Patricia Vázquez Rodríguez

Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures

Recent studies indicate that selective noradrenergic (atomoxetine) and serotonergic (citalopram) reuptake inhibitors may improve response inhibition in selected patients with Parkinsons disease, restoring behavioral performance and brain activity. We reassessed the behavioral efficacy of these drugs in a larger cohort and developed predictive models to identify patient responders. We used a double‐blind randomized three‐way crossover design to investigate stopping efficiency in 34 patients with idiopathic Parkinsons disease after 40 mg atomoxetine, 30 mg citalopram, or placebo. Diffusion‐weighted and functional imaging measured microstructural properties and regional brain activations, respectively. We confirmed that Parkinsons disease impairs response inhibition. Overall, drug effects on response inhibition varied substantially across patients at both behavioral and brain activity levels. We therefore built binary classifiers with leave‐one‐out cross‐validation (LOOCV) to predict patients’ responses in terms of improved stopping efficiency. We identified two optimal models: (1) a “clinical” model that predicted the response of an individual patient with 77–79% accuracy for atomoxetine and citalopram, using clinically available information including age, cognitive status, and levodopa equivalent dose, and a simple diffusion‐weighted imaging scan; and (2) a “mechanistic” model that explained the behavioral response with 85% accuracy for each drug, using drug‐induced changes of brain activations in the striatum and presupplementary motor area from functional imaging. These data support growing evidence for the role of noradrenaline and serotonin in inhibitory control. Although noradrenergic and serotonergic drugs have highly variable effects in patients with Parkinsons disease, the individual patients response to each drug can be predicted using a pattern of clinical and neuroimaging features. Hum Brain Mapp 37:1026–1037, 2016.

Atomoxetine restores the response inhibition network in Parkinson’s disease

Impairments in response inhibition in Parkinson’s disease may reflect loss of noradrenaline and impaired fronto-subcortical connectivity. Rae et al. show that the noradrenaline reuptake inhibitor atomoxetine can restore functional connectivity in the inhibition network. Individual treatment responses depend on disease severity, plasma drug concentration and anatomical connectivity within the network.

Atomoxetine Enhances Connectivity of Prefrontal Networks in Parkinson’s Disease

Cognitive impairment is common in Parkinson’s disease (PD), but often not improved by dopaminergic treatment. New treatment strategies targeting other neurotransmitter deficits are therefore of growing interest. Imaging the brain at rest (‘task-free’) provides the opportunity to examine the impact of a candidate drug on many of the brain networks that underpin cognition, while minimizing task-related performance confounds. We test this approach using atomoxetine, a selective noradrenaline reuptake inhibitor that modulates the prefrontal cortical activity and can facilitate some executive functions and response inhibition. Thirty-three patients with idiopathic PD underwent task-free fMRI. Patients were scanned twice in a double-blind, placebo-controlled crossover design, following either placebo or 40-mg oral atomoxetine. Seventy-six controls were scanned once without medication to provide normative data. Seed-based correlation analyses were used to measure changes in functional connectivity, with the right inferior frontal gyrus (IFG) a critical region for executive function. Patients on placebo had reduced connectivity relative to controls from right IFG to dorsal anterior cingulate cortex and to left IFG and dorsolateral prefrontal cortex. Atomoxetine increased connectivity from the right IFG to the dorsal anterior cingulate. In addition, the atomoxetine-induced change in connectivity from right IFG to dorsolateral prefrontal cortex was proportional to the change in verbal fluency, a simple index of executive function. The results support the hypothesis that atomoxetine may restore prefrontal networks related to executive functions. We suggest that task-free imaging can support translational pharmacological studies of new drug therapies and provide evidence for engagement of the relevant neurocognitive systems.

Tau burden and the functional connectome in Alzheimer’s disease and progressive supranuclear palsy

Prion-like, trans-neuronal spread of tau pathology in humans is controversial. By evaluating tau burden and functional connectivity in living patients, Cope et al. demonstrate relationships consistent with this in Alzheimers disease but not progressive supranuclear palsy. Tau distribution in the latter is better explained by metabolic demand and trophic support.

Neuroimaging of Inflammation in Memory and Related Other Disorders (NIMROD) study protocol: a deep phenotyping cohort study of the role of brain inflammation in dementia, depression and other neurological illnesses

Introduction Inflammation of the central nervous system is increasingly regarded as having a role in cognitive disorders such as dementia and depression, but it is not clear how such inflammation relates to other aspects of neuropathology, structural and functional changes in the brain and symptoms (as assessed via clinical and neuropsychological assessment and MRI). This study will explore these pathophysiological mechanisms using positron emission tomography (PET) which allows in vivo imaging of inflammation, amyloid and τ deposition, together with neuropsychological profiling, MRI and peripheral biomarker analysis. Methods and analysis Using PET imaging of the ligand [11C]PK11195, we will test for increased neuroinflammation in vivo in patients with Alzheimers disease, Lewy body dementia, frontotemporal dementia, progressive supranuclear palsy, late-onset depression and mild cognitive impairment, when compared to healthy controls. We will assess whether areas of inflammatory change are associated with amyloid and τ deposition (assessed using 11C-labelled Pittsburgh Compound B ([11C]PiB) and 18F-labelled AV-1451, respectively), as well as structural and connectivity markers found on MRI. Inflammatory biomarker analysis and immune-phenotyping of peripheral blood monocytes will determine the correlation between central inflammation and peripheral inflammation. Finally, we will examine whether central inflammatory markers seen on PET imaging are associated with global and domain specific cognitive impairments or predict cognitive decline over 12 months. Ethics and dissemination The study protocol was approved by the local ethics committee, East of England—Cambridge Central Research Ethics Committee (reference: 13/EE/0104). The study is also Administration of Radioactive Substances Advisory Committee (ARSAC) approved as part of this process. Data will be disseminated by presentation at national and international conferences and by publication, predominantly in journals of clinical neuroscience, neurology and psychiatry.

Multi-modal MRI investigation of volumetric and microstructural changes in the hippocampus and its subfields in mild cognitive impairment, Alzheimer's disease, and dementia with Lewy bodies

Background: Volumetric atrophy and microstructural alterations in diffusion tensor imaging (DTI) measures of the hippocampus have been reported in people with Alzheimers disease (AD) and mild cognitive impairment (MCI). However, no study to date has jointly investigated concomitant microstructural and volumetric changes of the hippocampus in dementia with Lewy bodies (DLB). Methods: A total of 84 subjects (23 MCI, 17 DLB, 14 AD, and 30 healthy controls) were recruited for a multi-modal imaging (3T MRI and DTI) study that included neuropsychological evaluation. Freesurfer was used to segment the total hippocampus and delineate its subfields. The hippocampal segmentations were co-registered to the mean diffusivity (MD) and fractional anisotropy (FA) maps obtained from the DTI images. Results: Both AD and MCI groups showed significantly smaller hippocampal volumes compared to DLB and controls, predominantly in the CA1 and subiculum subfields. Compared to controls, hippocampal MD was elevated in AD, but not in MCI. DLB was characterized by both volumetric and microstructural preservation of the hippocampus. In MCI, higher hippocampal MD was associated with greater atrophy of the hippocampus and CA1 region. Hippocampal volume was a stronger predictor of memory scores compared to MD within the MCI group. Conclusions: Through a multi-modal integration, we report novel evidence that the hippocampus in DLB is characterized by both macrostructural and microstructural preservation. Contrary to recent suggestions, our findings do not support the view that DTI measurements of the hippocampus are superior to volumetric changes in characterizing group differences, particularly between MCI and controls.

Erratum: Atomoxetine Enhances Connectivity of Prefrontal Networks in Parkinson’s Disease

Correction to: Neuropsychopharmacology advance online publication, 2 March 2016; doi:10.1038/npp.2016.18 Following the publication of this paper, the authors have changed the Funding and Disclosure section to read as follows: This work was funded by the Wellcome trust (103838), Parkinson’s UK, National Institute for Health Research’s Cambridge Biomedical Research Centre and the Medical Research Council (MC_US_A060_0016 and RG62761), and the James F McDonnell Foundation (21st century science initiative on Understanding Human Cognition).

In vivo coupling of tau pathology and cortical thinning in Alzheimer's disease

The deposition of neurofibrillary tangles in neurodegenerative disorders is associated with neuronal loss on autopsy; however, their in vivo associations with atrophy across the continuum of Alzheimers disease (AD) remain unclear.

INVESTIGATE THE RELATIONSHIP BETWEEN TAU AND NEUROINFLAMMATION IN ALZHEIMER’S DISEASE USING PET AND REACTION RATE MODELLING

in CBD was distinctly different from patterns in controls or patients with AD or PSP. Cortical atrophy measured with MRI was much more widespread than the cortical retention of F-AV1451 in CBD, and cortical AV-1451 uptake did not correlate with cortical thickness or glucose hypometabolism. These results were in sharp contrast to AD, where F-AV-1451 retention was more widespread than cortical atrophy and correlated well with cortical thickness and hypometabolism. Conclusions: Patients with CBD exhibited AV-1451 uptake in the motor cortex, corticospinal tract and basal ganglia contralateral to the affected body side, clearly different from controls and patients with AD or PSP. However, decreased F-Fluorodeoxyglucose (FDG) uptake and cortical atrophy, assessed with MRI, were more widespread than F-AV-1451 uptake and probably represent earlier, yet less specific, markers of pathology.

[ 18 F]AV-1451 PET IMAGING OF TAU PATHOLOGY PREDICTS WHITE MATTER HYPERINTENSITIES IN HEALTHY AGING, MILD COGNITIVE IMPAIRMENT AND ALZHEIMER'S DISEASE: THE NIMROD STUDY

and retrospective neuropsychological data from all patients were collected to investigate the retrospective cognitive decline. A linear mixed effects model was used to determine the effects of amyloid, tau, and vascular burden on cognitive decline independently or synergistically. Results: Mean follow-up periods were 4.38 years. Higher amyloid burden was associated with faster cognitive decline in attention, language, visuospatial, memory, frontal functions. Patients with tau braak stage 3 showed faster cognitive decline in all cognitive domains, not in memory function compared to patients with tau braak stage 2, whereas higher vascular burden was associated with faster decline only in calculation score. Significant interactions between amyloid and tau burden were found to be associated with faster decline in all cognitive domains, tau and vascular burden in attention, frontal and visuospatial function, amyloid and vascular burden in COWAT supermarket and calculation score. Amyloid, tau, and vascular burdens also synergistically affected attention, visuospatial and frontal functions. Conclusions: In SVCI patients, amyloid, tau and vascular burden, independently or interactively, contributed to longitudinal cognitive decline. Especially, amyloid and tau burden rather than vascular burden are more associated with cognitive decline.