Longitudinal Biomarker Study Research Articles

325 Longitudinal retrospective study of performance and biomarkers of energy balance and gastrointestinal functionality in unweaned calves subjected to transport or entire commercialization at arrival

Abstract Data from 347 unweaned male dairy beef calves enrolled in 3 studies from 2021 to 2023 were used to evaluate the impact of transport or entire commercialization (marketing and transport) on performance recovery [average daily gain (ADG) and concentrate intake (CI)] and biomarkers of energy balance [non-esterified fatty acids (NEFA), beta-hydroxybutyrate (BHB), and glucose] and gastrointestinal functionality [gut permeability (Cr-EDTA) and enterocyte mass (citrulline)] at farm arrival. Calves were distributed in 3 treatments according to the different managements subjected in the previous studies: calves from a sole dairy farm that were not fasted neither transported (CTR), calves from a sole dairy farm that were transported and fasted for 19 h (TRA), and multi-origin calves commercially marketed and transported for 9 h (COM). On arrival at the rearing farm (d 0), calves were allocated individually, and body weight (BW) was recorded. Calves were fed milk replacer twice daily, and they had ad libitum access to concentrate and water. Concentrate (CI) and milk replacer intake were recorded daily, and BW and the biomarkers of energy balance and gut dysfunction were obtained on d 0 (arrival), 1, 2, and 7. Data were analyzed with mixed models. An interaction (P < 0.01) between treatment and time was observed for CI. On d 0 CTR and TRA had similar CI, while COM had the least CI. On d 1, all treatments decreased CI except CTR. While TRA recovered CI to CTR levels, COM had 50% less CI compared with the other calves on d 7. The COM calves had the least (P < 0.01) ADG compared with CTR and TRA calves. On d 0, COM calves had greater (P < 0.01) concentrations of NEFA and BHB compared with TRA and CTR, and TRA greater (P < 0.01) than CTR calves. The COM calves did not recover NEFA and BHB basal concentrations by d 7 as observed in TRA calves. Concentration of Cr-EDTA was greater on d 0 for TRA calves compared with CTR and COM calves, however concentration of Cr-EDTA was greater during the first 7 d in COM calves compared with CTR and TRA calves. Finally, citrulline concentration was less in COM calves compared with CTR and TRA calves independently of the sampling day. The entire commercialization process, marketing and transportation, of unweaned dairy beef calves impairs intake recovery and growth, and these results are aligned with negative energy balance and comprised gastrointestinal functionality at farm arrival.

Associations between aerobic fitness and subsequent memory performance in non‐demented Presenilin‐1 E280A mutation carriers: A preliminary report from the Colombia‐Boston longitudinal biomarker study

AbstractBackgroundGreater aerobic fitness, objectively measured by VO2‐max, is considered a critical component of overall health and a strong predictor of cognitive functioning. It has been associated with less neurodegeneration in Alzheimer’s disease (AD) and greater functional brain connectivity and plasticity in healthy older adults. Yet, less is known about how it relates to AD progression in people at increased risk for dementia. In this study, we examined whether VO2‐max predicted memory decline in non‐demented mutation carriers and non‐carriers from a Colombian kindred with autosomal dominant AD (ADAD), and hypothesized that those with greater VO2‐max levels would exhibit slower cognitive decline.Methods12 Presenilin‐1 E280A mutation carriers (ages: μ = 39.61 years, SD:4.18) and 14 non‐carriers (ages: μ = 37.11 years, SD:6.59) underwent a standard graded maximal exercise test performed on a treadmill to assess their VO2‐max, which is the maximal rate of oxygen consumption during exercise, measured in milliliters of oxygen per minute per kilogram body mass. Participants also completed the CERAD word list learning and delayed recall, a measure of episodic memory, at baseline and again 18‐24 months later. Group differences were tested using the Mann‐Whitney U test. Linear mixed models were used to examine associations among baseline VO2 max and changes in CERAD word list test scores.ResultsVO2‐max levels did not differ between groups (p = .16). Compared to mutation non‐carriers, mutation carriers performed worse in word list learning (p = .008) and recall (p<.001) at baseline. VO2‐max levels were not associated with baseline word list learning (non‐carriers: p = .93; carriers: p = .76) or recall scores (non‐carriers: p = .82; carriers: p = .63). Baseline VO2‐max levels did not predict change in word list learning (non‐carriers: p = .47; carriers: p = .85) or recall scores (non‐carriers: p = .70; carriers: p = .87).ConclusionPreliminary findings suggest that aerobic fitness, which can be increased with exercise and is associated with greater health, does not relate to memory decline in preclinical ADAD. This is an ongoing longitudinal study, and we will continue to collect more physical activity data in this kindred to characterize these associations better. More research with larger samples is needed to elucidate whether physical activity could help delay AD progression regardless of aerobic fitness levels.

A longitudinal multimodal biomarker study of memory clinic MCI patients with MBI – are there links to Alzheimer disease?

AbstractBackgroundMild cognitive impairment (MCI) and mild behavioral impairment (MBI) are at‐risk states for incident dementia. MBI represents behavioral risk, and MCI represents cognitive risk. In memory clinic MCI patients, we interrogated the relationship between MBI status (+/‐), cerebral atrophy, cerebrospinal fluid (CSF) biomarkers, and incident all‐cause dementia and incident Alzheimer disease (AD) dementia.MethodMBI was operationalized as persistent neuropsychiatric symptoms (NPS) in MEMENTO study participants. MRI regions were selected a priori for Braak stages I‐V. CSF markers included amyloid‐β (Aβ), hyperphosphorylated‐tau (p‐tau), and tau. Linear regression models were fitted with regional thickness/volume or CSF markers as dependent variables, and MBI status as independent variable, adjusted for age, sex, and education. Logistic regression was conducted to investigate if MBI status was associated with amyloid‐β positivity (defined as <813 pg/mL), with MBI status as predictor, adjusting for age, sex, education and MMSE. Kaplan‐Meier curves were generated for dementia‐free survival out to 6 years. Cox proportional hazard regressions, adjusted for age, sex, education, MMSE score, and MCI subtype were utilized to investigate the rates of incident all‐cause dementia, as well as incident AD dementia, in MBI+ vs MBI‐ patients with MCI.ResultOf the 820 participants (mean age(±SD) 72.54(8.21), 57.80% female), 29.5% had MBI. Compared to MBI‐, MBI+ status was associated with lower entorhinal thickness (b = –0.066, p = 0.04) and smaller hippocampal volume (b = –0.069, p< 0.01). In the CSF subsample (n = 154, mean age = 69.6, 48.1% female), MBI predicted amyloid‐β positivity (odds ratio = 2.19, p = 0.05), and was associated with 7.4% lower Aβ42 level (p = 0.01), 17.8% higher CSF p‐tau/Aβ42 (p<0.01) and 18.9% higher t‐tau/Aβ42 ratio (p = 0.02). Longitudinally, MBI+ had lower dementia‐free survival (log rank test; p<0.0001), with adjusted hazard ratios (HRs) of 2.76 (95%CI 1.99‐3.8; p<0.001) for all‐cause dementia and 2.73 (95%CI 1.83‐4.07; p<0.001) for AD dementia.ConclusionMBI served as a clinical marker to identify a subgroup of MCI patients with Alzheimer disease‐related morphological changes in the entorhinal cortex and hippocampus, and CSF biomarkers consistent with AD. MCI with MBI had a greater incidence rate of AD dementia than MCI without MBI. MBI case status may be used to improve detection of prodromal AD in MCI.

22 Semantic Processing and its Relation to Brain Pathology in Individuals with Autosomal Dominant Alzheimer's Disease: Preliminary Findings from the Colombia-Boston Biomarker Study

Objective:Semantic processing dysfunction has been shown to be an early indicator of cognitive decline in Alzheimer's disease (AD) and has been linked to early accumulation of AD-pathology. We examined semantic processing and its relation to AD pathology in non-demented individuals from a Colombian kindred with autosomal dominant AD due to the Presenilin1 E280A mutation (PSEN1).Participants and Methods:A total of 13 cognitively unimpaired PSEN1 mutation carriers (mean age: 36.92± 4.94), 7 carriers with mild cognitive impairment (MCI; mean age: 45±2.65), and 17 family non-carriers (mean age: 36±6.38) from the Colombia-Boston (COLBOS) longitudinal biomarker study were included. We used the Bateria IV Woodcock-Munoz verbal analogies and text comprehension subtests to examine semantic processing, the Mini-Mental State Examination (MMSE) to assess global cognition and the CERAD word list delayed recall task to measure verbal memory. Participants also underwent PiB and flortaucipir-PET to measure mean cortical amyloid and regional tau burden (entorhinal cortex and precuneus), respectively. Mann-Whitney U tests and Spearman's Rho correlations compared group differences in semantic processing, and its associations with age and pathological markers. Post-hoc analyses excluded carriers with MCI and controlled for education.Results:Carriers (including cognitively unimpaired and symptomatic individuals) performed significantly worse on the MMSE (carriers: 14.55, non-carriers: 24.24; U=81.00, p=.006), CERAD word list delayed recall (carriers: 13.63, non-carriers: 25.32; U=48.00, p=.001), and text comprehension (carriers: 16.36, non-carriers: 23.81; l/=107.00, p=.042,) than non-carriers, and showed a trend towards worse performance on verbal analogies (carriers: 17.16, non-carriers: 23.68; U=124.50, p=.077). There were no differences in text comprehension or verbal analogies performance between cognitively-unimpaired carriers and non-carriers.Across the whole sample, age was negatively associated with performance on verbal analogies (r=-.341, p=.039), but not text comprehension (r=-.136, p=.428). Among carriers only, better MMSE and CERAD delayed recall performance was associated with higher verbal analogies (r=.561, p=<.001; r=.662, p=<.001, respectively) and text comprehension scores (r=.468, p=.004; r=.480, p=.003, respectively). Greater amyloid burden was associated with worse verbal analogies performance (r=-.432, p=.007) and text comprehension (r=-.430, p=.008). Greater entorhinal cortex (r=-.384, p=.016) and precuneus tau burden (r=-.318, p=.049) was associated with worse performance on verbal analogies, but not text comprehension. These associations did not survive when excluding carriers with MCI or controlling for education.Conclusions:Preliminary results show that non-demented mutation carriers had worse performance in semantic processing than non-carriers and performance was associated with markers of AD pathology. These findings suggest that changes in semantic processing may be early indicators of disease progression in individuals at increased risk for Alzheimer's disease dementia. Future studies with larger samples need to examine the role of education and the longitudinal trajectory of semantic processing dysfunction in AD.

Neurofilament light chain in spinal fluid and plasma in multiple system atrophy: a prospective, longitudinal biomarker study.

There is a critical need for reliable diagnostic biomarkers as well as surrogate markers of disease progression in multiple system atrophy (MSA). Neurofilament light chain (NfL) has been reported to potentially meet those needs. We therefore sought to explore the value of NfL in plasma (NfL-p) in contrast to cerebrospinal fluid (NfL-c) as a diagnostic marker of MSA, and to assess NfL-p and NfL-c as markers of clinical disease progression. Well-characterized patients with early MSA (n = 32), Parkinson's disease (PD; n = 21), and matched controls (CON; n = 15) were enrolled in a prospective, longitudinal study of synucleinopathies with serial annual evaluations. NfL was measured using a high-sensitivity immunoassay, and findings were assessed by disease category and relationship with clinical measures of disease progression. Measurements of NfL-c were highly reproducible across immunoassay platforms (Pearson, r = 0.99), while correlation between NfL-c and -p was only moderate (r = 0.66). NfL was significantly higher in MSA compared with CON and PD; the separation was essentially perfect for NfL-c, but there was overlap, particularly with PD, for NfL-p. While clinical measures of disease severity progressively increased over time, NfL-c and -p remained at stable elevated levels within subjects across serial measurements. Neither change in NfL nor baseline NfL were significantly associated with changes in clinical markers of disease severity. These findings confirm NfL-c as a faithful diagnostic marker of MSA, while NfL-p showed less robust diagnostic value. The significant NfL elevation in MSA was found to be remarkably stable over time and was not predictive of clinical disease progression.

Cardiac imaging and biomarkers for assessing myocardial fibrosis in children with hypertrophic cardiomyopathy

Myocardial fibrosis, as diagnosed on cardiac magnetic resonance imaging (cMRI) by late gadolinium enhancement (LGE), is associated with adverse outcomes in adults with hypertrophic cardiomyopathy (HCM), but its prevalence and magnitude in children with HCM have not been established. We investigated: (1) the prevalence and extent of myocardial fibrosis as detected by LGE cMRI; (2) the agreement between echocardiographic and cMRI measurements of cardiac structure; and (3) whether serum concentrations of N-terminal pro hormone B-type natriuretic peptide (NT-proBNP) and cardiac troponin-T are associated with cMRI measurements. A cross-section of children with HCM from 9 tertiary-care pediatric heart centers in the U.S. and Canada were enrolled in this prospective NHLBI study of cardiac biomarkers in pediatric cardiomyopathy (ClinicalTrials.gov Identifier: NCT01873976). The median age of the 67 participants was 13.8 years (range 1-18 years). Core laboratories analyzed echocardiographic and cMRI measurements, and serum biomarker concentrations. In 52 children with non-obstructive HCM undergoing cMRI, overall low levels of myocardial fibrosis with LGE >2% of left ventricular (LV) mass were detected in 37 (71%) (median %LGE, 9.0%; IQR: 6.0%, 13.0%; range, 0% to 57%). Echocardiographic and cMRI measurements of LV dimensions, LV mass, and interventricular septal thickness showed good agreement using the Bland-Altman method. NT-proBNP concentrations were strongly and positively associated with LV mass and interventricular septal thickness (P < .001), but not LGE. Low levels of myocardial fibrosis are common in pediatric patients with HCM seen at referral centers. Longitudinal studies of myocardial fibrosis and serum biomarkers are warranted to determine their predictive value for adverse outcomes in pediatric patients with HCM.

Detection and treatment of Alzheimer's disease in its preclinical stage.

Longitudinal multimodal biomarker studies reveal that the continuum of Alzheimer's disease (AD) includes a long latent phase, referred to as preclinical AD, which precedes the onset of symptoms by decades. Treatment during the preclinical AD phase offers an optimal opportunity for slowing the progression of disease. However, trial design in this population is complex. In this Review, we discuss the recent advances in accurate plasma measurements, new recruitment approaches, sensitive cognitive instruments and self-reported outcomes that have facilitated the successful launch of multiple phase 3 trials for preclinical AD. The recent success of anti-amyloid immunotherapy trials in symptomatic AD has increased the enthusiasm for testing this strategy at the earliest feasible stage. We provide an outlook for standard screening of amyloid accumulation at the preclinical stage in clinically normal individuals, during which effective therapy to delay or prevent cognitive decline can be initiated.

Frequency of anti-IgLON5 disease in patients who meet the clinical diagnostic criteria for progressive supranuclear palsy/corticobasal syndrome (S22.010)

<h3>Objective:</h3> To confirm the prevalence of anti-immunoglobulin-like cell adhesion molecule 5 (IgLON5) disease in patients who fulfill the diagnostic criteria for progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS). <h3>Background:</h3> Anti-IgLON5 disease can present symptoms that mimic PSP and CBS, including vertical supranuclear gaze palsy and parkinsonism. Some patients who are diagnosed with PSP or CBS are expected to have anti-IgLON5 antibodies; however, the frequency of such patients remains unknown. <h3>Design/Methods:</h3> We included 360 subjects enrolled in the Japanese Longitudinal Biomarker Study in PSP and Corticobasal Degeneration (JALPAC). We noted the age and sex of each patient and evaluated their diagnosis using diagnostic criteria for each subtype of PSP (PSP with Richardson’s syndrome [PSP-RS], PSP with parkinsonism [PSP-P], PSP-pure akinesia with gait freezing [PSP-PAGF], and PSP with cerebellar ataxia [PSP-C]), and using the revised Cambridge criteria and Armstrong criteria for CBS. In patients who fulfilled any diagnostic criteria, we then tested serum anti-IgLON5 antibodies via a cell-based assay. <h3>Results:</h3> Of 360 subjects in JALPAC, 223 fulfilled at least one of the diagnostic criteria for possible or probable PSP/CBS. The median age of these 223 patients was 73 (range 51–88) years; 123 (55%) were male. The numbers of patients who met each set of criteria were as follows: PSP-RS, 52; PSP-PAGF, 6; PSP-C, 2; CBS, 117; PSP-RS and CBS, 37; PSP-PAGF and CBS, 4; PSP-RS and PSP-PAGF, 1; PSP-RS and PSP-P, 1; PSP-P and CBS, 1; PSP-RS, PSP-PAGF, and CBS, 1; and PSP-RS, PSP-C, and CBS, 1. All 223 patients were negative for anti-IgLON5 antibodies. <h3>Conclusions:</h3> Anti-IgLON5 disease is likely absent or extremely rare in patients who meet the diagnostic criteria for PSP/CBS and have typical clinical presentations. Atypical symptoms such as sleep disturbance, dysautonomia, and respiratory failure may be crucial clinical features of anti-IgLON5 disease with PSP-/CBS-like presentations. <b>Disclosure:</b> Yoya Ono has nothing to disclose. Akira Takekoshi has nothing to disclose. Dr. Yoshikura has nothing to disclose. Dr. Takigawa has nothing to disclose. Ikuko Aiba has nothing to disclose. Ritsuko Hanajima has nothing to disclose. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for DAIICHI SANKYO COMPANY, LIMITED. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Eli Lilly Japan K.K.. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Otsuka Pharmaceutical Co., Ltd.. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Amgen Inc.. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Takeda Pharmaceutical Company Limited.. Dr. Kowa has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Kyowa Kirin Co., Ltd.. Dr. Kowa has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Chugai Pharmaceutical Co., Ltd.. Dr. Kowa has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for ONO PHARMACEUTICAL CO., LTD.. Dr. Kanazawa has nothing to disclose. Dr. ?? has nothing to disclose. Aya Tokumaru has nothing to disclose. Dr. Morita has nothing to disclose. Dr. Hasegawa has nothing to disclose. Kenji Nakashima has nothing to disclose. Dr. Ikeuchi has nothing to disclose. Dr. Kimura has nothing to disclose. Dr. Shimohata has nothing to disclose.

Longitudinal study of Alzheimer's disease biomarkers, allostatic load, and cognition among memory clinic patients

BackgroundAllostatic load (AL) is defined as the cumulative dysregulation of neuroendocrine, immunological, metabolic, and cardiovascular systems that increases the susceptibility to stress-related health problems. Several dementia and Alzheimer's disease (AD) risk factors have been identified, yet little is known about the role of AL and its associations with AD biomarkers (e.g., beta-amyloid (Aβ) or tau) and cognitive function among memory clinic patients. Hence, this study aims to assess the association between AL and AD biomarkers, cognitive performance, and cognitive decline after 3-years of follow-up. MethodsData from 188 memory clinic patients were derived from the Cortisol and Stress in AD (Co-STAR) study in Sweden. Participants underwent baseline assessments including blood tests for AL measures (including cortisol, thyroid stimulating hormone, cobalamin, homocysteine, leukocytes, glycated hemoglobin, albumin, high-density and low-density lipoprotein cholesterol, triglycerides, and creatinine), cerebrospinal fluid (CSF) sampling for AD biomarkers and neuropsychological tests including five cognitive domains. Linear regressions were conducted, adjusting for age, sex, and education. ResultsHigher AL was associated with lower CSF Aβ1-42 levels (β = −0.175, p = 0.025), reflecting higher brain levels of Aβ1-42. Stratified analyses suggested a significant association among women but not men, although the AL-sex interaction was not statistically significant. AL was not significantly associated with T-tau level (β = −0.030, p = 0.682) and P-tau level (β = 0.091, p = 0.980). There were no significant associations between AL and cognition or cognitive decline after 3 years. ConclusionThis study showed that higher AL was associated with increased brain amyloid accumulation. This suggests that AL may play a role in AD/dementia pathophysiology. Potential sex-related differences should be assessed in further larger studies.

Associations between plasma Neurofilament Light Chain (NfL), Sleep Quality and Cognition in individuals with autosomal‐dominant Alzheimer's Disease (ADAD): Findings from the Colombia‐Boston (COLBOS) biomarker study

AbstractBackgroundMethods available for in‐vivo diagnosis of Alzheimer's disease (AD) are expensive and invasive. Neurofilament light chain (NfL), a plasma‐based biomarker for neurodegeneration, is a promising marker for early detection in individuals at increased risk. We previously reported that Presenilin1 (PSEN1) E280A carriers have increased levels of plasma NfL relative to non‐carrier family members twenty years before the onset of clinical symptoms. Here, we examined whether baseline levels of plasma NfL predict self‐reported sleep quality and cognition 10 years later in non‐demented PSEN1‐E280A carriers and non‐carriers. MethodsA total of 51 PSEN1‐E280A carriers (mean age = 30.06, SD = 4.63), including 2 mildly impaired carriers and 49 age‐matched non‐carriers (mean age = 35.55, SD = 6.16) from the Colombia‐Boston (COLBOS) longitudinal biomarker study were included. Participants underwent blood sampling at baseline and completed the Pittsburgh Sleep Quality Index (PSQI), Mini Mental State Exam (MMSE), and memory testing (CERAD Word List) at follow‐up approximately 10 years later. Self‐reported sleep quality was assessed by calculating the PSQI score. Plasma NfL concentrations were measured with a single molecule array (Simoa) method. Linear regressions were used to examine associations among NfL levels, sleep quality, and memory.ResultsThere were no group differences, between carriers and non‐carriers, in baseline NfL levels, memory performance, or total PSQI scores (p&gt;0.05). However, carriers had lower MMSE scores than non‐carriers (carriers M=27.90; non‐carriers M=28.47; p = 0.05). Among the entire sample, baseline NfL levels predicted recall scores on the CERAD word list (p = 0.03) and MMSE performance (p = 0.02). Additionally, associations between NfL levels and age trended toward significance (p = 0.06). Sleep quality (PSQI) was not associated with age, memory performance, or NfL levels.ConclusionsPreliminary findings support the hypothesis that plasma NfL levels may predict memory function and overall cognitive status in ADAD. However, our findings suggest that NfL levels may not be associated with self‐reported sleep quality in individuals in prodromal stages of ADAD. Future work using objective sleep metrics and larger samples across the preclinical/prodromal spectrum will allow a more comprehensive examination of these associations.

TREM2 Variants in Parkinson’s Disease: Results from the Parkinson’s Progression Markers Initiative (PPMI) Study

AbstractBackgroundWhile TREM2 coding variants are known risk factors for Alzheimer’s disease, their contribution to Parkinson’s disease (PD) risk is less clear. We hypothesized that rare coding variants in TREM2 are associated with increased risk for Parkinson’s disease (PD), and that carriers of TREM2 coding variants represent a subtype of PD cases with different clinical characteristics and disease trajectory.Method TREM2 coding variants were obtained from the whole genome sequencing data available on LONI (https://ida.loni.usc.edu/) using VCFtools and annotated using Annovar for all individuals enrolled in the Parkinson’s Progression Markers Initiative (PPMI, N=1736), a longitudinal study of biomarkers of PD onset and progression. Of the 12 coding variants obtained, 8 variants that had reported or predicted pathogenic function were further analyzed. Fischer’s Exact 2‐sided tests were used to investigate enrichment of all variant carriers, as well as enrichment of specific variants with &gt;20 carriers in the cohort, in sporadic (non‐genetic) PD (sPD) cases compared to controls. Enriched variants were tested for association with PD‐related measures including the MDS‐Unified Parkinson’s Disease Rating Scale (MDS‐UPDRS) total score, Montreal Cognitive Assessment (MoCA) score, Geriatric Depression Scale (GDS)‐15 score, and the University of Pennsylvania Smell Identification Test (UPSIT) score.Result TREM2 variant carriers (total N=77) were enriched in PD cases compared to controls (p=0.002). Within variant analysis showed enrichment of p.R62H carriers (p=0.027), but not p.R47H carriers (p=0.667) in sPD. While there was no significant difference in MDS‐UPDRS (p=0.763) or MoCA (p=0.815) at baseline between p.R62H sPD carriers and non‐carriers, p.R62H carriers were more likely to have a MoCA score &lt;21 at a subsequent visit [HR (95% CI) = 2.78 (1.19‐6.49)], though this effect was not significant in an age‐adjusted model [HR (95% CI) = 2.28 (0.97‐5.34]. Compared to non‐carriers, p.R62H carriers showed a trend for more depressive symptoms (p=0.078) and had worse anosmia (p=0.002).Conclusion TREM2 rare coding variants are more common in PD, suggesting that TREM2 may contribute to the genetic etiology of this disease. Interestingly, p.R47H, a risk factor for Alzheimer’s disease, does not appear to contribute to sPD risk, whereas p.R62H may be a novel risk factor for PD.

The New Zealand Genetic Frontotemporal Dementia Study (FTDGeNZ): a longitudinal study of pre-symptomatic biomarkers

ABSTRACT The New Zealand Genetic Frontotemporal Dementia Study (FTDGeNZ) is an emerging longitudinal study of a large New Zealand pedigree with genetic frontotemporal dementia (FTD). Natural history studies of genetic FTD cohorts provide a unique opportunity to identify biomarkers of pre-symptomatic dementia, as carriers can be identified and studied decades before expected symptom onset. FTDGeNZ was established in 2016 with the aim of identifying the earliest pre-symptomatic biomarkers of FTD, in collaboration with international multi-centre cohorts. We enrolled 25 participants from a single family between April 2016 and August 2018. Participants were genotyped to determine whether they were pre-symptomatic carriers of the mutation (MAPT IVS 10 + 16 C > T), or non-carrier controls. Participants have undergone clinical assessments including neuropsychological and mood assessment; olfactory testing; assessment of social cognition; and blood collection for analyses of microRNA and protein fluid biomarkers annually. We have also performed structural and functional MRI of the brain and assessment of autobiographical memory biennially, and retinal imaging at baseline. Here, we describe the full study protocol and the baseline demographic and clinical characteristics of the FTDGeNZ cohort, and we highlight the latest findings in the field.

Prospective evaluation of immunological, molecular-genetic, image-based and microbial analyses to characterize tumor response and control in patients with unresectable stage III NSCLC treated with concurrent chemoradiotherapy followed by consolidation therapy with durvalumab (PRECISION): protocol for a prospective longitudinal biomarker study.

BackgroundConcurrent platinum-based chemoradiotherapy (CRT) followed by durvalumab maintenance treatment represents the new standard of care in unresectable stage III non-small cell lung cancer (NSCLC). In this prospective hypothesis-generating single-center study, we aim to identify a framework of prognostic and predictive biomarkers by longitudinal characterization of tumor- and patient (host)-related parameters over all phases of multimodal treatment.MethodsThis study will enroll 40 patients (≥18 years, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2, with a diagnosis of PD-L1 positive (≥1%), inoperable stage III NSCLC) with an indication for CRT followed by maintenance treatment with durvalumab according to European Medicines Agency (EMA) approval. Comprehensive analysis will include peripheral blood cellular and humoral immunophenotyping and circulating tumor DNA as well as gut/saliva microbiota analyses. Additional morphological analysis with 18F-FDG-PET/computed tomography (CT) before, 6 weeks, 6 and 12 months after the end of CRT is included. Statistical analysis using multiple testing will be used to examine the impact of different parameters on progression-free survival (PFS) and overall survival (OS) as well as tumor response and response duration.DiscussionThis protocol describes the methodology of a comprehensive biomarker study in order to identify a framework of prognostic and predictive markers for unresectable stage III NSCLC in a real-world setting.Trial RegistrationClinicalTrials.gov identifier (NCT05027165), data registered on August 2021.

Persistent Dissociation and Its Neural Correlates in Predicting Outcomes After Trauma Exposure.

Dissociation, a disruption or discontinuity in psychological functioning, is often linked with worse psychiatric symptoms; however, the prognostic value of dissociation after trauma is inconsistent. Determining whether trauma-related dissociation is uniquely predictive of later outcomes would enable early identification of at-risk trauma populations. The authors conducted the largest prospective longitudinal biomarker study of persistent dissociation to date to determine its predictive capacity for adverse psychiatric outcomes following acute trauma. All data were part of the Freeze 2 data release from the Advancing Understanding of Recovery After Trauma (AURORA) study. Study participants provided self-report data about persistent derealization (N=1,464), a severe type of dissociation, and completed a functional MRI emotion reactivity task and resting-state scan 2 weeks posttrauma (N=145). Three-month follow-up reports were collected of posttraumatic stress, depression, pain, anxiety symptoms, and functional impairment. Derealization was associated with increased ventromedial prefrontal cortex (vmPFC) activation in the emotion reactivity task and decreased resting-state vmPFC connectivity with the cerebellum and orbitofrontal cortex. In separate analyses, brain-based and self-report measures of persistent derealization at 2 weeks predicted worse 3-month posttraumatic stress symptoms, distinct from the effects of childhood maltreatment history and current posttraumatic stress symptoms. The findings suggest that persistent derealization is both an early psychological and biological marker of worse later psychiatric outcomes. The neural correlates of trauma-related dissociation may serve as potential targets for treatment engagement to prevent posttraumatic stress disorder. These results underscore dissociation assessment as crucial following trauma exposure to identify at-risk individuals, and they highlight an unmet clinical need for tailored early interventions.

Amygdala tau pathology in preclinical autosomal dominant Alzheimer’s disease

AbstractBackgroundThe amygdala has been found to be pathologically affected in early stages of Alzheimer’s disease (AD), with particular amygdala subnuclei being especially vulnerable. We used in vivo positron emission tomography (PET) imaging to examine whether amygdala tau accumulation could be observed in cognitively unimpaired PSEN‐1 mutation carriers who carry an autosomal‐dominant mutation in the Presenilin‐1 (PSEN‐1) gene and are determined to develop dementia in their early 50s. We further aimed to investigate associations between amygdala tau, age, amyloid deposition, and cognition in mutation carriers and non‐carrier family members.MethodA total of 29 PSEN‐1 mutation carriers (M age = 37.4 +/‐ 5.8 years) and 35 age‐matched non‐carriers (M age = 35.9 +/‐ 5.8 years) were recruited from the Colombia‐Boston (COLBOS) Longitudinal Biomarker Study, which follows Colombian families with autosomal‐dominant AD. Participants underwent PET, using Pittsburgh Compound B to measure mean cortical amyloid‐β and Flortaucipir for regional tau, and episodic memory testing (CERAD Word List Learning). Amygdala subnuclei were automatically segmented with FreeSurfer7. Spearman correlations were used to examine associations among amygdala tau, age, mean amyloid‐β, and memory performance.ResultCompared to non‐carriers, cognitively unimpaired mutation carriers had greater tau accumulation in the amygdala (p&lt;0.001). Unimpaired carriers had greater tau burden in amygdala compared to neocortical regions (vs. inferior temporal: t=2.3, p=0.03), suggesting early involvement of amygdala tau. Among amygdala subnuclei, basal and accessory basal nuclei had greater tau burden compared to the other subregions (vs. lateral nucleus: t=5.5, p&lt;0.0001) in unimpaired carriers. Greater amygdala tau burden was associated with older age (r=0.649, p&lt;0.0001), greater mean cortical amyloid (r=0.597, p=0.001) and worse memory performance (r=‐0.433, p= 0.019) in carriers. No significant associations were observed in the non‐carrier group.ConclusionAmygdala tau burden is associated with greater age, cortical amyloid burden, and worse memory in preclinical autosomal dominant Alzheimer’s disease. These results suggest that amygdala tau accumulation is evident in preclinical Alzheimer’s disease. Future studies should determine if amygdala tau (including subnuclei) can be used as an early indicator of Alzheimer’s disease progression. Longitudinal studies are needed to examine the associations between amygdala tau and onset of neuropsychiatric and behavioral symptoms.

Respiratory Disease Occupational Biomonitoring Collaborative Project (ROBoCoP): A longitudinal pilot study and implementation research in the Parisian transport company

The ROBoCoP project is launched within the EU COST Action CA16113 “CliniMARK” aiming to increase the number of clinically validated biomarkers and focused on chronic obstructive pulmonary disease (COPD) biomarker development and validation. ROBoCoP encompasses two consecutive studies consisting of a pilot study followed by a field study. The pilot study is a longitudinal exposure assessment and biomarker study aiming at: 1-understanding the suitability of the candidate biomarkers in surveying populations at risk such as workers exposed to COPD causing agents; 2-determining the best sampling plan with respect to the half-life of the candidate biomarkers; 3-implementing and validating the sampling procedures and analytical methods; 4-selecting the best suitable biomarkers to be measured in the field. Each study participant is surveyed every day during the 6–8 h work-shifts for two consecutive weeks. The field study has an implementation research designe that enabled us to demonstrate the applicability of the standardized protocol for biomarker measurements in occupational settings while also assessing the biomarkers’ validity. ROBoCoP will focus on particulate matter (PM) exposure measurements, exposure biomarkers and a series of effect biomarkers, including markers of lipoperoxidation: 8-isoprostane, malondialdehyd in exhaled breath condensate (EBC) and urine, potential markers of nitrosative stress: NO2−, NO3− and formate anion in EBC; markers of DNA oxidation: 8-hydroxy-2’deoxyguanosine in EBC and urine, marker of genotoxicity: micronuclei in buccal cells, and oxidative potential in exhaled air (OPEA). OPEA appears particularly promising as a clinical biomarker for detecting COPD, and will be tested independently and as part of a biomarker panel. COPD diagnosis will be performed by an experienced occupational physician according to international diagnostic standards and confirmed by a pulmonologist.This research will include approximatively 300 underground subway workers randomly selected from the personnel registry of a large Parisian transport company. Underground subways are suggested as the most PM polluted urban transport environment. We believe this occupational exposure is relevant for biomonitoring of workers and early detection of respiratory diseases.

Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes

The number of people affected by Type 2 diabetes mellitus (T2DM) is close to half a billion and is on a sharp rise, representing a major and growing public health burden. Given its mild initial symptoms, T2DM is often diagnosed several years after its onset, leaving half of diabetic individuals undiagnosed. While several classical clinical and genetic biomarkers have been identified, improving early diagnosis by exploring other kinds of omics data remains crucial. In this study, we have combined longitudinal data from two population-based cohorts CoLaus and DESIR (comprising in total 493 incident cases vs. 1360 controls) to identify new or confirm previously implicated metabolomic biomarkers predicting T2DM incidence more than 5 years ahead of clinical diagnosis. Our longitudinal data have shown robust evidence for valine, leucine, carnitine and glutamic acid being predictive of future conversion to T2DM. We confirmed the causality of such association for leucine by 2-sample Mendelian randomisation (MR) based on independent data. Our MR approach further identified new metabolites potentially playing a causal role on T2D, including betaine, lysine and mannose. Interestingly, for valine and leucine a strong reverse causal effect was detected, indicating that the genetic predisposition to T2DM may trigger early changes of these metabolites, which appear well-before any clinical symptoms. In addition, our study revealed a reverse causal effect of metabolites such as glutamic acid and alanine. Collectively, these findings indicate that molecular traits linked to the genetic basis of T2DM may be particularly promising early biomarkers.

PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer’s disease-causing Presenilin-1 E280A mutation carriers

BackgroundIn contrast to sporadic Alzheimer’s disease, autosomal dominant Alzheimer’s disease (ADAD) is associated with greater neuropathological evidence of cerebellar amyloid plaque (Aβ) deposition. In this study, we used positron emission tomography (PET) measurements of fibrillar Aβ burden to characterize the presence and age at onset of cerebellar Aβ deposition in cognitively unimpaired (CU) Presenilin-1 (PSEN1) E280A mutation carriers from the world’s largest extended family with ADAD. Methods18F florbetapir and 11C Pittsburgh compound B (PiB) PET data from two independent studies – API ADAD Colombia Trial (NCT01998841) and Colombia-Boston (COLBOS) longitudinal biomarker study were included. The tracers were selected independently by the respective sponsors prior to the start of each study and used exclusively throughout. Template-based cerebellar Aβ-SUVR (standard-uptake value ratios) using a known-to-be-spared pons reference region (cerebellar SUVR_pons), to a) compare 28–56-year-old CU carriers and non-carriers; b) estimate the age at which cerebellar SUVR_pons began to differ significantly in carrier and non-carrier groups; and c) characterize in carriers associations with age, cortical SUVR_pons, delayed recall memory, and API ADAD composite score. ResultsFlorbetapir and PiB cerebellar SUVR_pons were significantly higher in carriers than non-carriers (p < 0.0001). Cerebellar SUVR_pons began to distinguish carriers from non-carriers at age 34, 10 years before the carriers’ estimated age at mild cognitive impairment onset. Florbetapir and PiB cerebellar SUVR_pons in carriers were positively correlated with age (r = 0.44 & 0.69, p < 0.001), cortical SUVR_pons (r = 0.55 & 0.69, p < 0.001), and negatively correlated with delayed recall memory (r = −0.21 & −0.50, p < 0.05, unadjusted for cortical SUVR_pons) and API ADAD composite (r = −0.25, p < 0.01, unadjusted for cortical SUVR_pons in florbetapir API ADAD cohort). ConclusionThis PET study provides evidence of cerebellar Aβ plaque deposition in CU carriers starting about a decade before the clinical onset of ADAD. Additional studies are needed to clarify the impact of using a cerebellar versus pons reference region on the power to detect and track ADAD changes, even in preclinical stages of this disorder.

Inflammatory Proteins and Clinical Response to Psychological Therapy in Patients with Depression: An Exploratory Study.

In people with depression, immune dysfunctions have been linked with treatment non-response, but examinations of psychological therapy outcomes, particularly longitudinal biomarker studies, are rare. This study investigated relationships between inflammation, depressive subtypes and clinical outcomes to psychological therapy. Adults with depression (n = 96) were assessed before and after a course of naturalistically-delivered psychological therapy. In total, 32 serum inflammatory proteins were examined alongside therapy outcomes and depressive subtypes (somatic/cognitive symptom subtype, and bipolar/unipolar depression). Overall, 49% of participants responded to treatment. High levels of tumour necrosis factor (TNFα), interleukin-6 (IL-6) and soluble intracellular adhesion molecule-1 (sICAM1), and low interferon-γ (IFNγ), preceded a poorer response to therapy. After therapy, non-responders had elevated c-reactive protein (CRP), thymus and activation-regulated chemokine (TARC) and macrophage chemoattractant protein-4 (MCP4), and attenuated IFNy. Non-somatic depressive symptoms were universally not associated with proteins, while somatic-depressive symptom severity was positively correlated with several pro-inflammatory markers. In the somatic subgroup only, IL-6 and serum amyloid alpha (SAA) decreased between pre- and post-therapy timepoints. Regardless of treatment response, IL-7, IL-8, IL-15 and IL-17 increased over time. These results suggest that inflammation is associated with somatic symptoms of depression and non-response to psychological therapy. Future work may enhance the prospective prediction of treatment-response by examining larger samples of individuals undertaking standardised treatment programmes.

Multicentre longitudinal study of fluid and neuroimaging BIOmarkers of AXonal injury after traumatic brain injury: the BIO-AX-TBI study protocol

Introduction and aimsTraumatic brain injury (TBI) often results in persistent disability, due particularly to cognitive impairments. Outcomes remain difficult to predict but appear to relate to axonal injury. Several new...