Preclinical Changes Research Articles

Cognitive Outcomes in Autosomal-Dominant Alzheimer's Disease: A Comprehensive Review from a Colombian Kindred with the Presenilin-1 E280A Mutation.

The largest identified kindred worldwide with a single mutation causing autosomal-dominant Alzheimer's disease (ADAD) is a family from Antioquia, Colombia, carrying the Presenilin-1 (PSEN1) E280A (Paisa) mutation. The majority of mutation carriers develop dementia, typically commencing in their late 30 s, with a median onset age of 49 years. Cognitive decline is a hallmark feature. This review synthesizes the existing literature on neuropsychological assessments in PSEN1 E280A mutation carriers throughout their lifespan. We provide a comprehensive overview of cognitive outcomes in this unique population. We reviewed and integrated the published research, analyzing studies on neuropsychological assessments in PSEN1 E280A carriers. Our focus was on measures of verbal, semantic, episodic, and spatial memory, and encompassed other cognitive domains such as language, attention, visuospatial memory, and executive functioning. Verbal, semantic, episodic, and spatial memory emerged as the most sensitive indicators of preclinical changes in PSEN1 E280A carriers. Inconsistencies were noted in findings from tests assessing language, attention, visuospatial memory, and executive functioning, suggesting potential limitations in detecting early cognitive changes in PSEN1 mutation carriers. Specific cognitive tasks developed for this population proved effective but underutilized. The review underscores the importance of continued test development tailored to detect early cognitive changes in PSEN1 E280A carriers, potentially enhancing ADAD screening. Furthermore, investigating ADAD mutations in children may identify early changes in AD and enhance our understanding of neuropsychological functioning across the lifespan. This synthesis provides valuable insights for researchers, clinicians, and policymakers engaged in the study and management of ADAD.

The Effects of Positive Psychological Factors on the Mental Wellbeing of Medical Students.

Objective A well-established association exists between academic performance and levels of depression and anxiety among medical students. However, the effects of positive psychological factors on symptoms of depression and anxiety and academic performance have not been adequately studied. This study explores the relationship between the above variables and identifies positive psychological factors that can promote medical student wellbeing. Methods Medical students were surveyed at four time points during their first two years of medical education using Qualtrics. The surveys used a five-point Likert scale to assess students' levels of loneliness, religiosity, engaged living, life fulfillment, resilience, psychological wellbeing, and symptoms of depression and anxiety. Academic performance was measured using students' Comprehensive Basic Science Examinationscores. Linear mixed effect models with maximum likelihood estimation were used to investigate the relationship between positive psychological factors and scores on depression and anxiety as well as the relationship between demographic and psychological factors and exam scores. Results Seventy-two students completed the study. A significant positive correlation was observed between loneliness and symptoms of depression and anxiety, while the same symptoms had significant negative correlations with engaged living. None of the positive psychological factors were significantly predictive of exam scores. Conclusion Our findings suggest that medical students who develop meaningful relationships and live engaged lives are less likely to develop symptoms of depression and anxiety. Our study lays the groundwork for future research focusing on identifying and implementing pre-clinical curriculum changes aiming to improve medical students'mental health.

Allostatic load, adverse childhood experiences, executive functions, and BMI status in adolescents and young adults.

Chronic stress induces preclinical changes in the metabolic, cardiovascular, and immune systems. This phenomenon, known as allostatic load (AL), can impair executive functions (EF), which may be even more affected in individuals with excess weight due to their characteristic inflammatory state and cardiometabolic changes. Adverse childhood experiences (ACEs) contribute to AL and may influence executive functioning presumably via alterations within the hypothalamic-pituitary axis, including epigenetic modifications. We assess the relationship between AL and EF in youth with and without excess weight, and the effect ACEs on executive functioning. One hundred eighty-two adolescents and young adults (85 with normal weight and 97 with overweight/obesity; 10-21 years) were recruited. The estimated AL index included the following: systolic and diastolic blood pressure, glycated hemoglobin, high- and low-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein, fibrinogen, and cortisol. ACEs were measured using the Juvenile Victimization Questionnaire. The neuropsychological evaluation included the assessment of inhibition, working memory, and cognitive flexibility processes. AL was not significantly associated with executive functioning, and this relationship did not depend on body-weight status. ACEs, available for 57 of 182 participants, were significantly associated with poorer executive functioning. Our study shows that AL is not associated with executive functioning in adolescents and young adults. Since the current sample was young, we hypothesize that a longer exposure to AL might be required for its negative effects to surface. Nevertheless, exposure to early adversity seems to be associated with poorer executive functioning in youth.

Reduced macular thickness and vascular density in abnormal glucose metabolism patients: A meta-analysis of optical coherence tomography (OCT) and OCT angiography studies.

Alterations in macular thickness and vascular density before clinically visible diabetic retinopathy (DR) remain inconclusive. This study aimed to determine whether retinal manifestations in abnormal glucose metabolism (AGM) patients differ from those in the healthy individuals. PubMed, Embase, and Web of Science were searched between 2000 and 2021. The eligibility criteria were AGM patients without DR. Primary and secondary outcomes measured by optical coherence tomography (OCT) and OCT angiography (OCTA) were analyzed and expressed as standardized mean differences (SMDs) with 95% confidence intervals (CIs). A random-effects model was used in the data synthesis. The potential publication bias for the variables was evaluated using Egger's test. A total of 86 observational studies involving 13,773 participants and 15,416 eyes were included. OCT revealed that compared to healthy controls, the total macular thickness of AGM patients was thinner, including the thickness of fovea (-0.24, 95% CI [-0.39, -0.08]; P =0.002, I2 =87.7%), all regions of parafovea (-0.32, 95% CI [-0.54, -0.11]; P =0.003; I2 =71.7%) and the four quadrants of perifovea; the thickness of peripapillary retinal nerve fiber layer (pRNFL), macular retinal nerve fiber layer (mRNFL), and ganglion cell layer (GCL) also decreased. OCTA indicated that the superficial and deep vascular density decreased, the foveal avascular zone (FAZ) area enlarged, and the acircularity index (AI) reduced in AGM individuals. Retinal thinning and microvascular lesions have occurred before the advent of clinically detectable DR; OCT and OCTA may have the potential to detect these preclinical changes. PROSPERO; http://www.crd.york.ac.uk/prospero/ ; No. CRD42021269885.

Longitudinal normative standards for cognitive tests and composites using harmonized data from two Wisconsin AD-risk-enriched cohorts.

Published norms are typically cross-sectional and often are not sensitive to preclinical cognitive changes due to dementia. We developed and validated demographically adjusted cross-sectional and longitudinal normative standards using harmonized outcomes from two Alzheimer's disease (AD) risk-enriched cohorts. Data from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were combined. Quantile regression was used to develop unconditional (cross-sectional) and conditional (longitudinal) normative standards for 18 outcomes using data from cognitively unimpaired participants (N=1390; mean follow-up=9.25 years). Validity analyses (N=2456) examined relationships between percentile scores (centiles), consensus-based cognitive statuses, and AD biomarker levels. Unconditional and conditional centiles were lower in those with consensus-based impairment or biomarker positivity. Similarly, quantitative biomarker levels were higher in those whose centiles suggested decline. This study presents normative standards for cognitive measures sensitive to pre-clinical changes. Future directions will investigate potential clinical applications of longitudinal normative standards. Quantile regression was used to construct longitudinal norms for cognitive tests. Poorer percentile scores were related to concurrent diagnosis and Alzheimer's disease biomarkers. A ShinyApp was built to display test scores and norms and flag low performance.

Subclinical atherosclerosis in young adults predicting cardiovascular disease: The Cardiovascular Risk in Young Finns Study

Background and aimsAtherosclerosis is accompanied by pre-clinical vascular changes that can be detected using ultrasound imaging. We examined the value of such pre-clinical features in identifying young adults who are at risk of developing atherosclerotic cardiovascular disease (ASCVD). MethodsA total of 2641 individuals free of ASCVD were examined at the mean age of 32 years (range 24–45 years) for carotid artery intima-media thickness (IMT) and carotid plaques, carotid artery elasticity, and brachial artery flow-mediated endothelium-dependent vasodilation (FMD). The average follow-up time to event/censoring was 16 years (range 1–17 years). ResultsSixty-seven individuals developed ASCVD (incidence 2.5%). The lowest incidence (1.1%) was observed among those who were estimated of having low risk according to the SCORE2 risk algorithm (<2.5% 10-year risk) and who did not have plaque or high IMT (upper decile). The highest incidence (11.0%) was among those who were estimated of having a high risk (≥2.5% 10-year risk) and had positive ultrasound scan for carotid plaque and/or high IMT (upper decile). Carotid plaque and high IMT remained independently associated with higher risk in multivariate models. The distributions of carotid elasticity indices and brachial FMD did not differ between cases and non-cases. ConclusionsScreening for carotid plaque and high IMT in young adults may help identify individuals at high risk for future ASCVD.

Assessment of the radial peripapillary capillary plexus and retinal nerve fiber layer thickness in diabetic patients in comparison to normal age-matched individuals

Background Diabetic retinopathy (DR) is a major complication of diabetes, leading to vision impairment and blindness worldwide. As early detection is crucial, our study investigated the potential of radial peripapillary capillary plexus (RPCP) and retinal nerve fiber layer (RNFL) thickness as biomarkers for retinal assessment in diabetic patients. Methods We conducted a cross-sectional study involving 48 participants, categorized into three groups: healthy controls, diabetic patients without DR (No DR), and patients with mild to moderate nonproliferative DR (NPDR). Vascular density (VD) and RNFL thickness were evaluated using optical coherence tomography (OCT), and OCT-Angiography (OCT-A). Results The study showed a significant difference in VD among the three groups. The mean whole image VD% in the control group was 51.28%, while the No DR and NPDR groups had mean percentages of 49.27% and 49.46%, respectively (P=0.015). These differences were also significant for peripapillary VD (P=0.003), superior-hemi VD (P=0.035), and inferior-hemi VD percentage (P=0.002). Conversely, there were no significant differences in RNFL thickness among the groups (P=0.138). In the NPDR group, positive correlations were found between RNFL thickness and VD percentages, including superior-hemi RNFL thickness and superior-hemi VD% (r=0.724, P&lt;0.001), average whole RNFL thickness and whole image VD% (r=0.655, P&lt;0.001), and average whole RNFL thickness and peripapillary VD% (r=0.647, P&lt;0.001). Conclusion This research emphasizes the value of assessment of retinal VD thickness of the radial peripapillary plexus as an early indicator for preclinical diabetic retinal changes in diabetic patients.

Decline in proper name retrieval during story recall is associated with Alzheimer’s disease CSF biomarkers in cognitively unimpaired individuals

AbstractBackgroundRemembering names of people and places is a common problem in aging that is exacerbated in Alzheimer’s disease (AD). Because retrieval of proper names (PNs) has been associated with brain regions affected by AD (anterior and medial temporal lobe), PN retrieval may be an especially sensitive measure of early AD pathology. Extending results of a previous study from WRAP (Mueller et al., 2020), this study examined associations between cerebrospinal fluid (CSF) AD biomarkers and longitudinal delayed story recall PN retrieval.MethodParticipants were from the BIOCARD study, a cohort of late‐middle aged adults enriched for parental history of AD. Participants were cognitively unimpaired at baseline with longitudinal item‐level data from the Logical Memory (LM; WMS‐R) Story A recall (N = 218; M(SD) baseline age = 58(9); M(SD) follow‐up = 4.1(2.9) years). CSF amyloid beta (Ab42/40) and phosphorylated tau181 (p‐tau181) were measured using automated electrochemiluminescence assays; AD biomarker abnormality (+) was determined using the bottom quartile for Ab42/40 and the top quartile for p‐tau181. We calculated total Story A PNs (range 0‐4) and total score (0‐25). We performed longitudinal linear mixed effects (LME) models examining the interaction between time (LM age, centered) and last available Ab42/40 and/or p‐tau181 status as predictors of PNs and total recall (subject‐specific random intercepts).ResultOf the 218 participants included, forty‐nine (22.4%) were Ab42/40+, 60 (27.5%) were p‐tau181+, and the remainder were A‐/T‐ (Table 1). In LME models, CSF‐Ab42/40+*age was not a significant predictor of either outcome. The p‐tau181+*age interaction showed significantly greater annual decline in PNs in the p‐tau181+ group than the p‐tau181‐ group (interaction beta = ‐.01, p = .02; simple slope estimate p‐tau181‐ = .002, p‐tau181+ = ‐.01) (Table 2, Fig.1). Interaction patterns were weaker yet similar for total recall. In follow‐up analyses, 15 participants who converted to MCI or dementia were removed and results remained unchanged. In an exploratory model combining biomarker statuses, the Ab42/40+/p‐tau181+*age interaction was non‐significant.ConclusionAs in the WRAP study, these results from BIOCARD indicate that PN recall is more sensitive to preclinical change than the traditional story recall total score metric; results also indicate that decline is greatest in those with elevated CSF p‐tau. Future directions should include replication in other longitudinal cohorts.

37 The MAPP Room Memory Task: Examining Contextual Memory Using a Novel Computerized Task in Cognitively-Unimpaired Individuals with Autosomal Dominant Alzheimer’s Disease from the Colombia-Boston Biomarker Study

Objective:Contextual memory, which refers to the ability to remember spatial or temporal circumstances related to an event, is affected early in Alzheimer’s Disease (AD). Computerized cognitive tasks have been suggested to be an ecological way to assess memory, but there are few studies that utilize these tools. Studying contextual memory via a computerized task in a Colombian kindred with autosomal dominant AD due to the Presenilin-1 (PSEN1) E280A mutation and a well-characterized disease progression may help us understand contextual memory changes in the preclinical AD stage. In this study we investigated whether a novel computerized task examining contextual memory can help identify those at increased risk for dementia.Participants and Methods:A group of 31 non-carriers (mean age=38.97±6.11; mean education=11.45±4.34) and 15 cognitively unimpaired PSEN1E280A mutation carriers from the Colombia-Boston (COLBOS) Biomarker Study (mean age=35.67±5.50), mean education=10.60±3.83) performed the “MAPP Room Memory Task” on a computer. As part of this task, participants are asked to remember ten rooms and the specific location of a few objects for later recall. During the immediate recall phase, participants are asked to recognize the objects presented in each room (Immediate Object Recognition) and their location (Immediate Object Placement). During the subsequent delay phase of the task, participants are asked to select the correct room in which an object was first presented (Delayed Room Recognition) and place the objects previously seen in each room (Delayed Object Placement). We conducted Mann Whitney U tests to analyze differences between groups and Spearman Rho correlations to examine associations among the Room Memory Task performance, age, education, and Mini Mental State Examination (MMSE).Results:There were no differences in age or education between carriers and non-carriers (p&gt;0.05, for both). Carriers had worse Delayed Room Recognition than non-carriers (Carriers mean score=0.893±0.18, non-carriers mean score=0.987±0.05; U=168.0, p=0.02), while there were no differences in the other task conditions (all p&gt;0.05). In carriers, education was positively associated with Immediate Object Placement (rs=0.61, p=0.02), Delayed Object Placement (rs=0.76, p=0.001), and Delayed Room Recognition (rs=0.68, p=0.006). There were no significant associations between Room Memory Task conditions and age or MMSE scores in carriers. Further, no significant associations were observed between Room Memory Task performance, and age, education or MMSE scores in non-carriers.Conclusions:Our preliminary findings show that the MAPP Room Memory Task, in particular the Delayed Room Recognition condition, may be helpful to discriminate those at increased risk of dementia. Future studies with larger samples using the Room Memory Task and AD-related biomarkers are needed to examine whether this task can be sensitive to early preclinical changes associated with AD and can potentially help track disease progression in those at risk.

52 Memory Learning Curve and in vivo Brain Pathology in Non-Demented Individuals with Autosomal Dominant Alzheimer’s Disease: Findings from the Colombia-Boston Biomarker Study

Objective:Associative memory is impacted early in Alzheimer’s disease (AD). Poorer performance on associative memory tests has been related to greater amyloid and regional tau burden in preclinical AD. Our group previously examined the association of brain pathology and performance on the Free and Cued Selective Reminding Test (FCSRT) in Autosomal Dominant Alzheimer’s Disease (ADAD), finding that associative memory summary scores distinguished non-demented mutation carriers from non-carriers several years before clinical onset of cognitive impairment. In the current study, we examined whether FCSRT learning slopes were associated with brain pathology in a sample of ADAD carriers and non-carriers.Participants and Methods:There were 119 participants including 57 non-demented carriers of the Colombian kindred with the Presenilin1 E280A mutation and 62 non-carrier family members (mean age= 36.3, 60% female). Participants were administered the Mini-Mental State Examination (MMSE), a measure of global cognitive status, and the FCSRT, which consists of three trials in which participants are asked to freely recall the same list of 16 items. It is a well-established measure known to be sensitive to early changes in AD. A subsample of 69 participants (32 carriers and 37 non-carriers) underwent positron emission tomography (PET) to measure in vivo cortical amyloid-beta (Pittsburgh compound B, PiB), and regional tau (Flortaucipir, FTP) burden in entorhinal and precuneus regions, which are among the earliest sites of tau accumulation in this ADAD population. Mann Whitney U tests, Spearman correlations, and chi-square tests were used to examine group differences and relations among variables of interest. Learning slope was calculated by subtracting the number of items freely recalled in FCSRT Trial 1 from the number of items freely recalled in Trial 3.Results:Compared to non-carriers, carriers had greater cortical amyloid-ß and regional tau burden, lower MMSE scores (mean [SD]: carriers= 27.5 [2.7]; non-carriers= 28.8 [1.0]), and lower scores on total immediate/ delayed free/ cued recall scores on the FCSRT (all p&lt;.01). The groups did not differ on age, sex, or education level (all p&gt; 0.05). In the whole sample and in carriers only, we found that higher MMSE scores were associated with higher learning slope, meaning faster learning (whole group p= 0.25, p= 0.006; carriers p= 0.30, p=0.029). In the whole sample, we found that lower learning slope was associated with higher levels of amyloid (p=-.34, p=.006) and tau in the left, right, and bilateral precuneus region (p=-.43, p&lt;.001; p=-.46, p&lt;.001; p=-.45, p&lt;.001). In carriers only, lower learning slope was associated with higher tau burden in the left, right, and bilateral precuneus specifically (p=-.43, p=.017; p=-.48, p=.008; p=-.46, p=.010, respectively). No significant associations were found in non-carriers.Conclusions:These findings suggest that learning curves on an associative memory test may be sensitive to preclinical pathological changes in AD, specifically within the precuneus, a brain region known to be involved in cue reactivity, episodic memory retrieval, and mental imagery strategies. Future studies with larger samples are warranted to further examine associations between the FCSRT learning curves and regional tau accumulation in individuals with ADAD.

MRI-detected intraosseous bone marrow edema recedes after effective therapy of periodontitis

ObjectivesT2 STIR MRI sequences can detect preclinical changes associated with periodontal inflammation, i.e. intraosseous edema in the tooth-supporting bone. In this study, we assessed whether MRI can be used for monitoring periodontal disease.Material and methodsIn a prospective cohort study, we examined 35 patients with periodontitis between 10/2018 and 04/2019 by using 3D isotropic T2-weighted short tau inversion recovery (STIR) and Fast Field Echo T1-weighted Black bone sequences. All patients received standardized clinical exams before and three months after non-surgical periodontal therapy. Bone marrow edema extent was quantified in the STIR sequence at 922 sites before and after treatment. Results were compared with standard clinical findings. Non-parametric statistical analysis was performed.ResultsNon-surgical periodontal treatment caused significant improvement in mean probing depth (p < 0.001) and frequency of bleeding on probing (p < 0.001). The mean depth of osseous edema per site was reduced from a median [IQR] of 2 [1, 3] mm at baseline to 1 [0, 3] mm, (p < 0.001). Periodontal treatment reduced the frequency of sites with edema from 35 to 24% (p < 0.01).ConclusionThe decrease of periodontal bone marrow edema, as observed with T2 STIR MR imaging, is indicative of successful periodontal healing.Clinical relevance statementT2 STIR hyperintense bone marrow edema in the periodontal bone decreases after treatment and can therefore be used to evaluate treatment success. Furthermore, MRI reveals new options to depict hidden aspects of periodontitis.Key Points• T2 STIR hyperintense periodontal intraosseous edema was prospectively investigated in 35 patients with periodontitis before and after treatment and compared to clinical outcomes.• The frequency of affected sites was reduced from 35 to 24% (p < 0.001), and mean edema depth was reduced from a median [IQR] of 2 [1, 3] mm at baseline to 1 [0, 3] mm 3 months after treatment. (p < 0.001).• T2 STIR sequences can be used to monitor the posttreatment course of periodontitis.

Neuropsychological impairment in amyotrophic lateral sclerosis-frontotemporal spectrum disorder.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a rapid course, characterized by motor neuron dysfunction, leading to progressive disability and death. This Review, which is aimed at neurologists, psychologists and other health professionals who follow evidence-based practice relating to ALS and frontotemporal dementia (FTD), examines the neuropsychological evidence that has driven the reconceptualization of ALS as a spectrum disorder ranging from a pure motor phenotype to ALS-FTD. It focuses on changes in cognition and behaviour, which vary in severity across the spectrum: around 50% individuals with ALS are within the normal range, 15% meet the criteria for ALS-FTD, and the remaining 35% are in the mid-spectrum range with milder and more focal impairments. The cognitive impairments include deficits in verbal fluency, executive functions, social cognition and language, and apathy is the most prevalent behavioural change. The pattern and severity of cognitive and behavioural change predicts underlying regional cerebral dysfunction from brain imaging and post-mortem pathology. Our increased recognition of cognition and behaviour as part of the ALS phenotype has led to the development and standardization of assessment tools, which have been incorporated into research and clinical care. Measuring change over the course of the disease is vital for clinical trials, and neuropsychology is proving to be a biomarker for the earliest preclinical changes.

Effectiveness of Orthopantomograms as a Screening Tool for Osteoporosis: A Case-Control Study.

Introduction Osteoporosis is a disease that is characterised by low bone mineral density (BMD), and loss of structural and biomechanical properties that are essential in maintaining bone homeostasis. Osteoporosis is diagnosed by clinical measurement of BMD and is the best predictor of osteoporosis. The study was conducted with the aim of assessing the effectiveness of orthopantomogram (OPG) as a screening tool for osteoporosis in postmenopausal women and chronic drug users. Objectives The primary objective of the current study was to assess the mandibular cortical width and antegonial index in postmenopausal women and chronic drug users, the secondary objective was to compare the mandibular cortical width and antegonial index of postmenopausal women and chronic drug users with that of the control group (healthy individual). Methods Three groups were taken in this study with a sample size of 300 with 100 OPG in each group. The groups categorised in the study were postmenopausal women, patients under drugs (glucocorticoids, proton pump inhibitor, anti-epileptic drugs, selective serotonin reuptake inhibitor) and the control group and the parameters assessed were antegonial index and mandibular cortical width. Results Results were tabulated and analysed using Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows, IBM Corp., Version 26.0, Armonk, NY). The normality tests Kolmogorov-Smirnov and Shapiro-Wilks test results reveal that the variables (both indices) follow the normal distribution. The mandibular cortical width was 3.44, 2.66 and 2.96 in the normal, postmenopausal women and women on drugs respectively. The antegonial index was 163.5, 157.2 and 158.8 in the normal, postmenopausal women and women on drugs respectively. Conclusion From the above results, it is evident that there is a statistically significant reduction in antegonial index and mandibular cortical width in postmenopausal women compared to normal individuals.Alterations of this value are suggestive that early pre-clinical changes of osteoporosis can be detected in the high-risk group using OPG.

A protein panel in cerebrospinal fluid for diagnostic and predictive assessment of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease with heterogenous pathophysiological changes that develop years before the onset of clinical symptoms. These preclinical changes have generated considerable interest in identifying markers for the pathophysiological mechanisms linked to AD and AD-related disorders (ADRD). On the basis of our prior work integrating cerebrospinal fluid (CSF) and brain proteome networks, we developed a reliable and high-throughput mass spectrometry-selected reaction monitoring assay that targets 48 key proteins altered in CSF. To test the diagnostic utility of these proteins and compare them with existing AD biomarkers, CSF collected at baseline visits was assayed from 706 participants recruited from the Alzheimer's Disease Neuroimaging Initiative. We found that the targeted CSF panel of 48 proteins (CSF 48 panel) performed at least as well as existing AD CSF biomarkers (Aβ42, tTau, and pTau181) for predicting clinical diagnosis, FDG PET, hippocampal volume, and measures of cognitive and dementia severity. In addition, for each of those outcomes, the CSF 48 panel plus the existing AD CSF biomarkers significantly improved diagnostic performance. Furthermore, the CSF 48 panel plus existing AD CSF biomarkers significantly improved predictions for changes in FDG PET, hippocampal volume, and measures of cognitive decline and dementia severity compared with either measure alone. A potential reason for these improvements is that the CSF 48 panel reflects a range of altered biology observed in AD/ADRD. In conclusion, we show that the CSF 48 panel complements existing AD CSF biomarkers to improve diagnosis and predict future cognitive decline and dementia severity.

Effect of Pathway-Specific Polygenic Risk Scores for Alzheimer's Disease (AD) on Rate of Change in Cognitive Function and AD-Related Biomarkers Among Asymptomatic Individuals.

Genetic scores for late-onset Alzheimer's disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan. In this study, we leveraged longitudinal data from the Wisconsin Registry for Alzheimer's Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways. PRS and p-PRSs with and without APOE were constructed separately based on the significant SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers in a subset. Replication analyses were performed in an independent sample. We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of PRS/p-PRSs on rate of change in cognition, amyloid-β, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded. In addition to APOE, the p-PRSs can predict age-dependent changes in amyloid-β, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating amyloid-β and tau, long before the onset of clinical symptoms.

Mayo‐PACC: Optimizing a parsimonious Preclinical Alzheimer’s disease cognitive composite comprised of public‐domain measures

AbstractBackgroundPreclinical Alzheimer’s cognitive composites (PACC) are designed to detect subtle cognitive changes in clinical trials. PACCs often include measures of memory, attention, and semantic fluency, with variations based on available measures. We created a Mayo Clinic PACC (Mayo‐PACC) to address limitations of existing PACCs by prioritizing parsimony, non‐proprietary measures, clinical applicability, and psychometric properties. We developed a Mayo‐PACC and examined sensitivity to detecting longitudinal cognitive change in amyloid positive (A+) older adults relative to the Preclinical Alzheimer’s Cognitive Composite‐Revised (PACC‐R). Exploratory analyses included comparison to other composites.MethodParticipants included 614 individuals in the Mayo Clinic Study of Aging (428 A‐ and 186 A+) age 65‐85 who were cognitively unimpaired at baseline with 7 years mean follow‐up. A+ was defined as PiB‐PET meta‐ROI SUVR ≥ 1.48 (centiloid 22). The Mayo‐PACC included the AVLT sum of trials (trials 1‐5, short delay, long delay), Trails B and Animal fluency. Measures included in the PACC‐R and other comparison composites are listed in Table 1. We calculated study‐specific z‐scores and examined psychometric properties of component measures including test‐retest reliability, practice effects, and distributional properties (ceiling/floor effects, skew, kurtosis). We examined sensitivity to preclinical cognitive change using slope estimates (difference in annualized change across A+ and A‐ groups) from linear mixed models (LMMs) for each composite. A jackknife procedure was used to calculate the standard error and subsequent confidence intervals of differences in rates of change (A+&gt;A‐ indicating more significant decline in A+). Significance was determined based on whether the 95% Confidence Interval (CI) contained 0 (alpha = .05).ResultAll composites showed sensitivity to amyloid‐related longitudinal cognitive decline (A+&gt;A‐ annualized change p&lt;.05; see Table 2). Jack‐knife comparisons revealed comparable utility of Mayo‐PACC and PACC‐R (CI contained 0, see Table 3). Exploratory analyses revealed Mayo‐PACC performed similarly to an adaptation of the ADCS‐PACC, Global‐z, Memory‐z and Attention‐z. The Mayo‐PACC performed better than a 2‐measure Mayo‐PACC‐remote and a single memory measure.ConclusionThe Mayo‐PACC provides a parsimonious composite score that has comparable utility for detecting A+&gt;A‐ cognitive decline compared to the PACC‐R and other composites and can be widely used in both research and clinical settings.

Preclinical Cartilage Changes of the Knee Joint in Adolescent Competitive Volleyball Players: A Prospective T2 Mapping Study.

To investigate the potential effects of volleyball as a competitive sport in adolescence on the cartilage of knee joints using T2 mapping in MRI and identification of preclinical cartilage changes. Volleyball as an impact sport often leads to damage of the knee joint cartilage in adulthood. As T2 mapping is widely available and highly capable of detecting cartilage changes prior to conventional MRI sequences, such a detection may allow adolescent volleyball players to change their training regime before structural damage can occur to the cartilage and pose the risk of osteoarthritis. Comparative study of the patellar, femoral, and tibial cartilage of 60 knee joints using T2 mapping on 3 T MRI. In each case, both knees of 15 adolescent competitive volleyball athletes were compared with 15 controls. In the group of competitive athletes, more focal cartilage changes were detected in the medial facet of the patellofemoral cartilage and in the medial femoral condyle of the knee joint cartilage (p = .01 and p <.05, respectively). Furthermore, the latter showed a diffused increase in maximal T2 mapping values (p <.04 right and p = .05 left). The distribution of changes seems to further depend on the player's position. In adolescent volleyball players in competitive sports, T2 mapping demonstrates early cartilage changes in both the patellofemoral and medial femoral cartilages. The distribution of lesions depends on the player's position. Since the cascade from T2 relaxation time increase to conspicuous cartilage damage is well established, early counter-regulation (e. g., adapted training profile, targeted physiotherapy, and appropriate muscle building training) has the potential to prevent later damage. · Volleyball as a competitive sport in adolescence leads to preclinical knee cartilage changes.. · Cartilage changes are both focal and diffuse.. · Jumping-intensive player positions seem to show more patellofemoral and running-intensive more condylar cartilage changes.. · Early detection of these changes could prevent progression to cartilage damage through adapted training.. · Roth C, Hirsch F, Sorge I et al. Preclinical Cartilage Changes of the Knee Joint in Adolescent Competitive Volleyball Players: A Prospective T2 Mapping Study. Fortschr Röntgenstr 2023; 195: 913 - 923.

Early Retinal Microvascular Alterations in Young Type 1 Diabetic Patients without Clinical Retinopathy.

The purpose of this study is to identify and quantify preclinical changes with the help of optical coherence tomography angiography (OCTA) within the retinal microcirculation of young type 1 diabetes (T1D) patients without clinical signs of diabetic retinopathy (DR) and to compare these results with those obtained from healthy age-matched subjects. OCTA is currently used for monitoring diabetic retinopathy; however, there is no current consensus on which OCTA parameter alterations predict the first clinical signs of diabetic retinopathy. The main challenge that young patients with T1D face during the course of the disease is that they can rapidly progress to the development of DR, especially during adolescence. Moreover, they also present an increased risk of rapid progression toward advanced stages of DR and vision loss compared to type 2 diabetes patients, indicating the importance of early diagnosis and intervention. The limitations of the currently used screening procedures that led to the conceptualization of our study are the difficulties in performing fluorescein angiography tests for diagnosing the clinical signs of DR on young patients, namely the invasive procedure of dye injection, the risk of allergic reactions and the long duration of the examination. Moreover, given the long life expectancy of young T1D patients, it is essential to identify the preclinical changes in retinal microvasculature before reaching the first clinical signs quantifiable by FFA. The clinical study enrolled 119 subjects aged between 4 and 30 years old with a mean age of 13 years old, comprising 61 T1D patients with a mean duration of the disease of 4 years and 8 months and 58 healthy age-matched subjects for the control group. OCTA scans were performed using the RevoNX 130 OCTA device (Optopol) to evaluate the following retinal parameters: foveal avascular zone (FAZ) area, perimeter and circularity, overall foveal thickness, and superficial and deep vessel densities. Statistically significant differences between the two groups were identified for the following parameters: the FAZ area in the T1D group (0.42 ± 0.17) was larger than the control group (0.26 ± 0.080), the FAZ circularity (0.41 ± 0.11) was decreased compared to the control group (0.61 ± 0.08) and the FAZ perimeter was larger (3.63 ± 0.97) compared to the control group (2.30 ± 0.50). The overall foveal thickness was decreased in the T1D group (222.98 ± 17.33) compared to the control group (230.64 ± 20.82). The total vessel density of the superficial capillary plexus (SCP) on an investigated area of 6 X 6 mm centered around the fovea was decreased in the T1D group (37.4164 ± 2.14) compared to the control group (38.0241 ± 2.44). Our data suggest that specific imaging biomarkers such as FAZ perimeter, area and circularity, decreased overall foveal thickness and decreased vessel density in the SCP precede the clinical diagnosis of DR in young T1D patients and represent useful parameters in quantifying capillary nonperfusion in T1D patients without clinical signs of DR.

Optical Coherence Tomography Angiography in Retinal Vascular Disorders.

Traditionally, abnormalities of the retinal vasculature and perfusion in retinal vascular disorders, such as diabetic retinopathy and retinal vascular occlusions, have been visualized with dye-based fluorescein angiography (FA). Optical coherence tomography angiography (OCTA) is a newer, alternative modality for imaging the retinal vasculature, which has some advantages over FA, such as its dye-free, non-invasive nature, and depth resolution. The depth resolution of OCTA allows for characterization of the retinal microvasculature in distinct anatomic layers, and commercial OCTA platforms also provide automated quantitative vascular and perfusion metrics. Quantitative and qualitative OCTA analysis in various retinal vascular disorders has facilitated the detection of pre-clinical vascular changes, greater understanding of known clinical signs, and the development of imaging biomarkers to prognosticate and guide treatment. With further technological improvements, such as a greater field of view and better image quality processing algorithms, it is likely that OCTA will play an integral role in the study and management of retinal vascular disorders. Artificial intelligence methods-in particular, deep learning-show promise in refining the insights to be gained from the use of OCTA in retinal vascular disorders. This review aims to summarize the current literature on this imaging modality in relation to common retinal vascular disorders.

Continuous Glucose Monitoring-Derived Metrics and Capillary Vessel Density in Subjects with Type 1 Diabetes without Diabetic Retinopathy.

Optical coherence tomography angiography (OCTA) is an innovative and reliable technique detecting the early preclinical retinal vascular change in patients with diabetes. We have designed our study to evaluate whether an independent relationship exists between continuous glucose monitoring (CGM)-derived glucose metrics and OCTA parameters in young adult patients with type 1 diabetes without diabetic retinopathy (DR). Inclusion criteria were age ≥ 18 years, diagnosis of type 1 diabetes from ≥ 1 year, stable insulin treatment in the last three months, use of real-time CGM, and CGM wear time ≥ 70%. Each patient underwent dilated slit lamp fundus biomicroscopy to exclude the presence of DR. A skilled operator performed OCTA scans in the morning to avoid possible diurnal variation. CGM-derived glucose metrics from the last 2 weeks were collected through the dedicated software during OCTA. Forty-nine patients with type 1 diabetes (age 29 [18; 39] years, HbA1c 7.7 ± 1.0%) and 34 control subjects participated in the study. Vessel density (VD) of the whole image and parafoveal retina in the superficial (SCP) and deep capillary plexus (DCP) was significantly lower in patients with type 1 diabetes compared to controls. The coefficient of variation of average daily glucose, evaluated by CGM, significantly correlated with foveal and parafoveal VD in SCP and with foveal VD in DCP. High glucose variability might be responsible for the early increase of VD in these areas. Prospective studies may help understand if this pattern precedes DR. The difference we detected between patients with and without diabetes confirms that OCTA is a reliable tool for detecting early retinal abnormalities.