The neuroanatomical and neurochemical basis of apathy and impulsivity in frontotemporal lobar degeneration.

Apathy and impulsivity are common and often coexistent consequences of frontotemporal lobar degeneration (FTLD). They increase patient morbidity and carer distress, but remain under-estimated and poorly treated. Recent trans-diagnostic approaches that span the spectrum of clinical presentations of FTLD and parkinsonism, indicate that apathy and impulsivity can be fractionated into multiple neuroanatomical and pharmacological systems. These include ventral/dorsal fronto-striatal circuits for reward-sensitivity, response-inhibition, and decision-making; moderated by noradrenaline, dopamine, and serotonin. Improved assessment tools, formal models of cognition and behavior, combined with brain imaging and psycho-pharmacology, are creating new therapeutic targets and establishing principles for stratification in future clinical trials

Managing cognition in progressive supranuclear palsy

Cognitive impairment is integral to the syndrome of progressive supranuclear palsy. It is most commonly described as a frontal dysexecutive syndrome but other impairments include apathy, impulsivity, visuospatial and memory functions. Cognitive dysfunction may be exacerbated by mood disturbance, medication and communication problems. In this review we advocate an individualized approach to managing cognitive impairment in progressive supranuclear palsy with the education of caregivers as a central component. Specific cognitive and behavioral treatments are complemented by treatment of mood disturbances, rationalizing medications and a patient-centered approach to communication. This aims to improve patients' quality of life, reduce carer burden and assist people with progressive supranuclear palsy in decisions about their life and health, including discussions of feeding and end-of-life issues.This work was funded by the Medical Research Council (G1100464 to T Rittman) the Wellcome Trust (103838 to JB Rowe), the NIHR-Cambridge Biomedical Research Centre and the Beverley Sackler fellowship scheme (T Rittman, ITS Coyle-Gilchrist)

Monitoring the past and choosing the future: the prefrontal cortical influences on voluntary action.

Choosing between equivalent response options requires the resolution of ambiguity. One could facilitate such decisions by monitoring previous actions and implementing transient or arbitrary rules to differentiate response options. This would reduce the entropy of chosen actions. We examined voluntary action decisions during magnetoencephalography, identifying the spatiotemporal correlates of stimulus- and choice-entropy. Negative correlations between frontotemporal activity and entropy of past trials were observed after participants' responses, reflecting sequential monitoring of recent events. In contrast, choice entropy correlated negatively with prefrontal activity, before and after participants' response, consistent with transient activation of latent response-sets ahead of a decision and updating the monitor of recent decisions after responding. Individual differences in current choices were related to the strength of the prefrontal signals that reflect monitoring of the statistical regularities in previous events. Together, these results explain individual expressions of voluntary action, through differential engagement of prefrontal areas to guide sequential decisions

The Test Your Memory for Mild Cognitive Impairment (TYM-MCI)

BACKGROUND: To validate a short cognitive test: the Test Your Memory for Mild Cognitive Impairment (TYM-MCI) in the diagnosis of patients with amnestic mild cognitive impairment or mild Alzheimer’s disease (aMCI/AD). METHODS: Two hundred and two patients with mild memory problems were recruited. All had ‘passed’ the Mini-Mental State Examination (MMSE). Patients completed the TYM-MCI, the Test Your Memory test (TYM), MMSE and revised Addenbrooke’s Cognitive Examination (ACE-R), had a neurological examination, clinical diagnostics and multidisciplinary team review. RESULTS: As a single test, the TYM-MCI performed as well as the ACE-R in the distinction of patients with aMCI/AD from patients with subjective memory impairment with a sensitivity of 0.79 and specificity of 0.91. Used in combination with the ACE-R, it provided additional value and identified almost all cases of aMCI/AD. The TYM-MCI correctly classified most patients who had equivocal ACE-R scores. Integrated discriminant improvement analysis showed that the TYM-MCI added value to the conventional memory assessment. Patients initially diagnosed as unknown or with subjective memory impairment who were later rediagnosed with aMCI/AD scored poorly on their original TYM-MCI. CONCLUSION: The TYM-MCI is a powerful short cognitive test that examines verbal and visual recall and is a valuable addition to the assessment of patients with aMCI/AD. It is simple and cheap to administer and requires minimal staff time and training.JBR was supported by the Wellcome Trust (103838)

The behavioural variant frontotemporal dementia phenocopy syndrome is a distinct entity - evidence from a longitudinal study.

BACKGROUND: This study aimed to i) examine the frequency of C9orf72 expansions in a cohort of patients with the behavioural variant frontotemporal dementia (bvFTD) phenocopy syndrome, ii) observe outcomes in a group of phenocopy syndrome with very long term follow-up and iii) compare progression in a cohort of patients with the phenocopy syndrome to a cohort of patients with probable bvFTD. METHODS: Blood was obtained from 16 phenocopy cases. All met criteria for possible bvFTD and were labeled as phenocopy cases if they showed no functional decline, normal cognitive performance on the Addenbrooke's Cognitive Examination-Revised (ACE-R) and a lack of atrophy on brain imaging, over at least 3 years of follow-up. In addition, we obtained very long term follow-up data in 6 cases. A mixed model analysis approach determined the pattern of change in cognition and behaviour over time in phenocopy cases compared to 27 probable bvFTD cases. RESULTS: All 16 patients were screened for the C9orf72 expansion that was present in only one (6.25%). Of the 6 cases available for very long-term follow-up (13 - 21 years) none showed progression to frank dementia. Moreover, there was a decrease in the caregiver ratings of behavioural symptoms over time. Phenocopy cases showed significantly slower rates of progression compared to probable bvFTD patients (p < 0.006). CONCLUSION: The vast majority of patients with the bvFTD phenocopy syndrome remain stable over many years. An occasional patient can harbor the C9orf72 expansion. The aetiology of the remaining cases remains unknown but it appears very unlikely to reflect a neurodegenerative syndrome due to lack of clinical progression or atrophy on imaging

Apathy and impulsivity in frontotemporal lobar degeneration syndromes

Apathy and impulsivity are common and disabling consequences of frontotemporal lobar degeneration. They cause substantial carer distress, but their aetiology remains elusive. There are critical limitations to previous studies in this area including (i) the assessment of either apathy or impulsivity alone, despite their frequent co-existence; (ii) the assessment of behavioural changes within single diagnostic groups; and (iii) the use of limited sets of tasks or questions that relate to just one aspect of these multifactorial constructs. We proposed an alternative, dimensional approach that spans behavioural and language variants of frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome. This accommodates the commonalities of apathy and impulsivity across disorders and reveals their cognitive and anatomical bases. The ability to measure the components of apathy and impulsivity and their associated neural correlates across diagnostic groups would provide better novel targets for pharmacological manipulations, and facilitate new treatment strategies and strengthen translational models. We therefore sought to determine the neurocognitive components of apathy and impulsivity in frontotemporal lobar degeneration syndromes. The frequency and characteristics of apathy and impulsivity were determined by neuropsychological and behavioural assessments in 149 patients and 50 controls from the PIck’s disease and Progressive supranuclear palsy Prevalence and INcidence study (PiPPIN). We derived dimensions of apathy and impulsivity using principal component analysis and employed these in volumetric analyses of grey and white matter in a subset of 70 patients (progressive supranuclear palsy, n = 22; corticobasal syndrome, n = 13; behavioural variant, n = 14; primary progressive aphasias, n = 21) and 27 control subjects. Apathy and impulsivity were present across diagnostic groups, despite being criteria for behavioural variant frontotemporal dementia alone. Measures of apathy and impulsivity frequently loaded onto the same components reflecting their overlapping relationship. However, measures from objective tasks, patient-rated questionnaires and carer-rated questionnaires loaded onto separate components and revealed distinct neurobiology. Corticospinal tracts correlated with patients’ self-ratings. In contrast, carer ratings correlated with atrophy in established networks for goal-directed behaviour, social cognition, motor control and vegetative functions, including frontostriatal circuits, orbital and temporal polar cortex, and the brainstem. Components reflecting response inhibition deficits correlated with focal frontal cortical atrophy. The dimensional approach to complex behavioural changes arising from frontotemporal lobar degeneration provides new insights into apathy and impulsivity, and the need for a joint therapeutic strategy against them. The separation of objective tests from subjective questionnaires, and patient from carer ratings, has important implications for clinical trial design

Neurochemistry-enriched dynamic causal models of magnetoencephalography, using magnetic resonance spectroscopy

We present a hierarchical empirical Bayesian framework for testing hypotheses about neurotransmitters’ concertation as empirical prior for synaptic physiology using ultra-high field magnetic resonance spectroscopy (7T-MRS) and magnetoencephalography data (MEG). A first level dynamic causal modelling of cortical microcircuits is used to infer the connectivity parameters of a generative model of individuals’ neurophysiological observations. At the second level, individuals’ 7T-MRS estimates of regional neurotransmitter concentration supply empirical priors on synaptic connectivity. We compare the group-wise evidence for alternative empirical priors, defined by monotonic functions of spectroscopic estimates, on subsets of synaptic connections. For efficiency and reproducibility, we used Bayesian model reduction (BMR), parametric empirical Bayes and variational Bayesian inversion. In particular, we used Bayesian model reduction to compare alternative model evidence of how spectroscopic neurotransmitter measures inform estimates of synaptic connectivity. This identifies the subset of synaptic connections that are influenced by individual differences in neurotransmitter levels, as measured by 7T-MRS. We demonstrate the method using resting-state MEG (i.e., task-free recording) and 7T-MRS data from healthy adults. Our results confirm the hypotheses that GABA concentration influences local recurrent inhibitory intrinsic connectivity in deep and superficial cortical layers, while glutamate influences the excitatory connections between superficial and deep layers and connections from superficial to inhibitory interneurons. Using within-subject split-sampling of the MEG dataset (i.e., validation by means of a held-out dataset), we show that model comparison for hypothesis testing can be highly reliable. The method is suitable for applications with magnetoencephalography or electroencephalography, and is well-suited to reveal the mechanisms of neurological and psychiatric disorders, including responses to psychopharmacological interventions

Realistic loophole-free Bell test with atom-photon entanglement

The establishment of nonlocal correlations, obtained through the violation of a Bell inequality, is not only important from a fundamental point of view, but constitutes the basis for device-independent quantum information technologies. Although several nonlocality tests have been performed so far, all of them suffered from either the locality or the detection loopholes. Recent studies have suggested that the use of atom-photon entanglement can lead to Bell inequality violations with moderate transmission and detection efficiencies. In this paper we propose an experimental setup realizing a simple atom-photon entangled state that, under realistic experimental parameters available to date, achieves a significant violation of the Clauser-Horn-Shimony-Holt inequality. Most importantly, the violation remains when considering typical detection efficiencies and losses due to required propagation distances.Comment: 21 pages, 5 figures, 3 table, to appear in Nature Com

Looking beneath the surface: the importance of subcortical structures in frontotemporal dementia

Data availability: Data sharing is not applicable to this review article as no new data were generated or analysed in this study. Source study data may be available from the authors cited.Copyright © The Author(s) (2021). Whilst initial anatomical studies of frontotemporal dementia focussed on cortical involvement, the relevance of subcortical structures to the pathophysiology of frontotemporal dementia has been increasingly recognized over recent years. Key structures affected include the caudate, putamen, nucleus accumbens, and globus pallidus within the basal ganglia, the hippocampus and amygdala within the medial temporal lobe, the basal forebrain, and the diencephalon structures of the thalamus, hypothalamus and habenula. At the most posterior aspect of the brain, focal involvement of brainstem and cerebellum has recently also been shown in certain subtypes of frontotemporal dementia. Many of the neuroimaging studies on subcortical structures in frontotemporal dementia have been performed in clinically defined sporadic cases. However, investigations of genetically- and pathologically-confirmed forms of frontotemporal dementia are increasingly common and provide molecular specificity to the changes observed. Furthermore, detailed analyses of sub-nuclei and subregions within each subcortical structure are being added to the literature, allowing refinement of the patterns of subcortical involvement. This review focuses on the existing literature on structural imaging and neuropathological studies of subcortical anatomy across the spectrum of frontotemporal dementia, along with investigations of brain–behaviour correlates that examine the cognitive sequelae of specific subcortical involvement: it aims to ‘look beneath the surface’ and summarize the patterns of subcortical involvement have been described in frontotemporal dementia.The Dementia Research Centre is supported by Alzheimer's Research UK, Brain Research Trust and The Wolfson Foundation. This work was supported by the National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility as well as an Alzheimer's Society grant (AS-PG-16-007). MB is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). MB’s work is also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council (MRC), Alzheimer’s Society and Alzheimer’s Research UK. JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). JBR and MM were supported by the Cambridge University Centre for Parkinson-Plus, the Medical Research Council (SUAG/051 G101400) and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care