Alzheimer's disease neuropathologic change, Lewy body disease, and vascular brain injury in clinic- and community-based samples.
Ontology highlight
ABSTRACT:
SUBMITTER: Brenowitz WD
PROVIDER: S-EPMC5385292 | biostudies-literature | 2017 May
REPOSITORIES: biostudies-literature
Publications
Alzheimer's disease neuropathologic change, Lewy body disease, and vascular brain injury in clinic- and community-based samples.
Brenowitz Willa D WD Keene C Dirk CD Hawes Stephen E SE Hubbard Rebecca A RA Longstreth W T WT Woltjer Randy L RL Crane Paul K PK Larson Eric B EB Kukull Walter A WA
Neurobiology of aging 20170130
We examined the relationships between Alzheimer's disease neuropathologic change (ADNC), Lewy body disease (LBD), and vascular brain injury (VBI) in 2 large autopsy samples. Because findings may differ between study populations, data came from U.S. Alzheimer's Disease Centers contributing to the National Alzheimer's Coordinating Center (n = 2742) and from the population-based Adult Changes in Thought study (n = 499). Regardless of study population, over 50% of participants with ADNC had co-occur ...[more]
Similar Datasets
Project description:While plasma biomarkers for Alzheimer's disease (AD) are increasingly being evaluated for clinical diagnosis and prognosis, few population-based autopsy studies have evaluated their utility in the context of predicting neuropathological changes. Our goal was to investigate the utility of clinically available plasma markers in predicting Braak staging, neuritic plaque score, Thal phase, and overall AD neuropathological change (ADNC).We utilized a population-based prospective study of 350 participants with autopsy and antemortem plasma biomarker testing using clinically available antibody assay (Quanterix) consisting of Aβ42/40 ratio, p-tau181, GFAP, and NfL. We utilized a variable selection procedure in cross-validated (CV) logistic regression models to identify the best set of plasma predictors along with demographic variables, and a subset of neuropsychological tests comprising the Mayo Clinic Preclinical Alzheimer Cognitive Composite (Mayo-PACC). ADNC was best predicted with plasma GFAP, NfL, p-tau181 biomarkers along with APOE ε4 carrier status and Mayo-PACC cognitive score (CV AUC = 0.798). Braak staging was best predicted using plasma GFAP, p-tau181, and cognitive scores (CV AUC = 0.774). Neuritic plaque score was best predicted using plasma Aβ42/40 ratio, p-tau181, GFAP, and NfL biomarkers (CV AUC = 0.770). Thal phase was best predicted using GFAP, NfL, p-tau181, APOE ε4 carrier status and Mayo-PACC cognitive score (CV AUC = 0.754). We found that GFAP and p-tau provided non-overlapping information on both neuritic plaque and Braak stage scores whereas Aβ42/40 and NfL were mainly useful for prediction of neuritic plaque scores. Separating participants by cognitive status improved predictive performance, particularly when plasma biomarkers were included. Plasma biomarkers can differentially inform about overall ADNC pathology, Braak staging, and neuritic plaque score when combined with demographics and cognitive variables and have significant utility for earlier detection of AD.
| S-EPMC10478071 | biostudies-literature
Project description:ObjectiveWe evaluated disruption of the white matter (WM) network related with Alzheimer's disease (AD) and Lewy body disease (LBD), which includes Parkinson's disease and dementia with Lewy bodies.MethodsWe consecutively recruited 37 controls and 77 patients with AD-related cognitive impairment (ADCI) and/or LBD-related cognitive impairment (LBCI). Diagnoses of ADCI and LBCI were supported by amyloid PET and dopamine transporter PET, respectively. There were 22 patients with ADCI, 19 patients with LBCI, and 36 patients with mixed ADCI/LBCI. We investigated the relationship between ADCI, LBCI, graph theory-based network measures on diffusion tensor images, and cognitive dysfunction using general linear models after controlling for age, sex, education, deep WM hyperintensities (WMH), periventricular WMH, and intracranial volume.ResultsLBCI, especially mixed with ADCI, was associated with increased normalized path length and decreased normalized global efficiency. LBCI was related to the decreased nodal degree of left caudate, which was further associated with broad cognitive dysfunction. Decreased left caudate nodal degree was associated with decreased fractional anisotropy (FA) in the brain regions vulnerable to LBD. Compared with the control group, the LBCI group had an increased betweenness centrality in the occipital nodes, which was associated with decreased FA in the WM adjacent to the striatum and visuospatial dysfunction.ConclusionConcomitant ADCI and LBCI are associated with the accentuation of LBCI-related WM network disruption centered in the left caudate nucleus. The increase of occipital betweenness centrality could be a characteristic biologic change associated with visuospatial dysfunction in LBCI.
| S-EPMC8119831 | biostudies-literature
Project description:Alzheimer's disease (AD) is the most common cause of dementia with advancing age as its strongest risk factor. AD neuropathologic change (ADNC) is known to be associated with numerous DNA methylation changes in the human brain, but the oldest old (> 90 years) have so far been underrepresented in epigenetic studies of ADNC. Our study participants were individuals aged over 90 years (n = 47) from The 90+ Study. We analyzed DNA methylation from bulk samples in eight precisely dissected regions of the human brain: middle frontal gyrus, cingulate gyrus, entorhinal cortex, dentate gyrus, CA1, substantia nigra, locus coeruleus and cerebellar cortex. We deconvolved our bulk data into cell-type-specific (CTS) signals using computational methods. CTS methylation differences were analyzed across different levels of ADNC. The highest amount of ADNC related methylation differences was found in the dentate gyrus, a region that has so far been underrepresented in large scale multi-omic studies. In neurons of the dentate gyrus, DNA methylation significantly differed with increased burden of amyloid beta (Aβ) plaques at 5897 promoter regions of protein-coding genes. Amongst these, higher Aβ plaque burden was associated with promoter hypomethylation of the Presenilin enhancer 2 (PEN-2) gene, one of the rate limiting genes in the formation of gamma-secretase, a multicomponent complex that is responsible in part for the endoproteolytic cleavage of amyloid precursor protein into Aβ peptides. In addition to novel ADNC related DNA methylation changes, we present the most detailed array-based methylation survey of the old aged human brain to date. Our open-sourced dataset can serve as a brain region reference panel for future studies and help advance research in aging and neurodegenerative diseases.
| S-EPMC9710143 | biostudies-literature
Project description:AimsLewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but comorbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here we use digital histological methods to test the association between hippocampal SYN pathology and the distribution of tau and amyloid-beta (Aβ) pathology in LBD and contrast with AD subjects. We also correlate pathologic burden with antemortem episodic memory testing.MethodsHippocampal sections from 49 autopsy-confirmed LBD cases, 30 with no/low AD copathology (LBD - AD) and 19 with moderate/severe AD copathology (LBD + AD), and 30 AD patients were stained for SYN, tau, and Aβ. Sections underwent digital histological analysis of subfield pathological burden which was correlated with antemortem memory testing.ResultsLBD - AD and LBD + AD had similar severity and distribution of SYN pathology (P > 0.05), CA2/3 being the most affected subfield (P < 0.02). In LBD, SYN correlated with tau across subfields (R = 0.49, P < 0.001). Tau burden was higher in AD than LBD + AD (P < 0.001), CA1/subiculum and entorhinal cortex (ERC) being most affected regions (P = 0.04 to <0.01). However, tau pathology in LBD - AD was greatest in CA2/3, which was equivalent to LBD + AD. Aβ severity and distribution was similar between LBD + AD and AD. Total hippocampal tau and CA2/3 tau was inversely correlated with memory performance in LBD (R = -0.52, -0.69, P = 0.04, 0.009).ConclusionsOur findings suggest that tau burden in hippocampal subfields may map closely with the distribution of SYN pathology in subfield CA2/3 in LBD diverging from traditional AD and contribute to episodic memory dysfunction in LBD.
| S-EPMC7787184 | biostudies-literature
Project description:Comorbid Lewy body pathology is very common in Alzheimer's disease and may confound clinical trial design, yet there is no in vivo test to identify patients with this. Tissue (and/or radioligand imaging) studies have shown cardiac sympathetic denervation in Parkinson's disease and dementia with Lewy bodies, but this has not been explored in Alzheimer's subjects with Lewy bodies not meeting dementia with Lewy bodies clinicopathological criteria. To determine if Alzheimer's disease with Lewy bodies subjects show sympathetic cardiac denervation, we analysed epicardial and myocardial tissue from autopsy-confirmed cases using tyrosine hydroxylase and neurofilament immunostaining. Comparison of tyrosine hydroxylase fibre density in 19 subjects with Alzheimer's disease/dementia with Lewy bodies, 20 Alzheimer's disease with Lewy bodies, 12 Alzheimer's disease subjects without Lewy body disease, 19 Parkinson's disease, 30 incidental Lewy body disease and 22 cognitively normal without Alzheimer's disease or Lewy body disease indicated a significant group difference (P < 0.01; Kruskal-Wallis analysis of variance) and subsequent pair-wise Mann-Whitney U tests showed that Parkinson's disease (P < 0.05) and Alzheimer's disease/dementia with Lewy bodies (P < 0.01) subjects, but not Alzheimer's disease with Lewy bodies subjects, had significantly reduced tyrosine hydroxylase fibre density as compared with cognitively normal. Both Parkinson's disease and Alzheimer's disease/dementia with Lewy bodies subjects also showed significant epicardial losses of neurofilament protein-immunoreactive nerve fibre densities within the fibre bundles as compared with cognitively normal subjects (P < 0.01) and both groups showed high pathologic alpha-synuclein densities (P < 0.0001). Cardiac alpha-synuclein densities correlated significantly with brain alpha-synuclein (P < 0.001), while cardiac tyrosine hydroxylase and neurofilament immunoreactive nerve fibre densities were negatively correlated with the densities of both brain and cardiac alpha-synuclein, as well as Unified Parkinson's Disease Rating Scale scores (P < 0.05). The clear separation of Alzheimer's disease/dementia with Lewy bodies subjects from Alzheimer's disease and cognitively normal, based on cardiac tyrosine hydroxylase fibre density, is the first report of a statistically significant difference between these groups. Our data do not show significant sympathetic cardiac denervation in Alzheimer's disease with Lewy bodies, but strongly confirm that cardiac nuclear imaging with a noradrenergic radioligand is worthy of further study as a potential means to separate Alzheimer's disease from Alzheimer's disease/dementia with Lewy bodies during life.
| S-EPMC7008146 | biostudies-literature
Project description:We examined the effect of vascular or Lewy body co-pathologies in subjects with autopsy-confirmed Alzheimer's disease (AD) on the rate of cognitive and functional decline and transition to dementia.In an autopsy sample of prospectively characterized subjects from the National Alzheimer's Coordinating Center database, neuropathology diagnosis was used to define the groups of pure AD (pAD, n = 84), mixed vascular and AD (ADV, n = 54), and mixed Lewy body disease and AD (ADLBD, n = 31). Subjects had an initial Clinical Dementia Rating-Global (CDR-G) score <1, Mini-Mental State Examination ?15, a final visit CDR-G >1, ?3 evaluations, and Braak tangle stage ?III. We compared the rate of cognitive and functional decline between the groups.The rate of functional and cognitive decline was lower for ADV, and ADV patients had less severe deficits on CDR-G and the CDR-Sum of Boxes scores at the last visit than pAD and ADLBD patients. No significant differences were noted between ADLBD and pAD patients. After controlling for age at death, the odds of reaching CDR ?1 at the last visit were lower in the ADV subjects compared to the pAD subjects.The mean rate of functional and cognitive decline among ADV subjects was slower than among either pAD or ADLBD patients. Vascular pathology did not increase the odds of attaining CDR ?1 when occurring with AD in this national cohort.
| S-EPMC5451902 | biostudies-literature
Project description:IntroductionAn estimated 50% of patients with Lewy body dementias (LBD), including Parkinson's disease dementia (PDD) and Dementia with Lewy bodies (DLB), have co-occurring Alzheimer's disease (AD) that is associated with worse prognosis. This study tests an automated analysis of natural speech as an inexpensive, non-invasive screening tool for AD co-pathology in biologically-confirmed cohorts of LBD patients with AD co-pathology (SYN + AD) and without (SYN-AD).MethodsWe analyzed lexical-semantic and acoustic features of picture descriptions using automated methods in 22 SYN + AD and 38 SYN-AD patients stratified using AD CSF biomarkers or autopsy diagnosis. Speech markers of AD co-pathology were identified using best subset regression, and their diagnostic discrimination was tested using receiver operating characteristic. ANCOVAs compared measures between groups covarying for demographic differences and cognitive disease severity. We tested relations with CSF tau levels, and compared speech measures between PDD and DLB clinical disorders in the same cohort.ResultsAge of acquisition of nouns (p = 0.034, |d| = 0.77) and lexical density (p = 0.0064, |d| = 0.72) were reduced in SYN + AD, and together showed excellent discrimination for SYN + AD vs. SYN-AD (95% sensitivity, 66% specificity; AUC = 0.82). Lower lexical density was related to higher CSF t-Tau levels (R = -0.41, p = 0.0021). Clinically-diagnosed PDD vs. DLB did not differ on any speech features.ConclusionAD co-pathology may result in a deviant natural speech profile in LBD characterized by specific lexical-semantic impairments, not detectable by clinical disorder diagnosis. Our study demonstrates the potential of automated digital speech analytics as a screening tool for underlying AD co-pathology in LBD.
| S-EPMC9680016 | biostudies-literature
Project description:ObjectiveAlzheimer's disease neuropathologic change and alpha-synucleinopathy commonly co-exist and contribute to the clinical heterogeneity of dementia. Here, we examined tau epitopes marking various stages of tangle maturation to test the hypotheses that tau maturation is more strongly associated with beta-amyloid compared to alpha-synuclein, and within the context of mixed pathology, mature tau is linked to Alzheimer's disease clinical phenotype and negatively associated with Lewy body dementia.MethodsWe used digital histology to measure percent area-occupied by pathology in cortical regions among individuals with pure Alzheimer's disease neuropathologic change, pure alpha-synucleinopathy, and a co-pathology group with both Alzheimer's and alpha-synuclein pathologic diagnoses. Multiple tau monoclonal antibodies were used to detect early (AT8, MC1) and mature (TauC3) epitopes of tangle progression. We used linear/logistic regression to compare groups and test the association between pathologies and clinical features.ResultsThere were lower levels of tau pathology (β = 1.86-2.96, p < 0.001) across all tau antibodies in the co-pathology group compared to the pure Alzheimer's pathology group. Among individuals with alpha-synucleinopathy, higher alpha-synuclein was associated with greater early tau (AT8 β = 1.37, p < 0.001; MC1 β = 1.2, p < 0.001) but not mature tau (TauC3 p = 0.18), whereas mature tau was associated with beta-amyloid (β = 0.21, p = 0.01). Finally, lower tau, particularly TauC3 pathology, was associated with lower frequency of both core clinical features and categorical clinical diagnosis of dementia with Lewy bodies.InterpretationMature tau may be more closely related to beta-amyloidosis than alpha-synucleinopathy, and pathophysiological processes of tangle maturation may influence the clinical features of dementia in mixed Lewy-Alzheimer's pathology.
| S-EPMC10963284 | biostudies-literature
Project description:Fibrinogen is reportedly associated with neurodegenerative diseases (NDs), but the underlying causality remains controversial. Using Mendelian randomization (MR), this study aimed to assess the causal association between fibrinogen and Alzheimer's disease (AD), Parkinson's disease (PD), and Lewy body dementia (LBD). Genetic variants associated with fibrinogen and γ-fibrinogen were selected and used as instrumental variables. The effect estimates of the main analysis were obtained by inverse-variance weighting (IVW), complemented by sensitivity analyses to verify model assumptions, and multivariable MR was conducted to control for potential pleiotropic effect. Two-step MR was performed to assess the causal association through mediators. The main analysis suggested no causal association between genetically predicted plasma fibrinogen and γ-fibrinogen levels and the risk of AD, PD, and LBD. The effect estimates did not change in the follow-up sensitivity analyses and MVMR. However, the two-step MR analysis provides evidence that fibrinogen may contribute to the risk of AD via CRP levels. There was an inverse effect of adult height levels on the risk of AD. Our results support the effects of fibrinogen on the risk of AD through increasing plasma CRP levels. Our study found no evidence to support the effects of genetically determined fibrinogen and γ-fibrinogen levels on the risk of PD and LBD. Additionally, our findings suggested an inverse association between genetically determined adult height levels and the risk of AD. Future studies are needed to elucidate the underlying mechanisms and their clinical applications.
| S-EPMC9300417 | biostudies-literature
Project description:The vast majority of archived research and clinical pathological specimens are stored in the form of formalin fixed, paraffin-embedded (FFPE) tissues, but, unlike fresh frozen tissue samples, highly quantitative measures in FFPE tissues are limited to immunohistochemical and immunofluorescence thresholding image analysis studies, cell counting, and ordinal ranking systems. This poses a significant obstacle for clinical investigations that aim to correlate diagnostic markers of neurodegenerative diseases like Alzheimer's disease (AD) with parameters like age, gender, drug exposures, genotype, disease stage, co-morbidities, or environmental factors. To overcome this limitation, we have developed Luminex-based techniques and protocols for the quantification of amyloid ? and hyperphosphorylated Tau in FFPE brain sections. We validated the Luminex assay in FFPE sections from prefrontal cortex, hippocampus, and neostriatum from 30 cases that underwent prior neuropathological diagnostic assessment of AD following the current NIA-AA recommendations for AD: 10 cases diagnosed as not or low, 10 cases as intermediate, and 10 cases as high AD neuropathologic change. Consistent with the neuropathologic assessment, Luminex assay detected high amounts of amyloid beta in the frontal cortex and striatum, and high amounts of hyperphosphorylated Tau in the frontal cortex and hippocampus, of cases with high AD neuropathologic change. This assay can be expanded to detect diverse antigenic targets of interest, as we show here with IBA1 and GFAP. This novel approach supports multiplexed highly quantitative, molecularly specific neuropathology measures to further explore mechanisms of neurodegeneration in AD.
| S-EPMC6586549 | biostudies-literature