Attention deficits following ADEM ameliorated by guanfacine

The authors report here the case of a patient with severe deficits in arousal and sustained attention, associated with hemispatial neglect. These impairments were secondary to acute disseminated encephalomyelitis, with bilateral involvement of the medial nuclei and pulvinar of the thalamus. Treatment with the noradrenergic agonist guanfacine, previously used for attention deficits in attention deficit/hyperactivity disorder and stroke, was associated with a significant amelioration of both the spatial and sustained attention impairments in neglect. Guanfacine may prove to be a useful tool in the treatment of disorders of attention associated with neurological conditions

Randomised, double-blind, placebo-controlled crossover study of single-dose guanfacine in unilateral neglect following stroke

OBJECTIVE: Unilateral neglect is a poststroke disorder that impacts negatively on functional outcome and lacks established, effective treatment. This multicomponent syndrome is characterised by a directional bias of attention away from contralesional space, together with impairments in several cognitive domains, including sustained attention and spatial working memory. This study aimed to test the effects of guanfacine, a noradrenergic alpha-2A agonist, on ameliorating aspects of neglect.METHODS: Thirteen right hemisphere stroke patients with leftward neglect were included in a randomised, double-blind, placebo-controlled proof-of-concept crossover study that examined the effects of a single dose of guanfacine. Patients were tested on a computerised, time-limited cancellation paradigm, as well as tasks that independently assessed sustained attention and spatial working memory.RESULTS: On guanfacine, there was a statistically significant improvement in the total number of targets found on the cancellation task when compared with placebo (mean improvement of 5, out of a possible 64). However, there was no evidence of a change in neglect patients' directional attention bias. Furthermore, Bayesian statistical analysis revealed reliable evidence against any effects of guanfacine on search organisation and performance on our sustained attention and spatial working memory tasks.CONCLUSIONS: Guanfacine improves search in neglect by boosting the number of targets found but had no effects on directional bias or search organisation, nor did it improve sustained attention or working memory on independent tasks. Further work is necessary to determine whether longer term treatment with guanfacine may be effective for some neglect patients and whether it affects functional outcome measures.TRIAL REGISTRATION NUMBER: NCT00955253.</p

Metacognitive accuracy differences in Parkinson’s disease and REM sleep behavioral disorder relative to healthy controls

Background: Metacognition is the ability to monitor and self-assess cognitive performance. It can be impaired in neurodegenerative diseases, with implications for daily function, and the ability of patients to reliably report their symptoms to health professionals. However, metacognition has not been systematically assessed in early-mid stage Parkinson’s disease (PD) and REM sleep behavioral disorder (RBD), a prodrome of PD. Objectives: This study aimed to evaluate metacognitive accuracy and self-confidence in PD and RBD patients across various cognitive tasks. Methods: We conducted detailed computerized cognitive assessments with 19 cognitive tasks within an established PD and RBD cohort. Participants self-rated their performance post-task. Metacognitive accuracy was calculated by comparing these ratings against objective performance and further analyzed against clinical and mental health factors. Results: PD and RBD patients’ metacognitive accuracy aligned with control subjects. However, they exhibited lower confidence across cognitive domains, reflecting their reduced cognitive performance. A notable inverse correlation was observed between their confidence and MDS-UPDRS I and II scales and HADS anxiety and depression scores. Conclusion: Our findings indicate that patients with early to mid-stage PD and RBD are generally aware of their cognitive status, differing from other neurological disorders. The inverse relationship between patient confidence and symptoms of depression, anxiety, and daily life challenges underscores the impact of emotional and functional difficulties on their self-perception of cognitive abilities. This insight could be significant for understanding how these conditions affect mental health, aiding clinicians in developing more effective patient care strategies

Dementia risk and thalamic nuclei volumetry in healthy midlife adults: the PREVENT Dementia study

A reduction in the volume of the thalamus and its nuclei has been reported in Alzheimer’s disease, mild cognitive impairment and asymptomatic individuals with risk factors for early-onset Alzheimer’s disease. Some studies have reported thalamic atrophy to occur prior to hippocampal atrophy, suggesting thalamic pathology may be an early sign of cognitive decline. We aimed to investigate volumetric differences in thalamic nuclei in middle-aged, cognitively unimpaired people with respect to dementia family history and apolipoprotein ε4 allele carriership and the relationship with cognition. Seven hundred participants aged 40–59 years were recruited into the PREVENT Dementia study. Individuals were stratified according to dementia risk (approximately half with and without parental dementia history). The subnuclei of the thalamus of 645 participants were segmented on T1-weighted 3 T MRI scans using FreeSurfer 7.1.0. Thalamic nuclei were grouped into six regions: (i) anterior, (ii) lateral, (iii) ventral, (iv) intralaminar, (v) medial and (vi) posterior. Cognitive performance was evaluated using the computerized assessment of the information-processing battery. Robust linear regression was used to analyse differences in thalamic nuclei volumes and their association with cognitive performance, with age, sex, total intracranial volume and years of education as covariates and false discovery rate correction for multiple comparisons. We did not find significant volumetric differences in the thalamus or its subregions, which survived false discovery rate correction, with respect to first-degree family history of dementia or apolipoprotein ε4 allele status. Greater age was associated with smaller volumes of thalamic subregions, except for the medial thalamus, but only in those without a dementia family history. A larger volume of the mediodorsal medial nucleus (Pfalse discovery rate = 0.019) was associated with a faster processing speed in those without a dementia family history. Larger volumes of the thalamus (P = 0.016) and posterior thalamus (Pfalse discovery rate = 0.022) were associated with significantly worse performance in the immediate recall test in apolipoprotein ε4 allele carriers. We did not find significant volumetric differences in thalamic subregions in relation to dementia risk but did identify an interaction between dementia family history and age. Larger medial thalamic nuclei may exert a protective effect on cognitive performance in individuals without a dementia family history but have little effect on those with a dementia family history. Larger volumes of posterior thalamic nuclei were associated with worse recall in apolipoprotein ε4 carriers. Our results could represent initial dysregulation in the disease process; further study is needed with functional imaging and longitudinal analysis

Considerations for legal, ethical, and effective practice in dementia research

Dementia represents a potentially overwhelming health burden, both for the UK and worldwide. Addressing this fast-growing issue is a key priority for the government, health service and the public. Advances in care including the development of efficacious disease-modifying, and eventually curative, treatments can only be achieved through effective dementia research. Specifically, research directly involving participants with dementia is essential to further understanding. However, working with cognitively impaired participants with and without capacity to consent to research presents unique ethical and legal challenges. For clinicians and scientists on the frontline of dementia research, scenarios frequently arise that pose such challenges. A lack of guidance for a consistent approach in navigating these scenarios limits researchers’ ability to proceed with confidence. This represents a threat to the rights and wishes of research participants as well as the field at large, as it may lead to studies being unnecessarily terminated or, worse, poor practice. In this article, we take a multiprofessional approach, informed by carer input, to these issues. We review the relevant ethical and legal literature relating to the conduct of non-interventional research studies in patients with dementia. This includes a thorough recap of the Mental Capacity Act (2005), which provides a legal framework in England and Wales for conducting research with participants who lack capacity to consent. We also discuss the important, but sometimes incomplete, role of research ethics committees in guiding researchers. We then present and discuss a series of case vignettes designed to highlight areas of incomplete coverage by existing governance. These vignettes describe theoretical scenarios informed by our own real-word experiences of encountering ethical issues when conducting dementia research. They include scenarios in which participants demonstrate varying degrees of understanding of the research they are involved in and ability to communicate their wishes and feelings. Building on these vignettes, we then provide a checklist for researchers to work through when presented with similar scenarios. This checklist covers the key ethical, legal and practical considerations that we have argued for. Taken together, this article can act as a guide, previously lacking in the literature, for colleagues in the field to enable much needed ethical, legal and effective research

Role of right posterior parietal cortex in maintaining attention to spatial locations over time

Recent models of human posterior parietal cortex (PPC) have variously emphasized its role in spatial perception, visuomotor control or directing attention. However, neuroimaging and lesion studies also suggest that the right PPC might play a special role in maintaining an alert state. Previously, assessments of right-hemisphere patients with hemispatial neglect have revealed significant overall deficits on vigilance tasks, but to date there has been no demonstration of a deterioration of performance over time--a vigilance decrement--considered by some to be a key index of a deficit in maintaining attention. Moreover, sustained attention deficits in neglect have not specifically been related to PPC lesions, and it remains unclear whether they interact with spatial impairments in this syndrome. Here we examined the ability of right-hemisphere patients with neglect to maintain attention, comparing them to stroke controls and healthy individuals. We found evidence of an overall deficit in sustaining attention associated with PPC lesions, even for a simple detection task with stimuli presented centrally. In a second experiment, we demonstrated a vigilance decrement in neglect patients specifically only when they were required to maintain attention to spatial locations, but not verbal material. Lesioned voxels in the right PPC spanning a region between the intraparietal sulcus and inferior parietal lobe were significantly associated with this deficit. Finally, we compared performance on a task that required attention to be maintained either to visual patterns or spatial locations, matched for task difficulty. Again, we found a vigilance decrement but only when attention had to be maintained on spatial information. We conclude that sustaining attention to spatial locations is a critical function of the human right PPC which needs to be incorporated into models of normal parietal function as well as those of the clinical syndrome of hemispatial neglect

A predictive model using the mesoscopic architecture of the living brain to detect Alzheimer’s disease

Background: Alzheimer’s disease, the most common cause of dementia, causes a progressive and irreversible deterioration of cognition that can sometimes be difficult to diagnose, leading to suboptimal patient care. Methods: We developed a predictive model that computes multi-regional statistical morpho-functional mesoscopic traits from T1-weighted MRI scans, with or without cognitive scores. For each patient, a biomarker called “Alzheimer’s Predictive Vector” (ApV) was derived using a two-stage least absolute shrinkage and selection operator (LASSO). Results: The ApV reliably discriminates between people with (ADrp) and without (nADrp) Alzheimer’s related pathologies (98% and 81% accuracy between ADrp - including the early form, mild cognitive impairment - and nADrp in internal and external hold-out test sets, respectively), without any a priori assumptions or need for neuroradiology reads. The new test is superior to standard hippocampal atrophy (26% accuracy) and cerebrospinal fluid beta amyloid measure (62% accuracy). A multiparametric analysis compared DTI-MRI derived fractional anisotropy, whose readout of neuronal loss agrees with ADrp phenotype, and SNPrs2075650 is significantly altered in patients with ADrp-like phenotype. Conclusions: This new data analytic method demonstrates potential for increasing accuracy of Alzheimer diagnosis

Online cognitive monitoring technology for people with Parkinson’s disease and REM sleep behavioural disorder

Automated online cognitive assessments are set to revolutionise clinical research and healthcare. However, their applicability for Parkinson’s Disease (PD) and REM Sleep Behavioural Disorder (RBD), a strong PD precursor, is underexplored. Here, we developed an online battery to measure early cognitive changes in PD and RBD. Evaluating 19 candidate tasks showed significant global accuracy deficits in PD (0.65 SD, p = 0.003) and RBD (0.45 SD, p = 0.027), driven by memory, language, attention and executive underperformance, and global reaction time deficits in PD (0.61 SD, p = 0.001). We identified a brief 20-min battery that had sensitivity to deficits across these cognitive domains while being robust to the device used. This battery was more sensitive to early-stage and prodromal deficits than the supervised neuropsychological scales. It also diverged from those scales, capturing additional cognitive factors sensitive to PD and RBD. This technology offers an economical and scalable method for assessing these populations that can complement standard supervised practices

Comprehensive allostatic load risk index is associated with increased frontal and left parietal white matter hyperintensities in mid-life cognitively healthy adults

To date, there is a considerable heterogeneity of methods to score Allostatic Load (AL). Here we propose a comprehensive algorithm (ALCS) that integrates commonly used approaches to generate AL risk categories and assess associations to brain structure deterioration. In a cohort of cognitively normal mid-life adults (n = 620, age 51.3 ± 5.48 years), we developed a comprehensive composite for AL scoring incorporating gender and age differences, high quartile approach, clinical reference values, and current medications, to then generate AL risk categories. Compared to the empirical approach (ALES), ALCS showed better model fit criteria and a strong association with age and sex. ALSC categories were regressed against brain and white matter hyperintensity (WMH) volumes. Higher AL risk categories were associated with increased total, periventricular, frontal, and left parietal WMH volumes, also showing better fit compared to ALES. When cardiovascular biomarkers were removed from the ALSC algorithm, only left-frontal WMHV remained associated with AL, revealing a strong vascular burden influencing the index. Our results agree with previous evidence and suggest that sustained stress exposure enhances brain deterioration in mid-life adults. Showing better fit than ALES, our comprehensive algorithm can provide a more accurate AL estimation to explore how stress exposure enhances age-related health decline.</p