Apathy is extremely common in neurodegenerative disorders such as Parkinson’s disease. Muhammed et al. report that lack of sensitivity to rewards may underlie apathy, with dopamine playing a modulatory role. The study provides a basis for objective clinical markers of motivation and treatment efficacy in neurodegenerative conditions.

The distances between pairs of tactile stimuli oriented across the width of the hand dorsum are perceived as about 40% larger than equivalent distances oriented along the hand length. Clear anisotropies of varying magnitudes have been found on different sites on the limbs and less consistently on other parts of the body, with anisotropies on the center of the forehead, but not on the belly. Reported anisotropies on the center of the forehead, however, might reflect an artefact of categorical perception from the face midline, which might be comparable to the expansion of tactile distance perception observed for stimuli presented across joint boundaries. To test whether tactile anisotropy is indeed a general characteristic of the tactile representation of the face, we assessed the perceived distance between pairs of touches on the cheeks and three locations on the forehead: left, right, and center. Consistent with previous results, a clear anisotropy was apparent on the center of the forehead. Importantly, similar anisotropies were also evident on the left and right sides of the forehead and both cheeks. These results provide evidence that anisotropy of perceived tactile distance is not a specific feature of tactile organization at the limbs but it also exists for the face, and further suggest that the spatial distortions found for tactile distances that extend across multiple body parts are not present for stimuli that extend across the body midline.

IntroductionThe case for de-risking neurodegenerative research and development through highly informative experimental medicine studies early in the disease process is strong. Such studies depend on the availability of genetic as well as high-granularity, longitudinal, phenotypic data in healthy ageing individuals who can be recruited into early phase trials on the basis of their perceived dementia risk. Until now the creation of such research infrastructure has been hampered by the lack of expense and time required to gather the rich longitudinal data needed for adequate risk stratification. Dementias Platform UK (DPUK) is a public–private partnership that brings together data from over 40 cohorts in a standardised framework, which represent an until now unavailable opportunity to create such a resource through a streamlined brain health recontact platform based on existing cohorts, as well as prospectively collected data.Methods and analysisThe DPUK recontact platform consists of an opt-in (Great Minds, GM) and an opt-out component (Clinical Studies Register, CSR). GM requires invited DPUK cohort participants to consent to targeted recontact at the GM website and then to provide self-reported demographic and medical history information relevant to recruitment into clinical studies. Participants complete prospective browser-based and smartphone-based cognitive tests and are given the option for remote genetic and actigraphy testing. The GM data are linked to the retrospective DPUK cohort dataset, including genotypic and longitudinal phenotypic data. The CSR is a solution for cohorts explicitly allowing targeted recontact. Approved studies provide prescreening criteria on the basis of the CSR/GM dataset, and individuals meeting these criteria are offered participation directly (GM) or through the parent DPUK cohort (CSR). Descriptive statistics will be used to summarise the outcomes relevant to the number of participants engaged with the register. Its sample size is not defined but is limited by the size of the DPUK parent cohorts.Ethics and disseminationThe database was approved by the South Central–Oxford C Research Ethics Committee, reference 18/SC/0268 on the 27th of June 2018 and amended on the 1st of November 2019. The availability of the register to researchers will be disseminated through DPUK’s official communication channels as well as national and international scientific meetings.

Clinical apathy results in dysfunction of goal directed behaviour, a key component of which is the initiation of action. Previous work has suggested that blunting of reward sensitivity is an important mechanism underlying apathy. However, an additional component might be impoverished initiation of action itself. This study aims to investigate the link between motivation and motor output and its association with apathy and dopamine. An oculomotor task that measures pupillary and saccadic response to monetary incentives was used to assess reward sensitivity, first in 23 young and 18 elderly controls, and then in 22 patients with Parkinson’s disease tested ON and OFF dopaminergic medication. To distinguish between pupillary responses to anticipated reward alone versus responses associated with motor preparation, a saccadic ‘go/no-go’ task was performed. Half of the trials required a saccade to be initiated to receive a reward and in the remaining trials no action was required but reward was still obtained. No significant difference in pupil response was demonstrated between the two conditions in all groups tested, suggesting pupillary responses to rewards are not contingent upon motor preparation in Parkinson’s disease. Being ON or OFF dopamine did not influence this response either. Previous work demonstrated associations between apathy and pupillary reward insensitivity in Parkinson’s disease. Here we observed this effect only when an action was required to receive a reward, and only in the ON state. These findings suggest that apathy in Parkinson’s disease is linked to reduced reward sensitivity and that this is most prominently observed when actions have to be initiated to rewarding goals, with the effect modulated by being ON dopaminergic medication. OFF medication, there was no such strong relationship, and similarly in the ‘no-go’ conditions, either ON or OFF dopaminergic drugs. The results provide preliminary data which suggest that apathy in Parkinson’s disease is associated with a reduction in reward sensitivity and this is most evident when associated with initiation of goal directed actions in the presence of adequate dopamine.

BackgroundAlzheimer’s disease (AD), type 2 diabetes mellitus (characterised by insulin resistance) and depression are significant challenges facing public health. Research has demonstrated common comorbidities among these three conditions, typically focusing on two of them at a time.ObjectiveThe goal of this study, however, was to assess the inter-relationships between the three conditions, focusing on mid-life (defined as age 40–59) risk before the emergence of dementia caused by AD.MethodsIn the current study, we used cross-sectional data from 665 participants from the cohort study, PREVENT.FindingsUsing structural equation modelling, we showed that (1) insulin resistance predicts executive dysfunction in older but not younger adults in mid-life, that (2) insulin resistance predicts self-reported depression in both older and younger middle-aged adults and that (3) depression predicts deficits in visuospatial memory in older but not younger adults in mid-life.ConclusionsTogether, we demonstrate the inter-relations between three common non-communicable diseases in middle-aged adults.Clinical implicationsWe emphasise the need for combined interventions and the use of resources to help adults in mid-life to modify risk factors for cognitive impairment, such as depression and diabetes.

Apathy, a syndrome characterized by lack of motivation, is common across neurodegenerative conditions. Although it is now established to be associated with poor quality of life, mechanisms underlying the condition are poorly understood.Here we used two novel incentivised oculomotor paradigms to measure reward sensitivity in 30 Parkinson's disease (PD) patients, both ON and OFF dopaminergic medication, comparing them to age-matched controls. To distinguish between pupillary response to anticipated reward vs. response associated with motor preparation, a Go/NoGo version was performed in a further 20 PD cases.Reward sensitivity, indexed by pupillary dilation for reward, was greater in controls and PD ON compared to OFF (p<0.01). There was a significant correlation between pupil reward sensitivity and clinical apathy in PD (p<0.001), with apathetic individuals displaying less reward sensitivity. Pupillary reward sensitivity was observed regardless of whether a saccade was required. On diffusion-weighted MR imaging, reward sensitivity correlated with fractional anisotropy in the caudal cingulate zone of controls (p<0.05), an area previously implicated in motivation.Reward insensitivity may underlie lack of motivation in PD and is quantifiable using pupillary responses to rewards, independent of motor preparation. Dopaminergic medication can increase reward sensitivity and may be effective therapy for apathy, independent of motor control.

Introduction: As the global population ages, the economic, societal, and personal burdens associated with worsening cognition and dementia onset are growing. It is therefore becoming ever more critical to understand the factors associated with cognitive decline. One such factor is sleep. Adequate sleep has been shown to maintain cognitive function and protect against the onset of chronic disease, whereas sleep deprivation has been linked to cognitive impairment and the onset of depression and dementia. Objectives: Here, we aim to identify and explore mechanistic links between several sleep parameters, depressive symptoms and cognition in a cohort of middle-aged adults. Methods: We investigated data from the PREVENT dementia programme via structural equation modelling to illustrate links between predictor variables, moderator variables, and two cognitive constructs (i.e., Executive Function and Memory). Results: Our model demonstrated that sleep quality, and total hours of sleep were related to participants′ depressive symptoms, and that, participant apathy was related to higher scores on the Epworth Sleepiness and Lausanne NoSAS Scales. Subsequently, depressive symptoms, but not sleep or apathy ratings, were associated with Executive Function. Conclusions: We provide evidence for an indirect relationship between sleep and cognition mediated by depressive symptoms in a middle-aged population. Our results provide a base from which cognition, dementia onset, and potential points of intervention, may be better understood.

Introduction: The case for de-risking neurodegenerative research and development through highly informative experimental medicine studies early in the disease process is strong. Such studies depend on the availability of genetic as well as high-granularity, longitudinal, phenotypic data in healthy aging individuals who can be recruited into early phase trials on the basis of their perceived dementia risk. Until now the creation of such research infrastructure has been hampered by the lack of expense and time required to gather the rich longitudinal data needed for adequate risk stratification. Dementias Platform UK (DPUK) is a public-private partnership that brings together data from over 40 cohorts in a standardised framework, which represents an until now unavailable opportunity to create such a resource through a streamlined brain health re-contact platform based on existing cohorts, as well as prospectively collected data. Methods and analysis: The DPUK re-contact platform consists of an opt-in (Great Minds, GM) and an opt-out component (Clinical Studies register, CSR). GM requires invited DPUK cohort participants to consent to targeted re-contact at the GM website and then to provide self-reported demographic and medical history information relevant to recruitment into clinical studies. Participants complete prospective browser- and smartphone-based cognitive tests and are given the option for remote genetic and actigraphy testing. The GM data is linked to the retrospective DPUK cohort dataset, including genotypic and longitudinal phenotypic data. The CSR is a solution for cohorts explicitly allowing targeted re-contact. Approved studies provide pre-screening criteria on the basis of the CSR/GM dataset, and individuals meeting these criteria are offered participation directly (GM) or through the parent DPUK cohort (CSR). Descriptive statistics will be used to summarise the outcomes relevant to the number of participants engaged with the register. Its sample size is not defined but is limited by the size of the DPUK parent cohorts. Ethics and dissemination: The database was approved by the South Central - Oxford C Research Ethics Committee, reference 18/SC/0268 on the 27th of June 2018 and amended on the 1st of November 2019. The availability of the Register to researchers will be disseminated through DPUK official communication channels as well as national and international scientific meetings.