Faster Progression Research Articles

Final Results from RIBBIT: A Randomized Phase III Study to Evaluate Efficacy and Quality of Life in Patients with Metastatic Hormone Receptor-Positive, HER2-Negative Breast Cancer Receiving Ribociclib in Combination with Endocrine Therapy or Chemotherapy with or without Bevacizumab in the First-Line Setting

Background: We investigated the efficacy and health-related quality of life (HRQoL) in patients receiving either ribociclib plus endocrine therapy (ET) or chemotherapy with/without bevacizumab as first-line treatment of metastatic hormone receptor (HR)-positive, HER2-negative breast cancer (BC). Patients and Methods: In this randomized, phase III study (RIBBIT), 38 patients diagnosed with metastatic HR-positive, HER2-negative BC with presence of visceral metastases recruited between May 2018 and December 2020 were randomly assigned in a 1:1 ratio to either arm A (ribociclib + ET) or arm B (chemotherapy with/without bevacizumab) at 12 sites in Germany. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), overall survival (OS), patient-reported HRQoL, and frequency and type of adverse events. During study conduction, the recruitment rate was persistently and considerably lower than originally expected. Therefore, the recruitment was ended prematurely. The study was initially designed to enroll and randomize 158 patients. Results: Median [95% CI] PFS was 27.3 months [19.1 – NA, parameter not estimable] in arm A and 15.8 months [8.2 – NA] in arm B. Complete responses were achieved only in arm A (n = 2, 10.5%). The ORR [95% CI] between arm A (57.9% [33.5–79.7]) and arm B (52.6% [28.9–75.6]) was comparable. Median OS [95% CI] was not reached in arm A, while in arm B median OS was 28.4 months [25.0 – NA]. Patients in arm A reported less burden by side-effects. No new safety signals emerged. Conclusion: Treatment of patients with visceral metastatic HR-positive, HER2-negative BC with ribociclib in combination with ET showed a tendency toward a more favorable clinical outcome. Despite small numbers of patients and sites, this head-to-head comparison with chemotherapy supports the use of ribociclib with ET in patients with visceral metastasis at risk of fast disease progression.

Lysosomal Polygenic Burden Drives Cognitive Decline in Parkinson's Disease with Low Alzheimer Risk.

Genetics influence cognitive progression in Parkinson's disease, possibly through mechanisms related to Lewy and Alzheimer's disease pathology. Lysosomal polygenic burden has recently been linked to more severe Lewy pathology post mortem. To assess the influence of lysosomal polygenic burden on cognitive progression in Parkinson's disease patients with low Alzheimer's disease risk. Using Cox regression we assessed association between lysosomal polygenic scores and time to Montreal Cognitive Assessment score ≤ 21 in the Parkinson's Progression Markers Initiative cohort (n = 374), with replication in data from the Parkinson's Disease Biomarker Program (n = 777). Patients were stratified by Alzheimer's disease polygenic risk. The lysosomal polygenic score was associated with faster progression of cognitive decline in patients with low Alzheimer's disease risk in both datasets (P = 0.0032 and P = 0.0054, respectively). Our study supports complex interplay between genetics and neuropathology in Parkinson's disease-related cognitive impairment, emphasizing the role of lysosomal polygenic burden. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Machine learning and deep neural network-based learning in osteoarthritis knee.

Osteoarthritis (OA) of the knee joint is considered the commonest musculoskeletal condition leading to marked disability for patients residing in various regions around the globe. Application of machine learning (ML) in doing research regarding OA has brought about various clinical advances viz, OA being diagnosed at preliminary stages, prediction of chances of development of OA among the population, discovering various phenotypes of OA, calculating the severity in OA structure and also discovering people with slow and fast progression of disease pathology, etc. Various publications are available regarding machine learning methods for the early detection of osteoarthritis. The key features are detected by morphology, molecular architecture, and electrical and mechanical functions. In addition, this particular technique was utilized to assess non-interfering, non-ionizing, and in-vivo techniques using magnetic resonance imaging. ML is being utilized in OA, chiefly with the formulation of large cohorts viz, the OA Initiative, a cohort observational study, the Multi-centre Osteoarthritis Study, an observational, prospective longitudinal study and the Cohort Hip & Cohort Knee, an observational cohort prospective study of both hip and knee OA. Though ML has various contributions and enhancing applications, it remains an imminent field with high potential, also with its limitations. Many more studies are to be carried out to find more about the link between machine learning and knee osteoarthritis, which would help in the improvement of making decisions clinically, and expedite the necessary interventions.

Association of Neurofilament Light Chain, [18F]PI-2620 Tau-PET, TSPO-PET, and Clinical Progression in Patients With β-Amyloid-Negative CBS.

Corticobasal syndrome (CBS) with underlying 4-repeat tauopathy is a progressive neurodegenerative disease characterized by declining cognitive and motor functions. Biomarkers for assessing pathologic brain changes in CBS including tau-PET, 18 kDa translocator protein (TSPO)-PET, structural MRI, neurofilament light chain (NfL), or glial fibrillary acidic protein (GFAP) have recently been evaluated for differential diagnosis and disease staging, yet their association with disease trajectories remains unclear. Therefore, we performed a head-to-head comparison of neuroimaging (tau-PET, TSPO-PET, structural MRI) and plasma biomarkers (NfL, GFAP) as prognostic tools for longitudinal clinical trajectories in β-amyloid (Aβ)-negative CBS. We included patients with clinically diagnosed Aβ-negative CBS with clinical follow-up data who underwent baseline structural MRI and plasma-NfL analysis for assessing neurodegeneration, [18F]PI-2620-PET for assessing tau pathology, [18F]GE-180-PET for assessing microglia activation, and plasma-GFAP analysis for assessing astrocytosis. To quantify tau and microglia load, we assessed summary scores of whole-brain, cortical, and subcortical PET signal. For structural MRI analysis, we quantified subcortical and cortical gray matter volume. Plasma NfL and GFAP values were assessed using Simoa-based immunoassays. Symptom progression was determined using a battery of cognitive and motor tests (i.e., Progressive Supranuclear Palsy Rating Scale [PSPRS]). Using linear mixed models, we tested whether the assessed biomarkers at baseline were associated with faster symptom progression over time (i.e., time × biomarker interaction). Overall, 21 patients with Aβ-negative CBS with ∼2-year clinical follow-up data were included. Patients with CBS with more widespread global tau-PET signal showed faster clinical progression (PSPRS: B/SE = 0.001/0.0005, p = 0.025), driven by cortical rather than subcortical tau-PET. By contrast, patients with higher global [18F]GE-180-PET readouts showed slower clinical progression (PSPRS: B/SE = -0.056/0.023, p = 0.019). No association was found between gray matter volume and clinical progression. Concerning fluid biomarkers, only higher plasma-NfL (PSPRS: B/SE = 0.176/0.046, p < 0.001) but not GFAP was associated with faster clinical deterioration. In a subsequent sensitivity analysis, we found that tau-PET, TSPO-PET, and plasma-NfL showed significant interaction effects with time on clinical trajectories when tested in the same model. [18F]PI-2620 tau-PET, [18F]GE-180 TSPO-PET, and plasma-NfL show prognostic potential for clinical progression in patients with Aβ-negative CBS with probable 4-repeat tauopathy, which can be useful for clinical decision-making and stratifying patients in clinical trials.

Oscillatory vs. non-oscillatory subthalamic beta activity in Parkinson's disease.

Parkinson's disease is characterized by exaggerated beta activity (13-35Hz) in cortico-basal ganglia motor loops. Beta activity includes both periodic fluctuations (i.e. oscillatory activity) and aperiodic fluctuations reflecting spiking activity and excitation/inhibition balance (i.e. non-oscillatory activity). However, the relative contribution, dopamine dependency and clinical correlations of oscillatory vs. non-oscillatory beta activity remain unclear. We recorded, modelled and analysed subthalamic local field potentials in parkinsonian patients at rest while off or on medication. Autoregressive modelling with additive 1/f noise clarified the relationships between measures of beta activity in the time domain (i.e. amplitude and duration of beta bursts) or in the frequency domain (i.e. power and sharpness of the spectral peak) and oscillatory vs. non-oscillatory activity: burst duration and spectral sharpness are specifically sensitive to oscillatory activity, whereas burst amplitude and spectral power are ambiguously sensitive to both oscillatory and non-oscillatory activity. Our experimental data confirmed the model predictions and assumptions. We subsequently analysed the effect of levodopa, obtaining strong-to-extreme Bayesian evidence that oscillatory beta activity is reduced in patients on vs. off medication, with moderate evidence for absence of modulation of the non-oscillatory component. Finally, specifically the oscillatory component of beta activity correlated with the rate of motor progression of the disease. Methodologically, these results provide an integrative understanding of beta-based biomarkers relevant for adaptive deep brain stimulation. Biologically, they suggest that primarily the oscillatory component of subthalamic beta activity is dopamine dependent and may play a role not only in the pathophysiology but also in the progression of Parkinson's disease. KEY POINTS: Betaactivity in Parkinson's disease includes both true periodic fluctuations (i.e. oscillatory activity) and aperiodic fluctuationsreflecting spiking activity and synaptic balance (i.e. non-oscillatory activity). Therelative contribution, dopamine dependency and clinical correlations of oscillatory vs.non-oscillatory beta activity remain unclear. Burstduration and spectral sharpness are specifically sensitive to oscillatoryactivity, while burst amplitude and spectral power are ambiguously sensitive toboth oscillatory and non-oscillatory activity. Only theoscillatory component of subthalamic beta activity is dopamine-dependent. Stronger beta oscillatory activity correlates with faster motor progression of the disease.

Leveraging Foundation Models for Scientific Research Productivity

The objective of this work was to elucidate paths for expediting and enhancing scientific research productivity from theemerging AI paradigm of foundation models (e.g., ChatGPT). Faster scientific progress can benefit mankind by speeding up progress toward solutions to shared human problems like cancer, aging, climate change, or water scarcity. Challenges to foundation model adoption in science threaten to slow progress in such research areas. This study attempted to survey decision support systems and expert system literature to provide insights regarding these challenges. We first reviewed extant literature on these topics to try to identify adoption patterns that would be useful for this purpose. However, this attempt, using a bibliometric approach and a very high level traditional literature review, was unsuccessful due to the overly broad scope of the study. We then surveyed the existing scientific software domain, finding there to be a huge breadth in what constitutes scientific software.However, we do glean some lessons from previous patterns of adoption of scientific software by simply looking at historical examples (e.g., the electronic spreadsheet)

Enhancement of heat and mass transfer in drying systems for bio-economy and sustainable development

Drying techniques have been developed and improved over the course of human development since prehistoric times. Originally developed for the preservation and storage of food, drying techniques have been applied in many areas of industrial processes to achieve faster progress and development. Conventional and advanced drying techniques can be applied to achieve solutions for the numerous problems and challenges faced by humans now. In addition to the routine applications in daily life, drying techniques have been an integral part of bio-processing, food processing, thermo-chemical conversions, waste treatments, and so on. This review gives a brief overview of the developments in drying techniques that help in the progress of the bio-economy, thus achieving sustainable development goals for humanity.

Myopia progression patterns among paediatric patients in a clinical setting.

This retrospective analysis of electronic medical record (EMR) data investigated the natural history of myopic progression in children from optometric practices in Ireland. The analysis was of myopic patients aged 7-17 with multiple visits and not prescribed myopia control treatment. Sex- and age-specific population centiles for annual myopic progression were derived by fitting a weighted cubic spline to empirical quantiles. These were compared to progression rates derived from control group data obtained from 17 randomised clinical trials (RCTs) for myopia. Linear mixed models (LMMs) were used to allow comparison of myopia progression rates against outputs from a predictive online calculator. Survival analysis was performed to determine the intervals at which a significant level of myopic progression was predicted to occur. Myopia progression was highest in children aged 7 years (median: -0.67 D/year) and progressively slowed with increasing age (median: -0.18 D/year at age 17). Female sex (p < 0.001), a more myopic SER at baseline (p < 0.001) and younger age (p < 0.001) were all found to be predictive of faster myopic progression. Every RCT exhibited a mean progression higher than the median centile observed in the EMR data, while clinic-based studies more closely matched the median progression rates. The LMM predicted faster myopia progression for patients with higher baseline myopia levels, in keeping with previous studies, which was in contrast to an online calculator that predicted slower myopia progression for patients with higher baseline myopia. Survival analysis indicated that at a recall period of 12 months, myopia will have progressed in between 10% and 70% of children, depending upon age. This study produced progression centiles of untreated myopic children, helping to define the natural history of untreated myopia. This will enable clinicians to better predict both refractive outcomes without treatment and monitor treatment efficacy, particularly in the absence of axial length data.

Integrative NGS testing reveals clonal dynamics of adverse genomic defects contributing to a natural progression in treatment-naïve CLL patients.

Large-scale next-generation sequencing (NGS) studies revealed extensive genetic heterogeneity, driving a highly variable clinical course of chronic lymphocytic leukaemia (CLL). The evolution of subclonal populations contributes to diverse therapy responses and disease refractoriness. Besides, the dynamics and impact of subpopulations before therapy initiation are not well understood. We examined changes in genomic defects in serial samples of 100 untreated CLL patients, spanning from indolent to aggressive disease. A comprehensive NGS panel LYNX, which provides targeted mutational analysis and genome-wide chromosomal defect assessment, was employed. We observed dynamic changes in the composition and/or proportion of genomic aberrations in most patients (62%). Clonal evolution of gene variants prevailed over the chromosomal alterations. Unsupervised clustering based on aberration dynamics revealed four groups of patients with different clinical behaviour. An adverse cluster was associated with fast progression and early therapy need, characterized by the expansion of TP53 defects, ATM mutations, and 18p- alongside dynamic SF3B1 mutations. Our results show that clonal evolution is active even without therapy pressure and that repeated genetic testing can be clinically relevant during long-term patient monitoring. Moreover, integrative NGS testing contributes to the consolidated evaluation of results and accurate assessment of individual patient prognosis.

Evaluating motor progression of juvenile-onset Huntington's Disease: An Enroll-HD analysis

IntroductionJuvenile-onset Huntington's disease (JOHD) is characterized by a unique motor phenotype relative to patients with adult-onset Huntington's Disease (AOHD). This study characterized motor progression of JOHD to propose improved outcome measures for this group. MethodsWe used linear mixed effect regression models to compare progression of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score (TMS) and the chorea score between patients with JOHD and AOHD. We then evaluated all 31 subscales that make up the UHDRS over time within patients with JOHD to identify measures that may be used to track motor progression most reliably. ResultsThe JOHD cohort had faster TMS progression compared to AOHD (p = 0.006) but no group difference in the rate of change of chorea. Patients with JOHD did not show significant change in any of the chorea subscales. The subscales that changed most reliably over time amongst patients with JOHD were dysarthria, upper extremity dystonia, tandem walking, gait, bilateral pronate/supinate, bilateral finger-tapping, and tongue protrusion. When these subscales were summed, they progressed at a faster rate (7.07%, 95% CI [5.96–8.18]) than the TMS (4.92%, 95% CI [3.95–5.89]). ConclusionWhile the TMS changes at a significant rate in JOHD subjects, not all subscales that make up the TMS accurately represent the unique motor features of JOHD. A JOHD-specific scale performed better at tracking motor progression relative to the TMS. This scale may improve clinical care for patients with JOHD and allow for the development of more efficient clinical trials.

Assessment of Cerebral White Matter Involvement in Amyotrophic Lateral Sclerosis Patients With Disease Progression and Cognitive Impairment by Fixel-Based Analysis and Neurite Orientation Dispersion and Density Imaging.

Previous studies using emerging diffusion MRI techniques have revealed damage to the white matter (WM) microstructure in amyotrophic lateral sclerosis (ALS), particularly the influence of crossed fibers, but there is a lack of subgroup analyses. To detect WM microstructural changes in ALS patients using fixel-based analysis (FBA) and neurite orientation dispersion and density imaging (NODDI) MRI. Prospective. Thirty-six ALS patients (aged 60.50 ± 9.5 years) and 25 healthy controls (HCs) (aged 58.90 ± 8.1 years). 3 T; NODDI and FBA (b-values = 0, 1000, and 2500 seconds/mm2). Subgroups were performed according to progression rate and cognition, including fast and slow progression (FP/SP), ALS with and without cognitive impairment (ALS-ci/ALS-nci). Fiber density (FD), fiber-bundle cross-section (FC), combined fiber density and cross-section (FDC), neurite density index (NDI), orientation dispersion index (ODI), isotropic volume fraction (ISO), and fractional anisotropy (FA) were calculated and their correlation with clinical variables examined. Chi-square test, Mann-Whitney U test, two-sample t test, partial correlation analysis, and false discovery rate (FDR) corrected. A P-value <0.05 was considered significant. ALS patients had lower FD and FDC values predominantly in the corticospinal tract (CST) and corpus callosum (CC) regions, as well as lower NDI value in the CC, radial crown, and internal capsule compared to HCs. Subgroup analysis based on progression rate and cognitive function showed significant differences in FBA results. The FC in the right CST region was significantly lower in the FP than SP, and the FD in the CC region was significantly lower in the ALS-ci than ALS-nci. Furthermore, a negative correlation was found between the mean FC value and the rate of progression in ALS patients (r = -0.408). FBA is a powerful tool for detecting complex cerebral WM microstructural damage for evaluating ALS cognition and disease progression.

Using Powerlifting Athletes to Determine Strength Adaptations Across Ages in Males and Females: A Longitudinal Growth Modelling Approach.

Several retrospective studies of strength sport athletes have reported strength adaptations over months to years; however, such adaptations are not linear. We explored changes in strength over time in a large, retrospective sample of powerlifting (PL) athletes. Specifically, we examined the rate and magnitude of strength adaptation based on age category and weight class for PL competition total, and the squat, bench press, and deadlift, respectively. Mixed effects growth modelling was performed for each operationalised performance outcome (squat, bench press, deadlift, and total) as the dependent variables, with outcomes presented on both the raw, untransformed time scale and on the common logarithmic scale. Additionally, the fitted values were rescaled as a percentage. Collectively, the greatest strength gains were in the earliest phase of PL participation (~ 7.5-12.5% increase in the first year, and up to an ~ 20% increase after 10years). Females tended to display faster progression, possibly because of lower baseline strength. Additionally, female Masters 3 and 4 athletes (> 59years) still displayed ~ 2.5-5.0% strength improvement, but a slight strength loss was observed in Masters 4 (> 69years) males (~ 0.35%/year). Although directly applicable to PL, these findings provide population-level support for the role of consistent and continued strength training to improve strength across the age span and, importantly, to mitigate, or at least largely attenuate age-related declines in strength compared to established general population norms. This information should be used to encourage participation in strength sports, resistance training more generally, and to support future public health messaging.

Florbetapir PET-assessed demyelination is associated with faster tau accumulation in an APOE ε4-dependent manner.

The main objectives were to test whether (1) a decrease in myelin is associated with enhanced rate of fibrillar tau accumulation and cognitive decline in Alzheimer's disease, and (2) whether apolipoprotein E (APOE) ε4 genotype is associated with worse myelin decrease and thus tau accumulation. To address our objectives, we repurposed florbetapir-PET as a marker of myelin in the white matter (WM) based on previous validation studies showing that beta-amyloid (Aβ) PET tracers bind to WM myelin. We assessed 43 Aβ-biomarker negative (Aβ-) cognitively normal participants and 108 Aβ+ participants within the AD spectrum with florbetapir-PET at baseline and longitudinal flortaucipir-PET as a measure of fibrillar tau (tau-PET) over ~ 2 years. In linear regression analyses, we tested florbetapir-PET in the whole WM and major fiber tracts as predictors of tau-PET accumulation in a priori defined regions of interest (ROIs) and fiber-tract projection areas. In mediation analyses we tested whether tau-PET accumulation mediates the effect of florbetapir-PET in the whole WM on cognition. Finally, we assessed the role of myelin alteration on the association between APOE and tau-PET accumulation. Lower florbetapir-PET in the whole WM or at a given fiber tract was predictive of faster tau-PET accumulation in Braak stages or the connected grey matter areas in Aβ+ participants. Faster tau-PET accumulation in higher cortical brain areas mediated the association between a decrease in florbetapir-PET in the WM and a faster rate of decline in global cognition and episodic memory. APOE ε4 genotype was associated with a worse decrease in the whole WM florbetapir-PET and thus enhanced tau-PET accumulation. Myelin alterations are associated in an APOE ε4 dependent manner with faster tau progression and cognitive decline, and may therefore play a role in the etiology of AD.

Disease aggravation following surgery in a rare patient suspected to Fibrodysplasia (Myositis) ossificans progressiva: a case report

BackgroundFibrodysplasia ossificans progressiva (FOP) as a rare and heritable disorder with the infrequent genetic transmission of the condition is a catastrophic disorder of heterotopic ossification (HO) and a cause of extraskeletal bone formation in humans. Given the lack of effective treatment for this disease, the important point is to avoid aggravating factors such as bone biopsy, surgery, and intramuscular injection.Case presentationIn this report, we present a 52-year-old female patient, Kurdish ethnic, suspected to FOP who had a surgical intervention on the second toe of the right foot, which subsequently, it caused further deterioration of the disease in the person including necrosis and amputation of the distal phalanx of the second toe.ConclusionsAlthough, based on our investigation and the available scientific evidence, surgery may a cause for faster progression and worsening of the FOP disorder, but its proof requires further studies.

Fast accumulators of tau have higher levels of plasma pTau and stronger associations with amyloid in later Braak regions at baseline

AbstractBackgroundAccumulation of tau neurofibrillary tangles in Alzheimer’s disease (AD) follows a stereotypical pattern, known as Braak staging. As individuals show different rates of tau accumulation, depending on their initial stage, this potentially biases drug effects on tau pathology over time. We hypothesized that amyloid would be a driving force behind tau deposition in later Braak regions for those that were at earlier stages of the disease.Method79 individuals (CU: 57, MCI: 21, AD: 1) were recruited from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort. All individuals underwent baseline and 2‐year follow‐up amyloid ([18F]AZD4694) and tau ([18F]MK6240) PET imaging, as well as baseline plasma pTau181, pTau217, and pTau231 assessments. Differences in standardized uptake value ratios between the two timepoints in Braak I‐IV were used to separate fast accumulators of tau from slow accumulators, using the standard deviation of a Young group (n = 13).Pearson R’s were calculated between tau deposition in Braak regions IV‐VI and the neocortical amyloid load at baseline, within both these groups. Furthermore, a voxelwise analysis was performed to identify specific regional differences in amyloid SUVR between slow and fast progressors, while correcting for age, sex, ApoE4 carriership, as well as the individual’s Braak stage. In addition, an independent t‐test was performed to compare the levels of each pTau species at baseline.ResultFast accumulators had stronger increases (p &lt; 0.01) in tau accumulation in Braak region V and VI, compared to slower accumulators. Furthermore, the level of tau deposition in Braak region IV and V was positively associated (p &lt; 0.01) with the amyloid load in the neocortex, but only in the fast accumulator group (figure 1). The voxelwise analysis confirmed that faster progressors had stronger associations with amyloid‐PET (figure 2). Furthermore, those who accumulated tau at a faster rate also had higher levels of plasma pTau at baseline (figure 3).ConclusionTau deposition in later Braak regions is associated with a higher amyloid load and increased values of pTau181, pTau217 and pTau231 at baseline in individuals in early Braak stages that accumulate tau at a more rapid rate.

Prognostic value of Neurofilament light chain, [18F]‐PI2620 PET and [18F]GE‐180‐PET in amyloid‐negative Corticobasal Syndrome

AbstractBackgroundCorticobasal syndrome (CBS) with underlying 4‐repeat tauopathy is a progressive neurodegenerative disorder characterized by declining cognitive and motor functions. Biomarkers for assessing pathological brain changes in CBS including tau‐ and microglia‐PET or neurofilament light chain (NfL) have recently been evaluated for differential diagnosis and disease staging, yet the prognostic accuracy of these biomarkers for predicting disease trajectories remains unclear. To address this, we performed a head‐to‐head comparison of neuroimaging (tau‐PET, microglia‐PET) and plasma biomarker NfL as prognostic tools for future clinical trajectories in 21 CBS patients with longitudinal clinical data.MethodWe included 21 clinically diagnosed CBS patients with ∼2‐year clinical follow‐up data who underwent baseline [18F]PI‐2620‐PET for assessing tau pathology, [18F]GE‐180‐PET for microglia activation and plasma‐NfL for neurodegeneration. All patients were negative on amyloid biomarkers. To quantify tau and microglia load we assessed summary scores of whole‐brain, cortical and subcortical tracer signal. NfL was assessed using immunoassays on the Simoa platform. Symptom progression was determined using a battery of cognitive and motor tests. Using linear mixed models, we tested whether the assessed biomarkers at baseline were associated with faster progression of symptoms over time (i.e. time x biomarker interaction).ResultOverall, there was on average a rapid decline over time on the assessed clinical scores. For tau‐PET, CBS patients with higher global tau load showed faster clinical progression. This time x tau‐PET interaction was driven by cortical rather than subcortical tau‐PET load. Patients with higher [18F]GE‐180‐PET whole‐brain load showed slower clinical progression. Concerning plasma biomarker NfL, higher plasma‐NfL was prognostic of faster clinical deterioration. In a subsequent sensitivity analysis, we found that tau‐PET, microglia‐PET as well as plasma‐NfL showed significant (i.e. p&lt;0.05) interaction effects with time on clinical trajectories when tested in the same model, suggesting that these biomarkers explain unique variability in future disease trajectories.Conclusion[18F]PI‐2620 tau‐PET, [18F]GE‐180 microglia‐PET and plasma‐NfL show prognostic potential for clinical progression in CBS patients with probable 4‐repeat tauopathy, which can be useful for clinical decision making as well as stratifying patients in clinical trials.

Neurological disease in xeroderma pigmentosum: prospective cohort study of its features and progression.

Xeroderma pigmentosum (XP) results from biallelic mutations in any of eight genes involved in DNA repair systems, thus defining eight different genotypes (XPA, XPB, XPC, XPD, XPE, XPF, XPG and XP variant or XPV). In addition to cutaneous and ophthalmological features, some patients present with XP neurological disease. It is unknown whether the different neurological signs and their progression differ among groups. Therefore, we aim to characterize the XP neurological disease and its evolution in the heterogeneous UK XP cohort. Patients with XP were followed in the UK National XP Service, from 2009 to 2021. Age of onset for different events was recorded. Cerebellar ataxia and additional neurological signs and symptoms were rated with the Scale for the Assessment and Rating of Ataxia (SARA), the Inventory of Non-Ataxia Signs (INAS) and the Activities of Daily Living questionnaire (ADL). Patients' mutations received scores based on their predicted effects. Data from available ancillary tests were collected. Ninety-three XP patients were recruited. Thirty-six (38.7%) reported neurological symptoms, especially in the XPA, XPD and XPG groups, with early-onset and late-onset forms, and typically appearing after cutaneous and ophthalmological symptoms. XPA, XPD and XPG patients showed higher SARA scores compared to XPC, XPE and XPV. SARA total scores significantly increased over time in XPD (0.91 points/year, 95% confidence interval: 0.61, 1.21) and XPA (0.63 points/year, 95% confidence interval: 0.38, 0.89). Hyporeflexia, hypopallesthaesia, upper motor neuron signs, chorea, dystonia, oculomotor signs and cognitive impairment were frequent findings in XPA, XPD and XPG. Cerebellar and global brain atrophy, axonal sensory and sensorimotor neuropathies, and sensorineural hearing loss were common findings in patients. Some XPC, XPE and XPV cases presented with abnormalities on examination and/or ancillary tests, suggesting underlying neurological involvement. More severe mutations were associated with a faster progression in SARA total score in XPA (0.40 points/year per 1-unit increase in severity score) and XPD (0.60 points/year per 1-unit increase), and in ADL total score in XPA (0.35 points/year per 1-unit increase). Symptomatic and asymptomatic forms of neurological disease are frequent in XP patients, and neurological symptoms can be an important cause of disability. Typically, the neurological disease will be preceded by cutaneous and ophthalmological features, and these should be actively searched in patients with idiopathic late-onset neurological syndromes. Scales assessing cerebellar function, especially walking and speech, and disability can show progression in some of the groups. Mutation severity can be used as a prognostic biomarker for stratification purposes in clinical trials.

A multi‐site study of Alzheimer’s disease neuroimaging and cognitive biomarkers in 2819 cognitively normal individuals

AbstractBackgroundDeveloping effective Alzheimer’s disease (AD) biomarkers in cognitively normal (CN) individuals is crucial. Prior studies have identified neuroimaging and cognitive measures that are sensitive to preclinical AD. However, the generalizability of these biomarkers in large, multi‐site cohorts and their power to predict disease progression remain unclear. Structural MRI, tau PET and standardized cognitive tests of 2819 CN adults were pooled from three studies to investigate the power of these measures in discriminating β‐amyloid positivity (A+/‐) and predicting disease progression.MethodsT1‐weighted MRI and cognitive data of 2819 CN (A‐/A+: 1180/1540, Table 2) individuals from ADNI, HABS and A4 were included. Baseline medial temporal lobe structural measures were extracted from MRI (complete list in Table 1). For participants with prospective longitudinal MRI or cognitive measures (4.5 years), annualized change rate of each measurement was estimated. ANCOVA and receiver operating characteristic analyses were used to test biomarker differences between A+/A‐. In 563 CN with cross‐sectional tau PET available, stepwise linear mixed effect modeling was performed to identify the subset of baseline cross‐sectional biomarkers (tau, MRI and cognition) that yields the optimal model (smallest Akaike information criterion) in predicting longitudinal atrophy and cognitive decline. The area under the curve (AUC) of each model in discriminating the first (fast) and last (slow progressors) tertiles of each longitudinal measurement was reported.ResultsSignificant differences between A+/A‐ (Table 2) were observed in cross‐sectional tau (most significant), cross‐sectional and longitudinal cognitive, as well as longitudinal structural MRI measures. When predicting disease progression with baseline measures (Figure 1‐a), tau (selected in all the models) and cognitive biomarkers were included in the most predictive models while MRI biomarkers did not provide additional information. The selected biomarkers can identify fast versus slow progressors with AUCs ranging from 0.63‐0.78 (Figure 1‐b).ConclusionsThe results demonstrated that both cross‐sectional (tau PET and cognition) and longitudinal biomarkers (MRI and cognition) are sensitive to amyloid status in CN. In addition, baseline tau PET and cognitive measures provide complementary information in predicting disease progression regardless of amyloid status. This indicates that these biomarkers may have important utility in preclinical AD clinical trials and normal aging studies.

Evaluating the global cortical Centiloid value for predicting functional decline

AbstractBackgroundPrevious results on amyloid‐PET imaging for predicting functional decline are conflicting. Given that the Centiloid approach (CL) may serve for inclusion in anti‐amyloid trials, we investigated the extent to which CL may predict functional decline in the AMYPAD‐Prognostic and Natural History Study (PNHS), including 1094 participants.MethodWe analyzed, cross‐sectionally and longitudinally, the associations between CL and global and sum‐of‐boxes (SOB) Clinical Dementia Rating (CDR), and Instrumental Activity of Daily Living (IADL) scores. Mean follow‐up duration ranged from 2.7‐3.0 years (±1.1‐1.6) depending on the functional score. Longitudinal CDR‐SOB and IADL changes were modeled using linear mixed‐effects models with random intercepts and slopes, covarying age and sex, stratified by CDR global score. Analyses included comparisons between three CL groups (Aβ‐: CL&lt;12; grey‐zone: CL = 12‐50; Aβ+: CL&gt;50) and correlation between the baseline CL and the time for progression on the CDR global score.ResultThe baseline CL was significantly higher in CDR = 0 (Mdn = 6.6) than in CDR = 0.5 participants (Mdn = 17.2; p&lt;.001). Baseline CDR‐SOB was significantly higher in Aβ+ (M = 0.48) than in Aβ‐ (M = 0.12) and grey‐zone participants (M = 0.13, p‐values &lt;.001). Baseline IADL was (marginally) significantly lower in Aβ+ (Mdn = 81.3) than in Aβ‐ (Mdn = 82.8, p = .02) and grey‐zone participants (Mdn = 83.5, p = .08, Table 1). Baseline CL significantly predicted subsequent changes in CDR‐SOB and IADL, both in CDR = 0 and CDR = 0.5 participants, but only in the CL&gt;50 groups (βCL12‐50 = 0.03, p = .32,βCL&gt;50 = 0.14, p&lt;.001 for CDR‐SOB in CDR = 0 participants;βCL12‐50 = 0.19, p = .31,βCL&gt;50 = 1.04, p = .01 for CDR‐SOB in CDR = 0.5 participants;βCL12‐50 = ‐0.002, p = .99, βCL&gt;50 = ‐1.00, p = .08 for IADL in CDR = 0 participants; Fig.1). The participants who progressed from global CDR = 0 to CDR = 0.5 (N = 90) had a higher baseline CL (Mdn = 15.16) than stable participants (Mdn = 5.95, p = .002). However, the baseline CL was not associated with a shorter time of clinical progression (rs= ‐.02, p = .8; Fig.2).ConclusionCross‐sectionally, amyloid burden expressed in CL units was associated with functional outcomes. A baseline CL&gt;50 predicted subsequent functional decline in CDR‐SOB and IADL scores in clinically normal and mildly clinically impaired participants. At lower CL values, no functional decline was observed during a three‐year follow‐up. Clinically normal individuals with increasing global CDR scores had higher baseline CL values, but these values were not associated with faster clinical progression.

Diverse patterns of Tau radiotracer binding progression in Alzheimer’s disease: A two‐year tau PET imaging study

AbstractBackgroundPositron emission tomography (PET) imaging enables the in vivo detection of amyloid and tau pathologies. The longitudinal progression of [18F]‐flortaucipir PET imaging could be of interest to better understand the spatial and temporal relationships between tauopathy, cortical atrophy, and the cognitive decline.MethodWe explored the longitudinal progression of the tau radiotracer binding and of cortical atrophy over 2 years in a cohort of 27 prodromal/mild AD patients (positive CSF biomarkers and amyloid‐PET) compared with twelve amyloid‐negative controls. All subjects underwent a complete neuropsychological assessment, 3T brain MRI, [11C]‐PiB and [18F]‐flortaucipir PET imaging (Tau1), and were monitored annually over 2 years, with a second brain MRI and tau PET imaging (Tau2) after 2 years. We studied the longitudinal progression of tau radiotracer binding (Tau2‐Tau1) in AD patients and used mixed effects models to explore the relations between the progression of tau binding or cortical atrophy and cognitive decline.ResultWe found an average longitudinal increase in tau radiotracer binding in most cortical regions, especially in the frontal cortex, but an average decrease in the lateral temporoparietal cortex. In this region, individual analyses revealed two distinct evolutions of tau radiotracer binding according to Tau1 uptake: low‐Tau1 AD patients (SUVr&lt;1.6) demonstrated an increase in tau radiotracer uptake in all cortical regions and a slow clinical progression, whereas high‐Tau1 patients demonstrated a paradoxical plateauing or decrease of tau tracer uptake in the temporoparietal cortex and a faster clinical progression. Cognitive decline was weakly associated with Tau2‐Tau1, but strongly associated with the regional cortical atrophy progression.ConclusionOur results suggest that tau PET imaging could detect patients with a “more aggressive” biological form of AD characterized by high temporo‐parietal Tau1 binding. In these patients, the decrease of temporo‐parietal tau tracer binding over time could be due to the rapid transition to ghost tangles, for which the affinity of the radiotracer is lower. This information may be considered to improve the design of clinical trials and the definition of the neuroimaging outcomes (choice of the tau‐PET regions of interest, consideration of the evolution of cortical atrophy as a reliable reflection of the clinical progression).