scholarly journals Plasma p-tau181 Level Predicts Neurodegeneration and Progression to Alzheimer's Dementia: A Longitudinal Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Yan-Li Wang ◽  
Jinglong Chen ◽  
Zhong-Li Du ◽  
Haoyi Weng ◽  
Yuan Zhang ◽  
...  
Keyword(s):  
Sex Education ◽  
Cox Regression ◽  
Apoe Genotype ◽  
Hippocampal Volume ◽  
White Matter Hyperintensity ◽  
Csf Biomarkers ◽  
Linear Regression Models ◽  
Local Regression ◽  
Prodromal Ad ◽  
Risk Of Progression

Background: Plasma-based biomarkers would be potential biomarkers for early diagnosis of Alzheimer's disease (AD) because they are more available and cost-effective than cerebrospinal fluid (CSF) or neuroimaging. Therefore, we aimed to evaluate whether phosphorylated tau181 (p-tau181) in plasma could be an accurate AD predictor.Methods: Participants from the ADNI database included 185 cognitively unimpaired subjects with negative Aβ (CU–), 66 subjects with pre-clinical AD (CU with positive Aβ), 164 subjects with mild cognitive impairment with negative Aβ (MCI–), 254 subjects with prodromal AD (MCI with positive Aβ), and 98 subjects with dementia. Multiple linear regression models, linear mixed-effects models, and local regression were used to explore cross-sectional and longitudinal associations of plasma p-tau181 with cognition, neuroimaging, or CSF biomarkers adjusted for age, sex, education, and APOE genotype. Besides, Kaplan–Meier and adjusted Cox-regression model were performed to predict the risk of progression to dementia. Receiver operating characteristic analyses were performed to evaluate the predictive value of p-tau181.Results: Plasma p-tau181 level was highest in AD dementia, followed by prodromal AD and pre-clinical AD. In pre-clinical AD, plasma p-tau181 was negatively associated with hippocampal volume (β = −0.031, p-value = 0.017). In prodromal AD, plasma p-tau181 was associated with decreased global cognition, executive function, memory, language, and visuospatial functioning (β range −0.119 to −0.273, p-value < 0.05) and correlated with hippocampal volume (β = −0.028, p-value < 0.005) and white matter hyperintensity volume (WMH) volume (β = 0.02, p-value = 0.01). In AD dementia, increased plasma p-tau181 was associated with worse memory. In the whole group, baseline plasma p-tau181 was significantly associated with longitudinal increases in multiple neuropsychological test z-scores and correlated with AD-related CSF biomarkers and hippocampal volume (p-value < 0.05). Meanwhile, CU or MCI with high plasma p-tau181 carried a higher risk of progression to dementia. The area under the curve (AUC) of the adjusted model (age, sex, education, APOE genotype, and plasma p-tau181) was 0.78; that of additionally included CSF biomarkers was 0.84.Conclusions: Plasma p-tau181 level is related to multiple AD-associated cognitive domains and AD-related CSF biomarkers at the clinical stages of AD. Moreover, plasma p-tau181 level is related to the change rates of cognitive decline and hippocampal atrophy. Thus, this study confirms the utility of plasma p-tau181 as a non-invasive biomarker for early detection and prediction of AD.

scholarly journals CSF biomarkers in Olmsted County

Neurology ◽  
2020 ◽  
Vol 95 (3) ◽  
pp. e256-e267
Author(s):  
Argonde C. Van Harten ◽  
Heather J. Wiste ◽  
Stephen D. Weigand ◽  
Michelle M. Mielke ◽  
Walter K. Kremers ◽  
...  
Keyword(s):  
Sex Education ◽  
Csf Biomarkers ◽  
Latent Classes ◽  
Amyloid Pet ◽  
Strong Positive Correlation ◽  
Olmsted County ◽  
Linear Regression Models ◽  
Positive Correlation ◽  
Group 2 ◽  
T Tau

ObjectiveWe studied interrelationships between CSF biomarkers and associations with APOE ε4 genotype, demographic variables, vascular variables, and clinical diagnosis in Olmsted County, Minnesota.MethodsWe included 774 Mayo Clinic Study of Aging participants (693 cognitively unimpaired [CU]; 71 with mild cognitive impairment [MCI]). CSF β-amyloid 42 (Aβ42), total tau (t-tau), and hyperphosphorylated tau (p-tau) were analyzed using Aβ42 CSF, t-tau CSF, and p-tau (181P) CSF electrochemiluminescence immunoassays. Bivariate mixture models were used to evaluate latent classes. We used linear regression models to evaluate independent associations of APOE ε4, demographic factors, cardiovascular risk, and diagnosis with CSF biomarker levels. Results were weighted back to the Olmsted County population.ResultsInterrelationships between CSF Aβ42 and p-tau/t-tau were consistent with 2 latent classes in the general population. In subgroup 1 (n = 547 [71%]), we found a strong positive correlation between Aβ42 and p-tau (ρ = 0.81), while the correlation was much smaller in group 2 (ρ = 0.26, n = 227 [29%]). Group 2 was associated with older age, APOE ε4 genotype, a diagnosis of MCI, and elevated amyloid PET. Overall, APOE ε4 genotype and MCI were associated with Aβ42, while age was associated with p-tau/t-tau. There were no associations with sex, education, or vascular risk.ConclusionWe hypothesize the population without dementia can be subdivided into participants with and without biological Alzheimer disease (AD) based on the combination of CSF Aβ42 and p-tau/t-tau (represented also by the p-tau/t-tau/Aβ42 ratio). In those without biological AD, common factors such as CSF dynamics may cause a positive correlation between CSF Aβ42 and p-tau/t-tau, while AD leads to dissociation of these proteins.

scholarly journals Hippocampal Complex Atrophy in Poststroke and Mild Cognitive Impairment

2015 ◽  
Vol 35 (11) ◽  
pp. 1729-1737 ◽  
Author(s):  
Per Selnes ◽  
Ramune Grambaite ◽  
Mariano Rincon ◽  
Atle Bjørnerud ◽  
Leif Gjerstad ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Early Stage ◽  
Amyloid Β ◽  
Hippocampal Volume ◽  
White Matter Hyperintensity ◽  
Csf Biomarkers ◽  
Delayed Recall ◽  
Pathologic Processes ◽  
Hippocampal Complex

To investigate putative interacting or distinct pathways for hippocampal complex substructure (HCS) atrophy and cognitive affection in early-stage Alzheimer's disease (AD) and cerebrovascular disease (CVD), we recruited healthy controls, patients with mild cognitive impairment (MCI) and poststroke patients. HCSs were segmented, and quantitative white-matter hyperintensity (WMH) load and cerebrospinal fluid (CSF) amyloid-β concentrations were determined. The WMH load was higher poststroke. All examined HCSs were smaller in amyloid-positive MCI than in controls, and the subicular regions were smaller poststroke. Memory was reduced in amyloid-positive MCI, and psychomotor speed and executive function were reduced in poststroke and amyloid-positive MCI. Size of several HCS correlated with WMH load poststroke and with CSF amyloid-β concentrations in MCI. In poststroke and amyloid-positive MCI, neuropsychological function correlated with WMH load and hippocampal volume. There are similar patterns of HCS atrophy in CVD and early-stage AD, but different HCS associations with WMH and CSF biomarkers. WMHs add to hippocampal atrophy and the archetypal AD deficit delayed recall. In line with mounting evidence of a mechanistic link between primary AD pathology and CVD, these additive effects suggest interacting pathologic processes.

scholarly journals White matter hyperintensities and CSF Alzheimer disease biomarkers in preclinical Alzheimer disease

Neurology ◽  
2019 ◽  
Vol 94 (9) ◽  
pp. e950-e960 ◽  
Author(s):  
Anja Soldan ◽  
Corinne Pettigrew ◽  
Yuxin Zhu ◽  
Mei-Cheng Wang ◽  
Abhay Moghekar ◽  
...  
Keyword(s):  
White Matter ◽  
Alzheimer Disease ◽  
Symptom Onset ◽  
White Matter Hyperintensities ◽  
Cox Regression ◽  
Rate Of Change ◽  
Csf Biomarkers ◽  
Risk Of Progression ◽  
Fluid Attenuated Inversion Recovery ◽  
T Tau

ObjectiveRecent studies suggest that white matter hyperintensities (WMH) on MRI, which primarily reflect small vessel cerebrovascular disease, may play a role in the evolution of Alzheimer disease (AD). In a longitudinal study, we investigated whether WMH promote the progression of AD pathology, or alter the association between AD pathology and risk of progression from normal cognition to mild cognitive impairment (MCI).MethodsTwo sets of analyses were conducted. The relationship between whole brain WMH load, based on fluid-attenuated inversion recovery MRI, obtained in initially cognitively normal participants (n = 274) and time to onset of symptoms of MCI (n = 60) was examined using Cox regression models. In a subset of the participants with both MRI and CSF data (n = 204), the interaction of WMH load and CSF AD biomarkers was also evaluated.ResultsBaseline WMH load interacted with CSF total tau (t-tau) with respect to symptom onset, but not with CSF β-amyloid 1–42 or phosphorylated tau (p-tau) 181. WMH volume was associated with time to symptom onset of MCI among individuals with low t-tau (hazard ratio [HR] 1.35, confidence interval [CI] 1.06–1.73, p = 0.013), but not those with high t-tau (HR 0.86, CI 0.56–1.32, p = 0.47). The rate of change in the CSF biomarkers over time was not associated with the rate of change in WMH volumes.ConclusionThese results suggest that WMH primarily affect the risk of progression when CSF measures of neurodegeneration or neuronal injury (as reflected by t-tau) are low. However, CSF biomarkers of amyloid and p-tau and WMH appear to have largely independent and nonsynergistic effects on the risk of progression to MCI.

scholarly journals Associations of the Mediterranean diet with cognitive and neuroimaging phenotypes of dementia in healthy older adults

2019 ◽  
Vol 109 (2) ◽  
pp. 361-368 ◽  
Author(s):  
Aimee J Karstens ◽  
Lisa Tussing-Humphreys ◽  
Liang Zhan ◽  
Niranjini Rajendran ◽  
Jamie Cohen ◽  
...  
Keyword(s):  
Older Adults ◽  
Information Processing ◽  
Executive Functioning ◽  
Mediterranean Diet ◽  
Sex Education ◽  
Structural Integrity ◽  
Community Dwelling ◽  
White Matter Hyperintensity ◽  
Intracranial Volume ◽  
Linear Regression Models

ABSTRACTBackgroundAccumulating evidence suggests that higher Mediterranean diet (MedDiet) adherence is associated with higher global cognitive performance and brain structural integrity as well as decreased risk of Alzheimer disease (AD) and vascular dementia (VaD).ObjectivesWe directly examined cross-sectional associations between the MedDiet and cognitive and neuroimaging phenotypes associated with AD and VaD (separately) in a cohort of nondemented, nondepressed older adults.MethodsCommunity-dwelling older adults (n = 82; aged ∼68.8 y; 50% female, 50% minority) underwent dietary (Block Food Frequency Questionnaire 2005) and neuropsychological assessments and neuroimaging. MedDiet scores were quantified with the use of published criteria, and participants were divided into High and Low (median split) adherence groups. We focused our neuropsychological investigation on cognitive phenotypes primarily associated with AD [i.e., learning and memory (L&M)] and VaD (i.e., information processing and executive functioning). AD neuroimaging phenotypes consisted of hippocampal and dentate gyrus volumes quantified using T1-weighted images and the FreeSurfer 6.0 segmentation pipeline (http://surfer.nmr.mgh.harvard.edu). The VaD neuroimaging phenotype consisted of total white matter hyperintensity (WMH) volumes quantified using combined T1-weighted and T2-fluid-attenuated inversion recovery images. Neuroimaging metrics were adjusted for total intracranial volume. Separate multivariable linear regression models controlling for age, sex, education, body mass index, and caloric intake examined the associations between MedDiet groups (High compared with Low) and cognitive and neuroimaging outcomes.ResultsWhen compared with the Low MedDiet group, the High MedDiet group was associated with better L&M performance and larger dentate gyri. MedDiet adherence was not associated with information processing, executive functioning, or WMH.ConclusionResults highlight the association between increasing MedDiet adherence and specific cognitive and neuroimaging phenotypes that, when altered, are associated with AD.

The Effects of Mean of Visit-to-Visit Blood Pressure on Incident Brain Vascular Lesions and Functional-Cognitive Decline

2021 ◽  
pp. 1-12
Author(s):  
Bibek Gyanwali ◽  
Celestine Xue Ting Cai ◽  
Christopher Chen ◽  
Henri Vrooman ◽  
Chuen Seng Tan ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cognitive Decline ◽  
Hippocampal Volume ◽  
Intracranial Stenosis ◽  
Vascular Lesions ◽  
Linear Regression Models ◽  
Volume Functional ◽  
Mri Scans ◽  
The Mean

Background: Cerebrovascular disease (CeVD) is an underlying cause of cognitive impairment and dementia. Hypertension is a known risk factor of CeVD, but the effects of mean of visit-to-visit blood pressure (BP) on incident CeVD and functional-cognitive decline remains unclear. Objective: To determine the association between mean of visit-to-visit BP with the incidence and progression of CeVD [white matter hyperintensities (WMH), infarcts (cortical infarcts and lacunes), cerebral microbleeds (CMBs), intracranial stenosis, and hippocampal volume] as well as functional-cognitive decline over 2 years of follow-up. Methods: 373 patients from a memory-clinic underwent BP measurements at baseline, year 1, and year 2. The mean of visit-to-visit systolic BP, diastolic BP, pulse pressure, and mean arterial pressure were calculated. Baseline and year 2 MRI scans were graded for WMH, infarcts, CMBs, intracranial stenosis, and hippocampal volume. Functional-cognitive decline was assessed using locally validated protocol. Logistic and linear regression models with odds ratios, mean difference, and 95%confidence interval were constructed to analyze associations of visit-to-visit BP on CeVD incidence and progression as well as functional-cognitive decline. Results: Higher mean of visit-to-visit diastolic BP was associated with WMH progression. Higher tertiles of diastolic BP was associated with WMH progression and incident CMBs. There was no association between mean of visit-to-visit BP measures with incident cerebral infarcts, intracranial stenosis, change in hippocampal volume, and functional-cognitive decline. Conclusion: These findings suggest the possibility of hypertension-related vascular brain damage. Careful monitoring and management of BP in elderly patients is essential to reduce the incidence and progression of CeVD.

scholarly journals Peripheral Markers of Vascular Endothelial Dysfunction Show Independent but Additive Relationships with Brain-Based Biomarkers in Association with Functional Impairment in Alzheimer’s Disease

2021 ◽  
pp. 1-13
Author(s):  
Jonathan D. Drake ◽  
Alison B. Chambers ◽  
Brian R. Ott ◽  
Lori A. Daiello ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Functional Impairment ◽  
Amyloid Β ◽  
Intercellular Adhesion Molecule ◽  
Csf Biomarkers ◽  
Linear Regression Models ◽  
Cognitively Normal

Background: Cerebrovascular dysfunction confers risk for functional decline in Alzheimer’s disease (AD), yet the clinical interplay of these two pathogenic processes is not well understood. Objective: We utilized Alzheimer’s Disease Neuroimaging Initiative (ADNI) data to examine associations between peripherally derived soluble cell adhesion molecules (CAMs) and clinical diagnostic indicators of AD. Methods: Using generalized linear regression models, we examined cross-sectional relationships of soluble plasma vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-Selectin to baseline diagnosis and functional impairment (clinical dementia rating sum-of-boxes, CDR-SB) in the ADNI cohort (n = 112 AD, n = 396 mild cognitive impairment (MCI), n = 58 cognitively normal). We further analyzed associations of these biomarkers with brain-based AD biomarkers in a subset with available cerebrospinal fluid (CSF) data (n = 351). p-values derived from main effects and interaction terms from the linear regressions were used to assess the relationship between independent and dependent variables for significance (significance level was set at 0.05 a priori for all analysis). Results: Higher mean VCAM-1 (p = 0.0026) and ICAM-1 (p = 0.0189) levels were found in AD versus MCI groups; however, not in MCI versus cognitively normal groups. Only VCAM-1 was linked with CDR-SB scores (p = 0.0157), and APOE ɛ4 genotype modified this effect. We observed independent, additive associations when VCAM-1 and CSF amyloid-β (Aβ 42), total tau, phosphorylated tau (P-tau), or P-tau/Aβ 42 (all <  p = 0.01) were combined in a CDR-SB model; ICAM-1 showed a similar pattern, but to a lesser extent. Conclusion: Our findings indicate independent associations of plasma-based vascular biomarkers and CSF biomarkers with AD-related clinical impairment.

scholarly journals Assessment of Outcome Predictors after First Attack of Optic Neuritis

2011 ◽  
Vol 38 (6) ◽  
pp. 887-895 ◽  
Author(s):  
Mansoureh Mamarabadi ◽  
Hadie Razjouyan ◽  
Fatemeh Mohammadi ◽  
Mehdi Moghaddasi
Keyword(s):  
Risk Factors ◽  
Optic Neuritis ◽  
Corticosteroid Therapy ◽  
Cox Regression ◽  
Female Gender ◽  
Cumulative Probability ◽  
High Dose ◽  
Risk Of Progression ◽  
Dose Corticosteroid ◽  
Iranian Patients

Background:Optic Neuritis (ON) is one of the most common clinically isolated syndromes which develops into clinically diagnosed Multiple Sclerosis (CDMS) over time.Objective:To assess the conversion rate of Iranian patients presenting with idiopathic ON to CDMS as well as monitoring potential demographic and clinical risk factors.Methods:Atotal of 219 patients' medical records of idiopathic ON from March 2001 to May 2009 were reviewed. Demographic findings, ophthalmologic characteristics on admission and discharge, diagnostic approaches, type and dosage of therapy were retrospectively reviewed. A structured telephone interview was then conducted to identify patients who had subsequently been diagnosed with MS. Survival analysis was used to evaluate the cumulative probability of MS conversion and contributory risk factors.Results:From the 219 ON patients, 109 [age 11-51, female: 81%] were followed up. Among the male gender the mean age of patients developing MS was significantly lower (P=0.01). In cox regression model, female sex (p=0.07), bilateral ON (p=0.003), MRI abnormalities (p <0.001) and high dose (5g) corticosteroid therapy (p<0.001) were identified as risk factors for the development of MS. The two and five year cumulative probability of developing MS were 27% and 45%, respectively.Conclusions:Idiopathic ON in Iranian patients carries higher risk of progression to MS compared to other Asian countries. MRI lesions are the strongest independent risk factor of developing CDMS. Bilateral ON, female gender and high dose corticosteroid therapy are also important factors in predicting CDMS development.

scholarly journals Testosterone modifies the effect of APOE genotype on hippocampal volume in middle-aged men

Neurology ◽  
2010 ◽  
Vol 75 (10) ◽  
pp. 874-880 ◽  
Author(s):  
M. S. Panizzon ◽  
R. Hauger ◽  
A. M. Dale ◽  
L. J. Eaves ◽  
L. T. Eyler ◽  
...  
Keyword(s):  
Apoe Genotype ◽  
Hippocampal Volume ◽  
Middle Aged

Abstract WMP14: Association of Systolic Blood Pressure, LDL Cholesterol, and Hgb A1c With White Matter Hyperintensity on MRI in the ACCORDION MIND Study

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Adam H de Havenon ◽  
Tanya Turan ◽  
Rebecca Gottesman ◽  
Sharon Yeatts ◽  
Shyam Prabhakaran ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Risk Factor ◽  
Regression Models ◽  
Ldl Cholesterol ◽  
Vascular Risk Factor ◽  
White Matter Hyperintensity ◽  
Vascular Risk ◽  
Linear Regression Models ◽  
Risk Factor Profile ◽  
The Mean

Introduction: While retrospective studies have shown that poor control of vascular risk factors is associated with progression of white matter hyperintensity (WMH), it has not been studied prospectively. Hypothesis: We hypothesize that higher systolic blood pressure (SBP) mean, LDL cholesterol, and Hgb A1c will be correlated with WMH progression in diabetics. Methods: This is a secondary analysis of the Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes Follow-on Study (ACCORDION). The primary outcome was WMH progression, evaluated by fitting linear regression models to the WMH volume on the month 80 MRI and adjusting for the WMH volume on the baseline MRI. The primary predictors were the mean values of SBP, LDL, and A1c from baseline to month 80. We defined a good vascular risk factor profile as mean SBP <120 mm Hg and mean LDL <120 mg/dL. Results: We included 292 patients, with a mean (SD) age of 62.6 (5.3) years and 55.8% male. The mean number of SBP, LDL, and A1c measurements per patient was 17, 5, and 12. We identified 86 (29.4%) patients with good vascular risk factor profile. In the linear regression models, mean SBP and LDL were associated with WMH progression and in a second fully adjusted model they both remained associated with WMH progression (Table). Those with a good vascular risk factor profile had less WMH progression (β Coefficient -0.80, 95% CI -1.42, -0.18, p=0.012). Conclusions: Our data reinforce prior research showing that higher SBP and LDL is associated with progression of WMH in diabetics, likely secondary to chronic microvascular ischemia, and suggest that control of these factors may have protective effects. This study has unique strengths, including prospective serial measurement of the exposures, validated algorithmic measurement methodology for WMH, and rigorous adjudication of study data. Clinical trials are needed to investigate the effect of vascular risk factor reduction on WMH progression.

Alzheimer’s Disease-Related Neuropathology Among Patients with Medication Treated Type 2 Diabetes in a Community-Based Autopsy Cohort

2021 ◽  
pp. 1-10
Author(s):  
Douglas Barthold ◽  
Laura E. Gibbons ◽  
Zachary A. Marcum ◽  
Shelly L. Gray ◽  
C. Dirk Keene ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Sex Education ◽  
Descriptive Analysis ◽  
Neurofibrillary Tangle ◽  
Apoe Genotype ◽  
Severity Index ◽  
Neuritic Plaque ◽  
Braak Stage ◽  
Total N

Background: Diabetes is a risk factor for Alzheimer’s disease and related dementias (ADRD). Epidemiologic evidence shows an association between diabetes medications and ADRD risk; cell and mouse models show diabetes medication association with AD-related neuropathologic change (ADNC). Objective: This hypothesis-generating analysis aimed to describe autopsy-measured ADNC for individuals who used diabetes medications. Methods: Descriptive analysis of ADNC for Adult Changes in Thought (ACT) Study autopsy cohort who used diabetes medications, including sulfonylureas, insulin, and biguanides; total N = 118. ADNC included amyloid plaque distribution (Thal phasing), neurofibrillary tangle (NFT) distribution (Braak stage), and cortical neuritic plaque density (CERAD score). We also examined quantitative measures of ADNC using the means of standardized Histelide measures of cortical PHF-tau and Aβ 1–42. Adjusted analyses control for age at death, sex, education, APOE genotype, and diabetes complication severity index. Results: Adjusted analyses showed no significant association between any drug class and traditional neuropathologic measures compared to nonusers of that class. In adjusted Histelide analyses, any insulin use was associated with lower mean levels of Aβ 1–42 (–0.57 (CI: –1.12, –0.02)) compared to nonusers. Five years of sulfonylureas and of biguanides use was associated with lower levels of Aβ 1–42 compared to nonusers (–0.15 (CI: –0.28, –0.02), –0.31 (CI: –0.54, –0.07), respectively). Conclusion: Some evidence exists that diabetes medications are associated with lower levels of Aβ 1–42, but not traditional measures of neuropathology. Future studies are needed in larger samples to build understanding of the mechanisms between diabetes, its medications, and ADRD, and to potentially repurpose existing medications for prevention or delay of ADRD.

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