Protein fibril aggregation on red blood cells: a potential biomarker to distinguish neurodegenerative diseases from healthy aging.

Neurodegenerative diseases like Alzheimer's disease are characterized by the accumulation of misfolded proteins into fibrils in the brain. Atomic force microscopy is a nanoscale imaging technique that can be used to resolve and quantify protein aggregates from oligomers to fibrils. Recently, we characterized protein fibrillar aggregates adsorbed on the surface of red blood cells with atomic force microscopy from patients with neurocognitive disorders, suggesting a novel Alzheimer's disease biomarker. However, the age association of fibril deposits on red blood cells has not yet been studied in detail in healthy adults. Here, we used atomic force microscopy to visualize and quantify fibril coverage on red blood cells in 50 healthy adults and 37 memory clinic patients. Fibrillar protein deposits sporadically appeared in healthy individuals but were much more prevalent in patients with neurodegenerative disease, especially those with Alzheimer's disease as confirmed by positive CSF amyloid beta 1-42/1-40 ratios. The prevalence of fibrils on the red blood cell surface did not significantly correlate with age in either healthy individuals or Alzheimer's disease patients. The overlap in fibril prevalence on red blood cells between Alzheimer's disease and amyloid-negative patients suggests that fibril deposition on red blood cells could occur in various neurodegenerative diseases. Quantifying red blood cell protein fibril morphology and prevalence on red blood cells could serve as a sensitive biomarker for neurodegeneration, distinguishing between healthy individuals and those with neurodegenerative diseases. Future studies that combine atomic force microscopy with immunofluorescence techniques in larger-scale studies could further identify the chemical nature of these fibrils, paving the way for a comprehensive, non-invasive biomarker platform for neurodegenerative diseases.

Object-centered sensorimotor bias of torque control in the chronic stage following stroke.

When lifting objects whose center of mass (CoM) are not centered below the handle one must compensate for arising external torques already at lift-off to avoid object tilt. Previous studies showed that finger force scaling during object lifting may be impaired at both hands following stroke. However, torque control in object manipulation has not yet been studied in patients with stroke. In this pilot study, thirteen patients with chronic stage left hemispheric stroke (SL), nine patients with right hemispheric stroke (SR) and hand-matched controls had to grasp and lift an object with the fingertips of their ipsilesional hand at a handle while preventing object tilt. Object CoM and therewith the external torque was varied by either relocating a covert weight or the handle. The compensatory torque at lift-off (Tcom) is the sum of the torque resulting from (1) grip force being produced at different vertical finger positions (∆CoP × GF) and (2) different vertical load forces on both sides of the handle (∆Fy × w/2). When having to rely on sensorimotor memories, ∆CoP × GF was elevated when the object CoM was on the ipsilesional-, but decreased when CoM was on the contralesional side in SL, whereas ∆Fy × w/2 was biased in the opposite direction, resulting in normal Tcom. SR patients applied a smaller ∆CoP × GF when the CoM was on the contralesional side. Torques were not altered when geometric cues were available. Our findings provide evidence for an object-centered spatial bias of manual sensorimotor torque control with the ipsilesional hand following stroke reminiscent of premotor neglect. Both intact finger force-to-position coordination and visuomotor control may compensate for the spatial sensorimotor bias in most stroke patients. Future studies will have to confirm the found bias and evaluate the association with premotor neglect.

Intention to be force efficient improves high-level anticipatory coordination of finger positions and forces in young and elderly adults.

Successful object manipulation requires anticipatory high-level control of finger positions and forces to prevent object slip and tilt. Unlike young adults, who efficiently scale grip forces (GFs) according to surface conditions, old adults were reported to exert excessive grip forces. In this study, we theoretically show how grip force economy depends on the modulation of the centers of pressure on opposing grip surfaces (ΔCoP) according to object properties. In a grasp-to-lift study with young and elderly participants, we investigated how the instruction to lift the object with efficient GF influences the anticipation of torques, ΔCoP and GF control during complex variations of mass distributions and surface properties. Provision of the explicit instruction to strive for force efficiency prompted both age groups to optimize their ΔCoP modulation, although to a lesser degree in the elderly, and also led to a refinement of torque anticipation for a right-sided weight distribution in the young, but not the elderly participants. Consequently, marked drops in GF levels resulted. Furthermore, participants enhanced ΔCoP modulation and lowered GF safety ratios in challenging surface conditions. Higher GF in the elderly was due to decreased skin-surface friction but also worse ΔCoP modulation for lateralized mass distributions when trying to be force efficient. In contrast, safety margins were not elevated in the elderly, suggesting preserved GF control. Our findings demonstrate how task goals influence high-level motor control of object manipulation differentially in young and elderly participants and highlight the necessity to control for both instructions and friction when investigating GF control.NEW & NOTEWORTHY Previous studies have shown that forces are covaried as a function of centers of pressure (CoPs) to exert adequate torques. Here, we demonstrate that force-efficient object manipulation requires the modulation of CoPs and show that providing the instruction to be force efficient and challenging surface conditions elicits a GF safety ratio reduction as well as an optimization of anticipatory CoP modulation and torques in the young and, to a lesser degree, in the elderly.

Visual cues, expectations, and sensorimotor memories in the prediction and perception of object dynamics during manipulation.

When we grasp and lift novel objects, we rely on visual cues and sensorimotor memories to predictively scale our finger forces and exert compensatory torques according to object properties. Recently, it was shown that object appearance, previous force scaling errors, and previous torque compensation errors strongly impact our percept. However, the influence of visual geometric cues on the perception of object torques and weights in a grasp to lift task is poorly understood. Moreover, little is known about how visual cues, prior expectations, sensory feedback, and sensorimotor memories are integrated for anticipatory torque control and object perception. Here, 12 young and 12 elderly participants repeatedly grasped and lifted an object while trying to prevent object tilt. Before each trial, we randomly repositioned both the object handle, providing a geometric cue on the upcoming torque, as well as a hidden weight, adding an unforeseeable torque variation. Before lifting, subjects indicated their torque expectations, as well as reporting their experience of torque and weight after each lift. Mixed-effect multiple regression models showed that visual shape cues governed anticipatory torque compensation, whereas sensorimotor memories played less of a role. In contrast, the external torque and committed compensation errors at lift-off mainly determined how object torques and weight were perceived. The modest effect of handle position differed for torque and weight perception. Explicit torque expectations were also correlated with anticipatory torque compensation and torque perception. Our main findings generalized across both age groups. Our results suggest distinct weighting of inputs for action and perception according to reliability.

Torque-planning errors affect the perception of object properties and sensorimotor memories during object manipulation in uncertain grasp situations.

Predicting instead of only reacting to the properties of objects we grasp is crucial to dexterous object manipulation. Although we normally plan our grasps according to well-learned associations, we rely on implicit sensorimotor memories when we learn to interact with novel or ambiguous objects. However, little is known about the influence of sensorimotor predictions on subsequent perception and action. Here, young and elderly subjects repeatedly lifted an object in which the center of mass (CoM) was randomly varied between trials straight upward with the aim of preventing object tilts. After each lift, subjects indicated the location of the perceived CoM and reported how heavy the object felt. Surprisingly, we found that sensorimotor torque memories eventually causing initial lifting errors had substantial effects on the perception of torques, weight, and the torque planning for the next lift. Whereas subjects tended to partly retain their previous erroneous sensorimotor memories (instead of solely relying on the previously encountered torque for the upcoming motor plan), they perceived encountered torques to be stronger when they erroneously predicted them. Additionally, we found that torque prediction errors, as well as the actual torques, made the object feel heavier. By contrast, perception did not influence upcoming motor control. There were no major differences observed between the age groups. The sensorimotor impact on torque perception can be explained by internal feedforward prediction highlighting task-relevant errors, while the partial retention and adaptation of sensorimotor torque memories is reconciled with the trial-to-trial learning rule for motor adaptation. NEW & NOTEWORTHY The current study is the first to demonstrate in an object manipulation task in uncertainty that errors in the sensorimotor prediction of torques influence the perception of both torques and weight, whereas sensorimotor torque memories are partly retained and partly adapted to planning errors. Our results provide novel insights into the predictive mechanisms underpinning the common everyday task of object manipulation and further support theories about the predictive modulation of perception established in other neuroscientific disciplines.