Erroneous Compensation for Long-Latency Feedback Delays as Origin of Essential Tremor.

Essential tremor (ET), a movement disorder characterized by involuntary oscillations of the limbs during movement, remains to date not well understood. It has been recently suggested that the tremor originates from impaired delay compensation, affecting movement representation and online control. Here we tested this hypothesis directly with 24 ET patients (14 female; 10 male) and 28 neurologically intact (NI) human volunteers (17 female; 11 male) in an upper limb postural perturbation task. After maintaining their hand in a visual target, participants experienced perturbations of unpredictable direction and magnitude and were instructed to counter the perturbation and steer their hand back to the starting position. In comparison with NI volunteers, ET patients' early muscular responses (short and long-latency responses, 20-50 and 50-100 ms, respectively) were preserved or even slightly increased. However, they exhibited perturbation-dependent deficits when stopping and stabilizing their hand in the final target supporting the hypothesis that the tremor was generated by the feedback controller. We show in a computational model that errors in delay compensation accumulating over time produced the same small increase in initial feedback response followed by oscillations that scaled with the perturbation magnitude as observed in ET population. Our experimental results therefore validate the computational hypothesis that inaccurate delay compensation in long-latency pathways could be the origin of the tremor.

The spatial extent of tauopathy on [18F]MK-6240 tau PET shows stronger association with cognitive performances than the standard uptake value ratio in Alzheimer's disease.

PURPOSE: [18F]MK-6240, a second-generation tau PET tracer, is increasingly used for the detection and the quantification of in vivo cerebral tauopathy in Alzheimer's disease (AD). Given that neurological symptoms are better explained by the topography rather than by the nature of brain lesions, our study aimed to evaluate whether cognitive impairment would be more closely associated with the spatial extent than with the intensity of tau-PET signal, as measured by the standard uptake value ratio (SUVr). METHODS: [18F]MK6240 tau-PET data from 82 participants in the AD spectrum were quantified in three different brain regions (Braak ≤ 2, Braak ≤ 4, and Braak ≤ 6) using SUVr and the extent of tauopathy (EOT, percentage of voxels with SUVr ≥ 1.3). PET data were first compared between diagnostic categories, and ROC curves were computed to evaluate sensitivity and specificity. PET data were then correlated to cognitive performances and cerebrospinal fluid (CSF) tau values. RESULTS: The EOT in the Braak ≤ 2 region provided the highest diagnostic accuracies, distinguishing between amyloid-negative and positive clinically unimpaired individuals (threshold = 9%, sensitivity = 79%, specificity = 82%) as well as between prodromal AD and preclinical AD (threshold = 38%, sensitivity = 81%, specificity = 93%). The EOT better correlated with cognition than SUVr (∆R2 + 0.08-0.09) with the best correlation observed for EOT in the Braak ≤ 4 region (R2 = 0.64). Cognitive performances were more closely associated with PET metrics than with CSF values. CONCLUSIONS: Quantifying [18F]MK-6240 tau PET in terms of EOT rather than SUVr significantly increases the correlation with cognitive performances. Quantification in the mesiotemporal lobe is the most useful to diagnose preclinical AD or prodromal AD.

Definition of a Threshold for the Plasma Aß42/Aß40 Ratio Measured by Single-Molecule Array to Predict the Amyloid Status of Individuals without Dementia.

Alzheimer's disease (AD) is characterized by amyloid beta (Aß) plaques and hyperphosphorylated tau in the brain. Aß plaques precede cognitive impairments and can be detected through amyloid-positron emission tomography (PET) or in cerebrospinal fluid (CSF). Assessing the plasma Aß42/Aß40 ratio seems promising for non-invasive and cost-effective detection of brain Aß accumulation. This approach involves some challenges, including the accuracy of blood-based biomarker measurements and the establishment of clear, standardized thresholds to categorize the risk of developing brain amyloid pathology. Plasma Aß42/Aß40 ratio was measured in 277 volunteers without dementia, 70 AD patients and 18 non-AD patients using single-molecule array. Patients (n = 88) and some volunteers (n = 66) were subject to evaluation of amyloid status by CSF Aß quantification or PET analysis. Thresholds of plasma Aß42/Aß40 ratio were determined based on a Gaussian mixture model, a decision tree, and the Youden's index. The 0.0472 threshold, the one with the highest sensitivity, was retained for general population without dementia screening, and the 0.0450 threshold was retained for research and clinical trials recruitment, aiming to minimize the need for CSF or PET analyses to identify amyloid-positive individuals. These findings offer a promising step towards a cost-effective method for identifying individuals at risk of developing AD.

Comparison of plasma soluble and extracellular vesicles-associated biomarkers in Alzheimer's disease patients and cognitively normal individuals.

BACKGROUND: Amyloid-ß (Aß) and tau are brain hallmarks of Alzheimer's disease (AD), also present in blood as soluble biomarkers or encapsulated in extracellular vesicles (EVs). Our goal was to assess how soluble plasma biomarkers of AD pathology correlate with the number and content of EVs. METHODS: Single-molecule enzyme-linked assays were used to quantify Aß42/40 and tau in plasma samples and neurally-derived EVs (NDEVs) from a cohort of APOE ε4- (n = 168) and APOE ε4+ (n = 68) cognitively normal individuals and AD patients (n = 55). The ratio of CD56 (Neuronal cell-adhesion molecule) to CD81 signal measured by ELISA-DELFIA was used for the relative quantification of NDEVs in plasma samples. RESULTS: The soluble plasma Aß42/40 ratio is decreased in AD patients compared to cognitively normal individuals. The amount and content (Aß40, Aß42, tau) of plasma NDEVs were similar between groups. Plasma NDEVs quantity remain consistent with aging and between AD and CN individuals. However, the quantity of soluble biomarkers was negatively correlated to NDEVs number in cognitively normal individuals, while in AD patients, this correlation is lost, suggesting a shift in the mechanism underpinning the production and the release of these biomarkers in pathological conditions. CONCLUSION: Soluble plasma Aß42/40 ratio is the most robust biomarker to discriminate between AD patients and CN individuals, as it normalizes for the number of NDEVs. Analysis of NDEVs and their content pointed toward peculiar mechanisms of Aß release in AD. Further research on independent cohorts can confirm our findings and assess whether plasma Aß and tau need correction by NDEVs for better AD risk identification in CN populations.

Suspecting Non-Alzheimer's Pathologies and Mixed Pathologies: A Comparative Study Between Brain Metabolism and Tau Images.

BACKGROUND: Alzheimer's disease (AD) pathology can be disclosed in vivo using amyloid and tau imaging, unlike non-AD neuropathologies for which no specific markers exist. OBJECTIVE: We aimed to compare brain hypometabolism and tauopathy to unveil non-AD pathologies. METHODS: Sixty-one patients presenting cognitive complaints (age 48-90), including 32 with positive AD biomarkers (52%), performed [18F]-Fluorodeoxyglucose (FDG)-PET (brain metabolism) and [18F]-MK-6240-PET (tau). We normalized these images using data from clinically normal individuals (n = 30), resulting in comparable FDG and tau z-scores. We computed between-patients correlations to evaluate regional associations. For each patient, a predominant biomarker (i.e., Hypometabolism > Tauopathy or Hypometabolism≤Tauopathy) was determined in the temporal and frontoparietal lobes. We computed within-patient correlations between tau and metabolism and investigated their associations with demographics, cognition, cardiovascular risk factors (CVRF), CSF biomarkers, and white matter hypointensities (WMH). RESULTS: We observed negative associations between tau and FDG in 37 of the 68 cortical regions-of-interest (average Pearson's r = -0.25), mainly in the temporal lobe. Thirteen patients (21%) had Hypometabolism > Tauopathy whereas twenty-five patients (41%) had Hypometabolism≤Tauopathy. Tau-predominant patients were more frequently females and had greater amyloid burden. Twenty-three patients (38%) had Hypometabolism≤Tauopathy in the temporal lobe, but Hypometabolism > Tauopathy in the frontoparietal lobe. This group was older and had higher CVRF than Tau-predominant patients. Patients with more negative associations between tau and metabolism were younger, had worse cognition, and greater amyloid and WMH burdens. CONCLUSIONS: Tau-FDG comparison can help suspect non-AD pathologies in patients presenting cognitive complaints. Stronger Tau-FDG correlations are associated with younger age, worse cognition, and greater amyloid and WMH burdens.

Dissociating effects of aging and genetic risk of sporadic Alzheimer's disease on path integration.

Path integration is a spatial navigation ability that requires the integration of information derived from self-motion cues and stable landmarks, when available, to return to a previous location. Path integration declines with age and Alzheimer's disease (AD). Here, we sought to separate the effects of age and AD risk on path integration, with and without a landmark. Overall, 279 people participated, aged between 18 and 80 years old. Advanced age impaired the appropriate use of a landmark. Older participants furthermore remembered the location of the goal relative to their starting location and reproduced this initial view without considering that they had moved in the environment. This lack of adaptative behavior was not associated with AD risk. In contrast, participants at genetic risk of AD (apolipoprotein E ε4 carriers) exhibited a pure path integration deficit, corresponding to difficulty in performing path integration in the absence of a landmark. Our results show that advanced-age impacts landmark-supported path integration, and that this age effect is dissociable from the effects of AD risk impacting pure path integration.

Teamwork enables high level of early mobilization in critically ill patients.

BACKGROUND: Early mobilization in critically ill patients has been shown to prevent bed-rest-associated morbidity. Reported reasons for not mobilizing patients, thereby excluding or delaying such intervention, are diverse and comprise safety considerations for high-risk critically ill patients with multiple organ support systems. This study sought to demonstrate that early mobilization performed within the first 24 h of ICU admission proves to be feasible and well tolerated in the vast majority of critically ill patients. RESULTS: General practice data were collected for 171 consecutive admissions to our ICU over a 2-month period according to a local, standardized, early mobilization protocol. The total period covered 731 patient-days, 22 (3 %) of which met our local exclusion criteria for mobilization. Of the remaining 709 patient-days, early mobilization was achieved on 86 % of them, bed-to-chair transfer on 74 %, and at least one physical therapy session on 59 %. Median time interval from ICU admission to the first early mobilization activity was 19 h (IQR = 15-23). In patients on mechanical ventilation (51 %), accounting for 46 % of patient-days, 35 % were administered vasopressors and 11 % continuous renal replacement therapy. Within this group, bed-to-chair transfer was achieved on 68 % of patient-days and at least one early mobilization activity on 80 %. Limiting factors to start early mobilization included restricted staffing capacities, diagnostic or surgical procedures, patients' refusal, as well as severe hemodynamic instability. Hemodynamic parameters were rarely affected during mobilization, causing interruption in only 0.8 % of all activities, primarily due to reversible hypotension or arrhythmia. In general, all activities were well tolerated, while patients were able to self-regulate their active early mobilization. Patients' subjective perception of physical therapy was reported to be enjoyable. CONCLUSIONS: Mobilization within the first 24 h of ICU admission is achievable in the majority of critical ill patients, in spite of mechanical ventilation, vasopressor administration, or renal replacement therapy.