Single-Molecule Characterization and Super-Resolution Imaging of Alzheimer's Disease-Relevant Tau Aggregates in Human Samples.

Hyperphosphorylation and aggregation of the protein tau play key roles in the development of Alzheimer's disease (AD). While the molecular structure of the filamentous tau aggregates has been determined to atomic resolution, there is far less information available about the smaller, soluble aggregates, which are believed to be more toxic. Traditional techniques are limited to bulk measures and struggle to identify individual aggregates in complex biological samples. To address this, we developed a novel single-molecule pull-down-based assay (MAPTau) to detect and characterize individual tau aggregates in AD and control post-mortem brain and biofluids. Using MAPTau, we report the quantity, as well as the size and circularity of tau aggregates measured using super-resolution microscopy, revealing AD-specific differences in tau aggregate morphology. By adapting MAPTau to detect multiple phosphorylation markers in individual aggregates using two-color coincidence detection, we derived compositional profiles of the individual aggregates. We find an AD-specific phosphorylation profile of tau aggregates with more than 80 % containing multiple phosphorylations, compared to 5 % in age-matched non-AD controls. Our results show that MAPTau is able to identify disease-specific subpopulations of tau aggregates phosphorylated at different sites, that are invisible to other methods and enable the study of disease mechanisms and diagnosis.

Does repetitive transcranial magnetic stimulation improve cognitive function in age-related neurodegenerative diseases? A systematic review and meta-analysis.

OBJECTIVE: High-frequency, repetitive transcranial magnetic stimulation (rTMS) targeted over the dorsolateral prefrontal cortex (DLPFC) is widely used in research to promote neuroplasticity and cognitive enhancement. RTMS is a promising intervention to tackle cognitive decline in people with age-related neurodegenerative diseases. However, there is currently no systematic evidence examining the effects of DLPFC-targeted, high-frequency rTMS on cognitive function in this population. The aim of this systematic review was to evaluate the efficacy and moderators of this treatment intervention. METHODS: A comprehensive literature search of five electronic databases was performed to identify articles published before October, 2022. Following PRISMA guidelines, the identified articles were screened, data was extracted, and the methodological quality was assessed using the Cochrane tool, Risk of Bias 2. Meta-analyses were performed using R Studio (v.4.1.2). RESULTS: Sixteen studies involving 474 participants met the inclusion criteria, of which 8 studies measured global cognitive function. The results from the random-effects meta-analysis showed rTMS significantly improved global cognitive function relative to control groups shown by a large, significant effect size (g = 1.39, 95% CI, 0.34-2.43; p = 0.017). No significant effects were found between subgroups or for individual cognitive domains. CONCLUSIONS: High-frequency rTMS, targeted over the DLPFC, appears to improve global cognitive function in people with age-related neurodegenerative diseases. However, these results should be interpreted with caution due to the small number of studies included, and high between-study heterogeneity.

A systematic review of the diagnostic test accuracy of brief cognitive tests to detect amnestic mild cognitive impairment.

OBJECTIVE: People with amnestic mild cognitive impairment (aMCI) are at an increased risk of developing dementia. Efficient ways of identifying this 'at risk' population are required for larger-scale research studies. This systematic review describes the diagnostic accuracy of brief cognitive tests for detecting aMCI. METHODS: Fifteen databases were searched from 1999 to July 2013 to identify papers for inclusion. Prospective studies assessing the diagnostic test accuracy of simple and brief cognitive tests for identifying people with aMCI against a reference standard (Petersen criteria) were included. Sensitivity, specificity, positive and negative predictive values and likelihood ratios were calculated. Predictive validity and test-retest reliability were also extracted, when provided. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. RESULTS: Thirty-nine studies assessing 42 index tests were included. The Montreal Cognitive Assessment was the most comprehensively assessed test with evidence of high sensitivity for aMCI and good test-retest reliability, but low specificity was reported by the only study judged to be at low risk of bias. Other brief cognitive tests that include an assessment of word recall and multi-task tests that assess several cognitive domains were also found to exhibit high sensitivities and reasonable specificities. However, the confidence of the findings was affected by overall low quality of the contributing studies. CONCLUSION: Several brief cognitive tests have shown promising diagnostic test accuracy results for identifying aMCI. However, concerns over the quality of the constituent studies and lack of evidence on the predictive validity of these tests mean that new validation studies are warranted. Copyright © 2016 John Wiley & Sons, Ltd.

The validity of the Memory Alteration Test and the Test Your Memory test for community-based identification of amnestic mild cognitive impairment.

INTRODUCTION: This study investigated the validity of two brief cognitive tests (Memory Alteration Test [M@T] and Test Your Memory [TYM] test) for identifying people with aMCI in the community. METHODS: Older people were invited to participate by their general practitioner practice. Eligible participants were assessed for aMCI using an operationalized approach to the Petersen criteria and the M@T and TYM. RESULTS: Both tests demonstrated significant ability in discriminating between people with aMCI and controls (AUC = 0.91 for M@T and 0.80 for TYM [P < .001 for both]). M@T performed with higher sensitivity than TYM (85% vs. 63%) and similar specificity (84% vs. 87%). Both tests demonstrated moderate test-retest reliability (κ = ∼0.5) and took <10 minutes to administer. DISCUSSION: M@T and TYM are quick to administer. M@T demonstrated higher diagnostic test accuracy than TYM and could provide an efficient method for identifying aMCI in clinical and research settings.

Are syntactic representations similar in both reading and listening? Evidence from priming in first and second languages.

It is unclear to what extent natural differences between reading and listening result in differences in the syntactic representations formed in each modality. The present study investigated the occurrence of syntactic priming bidirectionally from reading to listening, and vice versa to examine whether reading and listening share the same syntactic representations in both first language (L1) and second language (L2). Participants performed a lexical decision task in which the experimental words were embedded in sentences with either an ambiguous or a familiar structure. These structures were alternated to produce a priming effect. The modality was manipulated whereby participants (a) first read part of the sentence list and then listened to the rest of the list (reading-listening group), or (b) listened and then read (listening-reading group). In addition, the study involved two within-modality lists in which participants either read or listened to the whole list. The L1 group showed within-modal priming in both listening and reading as well as a cross-modal priming effect. Although L2 speakers showed priming in reading, the effect was absent in listening and weak in the listening-reading condition. The absence of priming in L2 listening was attributed to difficulties in L2 listening rather than to an inability to produce abstract priming.

Identifying the needs of people with long COVID: a qualitative study in the UK.

OBJECTIVES: To identify the needs of people with long COVID (LC) in the UK. DESIGN: Qualitative study using the Framework Analysis to analyse focus group discussions. PARTICIPANTS: 25 adults with LC aged 19-76 years including 17 men and 8 women. Average disease duration was 80.1 weeks. SETTING: Eight focus groups were conducted in April 2023 online and in-person at the University of Leeds (UoL), UK. Recruitment routes included advertisement via Leeds Community Healthcare services, the English National Opera Breathe Programme and within the UoL. RESULTS: Three key themes/needs were identified. (Theme 1) Support systems including community groups, disability benefits, clinical services and employment support should be accessible and tailored to the needs of people with LC. (Theme 2) Research should investigate the physiology of symptoms, new clinical tests and treatment interventions to improve clinical understanding of the condition and symptom management. (Theme 3) Societal awareness should be promoted via local and national initiatives to educate the public about the condition and reduce stigma. CONCLUSIONS: Participants experienced varied and individual challenges to daily life due to LC. There is a need for government acknowledgement of LC as a disability to ensure people with LC have access to disability support and legal protection. Policy development should be patient-driven and acknowledge the individual needs of people with LC in order to improve their quality of life.

Splenium tract projections of the corpus callosum to the parietal cortex classifies Alzheimer's disease and mild cognitive impairment.

The corpus callosum (CC) is the largest bundle of white matter tracts in the brain connecting the left and right cerebral hemispheres. The posterior region of the CC, known as the splenium, seems to be relatively preserved throughout the lifespan and is regularly examined for indications of various pathologies, including Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI). However, the splenium has rarely been investigated in terms of its distinct inter-hemispheric tract bundles that project to bilateral occipital, parietal and temporal areas of the cortex. The aim of the present study was to determine if any of these sub-splenium tract bundles are specifically affected by individuals with AD and MCI compared to normal controls. Diffusion Tensor Imaging was used to directly examine the integrity of these distinct tract bundles and their diffusion metrics were compared between groups of MCI, AD, and control individuals. Results revealed that differences between MCI, AD, and controls were particularly evident at parietal tracts of the CC splenium and were consistent with an interpretation of compromised white matter integrity. Combined parietal tract diffusivity and density information strongly discriminated between AD patients and controls with an accuracy (AUC) of 97.19%. Combined parietal tract diffusivity parameters correctly classified MCI subjects against controls with an accuracy of 74.97%. These findings demonstrated the potential of examining the CC splenium in terms of its distinct inter-hemispheric tract bundles for the diagnosis of AD and MCI.

A computational suite for the structural and functional characterization of amyloid aggregates.

We developed the aggregate characterization toolkit (ACT), a fully automated computational suite based on existing and widely used core algorithms to measure the number, size, and permeabilizing activity of recombinant and human-derived aggregates imaged with diffraction-limited and super-resolution microscopy methods at high throughput. We have validated ACT on simulated ground-truth images of aggregates mimicking those from diffraction-limited and super-resolution microscopies and showcased its use in characterizing protein aggregates from Alzheimer's disease. ACT is developed for high-throughput batch processing of images collected from multiple samples and is available as an open-source code. Given its accuracy, speed, and accessibility, ACT is expected to be a fundamental tool in studying human and non-human amyloid intermediates, developing early disease stage diagnostics, and screening for antibodies that bind toxic and heterogeneous human amyloid aggregates.

Super-resolution imaging unveils the self-replication of tau aggregates upon seeding.

Tau is a soluble protein interacting with tubulin to stabilize microtubules. However, under pathological conditions, it becomes hyperphosphorylated and aggregates, a process that can be induced by treating cells with exogenously added tau fibrils. Here, we employ single-molecule localization microscopy to resolve the aggregate species formed in early stages of seeded tau aggregation. We report that entry of sufficient tau assemblies into the cytosol induces the self-replication of small tau aggregates, with a doubling time of 5 h inside HEK cells and 1 day in murine primary neurons, which then grow into fibrils. Seeding occurs in the vicinity of the microtubule cytoskeleton, is accelerated by the proteasome, and results in release of small assemblies into the media. In the absence of seeding, cells still spontaneously form small aggregates at lower levels. Overall, our work provides a quantitative picture of the early stages of templated seeded tau aggregation in cells.

The neural correlates of inhibiting pursuit to smoothly moving targets.

A previous study has shown that actively pursuing a moving target provides a predictive motor advantage when compared with passive observation of the moving target while keeping the eyes still [Burke, M. R., & Barnes, G. R. Anticipatory eye movements evoked after active following versus passive observation of a predictable motion stimulus. Brain Research, 15, 74-81, 2008b]. By using a novel paradigm based on combining a smooth pursuit stimulus with a go/no-go task, we have been able to reveal significant differences in brain activity for the inhibition of pursuit during the presentation of a smoothly moving target. Areas that show specific inhibitory and retinocentric velocity storage activity for the passive (no-go) condition include the dorsolateral pFC, the caudate, and the posterior cingulate. The FEFs, the supramarginal gyrus, the medial occipital gyrus, and the superior parietal lobe were found to be more involved in both the acquisition and response generation during no-go trials when compared with go trials. The go trials revealed higher activity than the no-go during the acquisition phase in the uncus and posterior cingulate. Furthermore, higher motor-related activity in the go task was found in the cerebellum. In summary, the areas involved in inhibiting smooth pursuit are consistent with the findings from the saccade literature, providing further evidence in support of overlapping cortical control networks.

Splenium tracts of the corpus callosum degrade in old age.

It is well established that the posterior region of the corpus callosum, known as the splenium, is relatively preserved during the course of normal ageing. However, the effect of age on its distinct interhemispheric tract bundles that project to bilateral occipital, parietal and temporal areas of the cortex, is largely unknown. In the present study, diffusion tensor imaging was used to directly examine the integrity of these distinct segregations and their diffusion metrics were compared between groups of young adults (n = 20, mean age = 30.75) and older adults (n = 19, mean age = 80.21). Results revealed that while occipital tracts were preserved in older adults, parietal and temporal segments were particularly impaired. These findings are the first to indicate the existence of selective alterations in the posterior region of the corpus callosum in older age.

The role of the posterior parietal cortex on cognition: An exploratory study.

Theta burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation (rTMS) that can be used to increase (intermittent TBS) or reduce (continuous TBS) cortical excitability. The current study provides a preliminary report of the effects of iTBS and cTBS in healthy young adults, to investigate the causal role of the posterior parietal cortex (PPC) during the performance of four cognitive functions: attention, inhibition, sequence learning and working memory. A 2 × 2 repeated measures design was incorporated using hemisphere (left/right) and TBS type (iTBS/cTBS) as the independent variables. 20 participants performed the cognitive tasks both before and after TBS stimulation in 4 counterbalanced experimental sessions (left cTBS, right cTBS, left iTBS and right iTBS) spaced 1 week apart. No change in performance was identified for the attentional cueing task after TBS stimulation, however TBS applied to the left PPC decreased reaction time when inhibiting a reflexive response. The sequence learning task revealed differential effects for encoding of the sequence versus the learnt items. cTBS on the right hemisphere resulted in faster responses to learnt sequences, and iTBS on the right hemisphere reduced reaction times during the initial encoding of the sequence. The reaction times in the 2-back working memory task were increased when TBS stimulation was applied to the right hemisphere. Results reveal clear differential effects for tasks explored, and more specifically where TBS stimulation on right PPC could provide a potential for further investigation into improving oculomotor learning by inducing plasticity-like mechanisms in the brain.

Exploring structural learning in handwriting.

Structural learning suggests that the human nervous system learns general rules that can be applied when controlling actions involving similar structures (e.g. using a variety of bicycles when learning to ride). These general rules can then facilitate skill acquisition in novel but related situations (e.g. a new bicycle). We tested this concept by investigating whether learned asymmetries in handwriting (greater ease in moving the hand rightwards and downwards within Western-educated populations) are present in the non-preferred hand as predicted by structural learning. We found these asymmetries in both hands of a right-handed population when tracing abstract shapes. We then ruled out biomechanical explanations by finding the same results with a left-handed population. These findings provide support for structural learning and explain: (1) the rapidity with which individuals can learn to write with their non-preferred hand; (2) the presence of a higher abstract (effector independent) level within voluntary motor control organisation.

Resting-state EEG power and connectivity are associated with alpha peak frequency slowing in healthy aging.

The individual alpha peak frequency (IAPF) of the human electroencephalography (EEG) typically experiences slowing with increasing age. Despite this hallmark change, studies that investigate modulations of conventional EEG alpha power and connectivity by aging and age-related neuropathology neglect to account for intergroup differences in IAPF. To investigate the relationship of age-related IAPF slowing with EEG power and connectivity, we recorded eyes-closed resting-state EEG in 37 young adults and 32 older adults. We replicated the finding of a slowed IAPF in older adults. IAPF values were significantly correlated with the frequency of maximum global connectivity and the means of their distributions did not differ, suggesting that connectivity was highest at the IAPF. Older adults expressed reduced global EEG power and connectivity at the conventional upper alpha band (10-12 Hz) compared with young adults. By contrast, groups had equivalent power and connectivity at the IAPF. The results suggest that conventional spectral boundaries may be biased against older adults or any group with a slowed IAPF. We conclude that investigations of alpha activity in aging and age-related neuropathology should be adapted to the IAPF of the individual and that previous findings should be interpreted with caution. EEG in the dominant alpha range may be unsuitable for examining cortico-cortical connectivity due to its subcortical origins.

Visual and visuomotor interhemispheric transfer time in older adults.

Older adults typically experience reductions in the structural integrity of the anterior channels of the corpus callosum. Despite preserved structural integrity in central and posterior channels, many studies have reported that interhemispheric transfer, a function attributed to these regions, is detrimentally affected by aging. In this study, we use a constrained event-related potential analysis in the theta and alpha frequency bands to determine whether interhemispheric transfer is affected in older adults. The crossed-uncrossed difference and lateralized visual evoked potentials were used to assess interhemispheric transfer in young (18-27) and older adults (63-80). We observed no differences in the crossed-uncrossed difference measure between young and older groups. Older adults appeared to have elongated transfer in the theta band potentials, but this effect was driven by shortened contralateral peak latencies, rather than delayed ipsilateral latencies. In the alpha band, there was a trend toward quicker transfer in older adults. We conclude that older adults do not experience elongated interhemispheric transfer in the visuomotor or visual domains and that these functions are likely attributed to posterior sections of the corpus callosum, which are unaffected by aging.

Sequence learning in two-dimensional smooth pursuit eye movements in humans.

Sequence learning is common to all motor systems and is an essential aspect of human behavior necessary for the acquisition of motor skill. Many previous studies have demonstrated the ability to observe, store, and repeat sequences in a variety of modalities resulting in reduced reaction time. Recently, it has been found that subjects can make predictive smooth eye movements to a sequence of discrete horizontal target motions (C. J. Collins & Barnes, 2005). The present study extends that paradigm into two dimensions of motion in order to investigate qualitative and quantitative differences in sequences of vertical (V) and horizontal (H) eye movements. The subjects performed sequences of four discrete velocity ramps repeated either four or eight times in succession. Baseline measurements were obtained to discrete individual smooth pursuit velocity ramps to H and V predictable (PRD) and randomized (RND) targets. We found that subjects could rapidly learn and anticipate individual components of a four-ramp sequence in two dimensions. The results showed clear asymmetries in the eye movements made to horizontal and vertical targets. We found that the latencies to H targets were shorter than latencies to V targets in both the PRD and RND conditions. We also found higher initial eye velocity (50 ms after target onset) to H targets than vertical targets during the PRD condition. Because these differences in H and V eye movements are present in both RND and PRD trials, this suggests that the observed differences are not due to retention of information but are inherent asymmetries within the system.

The involvement of the fronto-parietal brain network in oculomotor sequence learning using fMRI.

The basis of motor learning involves decomposing complete actions into a series of predictive individual components that form the whole. The present fMRI study investigated the areas of the human brain important for oculomotor short-term learning, by using a novel sequence learning paradigm that is equivalent in visual and temporal properties for both saccades and pursuit, enabling more direct comparisons between the oculomotor subsystems. In contrast with previous studies that have implemented a series of discrete ramps to observe predictive behaviour as evidence for learning, we presented a continuous sequence of interlinked components that better represents sequences of actions. We implemented both a classic univariate fMRI analysis, followed by a further multivariate pattern analysis (MVPA) within a priori regions of interest, to investigate oculomotor sequence learning in the brain and to determine whether these mechanisms overlap in pursuit and saccades as part of a higher order learning network. This study has uniquely identified an equivalent frontal-parietal network (dorsolateral prefrontal cortex, frontal eye fields and posterior parietal cortex) in both saccades and pursuit sequence learning. In addition, this is the first study to investigate oculomotor sequence learning during fMRI brain imaging, and makes significant contributions to understanding the role of the dorsal networks in motor learning.

Cognitive Control of Saccadic Eye Movements in Children with Developmental Coordination Disorder.

The ability to use advance information to prepare and execute a movement requires cognitive control of behaviour (e.g., anticipation and inhibition). Our aim was to explore the integrity of saccadic eye movement control in developmental coordination disorder (DCD) and typically developing (TD) children (8-12 years) and assess how these children plan and inhibit saccadic responses, the principal mechanisms within visual attention control. Eye movements and touch responses were measured (separately and concurrently) in Cued and Non-Cued conditions. We found that children with DCD had similar saccade kinematics to the TD group during saccade initiation. Advance information decreased hand movement duration in both groups during Cued trials, but decrements in accuracy were significantly worse in the DCD group. In addition, children with DCD exhibited greater inhibitory errors and inaccurate fixation during the Cued trials. Thus, children with DCD were reasonably proficient in executing saccades during reflexive (Non-Cued) conditions, but showed deficits in more complex control processes involving prediction and inhibition. These findings have implications for our understanding of motor control in children with DCD.

You've Got to Hand It to Them: Assessing Final Year Medical Students Knowledge of Hand Anatomy and Pathology.

BACKGROUND: Knowledge of hand anatomy and pathology is important for final year medical students as it frequently appears in examinations as a short case or in a written paper. Studies have shown that doctors in the Emergency Department have a deficient grasp of musculoskeletal anatomy secondary to a lack of dedicated teaching in medical school. METHODS: A questionnaire was handed out to 111 final year medical students. Students were asked to fill it out before and after dedicated upper limb teaching sessions during their rotation. The questionnaire consisted of an anatomical and pathological component. Students were tested on basic anatomy and pathology of several common upper limb conditions. RESULTS: There was a significant improvement in the medical students knowledge after the dedicated hand teaching. The identification of the carpal bones showed the most improvement overall. CONCLUSIONS: Basic musculoskeletal knowledge is essential to the practice of medicine. The majority of medical students gravitate towards a career in general practice or emergency medicine and good knowledge of upper limb anatomy is important. We have piloted a new interactive dedicated upper limb teaching module and have shown that there has been a significant improvement in students knowledge.

Age-Related Deficits in Visuospatial Memory Are due to Changes in Preparatory Set and Eye-Hand Coordination.

OBJECTIVES: Healthy aging is associated with a decline in visuospatial working memory. The nature of the changes leading to this decline in response of the eye and/or hand is still under debate. This study aims to establish whether impairments observed in performance on cognitive tasks are due to actual cognitive effects or are caused by motor-related eye-hand coordination. METHODS: We implemented a computerized version of the Corsi span task. The eye and touch responses of healthy young and older adults were recorded to a series of remembered targets on a screen. RESULTS: Results revealed differences in fixation strategies between the young and the old with increasing cognitive demand, which resulted in higher error rates in the older group. We observed increasing reaction times and durations between fixations and touches to targets, with increasing memory load and delays in both the eye and the hand in the older adults. DISCUSSION: Our results show that older adults have difficulty maintaining a "preparatory set" for durations longer than 5 s and with increases in memory load. Attentional differences cannot account for our results, and differences in age groups appear to be principally memory related. Older adults reveal poorer eye-hand coordination, which is further confounded by increasing delay and complexity.