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

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

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

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

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

The indirect relationship between sleep and cognition in the PREVENT Cohort: Identifying targets for intervention

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

Differential association of cerebral blood flow and anisocytosis in APOE ε4 carriers at midlife

Cerebral hemodynamic alterations have been observed in apolipoprotein ε4 (APOE4) carriers at midlife, however the physiological underpinnings of this observation are poorly understood. Our goal was to investigate cerebral blood flow (CBF) and its spatial coefficient of variation (CoV) in relation to APOE4 and a measure of erythrocyte anisocytosis (red blood cell distribution width – RDW) in a middle-aged cohort. Data from 563 participants in the PREVENT-Dementia study scanned with 3 T MRI cross-sectionally were analysed. Voxel-wise and region-of-interest analyses within nine vascular regions were run to detect areas of altered perfusion. Within the vascular regions, interaction terms between APOE4 and RDW in predicting CBF were examined. Areas of hyperperfusion in APOE4 carriers were detected mainly in frontotemporal regions. The APOE4 allele differentially moderated the association between RDW and CBF, an association which was more prominent in the distal vascular territories (p – [0.01, 0.05]). The CoV was not different between the considered groups. We provide novel evidence that in midlife, RDW and CBF are differentially associated in APOE4 carriers and non-carriers. This association is consistent with a differential hemodynamic response to hematological alterations in APOE4 carriers

Investigating the brain’s neurochemical profile at midlife in relation to dementia risk factors

Changes in the brain’s physiology in Alzheimer’s disease are thought to occur early in the disease’s trajectory. In this study our aim was to investigate the brain’s neurochemical profile in a midlife cohort in relation to risk factors for future dementia using single voxel proton magnetic resonance spectroscopy. Participants in the multi-site PREVENT-Dementia study (age range 40–59 year old) underwent 3T magnetic resonance spectroscopy with the spectroscopy voxel placed in the posterior cingulate/precuneus region. Using LCModel, we quantified the absolute concentrations of myo-inositol, total N-acetylaspartate, total creatine, choline, glutathione and glutamate-glutamine for 406 participants (mean age 51.1; 65.3% female). Underlying partial volume effects were accounted for by applying a correction for the presence of cerebrospinal fluid in the magnetic resonance spectroscopy voxel. We investigated how metabolite concentrations related to apolipoprotein ɛ4 genotype, dementia family history, a risk score (Cardiovascular Risk Factors, Aging and Incidence of Dementia -CAIDE) for future dementia including non-modifiable and potentially-modifiable factors and dietary patterns (adherence to Mediterranean diet). Dementia family history was associated with decreased total N-acetylaspartate and no differences were found between apolipoprotein ɛ4 carriers and non-carriers. A higher Cardiovascular Risk Factors, Aging, and Incidence of Dementia score related to higher myo-inositol, choline, total creatine and glutamate-glutamine, an effect which was mainly driven by older age and a higher body mass index. Greater adherence to the Mediterranean diet was associated with lower choline, myo-inositol and total creatine; these effects did not survive correction for multiple comparisons. The observed associations suggest that at midlife the brain demonstrates subtle neurochemical changes in relation to both inherited and potentially modifiable risk factors for future dementia