Cognitive decline is a common feature of Parkinson’s disease, and many of these cognitive deficits fail to respond to dopaminergic therapy. Therefore, targeting other neuromodulatory systems represents an important therapeutic strategy. Among these, the locus coeruleus-noradrenaline system has been extensively implicated in response inhibition deficits. Restoring noradrenaline levels using the noradrenergic reuptake inhibitor atomoxetine can improve response inhibition in some patients with Parkinson’s disease, but there is considerable heterogeneity in treatment response. Accurately predicting the patients who would benefit from therapies targeting this neurotransmitter system remains a critical goal, in order to design the necessary clinical trials with stratified patient selection to establish the therapeutic potential of atomoxetine. Here, we test the hypothesis that integrity of the noradrenergic locus coeruleus explains the variation in improvement of response inhibition following atomoxetine. In a double-blind placebo-controlled randomised crossover design, 19 people with Parkinson’s disease completed an acute psychopharmacological challenge with 40 mg of oral atomoxetine or placebo. A stop-signal task was used to measure response inhibition, with stop-signal reaction times obtained through hierarchical Bayesian estimation of an ex-Gaussian race model. Twenty-six control subjects completed the same task without undergoing the drug manipulation. In a separate session, patients and controls underwent ultra-high field 7 T imaging of the locus coeruleus using a neuromelanin-sensitive magnetisation transfer sequence. The principal result was that atomoxetine improved stop-signal reaction times in those patients with lower locus coeruleus integrity. This was in the context of a general impairment in response inhibition, as patients on placebo had longer stop-signal reaction times compared to controls. We also found that the caudal portion of the locus coeruleus showed the largest neuromelanin signal decrease in the patients compared to controls. Our results highlight a link between the integrity of the noradrenergic locus coeruleus and response inhibition in Parkinson’s disease patients. Furthermore, they demonstrate the importance of baseline noradrenergic state in determining the response to atomoxetine. We suggest that locus coeruleus neuromelanin imaging offers a marker of noradrenergic capacity that could be used to stratify patients in trials of noradrenergic therapy and to ultimately inform personalised treatment approaches.

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Hemiparkinsonism duration in patients with Parkinson's disease (PD) is a key time window to study early pathology of PD. We aimed to comprehensively explore the alterations of deformation and structural network in PD patients with hemiparkinsonism, which could potentially disclose the early biomarker for PD. Thirty-one PD patients with hemiparkinsonism and 37 age- and gender- matched normal controls were included in the present study. First of all, we normalized the left hemisphere of structural images as the contralateral side to the affected limbs. Deformation-based morphometry (DBM) was conducted to evaluate the brain atrophy and/or enlargement. structural networks were constructed by thresholding gray matter volume correlation matrices of 116 regions and analyzed using graph theoretical approaches (e.g., small-worldness, global, and nodal measures). Significantly decreased deformation values were observed in the temporoparietal regions like bilateral middle temporal gyri, ipsilateral precuneus and contralateral Rolandic operculum extending to supramarginal and postcentral gyri. Lower deformation values in contralateral middle temporal gyrus were negatively correlated with higher motor impairment which was dominated by akinesia/rigidity. Moreover, nodal reorganization of structural network mainly located in frontal, temporal, subcortex and cerebellum was bilaterally explored in PD patients with hemiparkinsonism. Increased nodal properties could be commonly observed in frontal lobes. Disruption of subcortex including basal ganglia and amygdala was detected by nodal local efficiency and nodal clustering coefficient. Twelve hubs, mainly from paralimbic-limbic and heteromodal networks, were disrupted and, alternatively, 14 hubs, most of which were located in frontal lobes, were additionally detected in PD patients with hemiparkinsonism. In conclusion, during hemiparkinsonism period, mild brain atrophy in the temporoparietal regions and widespread reorganization of structural network, e.g., enhanced frontal function and disruption of basal ganglia nodes, occurred in both hemispheres. With our data, we can also argue that MTG contralateral to the affected limbs (expressing clinically verified brain atrophy) might be a potential living biomarker to monitor disease progression. Therefore, the combination of DBM and structural network analyses can provide a comprehensive and sensitive evaluation for potential pathogenesis of early PD patients with hemiparkinsonism.

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Renin-angiotensin system-targeting antihypertensive drugs may be a potential treatment for reducing the incidence and progression of AD. Further studies on RAS-targeting antihypertensive drugs, especially large randomised clinical trials, should be conducted in the future.

Pramipexole ER is as safe and effective as pramipexole IR in the treatment of Parkinson's disease.

ObjectiveTo develop imaging biomarkers of diseases in the Lewy body spectrum and to validate these markers against postmortem neuropathologic findings.MethodsFour cognitively normal participants with Parkinson disease (PD), 4 with PD with cognitive impairments, and 10 with dementia with Lewy bodies underwent amyloid imaging with [11C]Pittsburgh compound B (PiB) and dopamine transporter (DAT) imaging with [11C]Altropane. All 18 had annual neurologic examinations. All cognitively normal participants with PD developed cognitive impairment before death. Neuropathologic examinations assessed and scored Braak Lewy bodies, Thal distribution of amyloid, Consortium to Establish a Registry for Alzheimer's Disease neuritic amyloid plaques, Braak neurofibrillary tangles, and cerebral amyloid angiopathy, as well as total amyloid plaque burden in the superior frontal, superior parietal, occipital, and inferior temporal cortical regions. PET data were expressed as the standardized uptake value ratio with cerebellar reference. Analyses accounted for the interval between imaging and autopsy.ResultsAll 18 patients met neuropathologic criteria for Lewy body disease; the DAT concentration was low in each case. All patients with elevated [11C]PiB retention measured in a neocortical aggregate had β-amyloid deposits at autopsy. [11C]PiB retention significantly correlated with neuritic plaque burden and with total plaque burden. [11C]PiB retention also significantly correlated with the severity of both Braak stages of neurofibrillary tangle and Lewy body scores. Neuritic plaque burden was significantly associated with neurofibrillary tangle pathology.ConclusionAntemortem [11C]Altropane PET is a sensitive measure of substantia nigra degeneration. [11C]PiB scans accurately reflect cortical amyloid deposits seen at autopsy. These findings support the use of molecular imaging in the evaluation of patients with Lewy body diseases.

ObjectiveEpidemiological studies have investigated the association between Parkinson disease (PD) occurrence and the risk of brain tumors, while the results remain controversial. We performed a meta-analysis to clarify the exact relationship between PD and brain tumors.MethodsA systematic literature search was conducted using PubMed, Embase, ScienceDirect and CBM (China Biology Medicine Disc) before February 2016. Eligible studies were those that reported risk estimates of brain tumors among patients with PD or vice versa. A random-effects model was used to calculate the pooled odds ratio (OR) of the outcomes. Subgroup analyses and sensitivity analysis were conducted to explore the potential sources of heterogeneity.ResultsIn total, eight studies involving 329,276 participants met our inclusion criteria. The pooled OR was 1.51 (95%CI 1.21–1.89), indicating that PD carried a higher risk of brain tumor. Analyses by temporal relationship found that the occurrence of brain tumor was significantly higher after the diagnosis of PD (OR 1.55, 95% CI 1.18–2.05), but not statistically significant before PD diagnosis (OR 1.21, 95%CI 0.93–1.58). Subgroup analysis showed that gender differences, ethnicity differences and the characteristic of the tumor (benign or malignant) did not make much change in the association between brain tumor and PD.ConclusionsOur meta-analysis collecting epidemiological studies suggested a positive association of PD with brain tumors, while the influence of anti-parkinson drugs and ascertainment bias could not be excluded. Further studies with larger sample size and more strict inclusion criteria should be conducted in the future.