Exploring the Usage of Text-Entry as a Digital Endpoint in Parkinson’s Disease

Tese de mestrado, Informática, 2022, Universidade de Lisboa, Faculdade de CiênciasNeurodegenerative diseases are a group of diseases characterised by the loss of neurons and tend to be fatal. The most researched being Parkinson’s disease, some connections have been established between this disease and the use of text-entry towards its diagnosis and monitoring. With such scattered information regarding neurodegenerative diseases and text-entry, a systematic review was carried out to show which diseases have been researched in that direction, being mainly PD but also MCI and MS. The main metrics collected were flight time, hold time and pressure. As previous research did not include clinicians participation towards the design of diagnosing and monitoring tools, this dissertation went a step further and worked together with clinicians to understand their expectations on data and its visualisations. Clinicians believe that text-entry does have potential towards the diagnosis and monitoring of neurodegenerative diseases. Clinicians also provided concepts of interest against recently suggested metrics, such as apraxia, bradykinesia and dyskinesia. Finally, it was possible to understand how clinicians would deem to be the best way to view the data for the patients’ assessments

Immunohistochemical and electrophysiological investigation of E/I balance alterations in animal models of frontotemporal dementia

Behavioural variant frontotemporal dementia (bvFTD) is a neurodegenerative disease characterised by changes in behaviour. Apathy, behavioural disinhibition and stereotyped behaviours are the first symptoms to appear and all have a basis in reward and pleasure deficits. The ventral striatum and ventral regions of the globus pallidus are involved in reward and pleasure. It is therefore reasonable to suggest alterations in these regions may underpin bvFTD. One postulated contributory factor is alteration in E/I balance in striatal regions. GABAergic interneurons play a role in E/I balance, acting as local inhibitory brakes, they are therefore a rational target for research investigating early biological predictors of bvFTD. To investigate this, we will carry out immunohistochemical staining for GABAergic interneurons (parvalbumin and neuronal nitric oxide synthase) in striatal regions of brains taken from CHMP2B mice, a validated animal model of bvFTD. We hypothesise that there will be fewer GABAergic interneurons in the striatum which may lead to ‘reward-seeking’ behaviour in bvFTD. This will also enable us to investigate any preclinical alterations in interneuron expression within this region. Results will be analysed using a mixed ANOVA and if significant, post hoc t-tests will be used. The second part of our study will involve extracellular recordings from CHMP2B mouse brains using a multi-electrode array (MEA). This will enable us to determine if there are alterations in local field potentials (LFP) in preclinical and symptomatic animals. We will also be able to see if neuromodulators such as serotonin and dopamine effect LFPs after bath application. We will develop slice preparations to preserve pathways between the ventral tegmental area and the ventral pallidum, an output structure of the striatum, and the dorsal raphe nucleus and the VP. Using the MEA we will stimulate an endogenous release of dopamine and serotonin using the slice preparations as described above. This will enable us to see if there are any changes in LFPs after endogenous release of neuromodulators. We hypothesise there will be an increase in LFPs due to loss of GABAergic interneurons

Motor Impairment Estimates via Touchscreen Typing Dynamics Toward Parkinson's Disease Detection From Data Harvested In-the-Wild

Parkinson's Disease (PD) is a neurodegenerative disorder with early non-motor/motor symptoms that may evade clinical detection for years after the disease onset due to their mildness and slow progression. Digital health tools that process densely sampled data streams from the daily human-mobile interaction can objectify the monitoring of behavioral patterns that change due to the appearance of early PD-related signs. In this context, touchscreens can capture micro-movements of fingers during natural typing; an unsupervised activity of high frequency that can reveal insights for users' fine-motor handling and identify motor impairment. Subjects' typing dynamics related to their fine-motor skills decline, unobtrusively captured from a mobile touchscreen, were recently explored in-the-clinic assessment to classify early PD patients and controls. In this study, estimation of individual fine motor impairment severity scores is employed to interpret the footprint of specific underlying symptoms [such as brady-/hypokinesia (B/H-K) and rigidity (R)] to keystroke dynamics that cause group-wise variations. Regression models are employed for each fine-motor symptom, by exploiting features from keystroke dynamics sequences from in-the-clinic data captured from 18 early PD patients and 15 healthy controls. Results show that R and B/H-K UPDRS Part III single items scores can be predicted with an accuracy of 78 and 70%, respectively. The generalization power of these trained regressors derived from in-the-clinic data was further tested in a PD screening problem using data harvested in-the-wild for a longitudinal period of time (mean ± std : 7 ± 14 weeks) via a dedicated smartphone application for unobtrusive sensing of their routine smartphone typing. From a pool of 210 active users, data from 13 self-reported PD patients and 35 controls were selected based on demographics matching with the ones in-the-clinic setting. The results have shown that the estimated index achieve {0.84 (R), 0.80 (B/H−K)} ROC AUC, respectively, with {sensitivity/specificity : 0.77/0.8 (R), 0.92/0.63 (B/H−K)}, on classifying PD and controls in-the-wild setting. Apparently, the proposed approach constitutes a step forward to unobtrusive remote screening and detection of specific early PD signs from mobile-based human-computer interaction, introduces an interpretable methodology for the medical community and contributes to the continuous improvement of deployed tools and technologies in-the-wild

Psr1p interacts with SUN/sad1p and EB1/mal3p to establish the bipolar spindle

Regular Abstracts - Sunday Poster Presentations: no. 382During mitosis, interpolar microtubules from two spindle pole bodies (SPBs) interdigitate to create an antiparallel microtubule array for accommodating numerous regulatory proteins. Among these proteins, the kinesin-5 cut7p/Eg5 is the key player responsible for sliding apart antiparallel microtubules and thus helps in establishing the bipolar spindle. At the onset of mitosis, two SPBs are adjacent to one another with most microtubules running nearly parallel toward the nuclear envelope, creating an unfavorable microtubule configuration for the kinesin-5 kinesins. Therefore, how the cell organizes the antiparallel microtubule array in the first place at mitotic onset remains enigmatic. Here, we show that a novel protein psrp1p localizes to the SPB and plays a key role in organizing the antiparallel microtubule array. The absence of psr1+ leads to a transient monopolar spindle and massive chromosome loss. Further functional characterization demonstrates that psr1p is recruited to the SPB through interaction with the conserved SUN protein sad1p and that psr1p physically interacts with the conserved microtubule plus tip protein mal3p/EB1. These results suggest a model that psr1p serves as a linking protein between sad1p/SUN and mal3p/EB1 to allow microtubule plus ends to be coupled to the SPBs for organization of an antiparallel microtubule array. Thus, we conclude that psr1p is involved in organizing the antiparallel microtubule array in the first place at mitosis onset by interaction with SUN/sad1p and EB1/mal3p, thereby establishing the bipolar spindle.postprin

Removal of antagonistic spindle forces can rescue metaphase spindle length and reduce chromosome segregation defects

Regular Abstracts - Tuesday Poster Presentations: no. 1925Metaphase describes a phase of mitosis where chromosomes are attached and oriented on the bipolar spindle for subsequent segregation at anaphase. In diverse cell types, the metaphase spindle is maintained at a relatively constant length. Metaphase spindle length is proposed to be regulated by a balance of pushing and pulling forces generated by distinct sets of spindle microtubules and their interactions with motors and microtubule-associated proteins (MAPs). Spindle length appears important for chromosome segregation fidelity, as cells with shorter or longer than normal metaphase spindles, generated through deletion or inhibition of individual mitotic motors or MAPs, showed chromosome segregation defects. To test the force balance model of spindle length control and its effect on chromosome segregation, we applied fast microfluidic temperature-control with live-cell imaging to monitor the effect of switching off different combinations of antagonistic forces in the fission yeast metaphase spindle. We show that spindle midzone proteins kinesin-5 cut7p and microtubule bundler ase1p contribute to outward pushing forces, and spindle kinetochore proteins kinesin-8 klp5/6p and dam1p contribute to inward pulling forces. Removing these proteins individually led to aberrant metaphase spindle length and chromosome segregation defects. Removing these proteins in antagonistic combination rescued the defective spindle length and, in some combinations, also partially rescued chromosome segregation defects. Our results stress the importance of proper chromosome-to-microtubule attachment over spindle length regulation for proper chromosome segregation.postprin