scholarly journals Association of amyloid-β CSF/PET discordance and tau load 5 years later

Neurology ◽  
2020 ◽  
Vol 95 (19) ◽  
pp. e2648-e2657 ◽  
Author(s):  
Juhan Reimand ◽  
Lyduine Collij ◽  
Philip Scheltens ◽  
Femke Bouwman ◽  
Rik Ossenkoppele ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Amyloid Β ◽  
Csf Biomarkers ◽  
Tau Pathology ◽  
Cognitively Normal ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Tau Pet

ObjectiveTo investigate the association between discordant β-amyloid (Aβ) PET and CSF biomarkers at baseline and the emergence of tau pathology 5 years later.MethodsWe included 730 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants without dementia (282 cognitively normal, 448 mild cognitive impairment) with baseline [18F]florbetapir PET and CSF Aβ42 available. Aβ CSF/PET status was determined at baseline using established cutoffs. Longitudinal data were available for [18F]florbetapir (Aβ) PET (baseline to 4.3 ± 1.9 years), CSF (p)tau (baseline to 2.0 ± 0.1 years), cognition (baseline to 4.3 ± 2.0 years), and [18F]flortaucipir (tau) PET (measured 5.2 ± 1.2 years after baseline to 1.6 ± 0.7 years later). We used linear mixed modeling to study the association between Aβ CSF/PET status and tau pathology measured in CSF or using PET. We calculated the proportion of CSF+/PET− participants who during follow-up (1) progressed to Aβ CSF+/PET+ or (2) became tau-positive based on [18F]flortaucipir PET.ResultsAβ CSF+/PET+ (n = 318) participants had elevated CSF (p)tau levels and worse cognitive performance at baseline, while CSF+/PET− (n = 80) participants were overall similar to the CSF−/PET− (N = 306) group. Five years after baseline, [18F]flortaucipir PET uptake in the CSF+/PET− group (1.20 ± 0.13) did not differ from CSF−/PET− (1.18 ± 0.08, p = 0.69), but was substantially lower than CSF+/PET+ (1.48 ± 0.44, p < 0.001). Of the CSF+/PET− participants, 21/64 (33%) progressed to Aβ CSF+/PET+, whereas only one (3%, difference p < 0.05) became tau-positive based on [18F]flortaucipir PET.ConclusionsAβ load detectable by both CSF and PET seems to precede substantial tau deposition. Compared to participants with abnormal Aβ levels on both PET and CSF, the CSF+/PET− group has a distinctly better prognosis.

scholarly journals Amyloid-β CSF/PET discordance vs tau load 5 years later: It takes two to tangle

2020 ◽  
Author(s):  
Juhan Reimand ◽  
Lyduine Collij ◽  
Philip Scheltens ◽  
Femke Bouwman ◽  
Rik Ossenkoppele ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cognitive Performance ◽  
Amyloid Β ◽  
Csf Biomarkers ◽  
Tau Pathology ◽  
Cognitively Normal ◽  
Tau Pet ◽  
Mixed Modelling

AbstractOBJECTIVETo investigate the association between discordant amyloid-β PET and CSF biomarkers at baseline and the emergence of tau pathology 5 years later.METHODSWe included 730 ADNI participants without dementia (282 cognitively normal, 448 mild cognitive impairment) with baseline [18F]Florbetapir PET and CSF Aβ42 available. Amyloid-β CSF/PET status was determined at baseline using established cut-offs. Longitudinal data was available for [18F]florbetapir (Aβ) PET (baseline to 4.3±1.9 years), CSF (p)tau (baseline to 2.0±0.1 years), cognition (baseline to 4.3±2.0 years), and [18F]flortaucipir (tau) PET (measured 5.2±1.2 years after baseline to 1.6±0.7 years later). We used linear mixed modelling to study the association between amyloid-β CSF/PET status and tau pathology measured in CSF or using PET. Additionally, we calculated the proportion of CSF+/PET-participants who during follow-up (i) progressed to amyloid-β CSF+/PET+, and/or (ii) became tau-positive based on [18F]flortaucipir PET.RESULTSAmyloid-β CSF+/PET+ (N=318) participants had elevated CSF (p)tau levels and worse cognitive performance at baseline, while CSF+/PET-(N=80) participants were overall similar to the CSF-/PET-(N=306) group. Five years after baseline, [18F]flortaucipir PET uptake in the CSF+/PET-group (1.20±0.13) did not differ from CSF-/PET-(1.18±0.08, p=0.69), but was substantially lower than CSF+/PET+ (1.48±0.44, p<0.001). Of the CSF+/PET-subjects, 21/64 (33%) progressed to amyloid-β CSF+/PET+, whereas only one (3%, difference p<0.05) became tau-positive based on [18F]flortaucipir PET.CONCLUSIONSSufficient amyloid-β load detectable by both CSF and PET is required before substantial tau deposition emerges. Compared to participants with abnormal amyloid-β levels on PET and CSF, the CSF+/PET-group has a distinctly better prognosis.

The Role of Apolipoprotein E ε4 in Early and Late Mild Cognitive Impairment

2021 ◽  
Vol 84 (6) ◽  
pp. 472-480
Author(s):  
Yulin Luo ◽  
Li Tan ◽  
Joseph Therriault ◽  
Hua Zhang ◽  
Ying Gao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Apolipoprotein E ◽  
Amyloid Β ◽  
Disease Assessment ◽  
Tau Pathology ◽  
Ε4 Allele ◽  
State Examination

<b><i>Background:</i></b> Apolipoprotein E (<i>APOE</i>) ε4 is highly associated with mild cognitive impairment (MCI). However, the specific influence of <i>APOE</i> ε4 status on tau pathology and cognitive decline in early MCI (EMCI) and late MCI (LMCI) is poorly understood. Our goal was to evaluate the association of <i>APOE</i> ε4 with cerebrospinal fluid (CSF) tau levels and cognition in EMCI and LMCI patients in the Alzheimer’s Disease Neuroimaging Initiative database, and whether this association was mediated by amyloid-β (Aβ). <b><i>Methods:</i></b> Participants were 269 cognitively normal (CN), 262 EMCI, and 344 LMCI patients. They underwent CSF Aβ42 and tau detection, <i>APOE</i> ε4 genotyping, Mini-Mental State Examination, (MMSE), and Alzheimer’s disease assessment scale (ADAS)-cog assessments. Linear regressions were used to examine the relation of <i>APOE</i> ε4 and CSF tau levels and cognitive scores in persons with and without Aβ deposition (Aβ+ and Aβ−). <b><i>Results:</i></b> The prevalence of <i>APOE</i> ε4 is higher in EMCI and LMCI than in CN (<i>p</i> &#x3c; 0.001 for both), and in LMCI than in EMCI (<i>p</i> = 0.001). <i>APOE</i> ε4 allele was significantly higher in Aβ+ subjects than in Aβ− subjects (<i>p</i> &#x3c; 0.001). Subjects who had a lower CSF Aβ42 level and were <i>APOE</i> ε4-positive experienced higher levels of CSF tau and cognitive scores in EMCI and/or LMCI. <b><i>Conclusions:</i></b> An <i>APOE</i> ε4 allele is associated with increased CSF tau and worse cognition in both EMCI and LMCI, and this association may be mediated by Aβ. We conclude that <i>APOE</i> ε4 may be an important mediator of tau pathology and cognition in the early stages of AD.

Pontine Arteriolosclerosis and Locus Coeruleus Oxidative Stress Differentiate Resilience from Mild Cognitive Impairment in a Clinical Pathologic Cohort

2021 ◽  
Vol 80 (4) ◽  
pp. 325-335
Author(s):  
Sarah C Kelly ◽  
Peter T Nelson ◽  
Scott E Counts,
Keyword(s):  
Oxidative Stress ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Locus Coeruleus ◽  
Tau Pathology ◽  
Cognitively Normal ◽  
Correlation And Regression Analysis ◽  
Severity Scores ◽  
Stress Burden ◽  
Normal Cognition

Abstract Locus coeruleus (LC) neurodegeneration is associated with cognitive deterioration during the transition from normal cognition to mild cognitive impairment (MCI) and Alzheimer disease (AD). However, the extent to which LC degenerative processes differentiate cognitively normal, “resilient” subjects bearing a high AD pathological burden from those with MCI or AD remains unclear. We approached this problem by quantifying the number of LC neurons and the percentage of LC neurons bearing AT8 tau pathology, TDP-43 pathology, or a marker for DNA/RNA oxidative damage, in well-characterized subjects diagnosed as normal cognition-low AD pathology (NC-LP), NC-high AD pathology (NC-HP), MCI, or mild/moderate AD. In addition, the severity of pontine arteriolosclerosis in each subject was compared across the groups. There was a trend for a step-wise ∼20% loss of LC neuron number between the NC-LP, NC-HP and MCI subjects despite a successive, significant ∼80%–100% increase in tau pathology between these groups. In contrast, increasing pontine arteriolosclerosis severity scores and LC oxidative stress burden significantly separated the NC-LP/HP and MCI/AD groups via comparative, correlation, and regression analysis. Pontine perfusion, as well as LC neuronal metabolic and redox function, may impact noradrenergic LC modulation of cognition during the preclinical and prodromal stages of AD.

scholarly journals 18F-MK-6240 PET for early and late detection of neurofibrillary tangles

Brain ◽  
2020 ◽  
Vol 143 (9) ◽  
pp. 2818-2830 ◽  
Author(s):  
Tharick A Pascoal ◽  
Joseph Therriault ◽  
Andrea L Benedet ◽  
Melissa Savard ◽  
Firoza Z Lussier ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Amyloid Β ◽  
Standardized Uptake Value ◽  
Braak Staging ◽  
High Affinity ◽  
Tau Pet ◽  
Transentorhinal Cortex

Abstract Braak stages of tau neurofibrillary tangle accumulation have been incorporated in the criteria for the neuropathological diagnosis of Alzheimer’s disease. It is expected that Braak staging using brain imaging can stratify living individuals according to their individual patterns of tau deposition, which may prove crucial for clinical trials and practice. However, previous studies using the first-generation tau PET agents have shown a low sensitivity to detect tau pathology in areas corresponding to early Braak histopathological stages (∼20% of cognitively unimpaired elderly with tau deposition in regions corresponding to Braak I–II), in contrast to ∼80–90% reported in post-mortem cohorts. Here, we tested whether the novel high affinity tau tangles tracer 18F-MK-6240 can better identify individuals in the early stages of tau accumulation. To this end, we studied 301 individuals (30 cognitively unimpaired young, 138 cognitively unimpaired elderly, 67 with mild cognitive impairment, 54 with Alzheimer’s disease dementia, and 12 with frontotemporal dementia) with amyloid-β 18F-NAV4694, tau 18F-MK-6240, MRI, and clinical assessments. 18F-MK-6240 standardized uptake value ratio images were acquired at 90–110 min after the tracer injection. 18F-MK-6240 discriminated Alzheimer’s disease dementia from mild cognitive impairment and frontotemporal dementia with high accuracy (∼85–100%). 18F-MK-6240 recapitulated topographical patterns consistent with the six hierarchical stages proposed by Braak in 98% of our population. Cognition and amyloid-β status explained most of the Braak stages variance (P &lt; 0.0001, R2 = 0.75). No single region of interest standardized uptake value ratio accurately segregated individuals into the six topographic Braak stages. Sixty-eight per cent of the cognitively unimpaired elderly amyloid-β-positive and 37% of the cognitively unimpaired elderly amyloid-β-negative subjects displayed tau deposition, at least in the transentorhinal cortex (Braak I). Tau deposition solely in the transentorhinal cortex was associated with an elevated prevalence of amyloid-β, neurodegeneration, and cognitive impairment (P &lt; 0.0001). 18F-MK-6240 deposition in regions corresponding to Braak IV–VI was associated with the highest prevalence of neurodegeneration, whereas in Braak V–VI regions with the highest prevalence of cognitive impairment. Our results suggest that the hierarchical six-stage Braak model using 18F-MK-6240 imaging provides an index of early and late tau accumulation as well as disease stage in preclinical and symptomatic individuals. Tau PET Braak staging using high affinity tracers has the potential to be incorporated in the diagnosis of living patients with Alzheimer’s disease in the near future.

scholarly journals Cerebrospinal Fluid Biomarkers and Prediction of Conversion in Patients with Mild Cognitive Impairment: 4-Year Follow-Up in a Routine Clinical Setting

2009 ◽  
Vol 9 ◽  
pp. 961-966 ◽  
Author(s):  
Alessia Lanari ◽  
Lucilla Parnetti
Keyword(s):  
Cerebrospinal Fluid ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Clinical Setting ◽  
Cognitive Disorders ◽  
Correct Prediction ◽  
Csf Biomarkers ◽  
Routine Clinical Setting ◽  
T Tau

Mild cognitive impairment (MCI) is a very common syndrome in elderly people, with a high risk of conversion to dementia. Several investigations have shown the usefulness of cerebrospinal fluid (CSF) biomarkers (Aβ42, total tau [T-tau], and phosphorylated tau [P-tau]) in predicting the progression to Alzheimer's disease (AD). We report a 4-year follow-up of MCI patients who underwent CSF evaluation for biomarker assessment, in order to further evaluate the usefulness of CSF analysis in predicting the conversion to dementia in a routine clinical setting. We identified 55 patients with MCI among the consecutive patients, referred from 2001 to 2003 to our Memory Clinic for cognitive disorders, who underwent a complete diagnostic assessment, including lumbar puncture (n = 273). At the end of the follow-up, 31 MCI patients (56%) did not progress to dementia (stable MCI), while 24 (44%) developed a dementia condition. At baseline, the mean levels of CSF Aβ42, T-tau, and P-tau were significantly altered in MCI patients who were converting to dementia with respect to those with stable MCI. All MCI patients with the three altered CSF biomarkers developed dementia within 1 year. Among the stable MCI patients, none showed all three pathological values and only one subject had the pathological value of P-tau. Early diagnosis of dementia and, specifically, a correct prediction of MCI outcome represent a primary goal. To this respect, the role of CSF biomarkers seems to be crucial in a routine clinical setting.

scholarly journals DEFINITIONS MATTER WHEN DIAGNOSING MILD COGNITIVE IMPAIRMENT

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S115-S115
Author(s):  
Carol Derby ◽  
Charles B Hall ◽  
Mindy Katz
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Incidence Rate ◽  
Population Based ◽  
Study Cohort ◽  
Dramatic Reduction ◽  
Cognitively Normal ◽  
Aging Study ◽  
Normal Cognition

Abstract Prior studies have shown that when standard diagnostic criteria are applied, the majority of individuals diagnosed with aMCI do not progress to clinical dementia, with a much larger proportion reverting to normal cognition. This suggests that a prospective confirmation of aMCI diagnosis may improve the specificity of the classification. We examined the rates of aMCI reversion using two definitions: one based on a single annual assessment, and one requiring a diagnosis over two consecutive annual assessments within the population based Einstein Aging Study Cohort. Using the definition that used a single annual assessment resulted in 224 incident aMCI cases in 5,321 person years of follow-up, for an incidence rate of 4.21 cases per 100 person years. Requiring the confirmatory diagnosis resulted in only 94 incident aMCI cases in 5736 person years of follow-up, for an incidence rate of 1.64 cases per 100 person years. 41% of the persons diagnosed with aMCI using the single annual assessment were cognitively normal at the next follow-up. Only 14% of the persons diagnosed with incident aMCI using the definition requiring later confirmation ever returned to being cognitively normal. When the aMCI definition that required confirmation was used, a dramatic reduction in the incidence rate of aMCI was observed in persons born after 1930, similar to what has been reported in the same cohort for dementia, but there was no such difference for the definition based on a single annual assessment.

scholarly journals Plasma β-amyloid in mild behavioural impairment – neuropsychiatric symptoms on the Alzheimer’s continuum

2021 ◽  
Author(s):  
Ruxin Miao ◽  
Hung-Yu Chen ◽  
Sascha Gill ◽  
James Naude ◽  
Eric E. Smith ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Neuropsychiatric Symptoms ◽  
Affective Dysregulation ◽  
Prodromal Alzheimer’S Disease ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Normal Cognition

AbstractIntroductionSimple markers are required to recognize older adults at higher risk for neurodegenerative disease. Mild behavioural impairment (MBI) and plasma β-amyloid (Aβ) have been independently implicated in the development of incident cognitive decline and dementia. Here we studied the associations between MBI and plasma Aβ42/Aβ40.MethodsParticipants with normal cognition (n = 86) or mild cognitive impairment (n = 53) were selected from the Alzheimer’s Disease Neuroimaging Initiative. MBI scores were derived from Neuropsychiatric Inventory items. Plasma Aβ42/Aβ40 ratios were assayed using mass spectrometry. Linear regressions were fitted to assess the association between MBI total score as well as MBI domain scores with plasma Aβ42/Aβ40.ResultsLower plasma Aβ42/Aβ40 was associated with higher MBI total score (p = 0.04) and greater affective dysregulation (p = 0.04), but not with impaired drive/motivation (p = 0.095) or impulse dyscontrol (p = 0.29) MBI domains.ConclusionIn persons with normal cognition or mild cognitive impairment, MBI was associated with low plasma Aβ42/Aβ40. Incorporating MBI into case detection can help capture preclinical and prodromal Alzheimer’s disease.

Long-Term Exposure to PM10 and in vivo Alzheimer’s Disease Pathologies

2021 ◽  
Author(s):  
Jun Ho Lee ◽  
Min Soo Byun ◽  
Dahyun Yi ◽  
Kang Ko ◽  
So Yeon Jeon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Amyloid Β ◽  
Aerodynamic Diameter ◽  
Cognitively Normal ◽  
Study Population

Background: Previous studies indicated an association between Alzheimer’s disease (AD) dementia and air particulate matter (PM) with aerodynamic diameter <10 μm (PM10), as well as smaller PM. Limited information, however, is available for the neuropathological links underlying such association. Objective: This study aimed to investigate the relationship between long-term PM10 exposure and in vivo pathologies of AD using multimodal neuroimaging. Methods: The study population consisted of 309 older adults without dementia (191 cognitively normal and 118 mild cognitive impairment individuals), who lived in Republic of Korea. Participants underwent comprehensive clinical assessments, 11C-Pittsburg compound B (PiB) positron emission tomography (PET), and magnetic resonance imaging scans. A subset of 78 participants also underwent 18F-AV-1451 tau PET evaluation. The mean concentration of PM with aerodynamic diameter <10 μm over the past 5 years (PM10mean) collected from air pollution surveillance stations were matched to each participant’s residence. Results: In this non-demented study population, of which 62% were cognitively normal and 38% were in mild cognitive impairment state, exposure to the highest tertile of PM10mean was associated with increased risk of amyloid-β (Aβ) positivity (odds ratio 2.19, 95% confidence interval 1.13 to 4.26) even after controlling all potential confounders. In contrast, there was no significant associations between PM10mean exposure and tau accumulation. AD signature cortical thickness and white matter hyperintensity volume were also not associated with PM10mean exposure. Conclusion: The findings suggest that long-term exposure to PM10 may contribute to pathological Aβ deposition.

Neuropsychological Criteria for Mild Cognitive Impairment in the Framingham Heart Study’s Old-Old

2018 ◽  
Vol 46 (5-6) ◽  
pp. 253-265 ◽  
Author(s):  
Christina G. Wong ◽  
Kelsey R. Thomas ◽  
Emily C. Edmonds ◽  
Alexandra J. Weigand ◽  
Katherine J. Bangen ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Operational Definition ◽  
Cox Models ◽  
Cognitively Normal ◽  
Incident Dementia ◽  
Heart Study ◽  
Risk Of Progression ◽  
Diagnostic Approaches

Background/Aims: Mild cognitive impairment (MCI) lacks a “gold standard” operational definition. The Jak/Bondi actuarial neuropsychological criteria for MCI are associated with improved diagnostic stability and prediction of progression to dementia compared to conventional MCI diagnostic approaches, although its utility in diagnosing MCI in old-old individuals (age 75+) is unknown. Therefore, we investigated the applicability of neuropsychological MCI criteria among old-old from the Framingham Heart Study. Methods: A total of 347 adults (ages 79–102) were classified as cognitively normal or MCI via Jak/Bondi and conventional Petersen/Winblad criteria, which differ on cutoffs for cognitive impairment and number of impaired scores required for a diagnosis. Cox models examined MCI status in predicting risk of progression to dementia. Results: MCI diagnosed by both the Jak/Bondi and Petersen/Winblad criteria was associated with incident dementia; however, when both criteria were included in the regression model together, only the Jak/Bondi criteria remained statistically significant. At follow-up, the Jak/Bondi criteria had a lower MCI-to-normal reversion rate than the Petersen/Winblad criteria. Conclusions: Our findings are consistent with previous research on the Jak/Bondi criteria and support the use of a comprehensive neuropsychological diagnostic approach for MCI among old-old individuals.

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