Amyloid Markers Research Articles

PET biomarkers in behavioral variant Frontotemporal dementia: analysis of an Argentine cohort.

AbstractBackgroundBehavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder characterized by early and progressive changes in behavior, emotional processing and executive control. This entity represents a diagnostic challenge in which positron emission tomography (PET) may play a key role in the diagnosis and follow‐up in vivo with a minimally invasive method. The aim of this work is to evaluate PET biomarkers in a cohort of patients with a clinical diagnosis of bvFTD.Method21 normal controls (NC: 64 ± 9 years) and 20 patients with a diagnosis of probable bvFTD (65 ± 7 years) were evaluated by: neurological, neuropsychological, neuropsychiatric evaluation and PET imaging biomarkers: [18F]‐FDG, [18F]‐AV1451 (TAU), [11C]‐PIB. For neuroimaging processing and analysis, they were spatially normalized to an FDG template. Group comparisons (voxel‐based) of each biomarker were performed by t‐test (SPM12) using cerebellar gray matter as reference tissue, and for inter‐biomarker uncoupling comparison a covariate of uptake in total cortex was used.ResultIn the statistical comparison between NC vs. bvFTD groups (p<0.05), hypometabolism is observed at the frontotemporal level and hypermetabolism in the precentral region (FDG). Amyloid marker (PIB) uptake shows no significant difference between groups in much of the cortex, except in the precentral region. TAU uptake shows a significant difference, greater in bvFTD, at frontal, parietal and precuneus levels. In the uncoupling between FDG and TAU biomarkers, it is observed that hypometabolism is related to an increase in TAU uptake in medial and inferior temporal regions. Differences between PIB and TAU are mainly observed in frontotemporal regions. There was an association between clinical symptoms (mainly apathy) and the anatomical distribution of [18F]‐FDG, [18F]‐AV1451 radiotracers (TAU).ConclusionPET biomarkers are a valuable tool in the diagnosis of bvFTD. The [11C]‐PIB may be of paramount importance in the differential diagnosis of FTvc FTD with Alzheimer’s disease. FDG is a very sensitive biomarker of neuronal metabolism and its variations, sometimes losing specificity. Advances in tracers such as [18F]‐AV1451 (TAU) can provide important information on the underlying neuropathological process. The combined use of these tools brings us closer to understanding the biological phenomena behind the cardinal symptoms of bvFTD.

Neuroimaging of new and novel Alzheimer’s Disease (AD) mice from the MODEL AD Consortium

AbstractBackgroundThe ability of preclinical neuroimaging in rodent models of Alzheimer’s Disease and Related Dementia (ADRD) to assess the progression of disease is increasingly providing novel insights into AD, like human AD imaging. Preclinical studies have the advantage of being able to directly correlate findings to the observed neuropathology. Recently, University of California Irvine and Indiana University School of Medicine along with Jackson Laboratories were awarded funding to design and phenotype relevant mouse models of late onset AD (LOAD), forming the MODEL AD consortium (https://www.model‐ad.org/). Imaging cores from these will utilize existing state of the art translationally relevant medical imaging methodologies as well as ascertain feasibility of emerging imaging methods for increased diagnostic sensitivity.MethodsTwo primary imaging modalities will be utilized: high‐field MRI (9.4T and 17.6T) and PET/CT. Deep MRI phenotyping are based on the accepted human‐AD standards like ADNI (Structural T2W, FLAIR, diffusion, perfusion (PWI), susceptibility, and functional MRI and MR spectroscopy). Novel histological vessel painting combined with PWI will assess vascular modifications. PET imaging will evaluate brain metabolism (18F‐FDG), regional perfusion (64Cu‐PTSM), amyloid (18F‐AV45), tau (18F‐AV1451), neuroinflammation (18F‐CPPC and 18F‐GSK1482160), and astrogliosis (18F‐FEBU) markers in new mouse models.ResultsMODEL AD consortia will utilize platform mice (Table 1) across their lifespans and effects after being fed a high fat diet. Known and emerging GWAS risk variants for AD will be added to these platform mice to better replicate human AD. Neuroimaging data will be presented from PET/CT and MRI, focusing on exemplars from relevant AD mouse models including platform mice. A long‐term goal of the MODEL‐AD Imaging cores is to co‐register MRI, PET/CT and vascular measures to concordant histopathological and spatial RNA data. The cores have developed state‐of‐the‐art analytical pipelines to process imaging data to support spatial and temporal localization of ADRD.ConclusionsThe MODEL AD consortium (UCI/IUSM/Jax) will develop new and novel AD mouse models and the imaging cores will deeply phenotype these models using existing and emerging neuroimaging methods and analytic approaches, using MRI and PET/CT. All data will be made available to AD researchers via the Sage Knowledge Network (https://adknowledgeportal.synapse.org/).

Neuroimaging of new and novel Alzheimer’s Disease (AD) mice from the MODEL AD Consortium

AbstractBackgroundThe ability of preclinical neuroimaging in rodent models of Alzheimer’s Disease and Related Dementia (ADRD) to assess the progression of disease is increasingly providing novel insights into AD, like human AD imaging. Preclinical studies have the advantage of being able to directly correlate findings to the observed neuropathology. Recently, University of California Irvine and Indiana University School of Medicine along with Jackson Laboratories were awarded funding to design and phenotype relevant mouse models of late onset AD (LOAD), forming the MODEL AD consortium (https://www.model‐ad.org/). Imaging cores from these will utilize existing state of the art translationally relevant medical imaging methodologies as well as ascertain feasibility of emerging imaging methods for increased diagnostic sensitivity.MethodTwo primary imaging modalities will be utilized: high‐field MRI (9.4T and 17.6T) and PET/CT. Deep MRI phenotyping are based on the accepted human‐AD standards like ADNI (Structural T2W, FLAIR, diffusion, perfusion (PWI), susceptibility, and functional MRI and MR spectroscopy). Novel histological vessel painting combined with PWI will assess vascular modifications. PET imaging will evaluate brain metabolism (18F‐FDG), regional perfusion (64Cu‐PTSM), amyloid (18F‐AV45), tau (18F‐AV1451), neuroinflammation (18F‐CPPC and 18F‐GSK1482160), and astrogliosis (18F‐FEBU) markers in new mouse models.ResultMODEL AD consortia will utilize platform mice (Table 1) across their lifespans and effects after being fed a high fat diet. Known and emerging GWAS risk variants for AD will be added to these platform mice to better replicate human AD. Neuroimaging data will be presented from PET/CT and MRI, focusing on exemplars from relevant AD mouse models including platform mice. A long‐term goal of the MODEL‐AD Imaging cores is to co‐register MRI, PET/CT and vascular measures to concordant histopathological and spatial RNA data. The cores have developed state‐of‐the‐art analytical pipelines to process imaging data to support spatial and temporal localization of ADRD.ConclusionThe MODEL AD consortium (UCI/IUSM/Jax) will develop new and novel AD mouse models and the imaging cores will deeply phenotype these models using existing and emerging neuroimaging methods and analytic approaches, using MRI and PET/CT. All data will be made available to AD researchers via the Sage Knowledge Network (https://adknowledgeportal.synapse.org/).

Genetic context controls microglia‐induced neuronal damage in Alzheimer’s disease

AbstractBackgroundThe activation of microglia and the loss of synapses have emerged as key events in Alzheimer’s disease (AD) progression, yet the relationship between these processes is not clear. Previous studies suggest genetic variation controls microglial activation in AD mouse models, so we evaluated how the elimination of brain microglia influenced synapses on hippocampal pyramidal cells across two genetically distinct AD mouse models.MethodUsing a viral approach, we labeled hippocampal neurons that project to the frontal cortex by expressing GFP in young (3m) inbred C57BL/6J and genetically distinct PWK/PhJ female mice with or without a transgenic (APP/PS1) allele that drives amyloid pathology. At 4m we placed half of the mice on diet formulated with CSF1R inhibitor PLX5622 to deplete brain microglia. At 8m, a time when plaque pathology is present in transgenic mice, we examined cognition using the delayed spatial task. We then analyzed the density and morphology of spines across multiple dendritic domains, as well as amyloid plaques and markers of disease‐associated (DAM) and interferon responding (IRM) states of IBA1+ microglia.ResultWhile spatial cognition was unaffected by PLX5622, we identified B6.APP/PS1 as susceptible and PWK.APP/PS1 as resilient to cognitive deficits at 8m. Across both strains, PLX5622 depleted hippocampal microglia but did not affect amyloid plaques. In contrast, we observed strain differences in spine synapse density and morphology. Compared to spine stability across PWK wild‐type (WT) and APP/PS1 mice, we measured increased density of small spines in B6.APP/PS1 mice (compared to WT). B6.APP/PS1 mice showed reduced spine density with PLX5622, whereas PWK.APP/PS1 mice remained unaltered. These changes in spine density corresponded to DAM being resistant to depletion with PLX5622 in APP/PS1 mice (especially B6), whereas IRM were susceptible, suggesting a neuroprotective role for IRM.ConclusionWe show here that genetic context determines how synapses on CA1 projection neurons respond to the depletion of brain microglia and AD transgenes. Since PWK.APP/PS1 are resistant to hippocampal neuronal damage with robust microglia activation, this strain can be leveraged to further study mechanisms of resilience to AD cognitive deficits and neuropathological damage that can be harnessed for better AD therapeutic treatments.

Toxoplasma gondii‐induced amyloid reduction and neuroimmune responses in Alzheimer’s disease

AbstractBackgroundToxoplasma gondii is a foodborne parasite that induces monocyte recruitment and microglial activation during infection of the brain. Similarly, in Alzheimer’s disease (AD), activated immune cells are often found in the brain and these localize near amyloid beta plaques. However, after infection with T. gondii in AD mouse models, there are fewer amyloid beta plaques in the brain, increased microglial activation, and decreased severity of AD symptoms. We hypothesize that T. gondii infection activates and enhances the phagocytic ability of microglia to clear amyloid beta.MethodFemale 5xFAD mice were infected with T. gondii or PBS treated, and their brains harvested after 6 weeks of infection. Brain tissue from these animals was analyzed for amyloid (Amyloglo) and immune cell markers for microglia, monocytes, and T cells (IBA1, CD68, CD11c, CD11b, CD45, CD3) by light sheet imaging, confocal microscopy, or flow cytometry. Mice were also fitted with headplates and cranial windows and injected with methoxy‐X04 (10 mg/kg) to enable longitudinal imaging of amyloid over the span of infection.ResultConfocal microscopy of brain sections and light sheet imaging of intact brains from infected and uninfected 5xFAD mice have shown increased microglial activation markers (IBA1 and CD68) and decreased amyloid surface area and volume throughout infected brains in infected animals. Infected mouse brains also have increased co‐localization of amyloid and CD68 compared to uninfected mouse brains. Two‐photon imaging reveals that amyloid plaque area in vivo no longer increases in infected mouse brains as early as three weeks post‐infection and lasts as long as thirteen weeks post‐infection. Additionally, after six weeks of infection, we see an increase in Disease Associate Microglia (DAM) by flow cytometry, as well as an influx of other immune cells in the brain of infected mice as compared to PBS treated control mice.ConclusionOur data show that infection with T. gondii increases microglial markers associated with the DAM profile and these cells likely increase phagocytosis of amyloid beta. Infection with T. gondii appears to modulate the neuroimmune environment, including responding microglial cells, resulting in a neuroprotective phenotype.

Lecanemab: Amyloid Reduction and Evidence of Downstream Biomarker Modification

AbstractBackgroundLecanemab is a humanized IgG1 monoclonal antibody that targets soluble aggregated Aβ species (protofibrils) which has demonstrated robust brain fibrillar amyloid reduction and slowing of clinical decline in a Phase 3 Study in early AD (Study 301). The objective of this analysis is to report biomarker results from Study 301.MethodsStudy 301 was a double‐blind, randomized, placebo‐controlled study of 1875 patients with early AD randomized to 10 mg/kg IV lecanemab or placebo for 18 months of treatment. Plasma, CSF, and imaging biomarkers of amyloid, tau, neurodegeneration, and gliosis were assessed.ResultsLecanemab met all primary and key secondary clinical endpoints with a high degree of statistical significance. Lecanemab improved markers of amyloid with reduction of brain amyloid by PET in as early as 3 months and improvement in CSF Aß42 and plasma Aß42/40. Biomarkers of tau showed improvement in CSF and plasma p‐tau181, and slowing of tau accumulation relative to placebo in the medial temporal regions by tau PET. For biomarkers of neurodegeneration and gliosis, there was improvement in CSF t‐tau, CSF neurogranin, and plasma GFAP. There were no significant differences in CSF or plasma Nf‐L between lecanemab and placebo. Volumetric MRI results were inconsistent, with reduced hippocampal atrophy on lecanemab, but greater cortical volume loss relative to placebo, possibly “pseudoatrophy” related to amyloid mobilization.ConclusionsLecanemab treatment resulted in significant reduction in amyloid plaques and a slowing of clinical decline. Improvements in biomarkers of amyloid, tau, neurodegeneration, and gliosis provide a biological basis for the treatment effects consistent with disease modification.

Evaluating brain age as a marker of autosomal dominant Alzheimer disease progression

AbstractBackgroundEstimates of “brain‐predicted age” quantify apparent brain age compared to normative trajectories of neuroimaging features. Brain‐predicted age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD). We used a previously‐trained model (DeepBrainNet [DBN], Bashyam et al., 2020), which requires minimal MRI pre‐processing, to predict brain age in the Dominantly Inherited Alzheimer Network (DIAN) and evaluated brain age as a marker of ADAD progression.MethodWe used DBN to predict brain age from minimally‐processed, whole‐brain T1 structural MRI scans in 265 ADAD mutation‐carriers (MCs) and 183 non‐carrier controls (NCs). We then tested whether the brain age gap (BAG; difference between predicted and true age) differed as a function of mutation and cognitive status, or estimated years until symptom onset (EYO), and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid‐ß‐42/40), phosphorylated tau (CSF and plasma pTau‐181), neurodegeneration (CSF and plasma neurofilament light [NFL]), and cognition (global neuropsychological composite and CDR‐sum of boxes). Finally, we compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of mutation variants (APP vs. PSEN1 before or after codon 200), APOE E4 carrier status, sex, and education.ResultDBN accurately predicted age in DIAN (Figure 1A). BAG was elevated in symptomatic and asymptomatic MCs, compared to NCs, beginning around ‐10 EYO (Figure 1B,C). BAG, hippocampal volume, and a cortical thickness summary followed similar trajectories across EYO (Figure 1D). BAG was positively associated with PiB PET, CSF and plasma pTau, and CSF and plasma NFL, and was associated with worse cognitive scores, especially in symptomatic MCs (Figure 2). BAG was most elevated in MCs with a PSEN1 mutation before codon 200, but did not differ as a function of APOE, sex, or education (Figure 3).ConclusionWe extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG tracks well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, DBN‐based BAG offers unique benefits in simplicity of data processing and interpretation.

Real‐world one‐year estimation of the candidates for lecanemab in a South Korean memory clinic

AbstractBackgroundResults from an 18‐month Phase 3 clinical trial showed that lecanemab reduced markers of amyloid on early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. As the lecanemab recently received accelerated approval by the US Food and Drug Administation, consideration for prescribing it in the right person, at the right dose and in a very carefully monitored way in a real‐world practice is necessary now.MethodIn this study, we aimed to estimate the candidates for lecanemab in a South Korean memory clinic based on one‐year clinical data. We reviewed retrospectively the medical records of a total 344 patients (211 females, 69.7±9.3 years old) who visited the memory clinic and took the amyloid PET at the department of Neurology, Ajou University Hospital in 2022. We tried to find the patients whose clinical characteristics fit with the inclusion as well as exclusion criteria from the Phase 4 clinical trial of lecanemab.ResultThe patients consisted of 14 subjective cognitive complaints, 139 mild cognitive impairments (MCI), 107 Alzheimer’s disease (AD) dementia, or 84 other neurodegenerative diseases whose amyloid positivity was 28.6%, 43.2%, 72.0%, or 10.7%, respectively. Among patients with evidence of amyloid deposition, 4 MCI and 38 AD dementia were within the exclusion criteria because they scored less than 22 at the Mini‐Mental State Examination (MMSE). Other 7 patients with AD dementia would be also excluded because they scored both Global Clinical Dementia Rating (CDR) score greater than 1 and <22 at the MMSE. One more AD dementia patient had no data of cognitive test. Finally, 56 patients with MCI and 31 patients with AD dementia met the criteria for using the lecanemab.ConclusionOur study showed that amyloid PET was already integrated in the real‐world Korean practice. In addition, the amyloid‐positivity data from real‐world practice in a South Korean memory clinic matched well with previous research data. It is expected that this pattern of the Korean practice might contribute to give real‐world data for prescribing the lecaemab in the future.

PK/PD analyses of ARIA‐E and isolated ARIA‐H in Lecanemab Clarity AD study

AbstractBackgroundClinical efficacy of lecanemab was confirmed in a Phase 3 trial (Clarity AD, NCT03887455), reducing markers of amyloid in early Alzheimer’s disease and slowing cognitive and functional decline as compared to placebo. However, some subjects experienced amyloid‐related imaging abnormalities (ARIA) associated with edema/effusion (ARIA‐E) or hemorrhage (ARIA‐H). PK/PD analyses were performed to explore the potential relationship between ARIA‐E and isolated ARIA‐H incidences with lecanemab exposure and key covariates.MethodThe Clarity AD trial randomized 1795 participants to receive lecanemab (N = 898, 10 mg/kg bi‐weekly) or placebo (N = 897). A total of 177 ARIA‐E incidences were observed from pooled Phase 2 (NCT01767311) and Phase 3 (Clarity AD) data. Additionally, a total of 150 participants from Clarity AD trial experienced treatment‐emergent isolated ARIA‐H (an ARIA‐H event without concurrent ARIA‐E). The ARIA‐E incidence rate was modeled as a function of lecanemab steady state exposures, and effects of potential covariates were explored. Graphical PK/PD analysis was performed to examine the relationship between isolated ARIA‐H and lecanemab steady‐state exposures.ResultThe observed ARIA‐E incidence was best modeled using lecanemab maximum concentration at steady‐state (Css,max) with ApoE4 genotype identified as a significant covariate. The model indicates a higher ARIA‐E incidence in homozygous carriers compared to non‐homozygous carriers or noncarriers (p<0.0001). At mean lecanemab Css,max = 305 µg/ml in subjects receiving 10 mg/kg bi‐weekly in Clarity AD, the model predicted a 5.45% (95% CI: 3.75% ‐ 7.84%) incidence of ARIA‐E in noncarriers, 9.85% (95% CI: 7.96% ‐ 12.1%) in heterozygous, and 28.0% (95% CI: 22.6% ‐ 34.1%) in homozygous carriers. No other covariate explored (age, sex, race, baseline MMSE, or occurrence of anti‐drug antibodies) had a statistically significant effect on ARIA‐E incidence. For isolated ARIA‐H, the graphical analysis identified no apparent relationship between isolated ARIA‐H incidence with lecanemab exposure. Isolated ARIA‐H incidence was associated with ApoE4 genotype, with homozygous having the highest isolated ARIA‐H incidence.ConclusionThe incidence of ARIA‐E increased with lecanemab Css,max. The incidence rate of isolated ARIA‐H was demonstrated independent of lecanemab exposure. The ApoE4 genotype impacts both ARIA‐E and isolated ARIA‐H, with increased incidences in homozygous carriers compared to heterozygous carriers or non‐carriers.

Association of Chronic Pain with Biomarkers of Neurodegeneration, Microglial Activation, and Inflammation in Cerebrospinal Fluid and Impaired Cognitive Function.

Debate surrounds the role of chronic pain as a risk factor for cognitive decline and dementia. This study aimed at examining the association of chronic pain with biomarkers of neurodegeneration using data from the Alzheimer's Disease Neuroimaging Initiative. Participants were classified using the ATN (amyloid, tau, neurodegeneration) classification. Chronic pain was defined as persistent or recurrent pain reported at baseline. For each ATN group, analysis of covariance models identified differences in cerebrospinal fluid (CSF) levels of amyloid β1-42 , phosphorylated tau 181 (ptau181 ), total tau (t-tau), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and cognitive function between chronic pain states. Differences in CSF levels of inflammatory markers between chronic pain states were further analyzed. Linear mixed effect models examined longitudinal changes. The study included 995 individuals, with 605 (60.81%) reporting chronic pain at baseline. At baseline, individuals with suspected non-Alzheimer pathophysiology and chronic pain showed increased CSF levels of t-tau and sTREM2. Chronic pain was associated with increased tumor necrosis factor α levels, irrespective of the ATN group. Longitudinally, an increase in ptau181 CSF levels was observed in chronic pain patients with negative amyloid and neurodegeneration markers. Amyloid-positive and neurodegeneration-negative chronic pain patients showed higher memory function cross-sectionally. No significant longitudinal decline in cognitive function was observed for any ATN group. Our study suggests that chronic pain induces neuronal damage and microglial activation in particular subgroups of patients along the AD spectrum. Further studies are needed to confirm these findings. ANN NEUROL 2023.

Cognitive Trajectories in Preclinical and Prodromal Alzheimer's Disease Related to Amyloid Status and Brain Atrophy: A Bayesian Approach.

Cognitive decline is a key outcome of clinical studies in Alzheimer's disease (AD). To determine effects of global amyloid load as well as hippocampus and basal forebrain volumes on longitudinal rates and practice effects from repeated testing of domain specific cognitive change in the AD spectrum, considering non-linear effects and heterogeneity across cohorts. We included 1,514 cases from three cohorts, ADNI, AIBL, and DELCODE, spanning the range from cognitively normal people to people with subjective cognitive decline and mild cognitive impairment (MCI). We used generalized Bayesian mixed effects analysis of linear and polynomial models of amyloid and volume effects in time. Robustness of effects across cohorts was determined using Bayesian random effects meta-analysis. We found a consistent effect of amyloid and hippocampus volume, but not of basal forebrain volume, on rates of memory change across the three cohorts in the meta-analysis. Effects for amyloid and volumetric markers on executive function were more heterogeneous. We found practice effects in memory and executive performance in amyloid negative cognitively normal controls and MCI cases, but only to a smaller degree in amyloid positive controls and not at all in amyloid positive MCI cases. We found heterogeneity between cohorts, particularly in effects on executive functions. Initial increases in cognitive performance in amyloid negative, but not in amyloid positive MCI cases and controls may reflect practice effects from repeated testing that are lost with higher levels of cerebral amyloid.

Neuropsychological predictors of conversion from mild cognitive impairment to dementia at different timepoints.

Impairment of episodic memory is largely considered the main cognitive marker of prodromic Alzheimer's disease (AD). Nevertheless, the neuropathological process in AD starts several years before and, apart from biomarkers well defined in the Amyloid (A), Tauopathy (T), Neurodegeneration (N) framework, early clinical and neuropsychological markers able to detect mild cognitive impairment (MCI) due to AD before the appearance of memory disorders are lacking in clinical practice. Investigations on semantic memory have shown promising results in providing an earlier marker of dementia in MCI patients. A total of 253 MCI subjects were followed up every 6months for 6years-186 converted to dementia and 67 remained stable at the sixth year of follow-up. Twenty-seven patients progressed in the first 2years (fast converters), 107 in the third to fourth year (intermediate converters), and 51 after the fourth year of follow-up (slow converters). Stable MCI subjects performed better than fast decliners in Mini-Mental State Examination (MMSE), several long-term memory scores, and category verbal fluency test (CFT); stable and intermediate converters differ only in MMSE and CFT tests; and stable and slow converters differ only in MMSE and phonological/semantic discrepancy score. Early impairment of semantic memory could predict the evolution to AD before the onset of episodic memory disorders, and the discrepancy between phonological and semantic verbal fluency could be able to detect this impairment in advance in respect of simple CFT tests. The assessment of different aspects of semantic memory and its degradation could represent an early cognitive marker to intercept MCI due to AD in clinical practice.

Impacts of baseline biomarkers on cognitive trajectories in subjective cognitive decline: the CoSCo prospective cohort study

BackgroundSubjective cognitive decline (SCD) is a risk factor for Alzheimer’s disease (AD); however, the rates of cognitive decline are variable according to underlying pathologies and biomarker status. We conducted an observational study and aimed to investigate baseline characteristics and biomarkers related with cognitive declines in SCD. Our study also assessed whether SCD participants showed different cognitive and biomarker trajectories according to baseline amyloid deposition.MethodsThis study is a part of a longitudinal cohort study conducted in multi-centers in South Korea between 2018 and 2021. Individuals (≥ 60 years old) with persistent cognitive complaint despite of normal cognitive functions were eligible for the study. All participants underwent neuropsychological tests, florbetaben PET scans, plasma amyloid markers, and brain MRI scans. Annual follow-up evaluations included neuropsychological tests and assessments for clinical progressions. Regional brain volumetry and amyloid burden represented by PET-based standardized uptake value ratio (SUVR) were measured. We compared cognitive and brain atrophic changes over 24 months between amyloid positive-SCD (Aβ + SCD) and amyloid negative-SCD (Aβ-SCD) groups. Baseline factors associated with cognitive outcomes were investigated.ResultsA total of 120 participants with SCD were enrolled and 107 completed follow-up evaluations. Aβ + SCD participants (n = 20, 18.5%) were older and more frequently APOE4 carriers compared with Aβ-SCD participants (n = 87). Baseline cognitive scores were not different between the two groups, except the Seoul Verbal Learning Test (SVLT) scores showing lower scores in the Aβ + SCD group. After 24 months, plasma amyloid markers were higher, and regional volumes (entorhinal, hippocampal, and pallidum) were smaller in the Aβ + SCD participants compared with Aβ-SCD participants adjusted by age, sex, and baseline volumes. SVLT delayed recall and controlled oral word association test (COWAT) scores indicated more declines in Aβ + SCD participants. Baseline left entorhinal volumes were related to verbal memory decline, while baseline frontal volumes and global SUVR values were related to frontal functional decline.ConclusionAβ + SCD participants showed more cognitive decline and medial temporal atrophic changes during 24 months. Baseline neurodegeneration and amyloid burden were related with future cognitive trajectories in SCD.Trial registrationThis study was registered at CRIS (KCT0003397).

Blood-Brain Barrier Dysfunction and Aβ42/40 Ratio Dose-Dependent Modulation with the ApoE Genotype within the ATN Framework.

The definition of Alzheimer's disease (AD) now considers the presence of the markers of amyloid (A), tau deposition (T), and neurodegeneration (N) essential for diagnosis. AD patients have been reported to have increased blood-brain barrier (BBB) dysfunction, but that has not been tested within the ATN framework so far. As the field is moving towards the use of blood-based biomarkers, the relationship between BBB disruption and AD-specific biomarkers requires considerable attention. Moreover, other factors have been previously implicated in modulating BBB permeability, including age, gender, and ApoE status. A total of 172 cognitively impaired individuals underwent cerebrospinal fluid (CSF) analysis for AD biomarkers, and data on BBB dysfunction, demographics, and ApoE status were collected. Our data showed that there was no difference in BBB dysfunction across different ATN subtypes, and that BBB damage was not correlated with cognitive impairment. However, patients with BBB disruption, if measured with a high Qalb, had low Aβ40 levels. ApoE status did not affect BBB function but had a dose-dependent effect on the Aβ42/40 ratio. These results might highlight the importance of understanding dynamic changes across the BBB in future studies in patients with AD.

Clinical outcomes of amyloid and tau markers according to vascular markers

AbstractBackgroundAlzheimer’s disease (AD) is characterized by amyloid beta (Aβ) aggregation [A] and tau aggregation reflecting neurofibrillary tangles [T]. These AD markers lead to neurodegeneration [N] and cognitive impairments. Recently, the ATN research framework of was presented by National Institute on Aging and Alzheimer’s Association. Cerebral small vessel disease (CSVD, [V]), which is one of most important cause of cognitive impairments, has an additive or synergistic effect on cognitive impairments with AD markers. In the present study, we investigated the frequency of ATV abnormalities in participants with varying degree of AD and CSVD markers. We also determined whether CSVD might synergistically affect cognitive decline with AD markers.MethodWe consecutively recruited 195 subjects (105 AD‐related cognitive impairment subjects, 86 subcortical vascular cognitive impairment subjects) from Samsung Medical Center. [A] and [T] positivities were determined by cut‐off values of Aβ and tau uptakes on PET using iterative outlier methods. [V] was assessed by the presence of severe white matter hyperintensity. All subjects underwent neuropsychological tests including Mini‐Mental State Exam (MMSE) and clinical dementia rating‐sum of boxes (CDR‐SOB). A linear mixed effect model was used to compare cognitive changes over time.ResultThe number of subjects of A‐T‐, A+T‐, and A+T+ groups were 16 (15.1%), 29 (27.4%), and 56 (52.8%) in the V‐ group; and 46 (51.7%), 33 (37.1%), and 8 (9.0%) in the V+ group. The linear mixed effects model analysis showed that A+/T+ were associated with worse cognitive decline, and its impact is higher in the V+ group than in the V‐ group (Figure).ConclusionOur findings suggested that there were interactive effects of AD markers and CSVD on cognitive decline. These findings demonstrate the importance of vascular factor management in patients with cognitive impairment and suggest that the ATV framework is useful in predicting cognitive decline in clinical practice.

Cross‐sectional and longitudinal associations of plasma makers of amyloid and tau pathology and neurodegeneration with gait speed

AbstractBackgroundHigher brain amyloid PET is associated with slower gait speed and has been hypothesized to play a role in age‐related mobility decline. With the development of blood‐based biomarkers of Alzheimer’s disease pathology, we examined whether plasma levels of amyloid‐beta (Aβ)40, Aβ42, the Aβ42/Aβ40 ratio, phosphorylated tau 181 (p‐tau181) and 217 (p‐tau217), total tau, and neurofilament light chain (NfL) were associated with gait speed.MethodThis study included 779 cognitively unimpaired participants (median age 75, 54.8% male, median follow‐up 6.8 years) in the Mayo Clinic Study of Aging with concurrent measurement of plasma biomarkers and gait speed. Individuals with chronic kidney disease or a history of stroke were excluded. The plasma markers (pg/mL) were measured on the Quanterix Simoa® HD‐1 analyzer (total tau, Aβ42, Aβ40, NfL) and the Meso Scale Discovery platform (p‐tau181, p‐tau217). Gait speed (m/s) was obtained by timing a self‐paced walk across 25 ft using a stopwatch. Linear mixed effects models, with subject‐specific intercepts and slopes for time since baseline, with z‐scored baseline plasma markers were used to predict cross‐sectional and longitudinal gait speed. All models adjusted for baseline age and sex.ResultAt baseline, higher Aβ42 [Beta = ‐0.019; 95%CI = (‐0.035, ‐0.004)], total‐tau [‐0.026; (‐0.041, ‐0.011)], and p‐tau181 [‐0.021; (‐0.036, ‐0.006)] were associated with slower gait speed. Gait speed decreased, on average, by about 0.015 m/s annually for those in this study. Each one standard deviation (SD) increase in baseline level of plasma Aβ40 [‐0.005; (‐0.007, ‐0.002)], NfL [‐0.006; (‐0.009, ‐0.004)], and p‐tau217 [‐0.004; (‐0.007, ‐0.001)] accelerated this decline over time. In contrast, each one SD increase in Aβ42/Aβ40 ratio [0.003; (0.001, 0.006)] mitigated decline. Additional analyses adjusting for Charlson comorbidity index, Beck Depression Inventory, body mass index, and APOE E4 allele status gave similar results.ConclusionBoth cross‐sectional and longitudinal associations of plasma markers of amyloid and tau pathology and neurodegeneration with gait speed among cognitively unimpaired individuals were present. Therefore, not only are these markers of cognitive changes, they are also related to motor changes such as those affecting gait speed.

Associations of Neurodegeneration Biomarkers in Cerebrospinal Fluid with Markers of Alzheimer's Disease and Vascular Pathology.

The National Institute on Aging-Alzheimer's Association Research Framework proposes defining Alzheimer's disease by grouping imaging and fluid biomarkers by their respective pathologic processes. The AT(N) structure proposes several neurodegenerative fluid biomarkers (N) including total tau (t-tau), neurogranin (Ng), and neurofilament light chain (NfL). However, pathologic drivers influencing each biomarker remain unclear. To determine whether cerebrospinal fluid (CSF)-neurodegenerative biomarkers (N) map differentially to Alzheimer's disease pathology measured by Aβ42 (an indicator of amyloidosis, [A]), p-tau (an indicator of tau deposition, [T]), and MRI vascular pathology indicators (measured by white-matter integrity, infarcts, and microbleeds [V]). Participants were from Mayo Clinic Study of Aging (MCSA) with CSF measures of NfL, Ng, t-tau, Aβ42, and p-tau and available MRI brain imaging. Linear models assessed associations between CSF neurodegeneration (N) markers, amyloid markers (A), tau (T), and vascular pathology (V). Participants (n = 408) had a mean age of 69.2±10.7; male, 217 (53.2%); cognitively unimpaired, 359 (88%). All three neurodegeneration biomarkers correlated with age (p < 0.001 for NfL and t-tau, p = 0.018 for Ng). Men had higher CSF-NfL levels; women had higher Ng (p < 0.001). NfL and t-tau levels correlated with infarcts (p = 0.009, p = 0.034 respectively); no biomarkers correlated with white-matter integrity. N biomarkers correlated with p-tau levels (T, p < 0.001). Higher Aβ42 levels associated with higher N-biomarker levels but only among cognitively unimpaired (A, p < 0.001). The influence of vascular pathology in the general population on CSF (N) biomarkers is modest, with greater influence of infarcts than white-matter disruption. Neurodegeneration markers more closely correlated with tau than amyloid markers.

Mitochondria-Directing Fluorogenic Probe: An Efficient Amyloid Marker for Imaging Lipid Metabolite-Induced Protein Aggregation in Live Cells and Caenorhabditis elegans.

The design and development of optical probes for sensing neurotoxic amyloid fibrils are active and important areas of research and are undergoing continuous advancements. In this paper, we have synthesized a red emissive styryl chromone-based fluorophore (SC1) for fluorescence-based detection of amyloid fibrils. SC1 records exceptional modulation in its photophysical properties in the presence of amyloid fibrils, which has been attributed to the extreme sensitivity of its photophysical properties toward the immediate microenvironment of the probe in the fibrillar matrix. SC1 also shows very high selectivity toward the amyloid-aggregated form of the protein as compared to its native form. The probe is also able to monitor the kinetic progression of the fibrillation process, with comparable efficiency as that of the most popular amyloid probe, Thioflavin-T. Moreover, the performance of SC1 is least sensitive to the ionic strength of the medium, which is an advantage over Thioflavin-T. In addition, the molecular level interaction forces between the probe and the fibrillar matrix have been interrogated by molecular docking calculations which suggest the binding of the probe to the exterior channel of the fibrils. The probe has also been demonstrated to sense protein aggregates from the Aβ-40 protein, which is known to be responsible for Alzheimer's disease. Moreover, SC1 exhibited excellent biocompatibility and exclusive accumulation at mitochondria which allowed us to successfully demonstrate the applicability of this probe to detect mitochondrial-aggregated protein induced by an oxidative stress indicator molecule 4-hydroxy-2-nonenal (4-HNE) in A549 cell lines as well as in a simple animal model like Caenorhabditis elegans. Overall, the styryl chromone-based probe presents a potentially exciting alternative for the sensing of neurotoxic protein aggregation species both in vitro as well as in vivo.

Systematic assessment of plasma biomarkers in spinocerebellar ataxia

Background and objectivesPlasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), phosphorylated-tau (p-tau), and β-amyloid (Aβ) have emerged as promising markers in several neurodegenerative disorders, but whether they can be used as biomarkers in spinocerebellar ataxias (SCA) is yet to be determined. This study aimed to identify sensitive plasma markers for SCA and investigate their effectiveness in tracking ataxia severity, cognition, non-motor symptoms, and brain atrophy. MethodsThis observational study recruited consecutive participants from Huashan Hospital and the CABLE study from November 2019. Patients with SCA were genetically diagnosed, grouped according to the ataxia severity, and compared with healthy older individuals and patients with multiple system atrophy type C (MSA-C). Plasma NfL, GFAP, p-tau, and Aβ levels were measured by Simoa in all participants. Analysis of covariance, Spearman correlation, and multivariable regression were used to explore candidate markers in SCA. ResultsA total of 190 participants (60 SCA, 56 MSA-C, and 74 healthy controls) were enrolled. Plasma NfL level increased early in the pre-ataxic stage of SCA (32.23 ± 3.07 vs. 11.41 ± 6.62 pg/mL in controls), was positively associated with the ataxia severity (r = 0.45, P = 0.005) and CAG repeat length (r = 0.51, P = 0.001), varied among the different SCA subtypes (39.57 ± 13.50 pg/mL in SCA3, which was higher than 28.17 ± 8.02 pg/mL in SCA2, 17.08 ± 6.78 pg/mL in SCA8, and 24.44 ± 18.97 pg/mL in rare SCAs; P < 0.05), and was associated with brainstem atrophy. NfL alone (area under the curve [AUC] 0.867) or combined with p-tau181 and Aβ (AUC 0.929), showed excellent performance in discriminating SCA patients from controls. Plasma GFAP distinguished SCA from MSA-C with moderate accuracy (AUC > 0.700) and correlated with cognitive performance and cortical atrophy. Changes in levels of p-tau181 and Aβ were observed in SCA patients compared to controls. They were both correlated with cognition, while Aβ was also associated with non-motor symptoms, such as anxiety and depression. DiscussionPlasma NfL may serve as a sensitive biomarker for SCA, and its level is elevated in the pre-ataxic stage. The different performance of NfL and GFAP indicates differences in the underlying neuropathology of SCA and MSA-C. Moreover, amyloid markers may be useful for detecting memory dysfunction and other non-motor symptoms in SCA.

Development of a home-based cognitive test for cognitive monitoring in subjective cognitive decline with high risk of Alzheimer's disease.

Subjective cognitive decline (SCD) indicates a self-perceived persistent cognitive worsening despite of normal performance in standard neuropsychological tests. Owing to its heterogeneity and potential risk of Alzheimer's disease, baseline biomarkers to predict cognitive decline are important. In the present study, we developed a home-based cognitive test (HCT) to monitor cognitive changes regularly without visiting hospitals. This study aims to compare cognitive and biomarker trajectories during a 48-month period between amyloid positive SCD and amyloid negative SCD subjects. Data will be collected from a prospective observational cohort study conducted in South Korea. Eighty participants with SCD aged ≥ 60 years are eligible for the study. All participants undergo annual neuropsychological tests and neurological examinations, bi-annual brain MRI scans and plasma amyloid markers, and baseline florbetaben Positron Emission Tomography scans. The amyloid burden and regional volumes will be measured. Cognitive and biomarker changes will be compared between the amyloid-positive SCD and amyloid negative SCD groups. Validation would be performed to assess reliability and feasibility of HCT. This study would suggest a perspective on SCD in terms of cognitive and biomarker trajectories. Baseline characteristics and biomarker status might affect faster cognitive decline and future biomarker trajectories. In addition, HCT could be an alternative option of in-person neuropsychological tests to track cognitive changes without visiting hospitals.