Disease Continuum Research Articles

Translational potential of synaptic alterations in Alzheimer's disease patients and amyloid precursor protein knock-in mice.

Synaptic dysfunction is an early event in Alzheimer's disease. Post-mortem studies suggest that alterations in synaptic proteins are associated with cognitive decline in Alzheimer's disease. We measured the concentration of three synaptic proteins, zinc transporter protein 3, dynamin1 and AMPA glutamate receptor 3 in cerebrospinal fluid of subjects with mild cognitive impairment (n = 18) and Alzheimer's disease (n = 18) and compared the levels to cognitively and neurologically healthy controls (n = 18) by using ELISA assay. In addition, we aimed to assess the translational potential of these synaptic proteins in two established amyloid precursor protein knock-in Alzheimer's disease mouse models by assessing the cerebrospinal fluid, hippocampal and cortical synaptic protein concentrations. Using ELISA, we measured in parallel these three proteins in cerebrospinal fluid and/or brain of 12- and 24-month-old AppNL-F and AppNL-G-F knock-in mice and AppWt control mice. The regional distribution and expression of these proteins were explored upon aging of the App knock-in models by quantitative immunofluorescence microscopy. Notably, we found a significant increase in concentrations of zinc transporter protein 3 and AMPA glutamate receptor 3 in cerebrospinal fluid of both patient groups compared with cognitively healthy controls. Dynamin1 concentration was significantly higher in Alzheimer's disease patients. Remarkably, patients with mild cognitive impairment who converted to Alzheimer's disease (n = 7) within 2 years exhibited elevated baseline cerebrospinal fluid zinc transporter protein 3 concentrations compared with mild cognitive impairment patients who did not convert (n = 11). Interestingly, similar to the alterations in Alzheimer's disease subjects, cerebrospinal fluid AMPA glutamate receptor 3 concentration was significantly higher in AppNL-G-F knock-in mice when compared with wild-type controls. Furthermore, we have detected age and brain regional specific changes of the three synaptic proteins in the hippocampus and prefrontal cortex of both AppNL-F and AppNL-G-F knock-in mice. Notably, all the three cerebrospinal fluid synaptic protein concentrations correlated negatively with concentrations in hippocampal lysates. The elevated zinc transporter protein 3 concentrations in the cerebrospinal fluid of converter versus non-converter mild cognitive impairment patients suggests a prospective role of zinc transporter 3 in differentiating dementia patients of the biological continuum of Alzheimer's disease. The increased cerebrospinal fluid concentrations of synaptic proteins in both patient groups, potentially reflecting synaptic alterations in the brain, were similarly observed in the amyloid precursor protein knock-in mouse models highlighting the translational potential of these proteins as markers for synaptic alterations. These synaptic markers could potentially help reduce the current disparities between human and animal model-based studies aiding the translation of preclinical discoveries of pathophysiological changes into clinical research.

Personalizing the Setting of Palliative Care Delivery for Patients with Advanced Cancer: "Care Anywhere, Anytime".

The specialty of palliative care has evolved over time to provide symptom management, psychosocial support, and care planning for patients with cancer throughout the disease continuum and in multiple care settings. This review examines the delivery and impact of palliative care in the outpatient, inpatient, and community-based settings. The article will discuss how these 3 palliative care settings can work together to optimize patient outcomes under a unifying model of palliative care "anywhere, anytime" and how to prioritize palliative care services when resources are limited. Many patients with advanced cancer receive care from each of the 3 branches of palliative care-outpatient, inpatient, and community-based settings-at some point along their disease trajectory. Early on, outpatient clinics provide longitudinal supportive care concurrent with active disease-modifying treatments. Telemedicine appointments can serve patients remotely to minimize their need to travel. When patients experience functional decline, community-based palliative care services can provide support and monitoring for patients at home. When patients develop acute symptomatic complications requiring admission, inpatient care consultation teams are essential for symptom management and goals-of-care discussions. For patients in severe distress, receiving care in a palliative care unit that provides intensive symptom control and facilitates complex discharge planning is ideal. Under a unifying model of palliative care designed to offer care "anywhere, anytime," the 3 branches of palliative care could work in unison to support each other, minimize gaps in care, and optimize patient outcomes.

Cardioprotective effect of thiotriazoline in cancer patients

Aim. To evaluate the effectiveness of morpholinium-methyl-triazolyl-thioacetate (thiotriazoline) as a cardioprotector in patients with non-Hodgkin’s lymphomas who received chemotherapy with the inclusion of anthracyclines.Material and methods. Fifty patients with non-Hodgkin’s lymphomas were examined on the background of antitumor therapy. The patients were divided into 2 following groups: group 1 (n=27) — standard chemotherapy; group 2 (n=23) — thiotriazoline as a cardioprotector. The quality of life was assessed using the SF-36 questionnaire; the level of troponin I and the natriuretic peptide NT-proBNP was determined; an electrocardiography and echocardiography were performed.Results. In the course of the study, significant differences (p<0,05) were found in following parameters: the severity of dyspnea and lower limb edema, alanine aminotransferase, aspartate aminotransferase, creatine phosphokinase, troponin I level, NT-proBNP, corrected QT interval, end systolic volume, left ventricular ejection fraction, E/A ratio. The results obtained indicate the clinical and paraclinical advantage of thiotriazoline and reflect its cardioprotective effect. Conclusion. The use of thiotriazoline makes it possible to prevent and slow down the cardiovascular disease continuum, leading to the development of heart failure or decompensation that exists in this category of patients. Keywords: cardio-oncology, thiotriazoline, heart failure, anthracyclines, cardiotoxicity>˂0,05) were found in following parameters: the severity of dyspnea and lower limb edema, alanine aminotransferase, aspartate aminotransferase, creatine phosphokinase, troponin I level, NT-proBNP, corrected QT interval, end systolic volume, left ventricular ejection fraction, E/A ratio. The results obtained indicate the clinical and paraclinical advantage of thiotriazoline and reflect its cardioprotective effect.Conclusion. The use of thiotriazoline makes it possible to prevent and slow down the cardiovascular disease continuum, leading to the development of heart failure or decompensation that exists in this category of patients.

Antibody-free measurement of cerebrospinal fluid tau phosphorylation across the Alzheimer’s disease continuum

BackgroundAlzheimer’s disease is characterized by an abnormal increase of phosphorylated tau (pTau) species in the CSF. It has been suggested that emergence of different pTau forms may parallel disease progression. Therefore, targeting multiple specific pTau forms may allow for a deeper understanding of disease evolution and underlying pathophysiology. Current immunoassays measure pTau epitopes separately and may capture phosphorylated tau fragments of different length depending on the non-pTau antibody used in the assay sandwich pair, which bias the measurement.MethodsWe developed the first antibody-free mass spectrometric method to simultaneously measure multiple phosphorylated epitopes in CSF tau: pT181, pS199, pS202, pT205, pT217, pT231, and pS396. The method was first evaluated in biochemically defined Alzheimer’s disease and control CSF samples (n = 38). All seven pTau epitopes clearly separated Alzheimer’s disease from non-AD (p < 0.001, AUC = 0.84–0.98). We proceeded with clinical validation of the method in the TRIAD (n = 165) and BioFINDER-2 cohorts (n = 563), consisting of patients across the full Alzheimer’s disease continuum, including also young controls (< 40 years), as well as patients with frontotemporal dementia and other neurodegenerative disorders.ResultsIncreased levels of all phosphorylated epitopes were found in Alzheimer’s disease dementia and Aβ positron emission tomography-positive patients with mild cognitive impairment compared with Aβ-negative controls. For Alzheimer’s disease dementia compared with Aβ-negative controls, the best biomarker performance was observed for pT231 (TRIAD: AUC = 98.73%, fold change = 7.64; BioFINDER-2: AUC = 91.89%, fold change = 10.65), pT217 (TRIAD: AUC = 99.71%, fold change = 6.33; BioFINDER-2: AUC = 98.12%, fold change = 8.83) and pT205 (TRIAD: AUC = 99.07%, fold change = 5.34; BioFINDER-2: AUC = 93.51%, fold change = 3.92). These phospho-epitopes also discriminated between Aβ-positive and Aβ-negative cognitively unimpaired individuals: pT217 (TRIAD: AUC = 83.26, fold change = 2.39; BioFINDER-2: AUC = 91.05%, fold change = 3.29), pT231 (TRIAD: AUC = 86.25, fold change = 3.80; BioFINDER-2: AUC = 78.69%, fold change = 3.65) and pT205 (TRIAD: AUC = 71.58, fold change = 1.51; BioFINDER-2: AUC = 71.11%, fold change = 1.70).ConclusionsWhile an increase was found for all pTau species examined, the highest fold change in Alzheimer’s disease was found for pT231, pT217 and pT205. Simultaneous antibody-free measurement of pTau epitopes by mass spectrometry avoids possible bias caused by differences in antibody affinity for modified or processed forms of tau, provides insights into tau pathophysiology and may facilitate clinical trials on tau-based drug candidates.

Altered anterior cingulate cortex subregional connectivity associated with cognitions for distinguishing the spectrum of pre-clinical Alzheimer's disease.

Subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) are considered part of the early progression continuum of Alzheimer's disease (AD). The anterior cingulate cortex (ACC), a hub of information processing and regulation in the brain, plays an essential role in AD pathophysiology. In the present study, we aimed to systematically identify changes in the functional connectivity (FC) of ACC subregions in patients with SCD and aMCI and evaluate the association of these changes with cognition. Functional connectivity (FC) analysis of ACC sub-regions was performed among 66 patients with SCD, 71 patients with aMCI, and 78 healthy controls (HCs). Correlation analyses were performed to examine the relationship between FC of altered ACC subnetworks and cognition. Compared to HCs, SCD patients showed increased FC of the bilateral precuneus (PCUN) and caudal ACC, left superior frontal gyrus (SFG) and subgenual ACC, left inferior parietal lobule (IPL) and dorsal ACC, left middle occipital gyrus (MOG) and dorsal ACC, and left middle temporal gyrus (MTG) and subgenual ACC, while aMCI patients showed increased FC of the left inferior frontal gyrus (IFG) and dorsal ACC and left medial frontal gyrus (MFG) and subgenual ACC. Compared to patients with SCD, patients with aMCI showed increased FC of the right MFG and dorsal ACC and left ACC and subgenual ACC, while the left posterior cingulate cortex (PCC) showed decreased FC with the caudal ACC. Moreover, some FC values among the altered ACC subnetworks were significantly correlated with episodic memory and executive function. SCD and aMCI, part of the spectrum of pre-clinical AD, share some convergent and divergent altered intrinsic connectivity of ACC subregions. These results may serve as neuroimaging biomarkers of the preclinical phase of AD and provide new insights into the design of preclinical interventions.

Simultaneous Mass Spectrometric quantification of multiple p‐tau species in plasma – findings along the Alzheimer´s disease continuum

AbstractBackgroundBlood phosphorylated tau (p‐tau) species at positions 181, 217 and 231 have been demonstrated accurate biomarkers of Alzheimer´s disease pathology. Comparisons to assess the performance of each phosphorylation along the Alzheimer´s disease (AD) continuum rely on the use of different immunoassays. In the current study, we simultaneously quantified the plasma concentration of six different phosphorylated (p‐tau 181, 199, 202, 205, 217 and 231), and two non‐phosphorylated, tau peptides using a targeted Mass Spectrometric (MS) method.MethodWe analysed a total of 224 samples from two centres, the TRIAD cohort (Canada) and the BioCogBank Paris Lariboisière cohort (France). Tau enrichment prior to MS analysis was performed by immunoprecipitation, using a combination of several non‐phospho‐tau antibodies, followed by tryptic digestion. A parallel reaction monitoring method with Orbitrap MS was used to measure the levels of targeted peptides. Group‐level comparisons were carried with non‐parametric tests. Cross‐sectional associations between plasma tau biomarkers and Aβ and tau PET were investigated using the locally estimated scatterplot smoothing (LOESS) method for local polynomial regression. Voxel‐wise correlations were performed between plasma and PET biomarkers using Rminc.ResultP‐tau231 levels were significantly increased in amyloid positive and tau negative (A+T‐) individuals compared to A‐T‐ (stratified by CSF biomarkers). Increases in p‐tau217 and p‐tau205 emerged later in the AD continuum, only when tau pathology was present (A+T+). Plasma p‐tau217, p‐tau231 and p‐tau205 were the site‐specific phosphorylations that showed higher correlations with Tau PET (Braak I‐VI) (R=0.7 p&lt;0.0001; R=0.53 p&lt;0.0001; and R=0.53 p&lt;0.0001; respectively) and with Aβ PET (R=0.66 p&lt;0.0001; R=0.56 p&lt;0.0001; R=0.45 p&lt;0.0001, respectively). LOESS analysis revealed that plasma p‐tau231 increases earlier in the disease progression, followed by p‐tau217 and p‐tau205, which showed a progressive increase along Braak stages and amyloid centiloid. Voxel‐wise analysis for tau PET were highest with p‐tau205 with associations in in the inferior, medial, and lateral temporal regions. For Aβ PET, p‐tau217 and p‐tau205 showed the highest associations with frontal, precuneus, posterior cingulate and temporal cortices.ConclusionOur results indicate that plasma p‐tau217, p‐tau231 and p‐tau205 are the site‐specific phosphorylations that better reflect amyloid and tau pathologies, although with different emergence along the AD continuum.

Oxidative stress biomarkers and longitudinal changes in human brain imaging across the Alzheimer’s disease continuum

AbstractBackgroundOxidative stress is critical for Alzheimer’s disease (AD) pathophysiology. Brain mitochondrial function, proteins, and lipids are susceptible to oxidative damage caused by reactive oxygen species. In turn, this damage leads to key AD‐like changes in the brain, such as impaired glucose metabolism (i.e., lower fluorodeoxyglucose, or FDG‐PET) and gray matter volume atrophy in AD‐sensitive regions. It is unknown if oxidative stress biomarkers like superoxide dismutase (SOD) proteins track these changes using longitudinal brain imaging data, and what mechanisms may be at work (Figure 1).MethodUsing Alzheimer’s Disease Neuroimaging Initiative (ADNI) data, 192 aged adults (75 unimpaired, 48 MCI, 69 AD) had annual CSF and FDG data available for over 6 years. A two‐phase MRM targeted proteomics panel was used to gauge CSF SOD1 levels from serum. Standard assays in CSF determined Aβ, p‐tau‐181, and total tau. Brain glucose uptake was determined using FDG SUVR calibrated to the pons. Brain volume was examined longitudinally using FreeSurfer.ResultLongitudinally, among SOD1 quartiles (Figure 2), the lowest SOD1 group showed marked hypometabolism among older adults at baseline (R2=0.528, p&lt;.001, “blue line”), but 6 years later instead predicted hypermetabolism (R2=0.389, p&lt;.001). The highest SOD1 group showed no association at baseline but at 6 years later predicted hypometabolism among older adults (R2=0.151, p&lt;.05, “dotted red line”). CSF Aβ and p‐tau‐181 fully mediated these effects (ps&lt;.01), such that lower Aβ and higher p‐tau‐181 over time resulted in higher SOD1 predicting less glucose uptake. Similarly, higher SOD1 was not related to atrophy in AD‐sensitive regions like parahippocampus at baseline, but 5 years later was strongly related to more brain atrophy (R2=0.207,p&lt;.001) (Figure 3), which was mediated by higher CSF total tau (p&lt;.001).ConclusionLike previous reports, we found that SOD1 initially showed neutral or ameliorative patterns, reflecting its classical role in reducing oxidative stress. With increased Aβ or p‐tau‐181 deposition over time, however, SOD1 became a marker of the degree of oxidative damage that may have occurred in neural tissue due to Aβ or tau.

Cerebrospinal Fluid Lactate Levels along the Alzheimer’s Disease Continuum and Associations with Blood‐Brain Barrier Integrity, Age, Cognition and Biomarkers

AbstractBackgroundCerebrospinal fluid (CSF) lactate levels have been suggested to be associated with disease severity and progression in several neurological diseases as an indicator of impaired energy metabolism, neuronal death or microglial activation. A small number of studies have examined CSF lactate levels in dementia due to Alzheimer’s disease (AD) and found higher values in AD patients compared to healthy controls (HC). However, these studies were mostly small in size, the inclusion criteria were not always well defined, and the diagnostic value and pathophysiological significance of CSF lactate in AD remains unclear.MethodsWe examined CSF lactate levels and potentially associated factors in a large (n=312), biologically and clinically well‐defined sample of patients with AD at the stage of mild cognitive impairment (MCI‐AD) and dementia (ADD), HC, and patients with frontotemporal lobar degeneration (FTLD).ResultsContrary to previous studies, patients with ADD and HC did not differ in CSF lactate levels. However, we found higher values for patients with MCI‐AD compared to those with ADD and to HC in univariate analysis, as well as for MCI‐AD compared to ADD when controlling for age and blood‐brain barrier integrity. CSF lactate levels were associated with age and blood‐brain barrier integrity but not with clinical severity or CSF biomarkers of AD.ConclusionCSF lactate does not indicate biological or clinical disease severity in AD, nor does it differentiate between patients with AD and healthy controls or patients with FTLD. However, higher CSF lactate levels were found in earlier stages of AD, which might be interpreted in the context of inflammatory processes.

Cerebral Perfusion and Cortical Thickness Predict Cognitive Impairment in a Community‐dwelling Cohort

AbstractBackgroundNeurodegeneration and cerebral perfusion are key neuroimaging biomarkers in the Alzheimer’s Disease continuum. ASL (arterial spin labeling) explores cerebral blood flow (CBF) and has aided in elucidating cerebrovascular health amongst people at risk of cognitive decline. Reduced cortical thickness (CT) on MRI is a neurodegeneration biomarker that also implicated in cognitive impairment. The influence of cortical thickness and perfusion in AD‐related regions on cognitive status is poorly understood. We explored markers to investigate the roles they had in cognitive impairment.MethodParticipants enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort (N= 535, Table 1) underwent baseline T1/ASL MRI. Participants were adjudicated as cognitively impaired (CI: mild cognitive impairment or AD) or cognitively unimpaired (CU) using NIA‐AA criteria by a consensus panel of experts. CT in an AD‐related temporal lobe meta‐ROI (region of interest) was calculated on T1 using FreeSurfer v5.3 and standardized. A homologous set of AD‐sensitive temporal lobe ROIs was used to extract mean CBF, which was log transformed for normality. A one‐way MANOVA (covariates: age, education, sex) assessed effects of CT and CBF on cognitive impairment. Bivariate models evaluated the associations of CT and CBF in relation to age, education, sex, and cognitive impairment. Linear regression was used to analyze whether cognitive impairment was predicted by CT and CBF (adjusted).ResultWe found both CBF and CT were associated with age (r2= ‐0.142, p&lt;0.01; r2= ‐0.339; p&lt;0.01) and cognitive status (r2= ‐0.188, p&lt;0.01; r2= ‐0.264; p&lt;0.01); respectively. CBF was also associated with sex (r2= 0.083; p=0.055) such that women had higher CBF. We also found that higher CBF was marginally associated with higher CT (r2= 0.083; p=0.055); this relationship was not significant when age, sex, and education were included in the model (r2= 0.886; p=0.376). Finally, we found both CT and CBF predicted cognitive impairment (p&lt;0.01; both unadjusted and adjusted, in models where each MRI marker was used to predict cognition), such that CBF and CT were higher in CU; further, both CBF and CT independently predicted cognitive status when together in a model (p&lt;0.008).ConclusionCortical thickness and CBF are predictive of cognitive impairment.

Davos Alzheimer’s Collaborative: Building a globally representative cohort through a technologically‐enabled approach

AbstractBackgroundIn January 2021, the Davos Alzheimer’s Collaborative (DAC) was launched to develop precision solutions to reduce barriers to AD research for globally underrepresented populations, including older adults from any ethnic/racial group and/or the lowest resource settings. To meet this DAC vision, the Global Cohort Development (GCD) program has been establishing collaborations with existing cohort studies around the world to collect new digital cognitive and behavioral phenotypic data and harmonize digital data with existing cohort data. DAC is also creating open‐source data processing and advanced analytic tools, and building the infrastructure necessary to make these data broadly, but securely accessible to the scientific community.MethodsFifteen cohorts from 13 countries have joined GCD, representing 25,000+ individuals. Each cohort is deploying a protocol using a tablet to document AD‐related cognitive and behavioral symptoms across the disease continuum, as well as a smartphone for remote detection and continuous monitoring of incident changes in these symptoms.ResultsWe will discuss the approach for launching a digital protocol across cohorts from multiple countries, where the participant mix varies in technology access and use, language, culture and education, and extensiveness of existing research infrastructure.ConclusionsGlobal population level research requires a significant paradigm shift in traditional methodology including study design, assessment practices, data accessibility infrastructure and analytic approaches. Achieving global reach that works regardless of available resources and expertise will require major realignment for AD research to be representative of everyone, and clinical assessment and care relevant and equitable to anyone.

MRI signatures of Brain Age in the Alzheimer’s disease continuum

AbstractBackgroundAge is the biggest risk factor for Alzheimer’s disease (AD). Substantial efforts to extract age signatures from magnetic resonance imaging (MRI) of the brain have achieved impressive accuracy and demonstrated these signatures were altered by neurological disorders including AD. In this work, we develop a deep learning model to characterize brain age signatures and examine their variation over the AD continuum.MethodA 3D deep ResNet model was implemented to learn the structural signatures of brain age in predicting the chronological age of the participants. The model was trained on 7372 T1‐weighted MRI scans from a combined lifespan cohort of 5848 cognitively normal participants (age: 8‐ 95 yrs) using a 10‐fold cross validation procedure. The model was then applied to the independent ADNI cohort (N=1175, 50‐98 yrs) to examine MRI derived brain age signatures variation in the AD continuum. The difference (∆age) between model predicted age and chronological age was used as the independent variable for group comparison using univariate ANCOVA tests, controlling for sex, education, and APOE4 gene dose, among five clinical groups: normal control (NC), normal to MCI converters (NC‐MCI), stable MCI (MCIs), MCI to AD converters (MCI‐AD), and AD patients.ResultThe ResNet model achieved an MAE=3.76 yrs and R2=0.93 across 10 folds in the lifespan cohort. In the baseline data of the ADNI cohort, model derived ∆age increased along the AD continuum as expected: NC (‐1.2yrs) &lt; NC‐MCI (‐0.7yrs) &lt; MCIs (‐0.3yrs) &lt; MCI‐AD (0.7yrs) &lt;AD (1.5yrs) (F=11.24, p&lt;0.0001). Post‐hoc pairwise comparison results are summarized in Table 1/Figure 2. Although the difference between NC and NC‐MCI did not reach significance (p=0.24) for the baseline data, comparison between the two groups using data from all visits was significant (p=0.0009), suggesting more subtle differences.ConclusionA ResNet model was developed that captures the MRI signatures of brain age with high accuracy in age prediction. The model detected group level differences along the AD continuum in the expected direction. Subtle changes in brain signatures were observable in normal participants who later developed cognitive impairment. Our technique provides a novel approach to investigate the relationship between aging and AD.

Amyloid PET in the Lewy Body disease continuum

AbstractBackgroundβ‐amyloid plaques, a pathological hallmark of Alzheimer’s disease, are common in dementia with Lewy bodies (DLB). However, little is known about when β‐amyloid levels increase throughout the Lewy body disease (LBD) continuum, from an early prodromal stage of isolated REM sleep behavior disorder (iRBD), to a stage of mild cognitive impairment‐Lewy bodies (MCI‐LB), and finally DLB. Our objective was to investigate β‐amyloid deposition throughout the LBD continuum, as well as the influence of sex and APOE ε4 status, as potential factors contributing to Alzheimer’s disease pathological changes.MethodPatients with iRBD (n=24), MCI‐LB (n=62), and DLB (n=82) from the Mayo Clinic Alzheimer’s Disease Research Center and Center for Sleep Medicine were included. β‐amyloid levels were measured by Pittsburgh compound B (PiB) PET and global cortical standard uptake value ratio (SUVR) was calculated. Global cortical PiB SUVR values from each clinical group were compared to each other and to cognitively unimpaired individuals (CU; n=100) balanced on age and sex from the Mayo Clinic Study of Aging (MCSA). Clinical groups were compared using ANCOVA after adjusting by age.ResultMCI‐LB and DLB patients had significantly higher global cortical PiB SUVR than CU participants, while PiB SUVR in iRBD patients was comparable to that of CU participants (Figure 1). DLB patients also had significantly higher global cortical PiB SUVR compared to iRBD patients (p=0.004). In MCI‐LB and DLB, global cortical PiB SUVR was higher in APOE ε4 carriers compared to APOE ε4 non‐carriers (p&lt;0.001), and women had higher global cortical PiB SUVR compared to men (p=0.024).ConclusionIn this cross‐sectional study, β‐amyloid pathology gradually increased throughout the clinically defined LBD continuum. Whereas β‐amyloid levels are comparable to cognitively unimpaired individuals in iRBD, a significant elevation in β‐amyloid levels coincides with cognitive impairment observed in MCI‐LB and DLB. Specifically, women and APOE ε4 carriers tend to have higher β‐amyloid levels than men and APOE ε4 non‐carriers. These findings have important implications for targeting patients within the LBD continuum, who may benefit from amyloid modifying therapies.

Designing Interventions Addressing Structural Racism to Reduce Kidney Health Disparities: A Report from a National Institute of Diabetes and Digestive and Kidney Diseases Workshop.

Structural racism embodies the many ways in which society fosters racial discrimination through "mutually reinforcing inequitable systems" that limit access to resources and opportunities that can promote health and well being among marginalized communities. To achieve health equity, and kidney health equity more specifically, structural racism must be eliminated. In February 2022, the National Institute of Diabetes and Digestive and Kidney Diseases convened the "Designing Interventions that Address Structural Racism to Reduce Kidney Health Disparities" workshop, which was aimed at describing the mechanisms through which structural racism contributes to health and health care disparities for people along the continuum of kidney disease and identifying actionable opportunities for interventional research focused on dismantling or addressing the effects of structural racism. Participants identified six domains as key targets for interventions and future research: (1) apply an antiracism lens, (2) promote structural interventions, (3) target multiple levels, (4) promote effective community and stakeholder engagement, (5) improve data collection, and (6) advance health equity through new health care models. There is an urgent need for research to develop, implement, and evaluate interventions that address the unjust systems, policies, and laws that generate and perpetuate inequities in kidney health.

Examining the Relationship Between Task-Switching and Speech Errors in Parkinson's Disease

<h3>Research Objectives</h3> To establish the link between cognitive flexibility deficits and errors in speech production in Parkinson's disease (PD). A secondary goal is to show that this relationship exists despite the presentation of "normal" overall cognitive functioning on a standard screening test (Montreal Cognitive Battery; MoCA). <h3>Design</h3> Regression (between-subjects). <h3>Setting</h3> University. <h3>Participants</h3> Fifteen people with PD and 15 adult controls participated in this study. All were native speakers of American English, had no upper respiratory tract infections, and passed depression and hearing screenings. People with PD varied on a continuum of overall disease and speech severity. Controls had no history of hearing, speech-language, or neurological disorders. All study procedures were approved by the Institutional Review Board. <h3>Interventions</h3> N/A. <h3>Main Outcome Measures</h3> 1) Metrics of cognitive flexibility (reaction times, error rates) 2) MoCA scores, speech errors (articulation errors, stuttering-like disfluencies, and other disfluencies) and 3) Speech rate. <h3>Results</h3> Results show that people with PD would present with impaired cognitive flexibility (slower reaction times to switch demands compared to controls) despite falling within normal range on standard clinical screenings of cognition (MoCA) and that people with PD and controls show an inverse relationship between cognitive flexibility and the number of errors during speech production with group differences in both flexibility and speech error rates occurring. <h3>Conclusions</h3> Our findings suggest that impairments in cognition in PD may occur earlier than previously thought and may only be apparent on more sensitive tests of cognitive flexibility that are typically not performed as standard-of-care. A relationship between cognitive flexibility and speech errors suggests a role of cognitive flexibility during speech-motor control. These deficits should be considered when recommending therapy and designing interventions. <h3>Author(s) Disclosures</h3> Funding for this work is through an internal grant by Seton Hall University. No other relevant disclosures.

Convergent and criterion validity of a computer adaptive self‐administered word list memory test and the Mayo Test Drive composite: correlations with traditional measures and group difference by PET imaging biomarker status in persons without dementia.

AbstractBackgroundMayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform optimized for remote self‐administered assessment that includes a computer adaptive word list memory test (Stricker Learning Span; SLS) and a measure of processing speed (Symbols Test). Study aims were to determine 1) convergent validity of MTD through correlations with in‐person neuropsychological measures and 2) criterion validity of MTD by qualitatively comparing the ability of Mayo Test Drive and in‐person administered neuropsychological measures to differentiate biomarker‐defined groups, independent of clinical diagnosis.MethodsMayo Clinic Study of Aging participants (N = 282) completed a brief remote cognitive assessment (mean age = 74, SD = 12; 262 CU and 20 MCI per consensus conference diagnosis; see Table 1). A subset of participants had brain amyloid and/or brain tau PET scans available within 3 years; overlapping groups were formed for 1) those on the Alzheimer’s disease (AD) continuum (A+, n = 31) or not (A‐, n = 57) and for 2) those with biological AD (A+T+, n = 19) or without any AD biomarkers (A‐T‐, n = 47). Primary outcome variables were SLS sum of trials, AVLT sum of trials, SYM Correct Trials response time, Digit Symbol Coding, MTD composite and Mayo‐PACC (AVLT sum of trials, Trails B, animals). Bivariate correlations were performed across all participants. Linear model ANOVAs were used to investigate biomarker subgroup differences; Hedge’s g effect sizes are reported.ResultsConvergent validity was supported through significant correlation (p’s &lt; .001) of SLS and AVLT (r = .63), SYM and Coding (r = ‐.64), and MTD composite with Mayo‐PACC (r = .67); see Table 2. MTD subtests showed expected relationships with age and education (p’s &lt; .05; Table 3). All MTD performances were significantly lower for A+ and A+T+ participants relative to A‐ or A‐T‐ (p’s&lt;.001; Table 4). All MTD outcome measures showed a similar or greater group difference effect size relative to traditional in‐person administered neuropsychological measures for separating A+ vs. A‐ and A+T+ vs. A‐T‐ groups. See Figure 1 and Table 4.ConclusionsMTD subtests show evidence of convergent validity through strong correlations with traditional in‐person cognitive measures. Preliminary analyses suggest MTD has promise for differentiating PET biomarker groups.

High tau PET binding reveals a constellation of beta‐amyloid positivity and fast cognitive decline

AbstractBackgroundBeta‐amyloid Positron Emission Tomography (PET) efficiently detects beta‐amyloid plaques supporting the presence of a pathophysiological landmark of Alzheimer’s disease (AD) continuum, but lacks specificity regarding the prediction of future cognitive status. The increasing validation of tau PET tracers raises questions about whether a tau PET biomarker could predict clinically relevant cognitive decline and its potentially beneficial role in the assessment of individuals who belong to the AD continuum.MethodWe identified 335 subjects [cognitive normal (CN; n=217), mild cognitive impairment (MCI; n=99), dementia (n=19)] with baseline beta‐amyloid and tau PET scans that have completed a follow‐up of at least two years, from the Alzheimer’s Disease Neuroimaging Initiative dataset. First, we assessed the accuracy of tau PET to discriminate the MCI patients that will convert to AD. Based on Alzheimer’s Disease Assessment Scale–Cognitive Subscale, we used linear mixed‐effects models to define the annual rate of cognitive change of all individuals and Gaussian mixture modelling to cluster them as either fast or slow decliners. Next, group comparisons and the accuracy of tau PET to discriminate between them were tested. Finally, the association between baseline tau PET SUVR and cognitive rate of change was assessed with linear modelsResultThe individuals with beta‐amyloid positivity and fast cognitive decline showed the highest tau PET binding values independently of baseline cognitive status, compared to the other groups (beta‐amyloid negative with fast or slow decline and beta‐amyloid positive with slow decline). Baseline tau PET binding could determine fast decliners with a beta‐amyloid positive scan with an accuracy of 85% (composite temporal region of interest). Similarly, tau PET binding accuracy was high in determining MCI patients that would be both beta‐amyloid positive and show progress in their diagnosis. Linear models showed that baseline tau PET binding is related to the annual rate of cognitive decline in beta‐amyloid positive individuals.ConclusionHigh baseline tau load is coupled with both beta‐amyloid pathology and an accelerated profile of cognitive decline. Tau PET imaging could offer substantial advantages over beta‐amyloid PET imaging since it provides important information about both the underlying pathophysiology and the prognosis of the disease.

Plasma glial fibrillary acidic protein is associated with reactive astrogliosis assessed via 18F‐SMBT‐1 PET

AbstractBackgroundReactive astrogliosis is an early event along the Alzheimer’s disease (AD) continuum. We have shown that plasma glial fibrillary acidic protein (GFAP), reflecting reactive astrogliosis, is elevated in cognitively unimpaired individuals with preclinical AD (Chatterjee et al., 2021). We reported similar findings using 18F‐SMBT‐1, a PET tracer for monoamine oxidase B (MAO‐B) (Villemagne et al., 2022). To provide further evidence of their relationship with reactive astrogliosis we investigated the association between GFAP and 18F‐SMBT‐1 in the same participants.MethodPlasma GFAP, Aβ42 and Aβ40 levels were measured using the Single Molecule Array platform in 71 participants comprising 54 healthy controls (12 Aβ+ and 42 Aβ‐), 11 MCI(3 Aβ+ and 8 Aβ‐) and 6 probable AD(5 Aβ+ and 1 Aβ‐) patients from the Australian Imaging, Biomarker &amp; Lifestyle Flagship Study of Ageing cohort. These participants also underwent 18F‐SMBT‐1 and Aβ PET imaging. Aβ imaging results were expressed in Centiloids (CL; ≥20 CL classified as Aβ+). 18F‐SMBT‐1 Standard Uptake Value Ratio (SUVR) were generated using the subcortical white matter as reference region. Linear regression analyses were carried out using plasma GFAP levels as the dependent variable and regional 18F‐SMBT‐1 SUVR as the independent variable, before and after adjusting for age, sex, soluble Aβ (plasma Aβ1‐42/Aβ1‐40 ratio) and insoluble Aβ (Aβ PET).ResultPlasma GFAP was significantly associated with 18F‐SMBT‐1 SUVR in brain regions of early Aβ deposition, such as the supramarginal gyrus (SG, β=.361, p=.002), posterior cingulate (PC, β=.308, p=.009), lateral temporal (LT, β=.299, p=.011), lateral occipital (LO, β=.313, p=.008) before adjusting for any covariates. After adjusting for covariates age, sex and soluble Aβ, GFAP was significantly associated with 18F‐SMBT‐1 PET signal in the SG (β=.333, p&lt;.001), PC (β=.278, p=.005), LT (β=.256, p=.009), LO (β=.296, p=.004) and superior parietal (SP, β=.243, p=.016). On adjusting for age, sex and insoluble Aβ, GFAP was significantly associated with SMBT‐1 PET in the SG (β=.211, p=.037) however only a trend towards significance was observed in the PC (β=.186, p=.052) and LT (β=.171, p=.067) (Figure 1).ConclusionThere is an association between plasma GFAP and regional SMBT‐1 PET that is primarily driven by brain Aβ load.

Validation of a fully automated lab developed test for plasma phospho‐tau 181 levels for Alzheimer’s disease diagnosis

AbstractBackgroundThe potential usefulness of plasma phosphorylated tau (pTau) measurements for identifying individuals likely to be on the Alzheimer’s disease (AD) continuum is evident from recent literature. Here we report the validation of an immunoassay for measurement of pTau181 in human plasma that will aid in the evaluation of Alzheimer’s pathology in cases presenting with mild cognitive impairment.MethodThe Simoa pTau‐181 assay is a fully automated 2‐step digital sandwich immunoassay that utilizes paramagnetic beads with capture antibodies and biotinylated detector antibodies. Digital detection is achieved using Simoa discs via SβG (Streptavidin‐ß‐galactosidase) and RGP (Resorufin‐β‐D‐galactopyranoside) amplification of specific pTau181 immune complexes. Harmonization to the Simoa pTau‐181 method described by Karikari et al (Mol Psychiatry. 2021;26(2):429‐442) using 80 samples, establishes commutability with published results from ADNI cohorts. Analytical validation on HD‐X instrument followed CLSI guidelines. Thirty‐four AD cases from the Amsterdam Dementia Cohort (age 66 ± 8 years) diagnosed according to the NIA‐AA diagnostic AD criteria and had a CSF biomarker‐confirmed AD diagnosis, 36 age‐ and sex‐matched (age 66 ± 8 years) cognitively healthy controls from the Dutch Brain Research Registry were included for clinical validation of this LDT.ResultThe limits of detection (LoD) and quantification (LoQ) were 0.056 pg/mL and 0.276, respectively. Repeatability and reproducibility across 3 reagent lots using samples across the measuring range were 4.25% (95%CI:2.84‐5.65), 9.42% (95% CI: 4.46‐14.37) respectively. Linearity was demonstrated per CLSI EP06‐A, as ≤15% deviation at all dilutions. Cross reactivity against full length unphosphorylated‐Tau441 and synthetic peptides for pTau231 and pTau217 epitopes was below LoQ. ROC analysis resulted in a high AUC (area under the curve) of 0.897 (95% CI 0.825 to 0.969). Applying the cut‐offs described in Karikari1 (17.7 pg/mL) for this cohort resulted in a sensitivity of 94%, specificity of 72%.ConclusionThis test demonstrated acceptable analytical performance for CLIA laboratory implementation. High AUC of 0.897 to discriminate AD from non‐AD cases helps both rule‐in or rule‐out scenarios, and further allows for setting of cut‐off values that not only take the pretest probability, impact on screening algorithm, treatment protocols into consideration but also the costs incurred by misdiagnosis.

Identification of Sex-Specific Genetic Variants Associated With Tau PET.

Important sex differences exist in tau pathology along the Alzheimer disease (AD) continuum, with women showing enhanced tau deposition compared with men, especially during the mild cognitive impairment (MCI) phase. This study aims to identify specific genetic variants associated with sex differences in regional tau aggregation, as measured with PET. Four hundred ninety-three participants (women, n = 246; men, n = 247) who self-identified as White from the AD Neuroimaging Initiative study, with genotyping data and 18F-Flortaucipir tau PET data, were included irrespective of clinical diagnosis (cognitively normal [CN], MCI, and AD). We focused on the genetic variants within 10 genes previously shown to have sex-dependent effects on AD to reduce the burden of multiple comparisons: BIN1, MS4A6A, DNAJA2, FERMT2, APOC1, APOC1P1, FAM193B, C2orf47, TYW5, and CR1. Multivariate analysis of variance was applied to identify genetic variants associated with tau PET data in 3 regions of interests (composite regions of Braak I, Braak III/IV, and Braak V/VI stages) in women and men separately. We controlled for age, scanner manufacture, amyloid status, APOE ε4 carriership, diagnosis (CN vs MCI vs AD), and the first 10 genetic principal components to adjust for population stratification. We identified 3 genetic loci within 3 different genes associated with tau deposits specifically in women: rs79711283 within DNAJA2, rs113357081 within FERMT2, and rs74614106 within TYW5. In men, we also identified 3 loci within CR1 associated with tau deposits: rs115096248, rs113698814, and rs78150633. Our findings revealed sex-specific genetic variants associated with tau deposition independent of APOE ε4, amyloid status, and clinical diagnosis. These results provide potential molecular targets for understanding the mechanism of sex-specific tau aggregation and developing sex-specific gene-guided precision prevention or therapeutic interventions for AD.

Association Between Neuropsychiatric Symptoms and Blood‐Based Autoantibody Biomarkers

AbstractBackgroundNeuropsychiatric symptoms are frequently observed along the Alzheimer disease (AD) continuum. Recent research has shown that blood‐based biomarkers are able to identify early AD‐related pathological changes associated with (1) preclinical AD (before the onset of clinical/functional symptoms), (2) mild cognitive impairment (MCI; with clinical symptoms and relatively spared functional decline), and (3) AD (obvious clinical and functional symptoms). Evidence for the potential diagnostic utility of serum autoantibodies has been extensively studied. The purpose of this study is to explore whether blood levels of specific autoantibodies used in the diagnostic biomarkers panels are linked with specific behavioral changes observed along the AD continuum.MethodUsing a customized panel of three AD‐specific autoantibody biomarkers and Luminex xMAP® technology, sera from patients (n=46; female = 30, mean age = 73.4) from the Memory and Aging Program at Rowan University were analyzed. All patients, irrespective of diagnosis (cognitively normal, MCI, AD) were included. The Neuropsychiatric Inventory (NPI) was used to gather data pertaining to neuropsychiatric symptoms. Partial correlations, controlling for age and education, for each neuropsychiatric symptom was employed.ResultTwo of the three autoantibody biomarkers showed an association with neuropsychiatric symptoms. Biomarkers 2 and 3 both showed a significant correlation with total neuropsychiatric score (r= .255, p= .047; r= .345, p= .01, respectively). Delusions, hallucinations, depression, anxiety, and irritability symptoms were not associated with either biomarker. Biomarker 2 was associated with apathy (r= .365, p=.007), agitation (r= .345, p= .011), disinhibition (r=.316, p=.018), and appetite changes (r= .302, p= .023). Biomarker 3 was associated with elation (r= .328, p= .015), aberrant motor behaviors (r= .331, p=.014), sleep behaviors (r= .483, p=.001), and appetite changes (r= .372, p=.006).ConclusionResults demonstrate an association between neuropsychiatric symptoms often observed in the AD continuum and specific blood‐based autoantibody biomarkers using Luminex xMAP® bead‐based technology. The autoantibody biomarker panel serves as an accurate, non‐invasive, and inexpensive diagnostic screener for preclinical AD, MCI, and AD. These biomarkers can not only distinguish different stages of AD, typically diagnosed using cognitive/functional assessments, increased blood levels of specific autoantibody biomarkers are also associated with commonly observed neuropsychiatric features.