Biology subjects

Bindoff, A.

Publications and source records attributed to Bindoff, A..

4 recordsLinked to original sources

bioRxiv2026

Large-scale Visuomotor Reaction Time Self-Testing Reveals Subtle Motor Changes in Older Adults with Subjective Cognitive Impairment

IntroductionAffordable tools for early Alzheimers disease (AD) detection could support drug development and early intervention. Subtle motor changes may indicate preclinical AD, but hand response selection and initiation speeds are understudied. This study assessed whether unsupervised, online visuomotor reaction time (RT) tests relate to subjective cognitive impairment (SCI), a validated high risk state for future conversion to AD MethodsA total of 910 participants (age 66.3{+/-}7.5, 70.8% female) completed assessments of simple and choice visuomotor RT tests at home as part of the online TAS Test protocol; they also completed the Cambridge Neuropsychological Test Automated Battery (CANTAB) episodic memory and executive function tests. Among them, 142 participants reported SCI. ResultsOn the TAS Test visuomotor tests, SCI was associated with 8.4% [1.4%, 15.4%] longer RT ( (p = .008; adjusted for task complexity), greater odds of time-out failure (OR = 1.35 [1.01, 1.81]; p = .037), and greater variance in RT (log-variance (SCI - comparison) = .094 [.028, .159]; p < .001). There were no significant differences between the SCI and comparison groups on any of the CANTAB tests. After adjusting for SCI status, none of the CANTAB tests were significantly associated with RT. DiscussionSCI was associated with longer and more variable visuomotor RT, and greater odds of time-out failure, while not being associated with tests of memory and executive function. Cognitive test scores did not explain a significant amount of variance in visuomotor RT. Taken together, these results support a hypothesis that people with SCI may be experiencing earlier visuomotor deficits that are distinct from (or precede) decline in episodic memory and executive function. Visuomotor tasks that record RT may be more sensitive to preclinical manifestations of cognitive decline than more traditional tests of cognitive function.

bioinformatics↗

bioRxiv2022

Temporal changes in the microglial proteome of male and female mice after a diffuse brain injury using label-free quantitative proteomics

Traumatic brain injury (TBI) triggers neuroinflammatory cascades mediated by microglia, which promotes tissue repair in the short-term. These cascades may exacerbate TBI-induced tissue damage and symptoms in the months to years post-injury. However, the progression of the microglial function across time post-injury and whether this differs between biological sexes is not well understood. In this study, we examined the microglial proteome in the days (3- and 7-days) to 1 month (28 days) after a midline fluid percussion injury (mFPI) in male and female mice using label-free quantitative proteomics. We identified a reduction in microglial proteins involved with clearance of neuronal debris via phagocytosis at 3- and 7-days post-injury. At 28 days post-injury pro-inflammatory proteins were decreased and anti-inflammatory proteins were increased in microglia. These results indicate a reduction in microglial clearance of neuronal debris in the days post-injury with a shift to anti-inflammatory function by 1 month. The changes in the microglial proteome that occurred across time post-injury did not differ between biological sexes. However, we did identify an increase in microglial proteins related to pro-inflammation as well as insulin and estrogen signalling in males compared with female mice that occurred with or without a brain injury. Although microglial response was similar between males and females up to 1 month following TBI, biological sex differences in the basal microglial proteome has implications for the efficacy of treatment strategies targeting the microglial response post-injury.

neuroscience↗

bioRxiv2022

Lysosomal alterations and decreased electrophysiological activity in CLN3 disease (966 bp deletion, E295K) patient-derived cortical neurons

CLN3 disease is a lysosomal storage disorder associated with fatal neurodegeneration that is caused by mutations in CLN3. Most individuals with CLN3 disease carry at least one allele with a 966 bp deletion in CLN3 which results in the deletion of exons 7 and 8. There is a need for more physiologically relevant human cell-based CLN3 disease models to better understand the cellular changes during the disease process. Using CRISPR/Cas9, we corrected the 966 bp deletion mutation in human induced pluripotent stem cells (iPSCs) of a compound heterozygous patient (CLN3 {Delta} 966 bp and E295K). The isogenic deletion-corrected and unedited CLN3 patient iPSCs were used for disease modeling. iPSC-derived neurons carrying this particular CLN3 mutation (CLN3 neurons) had lower functional activity as recorded using microelectrode arrays for most of the culture period. Proteomics analysis showed downregulation of proteins related to axon guidance and endocytosis at day in vitro (DIV) 14 and 42 in CLN3 neurons. This was accompanied by an increase in lysosomal-related proteins in CLN3 neurons. Western blot analysis revealed hyperglycosylation of the lysosomal marker, Lysosome Associated Membrane Protein 1 (LAMP1) in CLN3 neurons at DIV 14, 28 and 42, which was not apparent in control neurons. Ultrastructural analysis of CLN3 neurons showed numerous membrane-bound vacuoles containing diverse types of storage material, ranging from curvilinear deposits, multilamellar structures to osmiophilic deposits. Our findings suggest alterations in lysosomal function and neurodevelopment involving axon guidance and synaptic transmission in CLN3-deficient neuronal derivatives, which could be potential targets for therapy.

neuroscience↗

bioRxiv2021

Low intensity repetitive transcranial magnetic stimulation drives structural synaptic plasticity in the young and aged motor cortex.

BackgroundRepetitive transcranial magnetic stimulation (rTMS) is a non-invasive tool commonly used to drive neural plasticity in the young adult and aged brain. Recent data from mouse models have shown that even at subthreshold intensities (0.12 Tesla), rTMS can drive neuronal and glial plasticity in the motor cortex. However, the physiological mechanisms underlying subthreshold rTMS induced plasticity and whether these are altered with normal ageing are unclear. ObjectiveTo assess the effect of subthreshold rTMS, using the intermittent theta burst stimulation (iTBS) protocol on structural synaptic plasticity in the mouse motor cortex of young and aged mice. MethodsLongitudinal in vivo 2-photon microscopy was used to measure changes to the structural plasticity of pyramidal neuron dendritic spines in the motor cortex following a single train of subthreshold rTMS (in young adult and aged animals) or the same rTMS train administered on 4 consecutive days (in young adult animals only). Data were analysed with Bayesian hierarchical generalized linear regression models and interpreted with the aid of Bayes Factors (BF). ResultsWe found strong evidence (BF>10) that subthreshold rTMS altered the rate of dendritic spine losses and gains, dependent on the number of stimulation sessions and that a single session of subthreshold rTMS was effective in driving structural synaptic plasticity in both young adult and aged mice. ConclusionThese findings provide further evidence that rTMS drives synaptic plasticity in the brain and uncovers structural synaptic plasticity as a key mechanism of subthreshold rTMS induced plasticity.

neuroscience↗