Neurotransmitter deficits from frontotemporal lobar degeneration.

Frontotemporal lobar degeneration causes a spectrum of complex degenerative disorders including frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome, each of which is associated with changes in the principal neurotransmitter systems. We review the evidence for these neurochemical changes and propose that they contribute to symptomatology of frontotemporal lobar degeneration, over and above neuronal loss and atrophy. Despite the development of disease-modifying therapies, aiming to slow neuropathological progression, it remains important to advance symptomatic treatments to reduce the disease burden and improve patients' and carers' quality of life. We propose that targeting the selective deficiencies in neurotransmitter systems, including dopamine, noradrenaline, serotonin, acetylcholine, glutamate and gamma-aminobutyric acid is an important strategy towards this goal. We summarize the current evidence-base for pharmacological treatments and suggest strategies to improve the development of new, effective pharmacological treatments

Co‐occurrence of apathy and impulsivity in progressive supranuclear palsy

Background: Apathy and impulsivity are common consequences of progressive supranuclear palsy (PSP) and can worsen its prognosis. They can co-exist in the same patients although their concomitant prevalence remains unclear. Their relationship to emotional lability is also unknown. Objectives: To estimate the co-occurrence of apathy and impulsivity and their relationship to emotional lability in PSP. To characterize the demographic, clinical, and cognitive features of PSP patients with apathy and impulsivity. Methods: In a retrospective study of a long-term clinical cohort, we assessed the prevalence of apathy, impulsivity, and emotional lability from clinical interviews, medical records, and contemporary carer questionnaires. 154 patients with a diagnosis of probable or possible PSP (according to the 2017 Movement Disorder Society criteria) were identified. 64 of these patients had neuropathological confirmation of PSP. PSP patients with both apathy and impulsivity were compared in terms of demographic, clinical, and cognitive characteristics to PSP patients with either one or neither of these neuropsychiatric features. Results: Apathy and impulsivity co-existed in two-thirds of people with PSP. A fifth displayed emotional lability in addition to apathy and impulsivity. Apathy and impulsivity were more commonly co-expressed than by chance. There was no single demographic, clinical or cognitive feature that distinguished between PSP patients with versus without apathy and impulsivity. Conclusions: The co-existence of apathy and impulsivity in PSP suggests that these neuropsychiatric features may share similar risk factors and etio-pathogenetic mechanisms. Apathy and impulsivity should be jointly assessed when planning symptomatic treatments for detrimental behavioural problems caused by PSP.This study was co-funded by the Cambridge University Centre for Parkinson-Plus (RG95450) and the Medical Research Council (RG91365). The Cambridge Brain Bank is supported by the NIHR Cambridge Biomedical Research Centre. The authors also declare that there are no conflicts of interest relevant to this wor

Clinical progression of progressive supranuclear palsy: impact of trials bias and phenotype variants.

Funder: Cambridge Brain BankProgressive supranuclear palsy causes diverse clinical presentations, including classical Richardson's syndrome and several variant phenotypes. Clinical trials of disease-modifying therapies have recently been completed, with more planned for the next 2 years. However, many people with progressive supranuclear palsy do not meet eligibility criteria for these clinical trials. Understanding clinical progression with different phenotypes would improve trial design and enhance the accuracy of risk-benefit and cost-benefit assessments of new treatments for progressive supranuclear palsy. We set out to determine rates of motor and cognitive progression of possible, probable and definite progressive supranuclear palsy, with different phenotypes, from a representative cohort in a regional UK healthcare service. Longitudinal clinical data from people with Richardson's syndrome and variant phenotypes were analysed using linear mixed-modelling, using both the full and modified versions of the Progressive Supranuclear Palsy Rating Scale, Mini-Mental State Examination and the revised Addenbrooke's Cognitive Examination. Subgroup analyses considered patients meeting recent Phase II trial entry criteria and patients with neuropathological confirmation. Two hundred and twenty-seven patients [male = 59%, mean age (±standard deviation), 71.8 (±7.0) years] were followed for a mean 21.6 (±15.6) months. One hundred and seventy-four (77%) had Richardson's syndrome at the outset, 25 had cortical variant presentations (13%, frontal, corticobasal, speech and language variants) and 28 had subcortical variant presentations (14%, parkinsonism, postural instability and gait freezing variants). Across all participants, annual progression in Richardson's syndrome was faster than variant phenotypes on the Mini-Mental State Examination (-1.8 versus -0.9/year, P = 0.005) and revised Addenbrooke's Cognitive Examination (-5.3 versus -3.0/year, P = 0.01) but not the Progressive Supranuclear Palsy Rating Scale (9.0 versus 7.1/year, P = 0.2) nor the modified Progressive Supranuclear Palsy Rating Scale (2.7 versus 2.3/year, P = 0.4). However, for those with more than 1 years' follow-up, a significant difference was observed between Richardson's syndrome and variant phenotypes in Progressive Supranuclear Palsy Rating Scale (8.7 versus 6.3/year, P = 0.04). Survival was longer in variant phenotypes than Richardson's syndrome [7.3 (±3.9) versus 5.6 (±2.0) years, P = 0.02]. Pathologically confirmed cases (n = 49) supported these findings. Patients meeting basic trial-eligibility criteria (n = 129) progressed faster on the Progressive Supranuclear Palsy Rating Scale than trial-not-eligible patients (10.1 versus 6.1/year, P = 0.001). In conclusion, phenotypes other than Richardson's syndrome show slower progression and longer survival. Trial criteria do not select representative progressive supranuclear palsy cases. This has implications for trial design, and application of trial results to clinically more diverse patient populations

Building Strong for Tomorrow: Recommendations for the Organizational Design of the NOAA Climate Service

The U.S. Congress asked an expert panel of the National Academy of Public Administration to assist NOAA with a study and analysis of organizational options for a Climate Service within NOAA. Further, NOAA formally asked the Panel to provide an independent assessment of how NOAA should organize its climate capabilities and make recommendations for a Climate Service line office structure that would integrate NOAA's climate science and research with service delivery.Main FindingsThe Panel strongly supports the creation of a Climate Service to be established as a line office within NOAA.The Panel concluded that a NOAA Climate Service, properly configured and implemented, would be uniquely qualified to serve the public and private sectors as a lead federal agency for climate research and services, and to provide an ongoing accessible, authoritative clearinghouse for all federal science and services related to climate.The report also includes the Panel's observations and recommendations regarding the larger federal climate enterprise, key elements of support needed by the NOAA Climate Service and the importance to the new organization of a clear strategic plan and a comprehensive implementation plan. Additionally, the Panel offered observations about institutional change management in the federal sector, identified several management recommendations for implementation and addressed operational priorities and budget challenges

Yield response of corn and grain sorghum to row offsets on subsurface drip laterals

Subsurface drip irrigation (SDI) is a micro-irrigation system that could be adopted by producers in the semi-arid regions around the world for efficient use of water. Yet, several crop management issues related to SDI system need to be addressed to assess the feasibility of SDI. One such issue is the impact of crop row placement on crop performance, irrigation water use efficiency and yield under SDI. A study was conducted in the Southern U.S. Great Plains, in which drip tape laterals were buried 30 cm deep at 153 cm spacing, with two crop rows planted at 76 cm spacing, and irrigated with one tape. Corn (Zea mays L.) and grain sorghum (Sorghum bicolor L.) rows were offset from equidistance from the drip tape by 0, 8, 15, 23, and 38 cm using high precision guidance system (real time kinematics). This resulted in 5 treatments and 4 replications. This treatment structure was imposed on three irrigation (high, medium and low) regimes. Analysis of Variance showed no interaction between offset treatments and irrigation or year in corn and grain sorghum yields. The row offset did not impact the overall yield as the yield loss in row farther from the tape was compensated by the increased yield in row moved closer to the tape. The yield distribution ranged from 50% in both rows for 0 cm offset to 59% in row closer to the tape for 38 cm offset. The findings of this study suggests that while driver accuracy is important to maintain equal yields in neighboring crop rows, the overall yields are affected more by irrigation and climatic conditions and not by the row offsets with respect to SDI tape. This data suggests that SDI can be successful regardless of access to high precision guidance systems.Peer reviewedPlant and Soil Science

GABA-ergic Dynamics in Human Frontotemporal Networks Confirmed by Pharmaco-Magnetoencephalography.

To bridge the gap between preclinical cellular models of disease and in vivo imaging of human cognitive network dynamics, there is a pressing need for informative biophysical models. Here we assess dynamic causal models (DCM) of cortical network responses, as generative models of magnetoencephalographic observations during an auditory oddball roving paradigm in healthy adults. This paradigm induces robust perturbations that permeate frontotemporal networks, including an evoked 'mismatch negativity' response and transiently induced oscillations. Here, we probe GABAergic influences in the networks using double-blind placebo-controlled randomized-crossover administration of the GABA reuptake inhibitor, tiagabine (oral, 10 mg) in healthy older adults. We demonstrate the facility of conductance-based neural mass mean-field models, incorporating local synaptic connectivity, to investigate laminar-specific and GABAergic mechanisms of the auditory response. The neuronal model accurately recapitulated the observed magnetoencephalographic data. Using parametric empirical Bayes for optimal model inversion across both drug sessions, we identify the effect of tiagabine on GABAergic modulation of deep pyramidal and interneuronal cell populations. We found a transition of the main GABAergic drug effects from auditory cortex in standard trials to prefrontal cortex in deviant trials. The successful integration of pharmaco- magnetoencephalography with dynamic causal models of frontotemporal networks provides a potential platform on which to evaluate the effects of disease and pharmacological interventions.SIGNIFICANCE STATEMENT Understanding human brain function and developing new treatments require good models of brain function. We tested a detailed generative model of cortical microcircuits that accurately reproduced human magnetoencephalography, to quantify network dynamics and connectivity in frontotemporal cortex. This approach identified the effect of a test drug (GABA-reuptake inhibitor, tiagabine) on neuronal function (GABA-ergic dynamics), opening the way for psychopharmacological studies in health and disease with the mechanistic precision afforded by generative models of the brain

GABAergic cortical network physiology in frontotemporal lobar degeneration.

The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients' GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials

Redefining the multidimensional clinical phenotypes of frontotemporal lobar degeneration syndromes

The syndromes caused by frontotemporal lobar degeneration (FTLD) have highly heterogenous and overlapping clinical features. There has been great progress in the refinement of clinical diagnostic criteria in the last decade, but we propose that a better understanding of aetiology, pathophysiology and symptomatic treatments can arise from a transdiagnostic approach to clinical phenotype and brain morphometry. In a cross-sectional epidemiological study, we examined 310 patients with a syndrome likely to be caused by frontotemporal lobar degeneration, including behavioural variant frontotemporal dementia (bvFTD), the non-fluent (nfvPPA), semantic (svPPA) variants of primary progressive aphasia, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We also included patients with logopenic primary progressive aphasia (lvPPA) and those who met criteria for PPA but not one of the three subtypes. To date, forty-nine patients have a neuropathological diagnosis. A principal component analysis identified symptom dimensions that broadly recapitulated the core features of the main clinical syndromes. However, the subject-specific scores on these dimensions showed considerable overlap across the diagnostic groups. Sixty-two percent of participants had phenotypic features that met the diagnostic criteria for more than one syndrome. Behavioural disturbance was prevalent in all groups. Forty-four percent of patients with CBS had PSP-like features and thirty percent of patients with PSP had CBS-like features. Many patients with PSP and CBS had language impairments consistent with nfvPPA while patients with bvFTD often had semantic impairments. Using multivariate source-based morphometry on a subset of patients (n=133), we identified patterns of co-varying brain atrophy that were represented across the diagnostic groups. Canonical correlation analysis of clinical and imaging components found three key brain-behaviour relationships that revealed a continuous spectrum across the cohort rather than discrete diagnostic entities. In the forty-six patients with longitudinal follow up (mean 3.6 years) syndromic overlap increased with time. Together, these results show that syndromes associated with FTLD do not form discrete mutually exclusive categories from their clinical features or structural brain changes, but instead exist in a multidimensional spectrum. Patients often manifest diagnostic features of multiple disorders and deficits in behaviour, movement and language domains are not confined to specific diagnostic groups. It is important to recognise individual differences in clinical phenotype, both for clinical management and to understand pathogenic mechanisms. We suggest that the adoption of a transdiagnostic approach to the spectrum of FTLD syndromes provides a useful framework with which to understand disease progression, heterogeneity and treatment.This work was funded by the Holt Fellowship (AGM), British Academy (KAT, PF160048), Wellcome Trust (JBR, 103838), the PSP Association, the Medical Research Council, the National Institute for Health Research Cambridge Biomedical Research Centre and Cambridge Brain Bank; and the Cambridge Centre for Parkinson Plus