Synaptic Loss in Frontotemporal Dementia Revealed by [11 C]UCB-J Positron Emission Tomography.

OBJECTIVE: Synaptic loss is an early feature of neurodegenerative disease models, and is severe in post mortem clinical studies, including frontotemporal dementia. Positron emission tomography (PET) with radiotracers that bind to synaptic vesicle glycoprotein 2A enables quantification of synaptic density in vivo. This study used [11 C]UCB-J PET in participants with behavioral variant frontotemporal dementia (bvFTD), testing the hypothesis that synaptic loss is severe and related to clinical severity. METHODS: Eleven participants with clinically probable bvFTD and 25 age- and sex-matched healthy controls were included. Participants underwent dynamic [11 C]UCB-J PET, structural magnetic resonance imaging, and a neuropsychological battery, including the revised Addenbrooke Cognitive Examination, and INECO frontal screening. General linear models compared [11 C]UCB-J binding potential maps and gray matter volume between groups, and assessed associations between synaptic density and clinical severity in patients. Analyses were also performed using partial volume corrected [11 C]UCB-J binding potential from regions of interest (ROIs). RESULTS: Patients with bvFTD showed severe synaptic loss compared to controls. [11 C]UCB-J binding was reduced bilaterally in medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insular cortex, and medial temporal lobe. Synaptic loss in the frontal and cingulate regions correlated significantly with cognitive impairments. Synaptic loss was more severe than atrophy. Results from ROI-based analyses mirrored the voxelwise results. INTERPRETATION: In accordance with preclinical models, and human postmortem evidence, there is widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to severity. [11 C]UCB-J PET could support translational studies and experimental medicine strategies for new disease-modifying treatments for neurodegeneration. ANN NEUROL 2023;93:142-154.

Differential Synaptic Loss in ß-Amyloid Positive Versus ß-Amyloid Negative Corticobasal Syndrome.

BACKGROUND/OBJECTIVE: The corticobasal syndrome (CBS) is a complex asymmetric movement disorder, with cognitive impairment. Although commonly associated with the primary 4-repeat-tauopathy of corticobasal degeneration, clinicopathological correlation is poor, and a significant proportion is due to Alzheimer's disease (AD). Synaptic loss is a pathological feature of many clinical and preclinical tauopathies. We therefore measured the degree of synaptic loss in patients with CBS and tested whether synaptic loss differed according to ß-amyloid status. METHODS: Twenty-five people with CBS, and 32 age-/sex-/education-matched healthy controls participated. Regional synaptic density was estimated by [11C]UCB-J non-displaceable binding potential (BPND), AD-tau pathology by [18F]AV-1451 BPND, and gray matter volume by T1-weighted magnetic resonance imaging. Participants with CBS had ß-amyloid imaging with 11C-labeled Pittsburgh Compound-B ([11C]PiB) positron emission tomography. Symptom severity was assessed with the progressive supranuclear palsy-rating-scale, the cortical basal ganglia functional scale, and the revised Addenbrooke's Cognitive Examination. Regional differences in BPND and gray matter volume between groups were assessed by ANOVA. RESULTS: Compared to controls, patients with CBS had higher [18F]AV-1451 uptake, gray matter volume loss, and reduced synaptic density. Synaptic loss was more severe and widespread in the ß-amyloid negative group. Asymmetry of synaptic loss was in line with the clinically most affected side. DISCUSSION: Distinct patterns of [11C]UCB-J and [18F]AV-1451 binding and gray matter volume loss, indicate differences in the pathogenic mechanisms of CBS according to whether it is associated with the presence of Alzheimer's disease or not. This highlights the potential for different therapeutic strategies in CBSs. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Network connectivity and structural correlates of survival in progressive supranuclear palsy and corticobasal syndrome.

There is a pressing need to understand the factors that predict prognosis in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), with high heterogeneity over the poor average survival. We test the hypothesis that the magnitude and distribution of connectivity changes in PSP and CBS predict the rate of progression and survival time, using datasets from the Cambridge Centre for Parkinson-plus and the UK National PSP Research Network (PROSPECT-MR). Resting-state functional MRI images were available from 146 participants with PSP, 82 participants with CBS, and 90 healthy controls. Large-scale networks were identified through independent component analyses, with correlations taken between component time series. Independent component analysis was also used to select between-network connectivity components to compare with baseline clinical severity, longitudinal rate of change in severity, and survival. Transdiagnostic survival predictors were identified using partial least squares regression for Cox models, with connectivity compared to patients' demographics, structural imaging, and clinical scores using five-fold cross-validation. In PSP and CBS, between-network connectivity components were identified that differed from controls, were associated with disease severity, and were related to survival and rate of change in clinical severity. A transdiagnostic component predicted survival beyond demographic and motion metrics but with lower accuracy than an optimal model that included the clinical and structural imaging measures. Cortical atrophy enhanced the connectivity changes that were most predictive of survival. Between-network connectivity is associated with variability in prognosis in PSP and CBS but does not improve predictive accuracy beyond clinical and structural imaging metrics.

Longitudinal Synaptic Loss in Primary Tauopathies: An In Vivo [11 C]UCB-J Positron Emission Tomography Study.

BACKGROUND: Synaptic loss is characteristic of many neurodegenerative diseases; it occurs early and is strongly related to functional deficits. OBJECTIVE: In this longitudinal observational study, we determine the rate at which synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and we test the relationship with disease progression. METHODS: Our cross-sectional cohort included 32 participants with probable PSP and 16 with probable CBD (all amyloid-negative corticobasal syndrome), recruited from tertiary care centers in the United Kingdom, and 33 sex- and age-matched healthy control subjects. Synaptic density was estimated by positron emission tomography imaging with the radioligand [11 C]UCB-J that binds synaptic vesicle 2A. Clinical severity and cognition were assessed by the PSP Rating Scale and the Addenbrooke's cognitive examination. Regional [11 C]UCB-J nondisplaceable binding potential was estimated in Hammersmith Atlas regions of interest. Twenty-two participants with PSP/CBD had a follow-up [11 C]UCB-J positron emission tomography scan after 1 year. We calculated the annualized change in [11 C]UCB-J nondisplaceable binding potential and correlated this with the change in clinical severity. RESULTS: We found significant annual synaptic loss within the frontal lobe (-3.5%, P = 0.03) and the right caudate (-3.9%, P = 0.046). The degree of longitudinal synaptic loss within the frontal lobe correlated with the rate of change in the PSP Rating Scale (R = 0.47, P = 0.03) and cognition (Addenbrooke's Cognitive Examination-Revised, R = -0.62, P = 0.003). CONCLUSIONS: We provide in vivo evidence for rapid progressive synaptic loss, correlating with clinical progression in primary tauopathies. Synaptic loss may be an important therapeutic target and outcome variable for early-phase clinical trials of disease-modifying treatments. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Pre-diagnostic cognitive and functional impairment in multiple sporadic neurodegenerative diseases.

INTRODUCTION: The pathophysiological processes of neurodegenerative diseases begin years before diagnosis. However, pre-diagnostic changes in cognition and physical function are poorly understood, especially in sporadic neurodegenerative disease. METHODS: UK Biobank data were extracted. Cognitive and functional measures in individuals who subsequently developed Alzheimer's disease (AD), Parkinson disease, frontotemporal dementia, progressive supranuclear palsy, dementia with Lewy bodies, or multiple system atrophy were compared against individuals without neurodegenerative diagnoses. The same measures were regressed against time to diagnosis, after adjusting for the effects of age. RESULTS: There was evidence for pre-diagnostic cognitive impairment and decline with time, particularly in AD. Pre-diagnostic functional impairment and decline were observed in multiple diseases. DISCUSSION: The scale and longitudinal follow-up of UK Biobank participants provides evidence for cognitive and functional decline years before symptoms become obvious in multiple neurodegenerative diseases. Identifying pre-diagnostic functional and cognitive changes could improve selection for preventive and early disease-modifying treatment trials.

Temporal dynamics predict symptom onset and cognitive decline in familial frontotemporal dementia.

INTRODUCTION: We tested whether changes in functional networks predict cognitive decline and conversion from the presymptomatic prodrome to symptomatic disease in familial frontotemporal dementia (FTD). METHODS: For hypothesis generation, 36 participants with behavioral variant FTD (bvFTD) and 34 controls were recruited from one site. For hypothesis testing, we studied 198 symptomatic FTD mutation carriers, 341 presymptomatic mutation carriers, and 329 family members without mutations. We compared functional network dynamics between groups, with clinical severity and with longitudinal clinical progression. RESULTS: We identified a characteristic pattern of dynamic network changes in FTD, which correlated with neuropsychological impairment. Among presymptomatic mutation carriers, this pattern of network dynamics was found to a greater extent in those who subsequently converted to the symptomatic phase. Baseline network dynamic changes predicted future cognitive decline in symptomatic participants and older presymptomatic participants. DISCUSSION: Dynamic network abnormalities in FTD predict cognitive decline and symptomatic conversion. HIGHLIGHTS: We investigated brain network predictors of dementia symptom onset Frontotemporal dementia results in characteristic dynamic network patterns Alterations in network dynamics are associated with neuropsychological impairment Network dynamic changes predict symptomatic conversion in presymptomatic carriers Network dynamic changes are associated with longitudinal cognitive decline.

Does performance level affect initial ball flight kinematics in finger and wrist-spin cricket bowlers?

Spin bowling plays a fundamental role within the game of cricket yet little is known about the initial ball kinematics in elite and pathway spin bowlers or their relationship to performance. Therefore, the purpose of this study was to record three-dimensional ball kinematics in a large and truly high level cohort of elite and pathway finger-spin (FS) and wrist-spin (WS) bowlers, identifying potential performance measures that can be subsequently used in future research. A 22-camera Vicon motion analysis system captured retro-reflective markers placed on the seam (static) and ball (dynamic) to quantify ball kinematics in 36 FS (12 elite and 24 pathway) and 20 WS (eight elite and 12 pathway) bowlers. Results indicated that FS bowlers delivered the ball with an increased axis of rotation elevation, while wrist-spin bowlers placed greater amounts of revolutions on the ball. It also highlighted that ball release (BR) velocity, revolutions and velocity/revolution index scores for both groups and seam stability for FS bowlers, and seam azimuth angle and spin axis elevation angle for WS bowlers, were discriminators of playing level. As such these variables could be used as indicators of performance (i.e. performance measures) in future research.

Spatial characteristics of professional tennis serves with implications for serving aces: A machine learning approach.

This study sought to determine the features of an ideal serve in men's professional tennis. A total of 25,680 first serves executed by 151 male tennis players during Australian Open competition were classified as either aces or returned into play. Spatiotemporal (impact location, speed, projection angles, landing location and relative player locations) and contextual (score) features of each serve were extracted from Hawk-Eye data and used to construct a classification tree model (with decision rules) that predicted serve outcome. k-means clustering was applied to the landing locations to quantify optimal landing locations for aces. The classification tree revealed that (1) serve directionality, relative to the returner; (2) the ball's landing proximity to the nearest service box line and (3) serve speed classified aces with an accuracy of 87.02%. Hitting aces appeared more contingent on accuracy than speed, with serves directed >5.88° from the returner and landing <15.27 cm from a service box line most indicative of an ace. k-means clustering revealed four distinct locations (≈0.73 m wide × 2.35 m deep) in the corners of the service box that corresponded to aces. These landing locations provide empirically derived target locations for players to adhere to during practice and competition.

In Vivo Hip Morphology and Kinematics in Elite Baseball Pitchers.

PURPOSE: To compare passive and real-time active hip range of motion (ROM) in asymptomatic collegiate pitchers, to investigate whether differences in hip morphology and ROM exist between lead and trail hips, and to relate active hip ROM during the pitch to hip morphology and femoroacetabular impingement. METHODS: Eleven collegiate baseball pitchers participated in kinematic testing that involved throwing 4 fastball pitches while wearing a full-body inertial-based motion-capture system. Passive flexion and rotation of each hip were measured using a goniometer. Nine pitchers also underwent a computed tomography (CT) pelvic scan, from which subject-specific computer models for each hip were created. Morphologic measurements were calculated from the models, and the models were tested for impingement during simulated pitching. RESULTS: Hip flexion was the only passive ROM measurement showing a significant difference between the lead and trail hips (mean difference [MD], 4°; P = .027). During the pitching motion, within-individual differences were discovered between the lead and trail hips for flexion (MD, 34°; P < .0001), extension (MD, 26°; P < .0001), abduction (MD, 8°; P = .026), adduction (MD, 6°; P = .008), external rotation (MD, 20°; P = .001), and total arc of rotation (MD, 13°; P = .001). There were no significant differences in morphologic measures between the lead and trail hips. Dynamic CT modeling did not lead to bony impingement in any subject. CONCLUSIONS: Asymptomatic collegiate pitchers approach their extremes of passive hip rotation when executing a fastball pitch. No differences were found in passive hip ROM or morphology other than a small difference in passive hip flexion. Dynamic CT modeling did not show femoroacetabular impingement during the pitching motion. CLINICAL RELEVANCE: Hip dysmorphology or poor pitching mechanics may lead to a high risk of bony impingement because pitchers have little reserve hip motion during the fastball pitch.

Matchplay characteristics of Grand Slam tennis: implications for training and conditioning.

The purpose of this study was to probe the sex-based differences in the stroke and movement dynamics of Grand Slam hard-court tennis. Player and ball tracking data were collated for 102 male and 95 female players during the 2012-2014 Australian Open tournaments. Serve, serve return, groundstroke and movement data were compared between sexes. Serve statistics were the subject of the largest differences, with males achieving significantly faster speeds, aces and unreturned serves while also winning a greater percentage of service points. When returning serve, women contacted the ball closer to the net, lower to the ground and achieved flatter ball trajectories than males. Groundstroke frequencies were similar between sexes, although males hit with greater speed, flatter trajectories and impacted more shots inside the baseline. Distance covered per set or during points won or lost was not sex dependent, yet men exhibited faster average movement speeds. These findings highlight the need for sex-specific training and practice designs that cater to the different stroke dynamics, particularly in relation to the first serve and serve-return, as well as movement speeds.

Ball Speed and Release Consistency Predict Pitching Success in Major League Baseball.

Whiteside, D, Martini, DN, Zernicke, RF, and Goulet, GC. Ball speed and release consistency predict pitching success in Major League Baseball. J Strength Cond Res XX(X): 000-000, 2015-This study aimed to quantify how ball flight kinematics (i.e., ball speed and movement), release location, and variations therein relate to pitching success in Major League Baseball (MLB). One hundred ninety starting MLB pitchers met the inclusion criteria for this study. Ball trajectory information was collected for 76,000 pitches and inserted into a forward stepwise multiple regression model, which examined how (a) pitch selection, (b) ball speed, (c) ball movement (horizontal and lateral), (d) release location (horizontal and lateral), (e) variation in pitch speed, (f) variation in ball movement, and (g) variation in release location related to pitching success (as measured by fielding independent pitching-FIP). Pitch speed, release location variability, variation in pitch speed, and horizontal release location were significant predictors of FIP and, collectively, accounted for 24% of the variance in FIP. These findings suggest that (a) maximizing ball speed, (b) refining a consistent spatial release location, and (c) using varied pitch speeds should be primary foci for the pitching coach. However, between-pitcher variations underline how training interventions should be administered at the individual level, with consideration given to the pitcher's injury history. Finally, despite offering significant predictors of success, these three factors explained only 22% of the variance in FIP and should not be considered the only, or preeminent, indicators of a pitcher's effectiveness. Evidently, traditional pitching metrics only partly account for a pitcher's effectiveness, and future research is necessary to uncover the remaining contributors to success.

Grading the Functional Movement Screen: A Comparison of Manual (Real-Time) and Objective Methods.

Although intertester and intratester reliability have been common themes in Functional Movement Screen (FMS) research, the criterion validity of manual grading is yet to be comprehensively examined. This study compared the FMS scores assigned by a certified FMS tester to those measured by an objective inertial-based (IMU) motion capture system. Eleven female division I collegiate athletes performed 6 FMS exercises and were manually graded by a certified tester. Explicit kinematic thresholds were formulated to correspond to each of the grading criteria for each FMS exercise and then used to grade athletes objectively using the IMU data. The levels of agreement between the 2 grading methods were poor in all 6 FMS exercises and implies that manual grading of the FMS may be confounded by vague grading criteria. Evidently, more explicit grading guidelines are needed to improve the uniformity and accuracy of manual FMS grading and also facilitate the use of objective measurement systems in the grading process. Contrary to the approach that has been adopted in several previous studies, the potential for subjective and/or inaccurate FMS grading intimates that it may be inappropriate to assume that manual FMS grading provides a valid measurement tool. Consequently, the development and criterion validation of uniform grading procedures must precede research attempting to link FMS performance and injury rates. With manual grading methods seemingly susceptible to error, the FMS should be used cautiously to direct strength and/or conditioning programs.

Lumbar Mechanics in Tennis Groundstrokes: Differences in Elite Adolescent Players With and Without Low Back Pain.

Adolescent tennis players are at risk for low back pain (LBP). Recent research has demonstrated a potential mechanical etiology during serves; however, groundstrokes have also been suggested to load this region. Therefore, this study compared lumbar mechanics between players with and without a history of LBP during open and square stance tennis forehands and backhands. Nineteen elite, adolescent, male tennis players participated, 7 with a history of recurrent disabling LBP and 12 without. Differences in three-dimensional lumbar kinetics and kinematics were compared between pain/no pain groups and groundstrokes using linear mixed models (P < .01). There were no significant differences between pain/no pain groups. Relative to a right-handed player, groundstroke comparisons revealed that forehands had greater racquet velocity, greater lumbar right lateral flexion force, as well as upper lumbar extension/rightward rotation and lower lumbar right rotation/lateral flexion movements that were closer to or further beyond end of range than backhands. Backhands required upper lumbar leftward rotation that was beyond end range, while forehands did not. Given that players typically rotated near to their end of range during the backswing of both forehands and backhands, independent of pain, groundstrokes may contribute to the cumulative strain linked to LBP in tennis players.

A kinematic comparison of the overhand throw and tennis serve in tennis players: how similar are they really?

Tennis coaches often use the fundamental throwing skill as a training tool to develop the service action. However, recent skill acquisition literature questions the efficacy of non-specific training drills for developing complex sporting movements. Thus, this study examined the mechanical analogy of the throw and the tennis serve at three different levels of development. A 500 Hz, 22-camera VICON MX motion capture system recorded 28 elite female tennis players (prepubescent (n = 10), pubescent (n = 10), adult (n = 8)) as they performed flat serves and overhand throws. Two-way ANOVAs with repeated measures and partial correlations (controlling for group) assessed the strength and nature of the mechanical associations between the tasks. Preparatory mechanics were similar between the two tasks, while during propulsion, peak trunk twist and elbow extension velocities were significantly higher in the throw, yet the peak shoulder internal rotation and wrist flexion angular velocities were significantly greater in the serve. Furthermore, all of these peak angular velocities occurred significantly earlier in the serve. Ultimately, although the throw may help to prime transverse trunk kinematics in the serve, mechanics in the two skills appear less similar than many coaches seem to believe. Practitioners should, therefore, be aware that the throw appears less useful for priming the specific arm kinematics and temporal phasing that typifies the tennis serve.

Coordination and variability in the elite female tennis serve.

Enhancing the understanding of coordination and variability in the tennis serve may be of interest to coaches as they work with players to improve performance. The current study examined coordinated joint rotations and variability in the lower limbs, trunk, serving arm and ball location in the elite female tennis serve. Pre-pubescent, pubescent and adult players performed maximal effort flat serves while a 22-camera 500 Hz motion analysis system captured three-dimensional body kinematics. Coordinated joint rotations in the lower limbs and trunk appeared most consistent at the time players left the ground, suggesting that they coordinate the proximal elements of the kinematic chain to ensure that they leave the ground at a consistent time, in a consistent posture. Variability in the two degrees of freedom at the elbow became significantly greater closer to impact in adults, possibly illustrating the mechanical adjustments (compensation) these players employed to manage the changing impact location from serve to serve. Despite the variable ball toss, the temporal composition of the serve was highly consistent and supports previous assertions that players use the location of the ball to regulate their movement. Future work should consider these associations in other populations, while coaches may use the current findings to improve female serve performance.

The effect of age on discrete kinematics of the elite female tennis serve.

The importance of the flat serve in tennis is well documented, with an abundance of research evaluating the service technique of adult male players. Comparatively, the female and junior serves have received far less attention. Therefore, the aims of this study were to quantify the flat serve kinematics in elite prepubescent, pubescent, and postpubescent female tennis players. Full body, racket, and ball kinematics were derived using a 22-camera Vicon motion capture system. Racket velocity was significantly lower in the prepubescent group than in the two older groups. In generating racket velocity, the role of the serving arm appears to become more pronounced after the onset of puberty, whereas leg drive and "shoulder-over-shoulder" rotation mature even later in development. These factors are proposed to relate to strength deficits and junior players' intentions to reduce the complexity of the skill. Temporally, coupling perception (cues from the ball) and action (body movements) are less refined in the prepubescent serve, presumably reducing the "rhythm" (and dynamism) of the service action. Practically, there appears scope for equipment scaling to preserve kinematic relevance between the junior and senior serve and promote skill acquisition.

Effect of a common task constraint on the body, racket, and ball kinematics of the elite junior tennis serve.

The development of a powerful and accurate serve is a priority for most tennis players. Various drills are proposed to enhance characteristics of the serve such as ball speed and spin, yet research has failed to address their efficacy. The aim of this study was therefore to compare the kinematics of a flat serve with that of a service drill, where the player serves from the knees in an endeavour to promote specific changes in trunk, arm, racket, and ball motion. A 22-camera 250 Hz VICON MX motion analysis system captured the trunk, arm, racket, and ball kinematics of eight high-performance junior players hitting flat serves and knee serves. Paired t-tests assessed within-group kinematic differences between the two serve conditions. Changes in ball toss, trunk, arm, and racket kinematics were a manifestation of the constraints presented by the knee serve. These changes effected an increased angle of attack of the racket but without greater frontal plane trunk rotation, which represented primary objectives of the knee serve. In sum, partial support was offered to the use of the knee serve as an intervention that promotes immediate, specific changes in trunk and racket kinematics in the service actions of elite junior players.

Identifying healthy individuals with Alzheimer's disease neuroimaging phenotypes in the UK Biobank.

BACKGROUND: Identifying prediagnostic neurodegenerative disease is a critical issue in neurodegenerative disease research, and Alzheimer's disease (AD) in particular, to identify populations suitable for preventive and early disease-modifying trials. Evidence from genetic and other studies suggests the neurodegeneration of Alzheimer's disease measured by brain atrophy starts many years before diagnosis, but it is unclear whether these changes can be used to reliably detect prediagnostic sporadic disease. METHODS: We trained a Bayesian machine learning neural network model to generate a neuroimaging phenotype and AD score representing the probability of AD using structural MRI data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) Cohort (cut-off 0.5, AUC 0.92, PPV 0.90, NPV 0.93). We go on to validate the model in an independent real-world dataset of the National Alzheimer's Coordinating Centre (AUC 0.74, PPV 0.65, NPV 0.80) and demonstrate the correlation of the AD-score with cognitive scores in those with an AD-score above 0.5. We then apply the model to a healthy population in the UK Biobank study to identify a cohort at risk for Alzheimer's disease. RESULTS: We show that the cohort with a neuroimaging Alzheimer's phenotype has a cognitive profile in keeping with Alzheimer's disease, with strong evidence for poorer fluid intelligence, and some evidence of poorer numeric memory, reaction time, working memory, and prospective memory. We found some evidence in the AD-score positive cohort for modifiable risk factors of hypertension and smoking. CONCLUSIONS: This approach demonstrates the feasibility of using AI methods to identify a potentially prediagnostic population at high risk for developing sporadic Alzheimer's disease.

Spotting people with dementia early is challenging, but important to identify people for trials of treatment and prevention. We used brain scans of people with Alzheimer's disease, the commonest type of dementia, and applied an artificial intelligence method to spot people with Alzheimer's disease. We used this to find people in the Healthy UK Biobank study who might have early Alzheimer's disease. The people we found had subtle changes in their memory and thinking to suggest they may have early disease, and we also found they had high blood pressure and smoked for longer. We have demonstrated an approach that could be used to select people at high risk of future dementia for clinical trials.

Synaptic density affects clinical severity via network dysfunction in syndromes associated with frontotemporal lobar degeneration.

There is extensive synaptic loss from frontotemporal lobar degeneration, in preclinical models and human in vivo and post mortem studies. Understanding the consequences of synaptic loss for network function is important to support translational models and guide future therapeutic strategies. To examine this relationship, we recruited 55 participants with syndromes associated with frontotemporal lobar degeneration and 24 healthy controls. We measured synaptic density with positron emission tomography using the radioligand [11C]UCB-J, which binds to the presynaptic vesicle glycoprotein SV2A, neurite dispersion with diffusion magnetic resonance imaging, and network function with task-free magnetic resonance imaging functional connectivity. Synaptic density and neurite dispersion in patients was associated with reduced connectivity beyond atrophy. Functional connectivity moderated the relationship between synaptic density and clinical severity. Our findings confirm the importance of synaptic loss in frontotemporal lobar degeneration syndromes, and the resulting effect on behaviour as a function of abnormal connectivity.

Prediagnostic Progressive Supranuclear Palsy - Insights from the UK Biobank.

INTRODUCTION: Prediagnostic features of Parkinson's Disease are well described but prediagnostic Progressive Supranuclear Palsy (PSP) is less understood. The diagnosis of PSP is delayed by an average of three years after symptom onset. Understanding the changes that occur in the prediagnostic period will aid earlier diagnosis, clarify the natural history, and may aid the design of early disease-modifying therapy trials. We set out to identify motor and cognitive markers of prediagnostic PSP, with Parkinson's disease as a comparator condition, in a large prospective cohort. METHODS: Baseline UK Biobank data from 502,504 individuals were collected between 2006 and 2010. Subsequent PSP and Parkinson's disease cases were identified from primary and secondary care electronic health records' diagnostic coding data and death registry, with 5404 matched controls. RESULTS: 176 PSP cases (time to diagnosis 7.8 ± 2.8 years) and 2526 Parkinson's disease cases (time to diagnosis 7.8 ± 2.9 years) were identified. At baseline, those later diagnosed with PSP had slower reaction times, weaker hand grip, lower fluid intelligence, prospective memory, self-rated health scores and digit recall than controls. Reaction times were correlated with time to diagnosis. The PSP group had higher mortality than both Parkinson's disease and control groups. CONCLUSIONS: Motor slowing, cognitive dysfunction, and postural instability are clinical diagnostic features of PSP that are typically symptomatic three years before diagnosis. Objective markers of these features were evident on average 7.8 years before diagnosis. Our findings suggest the existence of a long prediagnostic phase in PSP, with subtle changes in motor and cognitive function.