Increased Amyloid Burden Research Articles

Sex/gender effects of glial reactivity on preclinical Alzheimer's disease pathology.

Glial reactivity may contribute to sex/gender differences in Alzheimer's disease (AD) pathophysiology. Here, we investigated the differential effect of cerebrospinal fluid (CSF) glial markers on AD pathology and neurodegeneration by sex/gender among cognitively unimpaired older adults at increased risk of developing AD. We included 397 participants from the ALFA+ cohort with CSF Aβ42/40, p-tau181, sTREM2, YKL40, and GFAP, magnetic resonance imaging-based hippocampal volume (n = 299), and amyloid burden (centiloids) measured with [18F] flutemetamol positron emission tomography (n = 341). We ran multiple linear regression models to assess the association between glial markers, AD pathology and hippocampal volumes and their interaction with sex/gender, usingFalse Discovery Rateto correctfor multiple comparisons. Glial markers significantly contributed to explain amyloid burden, tau pathology, and hippocampal volumes, beyond age and/or primary AD pathology in a sex/gender-specific manner. Compared to men, women showed increased amyloid burden (centiloids) and CSF p-tau181 with increasing levels of sTREM2 and YKL40, and YKL40 and GFAP, respectively. Compared to women, men with greater tau burden showed lower hippocampal volumes as CSF YKL40 levels increased. Overall, our findings suggest that glial reactivity may contribute to sex/gender differences in AD progression, mostly, downstream amyloid. Further research identifying sex/gender-specific temporal dynamics in AD development is warranted to inform clinical trials.

Hypertension and cerebral blood flow in the development of Alzheimer's disease.

We investigated the interactive associations between amyloid and hypertension on the entorhinal cortex (EC) tau and atrophy and the role of cerebral blood flow (CBF) as a shared mechanism by which amyloid and hypertension contribute to EC tau and regional white matter hyperintensities (WMHs). We analyzed data from older adults without dementia participating in the Add-Tau study (NCT02958670, n=138) or Alzheimer's Disease Neuroimaging Initiative (ADNI) (n=523) who had available amyloid-positron emission tomography (PET), tau-PET, fluid-attenuated inversion recovery (FLAIR), and T1-weighted magnetic resonance imaging (MRI). A subsample in both cohorts had available arterial spin labeling (ASL) MRI (Add-Tau: n=78; ADNI: n=89). The detrimental effects of hypertension on AD pathology and EC thickness were more pronounced in the Add-Tau cohort. Increased amyloid burden was associated with decreased occipital gray matter CBF in the ADNI cohort. In both cohorts, lower regional gray matter CBF was associated with higher EC tau and posterior WMH burden. Reduced cerebral perfusion may be one common mechanism through which hypertension and amyloid are related to increased EC tau and WMH volume. Hypertension is associated with increased entorhinal cortex (EC) tau, particularly in the presence of amyloid. Decreased cortical cerebral blood flow (CBF) is associated with higher regional white matter hyperintensity volume. Increasing amyloid burden is associated with decreasing CBF in the occipital lobe. MTL CBF and amyloid are synergistically associated with EC tau.

Deconstructing pathological tau by biological process in early stages of Alzheimer disease: a method for quantifying tau spatial spread in neuroimaging

Neuroimaging studies often quantify tau burden in standardized brain regions to assess Alzheimer disease (AD) progression. However, this method ignores another key biological process in which tau spreads to additional brain regions. We have developed a metric for calculating the extent tau pathology has spread throughout the brain and evaluate the relationship between this metric and tau burden across early stages of AD. 445 cross-sectional participants (aged≥50) who had MRI, amyloid PET, tau PET, and clinical testing were separated into disease-stage groups based on amyloid positivity and cognitive status (older cognitively normal control, preclinical AD, and symptomatic AD). Tau burden and tau spatial spread were calculated for all participants. We found both tau metrics significantly elevated across increasing disease stages (p<0.0001) and as a function of increasing amyloid burden for participants with preclinical (p<0.0001, p=0.0056) and symptomatic (p=0.010, p=0.0021) AD. An interaction was found between tau burden and tau spatial spread when predicting amyloid burden (p=0.00013). Analyses of slope between tau metrics demonstrated more spread than burden in preclinical AD (β=0.59), but then tau burden elevated relative to spread (β=0.42) once participants had symptomatic AD, when the tau metrics became highly correlated (R=0.83). Tau burden and tau spatial spread are both strong biomarkers for early AD but provide unique information, particularly at the preclinical stage. Tau spatial spread may demonstrate earlier changes than tau burden which could have broad impact in clinical trial design. This research was supported by the Knight Alzheimer Disease Research Center (Knight ADRC, NIH grants P30AG066444, P01AG026276, P01AG003991), Dominantly Inherited Alzheimer Network (DIAN, NIH grants U01AG042791, U19AG03243808, R01AG052550-01A1, R01AG05255003), and the Barnes-Jewish Hospital Foundation Willman Scholar Fund.

Cognitive Reserve in Parkinson's Disease without Dementia: β-Amyloid and Metabolic Assessment.

Cognitive reserve (CR) is the mismatch between preserved cognition and neuropathological damage. Amyloidopathy in Parkinson's disease (PD) could be associated with faster progression to dementia, but the putative protective effect of CR is unknown. To evaluate the effect of CR on β-amyloid burden and brain metabolism in non-demented PD subjects. Participants with PD (n = 53) underwent a clinical evaluation, [18 F]-fluorodeoxyglucose and [18 F]-flutemetamol positron emission tomography magnetic resonances, and were classified according to CR. The metabolic pattern of 16 controls was compared to PD subjects. The PD subjects showed hypometabolism mainly in the bilateral posterior cortex. Superior-CR subjects (n = 22) exhibited better cognitive performance, increased amyloid burden, and higher metabolism in several right hemisphere areas compared to low-medium-CR subjects (n = 31). Higher CR in non-demented PD is associated with better cognitive performance, which might reduce vulnerability to the effect of β-amyloid. Whether superior CR leads to protection against metabolic deterioration, and predominantly right hemisphere involvement, deserves further exploration.

Amyloid Burden Correlates with Electrocardiographic Findings in Patients with Cardiac Amyloidosis-Insights from Histology and Cardiac Magnetic Resonance Imaging.

Cardiac amyloidosis (CA) is associated with several distinct electrocardiographic (ECG) changes. However, the impact of amyloid depositions on ECG parameters is not well investigated. We therefore aimed to assess the correlation of amyloid burden with ECG and test the prognostic power of ECG findings on outcomes in patients with CA. Consecutive CA patients underwent ECG assessment and cardiac magnetic resonance imaging (CMR), including the quantification of extracellular volume (ECV) with T1 mapping. Moreover, seven patients underwent additional amyloid quantification using immunohistochemistry staining of endomyocardial biopsies. A total of 105 CA patients (wild-type transthyretin: 74.3%, variant transthyretin: 8.6%, light chain: 17.1%) were analyzed for this study. We detected correlations of total QRS voltage with histologically quantified amyloid burden (r = -0.780, p = 0.039) and ECV (r = -0.266, p = 0.006). In patients above the ECV median (43.9%), PR intervals were significantly longer (p = 0.016) and left anterior fascicular blocks were more prevalent (p = 0.025). In our survival analysis, neither Kaplan-Meier curves (p = 0.996) nor Cox regression analysis detected associations of QRS voltage with adverse patient outcomes (hazard ratio: 0.995, p = 0.265). The present study demonstrated that an increased amyloid burden is associated with lower voltages in CA patients. However, baseline ECG findings, including QRS voltage, were not associated with adverse outcomes.

White matter changes with cerebrovascular disease and Alzheimer’s disease pathologies

AbstractBackgroundWhite matter (WM) plays an important role in cognitive function and undergoes substantial changes due to aging and increase in AD and AD related dementia (AD/ADRD) pathologies. While recent work proposed measurement of global WM changes from diffusion MRI as biomarkers for Cerebrovascular disease (CVD) such as PSMD and free water, there needs to be a better understanding of WM changes due to AD/ADRD pathologies. The goal of our recent work was to understand white matter changes with CVD and AD – common pathologies in AD/ADRD ‐ utilizing data from Mayo Clinic Study of Aging and Mayo ADRC.MethodUsing diffusion MRI (dMRI) in 718 participants from Mayo Clinic Study of Aging (mean age = 71.1 years, 56% male), we investigated relationships between commonly used dMRI measures and vascular risk as well as global amyloid PET. In a subset of 233 participants who were amyloid‐PET positive and also competed Tau‐PET (flortaucipir) from Mayo Clinic Study of Aging and Mayo ADRC, we investigated associations between regional flortaucipir SUVRs in Braak stages and regional WM changes.ResultsWe found greater frontal lobe WM damage with increasing vascular risk across all dMRI measures. We previously validated the strong relationship between the genu of the corpus callosum (anterior interhemispheric connections) dMRI measurements made on antemortem scans and cerebrovascular pathology observed on postmortem tissue (Nguyen et. al. Acta Neuropathologica 2022) supporting the utility of genu of the corpus callosum dMRI measures as a potential CVD biomarker. Also, we found greater posterior WM damage with increasing amyloid burden. Among the 233 amyloid positive participants, we found spatially dependent WM degeneration associated with regional flortaucipir SUVRs in Braak stages with greater extent of posterior WM damage. Further, dMRI measurements of the WM damage provided complementary information about disease staging and progression of AD in addition to flortaucipir SUVR measurements.ConclusionsAnterior WM measurements may be more specific to CVD and posterior WM changes are seen with increasing AD pathological burden. Our results suggest that WM changes observed with CVD and typical AD may be different and have clinical utility for differential diagnosis and disease staging.

The effect of aquaporin‐4 mis‐localization on Aβ pathology in mice

AbstractBackgroundThe reduced clearance of amyloid‐beta (Aβ) is thought to contribute to the development of Alzheimer’s disease (AD) pathology, characterized by the deposition of Aβ plaques. Previous studies have shown that Aβ is cleared via the glymphatic system, a brain‐wide network of perivascular pathways that support exchange between cerebrospinal fluid and interstitial fluid within the brain. Such exchange is mediated by the water channel aquaporin‐4 (AQP4), localized at astrocytic endfeet. Research has found that the deletion or mislocalization of Aqp4 is associated with reduced Aβ clearance and, in turn, Aβ plaque formation.MethodIn this study, we evaluated how the deposition of Aβ plaques within a 5xFAD mouse model is impacted by either the mislocalization or deletion of perivascular AQP4. We utilized both the AQP4 knockout mouse and α‐syntrophin (Snta1) knockout mouse, which lacks perivascular AQP4 localization, and crossed them with a mouse model line of amyloidosis (5xFAD) to determine the effect on Aβ deposition. Mice were perfused at 18 weeks and amyloid‐beta, AQP4, and lectin were assessed by immunofluorescence. Amyloid β distribution was evaluated anterior to posterior through the brain utilizing regions of interests for entire slice, cortex, corpus callosum, hippocampus, subiculum, sub cortical structures, and amygdala when applicable.ResultWe observed that both the absence (Aqp4KO) and mislocalization (Snta1KO) of AQP4 significantly increases amyloid distribution across the brain, when compared with 5xFAD littermate controls. Further, the mislocalization of AQP4 resulted in a significant increase in the size of Aβ plaque deposition not present with AQP4 deletion.Conclusions highlights that the mislocalization of perivascular AQP4 has a greater impact on increased amyloid burden than the deletion of AQP4. In suggesting that the mechanism of AQP4 mislocalization may lie upstream of amyloid or tau pathology, targeting perivascular AQP4 localization may be provide a novel pathway toward secondary, or potentially primary prevention of Alzheimer’s disease.

Age-, sex-, and pathology-related variability in brain structure and cognition

This work aimed to investigate potential pathways linking age and imaging measures to early age- and pathology-related changes in cognition. We used [18F]-Flutemetamol (amyloid) and [18F]-Flortaucipir (tau) positron emission tomography (PET), structural MRI, and neuropsychological assessment from 232 elderly individuals aged 50–89 years (46.1% women, 23% APOE-ε4 carrier, 23.3% MCI). Tau-PET was available for a subsample of 93 individuals. Structural equation models were used to evaluate cross-sectional pathways between age, amyloid and tau burden, grey matter thickness and volumes, white matter hyperintensity volume, lateral ventricle volume, and cognition. Our results show that age is associated with worse outcomes in most of the measures examined and had similar negative effects on episodic memory and executive functions. While increased lateral ventricle volume was consistently associated with executive function dysfunction, participants with mild cognitive impairment drove associations between structural measures and episodic memory. Both age and amyloid-PET could be associated with medial temporal lobe tau, depending on whether we used a continuous or a dichotomous amyloid variable. Tau burden in entorhinal cortex was related to worse episodic memory in individuals with increased amyloid burden (Centiloid >12) independently of medial temporal lobe atrophy. Testing models for sex differences revealed that amyloid burden was more strongly associated with regional atrophy in women compared with men. These associations were likely mediated by higher tau burden in women. These results indicate that influences of pathological pathways on cognition and sex-specific vulnerabilities are dissociable already in early stages of neuropathology and cognitive impairment.

Using amyloid PET as a biomarker to detect progression of early Alzheimer disease

AbstractBackgroundAlzheimer’s disease (AD), the most common form of dementia, is a complex polygenic disease with genetic, cellular, pathologic, and clinical heterogeneity. Recently, significant attempts have been made for identifying AD biomarkers for reliably tracking disease progression in its early asymptomatic stages. To this end, amyloid PET imaging has provided useful information tracking accumulation of parenchymal amyloid beta (Aβ) deposits in the brain. Previous investigations have conducted genetic association studies of CSF Aβ42, both continuously as well as using a threshold for amyloid positivity, and identified novel genes and loci potentially contributing to the preclinical stage in AD. In a recent case‐control based study using amyloid PET as a quantitative trait, Raghavan et al., identified a novel locus for amyloidosis within RBFOX1 gene in 4,314 participants, however, further investigations are needed to replicate and expand on these findings.MethodIn order to investigate the underlying genetic basis for brain amyloidosis in AD, we systematically analyzed the largest collection of amyloid imaging data (N = 6,320), across multiple ethnicities from multicenter cohorts (ADRC, A4, DIAN, ADNI, ADNIDOD, UPitt, and HABS) as a quantitative trait to identify the functional variants and genes driving the association of AD. Furthermore, we have conducted diagnosis‐, gender‐, and APOE‐stratified analyses to investigate the effect of these variables on the brain amyloidosis.ResultPreliminary results found a strong APOE signal in chr19 (min P = 1e‐185) and a genome‐wide significant hit (P = 2e‐08) in the chromosome 7 (potentially, associated to TMEM106B gene) warranting further investigation (Fig. 1). Moreover, some suggestive signals were detected in chr10 (P = 1e‐07) and chr12 (P = 5e‐07). Consistent with previous finding, we found RBFOX1 to be associated with increased amyloid burden (β = 0.07), however, the signal was only nominally significant (P = 0.03). Additional analyses including multi‐ancestry meta‐analysis using FHS, AIBL, and EISAI cohorts and post‐GWAS analyses are ongoing.ConclusionThe identification of pre‐clinical AD‐specific molecular signatures and pathways will enable the characterization of appropriate therapeutic targets for the prevention and/or treatment of AD. Results generated from our investigation will further serve to generate prediction models for amyloid positivity and Mendelian Randomization (MR) analyses.

Cerebral Small Vessel Disease Burden Predicts Neurodegeneration and Clinical Progression in Prodromal Alzheimer's Disease.

Cerebral small vessel disease (CSVD) has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). This study aimed to comprehensively investigated the associations of CSVD burden with cognition and AD pathologies. A total of 546 non-demented participants (mean age, 72.1 years, range, 55-89; 47.4% female) were included. The longitudinal neuropathological and clinical correlates of CSVD burden were assessed using linear mixed-effects and Cox proportional-hazard models. Partial least squares structural equation model (PLS-SEM) was used to assess the direct and indirect effects of CSVD burden on cognition. We found that higher CSVD burden was associated with worse cognition (MMSE, β= -0.239, p = 0.006; MoCA, β= -0.493, p = 0.013), lower cerebrospinal fluid (CSF) Aβ level (β= -0.276, p < 0.001) and increased amyloid burden (β= 0.048, p = 0.002). In longitudinal, CSVD burden contributed to accelerated rates of hippocampus atrophy, cognitive decline, and higher risk of AD dementia. Furthermore, as the results of PLS-SEM, we observed both significant direct and indirect impact of advanced age (direct, β= -0.206, p < 0.001; indirect, β= -0.002, p = 0.043) and CSVD burden (direct, β= -0.096, p = 0.018; indirect, β= -0.005, p = 0.040) on cognition by Aβ-p-tau-tau pathway. CSVD burden could be a prodromal predictor for clinical and pathological progression. Simultaneously, we found that the effects were mediated by the one-direction-only sequence of pathological biomarker changes starting with Aβ, through abnormal p-tau, and neurodegeneration.

Identification of Genetic Loci and Sex Differences Associated with Amyloid Burden Using the AD‐BXD Mouse Population

AbstractBackgroundIn light of the rising prevalence of both diet‐induced obesity and Alzheimer’s Disease (AD) in the developed world, the influence of a high‐fat diet (HFD) on AD progression was investigated. Beta‐amyloid 1‐42 (Aβ42), in particular, was examined as little is known about the extent to which an individual’s genetics, sex, and diet determine the onset and progression of this classic AD neuropathology.MethodAD‐BXD mice were generated by crossing female 5XFAD mice to male members of the BXD reference panel (Neuner, et al. 2019). Cortical Aβ42 levels were quantified (ELISA) from four hundred and twenty‐two mice (235 female, 187 male) across 52 AD‐BXD strains fed either a 6kcal% extruded control diet (n = 227) or 45kcal% HFD (n = 195) at 10 weeks of age until 3, 6, or 14 months old.ResultWhile a 45kcal% HFD did not alter cortical Aβ42 levels in 5XFAD mice relative to control diet, there was a main effect of genetic background (strain) and sex. Specifically, wide variation in cortical Aβ42 was observed across the AD‐BXD mouse population that was highly heritable (h2≈0.9), and females displayed greater Aβ42 levels than males. Quantitative trait locus (QTL) mapping revealed significant genetic loci associated with increased amyloid burden with aging, indicating sequence differences on chromosomes (Chr) 19 and X that may underlie the observed sex differences when age was included as covariates. Furthermore, we identified several missense mutations within our Chr 19 QTL that could explain differences in Aβ42 phenotype, and expression QTL analysis is underway to identify putative regulatory variants of cortical amyloid burden.ConclusionWe found that genetic factors, strain and sex, are key determinants of cortical amyloid burden – but not diet (environmental factor) suggesting involvement of other regulators/pathways in eliciting cognitive decline in AD‐BXD mouse population (Dunn et. al., AAIC 2021) Resolving genetic modifiers of amyloid burden located on Chr 19 and X may reveal novel targets for anti‐amyloid therapeutics and provide a possible mechanistic explanation for why females (XX) are at a higher risk for developing AD than males (XY).

Investigating P2×7R‐mediated inflammatory signalling in Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is pathologically characterised by the presence of amyloid plaques and neurofibrillary tangles accompanied by a marked neuroinflammation which contributes to the onset and progression of AD. Astrocytes and microglia recognize danger‐associated molecular patterns (Aß, ATP) through a myriad of sensors including the purinergic receptor P2×7 (P2×7R). These interactions lead to the release of inflammatory mediators that could participate in damaging inter‐cellular cascades. Inhibition of P2×7R in AD models ameliorates cognitive deficits and supports a neuroprotective effect of P2×7R blockade in vivo. However, the cell type‐specific inflammatory signals downstream of P2×7R in AD are not fully understood.MethodWe used biochemical and histological methods, including in situ RNA detection (RNAscope), to examine P2×7R expression and localization relative to disease hallmarks and local inflammatory features in temporal and prefrontal cortex at different Braak stages. A series of P2×7R antagonists were used to study P2×7R‐mediated responses to inflammatory stimuli in primary glial cells and to assess the effects of P2×7R blockage on tau and synapse health in brain slice cultures.ResultWe found elevated levels of P2×7R in AD relative to control brain together with an increased amyloid burden, synapse mislocalization of tau and loss of synaptic markers. P2×7R was detected in human astrocytes as well as other neural cell types and its increased abundance was accompanied by an upregulation of inflammatory cytokines including CCL2 and IL‐1ß. In cultured astrocytes, P2×7R activation contributes to the production of the inflammatory cytokines CCL2, IL‐6 and the synaptotoxic molecule lipocalin‐2, whereas microglial P2×7R activation induces IL‐1ß secretion through the NLRP3 inflammasome pathway. Treatment of organotypic brain slice cultures with specific P2×7R antagonists suggests that P2×7R inhibition modulates glial function in response to neurodegenerative disease relevant stimulation.ConclusionThese data show that P2×7R expression is elevated in AD prior to marked synapse loss and point towards distinct P2×7R‐mediated responses in astrocytes and microglia. Ongoing work aims to determine if pharmacological blockade of P2×7R‐inflammatory signals has benefits for tau‐associated neurodegeneration in AD.

Abstract 14292: Association of Technetium Pyrophosphate Scan Grade With Adverse Remodeling and Burden in Cardiac Amyloidosis

Introduction: While technetium pyrophosphate (Tc-PyP) is known to be highly accurate for identifying transthyretin cardiac amyloidosis (ATTR-CA), it is currently unclear whether the grade of uptake observed on Tc-PyP correlates with either amyloid burden or adverse cardiac remodeling. Methods: At three academic medical centers, we retrospectively identified patients with confirmed ATTR-CA—defined in accordance with guidelines using either tissue biopsy or grade ≥2 Tc-PyP uptake—who underwent Tc-PyP and cardiac magnetic resonance (CMR) at 1.5T (Phillips, Siemens or GE). Left (LV) and right (RV) ventricular size, mass, and systolic function were quantified. T1 mapping including extracellular volume (ECV)—a surrogate for amyloid burden—was quantified according to guidelines. 3-hour Tc-PyP grade was assessed in accordance with guidelines. CMR markers were correlated with Tc-PyP grade using ANOVA with pair-wise comparisons made using t-test, Wilcoxon rank, or chi-squared as appropriate with p&lt;0.01 used to denote significance. Results: 45 patients were included (mean age 75.4 years, 75.6% male). Within the cohort, grade 0, 1, 2, and 3 uptake were present in 1(2%), 3(7%), 6(13%), and 35(78%) patients respectively. All patients with Tc-PyP grade &lt;2 were confirmed to have ATTR-CA by endomyocardial biopsy. Neither age, gender, or comorbidities differed significantly based on Tc-PyP uptake (Panel A). In univariate analysis, both indexed LV mass and ECV were significantly associated with Tc-PyP grade (Panel B). As compared to those with grade 2, patients with grade 3 Tc-PyP uptake had significantly higher ECV (p&lt;0.001) and indexed LV mass (p=0.003). Conclusions: The presence of higher Tc-PyP grade is associated with increasing amyloid burden and a greater degree of adverse LV remodeling. Higher Tc-PyP grade appears to be indicative of more advanced disease stage in this patient population.

Association of longitudinal cognitive decline with diffusion MRI in Gray Matter, Amyloid, and Tau deposition

Extracellular amyloid plaques in gray matter are the earliest pathological marker for Alzheimer's disease (AD), followed by abnormal tau protein accumulation. The link between diffusion changes in gray matter, amyloid and tau pathology, and cognitive decline is not well understood. We first performed cross-sectional analyses on T1-weighted imaging, diffusion MRI, and amyloid and tau PETs from the ADNI 2/3 database. We evaluated cortical volume, free-water, fractional anisotropy (FA), and amyloid and tau SUVRs in 171 cognitively normal, 103 MCI, and 44 AD individuals. When the 3 groups were combined, increasing amyloid burden was associated with reduced extracellular free-water in the entorhinal cortex and hippocampus in those with amyloid-negative status whereas increasing tau burden was associated with increased extracellular free-water regardless of amyloid status. Next, we found that for the MCI subjects, diffusion measures (free-water, FA) alone predicted MMSE score 2 years later with a high r-square value (87%), as compared to tau SUVRs (27%), T1 volume (36%), and amyloid SUVRs (75%). Diffusion measures represent a potent non-invasive marker for predicting cognitive decline.

Correlations between APOE4 allele and regional amyloid and tau burdens in cognitively normal older individuals

The correlations between apolipoprotein epsilon 4 (APOE4) status and regional amyloid, tau, and cortical thickness in cognitively normal elderly are not fully understood. Our cross-sectional study aimed to compare regional amyloid/tau burden, and cortical thickness according to APOE4 carrier status and assess correlations between APOE4 and Alzheimer’s disease (AD)-related biomarker burdens. We analyzed 185 cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Participants aged 55–90 with normal cognitive function were divided into amyloid ß-positive (Aß+) APOE4 carriers (group 1, n = 27), Aß+ APOE4 non-carriers (group 2, n = 29), and Aß− normal controls (group 0, n = 129). We compared amyloid depositions, tau depositions, and cortical thickness among the three groups and assessed correlations between APOE4 existence and imaging biomarkers adjusted for age and sex. The participants in group 2 were older than those in the other groups. The regional amyloid/tau standardized uptake value ratios (SUVRs) did not differ between groups 1 and 2, but the amyloid/tau SUVRs in most regions were numerically higher after adjusting for age difference. APOE4 allele had robust correlations with increased amyloid burden in the fronto-temporo-parietal cortical areas after adjustment for age and sex, but it had weaker and mixed correlations with the regional tau burden and did not have significant correlation with cortical thickness. We identified that the presence of APOE4 allele might be more highly associated with amyloid deposition than with other AD-related biomarkers such as tau or cortical thickness in cognitively normal elderly.

18F]ROStrace detects oxidative stress in vivo and predicts progression of Alzheimer’s disease pathology in APP/PS1 mice

BackgroundOxidative stress is implicated in the pathogenesis of the most common neurodegenerative diseases, such as Alzheimer’s disease (AD). However, tracking oxidative stress in the brain has proven difficult and impeded its use as a biomarker. Herein, we investigate the utility of a novel positron emission tomography (PET) tracer, [18F]ROStrace, as a biomarker of oxidative stress throughout the course of AD in the well-established APP/PS1 double-mutant mouse model. PET imaging studies were conducted in wild-type (WT) and APP/PS1 mice at 3 different time points, representing early (5 mo.), middle (10 mo.), and advanced (16 mo.) life (n = 6–12, per sex). Semi-quantitation SUVRs of the plateau phase (40–60 min post-injection; SUVR40–60) of ten brain subregions were designated by the Mirrione atlas and analyzed by Pmod. Statistical parametric mapping (SPM) was used to distinguish brain regions with elevated ROS in APP/PS1 relative to WT in both sexes. The PET studies were validated by ex vivo autoradiography and immunofluorescence with the parent compound, dihydroethidium.Results[18F]ROStrace retention was increased in the APP/PS1 brain compared to age-matched controls by 10 mo. of age (p < 0.0001) and preceded the accumulation of oxidative damage in APP/PS1 neurons at 16 mo. (p < 0.005). [18F]ROStrace retention and oxidative damages were higher and occurred earlier in female APP/PS1 mice as measured by PET (p < 0.001), autoradiography, and immunohistochemistry (p < 0.05). [18F]ROStrace differences emerged midlife, temporally and spatially correlating with increased Aβ burden (r2 = 0.30; p = 0.0016), which was also greatest in the female brain (p < 0.001).Conclusions[18F]ROStrace identifies increased oxidative stress and neuroinflammation in APP/PS1 female mice, concurrent with increased amyloid burden midlife. Differences in oxidative stress during this crucial time may partially explain the sexual dimorphism in AD. [18F]ROStrace may provide a long-awaited tool to stratify at-risk patients who may benefit from antioxidant therapy prior to irreparable neurodegeneration.

Morphological basis of Parkinson disease-associated cognitive impairment: an update

Cognitive impairment is one of the most salient non-motor symptoms of Parkinson disease (PD) that poses a significant burden on the patients and carers as well as being a risk factor for early mortality. People with PD show a wide spectrum of cognitive dysfunctions ranging from subjective cognitive decline and mild cognitive impairment (MCI) to frank dementia. The mean frequency of PD with MCI (PD-MCI) is 25.8% and the pooled dementia frequency is 26.3% increasing up to 83% 20years after diagnosis. A better understanding of the underlying pathological processes will aid in directing disease-specific treatment. Modern neuroimaging studies revealed considerable changes in gray and white matter in PD patients with cognitive impairment, cortical atrophy, hypometabolism, dopamine/cholinergic or other neurotransmitter dysfunction and increased amyloid burden, but multiple mechanism are likely involved. Combined analysis of imaging and fluid markers is the most promising method for identifying PD-MCI and Parkinson disease dementia (PDD). Morphological substrates are a combination of Lewy- and Alzheimer-associated and other concomitant pathologies with aggregation of α-synuclein, amyloid, tau and other pathological proteins in cortical and subcortical regions causing destruction of essential neuronal networks. Significant pathological heterogeneity within PD-MCI reflects deficits in various cognitive domains. This review highlights the essential neuroimaging data and neuropathological changes in PD with cognitive impairment, the amount and topographical distribution of pathological protein aggregates and their pathophysiological relevance. Large-scale clinicopathological correlative studies are warranted to further elucidate the exact neuropathological correlates of cognitive impairment in PD and related synucleinopathies as a basis for early diagnosis and future disease-modifying therapies.

Spatial Distribution and Hierarchical Clustering of β-Amyloid and Glucose Metabolism in Alzheimer's Disease.

Increased amyloid burden and decreased glucose metabolism are important characteristics of Alzheimer’s disease (AD), but their spatial distribution and hierarchical clustering organization are still poorly understood. In this study, we explored the distribution and clustering organization of amyloid and glucose metabolism based on 18F-florbetapir and 18F-fluorodeoxyglucose PET data from 68 AD patients and 20 cognitively normal individuals. We found that: (i) cortical regions with highest florbetapir binding were the regions with high glucose metabolism; (ii) the percentage changes of amyloid deposition were greatest in the frontal and temporal areas, and the hypometabolism was greatest in the parietal and temporal areas; (iii) brain areas can be divided into three hierarchical clusters by amyloid and into five clusters by metabolism using a hierarchical clustering approach, indicating that adjacent regions are more likely to be grouped into one sub-network; and (iv) there was a significant positive correlation in any pair of amyloid-amyloid and metabolism-metabolism sub-networks, and a significant negative correlation in amyloid-metabolism sub-networks. This may suggest that the influence forms and brain regions of AD on different pathological markers may not be synchronous, but they are closely related.

Infliximab and/or MESNA alleviate doxorubicin-induced Alzheimer's disease-like pathology in rats: A new insight into TNF-α/Wnt/β-catenin signaling pathway

AimsThe current study aimed to elucidate the neurotoxic potential of DOX to induce AD-like pathology paying attention to the role of wingless-integrated/β-catenin (Wnt/β-catenin) signaling pathway. A major aim was to evaluate the efficacy of infliximab (IFX) either individually or in combination with 2-mercaptoethane sulfonate sodium (MESNA) on the DOX-induced neurotoxicity in rats. MethodologyAD-like pathology was induced in adult male Wistar rats by intraperitoneal (i.p.) administration of DOX at a dose of 3.5 mg/kg twice a week for 3 weeks. DOX-injected rats were then treated with either INF at a single dose of 5 mg/kg i.p. (IFX group), MESNA at a dose of 160 mg/kg/day i.p. for 4 weeks (MESNA group) or their combination at the same specified doses (INF + MESNA group). At the end of the study period, behavioral assessment was performed and the brain tissue samples were harvested at sacrifice. Key findingsDOX-treated rats significantly exhibited AD-like brain injury, increased amyloid burden, enhanced neuroinflammation and apoptosis, and multifocal histological injury in the cerebral cortex with widespread vacuolations. IFX and MESNA significantly reversed all the aforementioned detrimental effects in the DOX-treated rats. SignificanceThe study has provided sufficient evidence of the potential of IFX and/or MESNA to ameliorate the DOX-induced neurotoxicity, with the best improvement observed with their combined administration. A new insight has been introduced into the critical role of Wnt/β-catenin activation.

Investigating P2X7R-mediated inflammatory signalling in Alzheimer's disease.

Neuroinflammation is thought to contribute to the onset and/or progression of Alzheimer´s disease (AD). Astrocytes and microglia sense danger-associated molecules (e.g. Aβ species, ATP) through membrane receptors including the purinergic receptor P2X7 (P2X7R). These interactions activate pro-inflammatory pathways and lead to the release of cytokines that participate in damaging inter-cellular cascades. Inhibition of P2X7R in AD models ameliorates cognitive deficits, pointing towards a neuroprotective effect of P2X7R blockade in vivo potentially associated with the modulation of inflammatory responses. However, the action of P2X7R and downstream signals on tau-mediated neurodegeneration in AD remains elusive. We used biochemical and immunohistochemical methods in combination with in-situ hybridization technology (RNAscope) in post-mortem AD and control (Braak 0-VI) BA9 prefrontal cortex to examine early changes in P2X7R expression, determine the spatial pattern of P2X7R activation relative to Aβ and pathological tau accumulation, and evaluate the association between P2X7R and local inflammatory responses. Primary glial and organotypic slice cultures are being used to model glial responses to physiological Aβ species and assess downstream effects on neurons, including alterations in tau and synapse health. We found elevated levels of P2X7R from Braak stage II relative to controls accompanied by an increased amyloid burden, synaptic mislocalization of tau and an altered astrocyte reactivity. P2X7R was markedly expressed in astrocytes surrounding AD hallmarks and also in disease-associated microglia neighbouring Aβ plaques. Investigation of inflammatory mediators linked with P2X7R-positive glia revealed higher activation of the NLRP3 inflammasome and NFkB pathways with disease progression. Preliminary data from in vitro and ex vivo models show inflammatory changes and tau redistribution to the synapses following stimulation with oligomeric Aß. These data suggest that P2X7R expression and activation are altered in the early stages of AD, prior to marked synapse loss. Ongoing studies aim to determine if the blockade of P2X7R-mediated inflammatory signals has benefits for tau-associated neurodegeneration in AD models.