen patients with the parkinsonian phenotype of MSA (MSA-P) with a mean disease duration of 2.9 years (range 2-5 years) were examined with [11 C](R)-PK11195 PET and compared with 10 healthy controls.Results: Patients with the parkinsonian phenotype of MSA showed a significant (P ≤ 0.01) mean increase in binding potentials compared with healthy controls in the caudate nucleus, putamen, pallidum, precentral gyrus, orbitofrontal cortex, presubgenual anterior cingulate cortex, and the superior parietal gyrus. No correlations between binding potentials and clinical parameters were found.Conclusions: In early clinical stages of the parkinsonian phenotype of MSA, there is widespread microglial activation as a marker of neuroinflammatory changes without correlation to clinical parameters in our patient population. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Reduced noradrenaline levels have been reported to occur in the motor cortices of PD patients postmortem. Imaging techniques have recently become available to specifically study noradrenergic terminal function in vivo using PET. The objective of this study was to evaluate cortical 11 C-MeNER binding in PD patients. Thirty PD patients and 12 healthy control subjects comparable in age, sex, and cognitive performance underwent PET imaging with 11 C-MeNER, a specific ligand of the noradrenaline transporter. Cortical noradrenaline transporter binding was compared at a voxel level using Statistical Parametric Mapping, whereas cortical thickness was assessed using FreeSurfer software with MRI. PD patients showed reduced 11 C-MeNER binding in the primary motor cortex unrelated to cortical thickness; other cortical regions did not differ between groups. In a subgroup analysis, patients with higher Hoehn & Yahr stage exhibited more pronounced 11 C-MeNER binding reductions. Loss of cortical noradrenergic projections to the primary motor cortex occurs in PD associated with disease stage. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Despite enormous advances in our current understanding of PD since James Parkinson described the "shaking palsy" 200 years ago, l-dopa, in clinical use since the 1960s, remains the gold standard of treatment. Virtually every patient with PD requires varying doses of l-dopa to manage motor and some nonmotor symptoms and retain an acceptable quality of life. However, after a period of treatment with l-dopa, a number of problems emerge; the key ones are motor and nonmotor fluctuations, a range of dyskinesias, and a combination of both. Nonmotor complications can range from behavioral problems to sensory, autonomic, and cognitive issues. Even with a wealth of data, both in animal models and in vivo imaging that address the pathophysiology of l-dopa-related motor and nonmotor complications, the treatment remains challenging and is an unmet need. Although refinement in types of dopamine replacement therapy and delivery systems have improved the management of l-dopa-related complications, the search for the ideal treatment continues. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease copathology is common in PD at autopsy. In non-PD subjects with mild cognitive impairment, tau depositions can be detected using 18F-AV-1451 PET. We hypothesized that 18F-AV-1451 PET would show tau aggregation in PD with mild cognitive impairment and correlate with cognitive dysfunction.Objectives: To describe tau aggregation in PD patients.Methods: Twenty-six PD patients and 23 controls had 18F-AV-1451 PET and neuropsychological assessment to detect mild cognitive impairment.Results: Nine PD patients (35%) were identified with mild cognitive impairment. Regional analyses showed no significant differences between groups. Voxel-wise analyses showed no correlation with cognitive domain z-scores within patients. One patient with mild cognitive impairment was estimated Braak tau stage 5; all other patients were stage 0.Conclusion: Our results indicate that tau pathology, as detected by 18F-AV-1451, is uncommon in PD with mild cognitive impairment and shows no significant correlation with cognitive dysfunction at this stage. © 2017 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Mild cognitive impairment (MCI) is prevalent in 15%-40% of Parkinson's disease (PD) patients at diagnosis. In this investigation, we study brain intra- and inter-network alterations in resting state functional magnetic resonance imaging (rs-fMRI) in recently diagnosed PD patients and characterise them as either cognitive normal (PD-NC) or with MCI (PD-MCI). Patients were divided into two groups, PD-NC ( N = 62) and PD-MCI ( N = 37) and for comparison, healthy controls (HC, N = 30) were also included. Intra- and inter-network connectivity were investigated from participants' rs-fMRIs in 26 resting state networks (RSNs). Intra-network differences were found between both patient groups and HCs for networks associated with motor control (motor cortex), spatial attention and visual perception. When comparing both PD-NC and PD-MCI, intra-network alterations were found in RSNs related to attention, executive function and motor control (cerebellum). The inter-network analysis revealed a hyper-synchronisation between the basal ganglia network and the motor cortex in PD-NC compared with HCs. When both patient groups were compared, intra-network alterations in RSNs related to attention, motor control, visual perception and executive function were found. We also detected disease-driven negative synchronisations and synchronisation shifts from positive to negative and vice versa in both patient groups compared with HCs. The hyper-synchronisation between basal ganglia and motor cortical RSNs in PD and its synchronisation shift from negative to positive compared with HCs, suggest a compensatory response to basal dysfunction and altered basal-cortical motor control in the resting state brain of PD patients. Hum Brain Mapp 38:1702-1715, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to investigate in vivo the ability of levodopa/carbidopa intestinal gel infusions to produce sustained striatal dopamine levels and to improve clinical outcomes in Parkinson's disease patients.Methods: Six advanced Parkinson's disease patients had serial [11 C]raclopride PET to assess levodopa/carbidopa intestinal gel infusion-induced rises in striatal dopamine as reflected by a fall in dopamine-D2/3 receptor availability. Parkinson's disease patients had baseline scan OFF-dopaminergic stimulation and 2 scans following initiation of levodopa/carbidopa intestinal gel infusions. Striatal D2/3 binding was measured in striatal subregions corresponding to sensorimotor, limbic, and cognitive/associative function.Results: Mean striatal [11 C]raclopride nondisplaceable binding potential decreased by 14.0% to 16.7% in sensorimotor, 12.0%-14.4% in limbic, and 8.7%-11.6% in cognitive/associative function subregions at 1- to 10-hour points (P < 0.01). Sensorimotor subregion [11 C]raclopride nondisplaceable binding potential reductions correlated with reductions in Unified Parkinson's Disease Rating Scale Part III scores over the course of the infusion (r = 0.81; P < 0.05).Conclusions: Levodopa/carbidopa intestinal gel infusions generate a stable rise in striatal dopamine levels and are associated with improvements in motor manifestations. © 2016 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: There is growing evidence that microglial activation plays a crucial role in the early pathological changes reported in Alzheimer's disease (AD). Multimodal neuroimaging can be used to detect micro‐ and macrostructural alterations together with molecular imaging to quantify metabolism and proteins expression. Diffusivity map, reflecting neuronal integrity, can be derived from diffusion‐weighted imaging, and is thought to be increased in AD following pathological alterations. We hypothesised that changes in diffusivity could be colocalized with microglial activation at different stages of the disease. Method: 56 patients (mean age=70.4, SD=8.5) cognitively normal (CN, n=15), with mild cognitive impairment (MCI, n=28) and with AD (n=12) were included in this study. All participants underwent diffusion tensor imaging (DTI), amyloid PET ([18F]flutemetamol) and TSPO PET ([11C]PBR28). DTI data were processed with FSL v.6.0 to compute mean diffusivity (MD) maps. Standard uptake ratio (SUVR) values were calculated in SPM12 to identify the amyloid deposition and microglial activation within cortical regions. Amyloid status (Aβ‐positive/Aβ‐negative) was determined from processed data using a cerebellar gray matter ratio with a binding value greater than the CN mean+2SD. Z score maps of MD and [11C]PBR28 SUVR were computed using CN amyloid negative participants as reference. Z score maps were then correlated using SPM8 and the BPM toolbox. Significance was set at a threshold of p<0.05 with an extended threshold of 50 voxels. Result: We found a significant positive correlation clusters between MD and PBR28‐SUVR Z score maps (higher diffusivity correlated with higher microglial activation) in MCI amyloid negative subjects in the temporal lobe (coordinates: 28 ‐3 ‐32, corrected p<0.001, k=7363). In MCI amyloid positive subjects, we found positive correlation in the parietal lobe (coordinates: ‐47 ‐41 39, corrected p=0.008, k=5712). Conclusion: We found colocalized diffusivity and microglial changes in the early stage of the disease, in the temporal lobe of MCI amyloid negative participants and in later stages of the disease, in the parietal lobe of MCI amyloid positive participants. These results suggest the potential of DTI diffusivity and microglial activation imaging in detecting early neuronal damage occurring in dementia. [ABSTRACT FROM AUTHOR]

Background: There is growing evidence that pathological changes in Alzheimer's disease (AD) begin several years before the symptom onset. Neuroimaging approaches can be used to detect microstructural alterations in the early stages of neurodegeneration using diffusion‐weighted MRI. Cortical grey matter mean diffusivity (cMD) is thought to be increased in AD following pathological alterations resulting in disrupted neuronal function, neuronal death and cellular atrophy. We hypothesised that changes in MD could be detected early in the disease progression and that they would be correlated with structural imaging biomarkers. Method: 72 patients (mean age=69.1, SD=9.2) cognitively normal (CN, n=21) and with mild cognitive impairment (MCI, n=51) were included in this study. All participants underwent T1‐weighted MPRAGE MRI, diffusion tensor imaging (DTI) and PET amyloid ([18F]flutemetamol). Regional cortical thickness was measured on T1‐MPRAGE using FreeSurfer v.6.0. DTI data were processed with FSL v.6.0 to compute MD maps. Standard uptake ratio (SUVR) values were calculated in SPM12 to identify the amyloid deposition within cortical regions. Amyloid status (Aβ‐positive/Aβ‐negative) was determined from processed data using a cerebellar gray matter reference to create target‐to‐cerebellar ratio. Subjects were considered positive with an uptake value of greater than mean+2SD of the control subjects. Student's t‐test were used to compare imaging modalities between CN and MCI participants. Pearson's correlation coefficients were calculated to assess the relationship between imaging modalities. Result: There was a significantly increased MD in MCI compared to CN participants in hippocampus (p=0.0213) and in medial temporal lobe (p=0.033). There were no significant group differences neither in whole brain mean cortical thickness (p=0.6984) nor in temporal cortical thickness (p=0.0923). Interestingly, when splitting subjects based on their amyloid status, we found that whole brain MD was significantly negatively correlated with whole brain cortical thickness in amyloid negative (CN+MCI amyloid negative, p<0.001) but not in amyloid positive (CN+MCI amyloid positive, p=0.99). Conclusion: We found that changes in gray matter diffusivity could be detected in the early stages of AD pathology. We also found that there is a direct relationship between MD and structural changes (i.e. cortical thickness) only before amyloid deposition suggesting that MD provides information about early microstructural changes before macrostructural changes. [ABSTRACT FROM AUTHOR]

Background: Recent studies have suggested that melatonin-a hormone produced by the pineal gland under circadian control-contributes to PD-related sleep dysfunction. We hypothesized that degenerative changes to the neural structures controlling pineal function (especially the suprachiasmatic nuclei of the anterior hypothalamus) may be responsible for reduced melatonin output in these patients. We compared hypothalamic volumes in PD patients with matched controls and determined whether volume loss correlated with reduced melatonin output in the PD group.Methods: A total of 12 PD patients and 12 matched controls underwent magnetic resonance imaging to determine hypothalamic volume. In addition, PD patients underwent 24-hour blood sampling in a controlled environment to determine serum melatonin concentrations using enzyme-linked immunosorbent assays.Results: PD patients had significantly reduced hypothalamic gray matter volume when compared with matched controls. Melatonin levels were significantly associated with hypothalamic gray matter volume and disease severity in PD patients.Conclusion: Melatonin levels are associated with hypothalamic gray matter volume loss and disease severity in PD patients. This provides anatomical and physiological support for an intrinsic sleep and circadian phenotype in PD. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

In this review the structural and functional imaging changes associated with the synucleinopathies PD, MSA, and dementias associated with Lewy bodies are reviewed. The role of imaging for supporting differential diagnosis, detecting subclinical disease, and following disease progression is discussed and its potential use for monitoring disease progression is debated. © 2016 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Ten to fifteen percent of Parkinson's disease (PD) patients recruited to clinical trials have scans without evidence of dopaminergic deficit, whose presence represents a heterogeneous patient population.Methods: A cohort of 41 patients with parkinsonism and scans without evidence of dopaminergic deficit at baseline, were subdivided into groups according to their final clinical diagnoses and nigrostriatal dopamine function assessed after 2 years of study. At follow up, 23 patients had clinically probable PD or unclassified parkinsonism with normal nigrostriatal dopamine imaging ("true" scans without evidence of dopaminergic deficit), nine were diagnosed with another tremulous condition, five had psychogenic parkinsonism, and four had phenoconverted to PD with reduced nigrostriatal dopamine function. We analyzed nonmotor symptoms at baseline and follow-up in subgroups of patients with scans without evidence of dopaminergic deficit in comparison with a random sample of 62 PD patients and 195 healthy controls (HCs). All patients were enrolled in the Parkinson's Progressive Marker's Initiative.Results: Patients who had true scans without evidence of dopaminergic deficit had more severe rapid eye movement sleep disorder, depression, anxiety, and autonomic dysfunction than HCs in addition to more frequent depressive symptoms and worse cardiovascular dysfunction than patients with PD (P = 0.038, P = 0.047, respectively). Patients with true scans without evidence of dopaminergic deficit had normal olfaction that was significantly better than that of patients with PD (P < 0.001). Subgroup analysis of the cohort with scans without evidence of dopaminergic deficit revealed that all patients shared similar nonmotor features irrespective of their final clinical diagnoses. Follow-up of subject groups showed stable nonmotor symptoms over 2 years of study.Conclusions: At an early symptomatic stage, patients with scans without evidence of dopaminergic deficit and long-standing parkinsonism exhibit nonmotor features that differ from those of patients with PD on mood and cardiovascular and olfactory function, but remain similar to patients with scans without evidence of dopaminergic deficit with alternative final diagnoses. [ABSTRACT FROM AUTHOR]

Background: The aim of this work was to investigate the cortical and white matter changes that underlie cognitive impairment in patients with incident Parkinson's disease (PD) disease using voxel-based morphometry and diffusion tensor imaging.Methods: Newly diagnosed nondemented PD (n = 125) and control subjects (n = 50) were recruited from the Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation in Parkinson's Disease Study and completed cognitive assessments and 3T structural and diffusion tensor MR imaging. Voxel-based morphometry was performed to investigate the relationship between gray matter volume and cognitive ability. Microstructural white matter changes were assessed with diffusion tensor imaging measures of fractional anisotropy and mean diffusivity using tract-based spatial statistics.Results: Increased mean diffusivity was observed bilaterally in subjects with PD, relative to controls (P = 0.019). Increased mean diffusivity was associated with performance on the semantic fluency and Tower of London tasks in frontal and parietal white matter tracts, including the cingulum, superior longitudinal fasciculus, inferior longitudinal fasciculus, and inferior fronto-occipital fasciculus. There was no difference in total gray matter volume between groups; however, bilateral reductions in frontal and parietal gray matter volume were associated with reduced performance on measures of executive function in PD subjects.Conclusions: At the earliest stages of PD, regionally specific increases in central white matter mean diffusivity are present and suggest early axonal damage. Such changes are not accompanied by significant gray matter volume loss and are consistent with proposed models of pathological progression of the disease. Structural MRI, especially diffusion tensor imaging analysis, offers potential as a noninvasive biomarker reflecting cognitive impairment in PD. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation has been established as a key component of Alzheimer's pathology. Numerous cross‐sectional studies have found associations between neuroinflammatory markers and neuronal damage in AD, suggesting neuroinflammation as a potential drive force of disease progression. However, there have been debate on whether neuroinflammation has a causal effect on disease progression. Here we questioned whether neuroinflammation is predictive of future cognitive decline in early stage of the disease. Method: 21 MCI patients were recruited and had baseline T1‐MRI and 11C‐PBR28 scans. Patients were followed up for at least one year (mean follow‐up period 3.1±1.3 years) and had mini‐mental state examinations (MMSE) at each visit. 19 of them had baseline 18F‐Flutemetamol PET, 11 had 18F‐AV1451 scans. 18F‐AV1451 and 11C‐PBR28 SUVR in the medial temporal lobe were measured, while PCA analyses were performed to evaluate uptakes in the neocortex for all 3 tracers. Principle components of temporal lobe volumetric measurements were computed as the neurodegeneration marker. A linear growth model was fitted for each subjects using all available time points, giving the intercept and slope of individual cognition trajectory. Age, intercept, 11C‐PBR28, and T1 MRI markers were then put into linear models to predict slope, and a backward model selection procedure was conducted. To further validate that neuroinflammation is not just a mediator of amyloid and tau pathologies, we further included amyloid and tau markers in the sub‐cohorts and inspected the final model. Result: The average baseline MMSE was 28±1.9 in the study cohort and the average annual change of MMSE was ‐0.46. We found 11C‐PBR28 SUVR in neocortex and MMSE intercept, but not temporal cortical thickness, were predictive of the slope of MMSE decline. In subgroups where 18F‐Flutemetamol and 18F‐AV1451 SUVRs were included respectively, we found neocortical amyloid and tau load were also predictive of MMSE slope, while 11C‐PBR28 SUVR remained its significance in the models. Conclusion: Our findings suggest that neuroinflammation is an independent factor that drives disease progression and cognitive decline in early stage of AD. Molecular imaging biomarkers may better predict patients' outcome as they detect underlying biological processes. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), dementia with Lewy bodies, frontotemporal dementia (FTD), and Huntington's disease (HD) are the main neurodegenerative causes of dementia. Causes and mechanisms of these diseases remain elusive. Neuroinflammation is increasingly emerging as an important pathological factor in their development. Positron emission tomography (PET) using [ 11 C]PK11195 represents a method of visualizing the microglial component of neuroinflammation via the translocator protein (TSPO) and we discuss the valuable insights this has yielded in neurodegenerative diseases. We discuss the limitations of this method and the development of second generation TSPO PET ligands which hope to overcome these limitations. We also discuss other methods of visualizing neuroinflammation and review the state of current dementia treatments targeted at neuroinflammation. It is our view that a multimodal investigation into neuroinflammation in AD, Parkinson's disease dementia, FTD and HD will yield valuable pathological insights which will usefully inform development of therapeutic targets and biomarkers. [ABSTRACT FROM AUTHOR]

T-cell-dependent antigenic stimulation drives the differentiation of B cells into antibody-secreting plasma cells and memory B cells, but how B cells regulate this process is unclear. We show that LKB1 expression in B cells maintains B-cell quiescence and prevents the premature formation of germinal centers ( GCs). Lkb1-deficient B cells ( BKO) undergo spontaneous B-cell activation and secretion of multiple inflammatory cytokines, which leads to splenomegaly caused by an unexpected expansion of T cells. Within this cytokine response, increased IL-6 production results from heightened activation of NF-κB, which is suppressed by active LKB1. Secreted IL-6 drives T-cell activation and IL-21 production, promoting T follicular helper ( TFH) cell differentiation and expansion to support a ~100-fold increase in steady-state GC B cells. Blockade of IL-6 secretion by BKO B cells inhibits IL-21 expression, a known inducer of TFH-cell differentiation and expansion. Together, these data reveal cell intrinsic and surprising cell extrinsic roles for LKB1 in B cells that control TFH-cell differentiation and GC formation, and place LKB1 as a central regulator of T-cell-dependent humoral immunity. [ABSTRACT FROM AUTHOR]

The rewarding properties of some abused drugs are thought to reside in their ability to increase striatal dopamine levels. Similar increases have been shown in response to expectation of a positive drug effect. The actions of opioid drugs on striatal dopamine release are less well characterized. We examined whether heroin and the expectation of heroin reward increases striatal dopamine levels in human opioid addiction. Ten opioid-dependent participants maintained on either methadone or buprenorphine underwent [(11) C]raclopride positron emission tomography imaging. Opioid-dependent participants were scanned three times, receiving reward from 50-mg intravenous heroin (diamorphine; pharmaceutical heroin) during the first scan to generate expectation of the same reward at the second scan, during which they only received 0.1-mg intravenous heroin. There was no heroin injection during the third scan. Intravenous 50-mg heroin during the first scan induced pronounced effects leading to high levels of expectation at the second scan. There was no detectable increase in striatal dopamine levels to either heroin reward or expectation of reward. We believe this is the first human study to examine whether expectation of heroin reward increases striatal dopamine levels in opioid addiction. The absence of detectable increased dopamine levels to both the expectation and delivery of a heroin-related reward may have been due to the impact of substitute medication. It does however contrast with the changes seen in abstinent stimulant users, suggesting that striatal dopamine release alone may not play such a pivotal role in opioid-maintained individuals. [ABSTRACT FROM AUTHOR]

The rewarding properties of some abused drugs are thought to reside in their ability to increase striatal dopamine levels. Similar increases have been shown in response to expectation of a positive drug effect. The actions of opioid drugs on striatal dopamine release are less well characterized. We examined whether heroin and the expectation of heroin reward increases striatal dopamine levels in human opioid addiction. Ten opioid-dependent participants maintained on either methadone or buprenorphine underwent [11 C]raclopride positron emission tomography imaging. Opioid-dependent participants were scanned three times, receiving reward from 50-mg intravenous heroin (diamorphine; pharmaceutical heroin) during the first scan to generate expectation of the same reward at the second scan, during which they only received 0.1-mg intravenous heroin. There was no heroin injection during the third scan. Intravenous 50-mg heroin during the first scan induced pronounced effects leading to high levels of expectation at the second scan. There was no detectable increase in striatal dopamine levels to either heroin reward or expectation of reward. We believe this is the first human study to examine whether expectation of heroin reward increases striatal dopamine levels in opioid addiction. The absence of detectable increased dopamine levels to both the expectation and delivery of a heroin-related reward may have been due to the impact of substitute medication. It does however contrast with the changes seen in abstinent stimulant users, suggesting that striatal dopamine release alone may not play such a pivotal role in opioid-maintained individuals. [ABSTRACT FROM AUTHOR]

ABSTRACT Cognitive decline is common in Parkinson's disease (PD), even in the early motor stage, and this non-motor feature impacts quality of life and prognosis tremendously. In this article, we discuss marker candidates for cognitive decline in PD from different angles, including functional and structural imaging techniques, biological fluid markers in cerebrospinal fluid, and blood genetic predictors, as well as gait as a surrogate marker of cognitive decline. Specifically, imaging-based markers of cognitive impairment in PD include cortical atrophy, reduced cortical metabolism, loss of cortical cholinergic and frontal dopaminergic function, as well as an increased cortical amyloid load. Reduced β-amyloid(1-42) in cerebrospinal fluid and lower plasma levels of epidermal growth factor are predictors for cognitive decline in PD. In addition, genetic variation in the apolipoprotein E ( APOE), catechol-O-methyltransferase ( COMT), microtubule-associated protein tau ( MAPT), and glucocerebrosidase ( GBA) genes may confer risk for cognitive impairment in PD; and gait disturbance may also indicate an increased risk for dementia. Other marker candidates have been proposed and are discussed. All of the current studies are hampered by gaps in our knowledge about the molecular causes of cognitive decline, which will have to be considered in future biomarker studies. © 2014 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

ABSTRACT Nonmotor symptoms (NMS) are common in patients with established Parkinson's disease (PD) and have a major impact upon quality of life. We investigated the significance of NMS in relation to health-related quality of life (HRQoL) in patients with newly diagnosed PD. Patients and healthy controls were recruited as part of the Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation in Parkinson's Disease Study. Prevalence of NMS was determined with the Non-Motor Symptom Questionnaire. HRQoL was recorded with the 39-item Parkinson's Disease Quality of Life Questionnaire (PDQ-39). Further assessments included measures of motor disability, depression, sleep, and cognition. One hundred and fifty-eight patients with newly diagnosed PD and 99 controls participated in this cross-sectional study. Patients reported greater numbers of NMS than controls (mean 8.3 ± 4.3 versus 2.8 ± 2.5 symptoms; P < 0.001). Patients reported lowest HRQoL in the domains assessing bodily discomfort, mobility, and activities of daily living. Motor and nonmotor symptoms impacted negatively upon HRQoL scores. Patients with the postural instability and gait difficulty motor subtype reported worse HRQoL, compared with those with tremor-dominant disease. Depression ( P < 0.001), incomplete bowel emptying ( P < 0.001), anxiety ( P < 0.001), impaired concentration ( P < 0.001), memory complaints ( P < 0.001), and insomnia ( P = 0.001) had the greatest negative impact upon HRQoL. NMS are common in patients with early PD and represent a significant cause of poorer health-related quality of life. Cognitive, neuropsychiatric, and sleep disturbances are particularly associated with reduced well-being. Screening and management of these symptoms should be prioritized at the time of diagnosis. © 2013 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Microglial activation has been found surrounding amyloid plaques and neurofibrillary tangles in brains of Alzheimer's subjects. In‐vivo imaging using 11C‐PBR28 (a marker of translocator protein over expressed in activated microglia) has demonstrated significant correlation between both amyloid (18F‐Flutematemol PET) and tau deposition (18F‐AV1451 PET). However, it is not clear whether tau or amyloid predominantly influence microglial activation. Methods: 11C‐PBR28, 18F‐Flutematemol, 18F‐AV1451 PET scans were performed on clinically diagnosed mild cognitive impairment and Alzheimer's dementia patients (n=20). 90‐120 minute summed 18F‐Flutematemol, 80‐100 minute summed 18F‐AV1451 and 60‐90 minute summed 11C‐PBR28 images were created. Tracer uptake in cerebellar grey matter was then sampled and individual image was divided by cerebellar uptake. The images were then smoothed with 6mm FWHM and analysed. Multiple regression analysis was performed using by VoxelStats package with 11C‐PBR28 as dependent variable, and 18F‐Flutematemol, 18F‐AV1451 and age as independent variable. Correction for multiple comparison was applied based on random field theory. Results: In the current model, amyloid deposition was found to contribute to elevated microglial activation in the posterior part of the brain including bilateral temporal, occipital lobe and posterior cingulate. While tau deposition contributed to neuroinflammation in wide‐spread areas covering bilateral frontal, temporal, parietal, occipital lobe and cingulate cortex. Conclusion: In the current model tau deposition had more unique contribution to microglial activation in MCI and AD cohort, suggesting that tau formation has a stronger association with microglial activation which is independent of amyloid deposition. [ABSTRACT FROM AUTHOR]

Background: Surgical resection is often recommended in adults with intestinal intussusception (AI) because of its potential association with malignancy. We provide a contemporary algorithm for managing AI by focusing on the probability of discovering a lead point. Methods: This is a retrospective study of adult patients with computed tomography (CT)-confirmed intussusception who underwent operative management of AI between 1996 and 2011 at a single academic institution. Results: Sixty-four patients were diagnosed with AI by CT scan and then managed operatively. The incidence of colonic (CI), small bowel (SBI), and retrograde intussusception (RI) was 14, 55, and 31 %, respectively. All patients with CI had a lead point, whereas none were found among patients with RI. Some 46 % of patients with SBI had a lead point. The probability of discovering a lead point in SBI was increased by past history of malignancy (RR, 3.7, p < 0.001), a mass seen on preoperative CT scan (RR, 2.9, p = 0.005), and age over 60 years (RR, 2.2, p = 0.07). Conclusions: A pathologic lead point is likely with CI but not with RI. Patients with SBI who are over the age of 60 years and have a history of malignancy or a mass noted on CT scan have a higher likelihood of harboring a pathologic lead point. [ABSTRACT FROM AUTHOR]

The loss of farmland biodiversity threatens the sustainability of ecosystem services delivered within agricultural landscapes. The functional trait approach has been successfully used in grassland systems to quantify trade-offs and synergies between services delivered directly by plant communities. Many of the services delivered by arable landscapes, however, depend on invertebrate consumers, and the application of the trait-based approach to these systems depends on quantifying functional relationships between trophic levels., Two data sets of plant and invertebrate communities from a range of annual crops and uncropped land habitats were analysed. The community-weighted means of plant functional traits were calculated for the vegetation samples and used as the explanatory variables in a multivariate analysis of plant species composition across habitats. The constrained axes scores were used in statistical models to explain the variance in associated total invertebrate abundance, phytophagous invertebrates and invertebrate numbers weighted by importance in the diet of farmland bird chicks., The multivariate analysis discriminated between plant communities characterized by ruderal traits (high specific leaf area and early flowering) and those with more competitive traits. More ruderal communities also supported proportionally more invertebrates. The suite of traits included in the analysis explained a greater proportion of the variance in invertebrate abundance between uncropped habitats, as opposed to between annual crops., The overlap between the plant traits that respond to disturbance (functional response traits) and those that affect the abundance of phytophagous invertebrates (functional effect traits) and the diet of farmland birds demonstrates the potential for using common functional metrics to integrate the assessment of an ecosystem service across different habitats particularly on uncropped land where intensity of disturbance is the main environmental driver., Synthesis. The quantification of functional linkages between arable plants and the abundance of their associated invertebrate consumer communities is the first step in extending the trait-based approach to quantify trade-offs and synergies between ecosystem services developed in grassland systems to landscapes dominated by arable crops. However, applying the functional approach to in-crop weed communities and other service providers such as pollinators will require the incorporation of additional response and effect traits. [ABSTRACT FROM AUTHOR]

Carabid beetles are important functional components of many terrestrial ecosystems. Here, we describe the first long-term, wide-scale and quantitative assessment of temporal changes in UK carabid communities, to inform nationwide management aimed at their conservation., Multivariate and mixed models were used to assess temporal trends over a 15-year period, across eleven sites in the UK Environmental Change Network. Sites covered pasture, field margins, chalk downland, woodland and hedgerows in the lowlands, moorland and pasture in the uplands, and grassland, heaths and bogs in montane locations., We found substantial overall declines in carabid biodiversity. Three-quarters of the species studied declined, half of which were estimated to be undergoing population reductions of > 30%, when averaged over 10-year periods. Declines of this magnitude are recognized to be of conservation concern. They are comparable to those reported for butterflies and moths and increase the evidence base showing that insects are undergoing serious and widespread biodiversity losses., Overall trends masked differences between regions and habitats. Carabid population declines (10-year trend, averaged across species) were estimated to be 52% in montane sites, 31% in northern moorland sites and 28% in western pasture sites (with at least 80% of species declining in each case). Conversely, populations in our southern downland site had 10-year increases of 48% on average. Overall, biodiversity was maintained in upland pasture, and populations were mostly stable in woodland and hedgerow sites., Synthesis and applications. Our results highlight the need to assess trends for carabids, and probably other widespread and ubiquitous taxa, across regions and habitats to fully understand losses in biodiversity. Land management should be underpinned by a consideration of how wide-scale environmental drivers interact with habitat structure. The stability of population trends in woodlands and hedgerows of species that are declining elsewhere puts these habitats at the fore-front of integrated landscape management aimed at preserving their ecosystem services. [ABSTRACT FROM AUTHOR]

Summary 1. There is an urgent need to accurately model how environmental change affects the wide-scale functioning of ecosystems, but advances are hindered by a lack of knowledge of how trophic levels are linked across space. It is unclear which theoretical approach to take to improve modelling of such interactions, but evidence is gathering that linking species responses to their functional traits can increase understanding of ecosystem dynamics. Currently, there are no quantitative studies testing how this approach might improve models of multiple, trophically interacting species, at wide spatial scales. 2. Arable weeds play a foundational role in linking food webs, providing resources for many taxa, including carabid beetles that feed on their seeds and weed-associated invertebrate prey. Here, we model associations between weeds and carabids across farmland in Great Britain (GB), to test the hypothesis that wide-scale trophic links between these groups are structured by their species functional traits. 3. A network of c. 250 arable fields, covering four crops and most lowland areas of GB, was sampled for weed, carabid and invertebrate taxa over 3 years. Data sets of these groups were closely matched in time and space, and each contained numerous species with a range of eco-physiological traits. The consistency of trophic linkages between multiple taxa sharing functional traits was tested within multivariate and log-linear models. 4. Robust links were established between the functional traits of taxa and their trophic interactions. Autumn-germinating, small-seeded weeds were associated with smaller, spring-breeding carabids, more specialised in seed feeding, whereas spring-germinating, large-seeded weeds were associated with a range of larger, autumn-breeding omnivorous carabids. These relationships were strong and dynamic, being independent of changes in invertebrate food resources and consistent across sample dates, crops and regions of GB. 5. We conclude that, in at least one system of interacting taxa, functional traits can be used to predict consistent, wide-scale trophic links. This conceptual approach is useful for assessing how perturbations affecting lower trophic levels are ramified throughout ecosystems and could be used to assess how environmental change affects a wider range of secondary consumers. [ABSTRACT FROM AUTHOR]

Objective: Patient outcome after traumatic brain injury (TBI) is highly variable. The underlying pathophysiology of this is poorly understood, but inflammation is potentially an important factor. Microglia orchestrate many aspects of this response. Their activation can be studied in vivo using the positron emission tomography (PET) ligand [11C](R)PK11195 (PK). In this study, we investigate whether an inflammatory response to TBI persists, and whether this response relates to structural brain abnormalities and cognitive function. Methods: Ten patients, studied at least 11 months after moderate to severe TBI, underwent PK PET and structural magnetic resonance imaging (including diffusion tensor imaging). PK binding potentials were calculated in and around the site of focal brain damage, and in selected distant and subcortical brain regions. Standardized neuropsychological tests were administered. Results: PK binding was significantly raised in the thalami, putamen, occipital cortices, and posterior limb of the internal capsules after TBI. There was no increase in PK binding at the original site of focal brain injury. High PK binding in the thalamus was associated with more severe cognitive impairment, although binding was not correlated with either the time since the injury or the extent of structural brain damage. Interpretation: We demonstrate that increased microglial activation can be present up to 17 years after TBI. This suggests that TBI triggers a chronic inflammatory response particularly in subcortical regions. This highlights the importance of considering the response to TBI as evolving over time and suggests interventions may be beneficial for longer intervals after trauma than previously assumed. ANN NEUROL 2011; [ABSTRACT FROM AUTHOR]

Graft-induced dyskinesias are a serious complication after neural transplantation in Parkinson's disease. One patient with Parkinson's disease, treated with fetal grafts 14 years ago and deep brain stimulation 6 years ago, showed marked improvement of motor symptoms but continued to suffer from OFF-medication graft-induced dyskinesias. The patient received a series of clinical and imaging assessments. Positron emission tomography and single-photon emission computed tomography 14 years posttransplantation revealed an elevated serotonin/dopamine transporter ratio in the grafted striatum compatible with serotonergic hyperinnervation. Inhibition of serotonin neuron activity by systemic administration of a 5-HT1A agonist suppressed graft-induced dyskinesias. Our data provide further evidence that serotonergic neurons mediate graft-induced dyskinesias in Parkinson's disease. Achieving a normal striatal serotonin/dopamine transporter ratio following transplantation of fetal tissue or stem cells should be necessary to avoid the development of graft-induced dyskinesias. © 2011 Movement Disorder Society [ABSTRACT FROM AUTHOR]

1. Assuring future food productivity and security will require that better use is made of pest regulation provided by naturally occurring ecological services. However, empirical evidence of large-scale regulatory effects that might be employed in agriculture is still relatively scarce. 2. Using data from 257 conventionally managed arable fields at the UK national scale, we examine whether changes in the long-term store of weed seed in the seedbank are consistent with regulation by seed predatory carabid beetles. 3. We test three expectations of a simple conceptual model for carabid seed predation. The relationships we estimate are consistent with the model and suggest that carabid predation of weed seeds shed onto the soil surface changes the amount of seed returned to the seedbank bringing about seedbank change and regulation. 4. Granivorous and omnivorous carabids regulated seedbank abundance, with effects being observed on monocotyledon seedbank abundance, in all crops, and on total seedbank abundance, in spring maize and winter oilseed rape; effects that were robust across fields with differing pesticide management and between regions of the UK. 5. We found evidence of density dependence, with increasing amounts of seed rain leading to stronger regulation of the seedbank. 6. Our results also suggest that correlations between seed predators and seed rain abundance, which might be used to infer important effects of seed predators, do not provide sufficient evidence to indicate regulation of the weed seedbank. 7. Synthesis and applications. A major challenge for the future is to manage ecological, pest control services in place of current pesticides with little or no additional risk to productivity and food security. Our work shows that carabid seed predators have regulatory effects on the seedbank that appear general and robust across a range of current cropping and farm management situations at the national scale. Environmental Stewardship methods already exist across Europe to enhance carabid numbers in farmland. This means that carabid seed predators fit within a working framework that could be used to promote integrated pest management alongside or even in place of herbicides. [ABSTRACT FROM AUTHOR]

In the last 25 years there have been enormous advances in brain imaging. In addition to utility in diagnosis, these have led to novel insights into the pathogenesis of basal ganglia disease and the role of dopamine and the basal ganglia in normal health. The authors review highlights of this work, with a focus on advances in Parkinson's disease, the dystonias, Huntington's disease, and the role of dopamine in cognition and reward signaling. Emerging areas for future development include studies of functional connectivity, the analysis of default mode networks, studies of novel neurochemical pathways, methods to study disease pathogenesis, and the application of imaging techniques to investigate animal models of disease. © 2011 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is an inherited neurodegenerative disorder associated with motor, cognitive and psychiatric deficits. This study, using a multimodal imaging approach, aims to assess in vivo the functional and structural integrity of regions and regional networks linked with motor, cognitive and psychiatric function. Predicting disease onset in at risk individuals is problematic and thus we sought to investigate this by computing the 5-year probability of HD onset (p5 HD) and relating it to imaging parameters. Using MRI, 11C-PK11195 and 11C-raclopride PET, we have investigated volumes, levels of microglial activation and D2/D3 receptor binding in CAG repeat-matched groups of premanifest and symptomatic HD gene carriers. Findings were correlated with disease-burden and UHDRS scores. Atrophy was detected in sensorimotor striatum (SMST), substantia nigra, orbitofrontal and anterior prefrontal cortex in the premanifest HD. D2/D3 receptor binding was reduced and microglial activation increased in SMST and associative striatum (AST), bed nucleus of the stria terminalis, the amygdala and the hypothalamus. In symptomatic HD cases this extended to involve atrophy in globus pallidus, limbic striatum, the red nuclei, anterior cingulate cortex, and insula. D2/D3 receptor binding was additionally reduced in substantia nigra, globus pallidus, limbic striatum, anterior cingulate cortex and insula, and microglial activation increased in globus pallidus, limbic striatum and anterior prefrontal cortex. In premanifest HD, increased levels of microglial activation in the AST and in the regional network associated with cognitive function correlated with p5 HD onset. These data suggest that pathologically activated microglia in AST and other areas related to cognitive function, maybe better predictors of clinical onset and stresses the importance of early cognitive assessment in HD. Hum Brain Mapp, 2011. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Objective The most widely studied positron emission tomography ligand for in vivo β-amyloid imaging is 11C-Pittsburgh compound B (11C-PIB). Its availability, however, is limited by the need for an on-site cyclotron. Validation of the 18F-labeled PIB derivative 18F-flutemetamol could significantly enhance access to this novel technology. Methods Twenty-seven patients with early-stage clinically probable Alzheimer disease (AD), 20 with amnestic mild cognitive impairment (MCI), and 15 cognitively intact healthy volunteers (HVs) above and 10 HVs below 55 years of age participated. The primary endpoint was the efficacy of blinded visual assessments of 18F-flutemetamol scans in assigning subjects to a raised versus normal uptake category, with clinical diagnosis as the standard of truth (SOT). As secondary objectives, we determined the correlation between the regional standardized uptake value ratios (SUVRs) for 18F-flutemetamol and its parent molecule 11C-PIB in 20 of the AD subjects and 20 of the MCI patients. We also determined test-retest variability of 18F-flutemetamol SUVRs in 5 of the AD subjects. Results Blinded visual assessments of 18F-flutemetamol scans assigned 25 of 27 scans from AD subjects and 1 of 15 scans from the elderly HVs to the raised category, corresponding to a sensitivity of 93.1% and a specificity of 93.3% against the SOT. Correlation coefficients between cortical 18F-flutemetamol SUVRs and 11C-PIB SUVRs ranged from 0.89 to 0.92. Test-retest variabilities of regional SUVRs were 1 to 4%. Interpretation 18F-Flutemetamol performs similarly to the 11C-PIB parent molecule within the same subjects and provides high test-retest replicability and potentially much wider accessibility for clinical and research use. ANN NEUROL 2010 [ABSTRACT FROM AUTHOR]

Objective: To compare the recovery of mobility and self-care functions among veteran amputees according to the timing and type of rehabilitation services received. Design: Observational study of inpatient rehabilitation care patterns of 2 types (specialized and consultative) with 2 timings (early and late). Setting: Data from inpatient specialized rehabilitation units (SRUs) and consultative services within 95 Veterans Affairs Medical Centers across the United States during fiscal years 2003 to 2004. Patients: Medical records of 1502 patients who received early or late consultative or specialized rehabilitation. Assessment of Risk Factors: Hypotheses were established and general categories of negative and positive risk factors specified a priori from available clinical characteristics. Linear mixed effects models were used to model motor Functional Independence Measure (FIM) gain scores on patient-level variables accounting for the correlation within the same facility. Main Outcome Measures: Recovery of activities of daily living (ADLs) and mobility (physical functioning) expressed as the magnitudes of gains in motor FIM scores achieved by rehabilitation discharge. Results: After adjustment, amputees who received specialized rehabilitation had motor FIM gains that were on average 8.0 points greater than those for amputees who received consultative rehabilitation. Although patients whose rehabilitation was delayed until after discharge from the index surgical stay tended to be more clinically complex, they had gains comparable to those of patients who received early rehabilitation. Advanced age, transfemoral amputation, paralysis, serious nutritional compromise, and psychosis were associated with lower motor FIM gains. The variance for the random effect for facility was statistically significant, suggesting extraneous variation within facility that was not explainable by observed patient-level variables. Conclusion: On the basis of this analysis, those patients who receive specialized rehabilitation can be expected to make comparatively greater gains than patients who receive consultative services, regardless of timing and clinical complexity. Findings highlight the need for clinicians to adjust prognostic expectations to both clinical severity and the type of rehabilitation that patients receive. [Copyright &y& Elsevier]